Systems and methods for treating vascular occlusions by induced cavitation within an aspiration catheter

Abstract

Systems and methods are provided for treating vascular occlusions by inducing cavitation within the lumen of a hollow cylindrical transducer supported at or near the distal end of an aspiration catheter. Drive circuitry is provided such that a thickness (radial) mode of the hollow cylindrical transducer is excited. The excitation is delivered at a suitable frequency and with a sufficiently long time duration such that ultrasound energy propagating into the lumen of the hollow cylindrical transducer establishes a standing wave pattern, leading to a pronounced increase in pressure along the axis of the transducer, thereby enabling the generation of cavitation with the lumen of the transducer. By controlling the suction applied to the aspiration catheter and the cavitation produced within the lumen of the transducer, histotripsy can be employed to facilitate the mechanically degradation of thrombus as it enters into the catheter tip during aspiration.

Description

SYSTEMS AND METHODS FOR TREATING VASCULAR OCCLUSIONS BY INDUCED CAVITATION WITHIN AN ASPIRATION CATHETERCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 612,937, titled “SYSTEMS AND METHODS FOR TREATING VASCULAR OCCLUSIONS BY INDUCED CAVITATION WITHIN AN ASPIRATION CATHETER” and filed on December 20, 2023, the entire contents of which is incorporated herein by reference.BACKGROUND

[0002] The occlusion of blood vessels with thrombus is a major cause of mortality and morbidity worldwide and it can occur in a range of contexts such as ischemic stroke, myocardial infarction, pulmonary embolism (PE) as well as in peripheral vessels (e.g., arms and legs) [1-7], Thrombotic occlusions are increasingly treated with catheter-based mechanical thrombectomy approaches, one of the most prominent of which is to aspirate clots through a hollow catheter lumen using externally applied suction [8-11], While aspiration thrombectomy techniques have had a significant impact on patient care, in many cases aspiration attempts are either not fully successful in extracting the entirely of thrombus material or require multiple passes to achieve. This can lead to less favourable treatment outcomes [12-14], A number of factors can contribute to clot extractions not being successful. These include the mechanical properties of the clots [15-19], Stiffer clots present challenges for aspiration as upon initial entry into the catheter tip they can ‘cork’ and be unable to be fully ingested, which may result in either clot dislodgement or fragmentation upon catheter pullback [20-22], Larger volume clots also present challenges as suction alone can be insufficient to fully ingest the material. As such there is considerable interest in improving aspiration thrombectomy technology to facilitate the complete ingestion of clots into the aspiration catheter.

[0003] It is well established that ultrasound can promote the degradation of thrombus (sonothrombolysis), and a range of methods have been investigated. At relatively low- pressure levels, ultrasound has been shown to enhance the activity of the thrombolytic enzymes [23-26], The use of ultrasound in combination with systemically injected microbubbles, both in the presence and absence of thrombolytic agents, has been demonstrated to facilitate thrombus degradation in vitro, in vivo, as well as in clinical studies [27-30], Considerable research has also been conducted to demonstrate the use of histotripsy to disrupt blood clots in vitro and in vivo [31-36], Histotripsy involves the use of high ultrasound pressures to create violent cavitation clouds that degrade tissue into anacellular liquid-like homogenate within the focal regions and has generally been implemented using large aperture spherically focused transducer configurations [37-39],

[0004] While the large majority of sonothrombolysis work to date has involved the use of extracorporeal transducers, intravascular catheter-based ultrasound thrombolysis devices have also been developed. The most prominent example of this is the EKOS catheter, which employs a series of transducers situated along its distal portion

[0040] , Its operation involves inserting the distal aspect of the catheter into soft thrombus, releasing tPA through small side ports along its length, which is then acted upon by the ultrasound. Typically, 6-24 hours infusion time is required (e.g., in PE) depending on the lytic agent dose and infusion rate [26,41 ,42], Efforts have been made to employ this system in conjunction with microbubbles in an in vitro setting

[0043] , A series of recent studies have also reported technical advances made towards developing a forward projecting ultrasound thrombolysis catheter, where the intention is to have a side channel to accommodate the injection of microbubbles or droplets [44,45], The ability of this configuration to degrade in vitro blood clots into debris has been shown successful over the time scale of tens of minutes

[0044] ,SUMMARY

[0005] Systems and methods are provided for treating vascular occlusions by inducing cavitation within the lumen of a hollow cylindrical transducer supported at or near the distal end of an aspiration catheter. Drive circuitry is provided such that a thickness (radial) mode of the hollow cylindrical transducer is excited. The excitation is delivered at a suitable frequency and with a sufficiently long time duration such that ultrasound energy propagating into the lumen of the hollow cylindrical transducer establishes a standing wave pattern, leading to a pronounced increase in pressure along the axis of the transducer, thereby enabling the generation of cavitation within the lumen of the transducer. By controlling the suction applied to the aspiration catheter and the cavitation produced within the lumen of the transducer, histotripsy can be employed to facilitate the mechanically degradation of thrombus as it enters into the catheter tip during aspiration.

[0006] Accordingly, in a first aspect, there is provided, a system for delivering ultrasound treatment to a vascular occlusion, the system comprising: a catheter comprising: an elongate body having a body lumen extending therethrough; and a hollow cylindrical ultrasound transducer supported by a distal region of the elongate body, such that an inner lumen of the hollow cylindrical ultrasound transducer is in fluid communication with the body lumen; andcontrol circuitry operably connected to the hollow cylindrical ultrasound transducer through the elongate body, the control circuitry being configured to perform operations comprising: delivering test drive signals to the hollow cylindrical ultrasound transducer for interrogating a frequency response of the hollow cylindrical ultrasound transducer; and employing a frequency-dependent electrical measure associated with the test drive signals to identify a standing wave frequency corresponding to a standing wave produced by intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer.

[0007] In some example implementations of the system, the control circuitry is configured such that a frequency range of the test drive signals corresponds a thickness mode when a pre-selected medium resides within the inner lumen.

[0008] In some example implementations of the system, the control circuitry is configured such that a frequency range of the test drive signals corresponds to a length mode when a pre-selected medium resides within the inner lumen.

[0009] In some example implementations of the system, the control circuitry is configured such that the test drive signals are configured to generate ultrasound within the inner lumen in absence of cavitation.

[0010] In some example implementations of the system, the control circuitry is configured such that the standing wave is characterized by a Bessel function of a first kind (order zero).

[0011] In some example implementations of the system, the control circuitry is configured such that the frequency-dependent electrical measure is an impedance spectrum derived from the test drive signals.

[0012] In some example implementations of the system, the control circuitry is configured such that the frequency-dependent electrical measure is derived from a ringdown signal.

[0013] In some example implementations of the system, the control circuitry is configured such that the test drive signals comprise a plurality of pulses having different frequencies.

[0014] In some example implementations of the system, the control circuitry is further configured to: identify a plurality of standing wave frequencies based on the frequencydependent electrical measure; sequentially deliver cavitation test drive signals at the plurality of standing wave frequencies, and obtain a respective ring-down signal associated with each standing wave frequency; process each ring-down signal to obtain a cavitation measure characterizing cavitation at the standing wave frequency; and employ the cavitationmeasures to select a suitable standing wave frequency for subsequent delivery of therapy drive signals.

[0015] The control circuitry may be configured such that the cavitation measures characterize an amount of cavitation produced at each standing wave frequency.

[0016] The control circuitry may be configured such that the cavitation measures characterize an efficiency of cavitation generation at each standing wave frequency.

[0017] In some example implementations of the system, the control circuitry is configured to employ the standing wave frequency to identify a material present in the inner lumen.

[0018] In some example implementations of the system, the control circuitry is configured to employ the standing wave frequency to identify the material present within the inner lumen by comparing the standing wave frequency to one or more reference standing wave frequencies, each reference standing wave frequency corresponding to a different material.

[0019] The control circuitry may be configured such that a plurality of standing wave frequencies are obtained based on the frequency-dependent electrical measure and compared with a plurality of sets of reference standing wave frequencies to identify the material, each set of reference standing wave frequencies corresponding to a different reference material.

[0020] The control circuitry may be configured such that the different materials include one or more of saline and blood.

[0021] The control circuitry may be configured such that the different materials include a thrombus.

[0022] The control circuitry may be further configured to employ the standing wave frequency to infer one or more properties of the thrombus.

[0023] The control circuitry may be further configured to employ the one or more properties of the thrombus to determine one or more treatment parameters for cavitationbased disruption of the thrombus via an intraluminal standing wave.

[0024] The control circuitry may be further configured such that the one or more treatment parameters comprise pulse length and inter-pulse interval.

[0025] In some example implementations of the system, the control circuitry is configured such that the different materials include one or more medical devices.

[0026] The control circuitry may be configured such that the one or more medical devices include a guidewire and a microcatheter.

[0027] The control circuitry may be configured such that identification of the medical device results in the generation of an alert.

[0028] The control circuitry may be configured such that delivery of ultrasound therapy is prevented when the medical device is identified.

[0029] The control circuitry may be configured such that aspiration is prevented when the medical device is identified.

[0030] In some example implementations of the system, the control circuitry is further configured to perform operations including: delivering a therapy drive signals to the hollow cylindrical ultrasound transducer, the therapy drive signals being provided with a frequency and a time duration suitable for exciting of the standing wave within the inner lumen, and with sufficient energy to generate a bubble cloud with the inner lumen.

[0031] The control circuitry may be configured such that the time duration is sufficiently long that an acoustic pressure envelope associated with the standing wave increases to a maximum value prior to completion of the time duration of the therapy drive signals.

[0032] The control circuitry may be configured such that the standing wave is generated based on excitation of a thickness mode of the hollow cylindrical ultrasound transducer.

[0033] The control circuitry may be configured such that the standing wave is generated based on excitation of a length mode of the hollow cylindrical ultrasound transducer.

[0034] The control circuitry may be configured such that the therapy drive signals excite both a thickness mode of the hollow cylindrical ultrasound transducer and a length mode of the hollow cylindrical ultrasound transducer.

[0035] In some example implementations of the system, the control circuitry is configured such that the therapy drive signals are first therapy drive signals, and wherein the control circuitry is further configured to deliver additional therapy drive signals capable of sustaining the bubble cloud.

[0036] The control circuitry may be configured such that the additional therapy drive signals are configured to excite a length mode of the hollow cylindrical ultrasound transducer.

[0037] The control circuitry may be configured such that the additional therapy drive signals have a lower amplitude than the first therapy drive signals.

[0038] The control circuitry may be further configured to intermittently deliver the therapy drive signals and the additional therapy drive signals to the hollow cylindrical ultrasound transducer.

[0039] In some example implementations, the system further comprises a pump in flow communication with the inner lumen of the hollow cylindrical ultrasound transducer, wherein the control circuitry is operably connected to the pump for controlling the pump.

[0040] The control circuitry may be configured to control the pump to perform aspiration.

[0041] The control circuitry may be configured to deliver the therapy drive signals during aspiration.

[0042] In some example implementations of the system, the control circuitry is configured to deliver the therapy drive signals prior to aspiration.

[0043] In some example implementations of the system, the control circuitry is configured to initiate aspiration prior to delivering the test drive signals and identifying the standing wave frequency.

[0044] In some example implementations of the system, the control circuitry is configured to process ultrasound signals received after delivery of the therapy drive signals.

[0045] The control circuitry may be configured to process ultrasound signals to infer a presence of cavitation, an absence of cavitation, or a degree of cavitation, within the inner lumen of the hollow cylindrical ultrasound transducer.

[0046] The control circuitry may be configured such that the ultrasound signals are ringdown signals associated with the standing wave generated in response to delivery of the therapy drive signals.

[0047] In some example implementations of the system, the control circuitry is configured such that the ultrasound signals are received by the hollow cylindrical ultrasound transducer.

[0048] In some example implementations, the system further comprises an additional ultrasound transducer configured to receive the ultrasound signals, wherein the control circuitry is operably connected to the additional ultrasound transducer.

[0049] The control circuitry may be configured such that the ultrasound signals are associated with a probe ultrasound pulse generated by probe drive signals delivered to the hollow cylindrical ultrasound transducer after delivery of the therapy drive signals.

[0050] The control circuitry may be configured such that the ultrasound signals associated with the probe ultrasound pulse are compared with ultrasound signals associated with a previously generated probe pulse to infer a change in a material residing within the inner lumen.

[0051] The control circuitry may be configured such that the ultrasound signals are processed to identify a material within the inner lumen.

[0052] The control circuitry may be configured to modify subsequently delivered therapy drive signals in response to the material identified to be currently residing within the inner lumen.

[0053] The control circuitry may be configured to modify control of the pump in response to the material identified to be currently residing to be within the inner lumen.

[0054] The control circuitry may be configured to control the pump to interrupt aspiration when the material identified to be currently residing within the inner lumen is blood.

[0055] In some example implementations of the system, the control circuitry is configured to perform the following operations after delivery of the therapy drive signals or after initiating aspiration: delivering additional test drive signals to the hollow cylindrical ultrasound transducer; employing a frequency-dependent electrical measure associated with the additional test drive signals to determine an updated standing wave frequency corresponding to the standing wave caused by intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer.

[0056] The control circuitry may be configured to employ the updated standing wave frequency to modify subsequently delivered therapy drive signals.

[0057] The control circuitry may be configured to employ the updated standing wave frequency to control the pump to modify aspiration.

[0058] The control circuitry may be configured to perform operations further comprising: identifying a property of a thrombus residing within the inner lumen according to the updated standing wave frequency.

[0059] The control circuitry may be configured to employ the property of the thrombus to modify subsequently delivered therapy drive signals .

[0060] In some example implementations of the system, the control circuitry is configured to perform operations further comprising: detecting a change in a material residing within the inner lumen according to a change in the standing wave frequency.

[0061] The control circuitry may be configured to modify subsequently delivered therapy drive signals in response to the detected change in the material.

[0062] The control circuitry may be configured to modify control of the pump in response to the detected change in the material.

[0063] In some example implementations of the system, the control circuitry is configured to perform operations further comprising: identifying a material currently residing within the inner lumen according to the updated standing wave frequency.

[0064] The control circuitry may be configured to modify subsequently delivered therapy drive signals in response to the material identified to be currently residing within the inner lumen.

[0065] In some example implementations of the system, the control circuitry is configured to modify the control of the pump in response to the material identified to be currently residing within the inner lumen.

[0066] The control circuitry may be configured to control the pump to interrupt aspiration when the material identified to be currently residing within the inner lumen is blood.

[0067] In some example implementations of the system, the control circuitry is configured to employ a temporal change in the standing wave frequency to monitor treatment.

[0068] In some example implementations of the system, the control circuitry is configured to employ a temporal change in the standing wave frequency to modify subsequently delivered therapy drive signals.

[0069] The control circuitry may be configured such that the temporal change is determined relative to a pre-treatment value of the standing wave frequency.

[0070] In some example implementations of the system, the control circuitry is configured to display a frequency dependence of the frequency-dependent electrical measure on a user interface and to obtain the standing wave frequency according to input from a user.

[0071] In some example implementations of the system, a diameter of the inner lumen is between 0.5 mm and 2.5 mm, or between 0.3 mm and 2.8 mm, or between 0.3 mm and 3.8 mm, or between 1 .3 mm and 7.8 mm.

[0072] In some example implementations of the system, a diameter of the end of the catheter is between 0.5 mm and 3 mm, or between 0.5 mm and 4 mm, or between 1 .5 mm and 8 mm.

[0073] In some example implementations of the system, the inner lumen is defined by a liner material contacting an inner surface of the hollow cylindrical ultrasound transducer.

[0074] In another aspect, there is provided a system for delivering ultrasound treatment to a vascular occlusion, the system comprising: a catheter comprising: an elongate body having a body lumen extending therethrough; and a hollow cylindrical ultrasound transducer supported by a distal region of the elongate body, such that an inner lumen of the hollow cylindrical ultrasound transducer is in fluid communication with the body lumen; and control circuitry operably connected to the hollow cylindrical ultrasound transducer through the elongate body, the control circuitry being configured to perform operations comprising: delivering therapy drive signals to the hollow cylindrical ultrasound transducer, the therapy drive signals being provided according to a frequency and a time duration, the frequency and time duration being suitable for exciting a standing wave within the inner lumen when a known reference material resides in the inner lumen, the standing wave being associated with intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer.

[0075] The control circuitry may be configured such that the reference material is a saline solution of 0.9% NaCI by weight.

[0076] The control circuitry may be configured such that the reference material is blood.

[0077] The control circuitry may be configured such that the reference material is a thrombus.

[0078] In some example implementations of the system, the control circuitry is configured such that the frequency is selectable among a plurality of reference frequencies, and wherein at least two of the plurality of reference frequencies correspond to different reference materials.

[0079] In another aspect, there is provided a method of delivering ultrasound treatment to a vascular occlusion, the method comprising: providing an intravascular ultrasound treatment catheter comprising an elongate body having a body lumen extending therethrough and a hollow cylindrical ultrasound transducer supported by a distal region of the elongate body, such that an inner lumen of the hollow cylindrical ultrasound transducer is in fluid communication with the body lumen; and delivering therapy drive signals to the hollow cylindrical ultrasound transducer, the therapy drive signals being provided with a standing wave frequency and a time duration suitable for excitation of a standing wave within the inner lumen, the standing wave being produced by intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer in response to the therapy drive signals, wherein the therapy drive signals are provided with sufficient energy to generate a bubble cloud with the inner lumen.

[0080] The thrombus may at least partially resides within the inner lumen and wherein the therapy drive signals are repeated one or more times such that the thrombus is at least partially eroded.

[0081] An aspiration device may be interfaced with the intravascular ultrasound treatment catheter, and wherein the thrombus is drawn into the inner lumen under control of the aspiration device.

[0082] In some example implementations of the method, the therapy drive signals are delivered during aspiration of the thrombus.

[0083] In some example implementations of the method, the time duration of the therapy drive signals is sufficiently long that an acoustic pressure envelope associated with the standing wave increases to a maximum value prior to completion of the time duration of the therapy drive signals.

[0084] In some example implementations of the method, the standing wave is generated based on excitation of a thickness mode of the hollow cylindrical ultrasound transducer.

[0085] In some example implementations of the method, standing wave is generated based on excitation of a length mode of the hollow cylindrical ultrasound transducer.

[0086] In some example implementations of the method, the therapy drive signals excite both a thickness mode of the hollow cylindrical ultrasound transducer and a length mode of the hollow cylindrical ultrasound transducer.

[0087] In some example implementations of the method, the therapy drive signals are first therapy drive signals, and wherein additional therapy drive signals are provided to sustaining the bubble cloud.

[0088] The additional therapy drive signals may be configured to excite a length mode of the hollow cylindrical ultrasound transducer.

[0089] The additional therapy drive signals may have a lower amplitude than the first therapy drive signals.

[0090] In some example implementations, the method further includes processing ultrasound signals received after delivery of the therapy drive signals.

[0091] The ultrasound signals may be processed to a presence of cavitation, an absence of cavitation, or a degree of cavitation, within the inner lumen of the hollow cylindrical ultrasound transducer.

[0092] The ultrasound signals may be ring-down signals associated with the standing wave generated in response to delivery of the therapy drive signals.

[0093] The ultrasound signals may be received by the hollow cylindrical ultrasound transducer.

[0094] An additional ultrasound transducer may be employed to receive the ultrasound signals.

[0095] In some example implementations of the method, the ultrasound signals are associated with a probe ultrasound pulse generated by probe drive signals delivered to the hollow cylindrical ultrasound transducer after delivery of the therapy drive signals.

[0096] The ultrasound signals may be associated with the probe ultrasound pulse are compared with ultrasound signals associated with a previously generated probe pulse to infer a change in a material residing within the inner lumen.

[0097] The ultrasound signals may be processed to identify a material within the inner lumen.

[0098] In some example implementations, the method further includes modifying subsequently delivered therapy drive signals in response to the material identified to be currently residing within the inner lumen.

[0099] In some example implementations, the method further includes modifying aspiration based on the material identified to be currently residing within the inner lumen.

[0100] In some example implementations, the method further includes interrupting aspiration when the material identified to be currently residing within the inner lumen is blood.

[0101] In some example implementations of the method, the standing wave frequency is identified by: delivering test drive signals to the hollow cylindrical ultrasound transducer for interrogating a frequency response of the hollow cylindrical ultrasound transducer; and employing a frequency-dependent electrical measure associated with the test drive signals to identify a standing wave frequency corresponding to a standing wave produced by intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer.

[0102] Aspiration may be initiated prior to delivering the test drive signals and identifying the standing wave frequency.

[0103] A frequency range of the test drive signals may corresponds a thickness mode when a pre-selected medium resides within the inner lumen.

[0104] In some example implementations of the method, a frequency range of the test drive signals corresponds to a length mode when a pre-selected medium resides within the inner lumen.

[0105] In some example implementations of the method, the test drive signals are configured to generate ultrasound within the inner lumen in absence of cavitation.

[0106] In some example implementations of the method, the standing wave is characterized by a Bessel function of a first kind (order zero).

[0107] In some example implementations of the method, the frequency-dependent electrical measure is an impedance spectrum derived from the test drive signals.

[0108] In some example implementations of the method, the frequency-dependent electrical measure is derived from a ringdown signal.

[0109] In some example implementations of the method, the test drive signals include a plurality of pulses having different frequencies.

[0110] In some example implementations, the method further includes: identifying a plurality of standing wave frequencies based on the frequency-dependent electrical measure; sequentially delivering cavitation test drive signals at the plurality of standing wave frequencies, and obtain a respective ring-down signal associated with each standing wave frequency; processing each ring-down signal to obtain a cavitation measure characterizing cavitation at the standing wave frequency; and employing the cavitation measures to select a suitable standing wave frequency for subsequent delivery of therapy drive signals.

[0111] The cavitation measures may characterize an amount of cavitation produced at each standing wave frequency.

[0112] The cavitation measures may characterize an efficiency of cavitation generation at each standing wave frequency.

[0113] In some example implementations, the method further includes employing the standing wave frequency to identify a material present in the inner lumen.

[0114] The standing wave frequency may be employed to identify the material present within the inner lumen by comparing the standing wave frequency to one or more reference standing wave frequencies, each reference standing wave frequency corresponding to a different material.

[0115] A plurality of standing wave frequencies may be obtained based on the frequency-dependent electrical measure and compared with a plurality of sets of reference standing wave frequencies to identify the material, each set of reference standing wave frequencies corresponding to a different reference material.

[0116] The different materials may include one or more of saline and blood.

[0117] The different materials may include a thrombus.

[0118] The standing wave frequency may be employed to infer one or more properties of the thrombus.

[0119] The one or more properties of the thrombus may be employed to determine one or more treatment parameters for cavitation-based disruption of the thrombus via an intraluminal standing wave.

[0120] The one or more treatment parameters may include pulse length and inter-pulse interval.

[0121] In some example implementations of the method, the different materials include one or more medical devices.

[0122] The one or more medical devices may include a guidewire and a microcatheter.

[0123] Identification of the medical device may result in generation of an alert.

[0124] Delivery of ultrasound therapy may be prevented when the medical device is identified.

[0125] Aspiration may be prevented when the medical device is identified.

[0126] A further understanding of the functional and advantageous aspects of the disclosure can be realized by reference to the following detailed description and drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0127] Embodiments are described with reference to the accompanying drawings. In the drawings, like reference numbers can indicate identical or functionally similar elements.

[0128] FIG. 1 A illustrates the distal aspect of an example catheter. Not shown is the possible presence of a radiopaque marker for visualization under angiography.

[0129] FIG. 1 B shows an example system for achieving intralumenal cavitation based on the controlled excitation of a hollow cylindrical ultrasound transducer supported at or near the distal end of an aspiration catheter.

[0130] FIGS. 2A and 2B show schematic overview of experimental configuration for hydrophone and ultrasound imaging experiments (FIG. 2A) and a photograph of experimental configuration for ultrasound imaging experiments and right, a closeup photo of a representative hollow cylindrical transducer (FIG. 2B).

[0131] FIGS. 2C and 2D show simulated length and thickness modes. FIG. 2C shows sagittal plane distribution of pressures for thickness and length modes respectively (normalized to the peak pressure of thickness mode). The internal pressure distribution in thickness mode is characterized by a primary on-axis peak, accompanied by a series of side-lobes that decay in amplitude towards the transducer luminal wall. FIG. 2D shows on- axis pressure distributions indicating that thickness mode generates higher internal pressures.

[0132] FIGS. 3A and 3B show the measured electrical impedance of a 2.5 mm length transducer, highlighting (FIG. 3A) the length mode at 690 kHz and the 3rdharmonic of the length mode at 1 .97 MHz, and (FIG. 3B) the thickness mode, which is associated with elevated impedance levels in the ~4.5-6.5 MHz range, within which there are several minima (e.g. 4.90 MHz).

[0133] FIGS. 4A and 4B show internal pressure maps at a selected frequency (4.9 MHz) within the thickness mode range of a 2.5 mm length transducer from hydrophone measurements (FIG. 4A) and simulations (FIG. 4B). Pressures are normalized to the peak pressure within each map.

[0134] FIGS. 5A and 5B show hydrophone measurements at different measured voltages. FIG. 5A shows how the estimated peak internal pressure rises linearly as a function of transducer voltage until reaching a maximum where pressures level off and standard deviation increases. FIG. 5B shows how the power spectra of hydrophone signals indicate the presence of broadband signals at higher transducer voltages.

[0135] FIG. 6Ashows a box plot of integrated power over the frequency range of 17.5 to 18.6 MHz situated between two harmonic peaks. Outliers indicated with ‘+’, which are light grey if associated with pulse exhibiting clear time domain ‘spikes’ and are grey otherwise.

[0136] FIG. 6B shows an example time domain hydrophone signal at a transducer voltage of 66 Vppshowing a steady waveform, similar in form to that for external pressure in FIGS. 14A-14D. The arrow denotes the end of the 10 ps voltage stimulation period of the pulse.

[0137] FIG. 6C shows how, at a higher voltage of 94 Vpp, a positive pressure spike (denoted by the asterisk) appears superimposed on the time signal.

[0138] FIG. 6D shows how, at a voltage of 123 Vpp, multiple spikes are seen.

[0139] FIG. 6E shows how, at a measured voltage of 163 Vpp, the waveform becomes unsteady with a substantial signal still present after the end of the transmit pulse (applied voltage).

[0140] FIG. 7A plots the probability of cavitation data (mean values shown in diamonds) and fitted sigmoid function as a function of transducer voltage.

[0141] FIG. 7B is a table detailing pulsing schemes used in the ultrasound imaging experiments.

[0142] FIGS. 8A, 8B, 8C, 8D and 8E show ultrasound images of the transducer under different operating conditions. FIG. 8A shows the transducer walls and water filled lumen visible when the cylindrical transducer is not transmitting. FIG. 8B shows a maximum intensity projection (MIP) over 100 frames of sonication with a 10 ps pulse length and 1.1 ms interval pulse scheme at 34 Vppshowing no cavitation, while FIG. 8C shows how a clear cavitation cloud can be seen at 127 Vpp. FIG. 8D shows a similar MIP at 155 Vpp, showing a larger cavitation cloud. FIG. 8E shows power spectra of the RF signals extracted from the centerline of the imaging probe with the 10 ps pulse length and 11 ms pulse interval scheme showing broadband noise at higher driving voltages.

[0143] FIG. 9 shows ultrasound imaging of cavitation clouds produced with different pulsing schemes. Images show MIPs across 10 frames of sonication.

[0144] FIGS. 10A and 10B show quantification of cavitation cloud area as a function of measured voltage at pulse intervals (PI) of 1 .1 , 11 , and 110 ms for a 10 (is pulse length (PL) (FIG. 10A) and 100 (is PL (FIG. 10B). Areas are normalized to the maximum area of the 10 ps PL and 11 ms PI case.

[0145] FIG. 11A shows ultrasound imaging of sonication at different frequencies highlighting three frequencies which show cavitation clouds.

[0146] FIG. 11 B shows simulated frequency sweep of on-axis pressures showing frequencies which produce high on-axis internal pressures.

[0147] FIG. 12 shows simulated on-axis pressures of length and thickness modes for different length transducers. In general, the thickness mode produces higher pressures than the length mode except for lengths of 1.2 and 2.2 mm. Lengths of 2.3 to 2.7 mm show high internal pressures of similar magnitudes across their lengths.

[0148] FIGS. 13A, 13B and 13C show simulated pressure distribution in thickness mode for matching and without matching respectively (10 us pulse applied). FIG. 13A shows sagittal plane distribution, FIG. 13B shows pressures cross the peak point (0.546 mm, dashlines in FIG. 13A), and FIG. 13C shows pressures on-axis indicate that the internal pressure distribution is not substantially impacted by matching, (normalized to the peak pressure of without matching)

[0149] FIGS. 14A, 14B, 14C and 14D show simulated time traces at internal and external peak on-axis positions. FIG. 14A and FIG. 14C show that the internal pressures (black) take approximately 10 ps to reach their peak. The occurrence of the peak at ~10 ps indicates that for this transducer configuration a pulse of at least this duration is needed to reach the highest internal pressures. For the 100 ps pulse, shown in FIG. 14C, there is then a reduction in amplitude followed by a period of constant amplitude. For both pulse lengths, there is a gradual decay in amplitude following the cessation of the stimulating voltages. In the early stages of both pulses, as seen in FIGS. 14B and FIG. 14D, the rise to the peak occurs in a stepped manner in 1.67 ps intervals as indicated with grey lines.

[0150] FIG. 15 shows a box plot of the integrated power spectrum (17.5-18.6 MHz ‘cavitation’ region) derived from transmission (signal) and noise-only segments of the received hydrophone. At higher voltages, the signal rises relative to the noise, consistent with the presence of cavitation within the lumen.

[0151] FIG. 16 illustrates how the cavitation cloud area in ultrasound imaging decays over time. The 100 ps pulses show a higher decay rate of cavitation area than the 10 ps pulses. The cavitation area values are normalized to their initial area.

[0152] FIG. 17 shows example erosion results for clots that were situated partially within the transducer employed in the present Examples. A thickness standing wave mode frequency was used. The pulse length, pulse interval and exposure duration are indicated. The first two rows are sagittal and coronal sections from a high frequency (40 MHz) 3D ultrasound scan of the clot following treatment. The hypoechogenic regions indicate where a histotripsy lesion (liquified zone) was induced. The last row is a gross pathology photograph of the bisected clots post treatment, where the lesion (hole) is clearly evident. These results show the first feasibility of the proposed clot erosion approach.

[0153] FIG. 18 shows an example of the aspiration of clots with and without ultrasound exposures. The same transducer configuration (2.5 / 3.3 mm inner and out diameter; 2.5 mm length) as used in FIG. 17 was employed with a pulsing scheme of 10 microsecond length, 1 kHz interval at a thickness mode standing wave frequency (4.9 MHz). The clot dimensions were ~3-4 mm in diameter and 4-5 mm in length. The results indicate an improved aspiration rate in the presence of ultrasound induced cavitation relative to aspiration alone.

[0154] FIG. 19 plots simulated on-axis pressures of length and thickness modes for different PZT5A hollow cylindrical transducer lengths. The transducer outer / inner diameterwas 1 .6 / 1 .2 mm. In general, one observes that the thickness mode produces higher pressures than the length mode.

[0155] FIG. 20 plots simulated on-axis pressures of length and thickness modes for different PZT4 hollow cylindrical transducer lengths. The transducer outer / inner diameter was 1 .6 / 1 .2 mm. In general, as was the case for PZT5A, one observes that the thickness mode produces higher pressures than the length mode.

[0156] FIG. 21 A shows a render of hollow cylindrical ultrasound transducer divided into multiple electrode segments for selective excitation (left), and demonstration of distinct pressure profiles produced by selective single electrode excitation (center) and all electrode excitation (right).

[0157] FIG. 21 B shows a kerfless version of the hollow cylindrical ultrasound transducer shown in FIG. 21A.DETAILED DESCRIPTION

[0158] Various embodiments and aspects of the disclosure will be described with reference to details discussed below. The following description and drawings are illustrative of the disclosure and are not to be construed as limiting the disclosure. Numerous specific details are described to provide a thorough understanding of various embodiments of the present disclosure. However, in certain instances, well-known or conventional details are not described in order to provide a concise discussion of embodiments of the present disclosure.

[0159] As used herein, the terms “comprises” and “comprising” are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in the specification and claims, the terms “comprises” and “comprising” and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.

[0160] As used herein, the term “exemplary” means “serving as an example, instance, or illustration,” and should not be construed as preferred or advantageous over other configurations disclosed herein.

[0161] As used herein, the terms “about” and “approximately” are meant to cover variations that may exist in the upper and lower limits of the ranges of values, such as variations in properties, parameters, and dimensions. Unless otherwise specified, the terms “about” and “approximately” mean plus or minus 25 percent or less.

[0162] As used herein, the phrases “thickness mode” and “radial mode”, when employed with reference to a cylindrical ultrasound transducer, refer to a frequency suitable for resonant excitation of mechanical vibrations in the thickness (radial) direction of the cylindrical transducer, and the generation of ultrasound waves that propagate inwardly, inthe radial direction, within the transducer lumen. A thickness (radial) mode, while having a frequency of maximum mechanical response, is generally characterized by an excitation bandwidth that spans a frequency range, such the thickness (radial) mode can be excited by electrical signals within the excitation bandwidth.

[0163] It is to be understood that unless otherwise specified, any specified range or group is as a shorthand way of referring to each and every member of a range or group individually, as well as each and every possible sub-range or sub-group encompassed therein and similarly with respect to any sub-ranges or sub-groups therein. Unless otherwise specified, the present disclosure relates to and explicitly incorporates each and every specific member and combination of sub-ranges or sub-groups.

[0164] As used herein, the term "on the order of', when used in conjunction with a quantity or parameter, refers to a range spanning approximately one tenth to ten times the stated quantity or parameter.Histotripsy and Aspiration Thrombectomy

[0165] Various example embodiments of the present disclosure enable the use of an intravascular aspiration catheter to deliver very high pressure ultrasound to induce violent cavitation within a thrombus, such that it undergoes mechanical degradation within the transducer lumen during aspiration. The process of mechanically degrading tissue in this manner is called histotripsy, which conventionally employs large aperture spherically focused transducers to create liquified tissue within the transducer focal regions. The present inventors set out to solve the technical problem of implementing this approach in the configuration of an aspiration catheter and generating sufficiently high pressures within the transducer lumen of a hollow cylindrical transducer of a scale that can be mounted within an aspiration catheter tip.

[0166] Accordingly, the motivation for the present disclosure was the development of an intravascular catheter-based ultrasound approach to improve the ability of aspiration thrombectomy to extract more challenging clots. Systems and methods are provided that employ a radially polarized hollow cylindrical transducer supported at or near the distal end of an aspiration catheter, and providing electrical driving signals to facilitate histotripsy within its lumen, thereby facilitating mechanically degrading of the thrombus as it enters into the catheter tip during aspiration.Hollow Cylindrical Ultrasound Transducers

[0167] Radially polarized hollow cylindrical transducers have been previously employed in a biomedical ultrasound context, such as for transcranial arrays

[0046] and catheter-basedapplications [47,48], This transducer geometry has length, circumferential and thickness resonant modes

[0049] , each of which are associated with different ultrasound emission patterns. These modes are typically referred to as thickness mode, length mode and circumferential mode, as described in US Patent Application No. 16 / 574,710, titled “SYSTEMS AND METHODS FOR TREATING VASCULAR OCCLUSIONS WITH CATHETER BASED ULTRASOUND” and filed on Sept. 18, 2019, the entire contents of which are incorporated herein by reference.

[0168] In the transcranial array context, a length mode resonance of cylindrical elements has been employed to project energy in a forward-looking direction. Catheter-based transducers have also been operated in thickness mode to radiate energy in an outward radial direction for interstitial heating [48,50] and thrombolysis applications [26,41 ,42], Accordingly, the thickness mode, which is of primary relevance to the present disclosure, has previously been employed in a number of devices for the purposes of radiating acoustic waves in an outward radial direction (as described in more detail in the Examples below). In such prior applications, the lumen is generally not fluid filled.

[0169] US Patent Application No. 16 / 574,710 provided the example that cavitation induced within the lumen of a hollow cylindrical ultrasound transducer supported by an aspiration catheter could be used to mechanically degrade thrombus with the objective of enhancing the performance of the aspiration process. For this application it was indicated that ultrasound frequencies and transducer oscillation modes that produced cavitation in front of the tip, at the tip, and within the tip could be implemented. Large-scale (outer diameter of approximately 6 to 12 cm) cylindrical transducers operating in thickness mode at low frequencies (approximately 8-40 kHz) have also been previously used to generate cavitation within their lumens to investigate basic aspects of cavitation [51 ,52],

[0170] In US Patent Application No. 16 / 574,710, it was taught that the thickness mode results in both (i) radially inwardly propagating waves into the lumen, as a result of vibrations of the luminal surface of the transducer and (ii) radially outwards propagating waves, a result of vibrations of the outer radial surface of the hollow cylindrical ultrasound transducer. Due to the curved geometry of the hollow cylindrical ultrasound transducer lumen wall, focusing effects would thereby generate pressure amplification.

[0171] As described in US Patent Application No. 16 / 574,710, stimulating a thickness mode at a frequency corresponding to the radial thickness resonance frequencies (0.5-20 MHz, for example) may result in a pronounced wave in the center of the tube. Specifically, US Patent Application No. 16 / 574,710 teaches that by selecting the inner lumen diameter to be equal to the thickness mode wavelength (within the lumen) or odd harmonics thereof, an amplified pressure peak would be generated on axis due to constructive interference. As willbe known to those skilled in the art, this constructive interference results from the superposition of converging and diverging waves (to and from center respectively), which act to create an interference pattern that is comprised of a primary pressure peak on axis, along with a series of side lobes of progressively decreasing amplitude away from the center axis. US Patent Application No. 16 / 574,710 teaches that the amplified pressure peak that results from constructive interference of waves within the transducer lumen does not favor cavitation within liquids for higher frequencies, but that it may be advantageous for converting liquid phase droplets to gas phase bubbles.

[0172] The present inventors set out to improve the ability of a catheter-based hollow cylindrical ultrasound transducer to achieve intraluminal cavitation when stimulated at a thickness mode. After further experimental investigations, which are detailed in the Examples section below, it was discovered that while the “constructive-interference-based” resonance mechanism described in US Patent Application No. 16 / 574,710 can be beneficial in generating an on-axis pressure peak by the superposition of primary ultrasound waves generated within the lumen, a second mechanism can be employed to achieve profoundly enhanced pressures. Moreover, this second resonance mechanism could be employed to achieve a greater increase in intraluminal pressure, and that this second resonance mechanism is better suited to the generation of intraluminal cavitation.

[0173] In stark contrast to the first resonance mechanism taught by US Patent Application No. 16 / 574,710, in which a superposition between radially inwardly-propagating and outwardly-propagating waves generated by the hollow cylindrical ultrasound transducer occurs when the inner lumen diameter is selected to be equal to the thickness mode wavelength or odd harmonics thereof, resulting in an on-axis pressure increase, the second mechanism, described in detail herein and demonstrated in the Examples section below, results from a resonance condition involving reflections from the internal lumen boundary when a suitable excitation frequency is selected, such that a standing wave pattern is generated in a radial direction within the lumen of the hollow cylindrical ultrasound transducer. This is distinct from other types of standing waves that can occur within hollow cylindrical lumens, such as one that occurs along the axis of symmetry in the length direction. As will be demonstrated below, the standing waves generated according to this second resonance mechanism can result in a substantially larger increase in on-axis pressure relative to the first constructive-interference-based resonance mechanism disclosed in US Patent Application No. 16 / 574,710.

[0174] Unlike the first constructive-interference-based resonance mechanism disclosed in US Patent Application No. 16 / 574,710, the development of a standing wave pattern according to the second resonance mechanism requires two criteria to be met: (i) excitationat a resonant frequency for generating a standing wave pattern within the transducer lumen, and (ii) providing sufficiently long pulse duration to facilitate the establishment of the standing wave pattern.

[0175] As illustrated in the Examples provided below, by examining a simulated time domain pressure pulse at a point on the central axis, it can be seen that the rise in pressure occurs in a series of steps, equal in duration to the propagation time within the main lumen, thereby being consistent with the establishment of a standing wave pattern. The stepped increase pattern is associated with the arrival of successive internally reflected waves. The rise does not continue indefinitely, as there is a degree of acoustic energy dissipation. This can occur due to, for example, the radiation of acoustic energy outwards from the transducer (e.g. from the outer cylindrical surface, or from ends of the transducer or lumen) or the absorption of energy by water within the lumen. In the specific example shown below, approximately 10 microseconds are required for a peak in amplitude to be reached.

[0176] By comparing the amplitude of the initial step that is associated with the focusing properties of the cylindrical geometry in combination with the (unreflected) interference pattern referred to in US Patent Application No. 16 / 574,710, to the final peak amplitude (which includes the standing wave pattern associated with reflections), it can be estimated that the standing wave aspect has increased the pressure by a factor of ~3.2, enabling the generation of cavitation within the transducer lumen. The use of the second standing-wave- based resonant mechanism therefore results in a surprising change in kind (large increase in acoustic pressure), as opposed to a mere increase in degree, relative to the first constructive-interference-based mechanism of US Patent Application No. 16 / 574,710.

[0177] As described in further detail below, unlike the resonance criteria associated with the first resonant mechanism involving constructive interference, the lateral pressure profile within the lumen associated with the second standing-wave-based resonant mechanism is based on a Bessel function of the first kind (order 0), which is described below with reference to FIG. 2C. This aspect is also readily apparent when considering FIG. 13B, also described below. It is noted that the resonance conditions associated with the Bessel function of the first kind (order zero) can occur for a ‘family’ or set of frequencies. The higher pressures occur when using a standing wave frequency that also corresponds to high electromechanical conversion efficiency (e.g. lying within the radial / thickness mode bandwidth, e.g. between 4.5-6.5 MHz).

[0178] Accordingly, various example embodiments of the present disclosure provide systems and methods in which a hollow cylindrical ultrasound transducer is supported by an intravascular aspiration catheter, where hollow cylindrical ultrasound transducer is provided with material properties and dimensions that facilitate the development of standing wavepatterns when excited according to thickness mode operating frequencies, and where electrical driving pulses are provided with sufficient duration to result in a pressure field that is sufficient to sustain intraluminal cavitation. The systems and methods of the present disclosure enable the initiation of cavitation sufficient for performing histotripsy within a hollow cylindrical ultrasound piezoelectric transducer with a much smaller outer diameter that is compatible with mounting within an aspiration catheter. In the Examples provided below, pressure fields are first examined using a combination of simulations and measurements, and cavitation is assessed and demonstrated with hydrophone measurements and a high frequency ultrasound imaging system.

[0179] It is noted that the length mode, and odd harmonics thereof, are also of interest as their stimulation can also result in potentially high internal pressure levels, as is also described in detail in the Examples below.

[0180] FIG. 2C of the present disclosure illustrates the lateral intraluminal pressure profile when a hollow cylindrical ultrasound transducer is excited with a thickness mode excitation frequency that supports the generation of standing waves. This pattern closely resembles a Bessel function of the first kind (order zero).

[0181] It is notable that there are a family of frequencies that can give rise to standing waves within the transducer lumen. However, the peak pressure that can be achieved within the lumen is also a function of the absolute vibration amplitudes at the selected frequency. Therefore, to achieve high pressures, it is preferred to employ a transducer dimensions having a wall thickness and inner lumen diameter such that the thickness mode resonant frequency corresponds to a standing wave mode frequency of the lumen. That is, there is an inherent interplay between the choice of wall thickness and lumen diameter with regard to achieving conditions suitable for the generation of standing waves when a thickness mode is excited. It is noted that the thickness mode resonant frequency peak for a given hollow cylindrical ultrasound transducer can be relatively diffuse, as shown in FIG. 3B, and within this peak range it can be possible to have, and to be able to select among, several standing wave frequencies.

[0182] Further, as noted above, it is also beneficial to employ a sufficiently long pulse to realize the development of the standing wave pattern such that the envelope of the time domain pressure signal reaches a peak. This temporal duration criterion will depend on the lumen diameter, wall thickness, and the extent to which ultrasound energy is dissipated.

[0183] With respect to length, it is notable that as the aspect ratio (length / outer diameter) of a hollow cylindrical ultrasound transducer becomes sufficiently low, electromechanical coupling between modes can occur. The wall thickness (outer / inner diameter difference) is an additional factor influencing mode coupling. As such, length may have some degree ofinfluence on the standing wave amplitudes, though in the case of the present examples, it is modest. This effect is described and investigated further in the Examples provided below.

[0184] In various example embodiments herein in which the hollow cylindrical ultrasound transducer is supported at or near the distal end of an intravascular aspiration catheter, the outer diameter of the hollow cylindrical ultrasound transducer may be constrained by the acceptable distal tip catheter diameter for the intended application, which in large part is constrained by vessel size. The approach described here can be adapted to a wide range of applications by scaling the size (in particular the outer diameter of the transducer) to be compatible with a variety of catheter calibres.

[0185] For example, in the context of large vessel occlusion acute stroke applications, current aspiration catheters are on the order of 1.7-1.9 mm in diameter at the distal tip. In example implementations in which the transducer is accommodated within the catheter sheath, the outer diameter of the transducer will be less than inner diameter of the catheter sheath. For the inner diameter selection, it may also be considered that a larger lumen will be advantageous in terms of presenting a reduced resistance to clot entry, which in turn would favor a reduced wall thickness. Thin wall thickness will be associated with higher resonant frequencies, and it may also be considered that there may be fabrication challenges, lower breakdown voltages and reduced vibration amplitude limits as the wall thickness is reduced.

[0186] Accordingly, in some example implementations, the catheter is provided such that the inner lumen of the hollow cylindrical piezoelectric transducer ranges between 0.3 and 14 mm and such that an outer diameter of the distal end of the catheter (e.g. including the diameter of the hollow cylindrical piezoelectric transducer and an outer jacket if present) ranges between 0.5 mm and 15 mm.

[0187] For neurology applications (e.g. acute ischemic stroke), the catheter is provided such that the inner lumen of the hollow cylindrical piezoelectric transducer ranges between 0.3 mm to 2.8 mm and such that an outer diameter of the distal end of the catheter (e.g. including the diameter of the hollow cylindrical piezoelectric transducer and an outer jacket if present) ranges between 0.5 mm to 3 mm.

[0188] For cardiac applications, the catheter is provided such that the inner lumen of the hollow cylindrical piezoelectric transducer ranges between 0.3 mm to 3.8 mm and such that an outer diameter of the distal end of the catheter (e.g. including the diameter of the hollow cylindrical piezoelectric transducer and an outer jacket if present) ranges between 0.5 mm to 4 mm.

[0189] For pulmonary applications (e.g. pulmonary embolism), the catheter is provided such that the inner lumen of the hollow cylindrical piezoelectric transducer ranges between1.3 mm to 7.8 mm and such that an outer diameter of the distal end of the catheter (e.g. including the diameter of the hollow cylindrical piezoelectric transducer and an outer jacket if present) ranges between 1 .5 mm to 8 mm.

[0190] For peripheral arteriovenous applications, the catheter is provided such that the inner lumen of the hollow cylindrical piezoelectric transducer ranges between 0.5 mm to 5.8 mm and such that an outer diameter of the distal end of the catheter (e.g. including the diameter of the hollow cylindrical piezoelectric transducer and an outer jacket if present) ranges between 0.7 mm to 6 mm.

[0191] The selection of transducer material (e.g. different PZT types, piezocomposites and other materials) will therefore be a consideration in terms of electromechanical efficiency, acoustic impedance (impacting reflections) and fabrication considerations. A range of different transducer materials can be employed. Nonlimiting examples are piezoceramics (e.g. with properties similar to PZT4, PZT5A, PZT5H), and piezo composites. An example embodiment is for the transducers to be radially poled, with electrodes (e.g. fired nickel or silver) on the inner and outer radial surfaces.The Length Mode and Internal Pressures

[0192] In some example implementations, cavitation is initiated via thickness mode stimulation with a transducer dimension configuration and frequency that creates standing waves within the transducer lumen. By transmitting successive pulses, a thrombus within the lumen will be progressively degraded. Such pulsing schemes are discussed in the present disclosure, in terms of pulse length and intervals between pulses.

[0193] Examples of the feasibility clot erosion via excitation of the thickness standing mode are shown in the example implementation shown in FIG. 17. The eroded zone is concentrated about the center axis of transducer, where pressures are highest. With longer exposure durations, the diameter of the eroded zone increases.

[0194] While the generation of standing waves via thickness mode stimulation may be sufficient to enhance aspiration, it may also be advantageous to employ approaches that expand the diameter of the eroded zone more rapidly, for example, via the additional stimulation of one or more longitudinal modes. While the present inventors have found that high pressures have been more readily achieved with a thickness mode standing wave condition, rather than a length mode operation, this does not preclude the possibility of employing a length mode operation. Accordingly, in some example embodiments, the hollow cylindrical ultrasound transducer may be stimulated such that the length mode is stimulated in conjunction with the standing wave thickness mode.

[0195] It is well known in the histotripsy literature that when a bubble cloud is initiated by a pulse, it will take time for the bubbles to fully dissipate. If a following pulse is sent before the cloud has fully dissipated, the bubble cloud could be ‘resurrected’ with a lower pulse amplitude than the original pulse. Without intending to be limited by theory, it is therefore considered that bubble clouds may be initiated with the standing wave thickness mode pulse(s), and that these may be followed (or interleaved with) length mode frequency (or harmonics thereof) pulses. This approach may be advantageous in that the length mode produces a radially focal zone that is larger than what could be produced by the thickness mode standing waves alone, and as such may be a means by which to enlarge the eroded zone.

[0196] It is noted there is a histotripsy method whereby a low amplitude pulse can be used to destroy residual bubbles that persist after a high amplitude pulse, before an ensuing high amplitude pulse is sent. The purpose of this can be to reduce the impact of residual bubbles in distorting the focus. This is referred to later as a conditioning pulse. It is also noted that it is possible, with the appropriate transducer dimensions, that standing waves could be produced with length mode (or harmonics thereof). Embodiments that employ standing waves of length modes to initiate or sustain cavitation are therefore considered.

[0197] It is noted that the spatial distribution of the length mode (or odd harmonics thereof) pressure within the lumen will be a function of the transducer dimensions and as such this would be taken into consideration in the design of a transducer operating in this mode. The origin of elevated luminal pressures when operating in length mode ultimately arises from the fact that when the transducer wall extends and contracts in the length direction there are necessarily associated contractions and expansions the radial thickness. The amplitude of these thickness expansions and contractions vary along the transducer length. In the example shown in FIG. 2C (right), these amplitudes are more pronounced in the center of the transducer length, which in turn gives rise to elevated pressures within the lumen in the vicinity of the transducer length center point. In third harmonic mode, there are two peaks along the transducer centerline. This pattern can potentially become more complex, due to factors such as electromechanical mode coupling. Illustrative examples of the on axis pressure profiles for length and thickness modes are shown as a function of length for two selected transducer dimensions (inner and outer diameters 2.5 / 3.3mm and 1 .2 / 1 ,6mm) for a PZT4 material in FIG. 12.Catheter Configuration

[0198] An example catheter configuration is shown in FIG. 1A. The catheter 100 has a contiguous lumen to enable the aspiration of clot material. It has an elongate body (sheath),which, in the present example illustration, is composed of a jacket 122 and wire braiding 124 for support and to enable flexibility. The hollow cylindrical ultrasound transducer 110 is mounted (supported) at or within the distal region of the elongate body (sheath), e.g. towards the distal tip. The hollow cylindrical ultrasound transducer 110 may be located, for example, at the tip, or inset from the tip. There may also be tapering of the inner portion of the catheter lumen to the transducer with a view to facilitating clot entry into the transducer lumen 115. That is, the taper could be provided such that the inner diameter of the catheter lumen decreases from its tip towards the distal transducer face. Similarly, a taper of the catheter lumen may be introduced from the proximal transducer end towards a distance proximal to the transducer proximal end. The taper in diameter may be linear or have other forms, according to what is advantageous to facilitating clot ingestion. As can be seen in FIG. 1 A, an inner lumen of the distal portion housing the hollow cylindrical ultrasound transducer 110 is in fluid communication with a body lumen of the elongate body (sheath) 120.

[0199] An inner liner 140 may also be provided, as shown, which can be contiguous along the length of the catheter. Electrode connections 130, which in this example are formed from a copper sheet material, may be interposed between the inner liner 140 and an inner electrode surface of the hollow cylindrical ultrasound transducer 110, as well as between an outer electrode surface of the hollow cylindrical ultrasound transducer and the outer sheath 122. It is noted that the electrodes on the transducer inner and outer surfaces can take different forms, such as fired silver or nickel. These may be distinct from the electrode material referred to above (in this case copper sheets, but could be other materials such as conductive epoxy), which serve the purpose of connecting the transducer electrodes to the coaxial cable.

[0200] Wires (conductive paths) connected to the two electrodes 130 are extended along the catheter length, for example, between the liner 140 and sheath 120 and exit at the proximal end for connection to the control system, for example, via coaxial cable 126.

[0201] The example catheter includes a distal compliant tip 150. One purpose of this tip is to facilitate the navigation of the catheter within the vessel in a manner that reduces the possibility of causing vessel damage. This can take different forms, such as those employed in standard aspiration catheters. The tip region may also simply be a molded aspect of the catheter sheath.

[0202] Other materials may also be situated between the transducer 110 and sheath 120, and between the liner 140 and transducer 110 with a view to their impact on promoting a desirable acoustic field within the transducer lumen (e.g. high pressure, distribution). In selecting material types and dimensions (e.g. thickness), it is recognized that the collectiveproperties of all these elements along with the transducer will determine the acoustic behavior and development of standing waves within the lumen.

[0203] The material forming the distal portion of the sheath (‘jacket’) 120 may influence the acoustic field within the lumen 115 of the cylindrical ultrasound transducer 110, as well as reduce the radially outward-going field with a view to safety of the vascular wall. Materials (e.g. nylon or other) and thicknesses (0.05-0.3mm) that are typically employed in aspiration catheters are considered for use in the present example catheter. Other materials, with higher or lower acoustic impendences are also considered with a view to enhancing the internal lumen pressures.

[0204] Similarly, the liner material adjacent to the transducer has the potential to impact the internal pressure levels through its potential influence in reflecting waves. Considerations may also be given to properties such as lubricity with a view to facilitating clot ingestion. For example, thin (e.g. 0.01-0.1mm) compliant medical grade liners such as PTFE or similar are considered for this purpose.Electrical impedance

[0205] The Examples described below demonstrate how the thickness mode electromechanical ‘resonant’ frequency can be diffuse, as evidenced in the electrical impedance measurements of FIG. 3B, which have the characteristic of a broad peak between ~4.5-6.5 MHz, which has several (3) local minima within it. These minima are associated with standing wave frequencies. This is evidenced by FIG. 11 , which shows pressure peaks at various frequencies, as well as preferential inducement of cavitation.

[0206] Accordingly, it is apparent that the impedance spectrum can therefore be employed to identify specific frequencies, within the bandwidth of the thickness mode, that are associated with the generation of standing waves. It will be understood that standing wave frequencies can be determined from an impedance spectrum or an alternative electrical spectral measure. The impedance spectrum (or other frequency-dependent electrical measures) can be measured by many different methods, such, as, for example, by sending a series of longer test drive signals for generating pulses (having a pulse envelope sufficiently long to have the possibility of achieving standing waves), each with a different frequency (i.e. delivering the test drive signals over a frequency range), and measuring the location and depth of the minima. As noted below, ring-down signals can also be processed to infer an electrical spectral response, such as an impedance spectrum. These can be impacted by what is in the transducer lumen. The possible material that can be in the lumen are: saline, blood (before, during and after suction), thrombus (partial or fully occupying; can have different properties) and bubbles (possibly present after a therapy pulse). Saline,blood, and thrombus will have different acoustic velocities. Given that the inner diameter is fixed, the specific standing wave frequency (i.e. impedance minima) will shift depending on the velocity (acoustic) of the material within it. In some example embodiments, a catheter system may include control (e.g. drive) circuitry pre-configured to deliver therapy drive signals to the hollow cylindrical ultrasound transducer for generating intraluminal standing waves within a known reference material. The therapy drive signals may be provided according to a frequency and a time duration that are suitable for exciting a standing wave within the inner lumen when the known reference material resides in the inner lumen (the standing wave being associated with intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer). The known reference material may be for example, a saline solution of 0.9% NaCI by weight, blood, and a thrombus having known properties (e.g. a reference thrombus or thrombus model). The control circuitry may be programmed such that the frequency is selectable among several selectable reference frequencies, where at least two of the plurality of reference frequencies correspond to different reference materials.

[0207] Examining the location (frequency) of minima in an impedance spectrum can provide a means by which to determine what is in the lumen and to determine a suitable operating frequency for generating intraluminal standing waves during the delivery of therapy (e.g. and to generate cavitation). This may be possible in absolute terms, or comparing the minima frequency relative to baseline values when saline (e.g. 0.9% NaCI by weight in water, optionally a heparinized saline solution, at a prescribed number of units of heparinized sodium per ml) is present prior to the commencement of the aspiration procedure. Additionally, as velocity can be frequency dependent, an analysis of multiple minima will be employed. Further, as clot properties (extraction-relevant ones such as viscoelasticity and stiffness) are variable this information (minima location) may be linked to clot properties. In turn this information can be used to inform treatment parameters (e.g. pulse length and interval).

[0208] For example, the presence of bubble clouds (i.e. persistent bubbles after a ‘therapy pulse’ within the lumen) would reduce the capacity to sustain and develop standing waves. This is because waves propagating within the lumen would be scattered, absorbed, reflected. Accordingly, the absence or reduction of the depth of the minima in the impedance frequency spectrum can provide an indicator of the presence and spatial extent of bubbles.

[0209] In one example embodiment, the standing wave frequency (e.g. frequencies of one or more minima in an impedance spectrum) and / or the spectral characteristics associated with a standing wave frequency (e.g. amplitude and bandwidth) can be processed, forexample for monitoring and / or control of treatment (e.g. control of the therapy pulses and / or control of an aspiration mechanism). In some example embodiments, the temporal evolution of the standing wave frequency (e.g. frequencies of one or more minima in an impedance spectrum) and / or the spectral characteristics associated with a standing wave frequency (e.g. amplitude and bandwidth) can be processed, for example for monitoring and / or control of treatment (e.g. control of the therapy pulses and / or control of an aspiration mechanism). For example, in some example implementations, machine learning methods (e.g. such as, for example statistical learning methods and deep learning methods) can be employed to process one or more standing wave frequencies, and / or to process one or more electrical spectral measures (e.g. an impedance spectrum), to generate output suitable for monitoring and / or control of treatment (e.g. control of the therapy pulses and / or control of an aspiration mechanism). Examples of suitable machine learning methods include, but are not limited to, support vector machines (SVMs), neural networks (NNs, both deep and shallow), decision tree ensembles, and reinforcement learning (RL). For supervised machine learning methods, mathematical models will be trained on, or fit to, input data, such as electrical spectra (e.g. impedance spectra, therapy pulse self-sensing) or portions thereof, and / or features derived from electrical spectra (e.g. wavelet packet Shannon entropy), that are labeled with respect to a parameter (e.g. transducer lumen contents, cavitation). Unsupervised machine learning methods (e.g. K-means clustering) can be trained similarly with unlabeled input data. Reinforcement learning methods can be trained through its interaction with the treatment system or computational models subject to some predefined reward / penalty function. Input data can be obtained from, though not limited to, previous treatments and can be preprocessed in some form (e.g. normalization, feature extraction). Input data can be split into training, validation, and test subsets to facilitate model training (e.g. model fit, hyperparameter tuning) and allow for evaluation of the suitability of the fitted model (e.g. cross-validation). Note that multiple methods can be used and that deep learning may be applicable.

[0210] Accordingly, in some example implementations, the frequency-dependence of electrical test drive signals delivered to the cylindrical ultrasound transducer can be monitored to identify one or more standing wave resonances within the bandwidth of the thickness mode. For example, the frequency-dependence of the electrical impedance, or the frequency-dependence of another suitable electrical measure (such as electrical current or realized voltage across the catheter) associated with the electrical driving signal / waveform, can be measured within a relevant frequency range associated with excitation of the thickness mode, in order to identify, or to permit the identification of, one or more resonant standing wave frequencies for thickness mode based excitation of the cylindrical ultrasound transducer.

[0211] In some example implementations, one or more of these standing wave resonant frequencies can be communicated to a user (e.g. via a user interface or display), enabling the user to set a suitable excitation frequency to facilitate the generation of a standing-wave- induced pressure increase within the lumen of the cylindrical ultrasound catheter.

[0212] In other example implementations, one or more of these standing wave resonant frequencies can be automatically selected and employed to drive the cylindrical ultrasound catheter to facilitate the generation of a standing-wave-induced intraluminal pressure increase. For example, this measurement and optionally feedback capacity (involving the setting of the driving frequency via the detection and selection of one or more standing-wave frequencies) may be incorporated into the control and processing system that is described in further detail below. By having the capacity to measure the standing wave frequencies for each catheter, a means is provided by which to compensate for potential variability in the manufacturing process.

[0213] In other example embodiments, intraluminal cavitation may be directly monitored, for example, via the use of signals detected with the hollow cylindrical ultrasound transducer, and / or via signals detected via one or more additional passive monitoring transducers, to detect the presence or absence of cavitation, and feedback may be provided to the user, or may be directly employed by the control and processing system, to identify suitable electrical driving conditions (e.g. a suitable driving frequency) to achieve intraluminal cavitation via standing-wave-induced intraluminal pressure enhancement. In some example implementations, direct acoustic monitoring of the presence or absence of cavitation may be employed to validate or confirm the selection of a suitable driving frequency based on indirect measurements involving the electrical driving signals.Example Workflow and Control Algorithm

[0214] From a clinician’s perspective, the intended workflow for the procedure can parallel that for aspiration mechanical thrombectomy using conventional aspiration catheters. The details of the clinical procedures employed can vary with the clinical scenario (e.g. acute ischemic stroke, pulmonary embolism, peripheral vascular occlusions such as deep venous thrombosis). A common aspect tends to be that the aspiration catheter is introduced into the target vessel through a larger guide catheter situated a distance proximal to the occlusion. Typically the aspiration catheter is then extended and navigated over a guidewire to be situated adjacent to, in contact with, the proximal end of the thrombotic occlusion. This is portion of the procedure is conducted under angiographic guidance and with the use of contrast injections to visualize the vasculature, perfusion, the occlusion location, and the catheter position.

[0215] Typically the aspiration system is then engaged for a period of time. The nature of the vacuum pressure (magnitude and possible time varying pattern of pressure) is system dependent. In the context of stroke, for example, the ADAPT procedure is employed, which entails engaging the vacuum for a period of time (direct contact aspiration), then pulling back the aspiration catheter into the guide catheter, then injecting contrast to assess the perfusion status of the vasculature. The retrieval of clot material and blood into the vacuum pump reservoir can be potentially observed by clinicians and is information that may be relevant to determining if clot retrieval has been successful, though does not indicate if residual clot material remains in the vessel. In some cases, a specialized wire is extended into the clot and then pulled back into the aspiration catheter with the objective of pulling the clot fully or partially into the aspiration catheter before the aspiration is engaged. Depending on the outcome of this as determined by the clinician, the procedure will be deemed sufficiently successful or further attempts at reperfusion may be made, either with an aspiration or stent retriever catheter.

[0216] According to one example workflow employing the present aspiration catheter, ultrasound exposures can be conducted during the aspiration process. In one example implementation, the therapy pulses will be initiated synchronously with (e.g. temporally overlapping with) or preceding the engagement of aspiration. In some example implementations, the system can control the relative timing of the aspiration and therapy pulse sequence transmission, while in other example implementations, the relative timing can be user-controlled.

[0217] In some example implementations, therapy pulses may be preceded by pulses that are delivered to facilitate the determination of a suitable operating frequency (e.g. impendence spectrum measurements) for generating the intraluminal standing wave, as described above.

[0218] In some example implementations, one or more ‘probe’ pulses (as described in further detail below) may be delivered to provide baseline signals that can be employed, for example, as a reference to subsequently assess for the presence of clot material, clot erosion information, the presence of bubbles and cavitation.

[0219] The presence of cavitation within fluids present within the transducer lumen may be tested for prior to the engagement of aspiration. During aspiration, electrical signals associated with generation of the therapy pulses, and / or acoustic reflections associated with the therapy pulses, may be analyzed for information relating to cavitation and erosion patterns.

[0220] The therapy pulses (or pulse sequences) may be interleaved with impedance measurements (pulses provided over a range of frequencies to facilitate spectrum impedance measurement) or probe pulses or other pulse sequences.

[0221] The amplitude, frequency and interval of the therapy pulses may be varied during the aspiration process, as well as the aspiration pressure or pressure patterns. This may be performed based on information obtained from the impedance measurements, probe pulses or therapy pulses (i.e. self-sensing signals). This information may also be used to determine when to cease the aspiration the process, for example if it is determined if the clot material has been ingested and only blood is being aspirated.

[0222] The treatment procedure then has the effect of creating cavitation within the thrombus as it passes through the lumen, degrading the mechanical integrity of a portion of the thrombus (liquefaction zone, or partial degradation for example of the fibrin network or cellular components) such that its aspiration through the transducer lumen and catheter is facilitated.

[0223] In other clinical scenarios, clot material can readily enter the catheter during the early stages of aspiration, but large volume of clot material can ‘clog’ the catheter thus requiring its removal and replacement to resume and complete the aspiration process. The embodiment in this context could involve a transducer that is substantially proximal to the tip, or the use of multiple transducers within the catheter.Temporal Characteristics of the Realized Pressure During a Pulse Transmission

[0224] In the present disclosure, it is observed in both simulations (FIGS. 14A-14D) and experiments (FIGS. 6B-6E) that there is a finite time for the pulse to rise to its peak level and after the transmit pulse (i.e. stimulating voltage) ends, there is a finite time duration for the decay of pressures. The characteristics of the initial rise is that it occurs in a stepped manner, consistent with the development of the arrival and contributions of successive reflections and the development of a standing wave pattern. The characteristics of the decay (for conditions that are below the cavitation threshold) is that the pressure reduces in a stepped manner, consistent with the dissipation of successive internal reflections.

[0225] It can be expected that the rise and decay of the signal will be influenced by the properties of the material within the transducer lumen. For example, with a water or saline filled lumen, the acoustic attenuation will be relatively low and the decay will therefore occur over a relatively long time. However, if clot material resides within the lumen, attenuation will be higher than for saline or blood and therefore the successive reflections will decay in amplitude more rapidly. As attenuation within the lumen will also impact the amplitude of the internally reflected waves that contribute to the standing wave, the steady state amplitude ofthe pressure wave envelope will also be impacted by the material present within the lumen. Higher attenuation levels can be expected to result in lower realized pressure amplitudes. It should also be noted that nonlinear propagation will occur within the lumen, which gives rise to pulse asymmetry and the development of harmonics of the transmit frequency.Attenuation within saline, blood and thrombus is frequency dependent (increases with frequency, with the degree of increase dependent on the material).

[0226] As the attenuation properties of clot (arising from both scattering and absorption) vary with its composition, the rise and decay timing as well as the peak pressure amplitude can be expected to vary with clot properties. Blood can also be expected to have a different rise and decay curves and peak amplitudes. Moreover, if there is a partially eroded region within the lumen, this can be expected to have different rise and decay characteristics and peak amplitude than an uneroded region.

[0227] Therefore, the rise and ‘ring down’ portions of the pressure pulse as well as the amplitude can be processed to provide information about the material within the transducer lumen. This information can be of value for determined exposure timing and schemes, and to monitor the treatment process.

[0228] In FIGS. 14A-14D and experiments (FIGS. 6B-6E) the pressure waveforms were signals at particular points in the field. Signals of the pressure waveform can be acquired for analysis.

[0229] In one example implementation, the transducer signals (from the primary therapy transducer and / or one or more passive ultrasound transducers) can be processed following the cessation of the ‘therapy’ transmit pulse, as the acoustic wave reflections will generate electrical signals when they impinge on the transducer surface.

[0230] Alternatively, ‘probe’ pulses that differ in amplitude, frequency and or duration could be sent (again, from the primary therapy transducer and / or one or more other ultrasound transducers). Multiple pulses could be employed, for example with different frequencies, which would be sensitive to frequency-dependent attenuation and possibly different spatial regions of the lumen.

[0231] Finally, the ring down temporal region can be expected to have distinct characteristics when bubbles are present. This could be due to continued bubble (or bubble cloud) oscillations, and or their impact on reflected wave propagation. Waves encountering bubbles or bubble clouds can be altered through scattering, absorption and reflection (e.g. in the case of a cloud boundary).

[0232] In general, it is expected that there is a reduction in amplitude of a wave propagating through a cloud. Typically with histotripsy, a cloud tends to be confined within the higher pressure regions of the transducer focus, and its characteristics can changeduring the erosion process (e.g. bubble density, sizes). It is also notable that the cloud will dissipate over time (milliseconds to 10s of milliseconds timescale typically is reported in the histotripsy literature). It should be noted that in the present example application, the present inventors have observed that bubbles can be present in the clot peripheral to liquified lesion zones (for example, hypoechogenic spots visible in FIG. 17). If bubbles are present within the lumen, for example, during a pulse or from a preceding pulse when another pulse is sent, the bubbles can impact the realized pressure distribution within the lumen. In such a case, it can be advantageous to send other pulse types (pressure, frequency).

[0233] Accordingly, as noted above, in some example embodiments, signals (e.g. selfsensing if one transducer is employed) from probe pulses (or probe pulse sequences) acquired preceding the commencement of the aspiration (and therapy pulse transmission) process and during the aspiration process can be processed and compared to extract information about material within the lumen.

[0234] For the probe pulses, one or more probe pulses may be sent in a sequence. The sequence can be comprised of the same pulses (i.e. a common set of pulses), or pulses that vary in one or more of center frequency, amplitude and length (duration). The time between pulses can be fixed or variable. A pulse can be sinusoidal with a rectangular or other envelope (e.g. tapered at ends, gaussian).

[0235] The pulses preceding the aspiration / therapy process can provide a baseline reference, as it is expected that there will be no thrombus within the transducer lumen. When thrombus is present in the lumen, in the absence of bubbles or cavitation, the received pulses will have an altered rise and fall time and peak amplitude relative to the baseline pulses. Different frequency probe pulses may be altered in a different manner.

[0236] During the treatment process, if the clot has undergone erosion or is damaged from the treatment process, the probe pulse may have different characteristics. This information can be used to control the treatment pulses, for example in frequency amplitude, pulse duration or interval. For example, if the clot has been fully ingested and blood is then being aspirated into the lumen, this will result in a change in the probe pulse characteristic. The detection of blood following the ingestion of the clot can be used as an indicator to cease the aspiration process in order to avoid the extraction of blood and possibly induce vessel collapse.

[0237] If bubbles are present during a probe pulse, due to sufficient time not passing between a therapy pulse and the probe pulse, the characteristics of the probe pulse will be altered (for example reduced amplitude and rise and decay times). Therefore, in some example embodiments, the timing of the probe pulses following therapy pulses can be selected to assess for bubbles.

[0238] For example, in one example implementation, if a sequence of probe pulses is sent between therapy pulses, the probe first could be timed such that bubbles are still present, and the last or later probe pulses could be used to indicate when bubbles have dissolved. This can be relevant to inform the treatment process. For example, it may be desirable to wait until bubbles from a given pulse have dissolved prior to sending another therapy pulse as their presence can influence the resulting pressure distribution.

[0239] An additional means by which probe pulses can be used to determine if thrombus or blood or saline is present within the lumen is to send an amplitude ramped sequence, to determine the threshold for cavitation. Cavitation thresholds or characteristics (e.g. frequency content or amplitude during the transmit phase of the pulse, ringdown characteristics after) may differ between these materials, and they may vary within thrombus depending on its properties (e.g. Youngs modulus). The latter information may be used to select therapy pulse characteristics. For example a high amplitude required to initiate cavitation within thrombus may suggest the use of different therapy pulse length or amplitude or interval. Similar to probe pulses, therapy pulses can also be analyzed for characteristics associated with the presence of saline, blood, thrombus, bubbles and cavitation.

[0240] The ringdown temporal portion of the received signals occurring after the cessation of the transmission of ultrasound therapy pulses (or probe pulses of sufficient amplitude to potentially initiate cavitation) can be used to indicate and / or quantify the presence and / or degree of cavitation. The physical basis for this is that the ringdown signal is associated in part with the internally reflected ultrasound waves, which dissipate over time. If the transmitted ultrasound results in the generation of a bubble cloud, the cloud will persist for a period of time following the cessation of the transmitted ultrasound. The presence of bubbles within the lumen will the attenuate the propagation of internally reflected waves more than if bubbles are not present. Thereby ringdown portion of the signal will therefore be lower in amplitude and / or temporal extent if the transmission has resulted in a cavitation cloud than if a cavitation cloud has not been generated. The amplitude and / or temporal extent of the ringdown will be reduced in a manner that is related to the degree of cavitation that has been elicited (e.g. number and density of bubbles), and can therefore be employed to assess, quantitatively or qualitatively, the presence / absence and / or degree of cavitation generated by a drive pulse.

[0241] In one example embodiment, drive signals could be delivered to the hollow cylindrical ultrasound transducer to generate ultrasound pulses at multiple frequencies that correspond to, or are proximal to in frequency, one or more frequencies that are known or expected to correspond to standing wave frequencies. For example, when an impedancespectrum (or other frequency dependent electrical measure) has been determined that facilitates identification of a plurality of standing wave frequencies, drive signals can be delivered at one or more of the standing wave frequencies (or at nearby frequencies) and the ring-down signal can be processed, as noted above, to assess cavitation produced at each standing wave frequency. For example, the multiple standing wave frequencies that can be seen in the minima within the thickness mode bandwidth in the impedance spectrum shown in FIG. 3B could each be tested for cavitation according to the present example ringdown assessment based method. The resultant ringdown portions of these signals can indicate or quantify the presence and / or degree or efficiency of cavitation at each standing wave frequency, and the resulting analysis may permit the selection of standing wave frequency for use in the delivery of subsequent therapy driving signals, the can provide a maximum amount of cavitation and / or a maximum efficiency.

[0242] It will be understood that several different ringdown assessment methods may be employed to assess cavitation at or near two or more standing wave frequencies. Fo example, in some example implementations, the cavitation thresholds for each tested frequency can be determined, for example, by varying driving amplitude, and compared to select the optimal frequency with the lowest threshold. Alternatively with a quantified metric of cavitation based on the ring down region, the varying responses to the same high amplitude driving pulse at different frequencies can be compared, so that an optimal driving frequency can be selected.

[0243] Accordingly, in some example embodiments, probe pulses can also be used to determine the extent of cavitation for the purposes of modifying (e.g. improving, optimizing) treatment parameters. For example, high amplitude probe pulses (with a sufficiently high amplitude for generating cavitation) can be sent at various frequencies, such that cavitation characteristics can be quantified to determine which frequency produces the most cavitation. This could also take the form of determining cavitation thresholds at various frequencies to determine which frequency has the lowest threshold and thus may be the optimal for treatment. The tested frequencies can be at or in the vicinity of standing wave frequencies that lie within the thickness mode bandwidth, or at other frequencies associated with cavitation.

[0244] Cavitation analysis during the ringdown and pulse-on phase can be done at a range of frequencies (e.g. thickness mode range or harmonics thereof, any standing wave mode, length mode and harmonics thereof). The analysis can take different forms (e.g. frequency, time, power, decay characteristics). In addition, impedance measurements can be conducted preceding and during the aspiration / treatment process- interleaved with therapy pulses and probe pulses. This can provide additional information, as indicated earlier, forexample about the presence of cavitation and the material within the lumen. In one example embodiment, machine learning methods (e.g. statistical learning methods and deep learning methods) can be employed of analysis and to extract information that can be used to inform in real time the treatment status (i.e. presence of cavitation or erosion or complete injection of clot) and for the control of transmit pulses and the aspiration component of the system. This can involve training with different materials within the lumen and during the aspiration process

[0245] In addition to therapy pulses (high amplitude pulse intended to elicit damage or degradation of the thrombus), in one example embodiment, ‘bubble conditioning pulses’ can be incorporated into the transmitted pulse sequences. The use and incorporation of bubble conditioning pulses can be informed by the above procedures when it is indicated that there is the presence of persistent bubbles within the lumen. The presence of bubbles within the lumen at the time a therapy pulse is initiated can be considered to be undesirable from the perspective of achieving a pressure level and spatial distribution that will promote progressive clot erosion.

[0246] In one example embodiment, bubble conditioning pulses can be used to destroy the bubbles prior to a therapy pulse transmission, for example with the use of a pressure amplitude that is sufficient to destroy the bubbles but is below a therapeutic threshold. For this, different frequencies can be employed to ensure that different spatial regions of the lumen are impacted. In another embodiment, a lower amplitude (below therapy level) pulse can be used for the purposes of displacing bubbles to a desired location (e.g. towards the axis of symmetry) prior to the transmission of the therapy pulse.

[0247] In some example implementations, therapy pulsing scheme sequences can be comprised of the same length, frequency and amplitude pulses that are repeated at fixed intervals. The length, frequency, amplitude and intervals can also be varied. This can be predetermined, or controlled based on information derived from impedance or self-sensing or a second transducer within the catheter. An example would be switching from a thickness mode frequency to a length mode frequency in order to radially enlarge the eroded zone and therefore achieve improved clot ingestion. In one example implementation, the interval of the length mode following the thickness mode may be reduced with a view to exploiting residual bubbles present following the thickness mode pulse.

[0248] In some example embodiments, conditioning pulses, impedance pulses and / or probe pulses may be part of the sequences delivered to the transducer.

[0249] The aspiration pressure level, which may involve time dependent variations, can also be controlled as part of this process.

[0250] The preceding approaches involve cavitation that is primarily internal to the transducer. It is also considered that in certain clinical circumstances, such as an occlusion that is very difficult to aspirate, that a forward projecting field will be incorporated into the process. In this circumstance, in addition to an aspiration component, the system would be configurated such that it is also possible to ‘push’ / pump fluid out of the distal catheter tip.

[0251] One example of a suitable sequence of operations could be as follows. First, the catheter tip would be navigated to be situated in close proximity with the proximal end of the occlusion. Standing wave thickness mode pulses could then be transmitted to initiate a cavitation cloud within the transducer lumen. During this time, the pump could be employed to displace fluid and bubbles outwards and in contact of proximity with the occlusion surface. Forward projected ultrasound pulses (e.g. length mode or harmonics thereof) could then be sent such that cavitation would occur at the occlusion surface. This process could then continue to erode and damage the surface.

[0252] To facilitate the formation of stable bubbles within the lumen, a small amount of blood could be pulled into the lumen prior to the insonation process. Plasma and possibly lyzed erythrocytes could then provide stabilizing molecules. Aspiration may then be done intermittently to retrieve debris from the eroding occlusion. This approach would require the transducer dimensions to support both high pressure internal standing waves, as well as forward projected length mode waves. As with the preceding approaches, similar monitoring and control approaches could be applied.Detection of Wires, Microcatheters or other Devices within the Transducer Lumen

[0253] Guide wire and or microcatheters may be used to facilitate the navigation of the aspiration catheter tip through the vasculature, to be situated adjacent to or in contact with the proximal aspect of the clot material that is intended to be extracted. The removal of such devices prior to initiating the vacuum is part of the existing clinical protocol for some conventional aspiration techniques, for example direct contact aspiration of clots within the cerebrovasculature. With other techniques, such as PE thrombus removal, wires or ‘separators’ can be present within the lumen of distal aspect of the aspiration catheter during the aspiration process, to facilitate the mechanical breakdown of thrombus material.

[0254] In general, an US enhanced aspiration catheter is intended to be operated without these devices situated within the lumen of the transducer. Their presence within the lumen would impact the resulting pressure field in a manner that may negatively impact the degree of cavitation that can be induced, and thereby the extent of clot degradation induced by the ultrasound. Accordingly, after the navigation stage, it will be desirable to remove suchdevices entirely, or retract them substantially so they do not interfere with the aspiration process, or impact the ultrasound field within or adjacent to the transducer lumen.

[0255] Accordingly, in one example embodiment, verification of removal or sufficiently retraction of such a device from the catheter lumen, prior to the commencement of the ultrasound enhanced aspiration process (meaning the application of a vacuum and or therapeutically relevant ultrasound pulse transmissions), may be performed using one or more probe pulses (e.g. one or more probe pulse sequences) transmitted by the hollow cylindrical ultrasound transducer, received (through self-sensing) and then analyzed to detect the possible presence of the device within or proximal to the transducer lumen.

[0256] The premise of this example detection method is that the presence of a device (e.g. wire or microcatheter) within or proximal to the transducer lumen will impact the internal ultrasound field through reflections and absorption. For example the ability to generate standing waves within the lumen may be compromised or altered. As a result, the selfsensing signals will be altered relative to the case of the lumen being filled with materials such as saline, blood, clot, contrast material or mixtures thereof. Such differences can provide a basis of detection.

[0257] One example method of detection of an intraluminal device is through the impact of the presence of internal devices on electrical impedance spectra. For example, they may alter the appearance of spectral features associated with standing waves. Impedance spectra can be derived from the ringdown portion of the signal of individual short pulses (e.g. 1-5 cycles). Such pulses may be averaged in the time or frequency (power spectra) domain to improve signal to noise ratios. Alternatively the impedance spectra may be derived from sequences of longer pulses with different center frequencies. Alternatively, these analyzes can be conducted on spectra derived from either the voltage or current self-sensing signals.

[0258] The spectral or temporal characteristics of individual pulses may also be used to provide information relevant to the detection of internal devices, separate from impedance spectra. Pulses can be of varied lengths (durations) or frequencies, including for example standing wave frequencies for lumens filled with blood, saline of contrast. Time domain analysis includes envelope and or phase characteristics. Sequences of pulses can be varied in amplitude, phase (e.g. 180 degree phase) and frequency. The analysis of pulse sequences can include examining how the pulse responses change. The pulse sequencies can also be combined for analysis, for example adding successive phase inversed pulses. Machine learning (e.g. statistical and deep learning) approaches can also be applied to the analysis.

[0259] If the analysis supports that a device is present within the lumen, the system can be employed to alert or otherwise notify the clinician of its presence and be prompted to retract the device, and may autonomously prevent the delivery of therapy pulses and / or aspiration.Alternate Transducer Configurations

[0260] The previous transducer configurations involved a hollow cylindrical ultrasound transducer with electrodes on the inner and outer radial surfaces. This creates a luminal pressure distribution with cylindrical symmetry. An alternative approach is to employ a transducer configuration that also, in addition to having the ability to achieve a symmetric pressure distribution, has the capacity to break this symmetry. In one embodiment, this is achieved by having the same type of radially polarized hollow cylindrical ultrasound transducers, but with variants of the transducer electrode configurations. One variant of this is to have multiple electrodes on either or both the inner or outer radial surfaces. Each electrode would occupy an arc of the surface and be separated from the adjacent electrode by a gap. Each electrode could extend the full length of the transducer. For example if the outer or inner surface had two electrodes, they would each occupy less than a 180 degree arc of the surface; if 4 were used each arc would be less than 90 degrees, etc. This is demonstrated in FIGS. 21 A and 21 B showing a hollow cylindrical ultrasound transducer with the outer surface divided into 4 equal arcs, with examples for both a partial kerf between electrodes (FIG. 21 A) and kerfless (FIG. 21 B). The pressure fields shown in FIG. 21 A demonstrate the difference between the excitation of a single electrode and all electrodes simultaneously, showing different field profiles. If multiple electrodes are employed on both the inner and outer surfaces, then in some example implementations, the number of electrodes on each surface would be equal and occupy the same arc extent and location, to create opposing pairs of electrodes. These electrode surfaces would then be connected to additional wires in the manner previously described in the original embodiment of the hollow cylindrical ultrasound transducer.

[0261] When an opposing electrode pair is stimulated (in the case of opposing pairs) or alternatively, in the case where only the outer or inner surface is divided into multiple electrodes, only one of the multiple electrodes is stimulated (along with the single electrode on the opposing surface) this will create spatially localized thickness mode expansions which will in turn result in a directional wave, similar to having a finite arc of a cylinder. This wave would also undergo reflections at the opposing inner surface. If the applied pulse length were sufficiently short, a travelling wave would be emitted, as opposed to a standing wave. To create a cylindrically symmetric field operating in standing wave mode, all of the multiple electrodes on a surface would be connected (with the external system) such that it would besimilar to the original hollow cylinder system. This would have higher achievable pressures than when single electrodes are stimulated, and thus would be more suitable to initiate a cavitation cloud.

[0262] One example operating scenario (method) of such an apparatus could include the stimulation of all electrodes (i.e. electrically ‘link’ all electrodes on a given surface), and transmit waves with pulse sequences similar to those employed with the previously described transducers. The single electrode configurations can then be used to create a directional fields, that can act to create erosion patterns that extend the erosion patterns towards the opposing transducer wall. In this scenario, the single electrode stimulation can follow a ‘linked’ electrode pulse (used to initiate a bubble cloud) such that acoustic radiation forces may be involved to translate the bubbles in the direction of the opposing wall. This can facilitate clot erosion. The particular electrodes selected for single electrode mode can then be varied such that the clot erosion pattern is expanded outwards from the center axis in different directions.

[0263] In another embodiment, rather than employing multiple electrodes on a surface, the hollow cylindrical ultrasound transducer can formed from an array of separate transducer elements (>=2). Each element would take the form of a cylindrical arc have a common axial length. Gaps (full kerfs, filled with material) would be present between elements, such that each of the elements are separate from one another. Each element would have separate electrode pairs. The operation of this configuration would be as described in the preceding section.

[0264] In another example embodiment, the standing wave patterns can be achieved with a thin layer of piezoelectric material that is conformed to be in a cylindrical shape. For example PVDF or co-polymer films which are mounted / adhered to a hollow cylinder (e.g. metal or plastic) for structural support and to provide acoustic properties than facilitate the generation of standing waves within the lumen. In this scenario, length mode operation is not achievable.Example Clinical Applications

[0265] It will be understood that the example systems and methods disclosed herein may be employed for a wide variety of clinical uses and interventions. The details of aspiration techniques can vary with the clinical scenario. In general, and as explained above, aspiration procedures involve first introducing an access catheter into the vasculature and navigating its tip under fluoroscopy guidance to a location proximal to the occlusion site. Contrast injections are employed during this process to generate a digital subtraction angiography (DSA) to create a vascular map and locate the occlusion site. The aspiration catheter is thenintroduced into the vasculature through the access catheter. Guide wires and or microcatheters within the aspiration catheter are employed to assist in navigating the aspiration catheter to be in proximity to or in contact with the proximal end to the clot, as inferred by the DSA indicated occlusion site. The size of the aspiration catheter employed is ultimately limited by the diameter of the target vessel. Smaller diameter catheters are associated with increased viscous resistance, which can limit the achievable vacuum pressures as well as the ability of the clot to enter and aspirate though the catheter. The approaches described in the present disclosure provide a means by which to improve the performance of aspiration by mechanically degrading clots as the enter the tip. The clinical workflow with the ultrasound enhanced catheter will largely parallel many aspects of conventional aspiration procedures.

[0266] In an acute stroke setting, aspiration thrombectomy procedures are used in a range of intracerebral vessels, such as the internal carotid, middle cerebral, basilar and vestibular arteries. Large vessel occlusions (LVOs) are typically considered to be in the internal carotid artery and M1 segment of the middle cerebral artery. In the context of stroke, variations of the ADAPT procedure is frequently employed. This entails first navigating the aspiration catheter tip to be in contact with the proximal end of the clot as described above. The guide wire is then extracted from the aspiration catheter and the vacuum is then applied for a period of time (direct contact aspiration), for example 1-3 minutes. The catheter is then retracted to be proximal to the original occlusion site for a period of time while still engaging the vacuum and then ultimately retracted back into the access catheter. The perfusion status of the vasculature is then reassessed with a contrast injection through the access catheter. The retrieval of clot material and blood into the vacuum pump reservoir can be potentially observed by clinicians and is information that may be relevant to determining if clot retrieval has been successful, though does not indicate if residual clot material remains in the vessel. In some cases, a specialized wire is extended into the clot and then pulled back into the aspiration catheter with the objective of pulling the clot fully or partially into the aspiration catheter before the aspiration vacuum is engaged. Depending on the outcome of the perfusion assessment, the clinician will be deemed sufficiently successful or further attempts at reperfusion may be made, either with an aspiration or stent retriever catheter. A challenge in the acute stroke setting is to achieve sufficient reperfusion success on the ‘first pass’, as this is associated with improved functional outcomes for patients. The first pass success rates for LVOs are at present not high (~25-35%, depending on how it is classified).Aspiration catheter sizes used for stroke LVOs range from ~5-7F. Smaller vessels (e.g. beyond the M1 segment of the MCA) necessitate the use of smaller catheters. The relatively small lumen size of the catheters employed in stroke treatments is a significant contributing factor that limits the ability of the clot to enter into and pass through the catheters. Theultrasound enhanced aspiration is intended promote the aspiration of clots in this setting. The clinical workflow will essentially follow that of ADAPT procedures. The presence of a guidewire or other device within the lumen will generally be precluded, as is frequently the case for ADAPT procedures, and will be tested for and the clinician notified if it is present.

[0267] Pulmonary embolism is a significant cause of cardiovascular based mortality and morbidity. Due to considerations of bleeding risk and limitations in effectiveness associated with the systemic administration of thrombolytic agents, catheter based mechanical thrombectomy procedures are increasingly employed. A number of different mechanical thrombectomy approaches and systems are employed. PE thrombotic occlusions can be situated at different levels of the pulmonary arterial tree, but are typically in larger vessels than for stroke applications, which enables the use of larger size aspiration catheters. This in turn requires the use of larger access catheters. In some cases, bilateral access is gained, with one side being used to generate a vascular map and assess perfusion status. Due to the potentially large clot volumes present, aspiration can be accompanied by the use of either a specialized wire or ‘separators’ that are advanced into the clot and retracted such that a) the portion of the clot external to the catheter is degraded mechanically prior to entry into the catheter and b) material within the catheter tip is fragmented to enable aspiration. This process has the potential to induce vascular injury. For larger clots, the catheter tip is advanced during the aspiration process. The aspiration of blood during this process can occur, particularly as the catheter bore size is large. Measures to mitigate this have been developed. For example, flow and pressure monitoring in the aspiration system to detect blood extraction, as well as approaches to return the blood to the patient. A wide range of aspiration catheters have been employed in PE. For the approach described above, 8-12F have been reported in clinical trials. Larger (16-24F) catheters have been employed with an alternative aspiration approach that employed the forward deployment of a mesh configuration into the clot to assist retrieval.

[0268] The ultrasound enhanced aspiration is intended to promote the aspiration of clots in this setting, which can be limited by large clot volumes. In one preferred embodiment, the workflow will depart from that described above in that use of wires and or separators to mechanically degrade the clot and clear the distal aspiration catheter tip of thrombus will not occur. Rather, there will be no wires and or separator within the aspiration catheter, as ultrasound will be employed instead to achieve the mechanical degradation of clot material. In another embodiment, a wire and or separator can be used in conjunction with ultrasound treatments. For example, ultrasound will remain off when the wires or separator is within the transducer lumen and performing the normal action of degrading the clot for a period of time, then this can be followed by the wire or separator will be retracted proximal to the transducer lumen and the ultrasound will be turned on to degrade clot material. These two phases canbe alternated, according to the clinician’s preference. The presence of a guidewire or other device within the lumen can be tested for and the clinician notified if it is present.

[0269] Aspiration thrombectomy procedures are performed in the peripheral vasculature (arms and legs). Deep venous thrombosis is one important condition, as it can give rise to PE. Arterial occlusions can give rise to limb ischemia and have the potential to be life threatening. The aspiration procedural approaches identified above can be employed. A wide range of vessel calibers can be occluded by thrombus, which necessitates the need for a range of aspiration catheter sizes (e.g, 3-12F). Subacute thrombus can be present which is associated with a reduced aspiration success due to its increased degree of structural organization and stiffness. This, coupled with potentially long occlusions, can present considerable challenges and reduced success rates for aspiration approaches. The ultrasound enhanced aspiration is intended promote the aspiration of clots in this setting. The clinical workflow may take the form as described above according to clinical considerations relating to the vessel size, thrombus length and properties.

[0270] Aspiration is also performed in the coronary tree. For example, in the setting of myocardial infarction, where thrombus removal from an infarcted vessel can be performed prior to other percutaneous interventions (e.g. angioplasty and stent placement). This can be performed manually with a syringe to initiate vacuum pressure. Continuous vacuum application with a vacuum system can also be applied, and may have superior sustained vacuum levels. The catheter sizes employed are dependent on where in the coronary tree the aspiration is performed; 5-6F has frequently been reported. The ultrasound enhanced aspiration is intended promote the aspiration of clots in this setting. The clinical workflow may take the form as described above.

[0271] The above is not intended to be a comprehensive list of catheter based aspiration of vascular occlusion applications. It is also notable that aspiration of thrombus and other materials is also performed outside of the setting of vascular occlusions. For example, intracerebral hemorrhage can be ‘needle’ aspirated through a burr hole introduced in the skull. The aspiration of intracardiac materials, such as thrombus, vegetation associated with implants or tumors can be conducted.Example System

[0272] FIG. 1 B provides a block diagram illustrating an example implementation of a system for performing intravascular cavitation-assisted disruption and aspiration of thrombus. Control and processing circuitry 200 is operably connected to hollow cylindrical ultrasound transducer 110 of catheter 100, optionally via transducer driver electronics / circuitry 580 (such, as, for example, pulse generation circuitry, amplifiers andswitches). Control and processing circuitry 200 is also operably connected to aspiration pump or mechanism 590.

[0273] The control and processing circuitry 200, which includes one or more processors 210 (for example, a CPU / microprocessor), bus 205, memory 215, which may include random access memory (RAM) and / or read only memory (ROM), a data acquisition interface 220, a display 225, external storage 230, one more communications interfaces 235, a power supply 240, and one or more input / output devices and / or interfaces 245 (e.g. a speaker, a user input device, such as a keyboard, a keypad, a mouse, a position tracked stylus, a position tracked probe, a foot switch, and / or a microphone for capturing speech commands).

[0274] The control and processing circuitry 200 may be programmed with programs, subroutines, applications or modules, which include executable instructions, which when executed by the one or more processors 210, causes the system to perform one or more methods described in the present disclosure. Such instructions may be stored, for example, in memory 215 and / or other storage.

[0275] In the example embodiment shown, module 250 is employed to measure one or more electrical parameters (e.g. electrical drive current or electrical impedance) or to perform direct ultrasound-based cavitation detection, in order to determine, within the resonance bandwidth of the thickness mode, one or more suitable drive frequencies for exciting the thickness mode of the hollow cylindrical ultrasound transducer 100. The aspiration-cavitation control module 260 includes executable instructions for controlling the pump 590 and the hollow cylindrical ultrasound transducer 110, such that cavitation is initiated within the lumen of the hollow cylindrical ultrasound transducer 110 during aspiration. The probe pulse analysis module 270 is employed to employ one or more predetermined relationships between ring-down signals and tissue types or materials residing within the lumen of the hollow cylindrical ultrasound transducer 110 to infer the presence of one or more tissues or materials within the lumen of the hollow cylindrical ultrasound transducer, and to optionally responsively control the generation of cavitation within the lumen of the hollow cylindrical ultrasound transducer based on the tissue or material detected.

[0276] Although only one of each component is illustrated in FIG. 1 B, any number of each component can be included in the control and processing circuitry 200. For example, a computer typically contains a number of different data storage media. Furthermore, although bus 205 is depicted as a single connection between all of the components, it will be appreciated that the bus 205 may represent one or more circuits, devices or communication channels which link two or more of the components. For example, in personal computers,bus 205 often includes or is a motherboard. Control and processing circuitry 200 may include many more or less components than those shown.

[0277] The control and processing circuitry 200 may be implemented as one or more physical devices that are coupled to processor 210 through one of more communications channels or interfaces. For example, control and processing circuitry 200 can be implemented using application specific integrated circuits (ASICs). Alternatively, control and processing circuitry 200 can be implemented as a combination of hardware and software, where the software is loaded into the processor from the memory or over a network connection.

[0278] Some aspects of the present disclosure can be embodied, at least in part, in software, which, when executed on a computing system, transforms a computing system into a specialty-purpose computing system that is capable of performing the methods disclosed herein. That is, the techniques can be carried out in a computer system or other data processing system in response to its processor, such as a microprocessor, executing sequences of instructions contained in a memory, such as ROM, volatile RAM, non-volatile memory, cache, magnetic and optical disks, or a remote storage device. Further, the instructions can be downloaded into a computing device over a data network in a form of compiled and linked version. Alternatively, the logic to perform the processes as discussed above could be implemented in additional computer and / or machine readable media, such as discrete hardware components as large-scale integrated circuits (LSI's), applicationspecific integrated circuits (ASIC's), or firmware such as electrically erasable programmable read-only memory (EEPROM's) and field-programmable gate arrays (FPGAs).

[0279] A computer readable medium can be used to store software and data which when executed by a data processing system causes the system to perform various methods. The executable software and data can be stored in various places including for example ROM, volatile RAM, non-volatile memory and / or cache. Portions of this software and / or data can be stored in any one of these storage devices. In general, a machine readable medium includes any mechanism that provides (i.e., stores and / or transmits) information in a form accessible by a machine (e.g., a computer, network device, personal digital assistant, manufacturing tool, any device with a set of one or more processors, etc.).

[0280] Examples of computer-readable media include but are not limited to recordable and non-recordable type media such as volatile and non-volatile memory devices, read only memory (ROM), random access memory (RAM), flash memory devices, floppy and other removable disks, magnetic disk storage media, optical storage media (e.g., compact discs (CDs), digital versatile disks (DVDs), etc.), among others. The instructions can be embodied in digital and analog communication links for electrical, optical, acoustical or other forms ofpropagated signals, such as carrier waves, infrared signals, digital signals, and the like. As used herein, the phrases “computer readable material” and “computer readable storage medium” refer to all computer-readable media, except for a transitory propagating signal per se.EXAMPLES

[0281] The following examples are presented to enable those skilled in the art to understand and to practice embodiments of the present disclosure. They should not be considered as a limitation on the scope of the disclosure, but merely as being illustrative and representative thereof.

[0282] Thrombotic occlusions of large blood vessels are increasingly treated with catheter based mechanical approaches, one of the most prominent being to employ aspiration to extract clots through a hollow catheter lumen. A central technical challenge for aspiration catheters is to achieve sufficient suction force to overcome the resistance of clot material entering into the distal tip. In this example, the feasibility of inducing cavitation within hollow cylindrical ultrasound transducers is considered with a view to ultimately using them to degrade the mechanical integrity of thrombus within the tip of an aspiration catheter.

[0283] Hollow cylindrical radially polarized PZT transducers with 3.3 / 2.5 mm outer / inner diameters were assessed. Finite element simulations and hydrophone experiments were used to investigate the pressure field distribution as a function of element length and resonant mode (thickness, length). Operating in thickness mode (~5 MHz) was found to be associated with the highest internal pressures, estimated to exceed 23 MPa. Cavitation was shown with hydrophone detection and high frequency ultrasound imaging (40 MHz) to be achievable within the transducer under degassed water (10%) conditions. Cavitation clouds occupied a substantial portion of the transducer lumen, in a manner that was dependent on the pulsing scheme employed (10 and 100 ps pulse lengths; 1.1 , 11 , and 110 ms pulse intervals). Collectively the results support the feasibility of achieving cavitation within a transducer compatible with mounting in the tip of an aspiration format catheter.Example 1: MethodsTransducer specifications

[0284] A PZT material suitable for high power applications, DL-47 (DeL Piezo Inc., FL, USA), similar to PZT-4D Navy I, was used. The elements were radially polled with silver fired electrodes on their inner and outer surfaces and had outer diameters of 3.3 mm and inner diameters of 2.5 mm. The diameters of the elements would be compatible with the eventual construction of an 11 F catheter, which is towards the large end of what is employed foraspiration approaches. This size did however enable the use of ultrasound imaging to assess internal cavitation clouds.Acoustic field simulations

[0285] Acoustic field simulations were performed using the finite element analysis (FEA) software package OnScale™ to identify the lengths and driving frequencies which maximized internal pressures. The material properties for DL-47 provided by the manufacturer, were used (FIG. 16) along with linear propagation conditions.

[0286] The cylindrical geometry (inner and outer diameter 2.5 and 3.3 mm respectively) was modeled as a 2D axisymmetric shape. The transducer was simulated in water with absorbing boundary conditions 3 mm from the transducer surfaces. Convergence studies were performed to determine an appropriate number of mesh elements. To obtain frequency dependent behavior such as complex impedance and displacement of the transducer surfaces, the driving function was set to a broadband single cycle 10 MHz pulse.

[0287] The time-domain charge and current traces as the transducer rings down were transformed to complex impedance with Fourier analysis. Similarly, the displacement over time due to the broadband impulse gave the frequency dependent displacement of the transducer configuration. In particular the axial displacement of a node along the top face of the transducer described any piston-like motion of the cylinder along its axis that was pronounced in length mode, while the lateral displacement of a node on the outer cylindrical surface centered along the length highlighted radial motion.

[0288] The thickness mode for each geometry was designated as the frequency which maximized the displacement of the outer surface in the radial direction. For generating pressure maps of the length and thickness modes, the driving function was set to a 50-cycle sine wave at the identified resonant frequency. The maximum pressure recorded at each spatial location was used to create a pressure map for the given geometry and frequency. When simulations were used in combination with hydrophone measurements to estimate the peak internal pressure levels (see below) 10 ps pulses were used.Experimental Configuration

[0289] FIG. 2A shows a schematic overview of experimental configuration for hydrophone and ultrasound imaging experiments. FIG. 2B shows photograph of experimental configuration for ultrasound imaging experiments and right, a closeup photo of a representative hollow cylindrical ultrasound transducer.

[0290] For the experimental studies, an element length of 2.5 mm was chosen based on simulation results. The cylindrical elements were cut to length using a diamond dicing saw. A 42-gauge micro coax wire was attached to the inner signal electrode and outer groundelectrode using conductive silver epoxy (Epotek H20E, Epoxy Technology Inc, MA, USA) and cured at 65 °C for 3 hours.

[0291] The electrical impedances of the transducers were measured as a function of frequency from 300 kHz to 8 MHz in 5 kHz steps using a network analyzer (AA-30.ZERO, RigExpert, Kyiv, Ukraine). The driving frequency for the majority of experiments was chosen to be 4.9 MHz, which corresponded to the first measured impedance minima within the simulated thickness mode frequency range. The voltages reported in the results were those measured during sonication directly across the transducer using a 10 MOhm 100:1 voltage probe and digitized (Picoscope 5242B, Pico Technology, Cambridgeshire, UK). It is noted that impedance matching would modestly raise the achieved voltage across the transducer and the achieved peak pressure (FIGS. 13A-13C), however it was not employed in the results reported here as it would have precluded the ability to conduct the swept frequency experiments, and it was found to be unnecessary to induce cavitation within the transducer lumen.Beam mapping and pressure measurements

[0292] FIGS. 4A and 4B shows a schematic of the experimental setup that was used for hydrophone measurements. The transducers were mounted in a tank of degassed deionized water. A planar fiber optic hydrophone with a 10 pm active element (Precision Acoustics Inc., Dorset, UK) was mounted to a computer controlled motorized 3D Stage (Velmex, NY, USA) with the axis of the hydrophone parallel with the axis of the transducers. A fiber optic hydrophone is necessary when testing unshielded piezoceramics close to their surfaces as conventional PVDF hydrophones were found to show large amplitude electrical coupling which could not be separated from the acoustic signal. The signal from the fiber optic hydrophone system was acquired by a PCI digitizer (DP310, Acqiris, Geneva, Switzerland) at a sampling rate of 420 MS / s. A USB camera with optical zoom attached to the stage facilitated alignment of the hydrophone to the transducer being tested. The driving circuit consisted of an RF power amplifier (A150, E&l, NY, USA) and a function generator (AFG3102, Tektronix, OR, USA). Synchronization of the sonication, hydrophone acquisition, and stage movement was controlled using a custom MATLAB application. The concentration of dissolved oxygen was maintained at approximately 10% (8%-11 %) saturation using a recirculating degasser and an optical dissolved oxygen probe (Vernier, OR, USA) and a temperature of 24 °C was maintained with a water heater. The transducer lumens were flushed with the degassed water prior to measurements. Alignment of transducer and hydrophone is necessary to obtain accurate pressure measurements. The transducer holder was fixed on two goniometers which could independently control the vertical and lateral rotational orientation of the transducer with respect to the hydrophone.

[0293] Hydrophone measurements were used to map pressure distribution at a low transmit voltage (20 Vppapplied) as well as to measure a single external field point at high transmit voltages. All reported measurements were done at the thickness mode resonant frequency (4.9 MHz) using 10 ps length pulses. When mapping pressures, the lateral scan was limited to ± 0.5 mm lateral to the center axis in order to avoid impinging on the cylinder walls.

[0294] Absolute internal pressure levels were not possible to measure directly with the hydrophone, as its presence would alter the field, and additionally acceptance angle considerations

[0053] precluded having calibrated measurements of the thickness mode waves which are orthogonally incident upon the hydrophone tip. As such, the approach taken was to make estimates of the maximum internal pressure as a function of voltage by measuring pressure at a single external point and using simulation estimates of the ratio of maximum internal pressure to that external point. For this procedure, the maximum (peak negative) pressure was recorded as a function of measured voltage with the hydrophone situated at the first on-axis pressure peak external to the transducer (0.3 mm from the face). The applied voltages were swept from 30 to 300 Vppin 10 Vppsteps with 5 seconds between each step. For a given sweep, a single pulse was transmitted at each voltage and the sweep was repeated to obtain a total of 25 acquisitions per voltage point. The resulting measured pressures were used to estimate the maximum internal pressures.Identification of cavitation signatures in hydrophone signals

[0295] The received hydrophone signals underwent spectral analysis to test for the presence of broadband signatures that were associated with inertial cavitation (IC). A 10 ps length 12.5% taper Tukey window centered over each received pulse was zero-padded to 100 ps before undergoing a fast Fourier transform. The average power spectra were then calculated and the power between 17.5 to 18.6 MHz was summed, which excluded harmonic frequencies associated with the transmitted pulse. As a point of reference, this process was repeated for the noise-only signal portion of the acquired traces in the 10 ps preceding the arrival of the ultrasound signal. A threshold set at 7 times the standard deviation of the integrated power over the 17.5 to 18.6 MHz range of this noise-only signal was used to determine the presence of cavitation, similar to the approach in

[0054] , Specifically, this criterion was applied to each pulse (25 / voltage point) and pulses that exceeded this threshold were considered to have cavitation present. This resulted in a probability of cavitation metric for each voltage level. This metric was then plotted as a function of voltage and fitted to a Sigmoid function with a nonlinear least squares regression.Observation of cavitation clouds by US imaging for different pulsing schemes

[0296] A VisualSonics Vevo 2100 imaging system with a 40 MHz (MS500D) probe was used for observing cavitation clouds generated within the lumen of the transducer. In addition, for a subset of experiments it was used to record acoustic RF emissions occurring within the transducer lumen to provide additional evidence of cavitation. Transmission power was set at the system’s minimum level of 2% and the beamformed RF data was digitized (256 MS / s) for image reconstruction or cavitation assessment. The probe was aligned with the transducer such that a plane including the axis of the transducer lumen was visible. The imaging field of view was set to a width of 3 mm and a depth range of 4 to 7 mm with the base of the cylindrical transducer situated at 7 mm. Imaging was conducted at the maximum rate of 916 frames / s. The transmission of a pulse by the cylindrical transducer during an image acquisition resulted in vertical ‘interference’ lines on the ultrasound image. A pulsedelay generator (Model 575, Berkeley Nucleonics Corp, CA, USA) was used to synchronize the triggering of the AWG with the imaging acquisition such that the position of the transmission interference band within the field of view could be moved by changing the trigger delay time. The interference band was positioned on the left side of the image (overlying the transducer wall) for recordings with the purpose of imaging the internal cavitation cloud, and it was positioned along the central axis of the transducer when the collected RF acoustic signals would be used for the purposes of cavitation detection. The time for the imaging system to acquire RF traces to form images within the lumen was within 0.5 ms of the end of the transmitted pulse, thus providing an assessment - through active detection - of the presence of bubbles in the immediate aftermath of exposures.

[0297] At the thickness mode frequency, pulse lengths of 10 and 100 ps were evaluated, using intervals of 1 .1 ms, 11 ms, and 110 ms (specific values determined by frame rate limitations). 100 sequential pulses were captured for the 1.1 ms and 11 ms pulse interval cases, while limitations of recording time restricted the 110 ms pulse interval case to 10 pulses. Applied voltages were swept for each pulsing scheme from 50 to 300 Vppin steps of 50 Vpp. Each sweep was repeated 5 times.

[0298] The bulk of the data was collected at the thickness mode defined by the impedance minima closest to the frequency with the highest simulated lateral displacement, however it was noted that there existed a number of distinct frequencies in the range of 4.5 to 6.3 MHz with impedance minima that were associated with simulated high internal pressures. Additional ultrasound imaging experiments were therefore conducted to assess cavitation generation over this frequency range. This was carried out using with 5 kHz steps at an applied voltage of 300 Vppwith 10 ps pulses, a 1.1 ms pulse interval and 5 pulses per frequency.Ultrasound image processing

[0299] The cavitation cloud images were processed using MATLAB (MathWorks, MA, USA). For qualitative visual comparisons, maximum intensity projections (MIPs) across 10 frames of sonication were used. For quantifying cloud area, individual frames were used. First, a binarization threshold was obtained using Otsu’s method

[0055] on a representative frame at an applied voltage of 300 Vppwhich showed a clear cavitation cloud. This threshold value was used to binarize all other frames. The resulting counts of white pixels within the lumen provided a measure of cloud size.

[0300] An additional experiment was conducted with 10 ps pulses and 11 ms intervals, where the transmission interference band was positioned along the central axis of the transducer in order to collect RF signals along this transmission band during sonication. In this case the RF data corresponds to the first full line of beamformed data extracted along this vertical path during the cylinder transducer transmitted pulse. Similar to the processing of the hydrophone data, power spectra were calculated for the received RF signals and then averaged across all sonication frames (500 frames) for each driving voltage.Example 2: Results Simulations

[0301] Representative pressure maps for transducers excited at their thickness mode (4.9 MHz) and length mode are shown in FIG. 2D. These general spatial distributions were typical for all lengths simulated, with the thickness modes showing higher on-axis pressures within the transducer lumen (FIG. 2B). In the lateral direction, the length mode results in a single elevated pressure lobe in the central portion of the lumen, whereas the thickness mode is characterized by a series of decaying side-lobes parallel to the main axis. Based on simulation results (FIG. 12), a transducer length of 2.5 mm was chosen for subsequent experimental studies. This length would allow for navigation through tortuous vessels for a catheter-based application while maintaining high on-axis internal pressures at the thickness mode along a substantial portion of the length of the transducer. For completeness, the simulated pressure distribution with and without impedance matching is shown in FIGS. 13A- 13C. This indicates that very similar results are obtained for both cases, the primary difference being a 13% increase in estimated peak pressure with matching. Example time domain signals for 10 and 100 ps pulses at the peak on axis pressure point (+ / - 0.546 mm) are shown in FIGS. 14A-14D. It was observed with simulations that during the initial stage (first ~10 ps) of the pulses, the on axis internal pressure increases in a sequence of steps before reaching a peak.Impedance measurements

[0302] FIGS. 3A and 3B shows a representative impedance measurement for a 2.5 mm transducer. Impedance minima associated with the length and 3rd harmonic length resonant modes are evident. A more diffuse impedance elevation is present between 4.5-6.5 MHz, which is punctuated by the presence of several sharp local minimal. As discussed in more detail later, these minima are consistent with the presence of standing wave frequencies occurring within a broader thickness mode resonant frequency range. Among the elements tested (N = 5), impedance values at the lower frequencies (< 2 MHz) were generally consistent with resonant modes falling within a 20 kHz window, however slight variations in wall thickness due to manufacturing tolerances would shift the position of the local minima within the 4.5-6.5 MHz bandwidth by up to 40 kHz. For the experiments performed here, each transducer was driven at its own specific thickness resonant mode frequency - defined as the frequency producing a maximum of simulated lateral wall displacements - of approximately 4.9 MHz ± 40 kHz. The measured transducer impedance at this frequency was ~12 Ohms.Hydrophone Measurements

[0303] Experimental peak pressure maps for the thickness mode (4.9 MHz) at low driving voltages show broad qualitative agreement with simulations, as seen in FIGS. 4A and 4B.

[0304] FIGS. 5A and 5B show hydrophone based measurements for a transducer as a function of measured voltage from 22 to 163 Vpp. FIG. 5A shows the estimated internal peak pressure increasing linearly with voltage until approximately 138 Vpp, at which point the pressure then levels up, but the standard deviations increase. FIG. 5B shows the power spectra of the waveforms at a subset of voltages, which indicate that broadband signal levels arise at higher voltage levels, consistent with the presence of cavitation. FIG. 7A shows the increasing probability of cavitation with increasing voltage, and a fitted sigmoid function shows a transition zone from between approximately 90 to 120 Vpp, consistent with the observations from the frequency and time-domain data. Within this transition zone only a subset of pulses would show evidence of cavitation, compared to above and below this region where all or none of the pulses respectively would show indications of cavitation. During the course of these experiments a 6% reduction in the measured pressure was observed. While modest, this suggests a change in performance of the transducer.Inspection of the transducer surfaces under a stereomicroscopy did not reveal evidence of damage.

[0305] A boxplot of integrated power within the 17.5 to 18.6 MHz bandwidth (a region which excludes transmitted signals) as a function of voltage is shown in FIG. 6A. These results are shown in terms of a decibel plot along with noise-only signals in FIG. 15. The increase inpower at higher voltage levels is consistent with the occurrence of cavitation, which is pronounced at the voltage levels associated with high variance in estimated pressures (>=143 Vpp). Example hydrophone traces for a range of voltage levels are shown in FIGS. 6B-6E for different voltage levels. FIG. 6B shows a trace example prior to the onset of cavitation. FIGS. 6C and 6D correspond to traces for outlier points at intermediate voltages (94 and 123 Vppcorresponding to estimated pressures of 15.9 and 20.8 MPa respectively), where time limited ‘spikes’ in the received signal are evident, consistent with the occurrence of discrete cavitation events (e.g., formation and inertial collapse of a bubble). FIG. 6E shows a representative trace in the high voltage regime (163 Vpp), which is characterized by a fluctuating envelope that is consistent with widespread cavitation within the lumen. It is also notable that the cavitation persists for a substantial time after the stimulating voltage ends. A cavitation probability curve is shown in FIG. 7A, where it is observed that there is a transition from no detected cavitation to a rapid increase in incidence, which reaches a zone at higher pressures where the probability is 100%. The 50% cavitation probability point corresponds to an estimated pressure level of 17.4 MPa.Cavitation Cloud Imaging

[0306] Cavitation was confirmed with US imaging, where the presence of hyperechoic regions associated with bubble formation within the transducer lumen could be visualized immediately (<0.5 ms) following sonication pulses. Six different pulsing schemes were evaluated as shown in FIG. 7B. Note that a different transducer was employed for this portion of the study than for the hydrophone experiments which has resulted in small differences in the measured voltages for the same requested amplifier voltage. FIG. 8A shows a frame prior to sonication, where the transducer’s walls and water filled lumen can be visualized. FIG. 8C shows a representative maximum intensity projection over 100 sonication frames with a pulse length of 10 ps, a pulse interval of 1.1 ms, and a voltage of 127 pp, showing the presence of bubbles, which is referred to as a cavitation cloud. FIG. 8D shows an example of this for a higher voltage (155 Vpp), which exhibits a larger cavitation cloud. A notable feature of all images is that the cavitation extends throughout a substantial portion of the transducer lumen and is not simply limited to the high pressure region along the central axis. FIG. 8E shows power spectra of the RF data acquired by the imaging transducer at select voltages. The broadband noise power becomes evident at the higher voltage levels, broadly consistent with the results shown in FIG. 5A for the hydrophone measurements. Note that the frequency range evaluated with the US imaging probe is higher due to the sensitivity bandwidth of the imaging probe (nominally denoted as a 40 MHz probe).

[0307] FIG. 9 shows representative maximum intensity projections from the generation of cavitation clouds at different pulse intervals and pulse lengths at 155 Vpp. The imageappearance suggests that cavitation activity appears to be substantially dependent on pulse length and interval. FIGS. 10A and 10B quantify the cavitation cloud areas as a function of voltage for the different pulse intervals and pulse lengths used (FIG. 7B). The results indicate that no cavitation was detected for the two lower voltage levels (34 and 67 Vpp) for any pulsing schemes. At 98 Vpp, some degree of cavitation is visible for all pulsing schemes, consistent with the detection of broadband signals and spikes in the hydrophone data. It is also observed that the 100 ps pulses produce a lower cavitation area than the 10 ps pulses.

[0308] FIG. 11 A shows representative US imaging examples from the frequency sweep results around the primary thickness mode frequency, acquired using the maximum transmit voltage. It was found that cavitation clouds could be generated within three main frequency bands centered at approximately 4.9, 5.6 and 6.1 MHz, and that the 4.9 MHz point produces the largest cloud. Between these bands, no or less cavitation was generated. Each of these frequencies corresponds closely with impedance minima as seen in FIGS. 3A and 3B. Simulations of the pressure distribution along the centerline of the transducer lumen, shown in FIG. 11 B, indicate that the frequency bands where cavitation is generated are associated with higher peak pressure levels. During the course of the cavitation imaging experiments, there was no trend in the metrics observed that would suggest a degradation of transducer performance over time.Example 3: Discussion

[0309] The results have demonstrated the feasibility of initiating cavitation clouds within the lumen of hollow cylindrical ultrasound transducers of a dimension compatible with being mounted within an intravascular catheter. This work has extended studies that have employed large scale transducers (~7-12 cm diameter) operating at low frequencies (~20 kHz) to create cavitation within their water filled lumens [51 ,52], In these studies, cavitation was initiated with pulse lengths on the order of 100s of milliseconds and detected with passive external receivers. Pressure levels and the gas saturation state of the water were not specified in these studies.

[0310] It is useful to consider these results in the context of histotripsy, which with few exceptions have involved the use of large high gain spherically focused transducer apertures, either single element or array based [31 ,37,56,57], Histotripsy is frequently categorized according to the characteristics of the pulses employed and the corresponding physical mechanisms involved in cloud formation

[0038] , The basis for what is often referred to as intrinsic histotripsy is to initiate cavitation clouds from pre-existing endogenous nanoscale cavitation nuclei with short (1-2 cycle) highly nonlinear pulses. In this case bubble growth occurs within the initial rarefactional phase and a relatively small cloud region is achievedwithin the central focal region

[0058] , Pulse lengths typically in the 5-20 cycle range exploit shock scattering, whereby a cloud is initiated in the early phase of the incident (shocked) pulse and the ensuing incident cycles are reflected and scattered by the initial cloud, inverting the higher positive pressures which then facilitates its growth [59,60], Boiling histotripsy generally employs nonlinear pulses on the order of 1-100 ms, where the longer timescale coupled with absorption results in temperature elevations that lowers the pressure threshold required to produce cavitation clouds [61-64], It is also notable that intermediate length pulses (0.1 ms) have also been reported [34,65], For longer pulses, the reflection of the incident wave by the cloud that is initiated in the early phase of the pulse can result in the cloud being extended towards the transducer.

[0311] The acoustic field within a hollow cylindrical ultrasound transducer stimulated in thickness mode is predominantly associated with cylindrical waves. Axisymmetric cylindrical waves can be viewed as the superposition of converging and diverging waves (to and from center respectively), which act to create an interference pattern that is comprised of a primary on axis pressure peak, along with a series of side lobes of progressively decreasing amplitude away from the center axis

[0066] , Reflections from the internal lumen boundary are also present, which for specific stimulation frequencies can result in a standing wave pattern. The conditions employed here resulted in a high-pressure region concentrated along the central axis of the lumen, along with side lobes of progressively decreasing amplitude spaced at a half a wavelength (~0.15 mm) (FIG. 2D, FIGS. 13A-13C). This is consistent with the presence of a predominantly cylindrical wave pattern. It is also evident that there are amplitude fluctuations along the center axis (FIG. 2B), which are attributed to the finite length of the transducer employed. For example, it has been established that as the aspect ratio (length / outer diameter) of a radially polarized transducer is reduced, mechanical coupling between modes can occur

[0067] ,

[0312] During the initial stage (~10 ps) of the pulses, the on axis internal pressure increases in a sequence of steps (FIG. 14A-14D). The interval of these steps (~1.67 ps) is approximately equal to the propagation time in water for a distance of 2.5 mm, similar to that of the inner diameter of the transducer. This stepped pattern is consistent with the progressive time delayed arrival of multiple internally reflected waves that constructively interfere and lead to increases in the peak pressure level. The degree of increase, relative to the initial arrival, occurring during this initial stage is an indication that internal reflections play a prominent role in achieving high internal pressures with this transducer configuration.

[0313] For the 100 ps case, after the initial peak at ~10 ps, a reduction occurs before the amplitude then levels off for the remainder of the 100 ps stimulation period. This intermediate stage is consistent with the development of standing wave interference pattern.After the end of the stimulation period there is a stepped decay of the pressure amplitudes, associated with the dissipation of internal reflections.

[0314] The occurrence of the maximum pressure at ~10 ps suggests that this is the minimum pulse duration that can be used to achieve the maximum pressure levels that can be produced within this transducer configuration (thickness mode resonant frequency / wavelength, internal diameter). When examining the frequency sweep results (FIGS. 11A and B) it can be seen that 5.6 and 6.1 MHz also produce higher pressure and cavitation levels. These correspond with minima in the impedance plots, which is consistent with their being associated with standing wave frequencies

[0068] , Reflected pulses do not impact focal pressures in the context of spherically focused transducer studies with shorter pulses (intrinsic and shock scattering cases), as the spatial pulse length is much smaller than the transducer focal lengths employed.

[0315] It is useful to consider the focal pressure gain for the conditions employed in this study. For a spherically focused transducer, the pressure gain can be estimated from the ratio of the peak on-axis pressure to the pressure at the transducer surface. In the absence of standing waves (and / or reflections from the inner surface) the pressure gain for a cylindrical transducer can be estimated in a similar manner. In the presence of standing waves, there is an additional increase in pressure beyond this focal gain, as evidenced by the stepped increase in pressure following the initial arrival of waves at the focal region (FIGS. 14A-14D). As standing waves impact the pressure at the luminal boundary, in their presence the luminal boundary pressure is no longer indicative of the pressure at the transducer surface arising solely from the electrical stimulation.

[0316] Therefore, to obtain a pressure gain metric that accounts for these two contributing effects, they are estimated independently though simulations and then combined to get a net ’effective’ focal gain. To estimate the gain associated with the focusing aspect, the ratio of the envelop amplitudes at the peak on-axis location (100 ps pulse; FIGS. 14A-14D) to the nearest point at the luminal wall was calculated. Specifically, the amplitudes were measured at a time point immediately prior to the arrival of reflections, which begin to contribute to the signals at 1.67 ps, as noted above. The additional gain associated with the standing wave pattern was estimated by the ratio of the peak amplitude of the 100 ps pulse to the height of the first step during the rise phase (i.e., the amplitude immediately prior to arrival reflection). The focusing and standing wave gains were estimated to be 15.8. and 3.2 respectively, which resulted in an effective gain of 50.6.

[0317] The estimated peak internal peak pressure increased linearly with voltage until approximately 130 Vpp(FIG. 5A), at which point it began to plateau. This corresponds to a maximum estimated internal pressure level of approximately 23 MPa. As the roll-off inpressure corresponds with the presence of high levels of internal cavitation (FIGS. 5-8), it is hypothesized that the presence of cavitation has limited the maximum estimated internal pressure from being higher. This may be due to a reduction in actual pressure within the transducer due to the presence of bubbles (attenuation and scattering effects) along with possible reductions in the pressure levels at the external hydrophone location due to bubbles impacting the forward projected ultrasound field. Therefore, the maximum possible achievable pressure level is expected to be higher than the estimated pressure levels reported here. Importantly, it should be emphasized that the reported pressures were estimated, not measured. While there was good qualitative agreement between the simulations and experiments in terms of the features present (i.e., high on-axis internal pressure), it is reasonable to expect that there will be differences between the two, which would lead to inaccuracies in the estimated internal pressures. Note that the nature of the directionality of the internal waves and the hydrophone acceptance angle precludes a quantitative comparison between the simulations and internal measurements

[0053] , Another factor contributing to inaccuracies of the estimated pressures is that the simulations employed linear propagation assumptions. While the high focal gain of the cylindrical waves will mitigate the development of propagation nonlinearities, it can be expected that these will become more prominent at higher pressure levels. This would in turn lead to asymmetric waveforms and reduce the peak negative pressure amplitude relative to the linear propagation case. Nonlinear propagation effects for the conditions relevant to this study, which involve a combination of traveling and standing waves, warrants investigation in future work.

[0318] The presence of cavitation within the transducer at higher voltages was demonstrated by both bubble emissions detection during transmission as well as by imaging the resulting bubble clouds following transmission. The form of the hydrophone-based cavitation probability curves as a function of voltage (or estimated pressure) are qualitatively similar to those previously reported in the histotripsy literature in water [60,69], phantom material and tissue

[0070] , As a point of reference for a spherically focused transducer, it was reported in

[0054] , for nominally single cycle pulses in 10% oxygen distilled water that cavitation emissions were detected beginning at as low as 17.7 MPa, with a 50% cavitation probability level at ~27 MPa peak negative pressure. For 5-20 cycle pulses (1 MHz) in filtered water, optically observed bubble cloud peak negative pressure onsets and 50% cavitation probabilities were respectively 15 and 22.3 MPa for f-number 0.9, and 21 and 24.2 MPa for f-number 0.9 transducers. The estimated 17.4 MPa 50% cavitation probability level reported here is lower than these previous studies, which may be due to inaccuracies of the estimated internal pressure levels or the possible presence of contaminants in the water.

[0319] The imaging data showed that the generated bubble clouds were present not only in the high-pressure region along the transducer axis (FIG. 8), but also throughout much of the lumen, and therefore ultrasound field. As the images were formed within 0.5 ms following the end of the cylinder transducer transmit pulse, this will provide an indication of the cavitation cloud size, unless bubble translation or dissolution effects were significant on this timescale. This diffuse cavitation region is in apparent contrast to the case of spherically focused transducers where the cavitation cloud is confined to the focal zone, with a possible degree of extension towards the proximal side for shock scattering and boiling histotripsy conditions. The distribution of cavitation throughout the lumen suggests a complex situation of scattering, reflection and absorption that may substantially and dynamically alter the spatiotemporal distribution of pressures within a larger portion of the beam for the pulses employed here. Reflections from the inner surface of the transducer may also play a role. This process warrants investigation in future work and an important element of this will be to examine the nonlinear propagation effects in the initial (pre-cloud formation) transmitted beam. One aspect of this is to ascertain the degree of pulse asymmetry within the lumen, which would provide insight into the extent to which polarity inversion upon reflection / scattering may drive the cloud evolution process.

[0320] The imaging data also indicated the impact of pulsing scheme on cloud area. A primary observation was that the 10 ps pulses resulted in larger bubble clouds than 100 ps pulses, for all pulse intervals. The cause of this remains to be established, but as cavitation will be initiated in the early phase of the 100 ps pulses, it can be inferred that the remaining portion of the pulse, which is lower in amplitude (FIG. 14B), acts to reduce the cloud area. This may involve factors such as radiation forces, bubble coalescence, and fragmentation and subsequent dissolution. Pulse interval had little impact on cloud area for the 10 ps case, whereas for the 100 ps case the 110 ms interval resulted in the largest cloud area. The latter trend appears counter to previous histotripsy work with spherically focused transducers and short pulse histotripsy work, where it has been shown that reducing pulse intervals can result in an increase in cloud density and size

[0071] , The basis for this is that if bubbles induced by one pulse have not dissolved at the time of arrival of the following pulse they can act as cavitation seeds that will thereby increase the resulting cloud density.

[0321] In FIG. 16, the cloud area reduction as a function of imaging frame following a transmit pulse (examined up to 10 ms) suggests that bubble dissolution may occur more rapidly for the 100 ps pulse than the 10 ps pulse, though this may not offer an explanation of why longer intervals increase the detected cloud area for the 100 ps case. An examination of the nature of the clouds (e.g., bubble sizes, distribution, and spatiotemporal evolution) in the setting of hollow cylindrical ultrasound transducers therefore requires further investigation,for example with the use of high-speed microscopy, as well considering of the impact of the cloud on the beam (e.g., attenuation effects). It may also be considered that the imaging method itself impacts the measurements

[0055] , in that the area results are based on scattering from bubbles at high frequencies and scattering size is both frequency and bubble size dependent. This may also be a factor in the 100 ps case, where the cloud distribution appeared to be preferentially skewed towards the lower aspect of the transducer lumen, raising the possibility of primary radiation forces coming into play.

[0322] As the ultimate motivation for this work is to use the transducers at the tip of an aspiration catheter to enhance aspiration thrombectomy performance, a necessary next step will be to investigate the feasibility of mechanically degrading thrombus. In a clinical aspiration scenario thrombus will occupy the transducer lumen. The formation and evolution of bubble clouds can be expected to be fundamentally different in this setting. One aspect of this is that the pressure thresholds for cloud formation can be expected to differ, as these are influenced by the Youngs modulus of the medium [57,58], Cloud characteristics such as dimension, bubble size and density, have also been shown to be altered when initiated within a viscoelastic medium

[0060] , The confining medium impacts the ability of bubbles to expand, translate and merge. Without intending to be limited by theory, it is reasonable to expect that the cloud and therefore erosion will be initiated along the central axis of the transducer where pressures are highest, and then progress outwards. Once formed, the evolution of the cloud and associated erosion pattern would be impacted by the influence of the cloud on the acoustic field in terms of shielding, scattering and reflections.

[0323] The outer dimension of the transducers employed here is a scale consistent with use in larger aspiration catheters. The incorporation of transducers of this dimension into a catheter format would entail the use of an outer sheath, which would result in an estimated outer catheter diameter of ~3.6 mm (11 F). Such a catheter would be compatible with the treatment of pulmonary embolism and deep venous thrombosis [9,72,73], where 12F commercial catheters (e.g., INDIGO™ Aspiration Catheters) can be employed.

[0324] The development of smaller catheter formats is also an area of interest, such as those used for stroke applications (e.g., middle cerebral artery M1 segment, distal internal carotid artery) where the outer dimension of widely employed aspiration catheters is on the order of 1.6-1.8 mm [74-77],

[0325] The incorporation of the transducers within a catheter format will also involve considerations of the impact of the sheath and mounting / backing materials on the internal pressure field. A thin liner material may also be employed to isolate the inner transducer wall from blood / clot material. This may impact the transducer behavior, and also act as a protective layer to reduce the potential for cavitation damage, though damage was notobserved in the present study. An additional consideration is the coupled effects of transducer wall thickness and lumen diameter. Wall thickness is a primary determinant of thickness mode frequency, and the specific lumen diameter can be expected to have a strong influence on the inner pressure field. As the choice of dimension of the transducer employed here was based in part on commercial availability, varying wall thickness was not considered, however the dependence of the pressure field on frequency (FIG. 1) suggests that wavelength and lumen dimension may have a strong influence on the interference pattern present within the lumen.Example 4: Aspiration Test

[0326] An aspiration test experiment was performed that involved having the transducer (same type as in the Examples above) mounted at the end of a compliant tube. 3 day retracted porcine blood clots (roughly cylindrical ~3-5mm diam, ~4-5mm in length) were then situated at the transducer opening and a vacuum was applied to attempt their aspiration. The vacuum was quite mild (-6” Hg) to test for an effect when clots were not well ingested. Control and US-on conditions were attempted and the metric was time to being aspirated through the transducer and into the tube (or not). The US conditions were 4.9 MHz, 10us pulse length, 300V, 1 kHz PRF. Results are shown in FIG. 18.Additional Internal Pressure Simulations

[0327] FIGS. 19 and 20 show results for a stroke compatible transducer diameter. Predicted pressures are actually higher than for the transducer described above. FIG. 19 shows results for PZT5A transducer material, while FIG. 20 pertains to PZT4.

[0328] The specific embodiments described above have been shown by way of example, and it should be understood that these embodiments may be susceptible to various modifications and alternative forms. It should be further understood that the claims are not intended to be limited to the particular forms disclosed, but rather to cover all modifications, equivalents, and alternatives falling within the spirit and scope of this disclosure.REFERENCES[1] C.W. Tsao, A.W. Aday, Z.l. Almarzooq, C.A.M. Anderson, P. Arora, C.L. Avery, C.M. Baker-Smith, A.Z. Beaton, A.K. Boehme, A.E. Buxton, Y. Commodore-Mensah, M.S.V. Elkind, K.R. Evenson, C. Eze-Nliam, S. Fugar, G. Generoso, D.G. Heard, S. Hiremath, J.E. Ho, R. Kalani, D.S. Kazi, D. Ko, D.A. Levine, J. Liu, J. Ma, J.W. Magnani, E.D. Michos, M.E. Mussolino, S.D. Navaneethan, N.I. Parikh, R. Poudel, M. Rezk-Hanna, G.A. Roth, N.S. Shah, M.-P. St-Onge, E.L. Thacker, S.S. Virani, J.H. Voeks, N.-Y. Wang, N.D. Wong, S.S. Wong, K. Yaffe, S.S. Martin, on behalf of the A.H.A.C. on E. and P.S.C. and S.S. Subcommittee, Heart Disease and Stroke Statistics — 2023 Update: A Report From the American Heart Association, Circulation. 147 (2023) e93-e621. https: / / doi.orq / 10.1161 / cir.0000000000001123.[2] V.F. Tapson, Acute Pulmonary Embolism, New Engl J Medicine. 358 (2008) 1037-1052. https: / / doi.Org / 10.1056 / nejmra072753.[3] D.T. Ko, T. Ahmed, P.C. Austin, W.J. Cantor, P. Dorian, M. Goldfarb, Y. Gong, M.M. Graham, J. Gu, N.M. Hawkins, T. Huynh, K.H. Humphries, M. Koh, Y. Lamarche, L.J. Lambert, P.R. Lawler, J.-F. Legare, H.Q. Ly, F. Qiu, A. ur R. Quraishi, D.Y. So, R.C. Welsh, H.C. Wijeysundera, G. Wong, A.T. Yan, Y. Gurevich, Development of Acute Myocardial Infarction Mortality and Readmission Models for Public Reporting on Hospital Performance in Canada, Cjc Open. 3 (2021) 1051-1059. https: / / doi.Org / 10.1016 / i.cico.2021.04.012.[4] A. Sailer, M.V. Revzin, J. Pollak, R. Ayyagari, H.R. Mojibian, N. Nezami, J.S. Pellerito, A.G. Marino, Deep Vein Thrombosis: Update on Mechanical Thrombectomy and Intravascular US, Radiographics. 42 (2022) E184-E185. https: / / doi.org / 10.1148 / rq.220031.[5] J.K. Holodinsky, P. Lindsay, A.Y.X. Yu, A. Ganesh, R.A. Joundi, M.D. Hill, Estimating the Number of Hospital or Emergency Department Presentations for Stroke in Canada, Can J Neurological Sci J Can Des Sci Neurologiques. (2022) 1-6. https: / / doi.Org / 10.1017 / cjn.2022.338.[6] J. Lin, Y. Chen, N. Jiang, Z. Li, S. Xu, Burden of Peripheral Artery Disease and Its Attributable Risk Factors in 204 Countries and Territories From 1990 to 2019, Frontiers Cardiovasc Medicine. 9 (2022) 868370. https: / / doi.org / 10.3389 / fcvm.2022.868370.[7] M. Heran, P. Lindsay, G. Gubitz, A. Yu, A. Ganesh, R. Lund, S. Arsenault, D. Bickford, D. Derbyshire, S. Doucette, E. Ghrooda, D. Harris, N. Kanya-Forstner, E. Kaplovitch, Z. Liederman, S. Martiniuk, M. McClelland, G. Milot, J. Minuk, E. Otto, J. Perry, R. Schlamp, D. Tampieri, B. van Adel, D. Volders, R. Whelan, S. Yip, N. Foley, E.E. Smith, D. Dowlatshahi, A. Mountain, M.D. Hill, C. Martin, M. Shamy, Canadian Stroke Best Practice Recommendations: Acute Stroke Management, 7 th Edition Practice Guidelines Update, 2022, Can J Neurological Sci J Can Des Sci Neurologiques. (2022) 1-31. https: / / doi.Org / 10.1017 / cjn.2022.344.[8] W.J. Powers, A. A. Rabinstein, T. Ackerson, O.M. Adeoye, N.C. Bambakidis, K. Becker, J. Biller, M. Brown, B.M. Demaerschalk, B. Hoh, E.C. Jauch, C.S. Kidwell, T.M. Leslie-Mazwi, B. Ovbiagele, P.A. Scott, K.N. Sheth, A.M. Southerland, D.V. Summers, D.L. Tirschwell, on behalf of the A.H.A.S. Council, Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association / American Stroke Association, Stroke. 50 (2019) e344-e418. https: / / doi.orq / 10.1161 / str.0000000000000211.[9] A.K. Sista, J.M. Horowitz, V.F. Tapson, M. Rosenberg, M.D. Elder, B.J. Schiro, S. Dohad, N.E. Amoroso, D.J. Dexter, C.T. Loh, D.A. Leung, B.K. Bieneman, P.E. Perkowski, M.L. Chuang, J.F. Benenati, E.-P. Investigators, Indigo Aspiration System for Treatment of Pulmonary Embolism Results of the EXTRACT-PE Trial, Jacc Cardiovasc Interventions. 14 (2021) 319-329. https: / / doi.orq / 10.1016 / i.icin.2020.09.053.

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Claims

CLAIMSWhat is claimed is:I CLAIM:1 . A system for delivering ultrasound treatment to a vascular occlusion, the system comprising: a catheter comprising: an elongate body having a body lumen extending therethrough; and a hollow cylindrical ultrasound transducer supported by a distal region of said elongate body, such that an inner lumen of said hollow cylindrical ultrasound transducer is in fluid communication with the body lumen; and control circuitry operably connected to said hollow cylindrical ultrasound transducer through said elongate body, said control circuitry being configured to perform operations comprising: delivering test drive signals to said hollow cylindrical ultrasound transducer for interrogating a frequency response of said hollow cylindrical ultrasound transducer; and employing a frequency-dependent electrical measure associated with the test drive signals to identify a standing wave frequency corresponding to a standing wave produced by intraluminal reflections of ultrasound waves generated by said hollow cylindrical ultrasound transducer.

2. The system according to claim 1 wherein said control circuitry is configured such that a frequency range of the test drive signals corresponds a thickness mode when a pre-selected medium resides within the inner lumen.

3. The system according to claim 1 wherein said control circuitry is configured such that a frequency range of the test drive signals corresponds to a length mode when a pre-selected medium resides within the inner lumen.

4. The system according to any one of claims 1 to 3 wherein said control circuitry is configured such that the test drive signals are configured to generate ultrasound within the inner lumen in absence of cavitation.

5. The system according to any one of claims 1 to 4 wherein said control circuitry is configured such that the standing wave is characterized by a Bessel function of a first kind (order zero).

6. The system according to any one of claims 1 to 5 wherein said control circuitry is configured such that the frequency-dependent electrical measure is an impedance spectrum derived from the test drive signals.

7. The system according to any one of claims 1 to 5 wherein said control circuitry is configured such that the frequency-dependent electrical measure is derived from a ringdown signal.

8. The system according to any one of claims 1 to 5 wherein said control circuitry is configured such that the test drive signals comprise a plurality of pulses having different frequencies.

9. The system according to any one of claims 1 to 8 wherein said control circuitry is further configured to: identify a plurality of standing wave frequencies based on the frequency-dependent electrical measure; sequentially deliver cavitation test drive signals at the plurality of standing wave frequencies, and obtain a respective ring-down signal associated with each standing wave frequency; process each ring-down signal to obtain a cavitation measure characterizing cavitation at the standing wave frequency; and employ the cavitation measures to select a suitable standing wave frequency for subsequent delivery of therapy drive signals.

10. The system according to claim 9 wherein said control circuitry is configured such that the cavitation measures characterize an amount of cavitation produced at each standing wave frequency.11 . The system according to claim 9 wherein said control circuitry is configured such that the cavitation measures characterize an efficiency of cavitation generation at each standing wave frequency.

12. The system according to any one of claims 1 to 11 wherein said control circuitry is configured to employ the standing wave frequency to identify a material present in the inner lumen.

13. The system according to claim 12 wherein said control circuitry is configured to employ the standing wave frequency to identify the material present within the inner lumen by comparing the standing wave frequency to one or more reference standing wave frequencies, each reference standing wave frequency corresponding to a different material.

14. The system according to claim 13 wherein said control circuitry is configured such that a plurality of standing wave frequencies are obtained based on the frequency-dependent electrical measure and compared with a plurality of sets of reference standing wave frequencies to identify the material, each set of reference standing wave frequencies corresponding to a different reference material.

15. The system according to claim 13 wherein said control circuitry is configured such that the different materials include one or more of saline and blood.

16. The system according to claim 13 wherein said control circuitry is configured such that the different materials include a thrombus.

17. The system according to claim 16 wherein said control circuitry is further configured to employ the standing wave frequency to infer one or more properties of the thrombus.

18. The system according to claim 17 wherein said control circuitry is further configured to employ the one or more properties of the thrombus to determine one or more treatment parameters for cavitation-based disruption of the thrombus via an intraluminal standing wave.

19. The system according to claim 18 wherein said control circuitry is further configured such that the one or more treatment parameters comprise pulse length and inter-pulse interval.

20. The system according to claim 13 wherein said control circuitry is configured such that the different materials include one or more medical devices.21 . The system according to claim 20 wherein said control circuitry is configured such that the one or more medical devices include a guidewire and a microcatheter.

22. The system according to claim 20 or 21 wherein said control circuitry is configured such that identification of the medical device results in the generation of an alert.

23. The system according to claim 20 or 21 wherein said control circuitry is configured such that delivery of ultrasound therapy is prevented when the medical device is identified.

24. The system according to claim 20 or 21 wherein said control circuitry is configured such that aspiration is prevented when the medical device is identified.

25. The system according to any one of claims 1 to 22 wherein said control circuitry is further configured to perform operations comprising: delivering a therapy drive signals to said hollow cylindrical ultrasound transducer, the therapy drive signals being provided with a frequency and a time duration suitable for exciting of the standing wave within the inner lumen, and with sufficient energy to generate a bubble cloud with the inner lumen.

26. The system according to claim 25 wherein said control circuitry is configured such that the time duration is sufficiently long that an acoustic pressure envelope associated with the standing wave increases to a maximum value prior to completion of the time duration of the therapy drive signals.

27. The system according to claim 25 or 26 wherein said control circuitry is configured such that the standing wave is generated based on excitation of a thickness mode of said hollow cylindrical ultrasound transducer.

28. The system according to claim 25 or 26 wherein said control circuitry is configured such that the standing wave is generated based on excitation of a length mode of said hollow cylindrical ultrasound transducer.

29. The system according to claim 25 or 26 wherein said control circuitry is configured such that the therapy drive signals excite both a thickness mode of said hollow cylindrical ultrasound transducer and a length mode of said hollow cylindrical ultrasound transducer.

30. The system according to any one of claims 25 to 29 wherein said control circuitry is configured such that the therapy drive signals are first therapy drive signals, and wherein said control circuitry is further configured to deliver additional therapy drive signals capable of sustaining the bubble cloud.31 . The system according to claim 30 wherein said control circuitry is configured such that the additional therapy drive signals are configured to excite a length mode of said hollow cylindrical ultrasound transducer.

32. The system according to claim 30 wherein said control circuitry is configured such that the additional therapy drive signals have a lower amplitude than the first therapy drive signals.

33. The system according to claim 30 wherein said control circuitry is further configured to intermittently deliver the therapy drive signals and the additional therapy drive signals to said hollow cylindrical ultrasound transducer.

34. The system according to any one of claims 25 to 33 further comprising a pump in flow communication with the inner lumen of said hollow cylindrical ultrasound transducer, wherein said control circuitry is operably connected to said pump for controlling said pump.

35. The system according to claim 34 wherein said control circuitry is configured to control said pump to perform aspiration.

36. The system according to claim 35 wherein said control circuitry is configured to deliver the therapy drive signals during aspiration.

37. The system according to claim 35 or 36 wherein said control circuitry is configured to deliver the therapy drive signals prior to aspiration.

38. The system according to any one of claims 34 to 37 wherein said control circuitry is configured to initiate aspiration prior to delivering the test drive signals and identifying the standing wave frequency.

39. The system according to any one of claims 34 to 38 wherein said control circuitry is configured to process ultrasound signals received after delivery of the therapy drive signals.

40. The system according to claim 39 wherein said control circuitry is configured to process ultrasound signals to infer a presence of cavitation, an absence of cavitation, or a degree of cavitation, within the inner lumen of said hollow cylindrical ultrasound transducer.41 . The system according to claim 39 wherein said control circuitry is configured such that the ultrasound signals are ring-down signals associated with the standing wave generated in response to delivery of the therapy drive signals.

42. The system according to any one of claims 39 to 41 wherein said control circuitry is configured such that the ultrasound signals are received by said hollow cylindrical ultrasound transducer.

43. The system according to any one of claims 39 to 41 further comprising an additional ultrasound transducer configured to receive the ultrasound signals, wherein said control circuitry is operably connected to said additional ultrasound transducer.

44. The system according to claim 39 wherein said control circuitry is configured such that the ultrasound signals are associated with a probe ultrasound pulse generated by probe drive signals delivered to said hollow cylindrical ultrasound transducer after delivery of the therapy drive signals.

45. The system according to claim 44 wherein said control circuitry is configured such that the ultrasound signals associated with the probe ultrasound pulse are compared with ultrasound signals associated with a previously generated probe pulse to infer a change in a material residing within the inner lumen.

46. The system according to claim 44 wherein said control circuitry is configured such that the ultrasound signals are processed to identify a material within the inner lumen.

47. The system according to claim 46 wherein said control circuitry is configured to modify subsequently delivered therapy drive signals in response to the material identified to be currently residing within the inner lumen.

48. The system according to claim 46 wherein said control circuitry is configured to modify control of said pump in response to the material identified to be currently residing to be within the inner lumen.

49. The system according to claim 46 wherein said control circuitry is configured to control said pump to interrupt aspiration when the material identified to be currently residing within the inner lumen is blood.

50. The system according to any one of claims 35 to 49 wherein said control circuitry is configured to perform the following operations after delivery of the therapy drive signals or after initiating aspiration: delivering additional test drive signals to said hollow cylindrical ultrasound transducer; employing a frequency-dependent electrical measure associated with the additional test drive signals to determine an updated standing wave frequency corresponding to the standing wave caused by intraluminal reflections of ultrasound waves generated by said hollow cylindrical ultrasound transducer.51 . The system according to claim 50 wherein said control circuitry is configured to employ the updated standing wave frequency to modify subsequently delivered therapy drive signals.

52. The system according to claim 50 wherein said control circuitry is configured to employ the updated standing wave frequency to control said pump to modify aspiration.

53. The system according to claim 50 wherein said control circuitry is configured to perform operations further comprising: identifying a property of a thrombus residing within the inner lumen according to the updated standing wave frequency.

54. The system according to claim 53 wherein said control circuitry is configured to employ the property of the thrombus to modify subsequently delivered therapy drive signals .

55. The system according to claim 50 wherein said control circuitry is configured to perform operations further comprising: detecting a change in a material residing within the inner lumen according to a change in the standing wave frequency.

56. The system according to claim 55 wherein said control circuitry is configured to modify subsequently delivered therapy drive signals in response to the detected change in the material.

57. The system according to claim 55 wherein said control circuitry is configured to modify control of said pump in response to the detected change in the material.

58. The system according to claim 50 wherein said control circuitry is configured to perform operations further comprising: identifying a material currently residing within the inner lumen according to the updated standing wave frequency.

59. The system according to claim 58 wherein said control circuitry is configured to modify subsequently delivered therapy drive signals in response to the material identified to be currently residing within the inner lumen.

60. The system according to claim 58 wherein said control circuitry is configured to modify the control of said pump in response to the material identified to be currently residing within the inner lumen.61 . The system according to claim 60 wherein said control circuitry is configured to control said pump to interrupt aspiration when the material identified to be currently residing within the inner lumen is blood.

62. The system according to claim 50 wherein said control circuitry is configured to employ a temporal change in the standing wave frequency to monitor treatment.

63. The system according to claim 50 wherein said control circuitry is configured to employ a temporal change in the standing wave frequency to modify subsequently delivered therapy drive signals.

64. The system according to claim 63 wherein said control circuitry is configured such that the temporal change is determined relative to a pre-treatment value of the standing wave frequency.

65. The system according to any one of claims 1 to 64 wherein said control circuitry is configured to display a frequency dependence of the frequency-dependent electrical measure on a user interface and to obtain the standing wave frequency according to input from a user.

66. The system according to any one of claims 1 to 65 wherein a diameter of the inner lumen is between 0.5 mm and 2.5 mm.

67. The system according to any one of claims 1 to 65 wherein a diameter of the inner lumen is between 0.3 mm and 2.8 mm.

68. The system according to any one of claims 1 to 65 wherein a diameter of the inner lumen is between 0.3 mm and 3.8 mm .

69. The system according to any one of claims 1 to 65 wherein a diameter of the inner lumen is between 1.3 mm and 7.8 mm.

70. The system according to any one of claims 1 to 65 wherein a diameter of the end of the catheter is between 0.5 mm and 3 mm.

71. The system according to any one of claims 1 to 65 wherein a diameter of the end of the catheter is between 0.5 mm and 4 mm.

72. The system according to any one of claims 1 to 65 wherein a diameter of the end of the catheter is between 1 .5 mm and 8 mm.

73. The system according to any one of claims 1 to 72 wherein the inner lumen is defined by a liner material contacting an inner surface of said hollow cylindrical ultrasound transducer.

74. A system for delivering ultrasound treatment to a vascular occlusion, the system comprising: a catheter comprising: an elongate body having a body lumen extending therethrough; and a hollow cylindrical ultrasound transducer supported by a distal region of said elongate body, such that an inner lumen of said hollow cylindrical ultrasound transducer is in fluid communication with the body lumen; and control circuitry operably connected to said hollow cylindrical ultrasound transducer through said elongate body, said control circuitry being configured to perform operations comprising: delivering therapy drive signals to said hollow cylindrical ultrasound transducer, the therapy drive signals being provided according to a frequency and a time duration, the frequency and time duration being suitable for exciting a standing wave within the inner lumen when a known reference material resides in the inner lumen, the standingwave being associated with intraluminal reflections of ultrasound waves generated by said hollow cylindrical ultrasound transducer.

75. The system according to claim 74 wherein said control circuitry is configured such that the reference material is a saline solution of 0.9% NaCI by weight.

76. The system according to claim 74 wherein said control circuitry is configured such that the reference material is blood.

77. The system according to claim 74 wherein said control circuitry is configured such that the reference material is a thrombus.

78. The system according to claim 74 wherein said control circuitry is configured such that the frequency is selectable among a plurality of reference frequencies, and wherein at least two of the plurality of reference frequencies correspond to different reference materials.

79. A method of delivering ultrasound treatment to a vascular occlusion, the method comprising: providing an intravascular ultrasound treatment catheter comprising an elongate body having a body lumen extending therethrough and a hollow cylindrical ultrasound transducer supported by a distal region of the elongate body, such that an inner lumen of the hollow cylindrical ultrasound transducer is in fluid communication with the body lumen; and delivering therapy drive signals to the hollow cylindrical ultrasound transducer, the therapy drive signals being provided with a standing wave frequency and a time duration suitable for excitation of a standing wave within the inner lumen, the standing wave being produced by intraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer in response to the therapy drive signals, wherein the therapy drive signals are provided with sufficient energy to generate a bubble cloud with the inner lumen.

80. The method according to claim 79 wherein a thrombus at least partially resides within the inner lumen and wherein the therapy drive signals are repeated one or more times such that the thrombus is at least partially eroded.81 . The method according to claim 80 wherein an aspiration device is interfaced with the intravascular ultrasound treatment catheter, and wherein the thrombus is drawn into the inner lumen under control of the aspiration device.

82. The method according to claim 80 wherein the therapy drive signals are delivered during aspiration of the thrombus.

83. The method according to any one of claims 79 to 82 wherein the time duration of the therapy drive signals is sufficiently long that an acoustic pressure envelope associated with the standing wave increases to a maximum value prior to completion of the time duration of the therapy drive signals.

84. The method according to any one of claims 79 to 83 wherein the standing wave is generated based on excitation of a thickness mode of the hollow cylindrical ultrasound transducer.

85. The method according to any one of claims 79 to 84 wherein the standing wave is generated based on excitation of a length mode of the hollow cylindrical ultrasound transducer.

86. The method according to any one of claims 79 to 85 wherein the therapy drive signals excite both a thickness mode of the hollow cylindrical ultrasound transducer and a length mode of the hollow cylindrical ultrasound transducer.

87. The method according to any one of claims 79 to 86 wherein the therapy drive signals are first therapy drive signals, and wherein additional therapy drive signals are provided to sustaining the bubble cloud.

88. The method according to claim 87 wherein the additional therapy drive signals are configured to excite a length mode of the hollow cylindrical ultrasound transducer.

89. The method according to claim 87 wherein the additional therapy drive signals have a lower amplitude than the first therapy drive signals.

90. The method according to any one of claims 79 to 89 further comprising processing ultrasound signals received after delivery of the therapy drive signals.91 . The method according to claim 90 wherein the ultrasound signals are processed to a presence of cavitation, an absence of cavitation, or a degree of cavitation, within the inner lumen of the hollow cylindrical ultrasound transducer.

92. The method according to claim 90 wherein the ultrasound signals are ring-down signals associated with the standing wave generated in response to delivery of the therapy drive signals.

93. The method according to any one of claims 90 to 92 wherein the ultrasound signals are received by the hollow cylindrical ultrasound transducer.

94. The method according to any one of claims 90 to 92 wherein an additional ultrasound transducer is employed to receive the ultrasound signals.

95. The method according to claim 90 wherein the ultrasound signals are associated with a probe ultrasound pulse generated by probe drive signals delivered to the hollow cylindrical ultrasound transducer after delivery of the therapy drive signals.

96. The method according to claim 95 wherein the ultrasound signals associated with the probe ultrasound pulse are compared with ultrasound signals associated with a previously generated probe pulse to infer a change in a material residing within the inner lumen.

97. The method according to claim 96 wherein the ultrasound signals are processed to identify a material within the inner lumen.

98. The method according to claim 97 further comprising modifying subsequently delivered therapy drive signals in response to the material identified to be currently residing within the inner lumen.

99. The method according to claim 97 further comprising modifying aspiration based on the material identified to be currently residing within the inner lumen.

100. The method according to claim 97 further comprising interrupting aspiration when the material identified to be currently residing within the inner lumen is blood.

101. The method according to any one of claims 79 to 100 wherein the standing wave frequency is identified, by: delivering test drive signals to the hollow cylindrical ultrasound transducer for interrogating a frequency response of the hollow cylindrical ultrasound transducer; and employing a frequency-dependent electrical measure associated with the test drive signals to identify a standing wave frequency corresponding to a standing wave produced byintraluminal reflections of ultrasound waves generated by the hollow cylindrical ultrasound transducer.

102. The method according to claim 101 wherein aspiration is initiated prior to delivering the test drive signals and identifying the standing wave frequency.

103. The method according to claim 101 wherein a frequency range of the test drive signals corresponds a thickness mode when a pre-selected medium resides within the inner lumen.

104. The method according to claim 101 wherein a frequency range of the test drive signals corresponds to a length mode when a pre-selected medium resides within the inner lumen.

105. The method according to any one of claims 101 to 104 wherein the test drive signals are configured to generate ultrasound within the inner lumen in absence of cavitation.

106. The method according to any one of claims 101 to 105 wherein the standing wave is characterized by a Bessel function of a first kind (order zero).

107. The method according to any one of claims 101 to 106 wherein the frequencydependent electrical measure is an impedance spectrum derived from the test drive signals.

108. The method according to any one of claims 101 to 106 wherein the frequencydependent electrical measure is derived from a ringdown signal.

109. The method according to any one of claims 101 to 106 wherein the test drive signals comprise a plurality of pulses having different frequencies.

110. The method according to any one of claims 101 to 109 further comprising: identifying a plurality of standing wave frequencies based on the frequencydependent electrical measure; sequentially delivering cavitation test drive signals at the plurality of standing wave frequencies, and obtain a respective ring-down signal associated with each standing wave frequency; processing each ring-down signal to obtain a cavitation measure characterizing cavitation at the standing wave frequency; and employing the cavitation measures to select a suitable standing wave frequency for subsequent delivery of therapy drive signals.

111. The method according to claim 110 wherein the cavitation measures characterize an amount of cavitation produced at each standing wave frequency.

112. The method according to claim 110 wherein the cavitation measures characterize an efficiency of cavitation generation at each standing wave frequency.

113. The method according to any one of claims 101 to 112 further comprising employing the standing wave frequency to identify a material present in the inner lumen.

114. The method according to claim 113 wherein the standing wave frequency is employed to identify the material present within the inner lumen by comparing the standing wave frequency to one or more reference standing wave frequencies, each reference standing wave frequency corresponding to a different material.

115. The method according to claim 114 wherein a plurality of standing wave frequencies are obtained based on the frequency-dependent electrical measure and compared with a plurality of sets of reference standing wave frequencies to identify the material, each set of reference standing wave frequencies corresponding to a different reference material.

116. The method according to claim 114 wherein the different materials include one or more of saline and blood.

117. The method according to claim 114 wherein the different materials include a thrombus.

118. The method according to claim 117 wherein the standing wave frequency is employed to infer one or more properties of the thrombus.

119. The method according to claim 118 wherein the one or more properties of the thrombus are employed to determine one or more treatment parameters for cavitation-based disruption of the thrombus via an intraluminal standing wave.

120. The method according to claim 119 wherein the one or more treatment parameters comprise pulse length and inter-pulse interval.121 . The method according to claim 114 wherein the different materials include one or more medical devices.

122. The method according to claim 121 wherein the one or more medical devices include a guidewire and a microcatheter.

123. The method according to claim 121 or 122 wherein identification of the medical device results in generation of an alert.

124. The method according to claim 121 or 122 wherein delivery of ultrasound therapy is prevented when the medical device is identified.

125. The method according to claim 121 or 122 wherein aspiration is prevented when the medical device is identified.

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