Ultrasound-induced cavitation for thrombolysis with a surface-modified wire

Abstract

A system for inducing localized cavitation includes an inducing wire for insertion into a vessel. The including wire has a surface-modified region configured to induce cavitation. The system also includes an ultrasonic transducer configured to deliver ultrasonic energy to a target region that includes the surface-modified region, thereby producing cavitation at a localized region about the surface-modified region. The system may be used intravenously for treatment of thrombi.

Description

FILED ELECTRONICALLY Docket No. 25KU005L-02TITLEULTRASOUND-INDUCED CAVITATION FOR THROMBOLYSIS WITH A SURFACE-MODIFIED WIRESTATEMENT OF GOVERNMENT INTEREST

[0001] This invention was made with government support under Grant No. HL 152420 awarded by the National Institutes of Health. The government has certain rights in the invention.PRIORITY

[0002] This application claims priority to and benefit of United States Provisional Patent Application No. 63 / 703,877 titled “ROUGHENED GUIDEWIRES, SYSTEMS, METHODS OF MANUFACTURE, AND METHODS OF USE” filed October 4, 2024, the entirety of which is incorporated herein by reference.BACKGROUND OF THE DISCLOSURE

[0003] Deep vein thrombosis (DVT), characterized by excessive blood clot (thrombus) formation in veins, is a major disease affecting more than 10 million people worldwide each year. Medical complications associated with DVT include pulmonary embolism (PE) and postthrombotic syndrome (PTS). PE is an acute life-threatening complication and is known to be induced by the debris of the blood clots when they break off from the central clot and block smaller blood vessel flowing into the lungs. The blockage of blood supply can cause severe damages to the lungs, resulting in breathing difficulties, and ultimately leading to death. Annually, as many as 100,000 patients die from PE in the United States. PTS is another costly chronic condition that develops in 30% to 75% of patients with DVT. PTS includes redness, swelling, ulcers and chronic leg pain, and it can lead to life-long suffering and potentially disability. The annual costs for DVT -related complications are $7 to $10 billion in the United States. Worldwide, the total cost can be as high as $69 billion annually.

[0004] Among the current standards of care, anticoagulants can prevent thrombus propagation; however, they do not dissolve existing thrombi and re-canalize vessels. Thrombolytic therapy that has been historically performed to dissolve clots may greatly increase the risk of bleeding, and their introduction may require hospitalization. Ultrasound-based treatment techniques have been evaluated as methods to induce effective thrombolysis. The advantage of ultrasound-based techniques is that they canDocket No. 25KU005L-02 dissolve blood clots quickly and re-canalize vessels (in some cases noninvasively) through cavitation. While ultrasound-based techniques may quickly remove blood clots, these techniques typically require high acoustic peak negative pressure (e.g., as high as 19 MPa) at relatively low ultrasonic frequencies, such as 500 kHz to 1 MHz. In order to achieve high ultrasonic pressure and deliver treatment to a blood clot, focused ultrasound may sometimes be employed. However, at such low ultrasonic frequencies, the focal spot of the ultrasonic field is usually larger than 10 mm in length, which is greater than the diameters of most veins. As a result, severe damage can occur to the surrounding tissue and vessel walls. This is especially problematic in areas with delicate structures that have limited surgical options, such as renal vein thrombus where vein access and removal is highly invasive. To increase the efficiency of ultrasound-based thrombolysis, microbubbles can be injected, however, this increases the risk of systemic toxicity and unwanted vascular and organ damages.SUMMARY

[0005] In some embodiments, a system for inducing localized cavitation includes an inducing wire for insertion into a vessel, the inducing wire having a surface-modified region. The system also includes an ultrasonic transducer configured to deliver ultrasonic energy to a target region that includes the surface-modified region.

[0006] In some embodiments, a method of performing thrombolysis includes inserting an inducing wire into a vessel, the inducing wire having a surface-modified region. The method includes positioning the inducing wire at or near a thrombus within the vessel and delivering ultrasonic energy to a target region that includes the surface- modified region of the inducing wire. In response to the ultrasonic energy, cavitation is produced within the vessel about the surface-modified region, and at least a portion of the thrombus is fragmented based on the cavitation.

[0007] This summary is provided to introduce a selection of concepts that are further described below in the detailed description. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used as an aid in limiting the scope of the claimed subject matter.

[0008] Additional features and advantages of embodiments of the disclosure will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of such embodiments. The features and advantages of such embodiments may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These andDocket No. 25KU005L-02 other features will become more fully apparent from the following description and appended claims or may be learned by the practice of such embodiments as set forth hereinafter.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] In order to describe the manner in which the above-recited and other features of the disclosure can be obtained, a more particular description will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. For better understanding, the like elements have been designated by like reference numbers throughout the various accompanying figures. While some of the drawings may be schematic or exaggerated representations of concepts, at least some of the drawings may be drawn to scale. Understanding that the drawings depict some example embodiments, the embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0010] FIG. 1 is a perspective view of an embodiment of a system for producing localized cavitation in a vessel, according to at least one embodiment of the present disclosure;

[0011] FIG. 2 is a schematic view of an inducing wire configured to include local cavitation, according to at least one embodiment of the present disclosure;

[0012] FIG. 3 illustrates example scanning electron micrographs (SEMs) of a surface- modified region of an inducing wire before and after surface treatment, according to at least one embodiment of the present disclosure;

[0013] FIGS. 4-1 to 4-3 illustrate an example process of performing thrombolysis, according to at least one embodiment of the present disclosure;

[0014] FIG. 5 illustrates a graph of peak passive cavitation detector (PCD) output plotted against applied peak negative pressure (PNP), according to at least one embodiment of the present disclosure;

[0015] FIG. 6 illustrates a graph quantifying thrombus removal, according to at least one embodiment of the present disclosure; and

[0016] FIG. 7 illustrates a method or a series of acts for performing thrombolysis, according to at least one embodiment of the present disclosure.DETAILED DESCRIPTION

[0017] This disclosure generally relates to systems, devices, and methods for thrombus disruption using ultrasound energy in cooperation with a surface-modified metallic wire. In some embodiments, an inducing wire includes a nitinol substrate havingDocket No. 25KU005L-02 a surface-modified region engineered with micro- and nano-scale features that retain gas nuclei when wetted. According to certain implementations, ultrasound energy is directed to a target region that includes the surface-modified region. The ultrasonic energy may be delivered from an external transducer positioned outside the body or from an intravascular transducer positioned within a vessel. The interaction of the acoustic field with the surface-modified region produces a localized cavitation bubble cloud confined to a thin interface adjacent the wire-thrombus boundary, enabling mechanical fragmentation of clot material while limiting energy deposition away from the treatment site. In this way, ultrasonic energy may be utilized to induce cavitation at low relative pressures, such as 0.8 MPa or lower, which may reduce or eliminate damage to surrounding tissue. For example, the ultrasonic energy may be focused to the specific target region, or may be unfocused to a general region including the target region based on the acoustic emissions being low-energy.

[0018] In some embodiments, the surface-modified region is a defined segment of the metallic substrate (e.g., nitinol) engineered to present micro- and / or nano-scale topography that retains gas nuclei when wetted and thereby lowers cavitation thresholds at the wire-thrombus interface. A gas nucleus as used herein may be a pocket or region of gas-phase fluid contacting and retained by recesses or other surface features of the surface-modified region of the wire. For example, the surface-modified region may provide various ridges, pockets, dimples, cavities, or other feature(s) which may retain gas (e.g., gas nuclei) when exposed to a liquid in a manner that prevents the surface- modified region from being fully wetted by the liquid. These gas nuclei may facilitate reducing a surface tension and / or surface contact of the fluid with the surface-modified region to promote formation of a gas phase of the liquid, pursuant to the cavitation process. The surface-modified region may be formed by laser etching, chemical etching, electrochemical etching, grit blasting, micro-machining, or peening. By way of example, a CCh-laser engraving process may be applied to create uneven terrain on the order of about 100 pm and / or an average surface roughness of about 0.12 pm relative to an untreated surface roughness of about 0.04 pm. The surface may be rendered hydrophobic intrinsically by the created roughness or by an applied coating to increase contact angle and stabilize trapped micro-pockets. These features increase nucleation- site density, promote bubble inception at low acoustic pressures (for example, near about 0.8 MPa peak negative pressure), and confine mechanical effects to a thin interface adjacent the wire while the metallic boundary enhances local pressure by reflection.Docket No. 25KU005L-02

[0019] FIG. 1 is a perspective view of an embodiment of a system 100 for producing localized cavitation in a vessel, according to at least one embodiment of the present disclosure. FIG. 1 illustrates a bench test system for providing acoustic energy to a target location 102 in a simulated blood vessel 104 with a blood clot in the vessel 104. In some embodiments, the system includes an inducing wire 106 and an acoustic energy source 108, such as a therapeutic ultrasound transducer. The inducing wire 106 may be a guidewire and / or a catheter wire positioned to extend to or near the target location 102 within the vessel 104. The acoustic energy source 108 is directed toward the target location 102. In some embodiments, the acoustic energy at reduced intensity and the inducing wire 106 individually are insufficient to promote cavitation in the vessel 104. In some embodiments, the combination of the inducing wire 106 and the applied acoustic energy promotes cavitation localized at an interface of the inducing wire 106 and the blood clot.

[0020] In some embodiments, the acoustic energy penetrates through surrounding tissue to the target location 102. In some embodiments, the inducing wire 106 is advanced intravascularly so that a surface-modified region of the inducing wire 106 is positioned directly at or near the target location 102 within the vessel 104. In some embodiments, the acoustic energy source 108 is positioned external to the body to transmit energy transcutaneously. In other embodiments, the acoustic energy source 108 is implemented as an intravascular ultrasound transducer positioned within the vessel 104 proximate the inducing wire 106. For example, the acoustic energy source 108 and the inducing wire 106 may be implemented in a same catheter for inserting and / or manipulating intravenously.

[0021] In some embodiments, the acoustic energy is focused, for example using a focused ultrasonic transducer configured to concentrate energy at or near the target location 102. In other embodiments, the acoustic energy is unfocused such that a broader region of the vessel 104 and / or surrounding tissue receives ultrasonic exposure. For example, in some cases the acoustic exposure is at levels less than those used for diagnostic imaging ultrasound, permitting unfocused ultrasound delivery to a general area while relying on the inducing wire 106 to localize cavitation at the interface at the target location 102. In some embodiments, the acoustic energy is delivered in a pulsed mode. In other embodiments, the acoustic energy is delivered in a continuous mode.

[0022] In some embodiments, the acoustic energy source 108 is controlled by a computing device 112. In at least one embodiment, the computing device 112 includes orDocket No. 25KU005L-02 is in communication with a computer readable medium (CRM) that contains instructions that, when read by the computing device 112, cause the computing device 112 to perform one or more methods described herein. For example, the computing device 112 may regulate one or more of timing, power, duty cycle, and / or frequency of the acoustic energy source 108. In some embodiments, the computing device 112 is in communication with one or more sensors 114 configured to detect cavitation and / or other aspects of the target location 102 and / or the vessel 104. For example, the one or more sensors 114 may include one or more of a pulse receiver or an oscilloscope for detecting, characterizing, and / or measuring induced cavitation. In such examples, the computing device 112 may modulate the acoustic energy source 108 based at least partially on information communicated by the one or more sensors 114. In some embodiments, the computing device 112 is in communication with one or more imaging or sensing devices for aiding guidance of the inducing wire 106.

[0023] In some embodiments, the system 100 includes one or more components to provide additional control over delivery of acoustic energy. For example, the system 100 may include one or more power amplifiers 116 in communication with the acoustic energy source 108. In some examples, the system 100 includes one or more function generators 118 in communication with the acoustic energy source 108 to control a phase and / or a frequency of the acoustic energy from the acoustic energy source 108. In some embodiments, the system 100 further includes a debris management element configured to capture and / or limit downstream migration of clot fragments during treatment. For example, the debris management element may comprise a filter sleeve disposed downstream of the target location 102 and coupled to a catheter body, and / or an aspiration lumen configured to remove liberated material from the vessel 104 during or after application of ultrasonic energy.

[0024] In some embodiments, the inducing wire 106 includes a nitinol substrate. In some embodiments, other suitable materials (e.g., suitable for interaction with the human body) may be used. In some embodiments, the inducing wire 106 has a surface-modified region configured to promote cavitation when exposed to acoustic energy. In some embodiments, the surface-modified region includes micro- and / or nano-scale features, for example, formed by etching to produce surface roughness. Micro-scale may refer to measurements between 1 micron and 1 millimeter. Nano-scale may refer to measurements between 1 nanometer and 1 micron. For example, a surface-modified region of the inducing wire 106 may be formed by one or more of laser etching, chemical etching,Docket No. 25KU005L-02 electrochemical etching, grit blasting, and / or mechanical roughening. In some embodiments, the surface-modified region includes a coating. In some examples, the surface-modified region is hydrophobic. The surface-modified region may be configured to induce cavitation by retaining micro-pockets and / or by increasing nucleation sites for cavitation. In some embodiments, the inducing wire 106 is integrated with a catheter body configured to position the inducing wire 106 at the target location 102.

[0025] In some embodiments, the inducing wire 106 is positioned such that the surface-modified region directly contacts the blood clot at the target location 102. In some embodiments, the inducing wire 106 is positioned adjacent to, but not in direct contact with, the blood clot. In some embodiments, the inducing wire 106 is held stationary during ultrasonic exposure. In other embodiments, the inducing wire 106 is translated incrementally along a length of the blood clot between periods of ultrasonic exposure.

[0026] In some embodiments, a condition of acoustic exposure at the target location 102 is monitored using the one or more sensors 114. In some embodiments, the one or more sensors 114 include a passive cavitation detector. In some embodiments, signals from the one or more sensors 114 are used to determine a cavitation onset threshold and to maintain acoustic exposure at or near the cavitation onset threshold during treatment.

[0027] In some embodiments, acoustic energy is applied to the target location 102 in the presence of the inducing wire 106. In some embodiments, the acoustic energy source 108 is positioned near or adjacent the target location 102 external to the body. In other embodiments, the acoustic energy source 108 is positioned intravascularly proximate the inducing wire 106. In some embodiments, the acoustic energy source 108 supplies ultrasonic energy to the target location 102 in bursts and / or continuously. In some embodiments, the acoustic field is focused at or near the surface-modified region of the inducing wire 106. In other embodiments, the acoustic field is unfocused and exposes a general region that includes the target location 102.

[0028] In some embodiments, the acoustic energy source 108 generates an acoustic wave by driving one or more transducer elements electrically. According to some implementations, an annular or bowl-shaped transducer structure assists in focusing the acoustic wave through a center of the acoustic energy source 108 and directing acoustic energy to the target location 102. In some embodiments, when focusing is used, a focal length is selected to concentrate energy at a target location within tissue while the acoustic energy source 108 is positioned outside of the body. In other embodiments, an intravascular acoustic energy source 108 emits acoustic energy locally within the vesselDocket No. 25KU005L-02104 without relying on a distant focal length. In some embodiments, application of acoustic energy at reduced intensity in combination with the inducing wire 106 promotes cavitation that in turn promotes thrombolysis of a blood clot.

[0029] In some embodiments, ultrasonic bursts are timed based at least in part on a detected cavitation signal. In some embodiments, ultrasonic bursts are timed based at least in part on a cardiac cycle and / or a respiratory cycle. In other embodiments, ultrasonic energy is delivered continuously, and one or more parameters (e.g., power and / or duty cycle of a modulated carrier) are adjusted to maintain cavitation at or near onset conditions. In some embodiments, the one or more sensors 114 include a passive cavitation detector configured to detect acoustic emissions indicative of cavitation activity proximate the inducing wire 106. In some embodiments, the system 100 further includes a calibration hydrophone positioned to measure acoustic pressure at or near the target location 102, for example to calibrate a peak negative pressure of the acoustic energy source 108 before and / or during treatment. In some embodiments, an imaging device (e.g., an ultrasound imaging probe or other imaging modality) is used to aid placement of the inducing wire 106 and / or to monitor treatment progress at the target location 102.

[0030] In some embodiments, the acoustic energy source 108 provides acoustic energy with a maximum positive pressure and / or a maximum negative pressure (below atmosphere) in a range having an upper value, a lower value, or upper and lower values including any of 0.1 Megapascals (MPa), 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.8 MPa, 1.0 MPa, 1.2 MPa, 1.4 MPa, 1.6 MPa, 1.8 MPa, 2.0 MPa, 2.5 MPa, 3.0 MPa, 4.0 MPa, 5.0 MPa, 6.0 MPa, 7.0 MPa, 8.0 MPa, 9.0 MPa, 10.0 MPa, or any values therebetween. For example, in some embodiments the pressure maximum is between 0.2 MPa and 2.5 MPa. In some embodiments, the acoustic exposure is selected to be lower than pressures commonly employed by ultrasound-only thrombolysis regimens (i.e., treatments that do not use an inducing wire). For example, such ultrasound-only approaches at comparable frequencies may utilize peak negative pressures of about about 10 MPa or higher to produce effective clot disruption, inclusive of regimens that further rely on exogenous microbubbles and / or thrombolytic agents administered in situ. By contrast, the present techniques can achieve effective thrombolysis at about 10 MPa peak negative pressure or less. In some embodiments, pressures of about 5 MPa or less may achieve effective thrombolysis with an inducing wire as described herein. In some implementations, approximately 1.8 MPa or less may achieve effective thrombolysis while maintaining localization at the wire-thrombus interface. Specific pressureDocket No. 25KU005L-02 selections may be adjusted based on vessel size, thrombus characteristics, and desired treatment time, with the inducing wire’s surface-modified region providing nucleation sites that reduce the acoustic threshold relative to ultrasound-only exposure. In this way, the present techniques may be achieved with lower relative peak negative pressures, for example, relative to other ultrasound thrombolysis techniques.

[0031] In some embodiments, the acoustic energy source 108 provides acoustic energy with a frequency in a range having an upper value, a lower value, or upper and lower values including any of 500 kilohertz (kHz), 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, 850 kHz, 900 kHz, 950 kHz, 1.0 megahertz (MHz), or any values therebetween. In at least one example, the frequency is about 500 kHz to 750 kHz.

[0032] In some embodiments, a duty cycle of the acoustic energy source 108 is in a range having an upper value, a lower value, or upper and lower values including any of 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any values therebetween. In some embodiments, the duty cycle is between 3% and 10% during operation.

[0033] In some embodiments, a treatment duration at the target location 102 is in a range having an upper value, a lower value, or upper and lower values of 1 second (s), 5 s, 10 s, 15 s, 30 s, 45 s, 60 s, 75 s, 90 s, 105 s, 120 s, or any values therebetween. In at least one example, the treatment duration is between 15 s and 120 s.

[0034] In some embodiments, operating at these reduced acoustic pressures (e.g., relative to other ultrasonic solutions) lowers the cavitation threshold and localizes activity to the wire-thrombus interface. For example, cavitation may initiate at about 0.8 MPa with the inducing wire 106 compared to about 1.8 MPa without the inducing wire 106 and / or a modified surface of the inducing wire 106. In some embodiments, using a moderate center frequency (e.g., about 500 kHz) with short, low-duty bursts (e.g., about 2,500 cycles at 20 Hz, approximately 10% duty cycle) provides lower time-averaged acoustic exposure than continuous or higher-duty regimens while achieving effective thrombus removal in about 2 minutes. In some cases, because spatial localization is provided by the inducing wire 106 rather than by very high focal intensities, the ultrasonic field may be unfocused or only lightly focused, thereby reducing off-target exposure relative to tightly focused, higher-intensity sonication. In this way, effective thrombolysis treatment may be achieved while reducing damage to surrounding tissues (or the vessel) based on lower relative ultrasonic energies that may not, on their own, cause significant damage.Docket No. 25KU005L-02

[0035] FIG. 2 is a schematic view of an inducing wire 206 configured to include local cavitation, according to at least one embodiment of the present disclosure. The inducing wire 206 includes a substrate 212 and a surface-modified region 220 on the substrate 212. The substrate 212 may be nitinol. For example, a nitinol wire having an outer diameter of about 0.9 mm may be used. Other biocompatible metals may be substituted while preserving the function of the inducing wire 206.

[0036] The surface-modified region 220 may be located near a distal end 222 of the inducing wire 206, may begin proximal to the distal end 222, and may have a length selected for a target application. The region 220 can be provided as a single continuous segment sized to correspond to a thrombus length or as multiple spaced segments. In some embodiments, the surface-modified region 220 is positioned on only a portion of the substrate 212, or may be positioned covering all or substantially all of the substrate 212.

[0037] The surface-modified region 220 may be produced through various processes. In one example, the substrate 212 is etched. For example, etching may be performed under a C Ch-laser beam, such as at about 100% frequency, about 95% power, and about 35% speed for approximately 50 cycles. The laser etching may be performed with an etching mode set to a vector setting and a hairline cut dimension to generate surface features on the order of about 100 pm. In some embodiments, other techniques for forming the surface-modified region 220 may be used, include chemical etching, electrochemical etching, and mechanical abrasion such as grit blasting, micro-machining, or peening. The surface-modified region 220 may include a coating or surface treatment. In some embodiments, the surface-modified region 220 is achieved based on growing crystalline structures on the substrate 212. In some embodiments, the surface-modified region 220 exhibits a hydrophobic behavior and / or may be configured to promote retention of trapped micro-pockets based on surface features and surface topology.

[0038] The surface-modified region 220 may include micro- and / or nano-scale features that produce uneven terrain in the form of bulges, grooves, dimples, crevices, or other features, shapes, or patterns. The surface-modified region 220 may have a surface roughness of at least about 0.08 pm, for example about 0.12 pm, whereas an untreated wire may exhibit an average surface roughness of about 0.04 pm. Features can have characteristic lateral dimensions on the order of tens of micrometers, for example around 100 pm. The surface-modified region 220 may be patterned as circumferential rings, helical paths, clustered patches, or alternating bands of surface features to achieve a desired nucleation-site density.Docket No. 25KU005L-02

[0039] In some embodiments, the surface-modified region 220 may be configured to promote localized cavitation by supplying stable gas nuclei. For example, roughness features create interstitial spaces that retain trapped micro-pockets when the inducing wire 206 is wetted by blood or other liquid. Under ultrasonic exposure, the negativepressure phase draws these nuclei into radial growth and subsequent collapse, producing localized inertial cavitation, micro-jets, and shear concentrated within a thin layer adjacent to the surface-modified region 220, for example on the order of tens of micrometers (e.g., less than about 100 pm).

[0040] Roughness and / or micro-pockets distributed along the surface-modified region 220 may give rise to multiple enhanced cavitation spots that can collectively fragment a clot at a wire-thrombus interface. For example, cavitation onset may occur near about 0.8 MPa peak negative pressure (PNP) or less due to the surface-modified region 220. In some embodiments, the ultrasonic energy may be provided at about 1.8 MPa or less to achieve effective cavitation in connection with the inducing wire 206. Further, ultrasound-only exposure at the same low PNP may remove a negligible amount of thrombus at these. Operating at approximately 1.8 MPa PNP can thus produce robust, localized cavitation with the region 220 while avoiding higher acoustic intensities typically required in the absence of nucleation sites.

[0041] In some embodiments, hydrophobic behavior at the surface-modified region 220 can resist complete wetting of the bulges, grooves, dimples, and crevices. For example, increased contact angle may limit liquid infiltration into the interstitial spaces, so small volumes of gas remain pinned within the micro-topography when the inducing wire 206 is immersed in blood or saline. This retained gas can serve as nuclei that are readily driven to grow and collapse during successive acoustic cycles.

[0042] In some implementations, hydrophobicity may be produced intrinsically by the micro- and nano-scale roughness of the region 220, which creates local de-wetting pockets. In some embodiments, hydrophobicity is achieved by surface features and / or an applied coating selected to increase contact angle. In some embodiments, maintaining gas within the surface features improves the likelihood of repeated bubble inception at the same locations, thereby reducing the acoustic pressure required to initiate cavitation and helping confine mechanical effects to a thin layer at the wire-thrombus interface.

[0043] In various embodiments, the substrate 212 may also serve as a hard acoustic boundary that reinforces the cavitation process through constructive superposition. For example, near the surface of the substrate 212, incident and reflected wave componentsDocket No. 25KU005L-02 add, effectively doubling local pressure amplitude. For example, a field adjusted to about 1.8 MPa PNP in the bulk may approach about 3.6 MPa PNP within regions immediately adjacent to the surface-modified region 220, further intensifying cavitation activity at the interface.

[0044] The combined effect of abundant nucleation sites on the surface-modified region 220 and pressure doubling at the substrate 212 can yield a synergistic reduction in cavitation threshold and a strong, spatially confined mechanical action against thrombus. This cavitation mechanism may enable use with focused or unfocused ultrasonic fields, as well as from external or intravascular transducers, while advantageously leveraging the surface-modified region 220 — rather than extreme focal intensities and / or elevated ultrasonic energies — to achieve cavitation at the target interface.

[0045] FIG. 3 illustrates example scanning electron micrographs (SEMs) of a surface- modified region 220 of an inducing wire 206 before and after surface treatment, according to at least one embodiment of the present disclosure. Panel (a) shows a zoomed-out SEM image of an etched nitinol wire, and panel (b) shows a zoomed-out SEM image of the nitinol wire before etching. Panel (c) shows a zoomed-in SEM image of the etched nitinol wire, with a dotted outline indicating bulges formed on the surface- modified region 220. Panel (d) shows a zoomed-in SEM image of the nitinol wire before treatment. The inducing wire 206 has an outer diameter of about 0.9 mm.

[0046] The etched surface shown in panels (a) and (c) may be produced by directing a CCE-laser beam over the nitinol substrate 212 using, for example, a vector setting with a hairline cut dimension at approximately 100% frequency, 95% power, and 35% speed for about 50 cycles to form surface features on the order of about 100 pm. SEM imaging may be performed at an accelerating voltage of about 5 kV to visualize the uneven terrain on the etched surface — including the circled bulges and adjacent crevices — in contrast to the comparatively smoother, unetched surface in panels (b) and (d).

[0047] Surface texture may be corroborated by atomic force microscopy to quantify roughness and obtain topography images (e.g., scan rate of about 1 Hz and scan size of about 5 pm). Representative measurements may indicate an average surface roughness of about 0.12 pm for etched wire surfaces and about 0.04 pm for unetched wire surfaces, consistent with the bulge formation observed in the SEM images. Post-process steps may include passivation, oxide control, precision cleaning, and sterilization.Docket No. 25KU005L-02

[0048] FIGS. 4-1 to 4-3 illustrate an example process of performing thrombolysis, according to at least one embodiment of the present disclosure. A vessel 404 includes a thrombus 430 (e.g., clot) that may at least partially block the vessel 404.

[0049] In some embodiments, an inducing wire 406 is inserted into the vessel 404 and positioned proximate the thrombus 430. For example, the inducing wire 406 may be positioned adjacent the thrombus 430 within a threshold distance, such as within about 1 mm of the thrombus 430. In other embodiments, the inducing wire 406 is positioned to touch the thrombus 430, or is inserted into the thrombus 430. As described herein, the inducing wire 406 includes a surface-modified region 420, and the inducing wire 406 may be oriented so that the surface-modified region 420 faces the thrombus 430.

[0050] In some embodiments, acoustic energy 432 is directed at the inducing wire 406 and / or the thrombus 430. For example, the acoustic energy 432 may be delivered from an external ultrasonic transducer positioned outside the body, or from an intravascular ultrasonic transducer positioned within the vessel 404. The acoustic energy 432 may be focused to converge at or near the surface-modified region 420, or may be unfocused (or lightly focused) and delivered to a broader area while relying on the surface-modified region 420 to localize the cavitation mechanism.

[0051] As shown in FIG. 4-2, based on the acoustic energy 432, cavitation may occur at or near the surface-modified region 420. A bubble cloud 434 may form and remain localized about the surface-modified region 420. The bubble cloud 434 may define, and / or be used to reference, a thrombus-wire interface region. For instance, the interface region may be an area adjacent to, contacting, or bounded by the bubble cloud 434. In some embodiments, the interface region is a zone influenced by the bubble cloud 434, for example a region that experiences a shock wave from bubble collapse. In some cases, bubbles nucleate at the surface-modified region 420 and then travel downstream from the bubble cloud 434 toward the interface region before collapsing.

[0052] In some embodiments, the bubble cloud 434 forms due to gas nuclei retained within the micro-topography of the surface-modified region 420. During negativepressure phases of the acoustic field, the nuclei expand; during positive-pressure phases, they collapse, producing inertial cavitation, micro-jets, and high shear concentrated near the surface of the inducing wire 406. The bubble cloud 434 may present a near-wire radius on the order of about 50-500 pm, depending on acoustic settings and local flow conditions.Docket No. 25KU005L-02

[0053] The relative placement of the bubble cloud 434 with respect to the thrombus 430 may vary. In one example, the bubble cloud 434 is near the thrombus 430, with a boundary of the bubble cloud 434 lying within a threshold distance, such as about 0.5 mm, from the thrombus surface. In another example, the bubble cloud 434 touches the thrombus 430 such that the bubble cloud 434 intersects the thrombus surface. In a further example, the bubble cloud 434 partially or entirely encompasses the thrombus 430. In some embodiments, bubbles nucleate at the surface-modified region 420 and, under acoustic streaming and blood flow, travel a short distance downstream (e.g., outside the bubble cloud 434) before collapsing at, adjacent to, or near the thrombus 430, thereby extending the zone of effective mechanical action.

[0054] In some embodiments, the acoustic exposure is delivered in pulses and / or continuous intervals selected to control cavitation while managing thermal deposition. By way of example, suitable pulse structures may include bursts of approximately 2,500 cycles at a center frequency of about 500 kHz with a repetition rate of about 20 Hz (approximately 10% duty cycle), and a treatment interval on the order of about 2 minutes at a site. In other embodiments, parameters are adjusted based on feedback (e.g., passive cavitation detection) to maintain conditions near cavitation onset; in bench settings, a calibration hydrophone may be used to verify peak negative pressure at or near the inducing wire 406.

[0055] FIG. 4-3 shows the thrombus 430 after an exposure interval. Due to cavitation activity, embolic fragments 434 — thrombus pieces liberated during treatment — may separate from the thrombus 430 and travel downstream within the vessel 404. In some embodiments, one or more debris-management approaches may be used (e.g., a filter element downstream and / or aspiration through a suitable lumen) to capture or remove fragments 434 as appropriate for a given clinical implementation. In some cases, fragmentation is achieved with little or no damage to surrounding tissue, such as the vessel wall, because cavitation is achieved through relatively low energy acoustics and mechanical effects are concentrated within a thin interface region adjacent the surface- modified region 420 rather than distributed broadly across the vessel 404.

[0056] In some embodiments, fragmentation is produced by repeated growth and collapse of cavitation bubbles in close proximity to the thrombus. For example, the collapse of cavitation bubbles may generate shock waves that exert forces on the thrombus 430, acting through several mechanisms to break up the clot. Micro-jet impingement may pit and / or tear the clot matrix at the thrombus surface; cyclic shear andDocket No. 25KU005L-02 acoustic streaming may erode and delaminate the thrombus edge; and / or repeated loading may induce matrix fatigue. Collectively, these effects may break the thrombus 430 into transportable fragments 434. In some embodiments, the metallic boundary of the inducing wire 406 reinforces this process by reflecting incident waves, increasing local pressure amplitude near the surface-modified region 420, and sustaining a dense population of cavitation events at the interface region.

[0057] FIG. 5 illustrates a graph of peak passive cavitation detector (PCD) output plotted against applied peak negative pressure (PNP), according to at least one embodiment of the present disclosure. The graph of FIG. 5 represents experimental results for three conditions in an agar phantom: an etched nitinol wire (0.9 mm diameter), an unetched nitinol wire (0.9 mm diameter), and no wire. Across all conditions, the measured PCD peak generally increased with PNP. Error bars represent the standard deviation from ten measurements (n = 10) at each pressure point.

[0058] For the unetched wire, the PCD curve exhibits a pronounced inflection at about 1.8 MPa PNP, where the peak signal jumps to more than twice the amplitude expected from a linear trend; this inflection is used as the cavitation threshold. In contrast, with the etched wire the inflection — and thus cavitation onset — appears at about 0.8 MPa PNP, indicating a substantial reduction in the pressure required to initiate inertial cavitation. In the no-wire condition, no cavitation was initiated at 0.8 MPa or 1.8 MPa PNP, and the PCD response remained consistent with noncavitating behavior at those pressures. At higher pressures, cavitation activity with the wire conditions was sustained, demonstrating that the surface modification as described herein enhances cavitation and lowers the required PNP relative to an unetched surface and to the absence of a wire.

[0059] FIG. 6 illustrates a graph quantifying thrombus removal, according to at least one embodiment of the present disclosure. The graph of FIG. 6 represents experimental results using 0.5-MHz focused ultrasound (FUS) at about 1.8 MPa peak negative pressure (PNP) with bursts of approximately 2,500 cycles at a repetition rate of about 20 Hz (about 10% duty cycle) for a treatment time of about 2 minutes. The graph of FIG. 6 represents 3 treatment conditions: a FUS-only group, FUS with an unetched wire, and FUS with an etched wire, as described herein. The FUS-only group showed negligible change in thrombus mass with a mean reduction of about -3.76 mg. The FUS with the unetched showed a larger reduction with a mean of about -68.99 mg. The FUS with the etched wire showed the greatest reduction with a mean of about -178.56 mg. Error annotations reflect n = 5 per group.Docket No. 25KU005L-02

[0060] Pairwise comparisons demonstrated statistical significance between groups: FUS-only vs. FUS-unetched-wire (p < 0.01), FUS-unetched-wire vs. FUS-etched-wire (p < 0.01), and FUS-only vs. FUS-etched-wire (p < 0.001). These results indicate that introducing a wire enhances thrombus removal relative to FUS alone, and that surface modification of the wire further amplifies the effect, consistent with enhanced cavitation at the wire-thrombus interface.

[0061] FIG. 7 illustrates a method 700 or a series of acts for performing thrombolysis, according to at least one embodiment of the present disclosure. While FIG. 7 illustrates according to one act, alternative acts may add to, omit, reorder, or modify any of the acts of FIG. 7.

[0062] In some embodiments, the method 700 includes an act 710 of inserting an inducing wire into a vessel, the inducing wire having a surface-modified region. In some embodiments, the method 700 includes an act 720 of positioning the inducing wire within 1 mm of the thrombus within the vessel. For example, the inducing wire may be positioned contacting the thrombus. The inducing wire may be positioned penetrating the thrombus. In some examples, the inducing wire may be positioned within 1 mm of the thrombus without contacting the thrombus.

[0063] In some embodiments, the method 700 includes an act 730 of delivering ultrasonic energy to a target region that includes the surface-modified region of the inducing wire. For example, the ultrasonic energy may be delivered at a peak negative pressure of about 1.8 MPa or less. In some embodiments, the ultrasonic energy is delivered transcutaneously or may be delivered intravenously.

[0064] In some embodiments, the method 700 includes an act 740 of producing, in response to the ultrasonic energy, cavitation within the vessel about the surface-modified region. In some embodiments, the method 700 includes an act 750 of fragmenting at least a portion of the thrombus based on the cavitation.

[0065] One or more specific embodiments of the present disclosure are described herein. These described embodiments are examples of the presently disclosed techniques. Additionally, in an effort to provide a concise description of these embodiments, not all features of an actual embodiment may be described in the specification. It should be appreciated that in the development of any such actual implementation, as in any engineering or design project, numerous embodiment-specific decisions will be made to achieve the developers’ specific goals, such as compliance with system -related and business-related constraints, which may vary from one embodiment to another.Docket No. 25KU005L-02Moreover, it should be appreciated that such a development effort might be complex and time consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill having the benefit of this disclosure.

[0066] The articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements in the preceding descriptions. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. Additionally, it should be understood that references to “one embodiment” or “an embodiment” of the present disclosure are not intended to be interpreted as excluding the existence of additional embodiments that also incorporate the recited features. For example, any element described in relation to an embodiment herein may be combinable with any element of any other embodiment described herein. Numbers, percentages, ratios, or other values stated herein are intended to include that value, and also other values that are “about” or “approximately” the stated value, as would be appreciated by one of ordinary skill in the art encompassed by embodiments of the present disclosure. A stated value should therefore be interpreted broadly enough to encompass values that are at least close enough to the stated value to perform a desired function or achieve a desired result. The stated values include at least the variation to be expected in a suitable manufacturing or production process, and may include values that are within 5%, within 1%, within 0.1%, or within 0.01% of a stated value.

[0067] A person having ordinary skill in the art should realize in view of the present disclosure that equivalent constructions do not depart from the spirit and scope of the present disclosure, and that various changes, substitutions, and alterations may be made to embodiments disclosed herein without departing from the spirit and scope of the present disclosure. Equivalent constructions, including functional “means-plus-function” clauses are intended to cover the structures described herein as performing the recited function, including both structural equivalents that operate in the same manner, and equivalent structures that provide the same function. It is the express intention of the applicant not to invoke means-plus-function or other functional claiming for any claim except for those in which the words ‘means for’ appear together with an associated function. Each addition, deletion, and modification to the embodiments that falls within the meaning and scope of the claims is to be embraced by the claims.

[0068] The terms “approximately,” “about,” and “substantially” as used herein represent an amount close to the stated amount that still performs a desired function or achieves a desired result. For example, the terms “approximately,” “about,” andDocket No. 25KU005L-02“substantially” may refer to an amount that is within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of a stated amount. Further, it should be understood that any directions or reference frames in the preceding description are merely relative directions or movements. For example, any references to “up” and “down” or “above” or “below” are merely descriptive of the relative position or movement of the related elements.

[0069] The present disclosure may be embodied in other specific forms without departing from its spirit or characteristics. The described embodiments are to be considered as illustrative and not restrictive. The scope of the disclosure is, therefore, indicated by the appended claims rather than by the foregoing description. Changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.INDUSTRIAL APPLICABILITY

[0070] The following description from sections Al to C5 includes various embodiments that, where feasible, may be combined in any permutation. For example, the embodiment of Al may be combined with any or all embodiments of the following paragraphs. Embodiments that describe acts of a method may be combined with embodiments that describe, for example, systems and / or devices. Any permutation of the following paragraphs is considered to be hereby disclosed for the purposes of providing “unambiguously derivable support” for any claim amendment based on the following paragraphs. Furthermore, the following paragraphs provide support such that any combination of the following paragraphs would not create an “intermediate generalization.”Al . A system for inducing localized cavitation, comprising: an inducing wire for insertion into a vessel, the inducing wire having a surface- modified region; and an ultrasonic transducer configured to deliver ultrasonic energy to a target region that includes the surface-modified region.A2. The system of Al, wherein the surface-modified region includes a surface roughness configured to retain gas nuclei when wetted.A3. The system of A2, wherein the surface roughness includes micro-scale surface features.Docket No. 25KU005L-02A4. The system of A2 or A3, wherein the surface roughness includes nano-scale surface features.A5. The system of any of A1-A4, wherein the ultrasonic transducer is positioned outside of the vessel and is configured to deliver the ultrasonic energy through the vessel.A6. The system of any of A1-A5, wherein the ultrasonic transducer is configured to deliver the ultrasonic energy from within the vessel.A7. The system of any of A1-A6, wherein the ultrasonic energy has a peak negative pressure PNP) of about 10 MPa or less.A8. The system of any of A1-A7, wherein the ultrasonic energy has a PNP of about 5 MPa or less.A9. The system of any of A1-A8, wherein the ultrasonic transducer is configured to deliver the ultrasonic energy as focused ultrasonic energy focused at the target region.A10. The system of any of A1-A9, wherein the ultrasonic transducer is configured to deliver the ultrasonic energy as unfocused ultrasonic energy.Al l. The system of any of A1-A10, further comprising a controller configured to control the ultrasonic transducer including one or more of controlling a peak negative pressure (PNP), frequency, burst length, repetition rate, or duty cycle of the ultrasonic transducer.Bl. A method of performing thrombolysis, comprising: inserting an inducing wire into a vessel, the inducing wire having a surface- modified region; positioning the inducing wire at or near a thrombus within the vessel; delivering ultrasonic energy to a target region that includes the surface-modified region of the inducing wire;Docket No. 25KU005L-02 producing, in response to the ultrasonic energy, cavitation within the vessel about the surface-modified region; and fragmenting at least a portion of the thrombus based on the cavitation.B2. The method of Bl, further comprising one of positioning the inducing wire within 1 mm of the thrombus; positioning the inducing wire contacting the thrombus; or positioning the inducing wire penetrating the thrombus.B3. The method of Bl or B2, further comprising delivering the ultrasonic energy at about 1.8 MPa or less.B4. The method of any of B1-B3, further comprising delivering the ultrasonic energy transcutaneously.Cl. A wire for inducing cavitation within a vessel, comprising: a biocompatible substrate for positioning intravenously; and a surface-modified region on the biocompatible substrate having an increased surface roughness.C2. The wire of Cl, wherein the biocompatible substrate is nitinol.C3. The wire of Cl or C2, wherein the increased surface roughness is an average surface roughness of about 0.12 um.C4. The wire of any of C1-C3, wherein the surface-modified region includes one or more of etched surface or a coating configured to induce cavitation in response to ultrasonic energy at peak negative pressures (PNP) of about 10 MPa or less.C5. The wire of any of C1-C4, wherein the surface-modified region includes surface features having a lateral dimension of about 100 um or less.

Claims

Docket No. 25KU005L-02CLAIMSWhat is claimed is:

1. A system for inducing localized cavitation, comprising: an inducing wire for insertion into a vessel, the inducing wire having a surface- modified region; and an ultrasonic transducer configured to deliver ultrasonic energy to a target region that includes the surface-modified region.

2. The system of claim 1, wherein the surface-modified region includes a surface roughness configured to retain gas nuclei when wetted.

3. The system of claim 2, wherein the surface roughness includes micro-scale surface features.

4. The system of claim 2, wherein the surface roughness includes nano-scale surface features.

5. The system of claim 1, wherein the ultrasonic transducer is positioned outside of the vessel and is configured to deliver the ultrasonic energy through the vessel.

6. The system of claim 1, wherein the ultrasonic transducer is configured to deliver the ultrasonic energy from within the vessel.

7. The system of claim 1, wherein the ultrasonic energy has a peak negative pressure (PNP) of about 10 MPa or less.

8. The system of claim 1, wherein the ultrasonic energy has a PNP of about 5 MPa or less.

9. The system of claim 1, wherein the ultrasonic transducer is configured to deliver the ultrasonic energy as focused ultrasonic energy focused at the target region.

10. The system of claim 1, wherein the ultrasonic transducer is configured to deliver the ultrasonic energy as unfocused ultrasonic energy.Docket No. 25KU005L-0211. The system of claim 1, further comprising a controller configured to control the ultrasonic transducer including one or more of controlling a peak negative pressure (PNP), frequency, burst length, repetition rate, or duty cycle of the ultrasonic transducer.

12. A method of performing thrombolysis, comprising: inserting an inducing wire into a vessel, the inducing wire having a surface- modified region; positioning the inducing wire within 1 millimeter of a thrombus within the vessel; delivering ultrasonic energy to a target region that includes the surface-modified region of the inducing wire; producing, in response to the ultrasonic energy, cavitation within the vessel about the surface-modified region; and fragmenting at least a portion of the thrombus based on the cavitation.

13. The method of claim 12, further comprising one of: positioning the inducing wire contacting the thrombus; or positioning the inducing wire penetrating the thrombus.

14. The method of claim 12, further comprising delivering the ultrasonic energy at about 1.8 MPa or less.

15. The method of claim 12, further comprising delivering the ultrasonic energy transcutaneously.

16. A wire for inducing cavitation within a vessel, comprising: a biocompatible substrate for positioning intravenously; and a surface-modified region on the biocompatible substrate having an increased surface roughness.

17. The wire of claim 16, wherein the biocompatible substrate is nitinol.

18. The wire of claim 16, wherein the increased surface roughness is an average surface roughness of about 0.12 um.Docket No. 25KU005L-0219. The wire of claim 16, wherein the surface-modified region includes one or more of etched surface or a coating configured to induce cavitation in response to ultrasonic energy at peak negative pressures (PNP) of about 0.8 MPa or less.

20. The wire of claim 16, wherein the surface-modified region includes surface features having a lateral dimension of about 100 um or less.

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