Devices incorporating photoacoustic elements and use of photoacoustic effects for ultrasound-based generation and imaging

Abstract

Photoacoustic responses can be used to generate mechanical responses. Using this phenomenon, ultrasound can be generated even at remote locations by routing a light guide such as a fiber optic cable to a location where ultrasound is beneficial. As described herein, photoacoustic responsive materials such as inflation fluids, balloon materials, or catheter shaft materials are used in coordination with such optical signal delivery systems to provide acoustic signal at the functional, distal end of a catheter. In this way, ultrasound can be generated by a catheter that is relatively smaller and more robust than systems relying on electrodes.

Description

Attorney Docket No. 19506.0001WOU1Devices Incorporating Photoacoustic Elements and Use of Photoacoustic Effects for Ultrasound-Based Generation and ImagingCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The contents of the co-pending U.S. provisional applications 63 / 682,203, 63 / 682,205, and 63 / 682,207, all filed on August 12, 2024, are hereby incorporated in their entirety by reference.BACKGROUND

[0002] Delivery of sonic treatment to the body is useful in a variety of contexts, such as for denervation, calcium debulking, treatment of chronic total occlusion, removal of thrombi or other obstructions, or providing or activating medications and other substances in the body. Often the sonic treatment is in the ultrasound regime.

[0003] In some circumstances, ultrasonic treatment can be provided transcutaneously, by a device outside the body. In other circumstances, precise delivery of sonic treatments is delivered more precisely using a catheter that is routed through the vasculature to a treatment region.

[0004] Catheters used to provide such treatments have attributes that prevent their use in some scenarios. Providing the ultrasonic treatment may use an electrode that causes a spark or cavitation in a carrier fluid around that electrode. These sparks tend to degrade the electrodes. Additionally, in order to reach typical treatment areas, the size of the catheter is inherently limited. Because of the limited initial size and the gradual ablation of the electrode during use, a typical electrode-based ultrasonic treatment delivery system may be limited to no more than a few dozen pulses of ultrasound before burning out and having to be replaced in its entirety. For patients this is expensive and inefficient, and may not provide sufficient ultrasonic treatment to accomplish the full desired treatment.SUMMARY

[0005] According to a first aspect, an ultrasound-emitting device includes a catheter extending from a proximal end to a distal end. The device includes several lumens therein. A balloon is arranged at the distal end, and an interior of the balloon is fluidically coupled to one of the lumens. The balloon can be inflated by a fluid routed through the associated lumen. An optical fiber is also arranged one of the lumens and extends from the proximal end to the distal end. The optical fiber is arranged to illuminate a photoacoustic material at the distal end.Attorney Docket No. 19506.0001WOU1

[0006] The device can also have a guidewire arranged through one of the lumens, and the guidewire can extend from the proximal end and past the distal end. The photoacoustic material can be a fluid. The balloon can be made of a polymer. The photoacoustic material can be the material that makes up the balloon, or a portion of the catheter, or both. The device can also include a tie layer disposed on a surface of the balloon, and a pharmaceutical coating coupled to the balloon by the tie layer. The tie layer can be made of a material that is susceptible to disruption by ultrasound.

[0007] The device can include a second balloon arranged between the balloon and the proximal end. An interior of the second balloon can be fluidically coupled to one of the lumens so the second balloon can be inflated by the fluid routed through that lumen. A second optical fiber can be arranged to illuminate a photoacoustic portion at the second balloon. The second optical fiber can be arranged in another of the lumens, and extend from the proximal end to the distal end. There can be apertures on an outer surface of the catheter between the balloon and the second balloon, the apertures in communication with a lumen.

[0008] The device can include an aspiration sleeve that circumscribes a portion of the catheter proximal to the balloon.

[0009] According to a second aspect, a method for generating ultrasound by an ultrasoundemitting device is disclosed. In the method, a fiber optic element is positioned in a lumen of a catheter such that the fiber optic element extends from a proximal end of the catheter to a distal end thereof. A balloon at a distal end of the catheter is inflated with a fluid. The fiber optic element is illuminated at the proximal end of with a series of light pulses, such that the series of light pulses travels through the fiber optic element and is delivered to the distal end. At least one of the balloon, the catheter, and / or the fluid includes a photoacoustic material. The photoacoustic material can generate ultrasonic emissions in response to the series of light pulses. The method can further involve applying the ultrasonic emissions to calcium deposits for calcium debulking, or applying the ultrasonic emissions to an atherosclerotic plaque or other blockage for treatment of arterial occlusion. The method can include disrupting a tie layer that couples a pharmaceutical coating to the balloon with the ultrasonic emissions. The method can include routing the distal end of the catheter to a target location along a guidewire prior to inflating the balloon. The fluid can produce photoacoustic pressure waves. The balloon can be polymer based. At least one fiber can extend from the proximal end to the distal end for use in imaging. The method can include inflating a second balloon located between the balloon and the proximal end, and illuminating a second fiber optic element at the proximal end of the catheter with the series of light pulses, such that the series of light pulses travels through theAttorney Docket No. 19506.0001WOU1 second fiber optic element and is delivered to the second balloon. The method can include aspirating a region arranged between the balloon and the second balloon and adjacent the catheter. The method can include aspirating a region proximal to the balloon with an aspiration sleeve that circumscribes a portion of the catheter. The method can cause denervation of an anatomical structure positioned in a region arranged adjacent the balloon.

[0010] According to a third aspect, an ultrasound-emitting device includes a catheter extending from a proximal end to a distal end, the catheter defining a multiple lumens. A balloon can be arranged at the distal end. An interior of the balloon can be fluidically coupled to a first one of the plurality of lumens. The device can include means for illuminating the interior of distal end by a light source arranged at the proximal end of the catheter.

[0011] The device can also include a guidewire arranged through a second one of the plurality of lumens, extending through the catheter from the proximal end and past the distal end thereof. The device can include a photoacoustic fluid arranged in the balloon and the first one of the plurality of lumens. The balloon can be made of a polymer. The balloon can be made of a photoacoustic material. The device can include a tie layer disposed on a surface of the balloon, and a coating coupled to the balloon by the tie layer, and the tie layer can be made of a material that is susceptible to disruption by the ultrasound. The device can include a second balloon between the balloon and the proximal end. An interior of the second balloon can be fluidically coupled to one of the lumens and the second balloon can be inflated by the fluid routed through its associated lumen. The means for illuminating the interior of the balloon can also illuminate the interior of the second balloon.

[0012] According to a third aspect, an ultrasound-emitting device can include a catheter extending from a proximal end to a distal end, the catheter defining multiple lumens therein. An optical fiber can be arranged in one of the lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material arranged at the distal end.

[0013] Optionally, the photoacoustic material can be a part of the catheter, or it can be a film or a coating arranged on the catheter or on the optical fiber. The system can include a guidewire arranged through one of the lumens and extending from the proximal end and past the distal end. The device can include a tie layer disposed on a surface of the catheter, and a pharmaceutical coating coupled to the catheter by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound.

[0014] According to a fourth embodiment, an ultrasound-emitting device includes a catheter extending from a proximal end to a distal end, the catheter defining multiple lumensAttorney Docket No. 19506.0001WOU1 therein. A balloon can be arranged at the distal end, and an interior of the balloon can be fluidically coupled to one of the lumens so that the balloon can be inflated by a fluid routed through the lumen. An optical fiber can be arranged in a second one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material at the distal end. An aspiration sleeve can be arranged around the catheter and closer to the proximal end than the balloon. The device can include a guidewire arranged through a third lumen of the catheter and extending from the proximal end and past the distal end. The fluid can be a photoacoustic fluid. The balloon can be made of a polymer. The balloon can be made of a photoacoustic material, and / or a portion of the catheter can be made of a photoacoustic material. The device can further include a tie layer disposed on a surface of the balloon and a pharmaceutical coating coupled to the balloon by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound.

[0015] According to a fifth aspect, a method for generating ultrasound by an ultrasoundemitting device is disclosed. The method includes positioning a fiber optic element in a lumen of a catheter such that the fiber optic element extends from a proximal end of the catheter to a distal end of the catheter. The method further includes illuminating the fiber optic element at the proximal end of the catheter with a series of light pulses, such that the series of light pulses travels through the fiber optic element and is delivered to the distal end.

[0016] Optionally, a portion of the catheter can be made of a photoacoustic material. The photoacoustic material can generate ultrasonic emissions in response to the series of light pulses. The method can further include applying the ultrasonic emissions to calcium deposits for calcium debulking, or applying the ultrasonic emissions to an atherosclerotic plaque or other blockage for treatment of arterial occlusion. The method can include disrupting a tie layer that couples a pharmaceutical coating to the catheter with the ultrasonic emissions. The method can include routing the distal end of the catheter to a target location along a guidewire. The fluid can be photoacoustic. The method can include inflating a balloon at the distal end of the catheter. The balloon can be polymer based. The balloon can be made of a material that is photoacoustic. At least one fiber can extend from the proximal end to the distal end for use in imaging. The method can further include inflating a second balloon located between the balloon and the proximal end, and illuminating a second fiber optic element at the proximal end of the catheter with the series of light pulses, such that the series of light pulses travels through the second fiber optic element and is delivered to the second balloon. The method can further include aspirating a region arranged between the balloon and the second balloon and adjacent the catheter. The method can further include aspirating a region proximal to the balloon withAttorney Docket No. 19506.0001WOU1 an aspiration sleeve that circumscribes a portion of the catheter. The method can further include denervating an anatomical structure positioned in a region arranged adjacent the balloon.

[0017] A variety of additional inventive aspects will be set forth in the description that follows. The inventive aspects can relate to individual features and to combinations of features. It is to be understood that both the forgoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the broad inventive concepts upon which the embodiments disclosed herein are based.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are incorporated in and constitute a part of the description, illustrate several aspects of the present disclosure. A brief description of the drawings is as follows:

[0019] FIG. l is a system for catheter-based ultrasonic therapy delivery.

[0020] FIGS. 2A and 2B are cross-sectional views of the catheter of FIG. 1 across line 2 — 2 thereof, according to two different embodiments.

[0021] FIG. 3 is a partial view of a catheter usable in the system of FIG. 1, depicting a distal end thereof.

[0022] FIG. 4A is a partial view of a catheter usable in the system of FIG. 1, depicting a distal end thereof, the catheter system having a multi-layer balloon.

[0023] FIGS. 4B and 4C are detailed cross-sectional views of the skin of the balloon of the catheter system of FIG. 4A.

[0024] FIG. 5A is a partial view of a catheter usable in the system of FIG. 1, depicting a distal end thereof, the catheter system having a drug coating.

[0025] FIGS. 5B and 5C are detailed cross-sectional views of the skin of the balloon of the catheter system of FIG. 5 A.

[0026] FIGS. 6A-6C are partial views of a catheter system usable in the system of FIG. 1, depicting a distal end thereof, the catheter system having multiple balloons at the distal end.

[0027] FIG. 7 is a partial view of a single-balloon catheter usable in the system of FIG. 1, as well as an aspiration subsystem coupled thereto.

[0028] FIG. 8 A is a partial view of a catheter usable in the system of FIG. 1, including a photoacoustic (also referred to as photoresponsive) shaft coating.

[0029] FIG. 8B is a cross-sectional view of the catheter of FIG. 8A, depicting one possible arrangement of fluid and optical pathways.Attorney Docket No. 19506.0001WOU1

[0030] FIG. 8C shows an alternative embodiment in which a catheter includes an acoustically emitting shaft without a balloon.

[0031] FIG. 9 is a flowchart of a method for providing sonic therapy using a catheter.

[0032] FIGS. 10A and 10B are partial views of a catheter system usable in the system of FIG. 1, depicting a distal end thereof, the catheter system having a balloon with a cutting element at the distal end.

[0033] FIG. 11 is a partial view of a catheter with a microneedle-coated balloon.

[0034] FIG. 12 is a partial view of a pair of catheters deployed in a vascular system, with a first upstream catheter delivering microbubbles and a second downstream catheter delivering ultrasound.

[0035] FIG. 13 is partial view of a catheter deployed in a vascular system and delivering microbubbles from an outer layer.

[0036] FIG. 14 is a partial view of a catheter deployed in a vascular system and delivering microbubbles from an interior lumen.

[0037] FIG. 15 is a partial view of a catheter with two balloons delivery microbubbles from an interior lumen.DETAILED DESCRIPTION

[0038] Reference will now be made in detail to exemplary aspects of the present disclosure that are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. Furthermore, when two similar embodiments are shown in different figures that have similar parts, those similar parts may be referred to using reference numbers iterated by a factor of 100. In such instances, the full description of those components may not be repeated, and it should be understood that they apply equally to the similar instances with similar reference numbers.

[0039] Throughout this application, therapies are described that rely upon delivery of sonic energy or ultrasonic pressure waves to the body. In many situations, the desired frequency of the treatment is ultrasonic (i.e., above about 20 kHz, and in some embodiments several MHz). As a matter of convenience, therefore, this application refers to delivery of ultrasonic treatments. However, it should be understood that in some situations delivery of therapies outside of this specific range may be desired. The systems and methods described herein are capable of providing therapies at any desired frequency, and can be configured to deliver either lower or higher frequency treatments as desired.Attorney Docket No. 19506.0001WOU1

[0040] Catheters and components thereof described herein can be used for thrombectomy, or for denervation, or for a variety of other uses. In general, the devices and methods described herein relate to the delivery of ultrasonic signal from a source located within the body. This ultrasound can be delivered alone, or it can be delivered in combination with chemical or mechanical treatments including drug delivery, aspiration, and the like.

[0041] One example of a use for the devices and methods described herein is in thrombectomy. Thrombectomy catheters are medical devices designed to remove blood clots from blood vessels, particularly in the context of treating conditions like stroke or deep vein thrombosis. Clot removal is necessary in many cases to restore blood flow and prevent further complications associated with clot obstruction. Thrombectomy procedures are often employed when anticoagulant medications alone prove insufficient in resolving the clot. The devices and techniques described herein could be used in several cases including chronic total occlusion. Similarly, calcium debulking or removal of other unwanted substances within the vasculature can be accomplished, or similarly differential acoustic absorption characteristics can be used to ablate clots or similar structures.

[0042] Various technologies are employed in thrombectomy catheters, including aspiration, mechanical thrombectomy, and ultrasound to break up or remove the clot or its component parts. Aspiration involves using suction to draw the clot into the catheter, while mechanical thrombectomy devices often use rotating or pulsating components to fragment and remove the clot. The choice of thrombectomy catheter depends on the specific characteristics of the clot and the patient's condition. Thrombectomy procedures are often performed by interventional radiologists or neurointerventionalists using imaging guidance, ensuring precise placement of the catheter and accurate removal of the clot.

[0043] Mechanical thrombectomy is often chosen for the removal of blood clots from arteries or veins with the help of a catheter that utilizes mechanical means such as a clot retriever or aspiration. A limiting factor with currently available thrombectomy catheter devices is the inability to treat wall-adherent and organized thrombus sufficiently. The flushing or sucking technique in aspiration thrombectomy does not effectively break the thrombus away from the wall of the vessel.

[0044] Disclosed herein is a thrombectomy catheter to remove, for example, wall adherent or otherwise organized clots more effectively by making novel use of ultrasonic waves generated by ultrasonic shockwave to dislodge the clots from the walls of the arteries or veins as well as to provide real time imaging, as described in more detail below with respect to FIG.Attorney Docket No. 19506.0001WOU1

[0045] Ultrasonic therapy delivered in this way can be used in a variety of contexts, beyond thrombectomy. In one example, renal denervation can be used as a treatment for uncontrolled hypertension. Similar approaches could be used to perform denervation to treat atrial fibrillation. A catheter can be used to deliver ultrasonic therapy to denervate overactive nerves in the renal arteries without damaging the renal arteries themselves. In another example, atherosclerosis can be treated by drug-eluting balloons. Ultrasound can be used to disrupt a drug coating or a tie layer holding the drug to the exterior of the balloon. In this way, loss of drug during transfer is reduced. Similarly, ultrasound can be used to monitor the extent of drug layer that has been disrupted or released from the device.

[0046] In another example, ultrasound can be used to assist in delivery of active agents through the blood-brain barrier (BBB). Currently, drugs, biologies, and other active agents which need to be delivered to the brain to effect treatment are designed with a molecular size small enough to cross through this barrier and are delivered systemically. However, many drugs cannot be effectively delivered in this way or modified for this delivery mode. Recently, external focused ultrasound (FUS) has been used with some success. FUS is still limited by the need for systemic delivery of an agent (e.g., microbubbles) and the size of molecules which can be passed through the BBB (< 150kDa). See, for example, “Ultrasound-mediated bloodbrain barrier opening: An effective drug delivery system for theranostics of brain diseases” by Jieqiong Wang, et.al. Advanced Drug Delivery Reviews, Volume 190, November 2022 (DOI: 10.1016 / j.addr.2022.114539).

[0047] As disclosed herein and discussed in further detail below, an endovascular catheter and / or a balloon catheter that can provide ultrasonic waves, such as embodiments of the photoacoustic balloon catheter disclosed herein, can be used to locally and temporarily open the BBB. In embodiments, the ultrasonic waves may be generated using various methods and energy sources, drug delivery may be incorporated via, e.g., the catheter or a coating on the catheter, and the balloon and / or catheter may incorporate various physical attributes to modify or improve the opening of the BBB. For example, a catheter configured for delivering a treatment across the BBB may incorporate features which effect the amount of time the BBB is open and / or the size or number of openings.

[0048] The blood-brain barrier (BBB) presents unique challenges for therapeutic delivery to brain tissue. The BBB is formed by tightly joined endothelial cells in brain blood vessels that act as a selective, protective barrier. While this barrier protects the brain from harmful substances, it also prevents many therapeutic drugs from reaching brain tissue where treatment is needed for conditions such as neurodegenerative diseases, brain tumors, and mental healthAttorney Docket No. 19506.0001WOU1 disorders. Current approaches using external focused ultrasound (FUS) require systemic delivery of microbubbles and are limited to molecules smaller than 150kDa. An endovascular approach that can locally and temporarily open the BBB would provide significant advantages over current systemic delivery methods.

[0049] Described herein is a novel application of local ultrasound delivery in conjunction with microbubble infusion and targeted drug administration for precise modulation of the blood-brain barrier. By combining these techniques, the disclosure aims to achieve localized and temporary opening of the epithelial cell lining, allowing for enhanced drug delivery while minimizing the potential infiltration of undesirable substances. In comparison to conventional methods that may leave the epithelial cell lining open for prolonged periods, up to four hours in some cases, this innovative approach promotes rapid closure of the barrier, ensuring efficient drug delivery with reduced risk of unwanted compounds breaching the barrier. Through the coordinated use of ultrasound, microbubbles, and carefully selected therapeutic agents, this disclosure offers a novel strategy for delivering drugs directly to specific sites within the body while preserving the integrity of the blood-brain barrier.

[0050] Ultrasound can be used for imaging as well, using arrangements of sensors called transducers that emit and / or receive acoustic pressure to map the region around the catheter. These acoustic waves can be echoes from acoustic pressure waves emitted by the transducer. The acoustic waves could also be generated through a photoacoustic effect, and the transducer can receive information for use in imaging or routing based on reflections from the photoacoustic emissions described above that are used for treatment. A source external to the body could also be used to generate ultrasound pressure waves that are detected by the transducer. Regardless, the transducer(s) can covert acoustic pressure waves into an electrical signal and the magnitude of the signal can be converted into image intensity. The time at which the acoustic pressure wave arrives at the transducer can be used to estimate the distance from the transducer at which the signal originated via the speed of sound in tissue in a time-of-flight analysis or the like. Ultrasound imaging with one or more transducers can monitor drug release, quantitate photoacoustic pressure waves, and make maps of anatomy (including diseases like calcification and thrombosis) in the vasculature. Importantly, the imaging can be done longitudinally to understand how disease changes as a function of time or therapy from the device. These transducers can be miniaturized and routed through the very small lumens of the catheter. The transducer can rotate across 360 degrees to map all sides of the vasculature. Similarly, the transducer may be stationary relative to the catheter, and the entire catheter mayAttorney Docket No. 19506.0001WOU1 rotate in the vasculature. These and other implementations are described in more detail below with respect to the drawings.

[0051] The deficiencies of existing catheter-based therapy delivery systems can be overcome by use of an electrode-free design. As described herein, an optically-driven system can be used to deliver ultrasonic therapy. Optically-driven ultrasound delivery enables the use of catheters having smaller diameter, because the relatively bulky electrode need not be positioned therein. Furthermore, ultrasound can be delivered for a much larger number of pulses, compared to electrodes that rely on cavitation or sparking that results in degradation or ablation of the electrode materials.

[0052] To accomplish these benefits, a balloon is provided that delivers the ultrasound, located at a distal end of a catheter using the photoacoustic effect. Either the balloon material itself or a fluid that fills the balloon has a nonzero coefficient of thermal expansion (CTE). A light guide, such as a fiber optic cable, provides light to the balloon. The fluid material should also be able to absorb the light to generate thermal energy and an accompanying photoacoustic emission. In some embodiments, rather than having the fluid itself absorb and expand or contract in response to heating, a balloon or catheter shaft can absorb the optical stimulation, be activated to produce a photoacoustic effect by the incoming light signal, and therefore generate the acoustic (e.g., ultrasound) signal.

[0053] The photoacoustic effect is a phenomenon in which light is absorbed by a material at specific locations therein. This absorption leads to localized heating, causing a rapid increase in temperature in these regions. This temperature increase is spatially confined to the site of the absorption however because the optical pulse width is shorter than the thermal propagation time and acoustic propagation time. As the temperature rises, the molecules undergo thermal expansion and create a localized pressure gradient within the material. This pressure gradient propagates outward from the region of light absorption to create a sound wave. The photoacoustic emission can have a different frequency, intensity, and wavelength response based on the material used, the duration of irradiation, and the solvent / other matrix materials.

[0054] The frequency of that emission is a property of the material and, in some circumstances, the light pulse duration. Typically, each pulse creates a damped oscillation of acoustic waves. See Gao et al, “Photoacoustic elastic oscillation and characterization,” Opt. Express 23, 20617-20628 (2015), though additional light pulses onto the material can be used to create additional bursts of acoustic energy.Attorney Docket No. 19506.0001WOU1

[0055] Light signal can be routed to the balloon from the opposite end of the catheter by routing the light guide through a lumen of the catheter. Each pulse of light can be used to generate a burst of photoacoustic emissions from the material that is illuminated.

[0056] Ultrasonic therapy delivered in this way can be used in a variety of contexts. In one example, renal denervation can be used as a treatment for uncontrolled hypertension. A catheter can be used to deliver ultrasonic therapy to denervate overactive nerves in the renal arteries without damaging the renal arteries themselves. In another example, atherosclerosis can be treated by drug-eluting balloons. Ultrasound can be used to disrupt a drug coating or a tie layer holding the drug to the exterior of the balloon. In this way, loss of drug during transfer efficacy is reduced. An ultrasonic drug-delivery catheter can be used to deliver drugs and other agents across the BBB with the necessity for systemic delivery of the agent. Ultrasound can be used for imaging as well, using arrangements of sensors that receive reflected ultrasonic waves to map the region around the catheter. These and other implementations are described in more detail below with respect to the drawings.

[0057] FIG. 1 shows a system for catheter-based ultrasound delivery. As shown in FIG. 1, an ultrasound-emitting system 100 includes a catheter 102 having a proximal end 104 and a distal end 106. A balloon 108 is arranged at the distal end 106, and a guidewire 110 optionally extends beyond the distal end 106 for routing the catheter 102 to a desired location. Illumination source 112 and fluid source 114 are arranged at the proximal end 104 of the catheter 102.

[0058] Ultrasound-emitting system 100 is one example of a system that can deliver ultrasonic therapy as described above and is shown in a simplified form in FIG. 1. More complex arrangements are shown and described in the subsequent figures. The version of ultrasound-emitting system 100 shown in FIG. 1 depicts just one simple combination of components that can be used to provide ultrasonic therapy.

[0059] Catheter 102 is a multi-lumen catheter that can be used to couple proximal end 104 to distal end 106. The lumens of catheter 102, which are shown in more detail with respect to FIG. 2, provide for delivery of light and fluid from illumination source 112 and fluid source 114, for example, as well as providing an aperture for guidewire 110. Other lumens can be used to provide access for an imaging transducer, as described in more detail with respect to FIG. 6B. Catheter 102 is also shown in a simplified form, and can include various other elements not depicted in FIG. 1, such as imaging sensors.

[0060] Proximal end 104 is a portion of catheter 102 that can be controlled, accessed, and manipulated throughout a procedure, as it remains outside of the patient. The term “proximal end,” as used throughout this application, refers to more than just the very end of the catheterAttorney Docket No. 19506.0001WOU1102. In some examples the proximal end 104 can extend for some length along catheter 102 from the far end thereof, to include any region of catheter 102 where access is provided to the lumens defined therein, or the region of the catheter 102 that is manipulated as it is directed into the patient.

[0061] Distal end 106, similarly, includes more than just the end face of catheter 102. Distal end 106 includes the region extending from the terminus of catheter 102 through the balloon 108 (or multiple balloons, as described with respect to FIGS. 6 and 8). Distal end 106 can also include various ports or aspiration features (as described with respect to FIGS. 7A-7C and 8).

[0062] Balloon 108 is an expandable element located at the distal end 106. Balloon 108 can receive power delivered through catheter 102 from illumination source 112. The interior of the balloon 108 can further be fluidically coupled to one of the lumens of catheter 102 so that the balloon 108 can be inflated or deflated by fluid source 114. FIG. 1 shows balloon 108 in an inflated form. That is, in the view shown in FIG. 1, balloon 108 is filled with fluid provided from fluid source 114. In a deflated form, balloon 108 sits substantially flush with the exterior of the remainder of catheter 102.

[0063] Illumination source 112 can include any of a variety of light sources, such as a laser, a diode, or a heat-based illumination source like a globar. In many embodiments, the light provided by illumination source 112 is modulated. In such embodiments, either the source itself can be turned on and off to modulate the light signal, or a modulator can be used in combination with a light source to provide the desired timing of the light. For example, a chopper or other obstruction can be used to modulate light produced by a constant illumination source 112 prior to its introduction to the optical fibers described herein and ultimate delivery to the distal end of the catheter 102 or balloon 108.

[0064] Digital acquisition system (DAQ) 113 can control the time of acoustic pulsing in the transducer. This system can also contain a motor drive unit and a console to display images. It can cause the transducer to emit pressure waves at desired intervals. It can also record acoustic pressure waves in the transducers and convert the pressure intensity into electrical signals for conversion to an image.

[0065] FIG. 2A is a cross-sectional view of the catheter 102 of FIG. 1 across line 2 — 2 thereof as depicted in FIG. 1. Catheter 102 is a multi-lumen catheter including, in the depicted example, first lumen 216, second lumen 218, and third lumen 220. In embodiments, each of first lumen 216, second lumen 218, and third lumen 220 can provide passage for an associated apparatus (e.g., guidewires, fibers, transducers, or the like) or fluids used with the catheter. InAttorney Docket No. 19506.0001WOU1 examples, first lumen 216 is used to provide a fluid through the catheter 102, such as for inflating balloon 108, and second lumen 218 provides passage for fiber optics to deliver illumination from a source, such as from illumination source 112, to the distal end of the catheter 102. In embodiments, third lumen 220 provides for drug delivery of one or more drugs. In other embodiments, third lumen 220 provides access for an intravascular ultrasound transducer. Although the example catheter 102 is shown with three lumens, 216, 218, and 220, it is to be understood that other numbers of lumens are contemplated and may be implemented depending on the application and other considerations of various implementations. In embodiments, catheter 102 may have one, two, four, five, six, etc. lumens to provide for delivery of various components and compounds.

[0066] The lumens (216, 218, 220, 222) shown in FIG. 2 A have identical sizes, but it should be understood that in alternative embodiments they may have different sizes commensurate to different uses. For example, it will often be the case that a larger or central lumen can be used for a guidewire. Some systems housed in the lumens may have a second guidewire.

[0067] FIG. 2B shows a front view of an alternative embodiment with a central guidewire lumen. As shown with the cross-hatching in the view of FIG. 2B, the lumens are separated by walls and form radially inner and outer passageways for fluid, light guides such as fiber optics, or electrical wiring to pass. It should be understood that the walls (hatched portions) and the lumens (216, 218, 220, 222) are not necessarily to scale. That is, the radial extent of each of the lumens 216, 218, 220, 222 as well as the wall (hatched) portions between them can vary as needed to route solid structures (e.g., transducers, optical fibers, guidewire) or liquids (e.g., inflation fluid) therein.

[0068] FIG. 3 is a partial view of a catheter 302 usable in the system of FIG. 1, depicting a distal end 306 thereof. Balloon 308 is arranged at the distal end 306 of the catheter 302, with some additional length of catheter 302 extending past balloon 308 where, in examples, a guidewire may emerge and provide steering of catheter 302. Figure 3 shows transducer 325. Transducer 325 can be moved more proximal or distal within the balloon to change the area being imaged including via a guidewire. The transducer 325 itself may contain driving shafts, distal markers, guide wires, mechanical rotation, or phased arrays, though these are not shown in detail in FIG. 3.

[0069] Balloon 308 can either contain a fluid that is photoresponsive or photoacoustic, or alternatively a mechanical structure such as the shaft of catheter 302 or the balloon 308 itself may exhibit the photoacoustic effect. In some embodiments, electrochromic polymers can beAttorney Docket No. 19506.0001WOU1 used to make the balloon. In such embodiments, the absorption properties of the balloon material or a portion thereof can be modified by applying a current or electrical potential to the balloon. This modification changes the absorption spectrum of the balloon, which could in turn change its photoacoustic properties.

[0070] Although only one transducer is shown in FIG. 3, multiple transducers may also be used in alternative embodiments. The transducer 325 shown in FIG. 3 is shown extending from a lumen inside the catheter, but it should be understood that it may be in any of the lumens in the catheter and may also emerge from an aperture such as 324. In some embodiments, such as transducer 825 in the lumen 816 in Figure 8B, described below, it may be located inside of the fluid that is used to inflate the balloon. In other instances, it may be in the interior such as lumen 620 in Figure 6B. Multimodal transducers might also be used that offer near-infrared spectroscopy or optical coherence tomography sensing. The details of these have been published extensively, e.g., Peng et al., Recent Advances in Transducers for Intravascular Ultrasound (IVUS) Imaging, Sensors EISSN 1424-8220 (19 May 2021) and Wang et al., Capacitive Micromachined Ultrasound Transducers for Intravascular Ultrasound Imaging, Microsystems & Nanoengineering (2020)6:73, and Yock & Fitzgerald, Intravascular Ultrasound: State of the Art and Future Directions, 81 The American Journal of Cardiology 7, supplement 1 (9 April 1998).

[0071] Fluid is delivered to balloon 308 through apertures 324 to inflate balloon 308. One or more of the apertures 324 may be in communication with, for example, first lumen 216 of FIG. 2 A. A fluid used to inflate balloon 308 may be selected based on photoacoustic characteristics, optical absorption characteristics, or other considerations depending on a specific implementation. In one example, the fluid used to inflate balloon 308 can be saline. In other examples, the fluid used to inflate the balloon 308 can be chosen based on its photoacoustic response characteristics, which can include frequency and intensity of acoustic emissions in response to received light at a particular wavelength or wavelengths. Ultrasound emitted using this photoacoustic response may be enhanced by use of a fluid with specific absorption properties, thermal properties, or cavitation properties, sometimes called a coupling medium. When the transducer used to emit and / or receive ultrasound waves is placed inside of the balloon, the fluid used to fill the balloons serves as a coupling medium.

[0072] The photoacoustic emissions produced by such a system reflect, refract, and transmit through the body in ways that make imaging or therapy of the body around the catheter possible. This property is useful in applications where controlled ultrasonic treatment, heating, and / or imaging are desired, as they can be used for positioning and targeting relative to a featureAttorney Docket No. 19506.0001WOU1 of interest for treatment. For example, targeted local ultrasound from a catheter positioned within a vessel of the brain can disrupt the BBB for effective delivery of therapeutic agents without the limitations of external FUS.

[0073] Some deficiencies of other catheter-based designs can be overcome through imaging the photoacoustic effect. When using many photoacoustic materials, the magnitude of the photoacoustic effect can be controlled by the intensity of the optical pulse. The pulse will move in different directions based on the position of the catheter, the position of the illumination sources, and the local anatomy. A transducer positioned at the distal end will be able to map and measure the photoacoustic pressure waves as they reflect, refract, and transmit through the body. In that way, the photoacoustic intensity can be increased or decreased based on the real-time feedback provided by the transducer. The directionality of the photoacoustic intensity can be changed based on the information / images determined by the transducer. This can be done quickly including video frame rates.

[0074] In various embodiments, the device includes a transducer (e.g., 325, 625, 825 as shown in the accompanying drawings) to record ultrasound pressure waves. This transducer may be a single element transducer or a miniaturized phase array or linear array, for example. The transducer may be positioned at or near the balloon or may be in the interior of the balloon when accessed through one of the channel s / lum ens in the catheter. The transducer can be acoustic coupled to the surrounding environment via the fluid used to fill the balloon or the liquid (e.g., blood) present in the vasculature. In embodiments, the transducer can be moved proximally or distally to record acoustic signals in different areas of the vasculature, either with the remainder of the catheter or separately from the catheter, such as back and forth within a lumen of the catheter.

[0075] The transducer itself may include a second guidewire to adjust position and angling, and this would be known to persons skilled in the state of the art as intravascular ultrasound (IVUS). The transducer can be used to emit and / or receive pressure waves. In one design, the transducer will both emit and receive pressure waves. These waves emitted from the transducer interact with surrounding tissue and some would return to the transducer. These waves could be used to make images that monitor changes to the surrounding physical environment, such as tissues.

[0076] In another design, the transducer would record only. The transducer could record acoustic pressure waves created by the balloon material or the photoacoustically-active fluid. The acoustic waves produced through a photoacoustic effect might also interact with the surrounding anatomy before being record. The transducer could in turn monitor the magnitudeAttorney Docket No. 19506.0001WOU1 and location of the photoacoustic pressure waves. The transducer could also monitor release of drug from the catheter due to changes in acoustic properties of the drug-carrying layer or through the presence of a photoacoustically-active element within the drug.

[0077] Some examples of suitable fluids that can be routed into balloon 308 include perfluorocarbons (PFCs) and liquid metals, like gallium-based alloys, which can be used in certain applications where thermal expansion is a key factor. Absorption of optical signal for thermal expansion can be accomplished through the use of ICG dye, methylene blue, or other similar materials. Additional examples are provided in Han et al., “Contrast Agents for Photoacoustic Imaging: A Review Focusing on the Wavelength Range,” Biosensors 2022, 12, 594 (DOI: 10.3390 / biosl2080594) (see Table 2) and Zackrisson et al., “Light In and Sound Out: Emerging Translational Strategies for Photoacoustic Imaging,” Cancer Research 74(4) (February 15, 2014). Suitable fluids for filling the balloon 308 can include liquids or gases, and can have a combination of optical absorption and thermal expansion that facilitate the use of light to create acoustic signal therefrom.

[0078] A mixture of fluids could be used where two components or more components are used each with a different absorption spectra. Different optical pulses at different wavelengths could be used to modulate / control the resulting photoacoustic signal. In embodiments, a pulse / echo from the transducer is used to map the anatomy at the site of therapy and obtain more details about the disease site. A therapy is then tailored based on the details about the disease site. This tailoring could include the frequency and amplitude of the photoacoustic effect, the duration of treatment, and the directionality of treatment. The optical pulses could then be selected to guide this treatment (wavelength, pulse width, pulse repetition rate). Using the wavelength of the strong absorber in the mixture would produce high photoacoustic effects. Using the wavelength of the weaker absorber in the mixture would produce weaker photoacoustic effects.

[0079] Optical fibers 322 are admitted to the interior of balloon 308, such as through apertures 324. Apertures 324 may be connected to one or more of lumens, 216, 218, and 200 of FIG. 2 and provide access to the interior of balloon 308 for various media and devices, such as fluid for inflation or optical fibers 322. For example, optical fibers 322 may be delivered to the interior of balloon 308 via an aperture 324 connected to a lumen, such as second lumen 218 of FIG. 2. The lumen provides passage for the light guide or optical fiber used to direct optical fibers 322 and light signal.

[0080] One or more optical fibers 322 are deployed into the interior of balloon 308 and deliver optical pulses. While balloon 308 is expanded with a fluid, such as saline or fluidsAttorney Docket No. 19506.0001WOU1 containing contrast media, the optical signal that causes photoacoustic pulses to be generated will be delivered to the fluid inside the balloons. As described above, the optical signal delivered at optical fibers 322 can result in photoacoustic response and acoustic emissions within the balloon 308 that can be used for treatments and imaging via the transducer 325.

[0081] Typically, an optical fiber 322 will be used that exhibits total internal reflection (TIR) such that light is only or substantially only emitted from the tip thereof. Using an optical fiber 322 that exhibits TIR reduces losses in power along the length of the optical fiber 322.

[0082] Although only one optical fiber 322 is shown in FIG. 3, it should be understood that there may be multiple such optical fibers 322 arranged throughout the balloon 308 extending from different ones of the apertures 324. The optical energy is converted into acoustic signal as the optical fiber(s) 322 are illuminated, either simultaneously or sequentially. The ultrasonic waves created in this way may be used to dislodge wall-adherent and organized thrombus, for example, or provide denervation at a nearby anatomical structure.

[0083] In embodiments, optical fibers 322 are arranged or activated to achieve particular ultrasound directionality. For example, optical fibers 322 may be forwardly- or circumferentially-arranged to activate or direct ultrasound toward a forward (or distal) direction relative to an origin or entry point of the catheter 302.

[0084] In embodiments, the optical fibers 322, the fluid filling the balloon 308, and the catheter 302 can be chosen to be compatible.

[0085] The diameter and optical index of a fiber affect which wavelengths are transmitted according to the so-called cutoff wavelength corresponding to the diameter of that fiber. This criterion, along with the sizes of lumens available for the fiber to pass through, determine the cutoff wavelength of a fiber. Core diameters of commonly-used fibers in embodiments can range from about 10 microns to about 1000 microns in some embodiments. A common diameter for a fiber used herein could be about 200 microns. The diameter may vary depending upon whether the light transmitted therein is infrared, near-infrared, visible, or ultraviolet. The fluid responds to incident light as a function of wavelength of that light.

[0086] Many materials are highly absorptive of infrared radiation. Thus, the fluid and the optical fiber may be selected to function well in the infrared regime. However, the catheter can provide a further consideration when choosing the fluid and operating wavelength. As described above, an advantage of the systems described herein is that they are smaller than electrode-based systems and thus able to access more portions of the vasculature. Thus, the fluid, the light source, and the catheter may be chosen such that the core diameter is smaller,Attorney Docket No. 19506.0001WOU1 such as by using a fluid and light source that operate at a lower wavelength so that the fiber will fit through the apertures in the catheter.

[0087] Thus, the fluid(s), balloon material, fiber diameter, and optical source are chosen so that the optical signal is at a wavelength that passes through the fiber, which is in turn small enough to fit through a corresponding lumen of the catheter, and be delivered to a fluid that is both absorptive at that wavelength as well as exhibiting photoacoustic response at that wavelength to transform the optical signal into acoustic signal at the balloon. As described above, in some embodiments there may be multiple photoacoustic materials, which could either take the form of multiple fluids or, alternatively, a photoacoustic fluid and a photoacoustic balloon skin itself. The multiple photoacoustic materials can be tuned for different photoacoustic emission profiles so that desired types of pulses can be generated with different light emissions delivered thereto.

[0088] In embodiments specifically configured for BBB applications, the system can incorporate microbubble delivery mechanisms. Microbubbles can be delivered either systemically or locally through the catheter system. When delivered locally, microbubbles can be injected through dedicated apertures in the catheter or through a separate lumen configured for microbubble delivery. The ultrasonic energy generated by the photoacoustic effect causes cavitation of these microbubbles, which creates localized disruption of the BBB endothelial cell junctions.

[0089] The microbubbles work synergistically with the ultrasonic balloon system. Microbubbles can be used under the focused ultrasound and can be delivered locally with energy of probe or balloon to help expedite opening of that barrier. The combination of locally delivered microbubbles and endovascular ultrasonic energy provides more precise control over BBB opening compared to external FUS systems that require systemic microbubble delivery.

[0090] For BBB applications, drug delivery can be accomplished through multiple mechanisms. In one embodiment, therapeutic agents are coated on the exterior surface of the balloon, similar to the drug-coated balloon arrangements described above. The ultrasonic energy not only opens the BBB but also disrupts tie layers holding the therapeutic coating to the balloon surface, providing synchronized drug release with BBB opening.

[0091] In another embodiment, therapeutic agents are delivered through apertures in the catheter shaft concurrent with BBB opening. This approach allows for delivery of larger molecules or biologies that cannot be effectively coated on balloon surfaces. The timing of drug delivery can be precisely controlled relative to the BBB opening, maximizing therapeuticAttorney Docket No. 19506.0001WOU1 uptake while minimizing systemic exposure. Example embodiments for microbubble delivery are shown in FIGS. 12-15 and discussed in further detail below.

[0092] Referring now to FIGS. 4 A, 4B, and 4C, the fluid need not always provide the acoustic signal. Rather, as shown in these drawings, the material that makes up the balloon 408 itself may produce the acoustic signal.

[0093] The embodiment shown in FIG. 4A looks very similar to the one of FIG. 3, and like parts are shown with like reference numbers, iterated by a factor of 100. In contrast to FIG. 3, however, FIGS. 4A, 4B, and 4C show a multi-layer balloon 408. That is, the skin of the balloon that is inflated via the apertures 424 is made up of multiple layers such that the balloon 408 produces an effect in response to optical stimulation.

[0094] FIGS. 4B and 4C show alternative versions of materials that can be used to form the balloon 408, in detail views. Typically just one type of material would be used in a balloon 408, but either of these, or a combination thereof, or other types of photoresponsive materials, could be used in various embodiments. Some examples are described, for example, in Chen et al., “Multilayered carbon nanotube yam based optoacoustic transducer with high energy conversion efficiency for ultrasound application,” Nano Energy, Volume 46, 2018, Pages 314- 321 (DOI: 10.1016 / j.nanoen.2018.02.006).

[0095] In the example shown in the detailed view of FIG. 4B, nanomaterials 432 are arranged at the interface between a first material 428 and a second material 430. As described in Chen, this arrangement can result in a freestanding optoacoustic transducer using continuous multilayered carbon nanotube yarns, gold nanoparticles and elastomeric polymer to create laser-generated ultrasound signal. In this embodiment, the fluid filling the balloon 408 need not have any particular coefficient of thermal expansion, nor would it require any particular absorptivity. Rather, the fluid need only transmit light from the fiber 422 to the balloon 408, which itself generates the acoustic signal.

[0096] Additional types of materials are contemplated, such as those described in Wu et al., “Polydimethylsiloxane / multi-walled carbon nanotube nanocomposite film prepared by ultrasonic-assisted forced impregnation with a superior photoacoustic conversion efficiency of 9.98 x 10'4,” 14 Journal of Nanophysics (October 24, 2020) and Link et al., “Laser-Induced Shape Changes of Colloidal Gold Nanorods Using Femtosecond and Nanosecond Laser Pulses,” J. Phys. Chem. B 6152-6163 (2000) (DOI: 10.102 l / jp000679t).

[0097] FIG. 4C shows an alternative structure for creating an optoacoustic transducer, in which alternating layers of positively and negatively charged material are interdigitated with one another, i.e., layer-by-layer assembly. In embodiments, these layers could beAttorney Docket No. 19506.0001WOU1 poly(allylamine hydrochloride (PAH) and polystyrene sulfonate (PSS). These polymer layers could immobilize optical absorbers (small molecules, nanoparticles) to produce the photoacoustic effect. The charged polymer layers themselves may produce photoacoustic effect: In embodiments, the electrochromic polymers poly(hexyl viologen) (PXV) and poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:SPS) could be used. These materials have tunable optical properties, including photoacoustic properties in many embodiments that are usable in the systems and methods described herein.

[0098] FIGS. 5 A, 5B, and 5C are similar to FIGS. 4A, 4B, and 4C, respectively. Like parts are again shown with like reference numbers, iterated by a factor of 100. In contrast to FIGS. 4A, 4B, and 4C, however, FIGS. 5A, 5B, and 5C show a multi-layer balloon with a coating 538.

[0099] FIG. 5A shows a balloon 508 inflated along a catheter 502, at a distal end 508 thereof. As described with respect to the similar embodiments above, a guidewire 526 extends from the furthest distal portion of the distal end 506, and a series of apertures 524 are arranged along the catheter 502 inside of the balloon 508. Some of the apertures 524 are usable to route fluid through the catheter 502 to the interior of the balloon 508 and cause inflation or deflation thereof. Others of the apertures 524 are used to provide access to the interior of the balloon 508 for optical fibers 522 that can create localized and timed photoacoustic emissions in any desired pattern, such as by driving the optical fibers 522 at a corresponding intensity level and frequency from the proximal end of the catheter 502.

[0100] Depending upon the mode of operation, an ultrasonic signal created either between the optical fibers 522 shining upon the fluid within the balloon 508, or by shining upon the skin of the balloon as described in FIGS. 4A, 4B, and 4C, is transferred outward from the balloon 508 to surrounding structures. In each of the modes of operation described herein the outer layer or skin of the balloon 508 vibrates to deliver such acoustic signal to the surrounding vasculature or other structures.

[0101] Taking advantage of this vibration, it may be beneficial to provide a layer of a coating 538 along the balloon 508 as shown in FIGS. 5 A, 5B, and 5C. The coating 538 can be, for example, a medication, a coagulant or embolic material, or an anticoagulant, or a dye or tagging material. Specific example materials that could be used as a coating 538 on the balloon 508 are aclitaxel, sirolimus, heparin, or other anti-inflammatory agents, for example. These coating 538 can be retained by the balloon, even during inflation or deflation, using a tie layer as described below that is only disrupted by appropriate levels or frequencies of acoustic signal.Attorney Docket No. 19506.0001WOU1

[0102] In embodiments, the coating 538 may have photoacoustic signal that can be detectable by the transducer. The change in photoacoustic signal intensity coming from the balloon exterior 508 / 538 can thus report the amount of coating 538 that has been released from the balloon into the surrounding environment. In other embodiments, coating 538 does not produce photoacoustic signal but does have a defined thickness on the ballon exterior as shown in Figure 5B and Figure 5C. This thickness of this layer could be measured with pulse / echo imaging from the transducer. The reduction in the layer thickness could then be correlated to release of coating 538 into the surrounding environment.

[0103] Depending upon the materials involved, the coating may be applied to the balloon 538 directly. In other examples, the coating 538 and the balloon 508 are either not compatible and will not stick to one another, or they may stick to one another too well to be disrupted by ultrasonic signal. Therefore, it may be preferably to use a tie layer that couples the coating 538 to the balloon 508. The tie layer can either be a separate layer from the coating 538 or it can be comixed with the coating 538 to provide an acceptable level of bond to the balloon.

[0104] The tie layer material, when used, can be selected from materials that will not be disrupted by the expansion of the balloon alone, but will be disrupted by the application of ultrasonic signal. The selection of an appropriate tie material is dependent upon both the balloon 508, the coating 538, and the expected levels of expansion of the balloon 508 and exposure to acoustic signal. The efficiency of these ties can be influenced by a variety of factors that are not described in detail herein, but are discussed, for example, in Cao et al., “The factors influencing the efficiency of drug-coated balloons,” Frontiers in Cardiovascular Medicine, 12 October 2022 (DOI: 10.3389 / fcvm / 2022.94776); Huan et al., “Acoustically active liposomes for drug encapsulation and ultrasound-triggered release,” 1665 Biochimica et Biophy sica Acta (BBA) - Biomembranes 1-2, pp. 134-141 (11 October 2004); Damien V. B. Batchelor et al., “Nested Nanobubbles for Ultrasound-Triggered Drug Release,” ACS Applied Materials & Interfaces 2020 12 (26), 29085-29093 (DOI: 10.1021 / acsami.0c07022); Klibanov et al., “Ultrasound-triggered release of materials entrapped in microbubble-liposome constructs: a tool for targeted drug delivery,” J Control Release. 2010 November 20; 148(1): 13-17. doi: 10.1016 / j.jconrel.2010.07.115; Delaney et al., “Making waves: how ultrasound-targeted drug delivery is changing pharmaceutical approaches,” Mater. Adv., 2022, 3, 3023 (DOI: 10.1039 / dlma01197a); Wilson et al., “Effective ultrasound-triggered drug release from stable nanocarriers,” bioRxiv 2021.12.14.471689 (DOI: https: / / doi.org / 10.1101 / 2021.12.14.471689); and Sirsi et al., “State-of-the-art materials for ultrasound-triggered drug delivery,” Advanced Drug Delivery Reviews, Vol. 72 pp. 3-14 (2014) (DOI: 10.1016 / j.addr.2013.12.010).Attorney Docket No. 19506.0001WOU1

[0105] FIG. 6A is a partial view of a catheter system 602 usable in the system of FIG. 1, depicting a distal end thereof, the catheter system having multiple balloons at the distal end. The first balloon 608 and the second balloon 609 are separated, in embodiments, by a length 640 of the catheter. In some implementations, a target region, such as a thrombus, is aligned with the length 640 of the catheter such that the target region is isolated when the first and second balloons 608, 609 are inflated. This alignment aides in isolation and directed treatment of the thrombus or other target. Transducer 625 can be positioned inside the proximal or distal balloons or may be located in between the two balloons, and is shown in phantom in FIG. 6A. The transducer can be used to create images that guide balloon deployment and expansion as described in Mudra et al., Ultrasound Guidance of Palmaz-Schatz Intracoronary Stenting With a Combined Intravascular Ultrasound Balloon Catheter, 90 Circulation 3 (September 1994).

[0106] The balloon catheter 602 described herein incorporates fiber optics 622 that deliver light to the balloons 608, 609 via a lumen as described in FIG. 2. The heating or vibration patterns of the fluid or balloon 608, 609 can be modulated to produce a corresponding frequency of acoustic signal from the balloons 608, 609. In embodiments, catheter 602 will have one more fiber optics 622 that travel through separate lumens to deliver illumination pulses to the interior of balloon 608, 609. Balloons 608, 609 are expanded, such as by saline or fluids containing contrast media, and light pulses will be delivered to the fluid inside the balloons 608, 609.

[0107] The optical energy is converted into heat, with thermoelastic expansion within the fluid or the balloon skin itself resulting in the generation of ultrasound waves and / or shockwaves by causing vibrations of balloons 608, 609 as described with respect to the other embodiments above. The ultrasound waves and / or shockwaves are directed to the isolated target area, e.g., consisting of thrombus. In embodiments, a pulse / echo from the transducer is used to map the anatomy at the site of therapy and obtain more details about the disease site. A therapy can then be tailored based on the details about the disease site. This tailoring could include the frequency and amplitude of the photoacoustic effect, the duration of treatment, and the directionality of treatment. The optical pulses could then be selected to guide this treatment by tuning the wavelength, pulse width, pulse repetition rate, or other attributes of the optically delivered signal. Using the wavelength of the strong absorber in a mixture within the balloon(s) would produce photoacoustic effects. For example, one wavelength may be associated with absorption by a weaker absorber in the mixture to produce weaker photoacoustic effects than a second, stronger absorber in the same mixture in the same balloon. In FIG. 6A, where multipleAttorney Docket No. 19506.0001WOU1 balloons are used, a different fluid or fluid mixture could be routed to each balloon through an associated catheter.

[0108] Though the example of FIG. 6A demonstrates the multi -balloon catheter 602 with two balloons 608, 609, those of skill in the art will understand that the multi-balloon catheter 602 may be configured with any number of balloons. For example, catheter 602 may be configured with three, four, six, eight etc. balloons to simultaneously, sequentially, or selectively target one or more areas along the length of the catheter 602. The balloons can have different sizes, shapes, and inflation fluids from one another, as needed to accomplish a desired outcome. For example, two or three or more balloons may be inflated and ultrasonically activated to target a particular area. In some implementations, a different two of the three or more balloons may be inflated and ultrasonically activated to target another area. In examples, multiple balloons may be inflated and ultrasonically activated to affect a large clot formation. The transducer described above can be used in pulse / echo mode here to image the formation or deformation of a clot, dispersion of medication, or perform other mapping or monitoring functions.

[0109] In some embodiments, a multi-balloon arrangement can be used to stop blood loss. For example, the most distal balloon used to fill the vasculature, while a second balloon is used to induce a clot through acoustic or thermal emissions. This can be used as an alternative to cauterization in some procedures.

[0110] The fiber optics 622 in each balloon can be activated or illuminated independently or together with one another in concert. When powered together, the acoustic emissions from each of the balloons 608 and 609 are synchronized, and advantageously it may only be necessary to route light through one or two lumens (see FIG. 2) within the catheter 602. As such, that catheter 602 may have a relatively small cross-sectional area and can be routed to areas of the vasculature where a larger catheter would not be able to reach.[OHl] In other examples, however, the fiber optics 622 may be separately illuminated or separately controlled. The fiber optics 622 can then be used to create acoustic signals from their respective balloons 608, 609 that will constructively or destructively interfere with one another. Additionally or alternatively, one of the balloons 608, 609 can be passive (that is, the fiber optics 622 therein are unpowered) while the other is activated to create acoustic signal. In this way, one balloon (e.g., 609) can be used for anchoring the catheter 602 in place while the other balloon (e.g., 608) provides ultrasonic signal to deliver the desired treatment. When illumination is provided separately, it may be necessary to route distinct fiber optics throughAttorney Docket No. 19506.0001WOU1 separate lumens of the catheter 602, unless the fiber optics have a small enough cross-section to cohabit a single lumen.

[0112] In use, the embodiment shown in FIG. 6A can be delivered around a target to be ablated. That is, the target to be ablated may be in the region labeled length 640 in FIG. 6A, arranged between the first balloon 608 and the second balloon 609. Acoustic pulses such as ultrasound can be delivered from one or both sides using the two balloons 608 and 609. A clot or other structure to be treated can be broken up and, due to the positions of the balloons 608 and 609, the constituent parts that are dislodged are not able to travel away but are instead trapped therebetween. Subsequently, balloon 608 can be deflated and aspiration can be used to remove those parts (see, e.g., FIG. 7). The transducer can be used in pulse / echo mode here to monitor the destruction of the thrombus. The images can be used to confirm that constituent parts that are dislodged around aspirated and not allowed to circulate in the vasculature.

[0113] FIG. 6B shows a cutaway perspective view, similar to that of FIG. 2B, in which a transducer 625 is shown. The transducer 625 is depicted emanating a region 650 of ultrasonic signal. The region 650 can be shaped and targeted based upon the geometry of the transducer 625 and how it is operated. The region 650 is not a physical substance but rather a series of acoustic waves at a desired frequency to produce a desired treatment, to create imaging signal, or both.

[0114] Like FIG. 2A, FIG. 6A includes four lumens, 616, 618, 620, and 622. Transducer 625 is in the first of these, lumen 616. It should be understood that, like in the other embodiments described herein, there could be more or fewer lumens than are shown in FIG. 6A. Lumens can be put to common purposes, such as by routing fluid through a lumen that also routes the transducer 625 or other physical components like fibers (not shown in FIG. 6B). In embodiments, there may be a separate guidewire that is used to route the transducer 625, in addition to a guidewire that is used to route the catheter 602 more generally.

[0115] Transducer 625 is arranged on an outer lumen, so that it is capable of producing acoustic signal that will pass through the catheter 602 to an adjacent structure. It may be desirable in some embodiments to route transducers relatively close to the outer edge of the catheters they are positioned in, so that they can easily be exposed at a surface thereof, or (as shown in FIG. 6B) so that they can provide acoustic signal through the wall thereof without significant acoustic impedance.

[0116] FIG. 6C is a partial view of a catheter system 602 usable in the system of FIG. 1, depicting a distal end 606 thereof, the catheter system having multiple balloons 608, 609 at the distal end and drug eluting apertures 642 in the length 640 between the two balloon 608, 609.Attorney Docket No. 19506.0001WOU1

[0117] The catheter shaft in between the balloons (i.e., the portion of catheter 602 along length 640) may include holes for infusing a drug out into the region adjacent the catheter 602, as indicated by the perforated exterior in that region in FIG. 6C. The catheter 602 can include one or more additional lumens to deliver medications infused to the thrombus in the area isolated by the balloons 608 and 609 along the catheter shaft. Upon infusing the medication and activating the ultrasound or shockwave, the drugs can be effectively directed into the thrombus to destroy the thrombus. This targeted treatment is particularly useful when the clot is located in a specific vessel or organ. Examples of drugs employed in this procedure include tissue plasminogen activator (tPA), such as alteplase, which is a thrombolytic agent that breaks down fibrin clots, and anticoagulants like heparin, which prevents further clot formation.

[0118] In addition to drug therapy, catheter-based procedures may involve the delivery of thrombin inhibitors and fibrinolytic agents like bivalirudin and urokinase, respectively. These drugs are delivered directly to the thrombus through the catheter, enabling a higher concentration at the clot site and reducing systemic effects. Moreover, as disclosed herein catheter-directed thrombolysis may incorporate the application of ultrasound to drive the drugs into the thrombus and effect breakup of the thrombus from the ultrasonic effects. This approach offers the advantage of localized treatment, minimizing the risk of bleeding complications associated with systemic drug administration.

[0119] In embodiments, the catheter devices disclosed herein are used for the delivery of microbubbles, such as in the context of penetrating the BBB to effect a treatment on the brain. While the examples of FIGS. 6 A and 6C depict two balloons adjacent to one another along the shaft of the catheter, other arrangements of multiple balloons are envisioned. For example, two or more balloons is arranged with an inner balloon within an outer balloon. The outer balloon may be inflated to oppose the walls of a vessel where the catheter is positioned, while the inner balloon is configured to provide ultrasonic waves and / or drug delivery as disclosed herein.

[0120] In a specific embodiment for BBB applications, a dual balloon configuration is employed where an outer balloon includes multiple apertures or holes for drug delivery, while an inner balloon provides the ultrasonic cavitation energy. The outer balloon serves as an apposition element to ensure good contact with the vessel wall, while the inner balloon contains the photoacoustic fluid and optical fibers for generating ultrasonic waves. Drug or therapeutic agents can be delivered through the space between the outer and inner balloons, with the apertures in the outer balloon allowing controlled release of the therapeutic agents concurrent with BBB opening. This dual balloon arrangement provides several advantages for BBB applications: (1) stable positioning against the vessel wall through the outer balloon, (2)Attorney Docket No. 19506.0001WOU1 controlled drug delivery through the inter-balloon space and outer balloon apertures, and (3) focused ultrasonic energy delivery through the inner balloon system. The ultrasonic energy opens the BBB while simultaneously driving the therapeutic agents through the temporarily opened barrier.

[0121] FIG. 7 is a partial view of a single-balloon catheter usable in the system of FIG. 3, as well as an aspiration subsystem 750 coupled thereto. In this example, the balloon catheter 702 (and in particular the balloon 708) will also act as a distal protection during clot dislodgement and can improve aspiration efficiency. Once the clot is dislodged, the aspiration catheter 750 can aspirate the clots effectively, or the device as a whole can be retracted to remove the dislodged material.

[0122] The aspiration catheter provides for the targeted removal of substances such as blood clots, pus, or other unwanted materials from specific areas within the body. The catheter is equipped with a dedicated lumen or channel through which fluids or materials can be aspirated. Depending on the procedure and application, these catheters may be compatible with various aspiration systems, including manual syringes or automated suction devices. Guidance through imaging modalities, such as fluoroscopy or ultrasonic imaging, including IVUS provided from the catheter 702, ensures precise placement of the catheter.

[0123] It should be understood that the aspiration functionality of FIG. 7 can be added to any of the other embodiments shown in FIG. 4, 5A, 5B, or 6 as well. In multi-balloon embodiments it may be necessary to deflate at least the relatively more proximal balloon to facilitate aspiration.

[0124] FIG. 8A shows an alternative embodiment in which a catheter 802 includes a balloon 808, but in which no fiber optic elements extend out of the balloon. Instead, the apertures 824 are used solely to provide fluid flow to inflate or deflate the balloon 808. The shaft 842 is made at least partially of an optically-responsive material, such that shining light upon the shaft 842 (as indicated with hatching) causes heating, cavitation, or emission of acoustic pulses.

[0125] In various embodiments, the photoresponsive portion of the catheter may be the body of the shaft itself (as depicted in FIG. 8A) or it could be made of component parts such as films or segments in or on the catheter shaft.

[0126] FIG. 8B shows the catheter 802, including lumens 816, 818, 820, and 821 extending therein, in cross-section. Lumens 816 and 818 provide fluid flow, which passes through apertures 824 and into balloon 808 for inflation and deflation. Meanwhile, aperture 820 holds one or more fiber optics 822. The fiber optics 822 can provide light to optically-Attorney Docket No. 19506.0001WOU1 responsive material that makes up the shaft 842. In the example of FIG. 8B, two fiber optics 822 are shown. While the illustrated examples depicts both fiber optics 822 at an extension within the catheter 802, when multiple fiber optics 822 are deployed with the lumen 820 they may be advanced individually and extended to different points within the catheter 802. For example, two fiber optics 822 may be deployed within the lumen 820 with a first fiber optic 822 held at a more proximal location while a second fiber optic 822 is further extended to a more distal location. Optionally, a light diffuser 844 layer or multiple layers can be used to distribute light from fiber optic 822 across the optically-responsive material that makes up the shaft 842. In embodiments, the optically-responsive material is a solid photoacoustic material including nanoparticles which heat faster than a remainder of the material, as described in more detail above with reference to FIGS. 4 and 5. A central lumen 821 may be arranged within the catheter 802, through which a guidewire 823 is extended.

[0127] It should be understood that there are a variety of different implementations of the embodiment shown in FIGS. 8A and 8B that would accomplish the result of emitting sonic waves at the shaft 842 via the photoacoustic effect. In some implementations, as described above with respect to the other embodiments, there can be multiple balloons, each of which can be configured with one or more fibers to provide light in desired locations or orientations. Similarly, aspiration, elution of medications or other materials, and balloon coatings can all be implemented using the acoustically-emitting shaft concept of FIGS. 8A and 8B. A transducer can be placed in one of the lumens 820 to monitor the magnitude of the photoacoustic effect.

[0128] FIG. 8C shows an alternative embodiment in which a catheter 802 includes an acoustically emitting shaft 842 without a balloon 808. The example of FIG. 8C includes central lumen 821 through which a guidewire 823 is extended. A lumen 820 surrounds the central lumen 821 and receives one or more fiber optics 822. The fiber optics 822 provide light to the shaft 842 which is constructed using optically responsive material which generates a photoacoustic effect in response to light generated by fiber optics 822. FIG. 9 is an example of a method 900 of using any of the catheters of FIGS. 1-8B.

[0129] The method 900 of FIG. 9 includes positioning a fiber optic element in a lumen at 902. As described above, in various embodiments light guides (such as fiber optic elements) can be arranged in one or more lumens, depending upon the number of balloons or, in some cases, the number of areas within each balloon to be illuminated. Multiple fibers could be used in some embodiments to provide different signals (e.g., different ultrasonic frequency signals) or to create constructive and destructive interference with other signal sources. In some embodiments, a fiber can be advanced within a lumen to a position where it can produce theAttorney Docket No. 19506.0001WOU1 photoacoustic effect, and retracted as desired. One or multiple fibers can each be advanced to one or more different positions along the catheter during use to produce a photoacoustic effect at specific locations and times.

[0130] The method 900 of FIG. 9 further includes routing the catheter to a target location at 904. For example, the catheter could be routed to a location of a clot, an artery where denervation should be performed, or another such target for a medical procedure. In some embodiments, such as those depicted above, a guidewire may be used to advance the catheter.

[0131] Although FIG. 9 shows the positioning of the catheter at the target location 904 occurring after positioning the fiber 902, in some embodiments these could be reordered. In other words, it is possible to route the catheter to a target location 904 prior to positioning the fiber 902 (or fibers) therein.

[0132] The method of FIG. 9 further includes inflating a balloon at 906. The catheter can include a balloon that is inflatable toward the distal end thereof. Inflating the balloon can be done temporarily, to prevent migration of materials (such as disrupted clot materials). In some embodiments, the balloon can also be part of a system that performs aspiration to remove such materials.

[0133] The method of FIG. 9 further includes illuminating the fiber optic element at 908. Illuminating the fiber optic (or other light guide) causes illumination of a photoresponsive material at the distal end of the catheter. That photoresponsive material can make up the balloon skin, the fluid that inflates the balloon, or part of the shaft of the catheter itself. The photoresponsive material, upon exposure to light at its photoacoustic wavelength, emits acoustic signal. In many embodiments, for example, the frequency of the photoacoustic output from the photoresponsive material can be ultrasonic, to provide for an ultrasonic therapy at the target location.

[0134] Optionally, the method of FIG. 9 can include a transducer to emit or receive reflected / refracted signal such as echoes for use in imaging. The acoustic signal generated by the photoresponsive material(s) may also reflect off of some surfaces, and can be used in echolocation or imaging to locate and identify objects in the vicinity of the distal end of the catheter through the transducer described above. The transducer could be used to emit and / or receive pressure waves. In one design, the device will emit and receive pressure waves. These waves emitted from the transducer would interact with surrounding tissue and some would return to the transducer. These waves could be used to make images that monitor tissue. In a second design, the transducer would record only. The transducer could record acoustic pressure waves created by the balloon material or the photoacoustically-active fluid. The acoustic wavesAttorney Docket No. 19506.0001WOU1 produced through a photoacoustic effect might also interact with the surrounding anatomy before being record. The transducer could in turn monitor the magnitude and location of the photoacoustic pressure waves. In a third design, the transducer could also monitor release of drug from the catheter due to changes in acoustic properties of the drug-carrying layer or through the presence of a photoacoustically-active element within the drug. Thus, it is understood that while step 910 (imaging) is shown to be between steps 908 and 912, the imaging could be done at multiple points to position the catheter, position the items in the lumens, monitor balloon inflation, stratify the disease at the site, monitor photoacoustic effect, monitor destruction of tissue, and monitor release of material from the balloon.

[0135] The method 900 also includes performing a treatment at step 912. Several examples of treatments which may be performed using the catheter devices of the present disclosure are discussed throughout. For instance, performing a treatment may include using ultrasonic waves generated by the catheter to break up calcium deposits or other occlusions, to denervate a targeted region for pain management or therapy for motor disorders, or to create a temporary opening in the BBB to allow a drug or other active agent to reach the brain. These examples are non-limiting, and performing a treatment at step 912 may extend to other procedures and treatments where an ultrasonic catheter is advantageously applied.

[0136] Referring now to FIGS. 10A and 10B, the device depicted in FIGS. 10A and 10B are similar to those of FIGS. 3, 4A, and 5 A. In contrast to FIGS. 3, 4A, and 5 A, however, FIGS. 10A and 10B show a balloon 1008 with a cutting element 1046. In FIGS. 10A and 10B, structures lying within balloon 1008 are obscured in order to more clearly depict cutting element 1046 affixed to the external surface of the balloon. Internal structures of balloon 1008 may be the same or similar to those shown in any of FIGS. 3, 4A, and 5A.

[0137] The generated ultrasound and the cutting elements working together provide increased efficiency for breaking calcium deposits or other occlusions that restrict flow within a vein or other body lumen. The examples shown in FIGS. 10A and 10B each depict three cutting elements 1046, but any number of cutting elements may be used. For instance, one, two, three, four, five, six, ten, fifteen, twenty, etc. cutting elements may be affixed to the balloon, depending, for example, on the size of the cutting elements, the size of the balloon, the arrangement of the cutting elements, etc. Cutting element 1046 may be arranged symmetrically around balloon 1008, as shown in FIG. 10 A, or asymmetrically as shown in FIG. 10B.

[0138] Symmetrical arrangement may be preferable for treatment of concentric calcium deposits and other concentric occlusions. Cutting elements may be arranged symmetricallyAttorney Docket No. 19506.0001WOU1 about a circumference of the balloon, as shown in the example of FIG. 10 A, or arranged symmetrically along a length of the balloon, e.g., from a proximal end to a distal end, or both. Cutting elements 1046 may be arranged symmetrically in one dimension, e.g., about the circumference of the balloon, and asymmetrically with respect to another dimension, e.g., disposed more toward the distal end.

[0139] Asymmetrical arrangement may be preferable for treatment of eccentric calcium deposits and occlusions. Cutting elements 1046 may be arranged asymmetrically about a circumference of the balloon. For example, FIG. 10B depicts an embodiment with the cutting elements arranged together in one area 1048a of the balloon’s circumference with another area 1048b, relatively opposite to the area 1048a, has no cutting elements.

[0140] Catheters with asymmetric cutting elements may incorporate other design features to enable a user to rotate the catheter or balloon so that the cutting element can be directed to the vascular structures that need to be cut or modified. For example, manual or mechanical steering may be used with a guidewire provided through a lumen in catheter 1002 and used to steer the cutting elements toward a target occlusion. Other possible manual steering configurations include pull wires, pre-shaped tips, and torque transmission.

[0141] In embodiments, cutting elements 1046 are attached to an external surface of the balloon using an attachment layer of polymer or adhesive. Some non-limiting examples of an attachment layer include UV-curable adhesives, silicone adhesives, polyurethane adhesives, and polyimide.

[0142] The attachment layer or layers used to attach the cutting element to the balloon may also be created with a photoacoustic transducer structure similar to that shown in FIG. 5B. For example, if an adhesive is used to attach cutting elements 1046 to balloon 1008, the adhesive may be mixed with materials such as particles (e.g., carbon nanotubes, gold nanoparticles, etc.) that can absorb the wavelength of a light that is delivered to the balloon catheter.

[0143] In embodiments, an additional tie layer and / or a drug coating may also be applied to this balloon surface, which may be released, for example, when the balloon is expanded, when the laser energy is delivered, or when ultrasound is generated. For example, the balloon 1008 may also have a coating on the surface that elutes a drug (e.g., Paclitaxel) to treat the target lesion. The drug coating may also utilize a tie layer that could be activated using the ultrasound generated or the laser energy supplied. The additional layer may be applied with similar considerations to those discussed with reference to the coating 538 in FIGS. 5A-5C.Attorney Docket No. 19506.0001WOU1

[0144] In embodiments, an additional tie layer and / or a drug coating may be applied to the cutting elements 1046 themselves, with similar considerations as those considered to application to the balloon. Applying the drug coating to the cutting elements 1046 may be advantageous, for example, for targeted delivery of the drug or other agent.

[0145] The balloon catheter 1002 may include a laser source and one or more optical fiber(s) that can deliver laser light to the inside of the balloon or into the inside of the balloon shaft. Balloon catheter 1002 may have one more lumen to incorporate one or more optical fibers to direct laser to the inside of the balloon or to the inside of the balloon shaft as well as to inject the fluid to inflate the balloon. Ballon may be a multi layer balloon as shown in FIGS. 4A-5C. As discussed above with respect to FIGS. 3-6C and 8A-8C, any of a fluid filling the balloon 1008, the balloon 1008 itself, portions of balloon 1008, portions of the shaft of catheter 1002, or both the balloon 1008 and the shaft may be configured as a photoacoustic transducer. The energy absorbed by the transducer structure, or the fluid is converted into heat and thermoelastic expansion resulting in generation of ultrasound waves. The ultrasound waves generated within or on the balloon at the target location enables treatment at the target location.

[0146] Alternatively or in addition, the ultrasound waves can allow imaging of the target location. For imaging application, the catheter may incorporate sensors that can detect the ultrasound signals generated as well as that of its response from the surrounding tissues thereby enabling photoacoustic imaging of the surrounding tissues while delivering the therapeutic treatment.

[0147] FIG. 11 is a partial view of an example catheter 1102 with a microneedle-covered balloon 1108. The example catheter 1102 has a balloon 1108 with rows of microneedles 1146 disposed across the surface of the balloon 1108. It should be understood that in alternative embodiments, the microneedles may not be arranged in rows, and may not cover the same portion of the balloon as shown in FIG. 11. For example, microneedles 1146 may be provided only along a portion of the radial extent of the balloon 1108, similar to the cutting elements of FIGS. 10A and 10B. Additionally, the microneedles 1146 may not be arranged in rows, and can be provided in other arrangements (such as hexagonal packing for increased density) as desired.

[0148] In embodiments, microneedles 1146 support target drug delivery. For example, the microneedles 1146 may be used for drug delivery, such as with a single or small number of rows arranged for targeted drug delivery at a precise location. In embodiments, the microneedles may be applied to mechanically provide access to a targeted delivery location. For example, the catheter 1102 may be disposed in a ventricle or vessel of the brain and, onceAttorney Docket No. 19506.0001WOU1 the balloon 1108 is inflated, the microneedles 1146 are massaged against the blood-brain barrier to create a region of permeability to allow delivery of pharmaceutical treatments and other agents.

[0149] Microneedles 1146 can be used without any drug or medicament thereon. It has been observed that the mechanical stimulation provided by microneedles 1146 can be sufficient to open the BBB. Accordingly, for some embodiments the microneedles 1146 are simple mechanical structures configured to provide this mechanical stimulation.

[0150] In addition to solid microneedles for purely mechanical manipulation, the use of coated microneedles, dissolving microneedles, and hollow microneedles is also contemplated.

[0151] In a coated microneedle embodiment, microneedles 1146 can be coated with a substance that is used to open the BBB. The substance can be, for example, a drug or other medicament that is sufficient to open the BBB, such as osmotic agents, including mannitol and the like. These agents, either alone or in combination with the physical manipulation of the BBB described above, can be used to temporarily open the BBB for delivery of desired therapeutics.

[0152] In a dissolving microneedle embodiment, microneedles 1146 can be made of a material that will biodegrade upon interaction with the BBB. The degradation of the dissolving microneedles 1146 can be caused, in some embodiments, by the application of ultrasound. That is, the balloon 1108 may emit or transmit an ultrasound signal (as described above with respect to FIGS. 1-8C) that can cause the dissolution of microneedles 1146 that have been inserted into the BBB.

[0153] In a hollow microneedle embodiment, the substance used to open the BBB can be contained inside microneedles 1146. Microneedles 1146 can inject the substance used to open the BBB in response to being inserted into the BBB, or in response to stimulus such as ultrasound, as described with respect to the dissolving microneedle embodiment.

[0154] Typically the BBB is opened with the intent to provide some material to the other side, such as a medication. Opening the BBB permits material from the blood side (where the catheter 1102 is located) into the central nervous system. It should be understood that while microneedles 1146 can be used to provide the substance that opens the BBB, they can equally be used to provide the medication or other substance for delivery to the central nervous system. In some embodiments, microneedles 1146 can provide both a substance to open the BBB as well as a substance to be delivered to the central nervous system. In other embodiments, the substance that opens the BBB can be routed through the bloodstream, while the microneedles 1146 merely open the BBB. In other embodiments, the substance that opens the BBB can beAttorney Docket No. 19506.0001WOU1 in the microneedles 1146, while the substance for delivery to the central nervous system is in the bloodstream.

[0155] FIG. 12 is a partial view of a pair of catheters 1202a, 1202b deployed in a vascular system, with a first upstream catheter 1202a delivering microbubbles 1204 and a second downstream catheter 1202b delivering ultrasound 1206.

[0156] Microbubbles 1204 are released into the vascular system at an upstream 1208 location and travel downstream 1210. Travel T demonstrates microbubbles 1204 flowing downstream. Ultrasound 1206 is emitted by a downstream catheter 1202b. When the microbubbles 1204 reach the location of the ultrasound 1206 emission, the microbubbles circulating in nearby blood vessels to oscillate in response to the pressure waves. This stable cavitation exerts mechanical forces on the endothelial cells of the BBB, temporarily disrupting the tight junctions between the cells of the BBB and increasing its permeability at the targeted site. As a result, drugs or other therapeutic agents that would ordinarily be blocked are able pass into the brain tissue. Importantly, this effect is both localized and transient, allowing the barrier to quickly reseal and preserve its protective function.

[0157] FIG. 12 shows both catheters 1202a and 1202b in close proximity, for ease of illustration. It should be understood that in many embodiments, catheter 1202a and catheter 1202b may be located distant from one another, so long as catheter 1202a is ‘upstream’ of catheter 1202b, in the sense that the microbubbles released by catheter 1202a are still in the bloodstream when it reaches the point where ultrasound is created by the second catheter 1202b, as indicated by the arrows T.

[0158] Catheters 1202a and 1202b are also simplified for purposes of illustration, and do not show the various balloons, cutters, or microneedles described above with respect to FIGS. 1-11. It should be understood that any of the ultrasound generation techniques and structures described in those embodiments could equally be used to create ultrasound in the embodiment shown in FIG. 12.

[0159] Various embodiments are envisioned for the release of the microbubbles. In some embodiments, microbubbles are generated within the catheter itself just prior to release. This may be accomplished by the controlled introduction of gas and a stabilizing liquid, e.g., a lipid or surfactant solution, through microfluidic or flow-focusing mechanisms inside the catheter. These systems allow for real-time production of uniformly sized microbubbles, which can then be released, sometimes immediately, into the bloodstream or ventricular system. In-catheter generation may promote bubble stability and precise control over their physical characteristics at the point of delivery.Attorney Docket No. 19506.0001WOU1

[0160] FIG. 13 is partial view of an example catheter 1302 delivering microbubbles 1304 from an outer sheath or layer 1312. In embodiments, the microbubbles may be pre-formed in suspension or stored in a pressurized reservoir. When catheter 1302 reaches a target site, the outer sheath 1312 retracts or deploys through small openings, allowing microbubbles 1304 to disperse radially into the surrounding fluid. This approach may be particularly advantageous when a more diffuse distribution of microbubbles is desired, such as in the ventricular system, where wide coverage may promote effective ultrasound interaction.

[0161] While FIG. 13 shows an emulsion of microbubbles in the outer sleeve of the catheter 1302, it should be understood that in alternative embodiments there may be a gas provided through a lumen (e.g., via outer sheath 1312) which is then bubbled into the bloodstream at the distal end 1314 thereof. In such embodiments, rather than the flared end shown in FIG. 13, there may be a pinhole aperture or other similar structure that will accomplish the transformation of the gas stream provided into bubbles. In any event, the bubbles are created and travel downstream (as indicated by the arrow T) towards the location where the ultrasound is generated, such as at a balloon 1308 consistent with any of the embodiments described with respect to FIGS. 1-8C.

[0162] FIG. 14 is a partial view of a catheter 1402 delivering microbubbles 1404 from an interior lumen. Microbubbles 1404 are released from apertures 1416. Photoacoustic emission devices 1414, such as fiber optics, may also be positioned within an interior lumen of catheter 1402 with apertures 1416 to allow positioning of the photoacoustic emission device 1414 for targeted ultrasound. In embodiments, either pre-formed or freshly generated microbubbles are injected directly into the target area using, for example, low-pressure infusion. In examples, this method and similar methods may allow for more directional control and precise timing.

[0163] Notably, in FIG. 14 the microbubbles are not proximate the balloon 1408. As such, ultrasound may be delivered in the manner described with respect to FIG. 6B, for example, or 8C (in which the ultrasound is emitted from the shaft of the catheter 1402 itself, towards the distal end 1406).

[0164] FIG. 15 is a partial view of a catheter 1502 with two balloons 1508, 1509 delivering microbubbles 1504 from an interior lumen. Microbubbles 1504 are released from apertures 1516. The catheter 1502 may be used with similar considerations to those discussed with reference to the dual ballon design in FIG. 6A. The use of two balloons provides for contained and therefore more targeted delivery of microbubbles and ultrasound.

[0165] ASPECTSAttorney Docket No. 19506.0001WOU1

[0166] According to a first aspect, an ultrasound-emitting device includes a catheter extending from a proximal end to a distal end, the catheter defining a plurality of lumens therein. A balloon is arranged at the distal end, wherein an interior of the balloon is fluidically coupled to a first one of the plurality of lumens and the balloon is inflated by a fluid routed through the first one of the plurality of lumens. An optical fiber is arranged in a second one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material at the distal end. A transducer can emit and / or receive acoustic waves including recording these waves, converting them to an electrical signal, using those signals to create an image, and using that image to direct a decision.

[0167] According to a second aspect, the device of the first aspect further includes a guidewire arranged through a third lumen of the catheter and extending from the proximal end and past the distal end.

[0168] According to a third aspect, the device of any one of the first or second aspects has the photoacoustic material as the fluid, the balloon, or a portion of the catheter.

[0169] According to a fourth aspect, the device of the third aspect where the photoacoustic material is the fluid has the balloon made of a polymer.

[0170] According to a fifth aspect, the device of any one of the first through fourth aspects further includes a tie layer disposed on a surface of the balloon and a pharmaceutical coating coupled to the balloon by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound.

[0171] According to a sixth aspect, the device of any one of the first through fifth aspects further includes a second balloon arranged between the balloon and the proximal end, wherein an interior of the second balloon is fluidically coupled to the first one of the plurality of lumens and the second balloon is inflated by the fluid routed through the first one of the plurality of lumens, and a second optical fiber arranged to illuminate a photoacoustic portion at the second balloon.

[0172] According to a seventh aspect, the device of the sixth aspect has the second optical fiber arranged in a third one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end.

[0173] According to an eighth aspect, the device of the seventh aspect further includes a plurality of apertures arranged on an outer surface of the catheter between the balloon and the second balloon, wherein the plurality of apertures are in communication with a fourth lumen of the plurality of lumens.Attorney Docket No. 19506.0001WOU1

[0174] According to a ninth aspect, the device of any one of the first through eighth aspects further includes an aspiration sleeve that circumscribes a portion of the catheter proximal to the balloon.

[0175] According to a tenth aspect, the device of any one of the first through ninth aspects further includes a cutting element arranged on an external surface of the balloon.

[0176] According to an eleventh aspect, the device of the tenth aspect has the cutting element as at least two cutting elements.

[0177] According to a twelfth aspect, the device of the eleventh aspect has the at least two cutting elements arranged symmetrically around a circumference of the balloon.

[0178] According to a thirteenth aspect, the device of any one of the eleventh or twelfth aspects has the at least two cutting elements arranged symmetrically along a length of the balloon.

[0179] According to a fourteenth aspect, the device of the eleventh aspect has the at least two cutting elements arranged asymmetrically around a circumference of the balloon.

[0180] According to a fifteenth aspect, the device of any one of the eleventh or fourteenth aspects has the at least two cutting elements arranged asymmetrically along a length of the balloon.

[0181] According to a sixteenth aspect, a method for generating ultrasound by an ultrasound-emitting device includes positioning a fiber optic element in a lumen of a catheter such that the fiber optic element extends from a proximal end of the catheter to a distal end of the catheter, inflating a balloon at a distal end of the catheter with a fluid, and illuminating the fiber optic element at the proximal end of the catheter with a series of light pulses, such that the series of light pulses travels through the fiber optic element and is delivered to the distal end.

[0182] According to a seventeenth aspect, the method of the sixteenth aspect has at least one of the balloon, the catheter, and / or the fluid comprising a photoacoustic material.

[0183] According to an eighteenth aspect, the method of the seventeenth aspect has the photoacoustic material generating ultrasonic emissions in response to the series of light pulses.

[0184] According to a nineteenth aspect, the method of the eighteenth aspect further includes applying the ultrasonic emissions to calcium deposits for calcium debulking.

[0185] According to a twentieth aspect, the method of the eighteenth aspect further includes applying the ultrasonic emissions to an atherosclerotic plaque or other blockage for treatment of arterial occlusion.Attorney Docket No. 19506.0001WOU1

[0186] According to a twenty-first aspect, the method of any one of the nineteenth or twentieth aspects further includes arranging the balloon such that a cutting element on an external surface of the balloon is positioned against at least one of the calcium deposits, the atherosclerotic plaque, or the other blockage.

[0187] According to a twenty-second aspect, the method of the eighteenth aspect further includes disrupting a tie layer that couples a pharmaceutical coating to the balloon with the ultrasonic emissions.

[0188] According to a twenty -third aspect, the method of any one of the sixteenth through twenty-second aspects further includes routing the distal end of the catheter to a target location along a guidewire prior to inflating the balloon.

[0189] According to a twenty-fourth aspect, the method of any one of the sixteenth through twenty-third aspects has the fluid as photoacoustic.

[0190] According to a twenty -fifth aspect, the method of the twenty-fourth aspect has the balloon as polymer based.

[0191] According to a twenty-sixth aspect, the method of any one of the sixteenth through twenty-fifth aspects includes at least one fiber extending from the proximal end to the distal end for use in imaging.

[0192] According to a twenty-seventh aspect, the method of any one of the sixteenth through twenty-sixth aspects further includes inflating a second balloon located between the balloon and the proximal end and illuminating a second fiber optic element at the proximal end of the catheter with the series of light pulses, such that the series of light pulses travels through the second fiber optic element and is delivered to the second balloon.

[0193] According to a twenty-eighth aspect, the method of the twenty-seventh aspect further includes aspirating a region arranged between the balloon and the second balloon and adjacent the catheter.

[0194] According to a twenty-ninth aspect, the method of the twenty-seventh aspect further includes creating images of a dislodged material to confirm aspiration.

[0195] According to a thirtieth aspect, the method of any one of the sixteenth through twenty-ninth aspects further includes aspirating a region proximal to the balloon with an aspiration sleeve that circumscribes a portion of the catheter.

[0196] According to a thirty-first aspect, the method of any one of the sixteenth through thirtieth aspects further includes denervating an anatomical structure positioned in a region arranged adjacent the balloon.Attorney Docket No. 19506.0001WOU1

[0197] According to a thirty-second aspect, a method of delivering an agent through the blood-brain barrier of a patient includes positioning a catheter within a vessel in the patient's brain, the catheter configured for local delivery of both ultrasonic waves and the agent, generating the ultrasonic waves from the catheter, and releasing the agent while the ultrasonic waves are being generated.

[0198] According to a thirty -third aspect, the method of the thirty-second aspect has the agent as at least one of a pharmaceutical agent and microbubbles.

[0199] According to a thirty-fourth aspect, the method of any one of the thirty-second or thirty-third aspects has the agent released by the ultrasonic waves wherein the agent is affixed to the catheter by a tie-layer and the tie-layer is configured to release in response to the ultrasonic waves.

[0200] According to a thirty-fifth aspect, a method of temporarily opening the blood-brain barrier includes positioning an endovascular catheter within a brain vessel, the catheter comprising a balloon and an optical fiber system configured to generate ultrasonic waves through photoacoustic effects, delivering microbubbles to a target location through the catheter or systemically, generating ultrasonic waves from the balloon to cause cavitation of the microbubbles and temporary opening of the blood-brain barrier, and delivering a therapeutic agent through the temporarily opened blood-brain barrier.

[0201] According to a thirty-sixth aspect, the method of the thirty-fifth aspect has the microbubbles delivered locally through apertures in the catheter.

[0202] According to a thirty-seventh aspect, the method of any one of the thirty -fifth or thirty-sixth aspects has the therapeutic agent coated on an exterior surface of the balloon and released by disruption of a tie layer through the ultrasonic waves.

[0203] The various embodiments described in the foregoing aspects are interoperable with one another and can be combined in numerous ways to achieve desired therapeutic outcomes. For example, the cutting elements described in aspects ten through fifteen can be incorporated into any of the device embodiments of aspects one through nine, while the aspiration features of aspect nine can be combined with the dual balloon configurations of aspects six through eight. Similarly, the method aspects sixteen through thirty-seven can incorporate any combination of the structural features described in the device aspects, allowing for customized treatment approaches that leverage multiple therapeutic modalities simultaneously. The photoacoustic materials, transducers, pharmaceutical coatings, and microbubble delivery systems can all be integrated together in various combinations to address specific clinicalAttorney Docket No. 19506.0001WOU1 needs, whether for thrombectomy, denervation, calcium debulking, or blood-brain barrier penetration applications.

[0204] Having described the preferred aspects and implementations of the present disclosure, modifications and equivalents of the disclosed concepts may readily occur to one skilled in the art. However, it is intended that such modifications and equivalents be included within the scope of the claims which are appended hereto.

Claims

Attorney Docket No. 19506. OOOlWOUlWhat is claimed is:

1. An ultrasound-emitting device comprising: a catheter extending from a proximal end to a distal end, the catheter defining a plurality of lumens therein; a balloon arranged at the distal end, wherein an interior of the balloon is fluidically coupled to a first one of the plurality of lumens and the balloon is inflated by a fluid routed through the first one of the plurality of lumens; an optical fiber arranged in a second one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material at the distal end; and a transducer that can emit and / or receive acoustic waves including recording these waves, converting them to an electrical signal, using those signals to create an image, and using that image to direct a decision.

2. The device of claim 1, further comprising a guidewire arranged through a third lumen of the catheter and extending from the proximal end and past the distal end.

3. The device of claim 1 or 2, wherein the photoacoustic material is the fluid.

4. The device of claim 3, wherein the balloon is made of a polymer.

5. The device of claim 1 or 2, wherein the photoacoustic material is the balloon.

6. The device of claim 1 or 2, wherein the photoacoustic material is a portion of the catheter.

7. The device of any preceding claim, further comprising: a tie layer disposed on a surface of the balloon; and a pharmaceutical coating coupled to the balloon by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound.

8. The device of claim any preceding claim, further comprising:Attorney Docket No. 19506.0001WOU1 a second balloon arranged between the balloon and the proximal end, wherein an interior of the second balloon is fluidically coupled to the first one of the plurality of lumens and the second balloon is inflated by the fluid routed through the first one of the plurality of lumens, and a second optical fiber arranged to illuminate a photoacoustic portion at the second balloon.

9. The device of claim 8, wherein the second optical fiber is arranged in a third one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end.

10. The device of claim 9, further comprising a plurality of apertures arranged on an outer surface of the catheter between the balloon and the second balloon, wherein the plurality of apertures are in communication with a fourth lumen of the plurality of lumens.

11. The device of any preceding claim, further comprising an aspiration sleeve that circumscribes a portion of the catheter proximal to the balloon.

12. The device of any preceding claim, further comprising a cutting element arranged out an external surface of the balloon.

13. The device of claim 12, wherein the cutting element is at least two cutting elements.

14. The device of claim 13, wherein the at least two cutting elements are arranged symmetrically around a circumference of the balloon.

15. The device of claim 13 or 14, wherein the at least two cutting elements are arranged symmetrically along a length of the balloon.

16. The device of claim 13, wherein the at least two cutting elements are arranged asymmetrically around a circumference of the balloon.

17. The device of claim 13 or 16, wherein the at least two cutting elements are arranged asymmetrically along a length of the balloon.Attorney Docket No. 19506.0001WOU118. A method for generating ultrasound by an ultrasound-emitting device, the method comprising: positioning a fiber optic element in a lumen of a catheter such that the fiber optic element extends from a proximal end of the catheter to a distal end of the catheter; inflating a balloon at a distal end of the catheter with a fluid; and illuminating the fiber optic element at the proximal end of the catheter with a series of light pulses, such that the series of light pulses travels through the fiber optic element and is delivered to the distal end.

19. The method of claim 18, wherein at least one of the balloon, the catheter, and / or the fluid comprises a photoacoustic material.

20. The method of claim 19, wherein the photoacoustic material generates ultrasonic emissions in response to the series of light pulses.

21. The method of claim 20, further comprising applying the ultrasonic emissions to calcium deposits for calcium debulking.

22. The method of claim 20, further comprising applying the ultrasonic emissions to an atherosclerotic plaque or other blockage for treatment of arterial occlusion.

23. The method of claim 21 or 22, further comprising arranging the balloon such that a cutting element on an external surface of the balloon is positioned against at least one of the calcium deposits, the atherosclerotic plaque, or the other blockage.

24. The method of claim 20, further comprising disrupting a tie layer that couples a pharmaceutical coating to the balloon with the ultrasonic emissions.

25. The method of any of claims 18-24, further comprising routing the distal end of the catheter to a target location along a guidewire prior to inflating the balloon.

26. The method of any of claims 18-25, wherein the fluid is photoacoustic.Attorney Docket No. 19506.0001WOU127. The method of claim 26, wherein the balloon is polymer based.

28. The method of any of claims 18-27, comprising at least one fiber extending from the proximal end to the distal end for use in imaging.

29. The method of any of claims 18-28, further comprising: inflating a second balloon located between the balloon and the proximal end; and illuminating a second fiber optic element at the proximal end of the catheter with the series of light pulses, such that the series of light pulses travels through the second fiber optic element and is delivered to the second balloon.

30. The method of claim 29, further comprising aspirating a region arranged between the balloon and the second balloon and adjacent the catheter.

31. The method of claim 29, further comprising creating images of a dislodged material to confirm aspiration.

32. The method of any of claims 18-31, further comprising aspirating a region proximal to the balloon with an aspiration sleeve that circumscribes a portion of the catheter.

33. The method of any of claims 18-32, further comprising denervating an anatomical structure positioned in a region arranged adjacent the balloon.

34. The method of claim 12 wherein a transducer is used to record a location and a magnitude of photoacoustic signal emanating from the source of photoacoustic effect and photoacoustic pressure waves reflecting / echoing off of the vasculature.

35. The method of claim 12 or 34, further comprising a transducer configured to perform pulse / echo imaging of surrounding anatomy to position the catheter.

36. The method of claim 35, further comprising using the transducer to create pulse / echo images of a plaque, blockage, calcium deposits, and the like to evaluate an extent of therapy.

37. An ultrasound-emitting device comprising:Attorney Docket No. 19506.0001WOU1 a catheter extending from a proximal end to a distal end, the catheter defining a plurality of lumens therein; a balloon arranged at the distal end, wherein an interior of the balloon is fluidically coupled to a first one of the plurality of lumens; and means for illuminating the interior of distal end by a light source arranged at the proximal end of the catheter.

38. The device of claim 37, further comprising a guidewire arranged through a second one of the plurality of lumens, extending through the catheter from the proximal end and past the distal end thereof.

39. The device of claim 37 or 38, further comprising a photoacoustic fluid arranged in the balloon and the first one of the plurality of lumens.

40. The device of claim 39, wherein the balloon is made of a polymer.

41. The device of any of claims 37-40, wherein the balloon is made of a photoacoustic material.

42. The device of claim 37, further comprising: a tie layer disposed on a surface of the balloon; and a coating coupled to the balloon by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound.

43. The device of any one of claims 37-42, further comprising a cutting element arranged out an external surface of the balloon.

44. The device of claim 43, wherein the cutting element is at least two cutting elements.

45. The device of claim 44, wherein the at least two cutting elements are arranged symmetrically around at least one of a circumference of the balloon and along a length of the balloon.Attorney Docket No. 19506.0001WOU146. The device of claim 44 or 45, wherein the at least two cutting elements are arranged asymmetrically around at least one of a circumference of the balloon and along a length of the balloon.

47. The device of any of claims 37-46, further comprising a second balloon arranged between the balloon and the proximal end, wherein an interior of the second balloon is fluidically coupled to the first one of the plurality of lumens and the second balloon is inflated by a fluid routed through the first one of the plurality of lumens, wherein the means for illuminating the interior of the balloon by a light source arranged at the proximal end of the catheter further illuminates the interior of the second balloon.

48. The device of any of claims 37-47 further comprising a transducer in one of the plurality of lumens or integrated into the catheter.

49. An ultrasound-emitting device comprising: a catheter extending from a proximal end to a distal end, the catheter defining a plurality of lumens therein; and an optical fiber arranged in one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material arranged at the distal end.

50. The device of claim 49, wherein the photoacoustic material is a part of the catheter.

51. The device of claim 49, wherein the photoacoustic material is a film or a coating arranged on the catheter or on the optical fiber.

52. The device of any of claims 49 or 50, further comprising a guidewire arranged through a third lumen of the catheter and extending from the proximal end and past the distal end.

53. The device of any of claims 49-52, further comprising: a tie layer disposed on a surface of the catheter; and a pharmaceutical coating coupled to the catheter by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound.Attorney Docket No. 19506.0001WOU154. The device of claim 53, further comprising a transducer to measure a photoacoustic amplitude of the tie layer or dimensions of the tie layer via acoustic imaging.

55. An ultrasound-emitting device comprising: a catheter extending from a proximal end to a distal end, the catheter defining a plurality of lumens therein; a balloon arranged at the distal end, wherein an interior of the balloon is fluidically coupled to a first one of the plurality of lumens and the balloon is inflated by a fluid routed through the first one of the plurality of lumens; an optical fiber arranged in a second one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material at the distal end; and an aspiration sleeve arranged around the catheter and closer to the proximal end than the balloon.

56. The device of claim 55, further comprising a guidewire arranged through a third lumen of the catheter and extending from the proximal end and past the distal end.

57. The device of claim 55, wherein the fluid is a photoacoustic fluid.

58. The device of claim 55, wherein the balloon is made of a polymer.

59. The device of claim 55, wherein the balloon is made of a photoacoustic material.

60. The device of claim 55, wherein a portion of the catheter is made of a photoacoustic material.

61. The device of claim 55, further comprising: a tie layer disposed on a surface of the balloon; and a pharmaceutical coating coupled to the balloon by the tie layer, wherein the tie layer comprises a material that is susceptible to disruption by ultrasound; and a transducer integrated into the catheter.Attorney Docket No. 19506.0001WOU162. The device of any one of claims 55-61, further comprising cutting elements arranged out an external surface of the balloon.

63. The device of claim 62, wherein the cutting elements are arranged symmetrically around at least one of a circumference of the balloon and along a length of the balloon.

64. A method for generating ultrasound by an ultrasound-emitting device, the method comprising: positioning a fiber optic element in a lumen of a catheter such that the fiber optic element extends from a proximal end of the catheter to a distal end of the catheter; and illuminating the fiber optic element at the proximal end of the catheter with a series of light pulses, such that the series of light pulses travels through the fiber optic element and is delivered to the distal end.

65. The method of claim 64, wherein a portion of the catheter comprises a photoacoustic material.

66. The method of claim 65, wherein the photoacoustic material generates ultrasonic emissions in response to the series of light pulses.

67. The method of claim 66, further comprising applying the ultrasonic emissions to calcium deposits for calcium debulking.

68. The method of claim 66, further comprising applying the ultrasonic emissions to an atherosclerotic plaque or other blockage for treatment of arterial occlusion.

69. The method of claim 68, further comprising disrupting a tie layer that couples a pharmaceutical coating to the catheter with the ultrasonic emissions.

70. The method of claim 65, further comprising routing the distal end of the catheter to a target location along a guidewire.Attorney Docket No. 19506.0001WOU171. The method of any of claims 65-70, wherein at least one fiber extends from the proximal end to the distal end for use in imaging.

72. The method of any of claims 65-71, wherein the fluid is photoacoustic.

73. The method of claim 72, further comprising inflating a balloon at the distal end of the catheter.

74. The method of claim 73, wherein the balloon is polymer based.

75. The method of claim 73, wherein the balloon is made of a material that is photoacoustic.

76. The method of any of claims 73-75, further comprising: inflating a second balloon located between the balloon and the proximal end; and illuminating a second fiber optic element at the proximal end of the catheter with the series of light pulses, such that the series of light pulses travels through the second fiber optic element and is delivered to the second balloon.

77. The method of claim 76, further comprising aspirating a region arranged between the balloon and the second balloon and adjacent the catheter.

78. The method of any of claims 73-77, further comprising aspirating a region proximal to the balloon with an aspiration sleeve that circumscribes a portion of the catheter.

79. The method of any of claims 73-78, further comprising denervating an anatomical structure positioned in a region arranged adjacent the balloon.

80. The device of any one of claims 64-79, further comprising cutting elements arranged out an external surface of the balloon.

81. The device of claim 80, wherein the cutting elements are arranged symmetrically around at least one of a circumference of the balloon and along a length of the balloon.Attorney Docket No. 19506. OOOlWOUl82. An ultrasound-emitting device comprising: a catheter extending from a proximal end to a distal end, the catheter defining a plurality of lumens therein; a balloon arranged at the distal end, wherein an interior of the balloon is fluidically coupled to a first one of the plurality of lumens and the balloon is inflated by a fluid routed through the first one of the plurality of lumens; an optical fiber arranged in a second one of the plurality of lumens, the optical fiber extending from the proximal end to the distal end and arranged to illuminate a photoacoustic material at the distal end; and a transducer that can emit and / or receive acoustic waves including recording these waves, converting them to an electrical signal, using those signals to create an image, and using that image to direct a decision.

83. A method of delivering an agent through the blood-brain barrier of a patient, the method comprising: positioning a catheter within a vessel in the patient’s brain, the catheter configured for local delivery of both ultrasonic waves and the agent; generating the ultrasonic waves from the catheter; and releasing the agent while the ultrasonic waves are being generated.

84. The method of claim 83, wherein the agent is at least one of a pharmaceutical agent and microbubbles.

85. The method of claim 83 or 84, wherein the agent is released by the ultrasonic waves wherein the agent is affixed to the catheter by a tie-layer and the tie-layer is configured to release in response to the ultrasonic waves.

86. A method of temporarily opening the blood-brain barrier comprising: positioning an endovascular catheter within a brain vessel, the catheter comprising a balloon and an optical fiber system configured to generate ultrasonic waves through photoacoustic effects; delivering microbubbles to a target location through the catheter or systemically; generating ultrasonic waves from the balloon to cause cavitation of the microbubbles and temporary opening of the blood-brain barrier; andAttorney Docket No. 19506. OOOlWOUl delivering a therapeutic agent through the temporarily opened blood-brain barrier.

87. The method of claim 86, wherein the microbubbles are delivered locally through apertures in the catheter.

88. The method of claim 86 or 87, wherein the therapeutic agent is coated on an exterior surface of the balloon and released by disruption of a tie layer through the ultrasonic waves.

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