Patent Description:
Intravesical therapy of the urinary bladder involves the bladder inner surface which is covered with transitional epithelium lining called urothelium, and glycosaminoglycans (GAG) units found on the urothelium. Both the urothelium and the GAG units may function as an important barrier to toxins and waste found in the urine, giving the bladder wall its low permeability characteristic. However, this compact and tight barrier may also restrict effective penetration of therapeutic agents delivered into the bladder during intravesical treatments. Some therapeutic molecules may not penetrate the bladder barrier at all.

Ultrasound cavitation is a mechanism by which acoustic waves can increase tissue permeability. Cavitation bubbles collapse on the tissues with high energy and open up pores in the tissues, which result in the increased permeability of the tissues to therapeutic agents.

The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative.

The invention is defined in independent claim <NUM> with further aspects being defined in dependent claims <NUM>-<NUM>. Methods of use are not part of the claimed invention and are left for illustrative purposes.

According to an aspect of some embodiments there is provided a catheter for ultrasonic-driven bladder therapeutic agent delivery, the catheter includes: a tube, two or more expandable portions mounted on the tube, one or more ultrasound transducers mounted on the tube between the two or more expandable portions, and a transducer sleeve disposed between the two or more expandable portions and accommodating the one or more transducers. According to some embodiments the transducer sleeve and the expandable portions include a single balloon. In some embodiments, the expandable portion comprises a stent.

According to some embodiments the maximal cross-sectional area of the transducer sleeve at an expanded state is smaller than the maximal cross-sectional area of any one of the expandable portions at least at their greatest circumference. According to some embodiments at least one of the expandable portions is spheroid and at least one of the expandable portions and the tube are concentric. According to some embodiments at least one of the expandable portions and the transducer are concentric.

According to some embodiments of the invention the tube includes at least one fluid port located within a lumen of at least one of the expandable portions and/or at least one fluid port along its length that opens to a lumen of a bladder. The port is configured to supply fluid into the lumen of the bladder and/or evacuate fluid out of the bladder.

According to some embodiments of the invention the transducer is elevated from a surface of the tube so that to define a gap between the transducer and the surface of the tube. According to some embodiments of the invention the greatest circumference of the transducer sleeve is less than <NUM>% of the greatest circumference of at least one expandable portion and/or the inflation pressure of the transducer sleeve is greater than the inflation pressure of the expandable portions. According to some embodiments of the invention the tube includes one or more conduits that supply therapeutic fluid via the port. According to some embodiments of the invention the tube includes one or more conduits that supply gassed fluid via the port. According to some embodiments of the invention the tube includes one or more conduits that supply fluid via the port.

According to some embodiments of the invention the transducer is configured to form cavitations in the gassed therapeutic fluid.

According to an aspect of some embodiments there is provided a catheter for ultrasonic-driven bladder therapeutic agent delivery, the catheter includes a tube, having a proximal portion and a distal end, a proximal expandable portion mounted on the proximal portion of the tube, one or more transducers mounted on the tube between the proximal expandable portion and the distal end, and a transducer sleeve between the proximal expandable portion and the distal end accommodating the one or more transducers. In some embodiments, one or more of the expandable portions comprises a balloon.

According to some embodiments of the invention the balloon is toroidal and/or configured to inflate distally towards the distal end. According to some embodiments of the invention the tube includes at least one fluid port along its length that opens to a lumen of a bladder and/or is located between the transducer and the balloon. According to some embodiments of the invention the port is configured to supply fluid into the lumen of the bladder and/or evacuate fluid out of the bladder.

According to some embodiments of the invention the greatest circumference of the transducer sleeve is less than <NUM>% of the greatest circumference of the balloon. According to some embodiments a volume is defined between the transducers and the transducer sleeve. According to some embodiments the inflation pressure of the transducer sleeve is greater than the inflation pressure of the balloon. According to some embodiments of the invention the tube includes one or more conduits that supply therapeutic fluid via the port.

According to an aspect of some embodiments there is provided a method for treating a bladder using a catheter for ultrasonic-driven bladder therapeutic agent delivery including: inserting a distal expandable portion of the catheter into the bladder via a urethra, expanding the expandable portion, supplying therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter, advancing the catheter in the bladder and inserting a proximal expandable portion of the catheter into the bladder, expanding the proximal expandable portion and trapping the therapeutic fluid between the distal expandable portion and the proximal expandable portion, and applying ultrasound to form cavitation in the therapeutic fluid. In some embodiments, the method for treating a bladder using a catheter for ultrasonic-driven bladder therapeutic agent delivery comprises supplying of therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter after stopping to emit ultrasound energy.

According to some embodiments the method includes supplying the therapeutic fluid through a port between the expandable portions. According to some embodiments of the invention the therapeutic fluid is gaseous therapeutic fluid.

According to an aspect of some embodiments there is provided a method for treating a bladder using a catheter for ultrasonic-driven bladder therapeutic agent delivery including: inserting a distal expandable portion of the catheter into the bladder via a urethra, expanding the expandable portion, supplying gassed fluid into the bladder through at least one fluid port in the catheter, emitting ultrasound energy and forming cavitations in the gassed fluid, draining the bladder content, supplying therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter, and emitting ultrasound energy and forming cavitations in the therapeutic fluid.

According to some embodiments the method includes draining and flushing the bladder with saline prior to supplying the gassed fluid into the bladder.

According to some embodiments the method includes stopping emitting ultrasound energy during the draining of the bladder content and/or the supplying of the therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter.

According to an aspect of some embodiments there is provided a catheter for ultrasonic-driven bladder therapeutic agent delivery, including: a tube having a proximal expandable portion and a distal end; and at least one transducer sleeve accommodating at least one ultrasound transducer mounted on the tube between the proximal expandable portion and the distal end.

According to an aspect of some embodiments there is provided a catheter wherein at least one expandable portion is expandable inside a bladder from a contracted state to an expanded state at which the expandable portion is urged against the bladder wall to form a sealed volume within the bladder between the expandable portion and a trigone area of said bladder.

In some embodiments, the catheter includes at least one additional expandable portion, wherein the transducer sleeve is disposed between the proximal and said at least one additional expandable portion. In some embodiments, the transducer sleeve and at least one of the expandable portions are in fluid communication.

In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is smaller than the maximal cross-sectional area of any one of the expandable portions at least at their greatest circumference. In some embodiments, at least one of the expandable portions is spheroid.

In some embodiments, at least one of the expandable portions and the tube are concentric. In some embodiments, at least one of the expandable portions and the transducer are concentric. In some embodiments, the tube comprises at least one fluid port located within a lumen of at least one of the expandable portions.

In some embodiments, the tube comprises at least two fluid ports in fluid communication with the lumen of the transducer sleeve and wherein fluid flow is maintained between the ports. In some embodiments, the transducer is positioned between the ports.

In some embodiments, the tube comprises at least one therapeutic fluid port along its length that opens to a lumen of a bladder. In some embodiments, the catheter includes a blind tip at the distal end, wherein the at least one therapeutic fluid port is positioned along the circumference of the tip. In some embodiments, the transducer is elevated from a surface of the tube so that to define a gap between the transducer and the surface of the tube.

In some embodiments, the catheter comprises at least one spacer positioned on the tube and wherein the transducer is mounted on the at least one spacer. In some embodiments, the greatest circumference of the transducer sleeve is less than <NUM>% of the greatest circumference of at least one expandable portion. In some embodiments, the tube comprises one or more conduits that supply fluid via said therapeutic fluid port.

In some embodiments, at least one expandable portion is toroidal. In some embodiments, at least one expandable portion is configured to inflate distally towards the distal end. In some embodiments, the catheter comprises at least one fluid port located between the transducer and at least one expandable portion.

In some embodiments, an expanded state a volume is defined between the transducer and the transducer sleeve.

According to an aspect of some embodiments there is provided a method for treating a bladder using a catheter for ultrasonic-driven bladder therapeutic agent delivery including: inserting a distal expandable portion of the catheter into the bladder via a urethra, expanding the expandable portion, supplying therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter, advancing the catheter in the bladder and inserting a proximal expandable portion of the catheter into the bladder, expanding the proximal expandable portion and trapping the therapeutic fluid between the distal expandable portion and the proximal expandable portion, and forming cavitations in the therapeutic fluid.

In some embodiments, the method includes supplying the therapeutic fluid through a port between the expandable portions. In some embodiments, the therapeutic fluid is gaseous therapeutic fluid.

According to an aspect of some embodiments there is provided a method for treating a bladder using a catheter for ultrasonic-driven bladder therapeutic agent delivery including: inserting a distal expandable portion of the catheter into the bladder via a urethra, supplying fluid into the bladder through at least one fluid port in the catheter, emitting ultrasound energy and forming cavitations in the gassed fluid, draining the bladder content, and supplying therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter. In some embodiments, said fluid is gassed.

In some embodiments, the method includes expanding a distal expandable portion of the catheter prior to supplying therapeutic fluid into the bladder. In some embodiments, the method includes draining and flushing the bladder with saline prior to supplying the gassed fluid into the bladder.

In some embodiments, the method includes stopping emitting ultrasound energy during the draining of the bladder content and/or the supplying of the therapeutic fluid into the bladder through at least one therapeutic fluid port in the catheter. In some embodiments, the method includes further advancing a proximal expandable portion prior to emitting ultrasound energy. In some embodiments, the method includes expanding proximal expandable portion prior to emitting ultrasound energy. Methods of use and/or treatment are not part of the claimed invention and are left for illustrative purposes.

Some of the challenges that exist in the ultrasound cavitation mechanism are in that cavitation may need to form in a fluid in proximity to the tissue surface to be treated to enhance therapeutic agent delivery. Moreover, the cavitation bubbles need to be prevented from forming near or on the ultrasonic transducer surface, thereby blocking the ultrasonic waves.

According to an aspect of some embodiments of the present invention there is provided a catheter for ultrasonic-driven bladder therapeutic agent delivery. In some embodiments, the catheter comprises a tube, one or more transducers mounted on the tube, at least one expandable portion, and a transducer sleeve. In some embodiments, the transducer sleeve is configured to enclose one or more transducers, wherein a volume is defined between the enclosed transducer and walls of the transducer sleeve. In some embodiments, the transducer sleeve is disposed between at least two expandable portions. In some embodiments, the transducer sleeve interconnects at least two expandable portions.

According to some embodiments of the invention, the tube comprises at least one fluid port configured to supply fluid to or remove fluid from at least one of the at least one expandable portion. In some embodiments, the expandable portion is inflated by fluid supplied into the portions via the fluid ports. The transducer sleeve is expandable.

According to some embodiments of the invention, the tube comprises at least one therapeutic fluid port configured to supply therapeutic fluid into the bladder. In some embodiments, the tube comprises at least one therapeutic fluid port at a distal end of the tube. In some embodiments, the tube comprises at least one therapeutic fluid port between the transducer sleeve and either one of the expandable portions. In some embodiments, the tube comprises at least one therapeutic fluid port between the transducer sleeve and a proximal expandable portion. As used herein, the term "Proximal" means close to the operator and away from the subject being treated and the term "Distal" means distant from the operator and towards the subject being treated. In some embodiments, fluid can be removed via the therapeutic fluid port.

In some embodiments the at least one expandable portion at an expanded state is shaped as a sphere or a spheroid. In some embodiments, the at least one expandable portion at an expanded state is toroidal. In some embodiments, the at least one expandable portion at an expanded state comprises a C-shaped cross-section. In some embodiments, the at least one expandable portion at an expanded state comprises an umbrella configuration. In some embodiments, the catheter comprises a expandable portion shaped at an expanded state as a "dog-bone" having two expanded portions interconnected by a transducer sleeve.

In some embodiments, the at least one expandable portion is configured to maintain at least a portion of the internal bladder surface distant from the transducer sleeve. In some embodiments, the transducer sleeve defines a lumen and the catheter transverses via the lumen. In some embodiments, one or more transducers are mounted on a portion of catheter inside the transducer sleeve lumen. In some embodiments, the transducer is surrounded by a fluid that occupies a volume defined between the transducer and the transducer sleeve surrounding the transducer. In some embodiments of the invention, the fluid cools the enclosed transducers. In some embodiments the fluid is an acoustic fluid for an efficient delivery of acoustic waves produced by a transducer.

According to some embodiments, the transducer sleeve at an expanded state is cylindrical. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is smaller than the maximal cross-sectional area of any one of the expandable portions at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is two thirds of a maximal cross-sectional area of the expandable portions at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is one third of the maximal cross-sectional area of the expandable portions at an expanded state at any point along their longitudinal axis. According to some embodiments, the tube, at least one of the expandable portions, and the transducer sleeve are concentric.

According to some embodiments of the invention, the expandable portions are configured to occupy a portion of the bladder volume at an inflated state, while defining a treatment volume defined by the transducer sleeve wall, walls of the expanded portions disposed at each end of the transducer sleeve and the bladder wall. In some embodiments, the expandable portions occupy at least one half of the bladder volume at an inflated state. In some embodiments, the expandable portions occupy between one third and two thirds of the bladder volume when bladder is at an inflated state. This configuration directs a therapeutic agent containing fluid within the bladder into the treatment volume in the vicinity of the transducer, while protecting sensitive regions of the bladder e.g., the vesical trigone, at the internal surface of the bladder from being treated by the therapeutic agent and/or being affected by energy transmitted by the transducer. In some embodiments of the invention, at least some of the expandable portions are configured to apply pressure on internal surfaces of the bladder at an expanded state.

According to some embodiments of the invention, at least one of the expandable portions is configured to engage the bladder wall at an expanded state and block drainage of fluid from the treatment volume to between the expandable portions and the bladder wall. In some embodiment, an expandable portion at an expanded state maintains the tube concentric with the bladder wall.

According to some embodiments of the invention, the expandable portions and the transducer sleeve are portions of the same balloon mounted on the tube. In some embodiments, the transducer sleeve is inelastic having fixed expanded dimensions. In some embodiments, the transducer sleeve is rigid or comprises a stiffening element.

According to some embodiments of the invention, the catheter comprises a gap between the transducer and the tube. In some embodiments, the gap is in the range of <NUM> to <NUM>. According to some embodiments, the gap is in the range of <NUM> to <NUM>. In some embodiments the transducer is connected to the tube via spacers.

According to an aspect of some embodiments of the present invention there is provided a catheter for ultrasonic-driven bladder therapeutic agent delivery. The catheter comprises a tube, a proximal expandable portion, one or more transducers mounted on the tube between the proximal expandable portion and a distal end of the tube and a transducer sleeve enclosing one or more of the transducers. In some embodiments, the transducer sleeve has deflated state and an expanded state.

In some embodiments, the proximal expandable portion and the transducer sleeve comprise distinct balloons. In some embodiments, the proximal expandable portion and the transducer sleeve comprise portions of one balloon. In some embodiments the proximal expandable portion at an expanded state is shaped as a sphere or spheroid. In some embodiments the proximal expandable portion at an expanded state is shaped as a toroid. In some embodiments, at least one of the proximal expandable portions at an expanded state comprises a C-shaped cross-section. In some embodiments, at least the proximal expandable portions at an expanded state comprises an umbrella configuration.

According to some embodiment of the invention, the tube comprises at least one therapeutic fluid port configured to supply therapeutic fluid into the bladder. In some embodiments, the therapeutic fluid port is located between the transducer sleeve and the proximal expandable portion. In some embodiments, fluid can be removed via the therapeutic fluid port.

According to some embodiments, the proximal expandable portion comprises a balloon that at an expanded state holds the tube at a pre-defined position within the bladder. In some embodiments the proximal expandable portion is configured to engage the bladder wall at an expanded state and block a drainage of fluid from a treatment volume within the bladder to between the proximal expandable portion wall and the bladder wall.

According to some embodiments of the invention, the transducer sleeve at an expanded state is cylindrical having a uniform cross section at least at a portion of its length. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is smaller than the maximal cross-sectional area of the proximal expandable portion at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is two thirds of a maximal cross-sectional area of the proximal expandable portion at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is less than <NUM>% the maximal cross-sectional area of the proximal expandable portion at an expanded state at any point along their longitudinal axis. According to some embodiments, the tube, the proximal expandable portion, and the transducer sleeve are concentric.

According to some embodiments of the invention, the transducer sleeve at an expanded state does not intersect with an imaginary cone extending between an apex located at the distal end of the tube, and a plane defined by the circumference of the expandable portion at an expanded state. According to some embodiment of the invention, the transducer sleeve is inelastic having limited expanded dimensions. In some embodiments, the transducer sleeve is rigid or comprises a stiffening element.

In some embodiments, the therapeutic agent fluid may be a non-gassed fluid. However, in some embodiments, the amount of cavitation bubbles generated in the therapeutic agent fluid are increased by providing a gassed therapeutic agent fluid. Therefore, according to an aspect of some embodiments of the present invention there is provided a method for increasing the amount of cavitation bubbles within a therapeutic agent used with a catheter for ultrasonic-driven bladder therapeutic agent delivery. In some embodiments, the method comprises pressurizing a sterile liquid with a gas and generating a "gassed liquid". In some embodiments, the method comprises releasing a therapeutic agent into the gassed liquid and forming a gassed therapeutic fluid. In some embodiments, the method comprises inserting the gassed therapeutic fluid into the bladder via a catheter for ultrasonic-driven bladder therapeutic agent delivery and forming cavitation in the therapeutic fluid. According to some embodiments of the invention, the method comprises, for example pressurizing a sterile liquid with a gas comprises pressurizing at a pressure of about <NUM> to <NUM> atmospheres and for a predetermined duration.

In some embodiments, the therapeutic agent fluid is mixed with a non-gassed fluid instead of a gassed fluid.

In some embodiments, the catheter comprises an expandable portion such as a balloon, a stent, or any combination thereof. In some embodiments, at least one expandable portion comprises a stent.

Reference is now made to <FIG> and <FIG>, collectively referred to as <FIG>, which is a side view with a perspective enlarged view, simplified illustration of a catheter for ultrasonic-driven bladder therapeutic agent delivery in accordance with some embodiments of the invention. As shown in <FIG>, a catheter <NUM> comprises a tube <NUM>, a transducer <NUM> mounted on tube <NUM> and an expandable portion <NUM> mounted on tube <NUM> and enclosing transducer <NUM>. In the exemplary embodiment depicted in <FIG>, the expandable portion <NUM> is a balloon. In some embodiments, expandable portion <NUM> comprises two expandable portions <NUM> and <NUM> coupled to and sandwiching a transducer sleeve <NUM> disposed in between. The tube <NUM> comprises at least one fluid ports <NUM> and <NUM>, configured to supply or to remove fluid out of at least one of the balloon <NUM> portions <NUM>, <NUM> and <NUM>. The transducer sleeve <NUM> encapsulates the transducer <NUM> and defines a volume between the walls of the transducer sleeve <NUM> and the transducer.

In some embodiments, the tube comprises one or more conduits, or in other words, fluid supply channels, (not shown) supplying fluid from a fluid source to one or more ports. The terms "conduits" and "fluid supply channels" as used herein are interchangeable. The one or more fluid supply channels are disposed inside the tube or along an outer surface of the tube. In some embodiments, a fluid flow is generated within the balloon <NUM> and at least within the internal volume of the transducer sleeve <NUM> by providing fluid via one of the fluid ports, e.g. port <NUM>, and removing fluid via another fluid port, e.g. port <NUM>.

The fluid provided into the balloon comprises an acoustic fluid. The term "acoustic fluid", as referred to herein, relates to a fluid with high cavitation energy threshold to prevent formation of cavitation bubbles in this liquid during operation of the ultrasound that would interfere with acoustic waves, and prevent damage to the catheter. The acoustic fluid allows efficient progression of ultrasound energy. An aspect of this fluid is that it reduces cavitation, which may block ultrasound energy from progressing from the transducer to the bladder internal surface. Such fluid is a degassed fluid, e.g. a degassed solution such as saline which went through boiling, or a solution which its gas content was filtered out. The acoustic fluid assists in transmitting the acoustic waves produced by the transducer <NUM> through the surface of the transducer sleeve <NUM> to the therapeutic fluid surrounding the transducer sleeve. The acoustic fluid can also cool the enclosed transducers <NUM>, for example by heat convection. By the cooling of the transducers, the transducers can be operated in desired parameters for a longer treatment duration. In addition, the overheating of the bladder tissues by heated transducers is avoided.

The acoustic fluid provided into the transducer sleeve <NUM> does not contain gas bubbles to serve as nucleation seeds for the generation of cavitation and therefore distances the cavitation phenomenon from the transducer <NUM> and towards the bladder wall. The ultrasound waves travel from the transducer through the acoustic fluid without generating cavitation, hence are free to travel through this medium towards the surface of the sleeve <NUM>. Then, the waves travel through the therapeutic fluid located in a therapeutic volume between the sleeve and the bladder towards the bladder tissue. In the therapeutic fluid cavitation is generated, thereby, resulting in the delivery of the therapeutic agent into the bladder. This allows the transducer to be disposed farther from the bladder internal surface than transducers exposed to therapeutic fluid inside the bladder. Production of cavitation increases the efficacy of the ultrasound treatment as described in detail in <CIT> to the same inventors.

As shown in the exemplary embodiment depicted in <FIG> and View A of <FIG>, the tube <NUM> comprises a tip <NUM> which comprises a plurality of fluid port(s) <NUM>. In some embodiments, tip <NUM> is convex and configured to allow easier insertion of the catheter into the bladder and reduce accidental damage to the interior surface of the bladder during the deployment of the catheter within the bladder. In some embodiments, tip <NUM> has oblong geometry having fluid ports at a distal end of the tip. In some embodiments, tip <NUM> has no ports. The bladder fluid ports <NUM> can be used, for example, for one or more of the following functions: inserting therapeutic fluid into the bladder, removing therapeutic fluid out of the bladder, inserting tissue cleaning fluid, such as saline to remove a therapeutic fluid, and removing fluid out of the bladder, e.g. urine filling a urine bladder prior to treatment.

In some embodiments, the shape of tip <NUM> is one of a toroid, torus, disk, sphere, and semi-sphere. In some embodiments, the tip <NUM> is rigid or semi-rigid. In some embodiments, the port(s) <NUM> are distributed along at least a portion of the circumference of the tip <NUM>. In some embodiments, the tip <NUM> comprises a surface <NUM> positioned distally in relation to the port(s) <NUM>. In some embodiments, the surface <NUM> is rounded. In some embodiments, the tip <NUM> is blind. In some embodiments, fluid flowing within tube <NUM> exits port(s) <NUM>.

A potential advantage of a plurality of openings (ports) is in that multiple ports provide a redundancy in cases of clogged ports when inserting or removing fluid. In some embodiments in which the transducer sleeve and an expandable portion are disposed on distinct balloons, at least one therapeutic fluid port can be disposed at the tube, between the transducer sleeve and the expandable portion. In some embodiments, at least one therapeutic fluid port can be disposed at the tube at a proximal tube portion which is not covered by any expandable portion.

In some embodiments, the fluid port(s) <NUM> are positioned radially around the longitudinal axis of the catheter and/or tube. In some embodiments, the fluid port(s) <NUM> are positioned such that a fluid streaming from the fluid port(s) <NUM> is ejected at a nonzero angle in relation to the longitudinal axis of the catheter and/or tube.

For example, in the exemplary embodiment depicted in <FIG> and View A of <FIG>, when the catheter <NUM> is inserted into a bladder such that tip <NUM> is urged against the wall of the bladder (e.g., the surface opposite the trigone) marked region <NUM>'', or other portions of the urinary bladder wall, the bladder wall does not obstruct the fluid port(s) <NUM>.

In some embodiments, the tip <NUM> comprises a distal opening of the distal portion 11b of tube <NUM>. In some embodiments, the tip <NUM> comprises at least one port <NUM> at the surface <NUM>. In some embodiments, the tip <NUM> comprises a cover comprising at least one aperture, such as a mesh. In some embodiments, the tip <NUM> cover is rigid or semi rigid. In some embodiments, the cover defines a volume around the tip <NUM>.

For example, in some embodiments, when the catheter <NUM> is inserted into a bladder such that the cover of tip <NUM> is urged against the wall of the bladder, for example, the distal portion of the bladder (such as the surface opposite the trigone) marked region <NUM>", or other portions of the urinary bladder wall, the bladder wall does not obstruct at least one aperture of the tip <NUM> cover.

In some embodiments, at least one of the transducer, at least one of the expandable portion, and the tube are concentric. In some embodiments, at least two expandable portions are concentric. In some embodiments, the transducer and at least one expandable portion are concentric. In some embodiments, the transducer sleeve and at least one expandable portion are concentric. In some embodiments, the transducer sleeve and the transducer are concentric.

An advantage of the concentric positions of the catheter, expandable portion, transducer sleeve and/or transducer is in that the catheter maintains equal distance between the internal bladder wall and the transducer, such that the treated portion of the bladder wall may receive equal or nearly-equal treatments. Additionally, in some embodiments, the treated portion of the bladder wall may receive predetermined varying treatment.

In some embodiments, the tube <NUM> comprises one or more conduits which supply fluid to one or more of the ports <NUM>/<NUM>/<NUM>. In some embodiments, each conduit opens to a specific port <NUM>/<NUM>/<NUM>. In some embodiments, each conduit opens to a separate port <NUM>/<NUM>/<NUM>. In some embodiments, a conduit opens to at least one of the ports <NUM>/<NUM>/<NUM>.

In some embodiments, tube lumen <NUM> comprises at least one conduit. In some embodiments, at least one conduit is in fluid communication with a proximal opening <NUM>/<NUM>/<NUM> of the catheter <NUM>.

In some embodiments, the catheter <NUM> comprises at least one proximal opening <NUM>/<NUM>/<NUM> through which fluid passes into and/or out of one or more ports <NUM>/<NUM>/<NUM>. In some embodiments, a proximal opening <NUM>/<NUM>/<NUM> is in fluid communication with a reservoir for fluid, such as, for example, a therapeutic fluid, a fluid (e.g. saline), a gassed fluid, and an acoustic fluid. In some embodiments, a proximal opening <NUM>/<NUM>/<NUM> is in fluid communication with a drainage bag. In some embodiments, at least one conduit is coupled to one or more of the proximal openings <NUM>/<NUM>/<NUM>. In some embodiments, each of the proximal openings <NUM>/<NUM>/<NUM> is in fluid communication with at least one of the ports <NUM>/<NUM>/<NUM>.

<FIG> is a perspective view simplified illustration of implementation of an ultrasonic-driven bladder therapeutic agent delivery inside a bladder <NUM> in accordance with some embodiments of the invention. In the exemplary embodiment depicted in <FIG>, expandable portions <NUM> and <NUM> are spheroid in geometry and in an expanded state. In some embodiments, both expandable spheroid portions <NUM> and <NUM> occupy a portion of the bladder volume, thereby forming a treatment volume <NUM> surrounding the transducer sleeve <NUM> between the expandable spheroid portions <NUM> and <NUM> and the bladder wall <NUM>. A potential advantage of this configuration is in that a therapeutic agent disposed within the bladder <NUM> will be directed into the treatment volume <NUM> between the transducer <NUM> and the bladder wall <NUM>, limiting the treatment on bladder tissues to section <NUM>' of the bladder wall and the treatment volume <NUM> and benefiting from the full effect of cavitation formed by transducer <NUM>. Additionally, in some embodiments, this configuration directs a therapeutic agent containing fluid within the bladder <NUM> into the treatment volume <NUM>, while protecting regions e.g., the vesical trigone, at the internal surface of the bladder <NUM> from being treated by the therapeutic agent and/or energy transmitted by the transducer <NUM>. In some embodiments, the expandable portions <NUM> and <NUM> occupy between <NUM>% and <NUM>% of the bladder volume at an expanded state. In some embodiments, the expandable portions <NUM> and <NUM> occupy between <NUM>% and <NUM>% of the bladder volume at an expanded state.

Normally, in a relaxed state, a bladder wall is undulated in shape. In some embodiments, the inflated balloon <NUM> applies tension in the internal surface <NUM> of the bladder <NUM> in a plurality of directions, thereby straightening at least a portion of the bladder wall of the bladder at least in region <NUM>' bordering the treatment volume <NUM> between expandable portion <NUM> and <NUM> as shown in <FIG>.

Since the expanded balloon has a predictable geometry and dimensions at a pre-defined pressure, the measurements of the treatment volume <NUM> surrounding the transducer <NUM> are also predictable. Expandable portions <NUM> and <NUM> can be designed to have a circumference at a fully expanded state that will define a pre-determined distance L1 between the transducer <NUM> and the bladder treated surface <NUM>'. In some embodiments, a uniform treatment is achieved by having the treated tissues at equidistance from the transducer. In some embodiments, the concentration of the therapeutic agent within the therapeutic fluid are determined by the predictable treatment volume <NUM>. Straightening and stretching the bladders' tissues contribute to the efficacy of the treatment by increasing the permeability of the therapeutic agent into the bladder tissues. In addition, such structural configuration stabilizes the bladder wall and increases the safety of the procedure by preventing the collapse of the bladder wall onto or close to the hot transducer surface. In addition, the transducer sleeve <NUM> prevent a direct contact between the bladder and the transducer <NUM>.

In some embodiments, and as described in greater detail elsewhere herein, one or more of the expandable portions is a stent.

In some embodiments, e.g., in treatment of the urinary bladder, the procedure is carried out when the bladder is positioned vertically or close to vertically wherein the trigone is lowest portion of the urinary bladder. In some embodiments, as shown in <FIG>, the distal expandable portion <NUM> does not seal a distal portion of the bladder (e.g., the surface opposite the trigone) marked region <NUM>". The therapeutic fluid provided through ports <NUM> can then flow into the volume <NUM>, e.g. by gravity or by pressure gradient. In some embodiments, the proximal expandable portion <NUM>, as illustrated in <FIG>, engages the proximal surface of the bladder. At an expanded state, the expandable portion <NUM> can block a drainage of fluid from the therapeutic volume <NUM> being pressed against the bladder wall. The expandable portion <NUM> can be pressed against and seal the proximal surface of the bladder (e.g. by static forces, such as gravity, fluid pressure, distal spheroid pressing against a distal bladder surface). Thereby, the therapeutic fluid remains within the therapeutic volume <NUM> during the treatment, while bladder tissues located beyond the expandable portion <NUM> are protected from being exposed and treated by the therapeutic fluid and the acoustic energy.

In some embodiments, the proximal and/or distal expandable portion <NUM>/<NUM> shields portions of the bladder wall from ultrasonic energy. In some embodiments, the proximal expandable portion <NUM> shields the trigone from ultrasonic energy. In some embodiments, the proximal and/or distal expandable portion <NUM>/<NUM> acts as a vessel for a cooling fluid flow which increases heat dissipation from the transducer.

In some embodiments, at least one of the proximal and/or distal expandable portion <NUM>/<NUM> is filled with fluid which has high acoustic impedance and therefore is non-conducive to ultrasound energy. In some embodiments, the non-conducive fluid inflates at least one of the proximal and/or distal expandable portion <NUM>/<NUM>. In some embodiments, the non-conducive fluid prevents transmission of ultrasound energy to the untreated areas of the bladder (e.g., the trigone).

A potential advantage of having the non-conducive fluid within one or more expandable portions <NUM>/<NUM> is in that ultrasound energy is not transmitted to portions of the bladder which are not treated.

In some embodiment of the invention, expandable portion <NUM> serves as a catheter support and fixes the position of the tube <NUM> within the bladder <NUM>. In some embodiments, fluid within one or more expanded portions engaging an internal surface <NUM> of the bladder <NUM>, cools the bladder by heat transfer between the bladder wall and the fluid.

In some embodiments, the volume and/or shape of the expandable portions <NUM>/<NUM> determine the distance between the bladder treated surface <NUM>' and the transducer <NUM>. In some embodiments, the volume and/or shape of the expandable portions <NUM>/<NUM> determine the distance between the bladder treated surface <NUM>' and the transducer sleeve <NUM>. In some embodiments, the distance between the bladder treated surface <NUM>' and the transducer <NUM> and/or the transducer sleeve <NUM> is predetermined.

The temperature of the bladder treated surface <NUM>' is correlated with the heat given off by the transducer. Therefore, increasing the distance between the transducer <NUM> and the bladder treated surface <NUM>' prevents over-heating of the bladder treated surface <NUM>'. In some embodiments, increasing the distance between the transducer <NUM> and the bladder treated surface <NUM>' permits heating of the transducer <NUM> to higher temperatures, for example, by increasing on-time and/or frequency emitted by the transducer.

In some embodiments, increasing the frequency emitted by the transducer increases the efficacy of the treatment by increasing the cavitation within the therapeutic fluid (and/or combination of the gassed fluid and therapeutic fluid). In some embodiments, increasing the on-time of the transducer increases the efficacy of the treatment by increasing the cavitation within the therapeutic fluid (and/or combination of the gassed fluid and therapeutic fluid).

As shown in <FIG>, according to some embodiment of the invention, expandable portions <NUM> and <NUM> define a cylinder <NUM> therebetween, the wall of the cylinder outlined by broken lines, congruent with the largest circumference of the expandable portions <NUM>/<NUM> at Y1 and Y2 respectively. In some embodiments and as explained in detail elsewhere herein, the maximal cross-sectional area of the transducer sleeve <NUM> taken at Y3 is smaller than the maximal cross-sectional area of the expanded portions <NUM> and <NUM>. In some embodiments a diameter D <NUM> of expandable portions <NUM> and <NUM> is between <NUM> and <NUM> at an expanded state. In some embodiments, a diameter D10 of expandable portions <NUM> and <NUM> is between <NUM> and <NUM> at an expanded state. In some embodiments, a diameter D20 of a transducer sleeve <NUM> is between <NUM> and <NUM>. In some embodiments, a diameter D20 of a transducer sleeve <NUM> is between <NUM> and <NUM>. In some embodiments, a diameter D20 of a transducer sleeve <NUM> is between <NUM> and <NUM>. In some embodiments a length L30 of the transducer sleeve is between <NUM> and <NUM> at an expanded state. In some embodiments a length L30 of the transducer sleeve is between <NUM> and <NUM> at an expanded state.

In some embodiments, the transducer sleeve at an expanded state is cylindrical having a uniform cross section at least at a portion of its length. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is smaller than the maximal cross-sectional area of the proximal expandable portion at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is two thirds of a maximal cross-sectional area of the proximal expandable portion at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is less than <NUM>% the maximal cross-sectional area of the proximal expandable portion at an expanded state at any point along their longitudinal axis. According to some embodiments, the tube, the proximal expandable portion, and the transducer sleeve are concentric.

In some embodiments, the length of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the length of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the length of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the length of the transducer <NUM> is <NUM>.

In some embodiments, the width of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the width of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the width of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the width of the transducer is <NUM>.

In some embodiments, the thickness of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the thickness of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the thickness of the transducer <NUM> is <NUM>-<NUM>. In some embodiments, the thickness of the transducer <NUM> is <NUM>.

In some embodiments, the balloon wall comprises regions having variable elasticity so that, for example, only portions of the balloon wall are elastically expandable. diametrically opposed faces 24a and 24c (<FIG>) of expandable portion <NUM> can be produced as an inelastic face, while a face 24b along the circumference of expandable portion <NUM> is elastically flexible, hence the expansion of portion <NUM> will be greater radially expansion along catheter tube <NUM>.

In some embodiments at least one of the expandable portions at an expanded state is shaped as at least one of a sphere, a spheroid and a toroid. In some embodiments, at least one of the expandable portions at an expanded state comprises a C-shaped cross-section. In some embodiments, at least one of the expandable portions at an expanded state comprises an umbrella configuration.

In some embodiments, the transducer sleeve at an expanded state is cylindrical. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is smaller than the maximal cross-sectional area of any one of the expandable portions at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is two thirds of a maximal cross-sectional area of the expandable portions at an expanded state at any point along their longitudinal axis. In some embodiments, the maximal cross-sectional area of the transducer sleeve at an expanded state is one third of the maximal cross-sectional area of the expandable portions at an expanded state at any point along their longitudinal axis. In some embodiments, the tube, at least one of the expandable portions, and the transducer sleeve are concentric.

In some embodiments of the invention, the expandable portions are configured to occupy a portion of the bladder volume at an inflated state, while defining a treatment volume defined by the transducer sleeve wall, walls of the expanded portions disposed at each end of the transducer sleeve and the bladder wall. In some embodiments, the expandable portions occupy at least one half of the bladder volume at an inflated state. In some embodiments, the expandable portions occupy between one third and two thirds of the bladder volume when bladder is at an inflated state. This configuration directs a therapeutic agent containing fluid within the bladder into the treatment volume in the vicinity of the transducer, while protecting sensitive regions of the bladder e.g., the vesical trigone, at the internal surface of the bladder from being treated by the therapeutic agent and/or being affected by energy transmitted by the transducer. In some embodiments of the invention, at least some of the expandable portions are configured to apply pressure on internal surfaces of the bladder at an expanded state.

In some embodiments, shaping of any of the balloons can done by: molding, differential thickness, varying materials, integral elements, etc. Another method for shaping any of the balloon portions can be by limiting its expansion by external elements, such as a sleeve or a net.

In some embodiments, the tube <NUM> has a uniform cross section throughout its length. In some embodiments, a distal portion 11b of tube <NUM> comprises a smaller diameter than the diameter of proximal portion 11a of tube <NUM>. In some embodiments, as shown in view A in <FIG>, portion 11b comprises the distal tip <NUM>. In some embodiments, portion 11b is connected to tube <NUM> under a proximal edge of transducer <NUM>. In some embodiments, transducer <NUM> is mounted on portion 11b of tube <NUM> so that an external surface of transducer <NUM> is positioned flush with proximal portion 11a of tube <NUM>. In some embodiments portion 11b comprises a narrow tube portion inserted within tube <NUM>.

In some embodiments, each of ports <NUM>/<NUM> are supplied by distinct fluid supply channel so that supplying fluid to expandable portion <NUM> via port <NUM> does not necessarily expand expandable portion <NUM> and vice versa, even though expandable portions <NUM>/<NUM> are in fluid communication via transducer sleeve <NUM>. In some embodiments port <NUM> is associated with a distinct fluid supply channel of the tube <NUM>. In some embodiments, port <NUM> is configured to be closed when providing fluid by port <NUM>. A potential advantage in the configuration of ports <NUM>/<NUM> is in that during deployment, expandable portion <NUM> is configured to be inflated while expandable portion <NUM> is still within urethra <NUM>, i.e., without expanding expandable portion within urethra <NUM>, which may be painful to the subject being treated.

Reference is now made to <FIG>, which are plan view simplified illustrations of the method of implementation of a catheter for ultrasonic-driven treatment of a bladder. As shown in <FIG>, the catheter for ultrasonic-driven treatment of a bladder is deployed by:.

Reference is now made to <FIG>, which is a flow chart of a method for deploying of a catheter for ultrasonic-driven treatment of a bladder wall in accordance to some embodiments of the invention and to corresponding <FIG>, which are side-view simplified illustrations of the method of implementation of a catheter for ultrasonic-driven treatment of a bladder. As shown in <FIG>, the catheter <NUM> for ultrasonic-driven treatment of a bladder <NUM> is deployed by:.

In some embodiments, the method comprises expanding the proximal expandable portion and trapping the therapeutic fluid between the distal expandable portion and the proximal expandable portion.

A potential advantage in using the method for deployment of the ultrasonic-driven catheter <NUM> is in that most of the therapeutic fluid does not remain trapped at a distal volume between the distal expandable portion <NUM> and the bladder wall <NUM>" opposite to the bladder trigone.

<FIG> is a plan view simplified illustration of the insertion of distal expandable portion <NUM> into bladder <NUM> through urethra <NUM>. In some embodiments, the proximal expandable portion <NUM> remains within the urethra <NUM>.

<FIG> is a plan view simplified illustration of the expanding of distal expandable portion <NUM> to an expanded state by providing fluid into distal expandable portion <NUM> via fluid port <NUM> (for example, as depicted by arrow <NUM>). In some embodiments, the distal expandable portion <NUM> and the proximal expandable portion <NUM> are in fluid communication. The fluid remains in distal expandable portion <NUM>, flow in the direction of proximal expandable portion <NUM> countered by external pressure applied to proximal expandable portion <NUM> by the urethra wall. Accordingly, the proximal expandable portion <NUM> remains contracted within the urethra due to pressure applied to the proximal expandable portion <NUM> by the urethra walls. In some embodiments, the proximal expandable portion <NUM> remains mostly contracted within the urethra.

<FIG> is a plan view simplified illustration of supplying of therapeutic fluid through the therapeutic fluid port(s) <NUM>. In some embodiments, the method comprises supplying therapeutic fluid through the therapeutic port(s) <NUM> into the volume <NUM> defined by the distal expanding portion <NUM> and the bladder wall (for example, as depicted by arrow <NUM>).

<FIG> is a plan view simplified illustration of the further advancing proximal portion <NUM> into bladder <NUM> through urethra <NUM>. In some embodiments, during the further advancement of the proximal portion <NUM> into bladder <NUM>, proximal portion <NUM> is freed from external pressure applied thereto by the urethra walls and at least a portion of the fluid inside the distal expandable portion <NUM> flows into the proximal expandable portion <NUM> to equalize pressures within expandable portions <NUM> and <NUM> in accordance with the law of LaPlace. In some embodiments, fluid inside the distal expandable portion <NUM> flows into the portion of the proximal expandable portion <NUM> which is within the bladder <NUM>. In some embodiments, the volume of the distal expandable portion <NUM> decreases due to fluid flow into the proximal expandable portion <NUM>. In some embodiments, the decrease in volume of the distal expandable portion <NUM> increases flow of therapeutic fluid into the bladder volume <NUM> surrounding the transducer sleeve <NUM>. In some embodiments, the decrease in volume of the distal expandable portion <NUM> creates or increases a distance <NUM> between the distal expandable portion <NUM> and the bladder wall, which increases flow of therapeutic fluid to volume <NUM>. In some embodiments, the partially expanded proximal expandable portion <NUM> provides a barrier for therapeutic fluid flowing into volume <NUM>.

<FIG> is a plan view simplified illustration of the expanding of portion <NUM> to an expanded state by providing fluid into portion <NUM> via fluid port <NUM> (for example, as depicted by arrow <NUM>). In some embodiments, expanding proximal expandable portion <NUM> to an expanded state by providing fluid via port <NUM> increases the volumes of both the proximal and distal expandable portions <NUM>/<NUM>.

In some embodiments, the expandable portions <NUM>/<NUM> are separate balloons. In some embodiments, during or after the further advancement of the proximal portion <NUM> into bladder <NUM>, at least a portion of the fluid inside the distal expandable portion <NUM> is removed via fluid port <NUM>. In some embodiments, the volume of the distal expandable portion <NUM> decreases. In some embodiments, during or after the further advancement of the proximal portion <NUM> into bladder <NUM>, the proximal expandable portion <NUM> is at least partially expanded by providing fluid via fluid port <NUM>. In some embodiments, once therapeutic fluid enters the volume <NUM> surrounding the transducer sleeve <NUM>, the distal expandable portion <NUM> is expanded by providing fluid into the distal expandable portion <NUM> via fluid port <NUM>.

In some embodiments, the ultrasonic-driven treatment performed by catheter <NUM> inserted within a bladder <NUM> is carried out by a method in accordance with some embodiments of the invention and includes:.

In some embodiments, the ultrasonic-driven treatment performed by catheter <NUM> inserted within a bladder <NUM> is terminated by the following method, according to some embodiments of the invention:.

Reference is now made to <FIG>, which is a flow chart of a method for the deployment of a catheter for ultrasonic-driven treatment of a bladder wall and the treatment of the bladder in accordance to some embodiments of the invention. As shown in <FIG>, the method for deployment of catheter <NUM> in bladder <NUM> is carried out as follows:.

In some embodiments of the invention and as further shown in <FIG>, deployment of the catheter is followed by a method of treatment of the bladder comprising:.

In summary and in accordance with some embodiments of the invention treatment of the bladder comprises at least the following methods:.

Reference is now made to <FIG> and <FIG>, collectively referred to as <FIG>, which are a side view and perspective view simplified illustration of a catheter for ultrasonic-driven bladder therapeutic agent delivery in accordance with some embodiments of the invention. As shown in <FIG>, a catheter <NUM> comprises a tube <NUM>, a proximal balloon <NUM> mounted on the tube <NUM>, and an expandable transducer sleeve <NUM>. Turning to the enlarged view B in <FIG>, in some embodiments, a distal portion 111b of tube <NUM> comprises a smaller diameter than the diameter of proximal portion 111a of tube <NUM>. In some embodiments, as shown in view B in <FIG>, portion 111b comprises the distal tip <NUM>. In some embodiments, portion 111b is connected to tube <NUM> under a proximal edge of transducer <NUM>. In some embodiments, transducer <NUM> is mounted on portion 111b of tube <NUM> so that an external surface of transducer <NUM> is positioned flush with proximal portion 111a of tube <NUM>. In some embodiments, portion 111b comprises a narrow tube portion inserted within tube <NUM>.

In some embodiments, a transducer <NUM> is mounted on tube <NUM> portion 111b between the proximal expandable portion <NUM> and a distal end <NUM> of the tube. In some embodiments, the transducer sleeve <NUM> accommodates and encapsulates the transducer <NUM> and enables a flow of fluid at the internal volume defined by the walls of transducer sleeve <NUM>. In some embodiments, the tube <NUM> comprises one or more therapeutic fluid port(s) <NUM> at a proximal portion 111a of the tube <NUM>, which is free of the expandable portions <NUM> and <NUM> and is exposed to the bladder volume.

In some embodiments, proximal balloon <NUM> is expandable from a collapsed state to an expanded state. In some embodiments, the expanded state is defined as the maximal inelastic expansion of the balloon. In some embodiments, the expanded state of the balloon is defined as a maximal elastic expansion wherein the balloon is elastic. The tube <NUM> comprises one or more fluid ports <NUM>, 115a and 115b, configured to supply fluid to or remove fluid from at least one of the expandable portions <NUM> and <NUM>. Expandable portions <NUM> and <NUM> are expandable by supplying fluid under positive pressure through at least one of the fluid ports <NUM>, 115a and 115b. In some embodiments, the tube <NUM> comprises one or more fluid supply channels (not shown), either inside the tube <NUM> and/or along an outer surface of the tube. In some embodiments, a fluid flow is generated within a lumen defined by walls of transducer sleeve <NUM> by providing fluid via one of the fluid ports, e.g. port 115a, and removing fluid via another fluid port, e.g. port 115b. In some embodiments, fluid supply port, e.g. port 115a and fluid removal port, e.g. port 115b are disposed on diametrically opposed surfaces of catheter <NUM>. In some embodiments, fluid supply port, e.g. port 115a is located on tube <NUM> portion 111b whereas the fluid removal port, e.g. port 115b is disposed on tube <NUM>. In some embodiments, fluid supply port, e.g. port 115a and fluid removal port, e.g. port 115b are disposed on opposite sides of transducer <NUM>. In some embodiments, fluid supply port, e.g. port 115a, and fluid removal port, e.g. port 115b, are circumferentially rotated in respect to each other.

In some embodiments, the fluid inputted into the balloon comprises an acoustic fluid. The acoustic fluid maintains a fixed distance between the surface of transducer <NUM> and transducer sleeve <NUM>. In some embodiments, the acoustic fluid assists in cooling the enclosed transducers <NUM>, for example by heat convection.

In some embodiments, cooling of the transducers helps in their operating in desired parameters for a longer treatment duration, thus, avoiding overheating the tissues while providing an effective treatment. In some embodiments, and as described in greater detail elsewhere herein, removing heat from the transducers prevents overheating of the bladder tissue, which permits an increase in the range of the operational parameters, such as, for example, longer treatment time and/or an increase in transducer frequency.

In some embodiments, e.g., in treatment of the urinary bladder, the procedure is carried out when the bladder is positioned vertically or close to vertically wherein the trigone is lowest portion of the urinary bladder. As shown in the exemplary embodiment depicted in <FIG>, which is a side view simplified illustration of implementation of an ultrasonic-driven bladder therapeutic agent delivery inside a bladder in accordance with some embodiments of the invention, the proximal balloon <NUM>, at an expanded state, engages the proximal surface of the bladder at the trigone area. The proximal balloon <NUM> occupies a volume of the bladder <NUM>, thereby forming a treatment volume <NUM>. Balloon <NUM> at an expanded state blocks drainage of fluid from volume <NUM> via the balloon wall which is urged against the bladder wall <NUM>. In some embodiments, balloon <NUM> is urged against and seals the proximal surface (trigone area) of the bladder <NUM>', for example by static forces, such as gravity or fluid pressure. Thereby, the therapeutic fluid remains within volume <NUM> during the treatment, while the proximal surface (trigone area) of the bladder <NUM>' located distally to proximal balloon <NUM> remains protected from exposure to the therapeutic fluid and the acoustic energy. In some embodiment of the invention, balloon <NUM> serves as a catheter base and fixes the position and orientation of the tube <NUM> in respect to the bladder as well as the elements mounted on the tube within the bladder <NUM>.

When a treatment is not required on a distal region or other regions of the bladder, therapeutic fluid can be provided into the bladder in an amount which will fill only a portion of the bladder. During treatment, due to gravitation, the level of fluid will be lower than pre-determined surfaces, so will not be treated by the therapeutic fluid and acoustic energy. As shown in <FIG>, which is a side view simplified illustration of implementation of an ultrasonic-driven bladder therapeutic agent delivery inside a bladder in accordance with some embodiments of the invention, therapeutic fluid partially fills volume <NUM> of the bladder <NUM>. Since the bladder <NUM> is oriented vertically, the direction of gravitation indicated by an arrow (G), the therapeutic fluid remains in between levels E1 and E2. During the treatment, only a portion of the bladder wall which is located distally (above) to proximal balloon <NUM> in region <NUM>" and within volume <NUM> will receive the therapeutic fluid and acoustic energy.

In some embodiments, the regions of the bladder wall affected by the treatment are defined by the following dimensions of elements of the catheter <NUM> such as, for example: the cross section of the proximal balloon <NUM>, the distance between port <NUM> and face 124b, and the distance between port <NUM> and the transducer sleeve <NUM>.

The transducer sleeve <NUM> isolates the transducer <NUM> from the therapeutic agent and prevents cavitation bubbles from forming near or on the transducer surface. Thereby, the transducer can be disposed farther from the bladder internal wall than in the absence of a transducer sleeve <NUM>. This allows distribution of cavitation bubbles within treatment volume <NUM>, to invoke cavitation on the bladder wall, thus increasing the efficacy of energy emitted towards the bladder wall by the transducers. Some parameters that determine the expanded geometrical shape of the transducer sleeve <NUM> can be: size and number of the transducers <NUM> it encloses, flow characteristic of the fluid within its internal volume, desired volume of the bladder extraneous to the transducer sleeve, etc. The transducer sleeve <NUM> can be characterized to be inelastic having a fixed expanded length, to be rigid or to comprise a stiffening element, and in some embodiments the sleeve can be pressurized to higher pressure than other expandable portions.

Turning to <FIG>, which is a side view simplified illustration of a catheter for ultrasonic-driven bladder therapeutic agent delivery in accordance with some embodiments of the invention. As shown in the exemplary embodiment depicted in <FIG>, during implementation, the geometry of the catheter <NUM> protects the wall of the bladder from collapsing onto transducer sleeve <NUM>. As shown in <FIG>, a bladder wall tends to conform to the geometry of the catheter <NUM> forming a cone <NUM> depicted in <FIG> by a phantom-line triangle <NUM>. In some embodiments, tip <NUM> of catheter <NUM> forms an apex <NUM> of cone <NUM> and a base <NUM> of cone <NUM> is formed at the maximal cross-sectional area of the proximal balloon <NUM> at an inflated state. In this configuration, the wall of the bladder is prevented from collapsing onto and contacting transducer sleeve <NUM> at an inflated state. This constraint can be driven for example by a requirement to maintain a distance between the transducer sleeve walls and the enclosed transducer e.g. in case the bladder surface collapses and engages the sleeve <NUM>, to avoid bending of the sleeve, etc. In some embodiments a diameter D110 of proximal balloon <NUM> is between <NUM> and <NUM> at an expanded state. In some embodiments, a diameter D110 of proximal balloon <NUM> is between <NUM> and <NUM> at an expanded state. In some embodiments, a diameter D120 of a transducer sleeve <NUM> is between <NUM> and <NUM>. In some embodiments, a diameter D120 of a transducer sleeve <NUM> is between <NUM> and <NUM>. In some embodiments, a diameter D120 of a transducer sleeve <NUM> is between <NUM> and <NUM>. In some embodiments a length L130 of the transducer sleeve is between <NUM> and <NUM> at an expanded state. In some embodiments a length L130 of the transducer sleeve is between <NUM> and <NUM> at an expanded state.

In some embodiments, catheter <NUM> can comprise two distinct balloons such as shown, for example, in <FIG>. In some embodiments, different pressures or different pressuring fluids can be used for the expansion of the proximal balloon <NUM> and the transducer sleeve <NUM> portions. In some embodiments, only portions of the wall of balloon <NUM> are elastically inflatable, while other portions are inelastic.

In some embodiments, a method for deployment of the ultrasonic-driven catheter according to some embodiments of the invention includes:.

In some embodiments, a method for treatment of a bladder wall using an ultrasonic-driven catheter according to some embodiments of the invention includes:.

In some embodiments, the ultrasonic-driven treatment performed by the catheter <NUM> inserted within a bladder <NUM> is terminated by the following method, according to some embodiments of the invention:.

In accordance to some embodiments of the invention, the deployment of the catheter for ultrasonic-driven treatment of a bladder wall and treatment is carried out within the bladder, by the following method:.

In some embodiments of the catheter for ultrasound-driven treatment of a bladder, at least one of the expandable portions at an expanded state is shaped as at least one of a sphere, a spheroid or a toroid. In some embodiments, at least one of the expandable portions at an expanded state comprises a C-shaped cross-section. In some embodiments, at least one of the expandable portions at an expanded state comprises an umbrella configuration.

For example, <FIG> shows an embodiment in which the expandable portion <NUM> is toroidal in geometry. In some embodiments, catheter <NUM> comprises a therapeutic fluid port <NUM> between a transducer sleeve <NUM> and the expandable portion <NUM>. In the exemplary embodiment shown in <FIG>, toroidal expandable portion <NUM> when inflated, expands distally, along catheter tube <NUM> towards tip <NUM> as indicated by arrows <NUM> and directing any therapeutic fluid supplied via therapeutic fluid port <NUM> into treatment volume <NUM> to surround transducer <NUM> thus increasing treatment efficacy.

A potential advantage in this configuration is in that the treatment area is more limited and therefore defined more accurately and that a lower amount of therapeutic fluid is required to treat a given area of bladder wall limiting waste of therapeutic fluid.

Shaping of any of the balloons can done by: molding, differential thickness, varying materials, integral elements, etc. Another method for shaping any of the balloon portions can be by limiting its expansion by external elements, such as a sleeve or a net.

In some embodiments, the catheter for ultrasound-driven treatment of a bladder is configured to comprise energy supply conduits for the ultrasound transducer <NUM>/<NUM>/<NUM>. Additionally, in some embodiments, the catheter for ultrasound-driven treatment of a bladder comprises one or more thermocouples disposed within one or more of the expandable portions. In some embodiments, the thermocouple is configured to measure fluid temperature within the treatment volume. In some embodiments, one or more thermocouples are configured to measure temperature of the bladder wall tissue to prevent overheating of the wall of the bladder. In some embodiments, one or more of the thermocouples are coupled to the bladder wall. In some embodiments, the thermocouple is configured to measure fluid temperature within one or more of the expandable portions and/or the transducer sleeve. In some embodiments, the thermocouple is configured to measure temperature over the surface of the transducer. In some embodiments, the catheter for ultrasound-driven treatment of a bladder comprises one or more pressure sensors within at least one of the expandable portions configured to monitor fluid pressure within the expandable portion. In the exemplary embodiments illustrated in <FIG> and <FIG>, the transducers <NUM>/<NUM> are cylindrical. However, in other embodiments, the transducer can be flat. In some embodiments, transducers <NUM>/<NUM> are mounted on the tube <NUM>/<NUM> by spacers <NUM>/<NUM> and <NUM>/<NUM>. Fixation of the transducer at a pre-determined location on the tube provides predictable and repeatable energy parameters.

In some embodiments, the spacers <NUM>/<NUM> and <NUM>/<NUM> are configured to support the transducers elevated from tube <NUM>/<NUM>, so to form a gap between the transducer and the tube <NUM>/<NUM>. In some embodiments the gap is in the range between <NUM> and <NUM>. In some embodiments the gap is in the range between <NUM> and <NUM>. In some embodiments, the gap is filled by acoustic fluid flowing within the enclosing transducer sleeve <NUM>/<NUM>, which can result in cooling of the transducer. In some embodiments, the gap is filled by acoustic fluid which flows within the transducer sleeve <NUM>/<NUM>, thereby transferring heat form the transducer.

In some embodiments, the one or more of the spacers <NUM>/<NUM>/<NUM>/<NUM> is mounted on the tube <NUM>/<NUM>. In some embodiments, the transducer <NUM>/<NUM> is mounted on one or more of the spacers <NUM>/<NUM>/<NUM>/<NUM>. In some embodiments, a transducer <NUM>/<NUM> is positioned onto one spacer <NUM>/<NUM>/<NUM>/<NUM>. In some embodiments, the transducer <NUM>/<NUM> is positioned on a plurality of spacers <NUM>/<NUM>/<NUM>/<NUM>. In some embodiments, the length of the spacer <NUM>/<NUM>/<NUM>/<NUM> is larger than the outermost radius of the spacer <NUM>/<NUM>/<NUM>/<NUM>. In some embodiments, the length of the spacer is at least <NUM>% of the length of the transducer <NUM>/<NUM>. In some embodiments, the length of the spacer <NUM>/<NUM>/<NUM>/<NUM> is up to <NUM>% of the length of the transducer <NUM>/<NUM>.

In some embodiments, the spacer <NUM>/<NUM>/<NUM>/<NUM> adds concentricity, electrical protection, and mechanical scaffold to the catheter for ultrasonic-driven bladder drug delivery. In some embodiments, distancing the transducer from the catheter and/or tube provides electrical insulation by having an isolation medium (e.g., air) between the transducer and the catheter.

Turning to <FIG>, which are simplified illustrations of side views of a catheter for ultrasonic-driven bladder drug delivery, in accordance with some embodiments of the present disclosure. As shown in <FIG>, normally open stents, e.g. expandable stents <NUM>, <NUM>, <NUM>, replaces at least some of expandable portions disclosed in the preceding embodiments, such as <NUM>, <NUM>, <NUM>, can be replaced by normally open stents, e.g. expandable stents <NUM>, <NUM>, <NUM>. Each of the stents <NUM>, <NUM>, <NUM> are configured as normally open and remains enclosed within a stent sleeve (not shown) prior to inserting the catheter <NUM>/<NUM> into a bladder. The stents are configured to open upon exposing out of the stent sleeve and to engage the bladder wall. Any of the stents can have a fluid sealing surface to block fluid within a bladder cavity volume defined within the bladder on one side of the sealing surface to flow into a bladder cavity volume defined on an opposite side of the stent sealing surface.

In the embodiments illustrated in <FIG> and <FIG>, the transducers are fixed to the tube by spacers (e.g. <NUM>/<NUM> and <NUM>/<NUM>). The fixation of the transducer at a pre-determined location and centralized around the tube, helps providing predictable and repeatable energy parameters. The spacers support the transducers, such that a gap is defined between the transducer and the tube. In some embodiments, the gap is in the range of <NUM> to <NUM>. In some embodiments, the gap is in the range of <NUM> to <NUM>. In some embodiments, the gap is filled by an acoustic fluid which flows within the enclosing transducer sleeve <NUM>/<NUM>/<NUM>/<NUM>, thereby cooling the transducer.

In some embodiments, at least one of stents <NUM>, <NUM>, <NUM> is replaceable by a balloon. In some embodiments, the catheter for ultrasonic-driven bladder drug delivery comprises at least one balloon, at least one stent, or any combination thereof.

The following are some examples of treatment parameters that enable an effective and safe treatment, according to some embodiments of the invention:.

In some embodiments, the ultrasound transducer is between <NUM>-<NUM>. In some embodiments, the ultrasound transducer is between <NUM>-<NUM>. In some embodiments, the ultrasound transducer is between <NUM>-<NUM>.

In some embodiments, the ultrasound transducer duty cycle is between <NUM>-<NUM>%. In some embodiments, the ultrasound transducer duty cycle is between <NUM>-<NUM>%. In some embodiments, the ultrasound transducer duty cycle is between <NUM>-<NUM>%.

In some embodiments, the ultrasound Isppa intensity is between <NUM>-<NUM> W/cm2. In some embodiments, the ultrasound Isppa intensity is between <NUM>-<NUM> W/cm2. In some embodiments, the ultrasound Isppa intensity is between <NUM>-<NUM> W/cm2.

The bladder distance from the ultrasound transducer ranges between <NUM>-<NUM>
In some embodiments, the total treatment time in which the transducer is in use ranges between <NUM>-<NUM> minutes. In some embodiments, the total treatment time in which the transducer is in use ranges between <NUM>-<NUM> minutes. In some embodiments, the total treatment time in which the transducer is in use ranges between <NUM>-<NUM> minutes.

In some embodiments, the acoustic fluid pressure ranges between <NUM> Mpa to 2Mpa. In some embodiments, the acoustic fluid pressure ranges between <NUM>. 5Mpa to 1MPa.

In some embodiments, <NUM>-<NUM> of fluid fill up the volume of the transducer sleeve. In some embodiments, <NUM>-<NUM> of fluid fill up the volume of the transducer sleeve. In some embodiments, <NUM>-<NUM> of fluid fill up the volume of the transducer sleeve.

In some embodiments, <NUM>-<NUM> of fluid fill up the volume of at least one expandable portion <NUM>/<NUM>/<NUM>/<NUM>. In some embodiments, <NUM>-<NUM> of fluid fill up the volume of at least one expandable portion <NUM>/<NUM>/<NUM>/<NUM>. In some embodiments, <NUM>-<NUM> of fluid fill up the volume of at least one expandable portion <NUM>/<NUM>/<NUM>/<NUM>.

In some embodiments, <NUM>-<NUM> of fluid is streamed into the bladder volume. In some embodiments, <NUM>-<NUM> of fluid is streamed into the bladder volume. In some embodiments, <NUM>-<NUM> of fluid is streamed into the bladder volume.

Gas bubbles in liquid serve as nucleation seeds for the generation of cavitation. Therefore, increasing the amount of gas bubbles in the therapeutic fluid increases the efficiency of the ultrasound treatment.

Additionally, ultrasound transducers introduced into the bladder are commonly limited in the level of energy they can emit. Additionally, the fluid medium partially blocks and/or slows down ultrasound waves traveling from the transducer towards the bladder wall, thereby exposing the bladder wall to energy which may be insufficient for driving the treatment agent onto the tissue. Hence, to achieve efficacious treatment of a bladder wall, the ultrasound transducer needs to be activated in close proximity to the bladder wall, which increases the risk of damage to the wall tissue due to exposure to excessive heat generated from the transducer.

Introduction of nucleation seeds, such as solid particles, semi-solids, microbubbles, and the like, in the therapeutic fluid distributes gas bubbles throughout the fluid. The gas bubbles closer to the transducer absorb a portion of the ultrasound radiation by forming cavitation, however the presence of gas bubbles throughout the treatment volume and especially in proximity to the bladder wall enables their activation (i.e., production of cavitation) even by the low energy ultrasound waves that would be ineffective in the absence of the nucleation seeds. Dispersing of the cavitation in the therapeutic fluid allows cavitation throughout the therapeutic fluid and not only in the layer encountered by ultrasound emitted waves in the immediate surroundings of the transducer sleeve.

The presence of these bubbles therefore reduces the energy threshold required for cavitation generation. This allows using less acoustic energy, thus making the treatment safer to tissues. In some embodiments, increasing the amount of cavitation bubbles within the therapeutic fluid liquid is prepared by adding gassed sterile liquid, such as saline within the therapeutic agent.

In some embodiments of the present invention there is provided a method for increasing the amount of cavitation bubbles within the therapeutic fluid liquid including:.

For example, in some embodiments, the gas is at least one of air, helium, nitrogen, oxygen, or any combination thereof. In some embodiments, the pressurizing of a sterile liquid with a gas is at a pressure of <NUM> to <NUM> atmospheres. In some embodiments, the predetermined duration is between <NUM>-<NUM> hours. In some embodiments, the predetermined duration is <NUM> hour.

When adding the gassed liquid into the therapeutic fluid, the equilibrium of gases is swayed toward the therapeutic agent, thereby increasing the gas content therein. When it decompresses (as pressure is immediately released) within the therapeutic agent, the equilibrium of gases is swayed back towards the surrounding atmosphere and the excess gas is released in the form of small bubbles. These small bubbles serve as cavitation nucleation sites during the treatment.

In some embodiments, the therapeutic fluid is mixed into the gassed fluid. in some embodiments, the gassed fluid is mixed into the therapeutic fluid. in some embodiments, the gassed fluid is a diluent for the therapeutic fluid.

The following experiment was done to determine the efficacy of treatments using catheter for ultrasonic-driven treatment of a bladder compared to untreated tissue and gold standard <NUM> units Botox® intravesical injections.

Reference is made to <FIG>, which is an exemplary chart of parameters of implementation of a catheter for ultrasonic-driven treatment of a bladder, in accordance with some embodiments of the invention. the following experiment was tested on <NUM> pigs.

In the present example, the ultrasonic-driven treatment of the bladder by implementation of the catheter for ultrasonic-driven treatment of a bladder begins by application of local anesthesia to the bladder <NUM>. Next, the catheter <NUM> is inserted at step <NUM> into bladder <NUM> through a urethra <NUM> and the expandable portions <NUM>, <NUM>, and transducer sleeve <NUM> are expanded at step <NUM> by inflating <NUM>-<NUM>. In the present example, the bladder <NUM> is washed twice with saline by supplying at step <NUM> saline and then draining the bladder <NUM> at step <NUM> through therapeutic fluid port(s) <NUM>.

Next, <NUM> of therapeutic fluid is then instilled to the bladder, and the expandable portions <NUM>, <NUM>, and transducer sleeve <NUM> are fully inflated inside the bladder to <NUM>. A pump is started to circulate acoustic fluid within the expandable portions <NUM>, <NUM>, and transducer sleeve <NUM>. The transducer is switched on at a frequency of <NUM> for <NUM> minutes, and turned off, as depicted by <FIG>. The duty cycle of the transduce is <NUM>%. Lastly, the therapeutic fluid is incubated within the bladder post-treatment for <NUM> minutes, as depicted by <FIG>.

In the present example, the therapeutic is botulinum toxin A (Botox®) solution in saline. The dose of the toxin is <NUM>-<NUM> units. In this example, the saline is normal sterile saline. In some embodiments, and in this example, the fluid is not gassed.

Additionally, <NUM> pigs were treated with the gold standard <NUM> units Botox® intravesical injections.

Pathological reports of the bladders, kidneys, urethras, ureters, and other organs were taken. Additionally, the efficacy of the treatments of catheter for ultrasonic-driven treatment of a bladder was compared to the gold standard <NUM> units Botox® intravesical injections and to a control group of pigs which did not received any treatment was measured by measuring the contractility of the detrusor muscle after each treatment.

Reference is made to <FIG>, which is a graph of the contractility of the detrusor muscle after each treatment: treatments using catheter for ultrasonic-driven treatment of a bladder compared to untreated tissue, and gold standard <NUM> units Botox® intravesical injections. The contractility of the detrusor muscle after each treatment as shown by the y-axis is a percent ratio of the contractility after a treatment in relation to the contractility of the detrusor muscle after receiving carbachol (CCh). The contractility vs. CCh ratio depicts how much each detrusor muscle contracted in relation to a maximal contraction achieved by the CCh treatment.

In the graph of <FIG>, <NUM>% contractility vs. CCh is consistent with no Botox® activity whereas lower percent of muscle activity is correlated with Botox® administration. It is shown that shows that both the treatments using catheter for ultrasonic-driven treatment and the gold standard <NUM> units Botox® intravesical injections achieved better results than the control group which was untreated, however, the efficacy of treatments using catheter for ultrasonic-driven treatment is at least the same or higher than the gold standard intravesical injections treatment.

For example, at a frequency of <NUM>, the bladders which received treatment using the catheter had a contractility vs. CCh ratio of about <NUM>%, whereas the bladders which received the intravesical injections had a contractility vs. CCh ratio of about <NUM>%, and the control group was at about <NUM>%.

At a frequency of <NUM>, the bladders which received treatment using the catheter had a contractility vs. CCh ratio of about <NUM>%, whereas the bladders which received the intravesical injections had a contractility vs. CCh ratio of about <NUM>%, and the control group was at <NUM>%.

The following experiment was done to determine the efficacy of treatments using catheter for ultrasonic-driven treatment of an Overactive bladder (OAB) in human patients. The parameters of implementation for the catheter for ultrasonic-driven treatment correspond to the table depicted by <FIG> and the parameters of the treatment in pigs shown in Example <NUM>. Ten humans were treated and observed for <NUM> days post procedure.

Results of the treatment in humans' bladders using the catheter for ultrasonic-driven treatment showed no adverse events, serious or non-serious. Additionally, specific data of bladder function was obtained from two patients pre and post procedure.

Patients suffering from an overactive bladder experience sudden urges to urinate and frequent urinations during both day and night, caused by involuntary contractions by the detrusor muscle.

Reference is made to <FIG>, which is a table of efficacy data from two human patients comparing pre-procedure bladder function to <NUM> days post procedure bladder function. As shown in <FIG>, the average volume of each micturation increased by <NUM>% and <NUM>% for patients <NUM> and <NUM>, respectively. Increase in the volume of each micturation is indicative of more urine filling up the bladder of the patient before urination. Additionally, the average number of nocturnal urinations has decreased by <NUM>% and <NUM>% for patients <NUM> and <NUM>, respectively, which corresponds to the increase in volume of each micturation. An increase in the volume of each micturation decreases the number of times a patient needs to urinate.

As shown in <FIG>, the average number of urinary incontinence for patient <NUM> decreased by <NUM>%. patient <NUM> experienced no change in the average number of urinary incontinence. The decrease of number of urinary incontinence shows the efficacy of the treatment using the catheter for ultrasonic-driven treatment in human patients suffering from OAB.

Lastly, post procedure OAB-q (<NUM> days post-procedure) were compared to pre-procedure OAB-q of patients <NUM> and <NUM>, showing a decrease of <NUM>% and <NUM>%, respectively. The decrease of the OAB-q scores indicates an increase in general wellbeing and decrease in severity of symptoms of OAB.

In the description and claims of the application, each of the words "comprise" "include" and "have", and forms thereof, are not necessarily limited to members in a list with which the words may be associated.

Claim 1:
A catheter for ultrasonic-driven bladder therapeutic agent delivery, comprising:
a tube (<NUM>) having (i) a first, proximal expandable portion (<NUM>), expandable via a respective first fluid port (<NUM>), (ii) a second expandable portion (<NUM>) expandable via a respective second fluid port (<NUM>), and (iii) a distal end, comprising a therapeutic fluid port configured to supply therapeutic fluid into the bladder; and
at least one inflatable transducer sleeve (<NUM>/<NUM>), accommodating at least one ultrasound transducer (<NUM>) , and mounted on said tube between said first, proximal expandable portion and said at least one second expandable portion,
characterised in that
said inflatable transducer sleeve is inflatable via one or more second fluid ports (115A, 115B), and wherein said inflatable transducer sleeve comprises degassed acoustic fluid, configured to allow acoustic waves to travel from the at least one ultrasound transducer to the transducer sleeve without generating cavitation.