US20070265560A1 - Ultrasound Therapy System - Google Patents
Ultrasound Therapy System Download PDFInfo
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- US20070265560A1 US20070265560A1 US11/739,629 US73962907A US2007265560A1 US 20070265560 A1 US20070265560 A1 US 20070265560A1 US 73962907 A US73962907 A US 73962907A US 2007265560 A1 US2007265560 A1 US 2007265560A1
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- therapeutic compound
- ultrasound
- catheter
- fluid delivery
- radiating member
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N7/00—Ultrasound therapy
- A61N7/02—Localised ultrasound hyperthermia
- A61N7/022—Localised ultrasound hyperthermia intracavitary
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
- A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
- A61B17/22012—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement
- A61B17/2202—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement the ultrasound transducer being inside patient's body at the distal end of the catheter
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
- A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
- A61M25/0026—Multi-lumen catheters with stationary elements
- A61M25/0032—Multi-lumen catheters with stationary elements characterized by at least one unconventionally shaped lumen, e.g. polygons, ellipsoids, wedges or shapes comprising concave and convex parts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
- A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
- A61B2017/22088—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance ultrasound absorbing, drug activated by ultrasound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
- A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
- A61B2017/22089—Gas-bubbles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
- A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
- A61M25/0026—Multi-lumen catheters with stationary elements
- A61M25/003—Multi-lumen catheters with stationary elements characterized by features relating to least one lumen located at the distal part of the catheter, e.g. filters, plugs or valves
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T29/00—Metal working
- Y10T29/49—Method of mechanical manufacture
- Y10T29/49826—Assembling or joining
Definitions
- the present invention relates generally to treatment of vascular occlusions, and more specifically to treatment of vascular occlusions with ultrasonic energy and a therapeutic compound having microbubbles.
- U.S. Pat. Nos. 4,821,740, 4,953,565 and 5,007,438 disclose the use of ultrasonic energy to enhance the effect of various therapeutic compounds.
- An ultrasonic catheter can be used to deliver ultrasonic energy and a therapeutic compound to a treatment site within a patient's body.
- Such an ultrasonic catheter typically includes an ultrasound assembly configured to generate ultrasonic energy and a fluid delivery lumen for delivering the therapeutic compound to the treatment site.
- ultrasonic catheters can be used to treat human blood vessels that have become partially or completely occluded by plaque, thrombi, emboli or other substances that reduce the blood carrying capacity of the vessel.
- the ultrasonic catheter is used to deliver solutions containing therapeutic compounds directly to the occlusion site.
- Ultrasonic energy generated by the ultrasound assembly enhances the effect of the therapeutic compounds.
- Such a device can be used in the treatment of diseases such as ischemic stroke, peripheral arterial occlusion or deep vein thrombosis.
- the ultrasonic energy enhances treatment of the occlusion with therapeutic compounds such as urokinase, tissue plasminogen activator (“tPA”), recombinant tissue plasminogen activator (“rtPA”) and the like.
- therapeutic compounds such as urokinase, tissue plasminogen activator (“tPA”), recombinant tissue plasminogen activator (“rtPA”) and the like.
- Certain therapeutic compounds contain a plurality of microbubbles having, for example, a gas formed therein.
- the efficacy of a therapeutic compound can be enhanced by the presence of the microbubbles contained therein.
- the microbubbles act as a nucleus for cavitation, which can help promote the dissolution and removal of a vascular occlusion.
- the mechanical agitation caused motion of the microbubbles can be effective in mechanically breaking up clot material. Therefore, ultrasound catheter systems configured for use with a microbubble-containing therapeutic compound have been developed.
- a method of treating a vascular occlusion located at a treatment site within a patient's vasculature comprises positioning an ultrasound catheter at the treatment site.
- the method further comprises delivering a microbubble compound from the ultrasound catheter to the vascular occlusion while ultrasound is off during a first treatment phase.
- the method further comprises pausing the delivery of the microbubble compound and delivering ultrasonic energy and therapeutic compound or cooling fluid from the ultrasound catheter to the vascular occlusion during a second treatment phase while the delivery of microbubble compound remains paused.
- a method of treating a vascular occlusion located at a treatment site within a patient's vasculature comprises passing an ultrasound catheter through the patient's vasculature to the treatment site.
- the ultrasound catheter includes at least one fluid delivery port.
- the method further comprises positioning the ultrasound catheter at the treatment site such that the at least one fluid delivery port is positioned within the occlusion.
- the method further comprises infusing a microbubble therapeutic compound from the ultrasound catheter into an internal portion of the occlusion.
- the method further comprises pausing delivery of the microbubble therapeutic compound from the ultrasound catheter after a first quantity has been infused into the occlusion.
- the method further comprises delivering ultrasonic energy and a therapeutic compound from the ultrasound catheter into the infused microbubble therapeutic compound.
- the method further comprises repositioning the ultrasound catheter at the treatment site.
- the method further comprises infusing a second quantity of microbubble therapeutic compound from the ultrasound catheter to the treatment site after the ultrasonic energy is delivered to the treatment site.
- an ultrasound catheter system comprises an elongate tubular body having an ultrasound radiating member and a fluid delivery lumen positioned therein.
- the system further comprises a fluid reservoir that is hydraulically coupled to a proximal portion of the fluid delivery lumen.
- the fluid delivery reservoir contains a microbubble therapeutic compound.
- the system further comprises an infusion pump configured to pump the microbubble therapeutic compound from the fluid reservoir into the fluid delivery lumen.
- the system further comprises control circuitry configured to send electrical activation power to the infusion pump and to the ultrasound radiating member. The control circuitry is configured such that the infusion pump and the ultrasound radiating member are not activated simultaneously.
- FIG. 1 is a schematic illustration of an ultrasonic catheter configured for insertion into large vessels of the human body.
- FIG. 2 is a cross-sectional view of the ultrasonic catheter of FIG. 1 taken along line 2 - 2 .
- FIG. 3 is a schematic illustration of an elongate inner core configured to be positioned within the central lumen of the catheter illustrated in FIG. 2 .
- FIG. 4 is a cross-sectional view of the elongate inner core of FIG. 3 taken along line 4 - 4 .
- FIG. 5 is a schematic wiring diagram illustrating an example technique for electrically connecting five groups of ultrasound radiating members to form an ultrasound assembly.
- FIG. 6 is a schematic wiring diagram illustrating an example technique for electrically connecting one of the groups of FIG. 5 .
- FIG. 7A is a schematic illustration of the ultrasound assembly of FIG. 5 housed within the inner core of FIG. 4 .
- FIG. 7B is a cross-sectional view of the ultrasound assembly of FIG. 7A taken along line 7 B- 7 B.
- FIG. 7C is a cross-sectional view of the ultrasound assembly of FIG. 7A taken along line 7 C- 7 C.
- FIG. 7D is a side view of an ultrasound assembly center wire twisted into a helical configuration.
- FIG. 8 illustrates the energy delivery section of the inner core of FIG. 4 positioned within the energy delivery section of the tubular body of FIG. 2 .
- FIG. 9 illustrates a wiring diagram for connecting a plurality of temperature sensors with a common wire.
- FIG. 10 is a block diagram of a feedback control system for use with an ultrasonic catheter.
- FIG. 11A is a side view of a treatment site.
- FIG. 11B is a side view of the distal end of an ultrasonic catheter positioned at the treatment site of FIG. 11A .
- FIG. 11C is a cross-sectional view of the distal end of the ultrasonic catheter of FIG. 11B positioned at the treatment site before a treatment.
- FIG. 11D is a cross-sectional view of the distal end of the ultrasonic catheter of FIG. 11C , wherein an inner core has been inserted into the tubular body to perform a treatment.
- FIG. 12A is a cross-sectional view of a distal end of an ultrasonic catheter configured for use within small vessels of a patient's vasculature.
- FIG. 12B is a cross-sectional view of the ultrasonic catheter of FIG. 12A taken through line 12 B- 12 B.
- FIG. 13 is a cross-sectional view of an ultrasound radiating member separated from a delivery lumen by a chamber.
- FIG. 14 is a cross-sectional view of an example technique for applying ultrasonic energy to an infused microbubble therapeutic compound.
- FIG. 15 is a schematic illustration of selected components of an example system that is capable of using a single controller to alternatively deliver ultrasonic energy and a microbubble therapeutic compound to an intravascular treatment site.
- FIG. 16A illustrates a laser patterned cavitation promoting surface.
- FIG. 16B illustrates a close up of a cavitation promoting surface.
- FIG. 17 is a graph showing the relative noise enhancement versus time during a 3.33-second snapshot obtained at time zero in a 30-minute ultrasound exposure. Each trace is an average over 10 snapshots.
- FIG. 18 is a graph showing the relative subharmonic enhancement versus time during a 3.33-second snapshot obtained at time zero in a 30-minute ultrasound exposure. Each trace is an average over 10 snapshots.
- FIG. 19A is a graph showing the maximum noise enhancement per snapshot illustrated as a function of ultrasound exposure time. Each point corresponds to an average of 10 snapshots.
- FIG. 19B is a graph showing a comparison of max ⁇ RNE ⁇ for the snapshot taken at time zero (0 min) and the average max ⁇ RNE ⁇ for snapshots obtained during the remainder of the 30-minute exposure. Error bars indicate standard deviation.
- FIG. 20A is a graph showing the average subharmonic enhancement per snapshot illustrated as a function of ultrasound exposure time. Each point corresponds to an average of 10 snapshots.
- FIG. 20B is a graph showing a comparison of ⁇ RSE> for the snapshot taken at time zero and the average ⁇ RSE> for snapshots obtained during the remainder of the 30-minute exposure. Error bars indicate standard deviation.
- ultrasonic catheters that can be used to enhance the efficacy of therapeutic compounds at a treatment site within a patient's body. Introduction.
- therapeutic compound refers broadly, without limitation, and in addition to its ordinary meaning, to a drug, medicament, dissolution compound, genetic material, neuroprotection compounds or any other substance capable of effecting physiological functions. Additionally, a mixture includes substances such as these is also encompassed within this definition of “therapeutic compound”. Examples of therapeutic compounds include thrombolytic compounds, anti-thrombosis compounds, and other compounds used in the treatment of vascular occlusions, including compounds intended to prevent or reduce clot formation.
- example therapeutic compounds include, but are not limited to, heparin, urokinase, streptokinase, tPA, rtPA and BB-10153 (manufactured by British Biotech, Oxford, UK).
- ultrasonic energy As used herein, the terms “ultrasonic energy”, “ultrasound” and “ultrasonic” refer broadly, without limitation, and in addition to their ordinary meaning, to mechanical energy transferred through longitudinal pressure or compression waves. Ultrasonic energy can be emitted as continuous or pulsed waves, depending on the parameters of a particular application. Additionally, ultrasonic energy can be emitted in waveforms having various shapes, such as sinusoidal waves, triangle waves, square waves, or other wave forms. Ultrasonic energy includes sound waves. In certain embodiments, the ultrasonic energy referred to herein has a frequency between about 20 kHz and about 20 MHz. For example, in one embodiment, the ultrasonic energy has a frequency between about 500 kHz and about 20 MHz.
- the ultrasonic energy has a frequency between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasonic energy has a frequency of about 2 MHz. In certain embodiments described herein, the average acoustic power of the ultrasonic energy is between about 0.01 watts and 300 watts. In one embodiment, the average acoustic power is about 15 watts.
- ultrasonic radiating member refers broadly, without limitation, and in addition to its ordinary meaning, to any apparatus capable of producing ultrasonic energy.
- An ultrasonic transducer which converts electrical energy into ultrasonic energy, is an example of an ultrasound radiating member.
- An example ultrasonic transducer capable of generating ultrasonic energy from electrical energy is a piezoelectric ceramic oscillator.
- Piezoelectric ceramics typically comprise a crystalline material, such as quartz, that changes shape when an electrical current is applied to the material. This change in shape, made oscillatory by an oscillating driving signal, creates ultrasonic sound waves.
- ultrasonic energy can be generated by an ultrasonic transducer that is remote from the ultrasound radiating member, and the ultrasonic energy can be transmitted, via, for example, a wire that is coupled to the ultrasound radiating member.
- the ultrasonic energy itself provides a therapeutic effect to the patient.
- therapeutic effects include preventing or reducing stenosis and/or restenosis; tissue ablation, abrasion or disruption; promoting temporary or permanent physiological changes in intracellular or intercellular structures; and rupturing micro-balloons or micro-bubbles for therapeutic compound delivery. Further information about such methods can be found in U.S. Pat. Nos. 5,261,291 and 5,431,663.
- the ultrasonic catheters described herein can be configured for application of ultrasonic energy over a substantial length of a body lumen, such as, for example, the larger vessels located in the leg.
- the ultrasonic catheters described herein can be configured to be inserted into the small cerebral vessels, in solid tissues, in duct systems and in body cavities.
- treatment with the ultrasonic catheter is performed outside the vascular system, such as within or at a tumor, in which the treatment is configured to kill malignant tissues by enhancing the delivery of a cancer drug to the tumor. Additional embodiments that can be combined with certain features and aspects of the embodiments described herein are described in U.S. patent application Ser. No. 10/291,891, filed 7 Nov. 2002, the entire disclosure of which is hereby incorporated herein by reference.
- FIG. 1 schematically illustrates an ultrasonic catheter 10 configured for use in the large vessels of a patient's anatomy.
- the ultrasonic catheter 10 illustrated in FIG. 1 can be used to treat long segment peripheral arterial occlusions, such as those in the vascular system of the leg.
- the ultrasonic catheter 10 generally includes a multi-component, elongate flexible tubular body 12 having a proximal region 14 and a distal region 15 .
- the tubular body 12 includes a flexible energy delivery section 18 located in the distal region 15 .
- the tubular body 12 and other components of the catheter 10 can be manufactured in accordance with a variety of techniques known to an ordinarily skilled artisan. Suitable materials and dimensions can be readily selected based on the natural and anatomical dimensions of the treatment site and on the desired percutaneous access site.
- the tubular body proximal region 14 comprises a material that has sufficient flexibility, kink resistance, rigidity and structural support to push the energy delivery section 18 through the patient's vasculature to a treatment site.
- materials include, but are not limited to, extruded polytetrafluoroethylene (“PTFE”), polyethylenes (“PE”), polyamides and other similar materials.
- PTFE polytetrafluoroethylene
- PE polyethylenes
- polyamides polyamides and other similar materials.
- the tubular body proximal region 14 is reinforced by braiding, mesh or other constructions to provide increased kink resistance and ability to be pushed.
- nickel titanium or stainless steel wires can be placed along or incorporated into the tubular body 12 to reduce kinking.
- the tubular body 12 has an outside diameter between about 0.060 inches and about 0.075 inches. In another embodiment, the tubular body 12 has an outside diameter of about 0.071 inches. In certain embodiments, the tubular body 12 has an axial length of approximately 105 centimeters, although other lengths can be used in other applications.
- the tubular body energy delivery section 18 comprises a material that is thinner than the material comprising the tubular body proximal region 14 .
- the tubular body energy delivery section 18 comprises a material that has a greater acoustic transparency than the material comprising the tubular body proximal region 14 .
- Thinner materials generally have greater acoustic transparency than thicker materials.
- Suitable materials for the energy delivery section 18 include, but are not limited to, high or low density polyethylenes, urethanes, nylons, and the like.
- the energy delivery section 18 comprises the same material or a material of the same thickness as the proximal region 18 .
- the tubular body 12 is divided into at least three sections of varying stiffness.
- the first section which includes the proximal region 14 , has a relatively higher stiffness.
- the second section which is located in an intermediate region between the proximal region 14 and the distal region 15 , has a relatively lower stiffness. This configuration further facilitates movement and placement of the catheter 10 .
- the third section which includes the energy delivery section 18 , has a relatively lower stiffness than the second section in spite of the presence of ultrasound radiating members which can be positioned therein.
- FIG. 2 illustrates a cross section of the tubular body 12 taken along line 2 - 2 in FIG. 1 .
- three fluid delivery lumens 30 are incorporated into the tubular body 12 .
- more or fewer fluid delivery lumens can be incorporated into the tubular body 12 .
- the arrangement of the fluid delivery lumens 30 provides a hollow central lumen 51 passing through the tubular body 12 .
- the cross-section of the tubular body 12 is substantially constant along the length of the catheter 10 .
- substantially the same cross-section is present in both the proximal region 14 and the distal region 15 of the tubular body 12 , including the energy delivery section 18 .
- the central lumen 51 has a minimum diameter greater than about 0.030 inches. In another embodiment, the central lumen 51 has a minimum diameter greater than about 0.037 inches. In an example embodiment, the fluid delivery lumens 30 have dimensions of about 0.026 inches wide by about 0.0075 inches high, although other dimensions can be used in other embodiments.
- the central lumen 51 extends through the length of the tubular body 12 . As illustrated in FIG. 1 , the central lumen 51 has a distal exit port 29 and a proximal access port 31 .
- the proximal access port 31 forms part of the backend hub 33 , which is attached to the tubular body proximal region 14 .
- the backend hub also includes a cooling fluid fitting 46 , which is hydraulically connected to the central lumen 51 .
- the backend hub 33 also includes a therapeutic compound inlet port 32 , which is hydraulically coupled to the fluid delivery lumens 30 , and which can also be hydraulically coupled to a source of therapeutic compound via a hub such as a Luer fitting.
- the central lumen 51 is configured to receive an elongate inner core 34 , an example embodiment of which is illustrated in FIG. 3 .
- the elongate inner core 34 includes a proximal region 36 and a distal region 38 .
- a proximal hub 37 is fitted on one end of the inner core proximal region 36 .
- One or more ultrasound radiating members 40 are positioned within an inner core energy delivery section 41 that is located within the distal region 38 .
- the ultrasound radiating members 40 form an ultrasound assembly 42 , which will be described in greater detail below.
- the inner core 34 has a cylindrical shape, with an outer diameter that permits the inner core 34 to be inserted into the central lumen 51 of the tubular body 12 via the proximal access port 31 .
- Suitable outer diameters of the inner core 34 include, but are not limited to, between about 0.010 inches and about 0.100 inches.
- the outer diameter of the inner core 34 is between about 0.020 inches and about 0.080 inches.
- the inner core 34 has an outer diameter of about 0.035 inches.
- the inner core 34 includes a cylindrical outer body 35 that houses the ultrasound assembly 42 .
- the ultrasound assembly 42 includes wiring and ultrasound radiating members, described in greater detail in FIGS. 5 through 7 D, such that the ultrasound assembly 42 is capable of radiating ultrasonic energy from the energy delivery section 41 of the inner core 34 .
- the ultrasound assembly 42 is electrically connected to the backend hub 33 , where the inner core 34 can be connected to a control system 100 via cable 45 (illustrated in FIG. 1 ).
- an electrically insulating potting material 43 fills the inner core 34 , surrounding the ultrasound assembly 42 , thus reducing or preventing movement of the ultrasound assembly 42 with respect to the outer body 35 .
- the thickness of the outer body 35 is between about 0.0002 inches and 0.010 inches. In another embodiment, the thickness of the outer body 35 is between about 0.0002 inches and 0.005 inches. In yet another embodiment, the thickness of the outer body 35 is about 0.0005 inches.
- the ultrasound assembly 42 includes a plurality of ultrasound radiating members 40 that are divided into one or more groups.
- FIGS. 5 and 6 are schematic wiring diagrams illustrating one technique for connecting five groups of ultrasound radiating members 40 to form the ultrasound assembly 42 .
- the ultrasound assembly 42 comprises five groups G 1 , G 2 , G 3 , G 4 , G 5 of ultrasound radiating members 40 that are electrically connected to each other.
- the five groups are also electrically connected to the control system 100 .
- the control circuitry 100 includes a voltage source 102 having a positive terminal 104 and a negative terminal 106 .
- the negative terminal 106 is connected to common wire 108 , which connects the five groups G 1 -G 5 of ultrasound radiating members 40 in series.
- the positive terminal 104 is connected to a plurality of lead wires 110 , which each connect to one of the five groups G 1 -G 5 of ultrasound radiating members 40 .
- each of the five groups G 1 -G 5 is connected to the positive terminal 104 via one of the lead wires 110 , and to the negative terminal 106 via the common wire 108 .
- each group G 1 -G 5 includes a plurality of ultrasound radiating members 40 .
- Each of the ultrasound radiating members 40 is electrically connected to the common wire 108 and to the lead wire 110 via a positive contact wires 112 .
- a substantially constant voltage difference will be applied to each ultrasound radiating member 40 in the group.
- the group illustrated in FIG. 6 includes twelve ultrasound radiating members 40 , in other embodiments, more or fewer ultrasound radiating members 40 can be included in the group. Likewise, more or fewer than five groups can be included within the ultrasound assembly 42 illustrated in FIG. 5 .
- FIG. 7A illustrates an example technique for arranging the components of the ultrasound assembly 42 (as schematically illustrated in FIG. 5 ) into the inner core 34 (as schematically illustrated in FIG. 4 ).
- FIG. 7A is a cross-sectional view of the ultrasound assembly 42 taken within group G 1 in FIG. 5 , as indicated by the presence of four lead wires 110 .
- group G 1 in FIG. 5 the ultrasound assembly 42
- lead wires 110 the lead wire connecting group G 5
- the common wire 108 includes an elongate, flat piece of electrically conductive material in electrical contact with a pair of ultrasound radiating members 40 .
- Each of the ultrasound radiating members 40 is also in electrical contact with a positive contact wire 112 .
- lead wires 110 are separated from the other components of the ultrasound assembly 42 , thus preventing interference with the operation of the ultrasound radiating members 40 as described above.
- the inner core 34 is filled with an insulating potting material 43 , thus deterring unwanted electrical contact between the various components of the ultrasound assembly 42 .
- FIGS. 7B and 7C illustrate cross sectional views of the inner core 34 of FIG. 7A taken along lines 7 B- 7 B and 7 C- 7 C, respectively.
- the ultrasound radiating members 40 are mounted in pairs along the common wire 108 .
- the ultrasound radiating members 40 are connected by positive contact wires 112 , such that substantially the same voltage is applied to each ultrasound radiating member 40 .
- the common wire 108 includes wide regions 108 W upon which the ultrasound radiating members 40 can be mounted, thus reducing the likelihood that the paired ultrasound radiating members 40 will short together. In certain embodiments, outside the wide regions 108 W, the common wire 108 can have a more conventional, rounded wire shape.
- the common wire 108 is twisted to form a helical shape before being fixed within the inner core 34 .
- the ultrasound radiating members 40 are oriented in a plurality of radial directions, thus enhancing the radial uniformity of the resulting ultrasonic energy field.
- each group G 1 , G 2 , G 3 , G 4 , G 5 can be independently powered.
- each group can be individually turned on or off, or can be driven at an individualized power level. This advantageously allows the delivery of ultrasonic energy to be “turned off” in regions of the treatment site where treatment is complete, thus preventing deleterious or unnecessary ultrasonic energy to be applied to the patient.
- the embodiments described above, and illustrated in FIGS. 5 through 7 include a plurality of ultrasound radiating members grouped spatially. That is, in such embodiments, the ultrasound radiating members within a certain group are positioned adjacent to each other, such that when a single group is activated, ultrasonic energy is delivered from a certain length of the ultrasound assembly. However, in modified embodiments, the ultrasound radiating members of a certain group may be spaced apart from each other, such that the ultrasound radiating members within a certain group are not positioned adjacent to each other. In such embodiments, when a single group is activated, ultrasonic energy can be delivered from a larger, spaced apart portion of the ultrasound assembly. Such modified embodiments can be advantageous in applications where a less focussed, more diffuse ultrasonic energy field is to be delivered to the treatment site.
- the ultrasound radiating members 40 comprise rectangular lead zirconate titanate (“PZT”) ultrasound transducers that have dimensions of about 0.017 inches by about 0.010 inches by about 0.080 inches. In other embodiments, other configurations and dimensions can be used.
- PZT lead zirconate titanate
- disc-shaped ultrasound radiating members 40 can be used in other embodiments.
- the common wire 108 comprises copper, and is about 0.005 inches thick, although other electrically conductive materials and other dimensions can be used in other embodiments.
- lead wires 110 are 36 gauge electrical conductors, and positive contact wires 112 are 42 gauge electrical conductors. However, other wire gauges can be used in other embodiments.
- suitable frequencies for the ultrasound radiating members 40 include, but are not limited to, from about 20 kHz to about 20 MHz. In one embodiment, the frequency is between about 500 kHz and about 20 MHz, and in another embodiment the frequency is between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasound radiating members 40 are operated with a frequency of about 2 MHz.
- FIG. 8 illustrates the inner core 34 positioned within the tubular body 12 . Details of the ultrasound assembly 42 , provided in FIG. 7A , are omitted for clarity. As described above, the inner core 34 can be slid within the central lumen 51 of the tubular body 12 , thereby allowing the inner core energy delivery section 41 to be positioned within the tubular body energy delivery section 18 .
- the materials comprising the inner core energy delivery section 41 , the tubular body energy delivery section 18 , and the potting material 43 all comprise materials having a similar acoustic impedance, thereby minimizing ultrasonic energy losses across material interfaces.
- FIG. 8 further illustrates placement of fluid delivery ports 58 within the tubular body energy delivery section 18 .
- holes or slits are formed from the fluid delivery lumen 30 through the tubular body 12 , thereby permitting fluid flow from the fluid delivery lumen 30 to the treatment site.
- a plurality of fluid delivery ports 58 can be positioned axially along the tubular body 12 .
- a source of therapeutic compound coupled to the inlet port 32 provides a hydraulic pressure which drives the therapeutic compound through the fluid delivery lumens 30 and out the fluid delivery ports 58 .
- fluid delivery ports 30 By spacing the fluid delivery lumens 30 around the circumference of the tubular body 12 substantially evenly, as illustrated in FIG. 8 , a substantially uniform flow of therapeutic compound around the circumference of the tubular body 12 can be achieved. Additionally, the size, location and geometry of the fluid delivery ports 58 can be selected to provide uniform fluid flow from the fluid delivery ports 30 to the treatment site. For example, in one embodiment, fluid delivery ports closer to the proximal region of the energy delivery section 18 have smaller diameters than fluid delivery ports closer to the distal region of the energy delivery section 18 , thereby allowing uniform delivery of therapeutic compound in the energy delivery section.
- the fluid delivery ports 58 have a diameter between about 0.0005 inches to about 0.0050 inches.
- the fluid delivery ports 58 have a diameter between about 0.001 inches to about 0.005 inches in the proximal region of the energy delivery section 18 , and between about 0.005 inches to about 0.0020 inches in the distal region of the energy delivery section 18 .
- the increase in size between adjacent fluid delivery ports 58 depends on a variety of factors, including the material comprising the tubular body 12 , and on the size of the fluid delivery lumen 30 .
- the fluid delivery ports 58 can be created in the tubular body 12 by punching, drilling, burning or ablating (such as with a laser), or by other suitable methods. Therapeutic compound flow along the length of the tubular body 12 can also be increased by increasing the density of the fluid delivery ports 58 toward the distal region of the energy delivery section.
- a spatially nonuniform flow of therapeutic compound from the fluid delivery ports 58 to the treatment site is to be provided.
- the size, location and geometry of the fluid delivery ports 58 can be selected to provide such nonuniform fluid flow.
- cooling fluid lumens 44 are formed between an outer surface 39 of the inner core 34 and an inner surface 16 of the tubular body 12 .
- a cooling fluid is introduced through the proximal access port 31 such that cooling fluid flows through cooling fluid lumens 44 and out of the catheter 10 through distal exit port 29 (see FIG. 1 ).
- the cooling fluid lumens 44 are substantially evenly spaced around the circumference of the tubular body 12 (that is, at approximately 120° increments for a three-lumen configuration), thereby providing substantially uniform cooling fluid flow over the inner core 34 .
- Such a configuration advantageously removes thermal energy from the treatment site.
- the flow rate of the cooling fluid and the power to the ultrasound assembly 42 can be adjusted to maintain the temperature of the inner core energy delivery section 41 , or of the treatment site generally, within a desired range.
- the inner core 34 can be rotated or moved within the tubular body 12 . Specifically, movement of the inner core 34 can be accomplished by maneuvering the proximal hub 37 while holding the backend hub 33 stationary.
- the inner core outer body 35 is at least partially constructed from a material that provides enough structural support to permit movement of the inner core 34 within the tubular body 12 without kinking of the tubular body 12 .
- the inner core outer body 35 comprises a material having the ability to transmit torque. Suitable materials for the inner core outer body 35 include, but are not limited to, polyimides, polyesters, polyurethanes, thermoplastic elastomers and braided polyimides.
- the fluid delivery lumens 30 and the cooling fluid lumens 44 are open at the distal end of the tubular body 12 , thereby allowing the therapeutic compound and the cooling fluid to pass into the patient's vasculature at the distal exit port 29 .
- the fluid delivery lumens 30 can be selectively occluded at the distal end of the tubular body 12 , thereby providing additional hydraulic pressure to drive the therapeutic compound out of the fluid delivery ports 58 .
- the inner core 34 can be prevented from passing through the distal exit port 29 by providing the inner core 34 with a length that is less than the length of the tubular body 12 .
- a protrusion is formed within the tubular body 12 in the distal region 15 , thereby preventing the inner core 34 from passing through the distal exit port 29 .
- the catheter 10 includes an occlusion device positioned at the distal exit port 29 .
- the occlusion device has a reduced inner diameter that can accommodate a guidewire, but that is less than the inner diameter of the central lumen 51 .
- suitable inner diameters for the occlusion device include, but are not limited to, between about 0.005 inches and about 0.050 inches.
- the occlusion device has a closed end, thus preventing cooling fluid from leaving the catheter 10 , and instead recirculating to the tubular body proximal region 14 .
- the tubular body 12 includes one or more temperature sensors 20 that are positioned within the energy delivery section 18 .
- the tubular body proximal region 14 includes a temperature sensor lead which can be incorporated into cable 45 (illustrated in FIG. 1 ).
- Suitable temperature sensors include, but are not limited to, temperature sensing diodes, thermistors, thermocouples, resistance temperature detectors (“RTDs”) and fiber optic temperature sensors which use thermalchromic liquid crystals.
- Suitable temperature sensor 20 geometries include, but are not limited to, a point, a patch or a stripe.
- the temperature sensors 20 can be positioned within one or more of the fluid delivery lumens 30 , and/or within one or more of the cooling fluid lumens 44 .
- FIG. 9 illustrates an example embodiment for electrically connecting the temperature sensors 20 .
- each temperature sensor 20 is coupled to a common wire 61 and is associated with an individual return wire 62 .
- n+1 wires are passed through the tubular body 12 to independently sense the temperature at n temperature sensors 20 .
- the temperature at a selected temperature sensor 20 can be determined by closing a switch 64 to complete a circuit between the return wire 62 associated with the selected thermocouple and the common wire 61 .
- the temperature can be calculated from the voltage in the circuit using, for example, a sensing circuit 63 , which can be located within the external control circuitry 100 .
- the temperature sensors 20 can be independently wired. In such embodiments, 2n wires are passed through the tubular body 12 to independently sense the temperature at n temperature sensors 20 . In still other embodiments, the flexibility of the tubular body 12 can be improved by using fiber optic based temperature sensors 20 . In such embodiments, flexibility can be improved because only n fiber optic members are used to sense the temperature at n independent temperature sensors 20 .
- FIG. 10 schematically illustrates one embodiment of a feedback control system 68 that can be used with the catheter 10 .
- the feedback control system 68 can be integrated into the control system 100 that is connected to the inner core 34 via cable 45 (as illustrated in FIG. 1 ).
- the feedback control system 68 allows the temperature at each temperature sensor 20 to be monitored and allows the output power of the energy source 70 to be adjusted accordingly.
- a physician can, if desired, override the closed or open loop system.
- the feedback control system 68 includes an energy source 70 , power circuits 72 and a power calculation device 74 that is coupled to the ultrasound radiating members 40 .
- a temperature measurement device 76 is coupled to the temperature sensors 20 in the tubular body 12 .
- a processing unit 78 is coupled to the power calculation device 74 , the power circuits 72 and a user interface and display 80 .
- the temperature at each temperature sensor 20 is determined by the temperature measurement device 76 .
- the processing unit 78 receives each determined temperature from the temperature measurement device 76 .
- the determined temperature can then be displayed to the user at the user interface and display 80 .
- the processing unit 78 includes logic for generating a temperature control signal.
- the temperature control signal is proportional to the difference between the measured temperature and a desired temperature.
- the desired temperature can be determined by the user (as set at the user interface and display 80 ) or can be preset within the processing unit 78 .
- the temperature control signal is received by the power circuits 72 .
- the power circuits 72 are configured to adjust the power level, voltage, phase and/or current of the electrical energy supplied to the ultrasound radiating members 40 from the energy source 70 . For example, when the temperature control signal is above a particular level, the power supplied to a particular group of ultrasound radiating members 40 is reduced in response to that temperature control signal. Similarly, when the temperature control signal is below a particular level, the power supplied to a particular group of ultrasound radiating members 40 is increased in response to that temperature control signal.
- the processing unit 78 monitors the temperature sensors 20 and produces another temperature control signal which is received by the power circuits 72 .
- the processing unit 78 optionally includes safety control logic.
- the safety control logic detects when the temperature at a temperature sensor 20 exceeds a safety threshold.
- the processing unit 78 can be configured to provide a temperature control signal which causes the power circuits 72 to stop the delivery of energy from the energy source 70 to that particular group of ultrasound radiating members 40 .
- the ultrasound radiating members 40 are mobile relative to the temperature sensors 20 , it can be unclear which group of ultrasound radiating members 40 should have a power, voltage, phase and/or current level adjustment. Consequently, each group of ultrasound radiating members 40 can be identically adjusted in certain embodiments.
- the power, voltage, phase, and/or current supplied to each group of ultrasound radiating members 40 is adjusted in response to the temperature sensor 20 which indicates the highest temperature. Making voltage, phase and/or current adjustments in response to the temperature sensed by the temperature sensor 20 indicating the highest temperature can reduce overheating of the treatment site.
- the processing unit 78 can also be configured to receive a power signal from the power calculation device 74 .
- the power signal can be used to determine the power being received by each group of ultrasound radiating members 40 .
- the determined power can then be displayed to the user on the user interface and display 80 .
- the feedback control system 68 can be configured to maintain tissue adjacent to the energy delivery section 18 below a desired temperature.
- tissue at the treatment site is to have a temperature increase of less than or equal to approximately 6° C.
- the ultrasound radiating members 40 can be electrically connected such that each group of ultrasound radiating members 40 generates an independent output.
- the output from the power circuit maintains a selected energy for each group of ultrasound radiating members 40 for a selected length of time.
- the processing unit 78 can comprise a digital or analog controller, such as a computer with software.
- the computer can include a central processing unit (“CPU”) coupled through a system bus.
- the user interface and display 80 can include a mouse, a keyboard, a disk drive, a display monitor, a nonvolatile memory system, and/or other computer components.
- program memory and/or data memory is also coupled to the bus.
- a profile of the power to be delivered to each group of ultrasound radiating members 40 can be incorporated into the processing unit 78 , such that a preset amount of ultrasonic energy to be delivered is pre-profiled.
- the power delivered to each group of ultrasound radiating members 40 is provided according to the preset profiles.
- the ultrasound radiating members are operated in a pulsed mode.
- the time average power supplied to the ultrasound radiating members is between about 0.1 watts and about 2 watts.
- the time average power supplied to the ultrasound radiating members is between about 0.5 watts and about 1.5 watts.
- the time average power supplied to the ultrasound radiating members is approximately 0.6 watts or approximately 1.2 watts.
- the duty cycle is between about 1% and about 50%.
- the duty cycle is between about 5% and about 25%.
- the duty cycles is approximately 7.5% or approximately 15%.
- the pulse averaged power is between about 0.1 watts and about 20 watts.
- the pulse averaged power is between approximately 5 watts and approximately 20 watts.
- the pulse averaged power is approximately 8 watts or approximately 16 watts.
- the amplitude during each pulse can be constant or varied.
- the pulse repetition rate is between about 5 Hz and about 150 Hz. In another embodiment, the pulse repetition rate is between about 10 Hz and about 50 Hz. In yet another embodiment, the pulse repetition rate is approximately 30 Hz. In an example embodiment, the pulse duration is between about 1 millisecond and about 50 milliseconds. In another embodiment, the pulse duration is between about 1 millisecond and about 25 milliseconds. In yet another embodiment, the pulse duration is approximately 2.5 milliseconds or approximately 5 milliseconds.
- the ultrasound radiating members are operated at an average power of approximately 0.6 watts, a duty cycle of approximately 7.5%, a pulse repetition rate of approximately 30 Hz, a pulse average electrical power of approximately 8 watts and a pulse duration of approximately 2.5 milliseconds.
- the ultrasound radiating member used with the electrical parameters described herein has an acoustic efficiency greater than approximately 50%. In another embodiment, the ultrasound radiating member used with the electrical parameters described herein has an acoustic efficiency greater than approximately 75%.
- the ultrasound radiating members can be formed in a variety of shapes, such as, cylindrical (solid or hollow), flat, bar, triangular, and the like.
- the length of the ultrasound radiating member is between about 0.1 cm and about 0.5 cm, and the thickness or diameter of the ultrasound radiating member is between about 0.02 cm and about 0.2 cm.
- FIGS. 11A through 11D illustrate an example method for using certain embodiments of the ultrasonic catheter 10 describe herein.
- a guidewire 84 similar to a guidewire used in typical angioplasty procedures is directed through a patient's vessels 86 to a treatment site 88 that includes a clot 90 .
- the guidewire 84 is optionally directed through the clot 90 .
- Suitable vessels 86 include, but are not limited to, the large periphery blood vessels of the body.
- the ultrasonic catheter 10 also has utility in various imaging applications or in applications for treating and/or diagnosing other diseases in other body parts.
- the tubular body 12 is slid over and is advanced along the guidewire 84 , for example using conventional over-the-guidewire techniques.
- the tubular body 12 is advanced until the energy delivery section 18 is positioned at the clot 90 .
- radiopaque markers are optionally positioned along the tubular body energy delivery section 18 to aid in the positioning of the tubular body 12 within the treatment site 88 .
- the guidewire 84 is withdrawn from the tubular body 12 by pulling the guidewire 84 from the proximal region 14 of the catheter 10 while holding the tubular body 12 stationary. This leaves the tubular body 12 positioned at the treatment site 88 .
- the inner core 34 is then inserted into the tubular body 12 until the ultrasound assembly 42 is positioned at least partially within the energy delivery section 18 .
- the ultrasound assembly 42 can be configured to be positioned at least partially within the energy delivery section 18 when the inner core 24 abuts the occlusion device at the distal end of the tubular body 12 .
- the ultrasound assembly 42 is activated to deliver ultrasonic energy to the clot 90 .
- ultrasonic energy having a frequency between about 20 kHz and about 20 MHz is delivered to the treatment site.
- the ultrasound assembly 42 includes sixty ultrasound radiating members 40 spaced over a length of approximately 30 to approximately 50 cm.
- the catheter 10 can be used to treat an elongate clot 90 without requiring moving or repositioning the catheter 10 during the treatment.
- the inner core 34 can be moved or rotated within the tubular body 12 during the treatment. Such movement can be accomplished by maneuvering the proximal hub 37 of the inner core 34 while holding the backend hub 33 stationary.
- arrows 48 indicate that a cooling fluid can be delivered through the cooling fluid lumen 44 and out the distal exit port 29 .
- arrows 49 indicate that a therapeutic compound can be delivered through the fluid delivery lumen 30 and out the fluid delivery ports 58 to the treatment site 88 .
- the cooling fluid can be delivered before, after, during or intermittently with the delivery of ultrasonic energy.
- the therapeutic compound can be delivered before, after, during or intermittently with the delivery of ultrasonic energy. Consequently, the methods illustrated in FIGS. 11A through 11D can be performed in a variety of different orders than that described above.
- the therapeutic compound and ultrasonic energy are delivered until the clot 90 is partially or entirely dissolved. Once the clot 90 has been sufficiently dissolved, the tubular body 12 and the inner core 34 are withdrawn from the treatment site 88 .
- Ultrasonic catheters can also be specifically configured to use in the small vessels of a patient's vasculature, such as in the vasculature of a patient's brain.
- the catheter is provided with an energy delivery section having increased flexibility, thereby facilitating delivery of the catheter through narrow vessels having small radius turns.
- FIGS. 12A and 12B are cross-sectional views of the distal region of an example ultrasonic catheter configured for use in the small vasculature.
- an example ultrasonic catheter configured for use in small vessels comprises a multi-component tubular body 202 having a proximal region and a distal region 206 .
- the catheter tubular body 202 includes an outer sheath 208 that is positioned upon an inner core 210 .
- the outer sheath 208 comprises extruded Pebax®, PTFE, polyetheretherketone (“PEEK”), PE, polyamides, braided polyamides and/or other similar materials.
- the outer sheath distal region 206 is adapted for advancement through vessels having a small diameter, such as those in the vasculature of the brain.
- the outer sheath distal region 206 has an outer diameter between about 2 French and about 5 French. In another embodiment, outer sheath distal region 206 has an outer diameter of about 2.8 French. In one example embodiment, the outer sheath 208 has an axial length of approximately 150 centimeters.
- the outer sheath 208 comprises a braided tubing formed of, for example, high or low density polyethylenes, urethanes, nylons, and the like. This configuration enhances the flexibility of the tubular body 202 .
- the outer sheath 208 can be formed with a variable stiffness from the proximal to the distal end. To achieve this, a stiffening member may be included along the proximal end of the tubular body 202 .
- the inner core 210 defines, at least in part, a delivery lumen 212 , which, in an example embodiment, extends longitudinally along the catheter.
- the delivery lumen 212 has a distal exit port 214 , and is hydraulically connected to a proximal access port (not shown). Similar to the large vessel ultrasonic catheter described herein, the proximal access port can be connected to a source of therapeutic compound or cooling fluid that is to be delivered through the delivery lumen 212 .
- the delivery lumen 212 is configured to receive a guide wire (not shown).
- the guidewire has a diameter of between approximately 0.008 and approximately 0.012 inches. In another embodiment, the guidewire has a diameter of about 0.010 inches.
- the inner core 210 comprises polyamide or a similar material which can optionally be braided to increase the flexibility of the tubular body 202 .
- the tubular body distal region 206 includes an ultrasound radiating member 224 .
- the ultrasound radiating member 224 comprises an ultrasound transducer, which converts, for example, electrical energy into ultrasonic energy.
- the ultrasonic energy can be generated by an ultrasound transducer that is remote from the ultrasound radiating member 224 and the ultrasonic energy can be transmitted via, for example, a wire to the ultrasound radiating member 224 .
- the ultrasound radiating member 224 is configured as a hollow cylinder. As such, the inner core 210 extends through the lumen of the ultrasound radiating member 224 .
- the ultrasound radiating member 224 is secured to the inner core 210 in a suitable manner, such as using an adhesive.
- a potting material can also be used to further secure the ultrasound radiating member 224 to the inner core 210 .
- the ultrasound radiating member 224 can have a different shape.
- the ultrasound radiating member 224 can take the form of a solid rod, a disk, a solid rectangle or a thin block.
- the ultrasound radiating member 224 can comprise a plurality of smaller ultrasound radiating members.
- the illustrated configuration advantageously provides enhanced cooling of the ultrasound radiating member 224 .
- a therapeutic compound can be delivered through the delivery lumen 212 . As the therapeutic compound passes through the lumen of the ultrasound radiating member 224 , the therapeutic compound can advantageously remove excess heat generated by the ultrasound radiating member 224 .
- a fluid return path can be formed in the region 238 between the outer sheath 208 and the inner core 21 such that coolant from a coolant system can be directed through the region 238 .
- the ultrasound radiating member 224 produces ultrasonic energy having a frequency of between about 20 kHz and about 20 MHz. In one embodiment, the frequency of the ultrasonic energy is between about 500 kHz and about 20 MHz, and in another embodiment the frequency of the ultrasonic energy is between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasonic energy has a frequency of about 3 MHz.
- ultrasonic energy is generated from electrical power supplied to the ultrasound radiating member 224 through a wires 226 , 228 that extend through the catheter body 202 .
- the wires 226 , 228 cab be secured to the inner core 210 , lay along the inner core 210 and/or extend freely in the region 238 between the inner core 210 and the outer sheath 208 .
- the first wire 226 is connected to the hollow center of the ultrasound radiating member 224
- the second wire 228 is connected to the outer periphery of the ultrasound radiating member 224 .
- the ultrasound radiating member 224 comprises a transducer formed of a piezoelectric ceramic oscillator or a similar material.
- the catheter further includes a sleeve 230 that is generally positioned about the ultrasound radiating member 224 .
- the sleeve 230 is comprises a material that readily transmits ultrasonic energy. Suitable materials for the sleeve 230 include, but are not limited to, polyolefins, polyimides, polyester and other materials having a relatively low absorbance of ultrasonic energy.
- the proximal end of the sleeve 230 can be attached to the outer sheath 208 with an adhesive 232 .
- a shoulder 227 or notch can be formed in the outer sheath 208 for attachment of the adhesive 232 thereto.
- the outer sheath 208 and the sleeve 230 have substantially the same outer diameter.
- the distal end of the sleeve 230 can be attached to a tip 234 .
- the tip 234 is also attached to the distal end of the inner core 210 .
- the tip 234 is between about 0.5 mm and about 4.0 mm long. In another embodiment, the tip is about 2.0 mm long.
- the tip 234 is rounded in shape to reduce trauma or damage to tissue along the inner wall of a blood vessel or other body structure during advancement of the catheter to a treatment site.
- the catheter includes at least one temperature sensor 236 in the tubular body distal region 206 .
- the temperature sensor 236 can be positioned on or near the ultrasound radiating member 224 .
- Suitable temperature sensors include but are not limited to, diodes, thermistors, thermocouples, RTDs and fiber optic temperature sensors that used thermalchromic liquid crystals.
- the temperature sensor 236 is operatively connected to a control system via a control wire that extends through the tubular body 202 .
- the control box includes a feedback control system having the ability to monitor and control the power, voltage, current and phase supplied to the ultrasound radiating member 224 .
- the small vessel ultrasound catheters disclosed herein can be used to remove an occlusion from a small blood vessel.
- a guidewire is percutaneously inserted into the patient's vasculature at a suitable insertion site.
- the guidewire is advanced through the vasculature toward a treatment site where the vessel is wholly or partially occluded.
- the guidewire is then directed at least partially through the thrombus.
- the catheter After advancing the guidewire to the treatment site, the catheter is then inserted into the vasculature through the insertion site, and advanced along the guidewire towards the treatment site using, for example, over-the-guidewire techniques.
- the catheter is advanced until the tubular body distal region 206 is positioned near or in the occlusion.
- the tubular body distal region 206 optionally includes one or more radiopaque markers to aid in positioning the catheter at the treatment site.
- the guidewire can then be withdrawn from the delivery lumen 212 .
- a source of therapeutic compound such as a syringe with a Luer fitting, can then be attached to the proximal access port. This allows the therapeutic compound to be delivered through the delivery lumen 212 and the distal exit port 214 to the occlusion.
- the ultrasound radiating member 224 can then be activated to generate ultrasonic energy.
- the ultrasonic energy has a frequency between about 20 kHz and about 20 MHz.
- the frequency of the ultrasonic energy is between about 500 kHz and about 20 MHz, and in another embodiment the frequency of the ultrasonic energy is between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasonic energy has a frequency of about 3 MHz.
- the therapeutic compound and ultrasound energy can be applied until the occlusion is partially or entirely dissolved. Once the occlusion has been sufficiently dissolved, the catheter can be withdrawn from the treatment site.
- the therapeutic compound delivered to the treatment site includes a plurality of microbubbles having, for example, a gas formed therein.
- a therapeutic compound containing microbubbles is referred to herein as a “microbubble compound” or “microbubble therapeutic compound”.
- the microbubbles are formed by entrapping microspheres of gas into a therapeutic compound. In one embodiment, this is accomplished by agitating the therapeutic compound while blowing a gas into the therapeutic compound. In another embodiment, this is accomplished by exposing the therapeutic compound to ultrasonic energy with a sonicator under a gaseous atmosphere while vibrating the therapeutic compound. Other techniques for forming the microbubbles are used in other embodiments.
- Example gases that are usable to form the microbubbles include, but are not limited to, air, oxygen, carbon dioxide, octafluoropropane, and inert gases.
- the microbubble therapeutic compound wholly or partially comprises a suspension of perflutren lipid microspheres, such as that available under the brand name DEFINITY®, which is available from Bristol-Myers Squibb Medical Imaging, Inc. (New York, N.Y.).
- the microbubbles comprise octafluoropropane (C 3 F 8 ) encapsulated in an outer lipid shell.
- the microbubble therapeutic compound is optionally diluted in a phosphate buffered saline solution.
- a hemacytometer, microscope and digital camera are usable to view consistent volumes of a microbubble therapeutic compound, thereby enabling quantitative determination of certain properties of the microbubbles in the therapeutic compound.
- properties include quantity of microbubbles per unit volume and microbubble size distribution.
- such properties are affected by factors such as (a) the temperature at which the microbubble therapeutic compound is stored; (b) the physical handling of the microbubble therapeutic compound by vibrating for a time period or allowing to settle for a time period; (c) the handling of the microbubble therapeutic compound with a syringe; (d) the exposure of the microbubble therapeutic compound to the atmosphere; and (e) the dilution of the microbubble therapeutic compound.
- the microbubble therapeutic compound preferably includes between approximately 4 ⁇ 10 6 and approximately 12 ⁇ 10 9 microbubbles per milliliter of liquid, more preferably between about 8 ⁇ 10 6 and about 10 ⁇ 10 9 microbubbles per milliliter of liquid, and most preferably approximately 4 ⁇ 10 7 microbubbles per milliliter of liquid.
- the quantity of microbubbles per unit volume of carrier fluid is manipulated by diluting the microbubble therapeutic compound in a neutral solution, such as a phosphate buffered saline solution.
- the microbubbles preferably have an average diameter that is preferably between approximately 0.01 ⁇ m and approximately 100 ⁇ m and more preferably between approximately 0.4 ⁇ m and approximately 6 ⁇ m.
- the microbubble therapeutic compound is passed through the delivery lumen at a flow rate that is preferably between about 1 mL per hour and about 120 mL per hour, that is more preferably between about 10 mL per hour and about 100 mL per hour, and that is most preferably between about 18 mL per hour and about 22 mL per hour.
- a syringe pump is used to regulate the infusion of microbubble therapeutic compound into the delivery lumen.
- Other microbubble and delivery parameters are used in other embodiments.
- pulsed ultrasonic energy having a frequency between about 1 MHz and about 3 MHz (preferably about 1.7 MHz) delivered for between about 15 minutes and about 45 minutes (preferably about 30 minutes) advantageously provides a spatial peak negative pressure of between about 1 MPa and about 2 MPa (preferably between about 1.5 MPa and 2 MPa), which is sufficient to generate therapeutically beneficial cavitation at the treatment site.
- the volume of microbubble therapeutic compound delivered to the catheter treatment zone depends on the size of the treatment zone.
- Table A lists the approximate bolus volume for a treatment zone of a particular size. The values listed in the table are approximate and can be varied at the physician's discretion.
- the bolus volume corresponding to a treatment zone of approximately 6 cm is between approximately 0.5 and 2.5 mL; for a treatment zone of approximately 12 cm the bolus volume is between approximately 2 and 4 mL; for a treatment zone of approximately 18 cm the bolus volume is between approximately 3 and 5 mL; for a treatment zone of approximately 24 cm the bolus volume is between approximately 5 and 7 mL; for a treatment zone of approximately 30 cm the bolus volume is between approximately 6 and 8 mL; for a treatment zone of approximately 40 cm the bolus volume is between approximately 8 and 11 mL; and for a treatment zone of approximately 50 cm the bolus volume is between approximately 11 and 13 mL.
- the fluid in which the microbubbles are suspended does not have therapeutic properties itself, but is merely configured to deliver the microbubbles to the treatment site.
- the fluid in which the microbubbles are suspended has therapeutic properties, such as a solution containing rtPA that is diluted to a concentration of, for example, between about 2500 IU mL ⁇ 1 and about 7500 IU mL ⁇ 1 .
- some microbubbles can be infused with a drug with therapeutic properties.
- the drug infused microbubbles may also entrap a gas in addition to the drug.
- the entrapped gas itself may be a drug with therapeutic properties, such as nitric oxide.
- microbubbles can be delivered to the treatment site and be used to deliver drug to the treatment site when the bubble pops.
- Drug infused microbubbles can be mixed with non-drug infused microbubbles and be delivered as a mixture. Popping of the drug infused microbubbles, such as through a cavitation process, can be facilitated or enhanced with ultrasound treatment.
- delivering a microbubble therapeutic compound through an optional syringe pump, through a catheter fluid delivery lumen, and past an activated ultrasound radiating member will reduce (a) the concentration of microbubbles delivered to the treatment site, and/or (b) the average size of the microbubbles delivered to the treatment site. Therefore, in an example embodiment the ultrasound radiating member is not activated until all or a portion of the microbubble therapeutic compound is delivered to the treatment site.
- a first portion of the microbubble therapeutic compound is delivered to the treatment site before the ultrasound radiating member is activated, and a second portion of the microbubble therapeutic compound is delivered to the treatment site after the ultrasound radiating member is activated.
- the microbubble therapeutic compound is delivered to the treatment site only when the ultrasound radiating member is active.
- additional measures are taken to provide a sufficient density of microbubbles at the treatment site. Examples of such additional measures include using a microbubble therapeutic compound with an increased microbubble density, and providing an insulating chamber around the fluid delivery lumen, as described in greater detail below.
- the efficacy of an ultrasound-based vascular occlusion treatment is enhanced by the presence of microbubbles at the treatment site.
- the microbubbles act as a nucleus for cavitation, thus allowing cavitation to be induced at lower levels of ultrasonic energy. Therefore, it is possible to increase the treatment efficacy as a result of cavitation without increasing the amount of ultrasonic energy delivered to the treatment site.
- cavitation also promotes more effective diffusion and penetration of the therapeutic compound into surrounding tissues, such as the clot material. This effect is often referred to as “microstreaming”.
- the “microjet” mechanical agitation caused by motion of the microbubbles is effective in mechanically breaking up clot material.
- microbubbles While certain vascular treatments are enhanced by the presence of microbubbles at the treatment site, certain intravascular catheter features have an adverse affect on the delivery of a microbubble therapeutic compound to an intravascular treatment site. For example, in certain configurations microbubbles have a tendency to accumulate in and clog the fluid delivery ports 58 and the fluid delivery lumens 30 , especially in embodiments wherein a temperature sensor 20 is positioned therein. For example, see the example embodiment illustrated in FIG. 8 . This effect is particularly problematic in embodiments wherein the size of the microbubbles are not significantly smaller than the size of the fluid delivery ports 58 .
- the microbubbles have an average diameter of between approximately 0.01 ⁇ m and approximately 100 ⁇ m, and the fluid delivery ports 58 have an average diameter between about 28 ⁇ m and about 48 ⁇ m.
- a portion of the microbubbles are destroyed as a result of the infusion pressure used to deliver the therapeutic compound through the delivery lumens and/the or shear stresses generated by fluid flow through the delivery lumens. The extent to which these structural catheter features affect the concentration of microbubbles that is ultimately delivered to the treatment site depends on several factors, including the flow rate of microbubble therapeutic compound through the delivery lumen and the concentration of the microbubble therapeutic compound delivered through the delivery lumen.
- microbubbles in a microbubble therapeutic compound occasionally cavitate and/or burst when exposed to ultrasonic energy, regardless of whether that exposure occurs inside or outside the fluid delivery lumens of the ultrasonic catheter.
- cavitation occurs within the fluid delivery lumens of the ultrasonic catheter, this not only reduces the quantity of microbubbles delivered to the treatment site, but it also increases the risk of damaging the fluid delivery lumens due to the energy released as a result of the cavitation.
- the extent to which cavitation occurs within the fluid delivery lumens of an ultrasonic catheter depends on factors such as the flow rate of microbubbles through the lumen (which is proportional to the time the microbubbles are exposed to ultrasonic energy), the concentration of microbubbles in the therapeutic compound (which is proportional to the amount of acoustic shielding for the microbubbles) and the number of active ultrasound radiating members in the catheter (which is proportional to the amount of ultrasonic energy delivered to the lumen).
- the ultrasonic catheter is configured such that the presence of a microbubble therapeutic compound in the delivery lumens does not substantially effect the operation of the ultrasound radiating members.
- the catheter design and/or the treatment techniques are modified to reduce cavitation within the catheter fluid delivery lumens and/or to preserve the quantity of microbubbles delivered to the treatment site. Consequently, in certain embodiments, such modifications advantageously improve the efficacy of a microbubble-based vascular occlusion treatment.
- an insulating chamber is used to reduce the amount of ultrasonic energy that is delivered into the catheter fluid delivery lumen.
- an insulating chamber is positioned between the ultrasound radiating member and the delivery lumen.
- the insulating chamber is filled with a material that does not efficiently transmit ultrasonic energy, thereby reducing the amount of ultrasonic energy reaching the fluid delivery lumen.
- Example materials that are put into the insulating chamber include, but are not limited to, air, nitrogen and oxygen.
- an evacuated chamber is used.
- FIG. 13 illustrates an example embodiment of an ultrasound catheter having an ultrasound radiating member 320 separated from a delivery lumen 338 by an insulating chamber 330 .
- the ultrasound radiating member 320 is offset from the delivery lumen 338 using spacers 316 and support members 318 .
- Other insulating chamber configurations are used in other embodiments. Additional information on using insulating chambers to spatially direct ultrasonic energy is provided in U.S. Pat. Nos. 6,582,392 and 6,676,626, the entire disclosure of which is incorporated herein by reference.
- a microbubble therapeutic compound is infused intra-arterially or intravenously to the treatment site before the ultrasound radiating members are activated. Therefore, once the ultrasound radiating members begin to generate ultrasonic energy, the microbubble therapeutic compound is already at the treatment site.
- the microbubble therapeutic compound is delivered using the same catheter that is used to the deliver the ultrasonic energy in some embodiments.
- the microbubble therapeutic compound is delivered using a different catheter than that used to deliver the ultrasonic energy in other embodiments.
- the microbubble therapeutic compound is delivered to the treatment site via the general vascular circulation in still other embodiments. Regardless of how the initial delivery of microbubbles to the treatment site is accomplished, ultrasonic energy is delivered to the treatment site after the delivery of microbubbles has occurred.
- a therapeutic compound or a cooling fluid is optionally delivered to the treatment site during ultrasonic energy delivery, thereby enhancing the treatment efficacy and/or helping to cool the ultrasound radiating members.
- a microbubble therapeutic compound is delivered to the treatment site to supplement the concentration of microbubbles provided at the treatment site provided by the initial delivery of microbubbles.
- a cooling element is used to help moderate the temperature of the treatment site.
- a microbubble therapeutic compound is delivered to the treatment site intermittently with ultrasonic energy.
- the microbubble therapeutic compound is delivered without ultrasonic energy during a first treatment phase.
- delivery of the microbubble therapeutic compound is paused and ultrasonic energy is delivered to the treatment site during a second treatment phase.
- the first and second treatment phases are alternately repeated several times.
- the duration of the first and second phases are each on the order of approximately a few minutes.
- the first and second phases each have a duration that is preferably between about 1 minute and about 20 minutes, that is more preferably between about 2 minutes and about 7 minutes, and that is most preferably between about 3 minutes and about 4 minutes.
- the first and second treatment phases have different durations.
- the delivery of microbubble therapeutic compound and ultrasonic energy advantageously reduces the amount of cavitation that occurs within the catheter fluid delivery lumen or lumens.
- the therapeutic compound delivered to the treatment site is alternated between a therapeutic compound that contains microbubbles and a therapeutic compound that does not contain microbubbles.
- the phases wherein ultrasonic energy is delivered correspond to the phases during in which the therapeutic compound that does not contain microbubbles is delivered.
- the microbubble therapeutic compound is injected directly into a vascular obstruction at the treatment site.
- FIG. 14 illustrates a catheter 400 having a distal end that is positioned within an occlusion 410 in a patient's vasculature 420 .
- a microbubble therapeutic compound 430 has been infused into the occlusion 410 from the catheter 400 .
- one or more ultrasound radiating members 440 mounted within the catheter 400 is energized, thereby delivering ultrasonic energy to the occlusion 410 and the infused microbubble therapeutic compound 430 .
- the catheter 400 is optionally repositioned during the treatment to direct additional ultrasonic energy into a larger portion of the occlusion 410 and the infused microbubble therapeutic compound 430 .
- ultrasonic energy is applied to the microbubbles suspended within the occlusion, thereby causing mechanical agitation and/or cavitation of the microbubbles.
- the mechanical agitation and/or cavitation of the microbubbles assists faster enzyme mediated lysis of the clot and/or generates microholes that increase the clot surface area available to interact with lysing enzymes.
- control circuitry is used to selectively activate certain ultrasound radiating members in the catheter.
- such control circuitry is also used to selectively activate an infusion pump that controls delivery of a microbubble therapeutic compound through the catheter fluid delivery lumens.
- the control circuitry is capable of controlling a wide variety of infusion pump configurations, such as a rotating syringe pump, a peristaltic pump, or another pump that is capable of developing pressure differentials slowly.
- FIG. 15 illustrates an intravascular catheter 500 that is capable of receiving a fluid from a first reservoir 502 that contains a microbubble therapeutic compound.
- the catheter 500 is also capable of receiving an ultrasound control signal from an ultrasound signal generator 504 .
- Controller 506 is configured to control the ultrasound signal generator 504 and an infusion pump 508 that is coupled to the first reservoir 502 .
- the controller 506 is also optionally configured to control an agitator 510 that is capable of vibrating, rotating, or otherwise agitating the first reservoir 502 .
- this configuration is advantageously capable of using a single controller 506 to alternatively cause ultrasonic energy and a microbubble therapeutic compound to be delivered from the catheter 500 to the treatment site.
- the controller 506 is optionally configured to periodically agitate the first reservoir 502 to preserve the concentration of microbubbles in the microbubble therapeutic compound held therein.
- the intravascular catheter 500 is optionally also capable of receiving a fluid from a second reservoir 512 that contains a therapeutic compound that does not include microbubbles.
- the infusion pump 508 is also coupled to the second reservoir, as is configured such that the controller 506 can be used to independently control delivery of fluids from the first reservoir 502 and the second reservoir 512 to the catheter 500 .
- This configuration advantageously allows the controller 506 to be used to alternate delivery of a microbubble therapeutic compound and a therapeutic compound that does not include microbubbles to the catheter 500 .
- clot reduction enhancement is defined as the clot weight reduction as compared before and after treatment.
- other techniques for promoting cavitation at the treatment site include supplying an ultrasound contrast agent to the treatment site and/or using an ultrasound catheter that includes a cavitation promoting surface. Use of such techniques reduces the acoustic pressure amplitude required to initiate cavitation, and therefore allows lower levels of ultrasonic energy to be delivered to the treatment site from the ultrasound assembly. This provides several advantages, such as prolonging the life of an ultrasound radiating member and reducing the likelihood of causing thermal damage to the treatment site.
- cavitation is used to enhance the delivery and/or effect of a therapeutic compound in certain embodiments, cavitation promotes clot dissolution even in the absence of a therapeutic compound. Indeed, in the context of treating a vascular occlusion, the beneficial effect of cavitation in the absence of a therapeutic compound is often greater than the beneficial effect of a therapeutic compound alone.
- cavitation promoting surfaces and ultrasound contrast agents are independently capable of inducing cavitation at an intravascular treatment site
- cavitation is induced at an intravascular treatment site using a cavitation promoting surface, but without using an ultrasound contrast agent.
- Such embodiments advantageously simplify the treatment procedure by eliminating the need to monitor the concentration of the ultrasound contrast agent at the treatment site, reduce the treatment cost, and reduce the risk of systemic complications caused by the ultrasound contrast agent.
- cavitation is induced at an intravascular treatment site using a ultrasound contrast agent, but without using a cavitation promoting surface.
- Such embodiments advantageously are usable with conventional ultrasound catheters that have not been modified to include the cavitation promoting surface.
- both a cavitation promoting surface and an ultrasound contrast agent are used to enhance cavitation at the treatment site.
- a ultrasound contrast agent, a cavitation promoting surface, or both, are used to promote cavitation
- the generation of free microbubbles at the treatment site is optionally manipulated by adjusting the frequency, peak pressure and duration of ultrasonic energy delivered to the treatment site.
- a catheter with a cavitation promoting surface is used to deliver a microbubble therapeutic compound to an internal portion of a vascular occlusion, as opposed to the fluid medium surrounding the occlusion. This is particularly important in view of the observation that the viscoelastic properties of the surrounding medium affect how microbubbles respond to ultrasonic energy.
- a cavitation promoting surface is obtained by patterning a catheter surface with an ablative laser.
- an excimer laser with mask projection technique can be used to precisely pattern features onto the catheter surface.
- the features are holes that are generally circular in shape. In other embodiments, the holes are oval, rectangular, triangular or another geometrical shape.
- the features are approximately 15 ⁇ m in diameter and/or depth. In other embodiments, the features are between approximately 1 and 100 ⁇ m in diameter and/or depth. In some embodiments, the features can be separated by approximately 25 ⁇ m. In other embodiments, the features can be separately by a distance between approximately 1 and 100 ⁇ m.
- the cavitation promoting surface 3010 comprises holes 3020 that are formed on a portion of the catheter surface 3000 .
- the holes 3020 do not extend through the catheter body, but instead are formed as surface features on the exterior catheter surface 3000 .
- the cavitation promoting surface 3010 can be formed on the portion of the catheter surface 3000 that is proximate the ultrasound radiating members and/or the energy delivery section of the catheter.
- a cavitation promoting surface is obtained by grit blasting a catheter surface with an angular media.
- one suitable angular media is a powder of aluminum oxide particles having an average diameter of approximately 25 ⁇ m.
- Aluminum oxide and other similar angular media are dry media, which advantageously facilitate cleaning of the catheter surface after the roughening treatment is performed.
- the angular media has a diameter between approximately 1 and 100 ⁇ m.
- a cavitation promoting surface is obtained by scoring a catheter surface.
- the depth and/or width of the scoring is between approximately 1 and 100 ⁇ m.
- the scoring is a single continuous spiral that winds around the catheter surface.
- the scoring is formed from multiple intersecting spirals that form a cross-hatched pattern on the catheter surface.
- the scoring is formed by parallel and non-intersecting scores.
- a cavitation promoting surface is obtained by etching a catheter surface.
- the etching is done with chemicals, plasma or laser.
- An etch mask can be applied to the catheter surface to limit etching to appropriate areas of the catheter surface.
- the etching results in features similar to those produced by laser ablation, scoring or grit blasting.
- a hydrophobic coating is applied to the catheter surface either before or after the cavitation promoting surface is formed as described herein.
- the hydrophobic coating is formed, for example, from parylene.
- application of the hydrophobic coating lowers the surface energy between blood and the cavitation promoting surface allowing for easier bubble liberation.
- a cavitation promoting surface is obtained by coating a catheter surface with a superhydrophobic material with nanoscale porous structures.
- a coating material consists of polypropylene with an appropriate solvent, such as p-xylene, and the appropriate nonsolvent, such as methyl ethyl ketone, which is used to precipitate the dissolved polypropylene out of the solvent. After precipitation, the solvent and nonsolvent is removed by evaporation, leaving a film of porous material.
- the porous structures provide gas entrapment sites for cavitation nuclei while the superhydrophobic properties reduce the surface energy allowing for easier bubble liberation.
- a cavitation promoting surface is obtained by attaching a porous ceramic, resin, polymer or metal material to a catheter surface.
- the porous structure acts as a source of entrapped gas for cavitation nuclei.
- ultrasonic energy accelerates enzymatic fibrinolysis through non-thermal mechanisms by increasing transport of drug molecules into the clot.
- Mechanical effects of ultrasonic energy such as streaming, radiation force and cavitation have the ability to influence drug transport.
- Acoustic cavitation is generally acknowledged as playing a significant role in ultrasound-accelerated fibrinolysis.
- the addition of ultrasound contrast agents has been shown to increase the effectiveness of ultrasound-accelerated enzymatic fibrinolysis.
- Mechanisms related to both inertial cavitation for example, intense localized stresses and micro-jets
- stable cavitation for example, cavitation micro-streaming and bubble translation
- the type of cavitation activity occurring at the treatment site is determined by analyzing frequency components in the scattered acoustic emissions from the treatment site. For example subharmonic emission at half the driving frequency, which is a characteristic of stable nonlinear bubble oscillation, provides a general indicator for stable cavitation activity. Broadband noise, which is manifested as an elevation in the signal amplitude between the harmonic peaks in the fast Fourier transform (“FFT”) magnitude spectrum, provides a general indicator for inertial cavitation activity. In the absence of cavitation, only the fundamental ultrasound drive signal and its harmonics are present, aside from broadband electrical background noise.
- FFT fast Fourier transform
- the broadband noise in a particular signal is quantified by integrating the “inter-peak” noise amplitude NA between 4 and 10 MHz. Other frequency spectra are used in other embodiments.
- a true rise in broadband noise over baseline due to inertial cavitation is identified by setting a detection threshold.
- IC count a total number of ultrasound bursts containing inertial cavitation
- subharmonic emission in a particular signal is identified by the presence of a subharmonic peak in the FFT magnitude spectrum at one half of the fundamental frequency.
- the FFT magnitude spectrum is computed and the magnitude at the subharmonic frequency was taken as the subharmonic amplitude SA.
- each digitized burst yields a single measure of the relative subharmonic enhancement, for which it is possible to plot as a function of time over the duration of the snapshot.
- the subharmonic quantities are averaged over the n bursts to yield the average subharmonic enhancement ⁇ RSE>.
- the average value of ⁇ RSE> is optionally compiled from m independent snapshots and compared between treatment groups, thereby enabling further statistical analysis.
- FIG. 17 A plot illustrating RNE as a function of time during a 3.33-second snapshot for an example 30-minute ultrasound exposure within a clot is illustrated in FIG. 17 .
- FIG. 18 A plot illustrating RSE as a function of time during a 3.33-second snapshot for an example ultrasound exposure within a clot is illustrated in FIG. 18 .
- Data from four treatment protocols are illustrated in FIGS. 17 and 18 : therapeutic compound and ultrasonic energy (D+US); therapeutic compound, ultrasonic energy, and microbubbles (D+US+MB); therapeutic compound, ultrasonic energy, and microbubbles that were previously exposed to ultrasound (D+US+MB(pre)); and ultrasonic energy and microbubbles (US+MB).
- both RNE and RSE remained at baseline.
- cavitation signals were high and were substantially identical for the two protocols in which the microbubbles were not pre-exposed to ultrasonic energy (D+US+MB and US+MB).
- RNE increased rapidly to a peak value within about 0.1 seconds, decreased toward baseline, crossed below the detection threshold (NET ⁇ 0.24) at about 0.4 seconds, and settled to baseline by about 1.0 seconds.
- RSE increased to a peak value within about 0.1 seconds.
- RSE did not settle back to baseline, but instead remained at a slightly elevated value during the remainder of the snapshot.
- Table B lists the total number of IC counts observed for the different treatment protocols.
- IC counts were only observed during the initial snapshot in the 30-minute exposure. The number of counts was greatest for the two protocols in which microbubbles were not pre-exposed to ultrasound (D+US+MB and US+MB). In the absence of microbubbles (D+US), two IC counts were recorded.
- lysis enhancement due to ultrasonic energy increased significantly, confirming the synergistic effect of microbubbles and therapeutic compound.
- Inertial cavitation observed as broadband noise in the acoustic signal, was present only at the start of the ultrasound exposure, and disappeared completely in less than one second.
- Subharmonic emission an indicator for stable cavitation activity, was greatest at the start of the exposure, subsequently decreased in amplitude, yet persisted for the remainder of the 30-minute treatment.
- inertial cavitation is explained by liberated microbubbles yielding sub-resonant bubbles (for example, bubbles smaller than resonance size at 1.7 MHz) that break up upon collapse, thereby forming very small bubbles that are quickly driven to dissolution by the compressive force of surface tension.
- sub-resonant bubbles for example, bubbles smaller than resonance size at 1.7 MHz
- microbubbles In the presence of microbubbles alone, ultrasound exposure resulted in no measurable lysis, indicating that mechanical disruption (for example, fragmentation) of the clot was not a contributing mechanism for lysis. This lack of effect is not surprising because of the limited duration of inertial cavitation observed.
- the microbubbles are replenished, or the acoustic parameters (such as acoustic pressure amplitude, pulse length, or duty cycle) are modified to increase the persistence and quantity of inertial cavitation to an extent where mechanical effects alone become important.
- the cavitation activity that occurred at the start of the treatment was significantly reduced compared to the other microbubble-based protocols.
- inertial cavitation was substantially eliminated: only the first ultrasound burst contained broadband noise.
- a possible explanation for this result is that all of the candidate sub-resonant bubbles were “used up” in the pre-exposure and thus were not available to nucleate inertial cavitation when the therapeutic compound was present.
- the low-amplitude subharmonic emission was still present during the 30-minute exposure and at the same magnitude as in the other protocols with microbubbles. Without being limited by theory, this result suggests the presence of super-resonant bubbles.
- Super-resonant bubbles are large bubbles that are less influenced by surface tension, that do not dissolve as quickly as smaller bubble, and that are held in place by the dense fibrin matrix of the clot. Lysis enhancement in such embodiments was substantially the same as that obtained for treatments in which microbubbles were not pre-exposed to ultrasound.
- the additional lysis enhancement due to microbubbles is correlated to the presence of the subharmonic emission, thus identifying an important role for stable cavitation in microbubble-enhanced ultrasound-accelerated fibrinolysis.
- Mechanisms related to stable cavitation such as steady micro-streaming, enhance fibrinolysis by promoting local mass transfer and thus the rate of penetration of the therapeutic compound into the clot matrix.
- inertial cavitation is optionally reduced or eliminated without adversely effecting the enhancement of ultrasound-accelerated fibrinolysis in the presence of microbubbles.
- subharmonic emission was used as a general indicator for stable cavitation.
- other types of stable bubble activity including oscillations that occur below the pressure threshold for subharmonic emission, occur simultaneously and are also responsible for lysis enhancement.
- surface waves on the bubble wall which have been associated with subharmonic emissions, are effective in generating micro-streaming flows around bubbles undergoing repetitive large amplitude motion.
Abstract
Description
- This application claims the benefit of U.S. Provisional Application 60/794,330 (filed Apr. 24, 2006) and U.S. Provisional Application 60/799,119 (filed May 9, 2006), which are hereby incorporated by reference in their entirety.
- The present invention relates generally to treatment of vascular occlusions, and more specifically to treatment of vascular occlusions with ultrasonic energy and a therapeutic compound having microbubbles.
- Several medical applications use ultrasonic energy. For example, U.S. Pat. Nos. 4,821,740, 4,953,565 and 5,007,438 disclose the use of ultrasonic energy to enhance the effect of various therapeutic compounds. An ultrasonic catheter can be used to deliver ultrasonic energy and a therapeutic compound to a treatment site within a patient's body. Such an ultrasonic catheter typically includes an ultrasound assembly configured to generate ultrasonic energy and a fluid delivery lumen for delivering the therapeutic compound to the treatment site.
- As taught in U.S. Pat. No. 6,001,069, ultrasonic catheters can be used to treat human blood vessels that have become partially or completely occluded by plaque, thrombi, emboli or other substances that reduce the blood carrying capacity of the vessel. To remove or reduce the occlusion, the ultrasonic catheter is used to deliver solutions containing therapeutic compounds directly to the occlusion site. Ultrasonic energy generated by the ultrasound assembly enhances the effect of the therapeutic compounds. Such a device can be used in the treatment of diseases such as ischemic stroke, peripheral arterial occlusion or deep vein thrombosis. In such applications, the ultrasonic energy enhances treatment of the occlusion with therapeutic compounds such as urokinase, tissue plasminogen activator (“tPA”), recombinant tissue plasminogen activator (“rtPA”) and the like. Further information on enhancing the effect of a therapeutic compound using ultrasonic energy is provided in U.S. Pat. Nos. 5,318,014, 5,362,309, 5,474,531, 5,628,728, 6,001,069 and 6,210,356.
- Certain therapeutic compounds contain a plurality of microbubbles having, for example, a gas formed therein. The efficacy of a therapeutic compound can be enhanced by the presence of the microbubbles contained therein. The microbubbles act as a nucleus for cavitation, which can help promote the dissolution and removal of a vascular occlusion. Furthermore, the mechanical agitation caused motion of the microbubbles can be effective in mechanically breaking up clot material. Therefore, ultrasound catheter systems configured for use with a microbubble-containing therapeutic compound have been developed.
- In one embodiment of the present invention, a method of treating a vascular occlusion located at a treatment site within a patient's vasculature comprises positioning an ultrasound catheter at the treatment site. The method further comprises delivering a microbubble compound from the ultrasound catheter to the vascular occlusion while ultrasound is off during a first treatment phase. The method further comprises pausing the delivery of the microbubble compound and delivering ultrasonic energy and therapeutic compound or cooling fluid from the ultrasound catheter to the vascular occlusion during a second treatment phase while the delivery of microbubble compound remains paused.
- In one embodiment of the present invention, a method of treating a vascular occlusion located at a treatment site within a patient's vasculature comprises passing an ultrasound catheter through the patient's vasculature to the treatment site. The ultrasound catheter includes at least one fluid delivery port. The method further comprises positioning the ultrasound catheter at the treatment site such that the at least one fluid delivery port is positioned within the occlusion. The method further comprises infusing a microbubble therapeutic compound from the ultrasound catheter into an internal portion of the occlusion. The method further comprises pausing delivery of the microbubble therapeutic compound from the ultrasound catheter after a first quantity has been infused into the occlusion. The method further comprises delivering ultrasonic energy and a therapeutic compound from the ultrasound catheter into the infused microbubble therapeutic compound. The method further comprises repositioning the ultrasound catheter at the treatment site. The method further comprises infusing a second quantity of microbubble therapeutic compound from the ultrasound catheter to the treatment site after the ultrasonic energy is delivered to the treatment site.
- In one embodiment of the present invention, an ultrasound catheter system comprises an elongate tubular body having an ultrasound radiating member and a fluid delivery lumen positioned therein. The system further comprises a fluid reservoir that is hydraulically coupled to a proximal portion of the fluid delivery lumen. The fluid delivery reservoir contains a microbubble therapeutic compound. The system further comprises an infusion pump configured to pump the microbubble therapeutic compound from the fluid reservoir into the fluid delivery lumen. The system further comprises control circuitry configured to send electrical activation power to the infusion pump and to the ultrasound radiating member. The control circuitry is configured such that the infusion pump and the ultrasound radiating member are not activated simultaneously.
- Example embodiments of the vascular occlusion treatment system are illustrated in the accompanying drawings, which are for illustrative purposes only. The drawings comprise the following figures, in which like numerals indicate like parts.
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FIG. 1 is a schematic illustration of an ultrasonic catheter configured for insertion into large vessels of the human body. -
FIG. 2 is a cross-sectional view of the ultrasonic catheter ofFIG. 1 taken along line 2-2. -
FIG. 3 is a schematic illustration of an elongate inner core configured to be positioned within the central lumen of the catheter illustrated inFIG. 2 . -
FIG. 4 is a cross-sectional view of the elongate inner core ofFIG. 3 taken along line 4-4. -
FIG. 5 is a schematic wiring diagram illustrating an example technique for electrically connecting five groups of ultrasound radiating members to form an ultrasound assembly. -
FIG. 6 is a schematic wiring diagram illustrating an example technique for electrically connecting one of the groups ofFIG. 5 . -
FIG. 7A is a schematic illustration of the ultrasound assembly ofFIG. 5 housed within the inner core ofFIG. 4 . -
FIG. 7B is a cross-sectional view of the ultrasound assembly ofFIG. 7A taken alongline 7B-7B. -
FIG. 7C is a cross-sectional view of the ultrasound assembly ofFIG. 7A taken alongline 7C-7C. -
FIG. 7D is a side view of an ultrasound assembly center wire twisted into a helical configuration. -
FIG. 8 illustrates the energy delivery section of the inner core ofFIG. 4 positioned within the energy delivery section of the tubular body ofFIG. 2 . -
FIG. 9 illustrates a wiring diagram for connecting a plurality of temperature sensors with a common wire. -
FIG. 10 is a block diagram of a feedback control system for use with an ultrasonic catheter. -
FIG. 11A is a side view of a treatment site. -
FIG. 11B is a side view of the distal end of an ultrasonic catheter positioned at the treatment site ofFIG. 11A . -
FIG. 11C is a cross-sectional view of the distal end of the ultrasonic catheter ofFIG. 11B positioned at the treatment site before a treatment. -
FIG. 11D is a cross-sectional view of the distal end of the ultrasonic catheter ofFIG. 11C , wherein an inner core has been inserted into the tubular body to perform a treatment. -
FIG. 12A is a cross-sectional view of a distal end of an ultrasonic catheter configured for use within small vessels of a patient's vasculature. -
FIG. 12B is a cross-sectional view of the ultrasonic catheter ofFIG. 12A taken throughline 12B-12B. -
FIG. 13 is a cross-sectional view of an ultrasound radiating member separated from a delivery lumen by a chamber. -
FIG. 14 is a cross-sectional view of an example technique for applying ultrasonic energy to an infused microbubble therapeutic compound. -
FIG. 15 is a schematic illustration of selected components of an example system that is capable of using a single controller to alternatively deliver ultrasonic energy and a microbubble therapeutic compound to an intravascular treatment site. -
FIG. 16A illustrates a laser patterned cavitation promoting surface. -
FIG. 16B illustrates a close up of a cavitation promoting surface. -
FIG. 17 is a graph showing the relative noise enhancement versus time during a 3.33-second snapshot obtained at time zero in a 30-minute ultrasound exposure. Each trace is an average over 10 snapshots. -
FIG. 18 is a graph showing the relative subharmonic enhancement versus time during a 3.33-second snapshot obtained at time zero in a 30-minute ultrasound exposure. Each trace is an average over 10 snapshots. -
FIG. 19A is a graph showing the maximum noise enhancement per snapshot illustrated as a function of ultrasound exposure time. Each point corresponds to an average of 10 snapshots. -
FIG. 19B is a graph showing a comparison of max{RNE} for the snapshot taken at time zero (0 min) and the average max{RNE} for snapshots obtained during the remainder of the 30-minute exposure. Error bars indicate standard deviation. -
FIG. 20A is a graph showing the average subharmonic enhancement per snapshot illustrated as a function of ultrasound exposure time. Each point corresponds to an average of 10 snapshots. -
FIG. 20B is a graph showing a comparison of <RSE> for the snapshot taken at time zero and the average <RSE> for snapshots obtained during the remainder of the 30-minute exposure. Error bars indicate standard deviation. - As set forth above, methods and apparatuses have been developed that allow a vascular occlusion to be treated using both ultrasonic energy and a therapeutic compound having a controlled temperature. Disclosed herein are several example embodiments of ultrasonic catheters that can be used to enhance the efficacy of therapeutic compounds at a treatment site within a patient's body. Introduction.
- As used herein, the term “therapeutic compound” refers broadly, without limitation, and in addition to its ordinary meaning, to a drug, medicament, dissolution compound, genetic material, neuroprotection compounds or any other substance capable of effecting physiological functions. Additionally, a mixture includes substances such as these is also encompassed within this definition of “therapeutic compound”. Examples of therapeutic compounds include thrombolytic compounds, anti-thrombosis compounds, and other compounds used in the treatment of vascular occlusions, including compounds intended to prevent or reduce clot formation. In applications where human blood vessels that have become partially or completely occluded by plaque, thrombi, emboli or other substances that reduce the blood carrying capacity of a vessel, example therapeutic compounds include, but are not limited to, heparin, urokinase, streptokinase, tPA, rtPA and BB-10153 (manufactured by British Biotech, Oxford, UK).
- As used herein, the terms “ultrasonic energy”, “ultrasound” and “ultrasonic” refer broadly, without limitation, and in addition to their ordinary meaning, to mechanical energy transferred through longitudinal pressure or compression waves. Ultrasonic energy can be emitted as continuous or pulsed waves, depending on the parameters of a particular application. Additionally, ultrasonic energy can be emitted in waveforms having various shapes, such as sinusoidal waves, triangle waves, square waves, or other wave forms. Ultrasonic energy includes sound waves. In certain embodiments, the ultrasonic energy referred to herein has a frequency between about 20 kHz and about 20 MHz. For example, in one embodiment, the ultrasonic energy has a frequency between about 500 kHz and about 20 MHz. In another embodiment, the ultrasonic energy has a frequency between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasonic energy has a frequency of about 2 MHz. In certain embodiments described herein, the average acoustic power of the ultrasonic energy is between about 0.01 watts and 300 watts. In one embodiment, the average acoustic power is about 15 watts.
- As used herein, the term “ultrasound radiating member” refers broadly, without limitation, and in addition to its ordinary meaning, to any apparatus capable of producing ultrasonic energy. An ultrasonic transducer, which converts electrical energy into ultrasonic energy, is an example of an ultrasound radiating member. An example ultrasonic transducer capable of generating ultrasonic energy from electrical energy is a piezoelectric ceramic oscillator. Piezoelectric ceramics typically comprise a crystalline material, such as quartz, that changes shape when an electrical current is applied to the material. This change in shape, made oscillatory by an oscillating driving signal, creates ultrasonic sound waves. In other embodiments, ultrasonic energy can be generated by an ultrasonic transducer that is remote from the ultrasound radiating member, and the ultrasonic energy can be transmitted, via, for example, a wire that is coupled to the ultrasound radiating member.
- In certain applications, the ultrasonic energy itself provides a therapeutic effect to the patient. Examples of such therapeutic effects include preventing or reducing stenosis and/or restenosis; tissue ablation, abrasion or disruption; promoting temporary or permanent physiological changes in intracellular or intercellular structures; and rupturing micro-balloons or micro-bubbles for therapeutic compound delivery. Further information about such methods can be found in U.S. Pat. Nos. 5,261,291 and 5,431,663.
- The ultrasonic catheters described herein can be configured for application of ultrasonic energy over a substantial length of a body lumen, such as, for example, the larger vessels located in the leg. In other embodiments, the ultrasonic catheters described herein can be configured to be inserted into the small cerebral vessels, in solid tissues, in duct systems and in body cavities. In other embodiments, treatment with the ultrasonic catheter is performed outside the vascular system, such as within or at a tumor, in which the treatment is configured to kill malignant tissues by enhancing the delivery of a cancer drug to the tumor. Additional embodiments that can be combined with certain features and aspects of the embodiments described herein are described in U.S. patent application Ser. No. 10/291,891, filed 7 Nov. 2002, the entire disclosure of which is hereby incorporated herein by reference.
- Overview of a Large Vessel Ultrasonic Catheter.
-
FIG. 1 schematically illustrates anultrasonic catheter 10 configured for use in the large vessels of a patient's anatomy. For example, theultrasonic catheter 10 illustrated inFIG. 1 can be used to treat long segment peripheral arterial occlusions, such as those in the vascular system of the leg. - As illustrated in
FIG. 1 , theultrasonic catheter 10 generally includes a multi-component, elongate flexibletubular body 12 having aproximal region 14 and adistal region 15. Thetubular body 12 includes a flexibleenergy delivery section 18 located in thedistal region 15. Thetubular body 12 and other components of thecatheter 10 can be manufactured in accordance with a variety of techniques known to an ordinarily skilled artisan. Suitable materials and dimensions can be readily selected based on the natural and anatomical dimensions of the treatment site and on the desired percutaneous access site. - For example, in an example embodiment, the tubular body
proximal region 14 comprises a material that has sufficient flexibility, kink resistance, rigidity and structural support to push theenergy delivery section 18 through the patient's vasculature to a treatment site. Examples of such materials include, but are not limited to, extruded polytetrafluoroethylene (“PTFE”), polyethylenes (“PE”), polyamides and other similar materials. In certain embodiments, the tubular bodyproximal region 14 is reinforced by braiding, mesh or other constructions to provide increased kink resistance and ability to be pushed. For example, nickel titanium or stainless steel wires can be placed along or incorporated into thetubular body 12 to reduce kinking. - For example, in an embodiment configured for treating thrombus in the arteries of the leg, the
tubular body 12 has an outside diameter between about 0.060 inches and about 0.075 inches. In another embodiment, thetubular body 12 has an outside diameter of about 0.071 inches. In certain embodiments, thetubular body 12 has an axial length of approximately 105 centimeters, although other lengths can be used in other applications. - In an example embodiment, the tubular body
energy delivery section 18 comprises a material that is thinner than the material comprising the tubular bodyproximal region 14. In another example embodiment, the tubular bodyenergy delivery section 18 comprises a material that has a greater acoustic transparency than the material comprising the tubular bodyproximal region 14. Thinner materials generally have greater acoustic transparency than thicker materials. Suitable materials for theenergy delivery section 18 include, but are not limited to, high or low density polyethylenes, urethanes, nylons, and the like. In certain modified embodiments, theenergy delivery section 18 comprises the same material or a material of the same thickness as theproximal region 18. - In an example embodiment, the
tubular body 12 is divided into at least three sections of varying stiffness. The first section, which includes theproximal region 14, has a relatively higher stiffness. The second section, which is located in an intermediate region between theproximal region 14 and thedistal region 15, has a relatively lower stiffness. This configuration further facilitates movement and placement of thecatheter 10. The third section, which includes theenergy delivery section 18, has a relatively lower stiffness than the second section in spite of the presence of ultrasound radiating members which can be positioned therein. -
FIG. 2 illustrates a cross section of thetubular body 12 taken along line 2-2 inFIG. 1 . In the embodiment illustrated inFIG. 2 , threefluid delivery lumens 30 are incorporated into thetubular body 12. In other embodiments, more or fewer fluid delivery lumens can be incorporated into thetubular body 12. In such embodiments, the arrangement of thefluid delivery lumens 30 provides a hollowcentral lumen 51 passing through thetubular body 12. The cross-section of thetubular body 12, as illustrated inFIG. 2 , is substantially constant along the length of thecatheter 10. Thus, in such embodiments, substantially the same cross-section is present in both theproximal region 14 and thedistal region 15 of thetubular body 12, including theenergy delivery section 18. - In certain embodiments, the
central lumen 51 has a minimum diameter greater than about 0.030 inches. In another embodiment, thecentral lumen 51 has a minimum diameter greater than about 0.037 inches. In an example embodiment, thefluid delivery lumens 30 have dimensions of about 0.026 inches wide by about 0.0075 inches high, although other dimensions can be used in other embodiments. - In an example embodiment, the
central lumen 51 extends through the length of thetubular body 12. As illustrated inFIG. 1 , thecentral lumen 51 has adistal exit port 29 and aproximal access port 31. Theproximal access port 31 forms part of thebackend hub 33, which is attached to the tubular bodyproximal region 14. In such embodiments, the backend hub also includes a coolingfluid fitting 46, which is hydraulically connected to thecentral lumen 51. In such embodiments, thebackend hub 33 also includes a therapeuticcompound inlet port 32, which is hydraulically coupled to thefluid delivery lumens 30, and which can also be hydraulically coupled to a source of therapeutic compound via a hub such as a Luer fitting. - The
central lumen 51 is configured to receive an elongateinner core 34, an example embodiment of which is illustrated inFIG. 3 . In such embodiments, the elongateinner core 34 includes aproximal region 36 and adistal region 38. Aproximal hub 37 is fitted on one end of the inner coreproximal region 36. One or moreultrasound radiating members 40 are positioned within an inner coreenergy delivery section 41 that is located within thedistal region 38. Theultrasound radiating members 40 form anultrasound assembly 42, which will be described in greater detail below. - As shown in the cross-section illustrated in
FIG. 4 , which is taken along lines 4-4 inFIG. 3 , in an example embodiment, theinner core 34 has a cylindrical shape, with an outer diameter that permits theinner core 34 to be inserted into thecentral lumen 51 of thetubular body 12 via theproximal access port 31. Suitable outer diameters of theinner core 34 include, but are not limited to, between about 0.010 inches and about 0.100 inches. In another embodiment, the outer diameter of theinner core 34 is between about 0.020 inches and about 0.080 inches. In yet another embodiment, theinner core 34 has an outer diameter of about 0.035 inches. - Still referring to
FIG. 4 , theinner core 34 includes a cylindricalouter body 35 that houses theultrasound assembly 42. Theultrasound assembly 42 includes wiring and ultrasound radiating members, described in greater detail inFIGS. 5 through 7 D, such that theultrasound assembly 42 is capable of radiating ultrasonic energy from theenergy delivery section 41 of theinner core 34. Theultrasound assembly 42 is electrically connected to thebackend hub 33, where theinner core 34 can be connected to acontrol system 100 via cable 45 (illustrated inFIG. 1 ). In an example embodiment, an electrically insulatingpotting material 43 fills theinner core 34, surrounding theultrasound assembly 42, thus reducing or preventing movement of theultrasound assembly 42 with respect to theouter body 35. In one embodiment, the thickness of theouter body 35 is between about 0.0002 inches and 0.010 inches. In another embodiment, the thickness of theouter body 35 is between about 0.0002 inches and 0.005 inches. In yet another embodiment, the thickness of theouter body 35 is about 0.0005 inches. - In an example embodiment, the
ultrasound assembly 42 includes a plurality ofultrasound radiating members 40 that are divided into one or more groups. For example,FIGS. 5 and 6 are schematic wiring diagrams illustrating one technique for connecting five groups ofultrasound radiating members 40 to form theultrasound assembly 42. As illustrated inFIG. 5 , theultrasound assembly 42 comprises five groups G1, G2, G3, G4, G5 ofultrasound radiating members 40 that are electrically connected to each other. The five groups are also electrically connected to thecontrol system 100. - Still referring to
FIG. 5 , in an example embodiment, thecontrol circuitry 100 includes avoltage source 102 having apositive terminal 104 and anegative terminal 106. Thenegative terminal 106 is connected tocommon wire 108, which connects the five groups G1-G5 ofultrasound radiating members 40 in series. Thepositive terminal 104 is connected to a plurality oflead wires 110, which each connect to one of the five groups G1-G5 ofultrasound radiating members 40. Thus, under this configuration, each of the five groups G1-G5, one of which is illustrated inFIG. 6 , is connected to thepositive terminal 104 via one of thelead wires 110, and to thenegative terminal 106 via thecommon wire 108. - Referring now to
FIG. 6 , each group G1-G5 includes a plurality ofultrasound radiating members 40. Each of theultrasound radiating members 40 is electrically connected to thecommon wire 108 and to thelead wire 110 via apositive contact wires 112. Thus, when wired as illustrated, a substantially constant voltage difference will be applied to eachultrasound radiating member 40 in the group. Although the group illustrated inFIG. 6 includes twelveultrasound radiating members 40, in other embodiments, more or fewerultrasound radiating members 40 can be included in the group. Likewise, more or fewer than five groups can be included within theultrasound assembly 42 illustrated inFIG. 5 . -
FIG. 7A illustrates an example technique for arranging the components of the ultrasound assembly 42 (as schematically illustrated inFIG. 5 ) into the inner core 34 (as schematically illustrated inFIG. 4 ).FIG. 7A is a cross-sectional view of theultrasound assembly 42 taken within group G1 inFIG. 5 , as indicated by the presence of fourlead wires 110. For example, if a cross-sectional view of theultrasound assembly 42 was taken within group G4 inFIG. 5 , only onelead wire 110 would be present (that is, the one lead wire connecting group G5). - In the example embodiment illustrated in
FIG. 7A , thecommon wire 108 includes an elongate, flat piece of electrically conductive material in electrical contact with a pair ofultrasound radiating members 40. Each of theultrasound radiating members 40 is also in electrical contact with apositive contact wire 112. Because thecommon wire 108 is connected to thenegative terminal 106, and thepositive contact wire 112 is connected to thepositive terminal 104, a voltage difference can be created across eachultrasound radiating member 40. In such embodiments,lead wires 110 are separated from the other components of theultrasound assembly 42, thus preventing interference with the operation of theultrasound radiating members 40 as described above. For example, in an example embodiment, theinner core 34 is filled with an insulatingpotting material 43, thus deterring unwanted electrical contact between the various components of theultrasound assembly 42. -
FIGS. 7B and 7C illustrate cross sectional views of theinner core 34 ofFIG. 7A taken alonglines 7B-7B and 7C-7C, respectively. As illustrated inFIG. 7B , theultrasound radiating members 40 are mounted in pairs along thecommon wire 108. Theultrasound radiating members 40 are connected bypositive contact wires 112, such that substantially the same voltage is applied to eachultrasound radiating member 40. As illustrated inFIG. 7C , thecommon wire 108 includes wide regions 108W upon which theultrasound radiating members 40 can be mounted, thus reducing the likelihood that the pairedultrasound radiating members 40 will short together. In certain embodiments, outside the wide regions 108W, thecommon wire 108 can have a more conventional, rounded wire shape. - In a modified embodiment, such as illustrated in
FIG. 7D , thecommon wire 108 is twisted to form a helical shape before being fixed within theinner core 34. In such embodiments, theultrasound radiating members 40 are oriented in a plurality of radial directions, thus enhancing the radial uniformity of the resulting ultrasonic energy field. - The wiring arrangement described above can be modified to allow each group G1, G2, G3, G4, G5 to be independently powered. Specifically, by providing a separate power source within the
control system 100 for each group, each group can be individually turned on or off, or can be driven at an individualized power level. This advantageously allows the delivery of ultrasonic energy to be “turned off” in regions of the treatment site where treatment is complete, thus preventing deleterious or unnecessary ultrasonic energy to be applied to the patient. - The embodiments described above, and illustrated in
FIGS. 5 through 7 , include a plurality of ultrasound radiating members grouped spatially. That is, in such embodiments, the ultrasound radiating members within a certain group are positioned adjacent to each other, such that when a single group is activated, ultrasonic energy is delivered from a certain length of the ultrasound assembly. However, in modified embodiments, the ultrasound radiating members of a certain group may be spaced apart from each other, such that the ultrasound radiating members within a certain group are not positioned adjacent to each other. In such embodiments, when a single group is activated, ultrasonic energy can be delivered from a larger, spaced apart portion of the ultrasound assembly. Such modified embodiments can be advantageous in applications where a less focussed, more diffuse ultrasonic energy field is to be delivered to the treatment site. - In an example embodiment, the
ultrasound radiating members 40 comprise rectangular lead zirconate titanate (“PZT”) ultrasound transducers that have dimensions of about 0.017 inches by about 0.010 inches by about 0.080 inches. In other embodiments, other configurations and dimensions can be used. For example, disc-shapedultrasound radiating members 40 can be used in other embodiments. In an example embodiment, thecommon wire 108 comprises copper, and is about 0.005 inches thick, although other electrically conductive materials and other dimensions can be used in other embodiments. In an example embodiment,lead wires 110 are 36 gauge electrical conductors, andpositive contact wires 112 are 42 gauge electrical conductors. However, other wire gauges can be used in other embodiments. - As described above, suitable frequencies for the
ultrasound radiating members 40 include, but are not limited to, from about 20 kHz to about 20 MHz. In one embodiment, the frequency is between about 500 kHz and about 20 MHz, and in another embodiment the frequency is between about 1 MHz and about 3 MHz. In yet another embodiment, theultrasound radiating members 40 are operated with a frequency of about 2 MHz. -
FIG. 8 illustrates theinner core 34 positioned within thetubular body 12. Details of theultrasound assembly 42, provided inFIG. 7A , are omitted for clarity. As described above, theinner core 34 can be slid within thecentral lumen 51 of thetubular body 12, thereby allowing the inner coreenergy delivery section 41 to be positioned within the tubular bodyenergy delivery section 18. For example, in an example embodiment, the materials comprising the inner coreenergy delivery section 41, the tubular bodyenergy delivery section 18, and thepotting material 43 all comprise materials having a similar acoustic impedance, thereby minimizing ultrasonic energy losses across material interfaces. -
FIG. 8 further illustrates placement offluid delivery ports 58 within the tubular bodyenergy delivery section 18. As illustrated, holes or slits are formed from thefluid delivery lumen 30 through thetubular body 12, thereby permitting fluid flow from thefluid delivery lumen 30 to the treatment site. A plurality offluid delivery ports 58 can be positioned axially along thetubular body 12. Thus, a source of therapeutic compound coupled to theinlet port 32 provides a hydraulic pressure which drives the therapeutic compound through thefluid delivery lumens 30 and out thefluid delivery ports 58. - By spacing the
fluid delivery lumens 30 around the circumference of thetubular body 12 substantially evenly, as illustrated inFIG. 8 , a substantially uniform flow of therapeutic compound around the circumference of thetubular body 12 can be achieved. Additionally, the size, location and geometry of thefluid delivery ports 58 can be selected to provide uniform fluid flow from thefluid delivery ports 30 to the treatment site. For example, in one embodiment, fluid delivery ports closer to the proximal region of theenergy delivery section 18 have smaller diameters than fluid delivery ports closer to the distal region of theenergy delivery section 18, thereby allowing uniform delivery of therapeutic compound in the energy delivery section. - For example, in one embodiment in which the
fluid delivery ports 58 have similar sizes along the length of thetubular body 12, thefluid delivery ports 58 have a diameter between about 0.0005 inches to about 0.0050 inches. In another embodiment in which the size of thefluid delivery ports 58 changes along the length of thetubular body 12, thefluid delivery ports 58 have a diameter between about 0.001 inches to about 0.005 inches in the proximal region of theenergy delivery section 18, and between about 0.005 inches to about 0.0020 inches in the distal region of theenergy delivery section 18. The increase in size between adjacentfluid delivery ports 58 depends on a variety of factors, including the material comprising thetubular body 12, and on the size of thefluid delivery lumen 30. Thefluid delivery ports 58 can be created in thetubular body 12 by punching, drilling, burning or ablating (such as with a laser), or by other suitable methods. Therapeutic compound flow along the length of thetubular body 12 can also be increased by increasing the density of thefluid delivery ports 58 toward the distal region of the energy delivery section. - In certain applications, a spatially nonuniform flow of therapeutic compound from the
fluid delivery ports 58 to the treatment site is to be provided. In such applications, the size, location and geometry of thefluid delivery ports 58 can be selected to provide such nonuniform fluid flow. - Referring still to
FIG. 8 , placement of theinner core 34 within thetubular body 12 further defines coolingfluid lumens 44. Coolingfluid lumens 44 are formed between anouter surface 39 of theinner core 34 and aninner surface 16 of thetubular body 12. In certain embodiments, a cooling fluid is introduced through theproximal access port 31 such that cooling fluid flows through coolingfluid lumens 44 and out of thecatheter 10 through distal exit port 29 (seeFIG. 1 ). In an example embodiment, the coolingfluid lumens 44 are substantially evenly spaced around the circumference of the tubular body 12 (that is, at approximately 120° increments for a three-lumen configuration), thereby providing substantially uniform cooling fluid flow over theinner core 34. Such a configuration advantageously removes thermal energy from the treatment site. As will be explained below, the flow rate of the cooling fluid and the power to theultrasound assembly 42 can be adjusted to maintain the temperature of the inner coreenergy delivery section 41, or of the treatment site generally, within a desired range. - In an example embodiment, the
inner core 34 can be rotated or moved within thetubular body 12. Specifically, movement of theinner core 34 can be accomplished by maneuvering theproximal hub 37 while holding thebackend hub 33 stationary. The inner coreouter body 35 is at least partially constructed from a material that provides enough structural support to permit movement of theinner core 34 within thetubular body 12 without kinking of thetubular body 12. Additionally, in an example embodiment, the inner coreouter body 35 comprises a material having the ability to transmit torque. Suitable materials for the inner coreouter body 35 include, but are not limited to, polyimides, polyesters, polyurethanes, thermoplastic elastomers and braided polyimides. - In an example embodiment, the
fluid delivery lumens 30 and the coolingfluid lumens 44 are open at the distal end of thetubular body 12, thereby allowing the therapeutic compound and the cooling fluid to pass into the patient's vasculature at thedistal exit port 29. In a modified embodiment, thefluid delivery lumens 30 can be selectively occluded at the distal end of thetubular body 12, thereby providing additional hydraulic pressure to drive the therapeutic compound out of thefluid delivery ports 58. In either configuration, theinner core 34 can be prevented from passing through thedistal exit port 29 by providing theinner core 34 with a length that is less than the length of thetubular body 12. In other embodiments, a protrusion is formed within thetubular body 12 in thedistal region 15, thereby preventing theinner core 34 from passing through thedistal exit port 29. - In other embodiments, the
catheter 10 includes an occlusion device positioned at thedistal exit port 29. In such embodiments, the occlusion device has a reduced inner diameter that can accommodate a guidewire, but that is less than the inner diameter of thecentral lumen 51. Thus, theinner core 34 is prevented from extending past the occlusion device and out thedistal exit port 29. For example, suitable inner diameters for the occlusion device include, but are not limited to, between about 0.005 inches and about 0.050 inches. In other embodiments, the occlusion device has a closed end, thus preventing cooling fluid from leaving thecatheter 10, and instead recirculating to the tubular bodyproximal region 14. These and other cooling fluid flow configurations permit the power provided to theultrasound assembly 42 to be increased in proportion to the cooling fluid flow rate. Additionally, certain cooling fluid flow configurations can reduce exposure of the patient's body to cooling fluids. - In an example embodiment, such as illustrated in
FIG. 8 , thetubular body 12 includes one ormore temperature sensors 20 that are positioned within theenergy delivery section 18. In such embodiments, the tubular bodyproximal region 14 includes a temperature sensor lead which can be incorporated into cable 45 (illustrated inFIG. 1 ). Suitable temperature sensors include, but are not limited to, temperature sensing diodes, thermistors, thermocouples, resistance temperature detectors (“RTDs”) and fiber optic temperature sensors which use thermalchromic liquid crystals.Suitable temperature sensor 20 geometries include, but are not limited to, a point, a patch or a stripe. Thetemperature sensors 20 can be positioned within one or more of thefluid delivery lumens 30, and/or within one or more of the coolingfluid lumens 44. -
FIG. 9 illustrates an example embodiment for electrically connecting thetemperature sensors 20. In such embodiments, eachtemperature sensor 20 is coupled to acommon wire 61 and is associated with anindividual return wire 62. Accordingly, n+1 wires are passed through thetubular body 12 to independently sense the temperature atn temperature sensors 20. The temperature at a selectedtemperature sensor 20 can be determined by closing aswitch 64 to complete a circuit between thereturn wire 62 associated with the selected thermocouple and thecommon wire 61. In embodiments wherein thetemperature sensors 20 are thermocouples, the temperature can be calculated from the voltage in the circuit using, for example, asensing circuit 63, which can be located within theexternal control circuitry 100. - In other embodiments, the
temperature sensors 20 can be independently wired. In such embodiments, 2n wires are passed through thetubular body 12 to independently sense the temperature atn temperature sensors 20. In still other embodiments, the flexibility of thetubular body 12 can be improved by using fiber optic basedtemperature sensors 20. In such embodiments, flexibility can be improved because only n fiber optic members are used to sense the temperature at nindependent temperature sensors 20. -
FIG. 10 schematically illustrates one embodiment of afeedback control system 68 that can be used with thecatheter 10. Thefeedback control system 68 can be integrated into thecontrol system 100 that is connected to theinner core 34 via cable 45 (as illustrated inFIG. 1 ). Thefeedback control system 68 allows the temperature at eachtemperature sensor 20 to be monitored and allows the output power of theenergy source 70 to be adjusted accordingly. A physician can, if desired, override the closed or open loop system. - In an example embodiment, the
feedback control system 68 includes anenergy source 70,power circuits 72 and apower calculation device 74 that is coupled to theultrasound radiating members 40. Atemperature measurement device 76 is coupled to thetemperature sensors 20 in thetubular body 12. Aprocessing unit 78 is coupled to thepower calculation device 74, thepower circuits 72 and a user interface anddisplay 80. - In an example method of operation, the temperature at each
temperature sensor 20 is determined by thetemperature measurement device 76. Theprocessing unit 78 receives each determined temperature from thetemperature measurement device 76. The determined temperature can then be displayed to the user at the user interface anddisplay 80. - In an example embodiment, the
processing unit 78 includes logic for generating a temperature control signal. The temperature control signal is proportional to the difference between the measured temperature and a desired temperature. The desired temperature can be determined by the user (as set at the user interface and display 80) or can be preset within theprocessing unit 78. - In such embodiments, the temperature control signal is received by the
power circuits 72. Thepower circuits 72 are configured to adjust the power level, voltage, phase and/or current of the electrical energy supplied to theultrasound radiating members 40 from theenergy source 70. For example, when the temperature control signal is above a particular level, the power supplied to a particular group ofultrasound radiating members 40 is reduced in response to that temperature control signal. Similarly, when the temperature control signal is below a particular level, the power supplied to a particular group ofultrasound radiating members 40 is increased in response to that temperature control signal. After each power adjustment, theprocessing unit 78 monitors thetemperature sensors 20 and produces another temperature control signal which is received by thepower circuits 72. - In an example embodiment, the
processing unit 78 optionally includes safety control logic. The safety control logic detects when the temperature at atemperature sensor 20 exceeds a safety threshold. In this case, theprocessing unit 78 can be configured to provide a temperature control signal which causes thepower circuits 72 to stop the delivery of energy from theenergy source 70 to that particular group ofultrasound radiating members 40. - Because, in certain embodiments, the
ultrasound radiating members 40 are mobile relative to thetemperature sensors 20, it can be unclear which group ofultrasound radiating members 40 should have a power, voltage, phase and/or current level adjustment. Consequently, each group ofultrasound radiating members 40 can be identically adjusted in certain embodiments. For example, in a modified embodiment, the power, voltage, phase, and/or current supplied to each group ofultrasound radiating members 40 is adjusted in response to thetemperature sensor 20 which indicates the highest temperature. Making voltage, phase and/or current adjustments in response to the temperature sensed by thetemperature sensor 20 indicating the highest temperature can reduce overheating of the treatment site. - The
processing unit 78 can also be configured to receive a power signal from thepower calculation device 74. The power signal can be used to determine the power being received by each group ofultrasound radiating members 40. The determined power can then be displayed to the user on the user interface anddisplay 80. - As described above, the
feedback control system 68 can be configured to maintain tissue adjacent to theenergy delivery section 18 below a desired temperature. For example, in certain applications, tissue at the treatment site is to have a temperature increase of less than or equal to approximately 6° C. As described above, theultrasound radiating members 40 can be electrically connected such that each group ofultrasound radiating members 40 generates an independent output. In certain embodiments, the output from the power circuit maintains a selected energy for each group ofultrasound radiating members 40 for a selected length of time. - The
processing unit 78 can comprise a digital or analog controller, such as a computer with software. In embodiments wherein theprocessing unit 78 is a computer, the computer can include a central processing unit (“CPU”) coupled through a system bus. In such embodiments, the user interface anddisplay 80 can include a mouse, a keyboard, a disk drive, a display monitor, a nonvolatile memory system, and/or other computer components. In an example embodiment, program memory and/or data memory is also coupled to the bus. - In another embodiment, in lieu of the series of power adjustments described above, a profile of the power to be delivered to each group of
ultrasound radiating members 40 can be incorporated into theprocessing unit 78, such that a preset amount of ultrasonic energy to be delivered is pre-profiled. In such embodiments, the power delivered to each group ofultrasound radiating members 40 is provided according to the preset profiles. - In an example embodiment, the ultrasound radiating members are operated in a pulsed mode. For example, in one embodiment, the time average power supplied to the ultrasound radiating members is between about 0.1 watts and about 2 watts. In another embodiment, the time average power supplied to the ultrasound radiating members is between about 0.5 watts and about 1.5 watts. In yet another embodiment, the time average power supplied to the ultrasound radiating members is approximately 0.6 watts or approximately 1.2 watts. In an example embodiment, the duty cycle is between about 1% and about 50%. In another embodiment, the duty cycle is between about 5% and about 25%. In yet another embodiment, the duty cycles is approximately 7.5% or approximately 15%. In an example embodiment, the pulse averaged power is between about 0.1 watts and about 20 watts. In another embodiment, the pulse averaged power is between approximately 5 watts and approximately 20 watts. In yet another embodiment, the pulse averaged power is approximately 8 watts or approximately 16 watts. The amplitude during each pulse can be constant or varied.
- In an example embodiment, the pulse repetition rate is between about 5 Hz and about 150 Hz. In another embodiment, the pulse repetition rate is between about 10 Hz and about 50 Hz. In yet another embodiment, the pulse repetition rate is approximately 30 Hz. In an example embodiment, the pulse duration is between about 1 millisecond and about 50 milliseconds. In another embodiment, the pulse duration is between about 1 millisecond and about 25 milliseconds. In yet another embodiment, the pulse duration is approximately 2.5 milliseconds or approximately 5 milliseconds.
- For example, in one particular embodiment, the ultrasound radiating members are operated at an average power of approximately 0.6 watts, a duty cycle of approximately 7.5%, a pulse repetition rate of approximately 30 Hz, a pulse average electrical power of approximately 8 watts and a pulse duration of approximately 2.5 milliseconds.
- In an example embodiment, the ultrasound radiating member used with the electrical parameters described herein has an acoustic efficiency greater than approximately 50%. In another embodiment, the ultrasound radiating member used with the electrical parameters described herein has an acoustic efficiency greater than approximately 75%. As described herein, the ultrasound radiating members can be formed in a variety of shapes, such as, cylindrical (solid or hollow), flat, bar, triangular, and the like. In an example embodiment, the length of the ultrasound radiating member is between about 0.1 cm and about 0.5 cm, and the thickness or diameter of the ultrasound radiating member is between about 0.02 cm and about 0.2 cm.
-
FIGS. 11A through 11D illustrate an example method for using certain embodiments of theultrasonic catheter 10 describe herein. As illustrated inFIG. 11A , aguidewire 84 similar to a guidewire used in typical angioplasty procedures is directed through a patient'svessels 86 to atreatment site 88 that includes aclot 90. Theguidewire 84 is optionally directed through theclot 90.Suitable vessels 86 include, but are not limited to, the large periphery blood vessels of the body. Additionally, as mentioned above, theultrasonic catheter 10 also has utility in various imaging applications or in applications for treating and/or diagnosing other diseases in other body parts. - As illustrated in
FIG. 11B , thetubular body 12 is slid over and is advanced along theguidewire 84, for example using conventional over-the-guidewire techniques. Thetubular body 12 is advanced until theenergy delivery section 18 is positioned at theclot 90. In certain embodiments, radiopaque markers (not shown) are optionally positioned along the tubular bodyenergy delivery section 18 to aid in the positioning of thetubular body 12 within thetreatment site 88. - As illustrated in
FIG. 10C , after thetubular body 12 is delivered to thetreatment site 88, theguidewire 84 is withdrawn from thetubular body 12 by pulling theguidewire 84 from theproximal region 14 of thecatheter 10 while holding thetubular body 12 stationary. This leaves thetubular body 12 positioned at thetreatment site 88. - As illustrated in
FIG. 10D , theinner core 34 is then inserted into thetubular body 12 until theultrasound assembly 42 is positioned at least partially within theenergy delivery section 18. In one embodiment, theultrasound assembly 42 can be configured to be positioned at least partially within theenergy delivery section 18 when theinner core 24 abuts the occlusion device at the distal end of thetubular body 12. Once theinner core 34 is positioned in such that theultrasound assembly 42 is at least partially within the energy delivery section, theultrasound assembly 42 is activated to deliver ultrasonic energy to theclot 90. As described above, in one embodiment, ultrasonic energy having a frequency between about 20 kHz and about 20 MHz is delivered to the treatment site. - In an example embodiment, the
ultrasound assembly 42 includes sixtyultrasound radiating members 40 spaced over a length of approximately 30 to approximately 50 cm. In such embodiments, thecatheter 10 can be used to treat anelongate clot 90 without requiring moving or repositioning thecatheter 10 during the treatment. However, in modified embodiments, theinner core 34 can be moved or rotated within thetubular body 12 during the treatment. Such movement can be accomplished by maneuvering theproximal hub 37 of theinner core 34 while holding thebackend hub 33 stationary. - Still referring to
FIG. 11D ,arrows 48 indicate that a cooling fluid can be delivered through the coolingfluid lumen 44 and out thedistal exit port 29. Likewise,arrows 49 indicate that a therapeutic compound can be delivered through thefluid delivery lumen 30 and out thefluid delivery ports 58 to thetreatment site 88. - The cooling fluid can be delivered before, after, during or intermittently with the delivery of ultrasonic energy. Similarly, the therapeutic compound can be delivered before, after, during or intermittently with the delivery of ultrasonic energy. Consequently, the methods illustrated in
FIGS. 11A through 11D can be performed in a variety of different orders than that described above. In an example embodiment, the therapeutic compound and ultrasonic energy are delivered until theclot 90 is partially or entirely dissolved. Once theclot 90 has been sufficiently dissolved, thetubular body 12 and theinner core 34 are withdrawn from thetreatment site 88. - Overview of a Small Vessel Ultrasonic Catheter.
- Ultrasonic catheters can also be specifically configured to use in the small vessels of a patient's vasculature, such as in the vasculature of a patient's brain. In such a configuration, the catheter is provided with an energy delivery section having increased flexibility, thereby facilitating delivery of the catheter through narrow vessels having small radius turns.
FIGS. 12A and 12B are cross-sectional views of the distal region of an example ultrasonic catheter configured for use in the small vasculature. - Similar to the large vessel ultrasonic catheter described herein, an example ultrasonic catheter configured for use in small vessels comprises a multi-component
tubular body 202 having a proximal region and adistal region 206. In such embodiments, the cathetertubular body 202 includes anouter sheath 208 that is positioned upon aninner core 210. In one embodiment, theouter sheath 208 comprises extruded Pebax®, PTFE, polyetheretherketone (“PEEK”), PE, polyamides, braided polyamides and/or other similar materials. The outer sheathdistal region 206 is adapted for advancement through vessels having a small diameter, such as those in the vasculature of the brain. In an example embodiment, the outer sheathdistal region 206 has an outer diameter between about 2 French and about 5 French. In another embodiment, outer sheathdistal region 206 has an outer diameter of about 2.8 French. In one example embodiment, theouter sheath 208 has an axial length of approximately 150 centimeters. - In a modified embodiment, the
outer sheath 208 comprises a braided tubing formed of, for example, high or low density polyethylenes, urethanes, nylons, and the like. This configuration enhances the flexibility of thetubular body 202. For enhanced maneuverability, especially the ability to be pushed and rotated, theouter sheath 208 can be formed with a variable stiffness from the proximal to the distal end. To achieve this, a stiffening member may be included along the proximal end of thetubular body 202. - The
inner core 210 defines, at least in part, adelivery lumen 212, which, in an example embodiment, extends longitudinally along the catheter. Thedelivery lumen 212 has adistal exit port 214, and is hydraulically connected to a proximal access port (not shown). Similar to the large vessel ultrasonic catheter described herein, the proximal access port can be connected to a source of therapeutic compound or cooling fluid that is to be delivered through thedelivery lumen 212. - In an example embodiment, the
delivery lumen 212 is configured to receive a guide wire (not shown). In such embodiments, the guidewire has a diameter of between approximately 0.008 and approximately 0.012 inches. In another embodiment, the guidewire has a diameter of about 0.010 inches. In an example embodiment, theinner core 210 comprises polyamide or a similar material which can optionally be braided to increase the flexibility of thetubular body 202. - Still referring to
FIGS. 12A and 12B , the tubular bodydistal region 206 includes anultrasound radiating member 224. In such embodiments, theultrasound radiating member 224 comprises an ultrasound transducer, which converts, for example, electrical energy into ultrasonic energy. In a modified embodiment, the ultrasonic energy can be generated by an ultrasound transducer that is remote from theultrasound radiating member 224 and the ultrasonic energy can be transmitted via, for example, a wire to theultrasound radiating member 224. - In the illustrated embodiment, the
ultrasound radiating member 224 is configured as a hollow cylinder. As such, theinner core 210 extends through the lumen of theultrasound radiating member 224. Theultrasound radiating member 224 is secured to theinner core 210 in a suitable manner, such as using an adhesive. A potting material can also be used to further secure theultrasound radiating member 224 to theinner core 210. - In other embodiments, the
ultrasound radiating member 224 can have a different shape. For example, theultrasound radiating member 224 can take the form of a solid rod, a disk, a solid rectangle or a thin block. In still other embodiments, theultrasound radiating member 224 can comprise a plurality of smaller ultrasound radiating members. The illustrated configuration advantageously provides enhanced cooling of theultrasound radiating member 224. For example, in one embodiment, a therapeutic compound can be delivered through thedelivery lumen 212. As the therapeutic compound passes through the lumen of theultrasound radiating member 224, the therapeutic compound can advantageously remove excess heat generated by theultrasound radiating member 224. In another embodiment, a fluid return path can be formed in theregion 238 between theouter sheath 208 and theinner core 21 such that coolant from a coolant system can be directed through theregion 238. - In an example embodiment, the
ultrasound radiating member 224 produces ultrasonic energy having a frequency of between about 20 kHz and about 20 MHz. In one embodiment, the frequency of the ultrasonic energy is between about 500 kHz and about 20 MHz, and in another embodiment the frequency of the ultrasonic energy is between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasonic energy has a frequency of about 3 MHz. - In the illustrated embodiment, ultrasonic energy is generated from electrical power supplied to the
ultrasound radiating member 224 through awires catheter body 202. Thewires inner core 210, lay along theinner core 210 and/or extend freely in theregion 238 between theinner core 210 and theouter sheath 208. In the illustrated configuration, thefirst wire 226 is connected to the hollow center of theultrasound radiating member 224, while thesecond wire 228 is connected to the outer periphery of theultrasound radiating member 224. In such embodiments, theultrasound radiating member 224 comprises a transducer formed of a piezoelectric ceramic oscillator or a similar material. - Still referring to the example embodiment illustrated in
FIGS. 12A and 12B , the catheter further includes asleeve 230 that is generally positioned about theultrasound radiating member 224. Thesleeve 230 is comprises a material that readily transmits ultrasonic energy. Suitable materials for thesleeve 230 include, but are not limited to, polyolefins, polyimides, polyester and other materials having a relatively low absorbance of ultrasonic energy. The proximal end of thesleeve 230 can be attached to theouter sheath 208 with an adhesive 232. To improve the bonding of the adhesive 232 to theouter sheath 208, ashoulder 227 or notch can be formed in theouter sheath 208 for attachment of the adhesive 232 thereto. In an example embodiment, theouter sheath 208 and thesleeve 230 have substantially the same outer diameter. - In a similar manner, the distal end of the
sleeve 230 can be attached to atip 234. As illustrated, thetip 234 is also attached to the distal end of theinner core 210. In an example embodiment, thetip 234 is between about 0.5 mm and about 4.0 mm long. In another embodiment, the tip is about 2.0 mm long. In the illustrated example embodiment, thetip 234 is rounded in shape to reduce trauma or damage to tissue along the inner wall of a blood vessel or other body structure during advancement of the catheter to a treatment site. - Referring now to the example embodiment illustrated in
FIG. 12B , the catheter includes at least onetemperature sensor 236 in the tubular bodydistal region 206. Thetemperature sensor 236 can be positioned on or near theultrasound radiating member 224. Suitable temperature sensors include but are not limited to, diodes, thermistors, thermocouples, RTDs and fiber optic temperature sensors that used thermalchromic liquid crystals. In an example embodiment, thetemperature sensor 236 is operatively connected to a control system via a control wire that extends through thetubular body 202. As described above for the large vessel ultrasonic catheter, the control box includes a feedback control system having the ability to monitor and control the power, voltage, current and phase supplied to theultrasound radiating member 224. Thus, the temperature along the relevant region of the catheter can be monitored and controlled for optimal performance. Details of the control box can also be found in U.S. patent application Ser. No. 10/309,388, filed 3 Dec. 2002, the entire disclosure of which is hereby incorporated herein by reference. - The small vessel ultrasound catheters disclosed herein can be used to remove an occlusion from a small blood vessel. In an example method of use, a guidewire is percutaneously inserted into the patient's vasculature at a suitable insertion site. The guidewire is advanced through the vasculature toward a treatment site where the vessel is wholly or partially occluded. The guidewire is then directed at least partially through the thrombus.
- After advancing the guidewire to the treatment site, the catheter is then inserted into the vasculature through the insertion site, and advanced along the guidewire towards the treatment site using, for example, over-the-guidewire techniques. The catheter is advanced until the tubular body
distal region 206 is positioned near or in the occlusion. The tubular bodydistal region 206 optionally includes one or more radiopaque markers to aid in positioning the catheter at the treatment site. - After placing the catheter at the treatment site, the guidewire can then be withdrawn from the
delivery lumen 212. A source of therapeutic compound, such as a syringe with a Luer fitting, can then be attached to the proximal access port. This allows the therapeutic compound to be delivered through thedelivery lumen 212 and thedistal exit port 214 to the occlusion. - The
ultrasound radiating member 224 can then be activated to generate ultrasonic energy. As described above, in an example embodiment, the ultrasonic energy has a frequency between about 20 kHz and about 20 MHz. In one embodiment, the frequency of the ultrasonic energy is between about 500 kHz and about 20 MHz, and in another embodiment the frequency of the ultrasonic energy is between about 1 MHz and about 3 MHz. In yet another embodiment, the ultrasonic energy has a frequency of about 3 MHz. The therapeutic compound and ultrasound energy can be applied until the occlusion is partially or entirely dissolved. Once the occlusion has been sufficiently dissolved, the catheter can be withdrawn from the treatment site. - Further information on example methods of use, as well as on modified small vessel catheter constructions, are available in U.S. patent application Ser. No. 10/309,417, filed 3 Dec. 2002, the entire disclosure of which is hereby incorporated herein by reference.
- Treatment of Vascular Occlusions Using Ultrasonic Energy and Microbubbles.
- In certain embodiments, the therapeutic compound delivered to the treatment site includes a plurality of microbubbles having, for example, a gas formed therein. A therapeutic compound containing microbubbles is referred to herein as a “microbubble compound” or “microbubble therapeutic compound”. In an example embodiment, the microbubbles are formed by entrapping microspheres of gas into a therapeutic compound. In one embodiment, this is accomplished by agitating the therapeutic compound while blowing a gas into the therapeutic compound. In another embodiment, this is accomplished by exposing the therapeutic compound to ultrasonic energy with a sonicator under a gaseous atmosphere while vibrating the therapeutic compound. Other techniques for forming the microbubbles are used in other embodiments. Example gases that are usable to form the microbubbles include, but are not limited to, air, oxygen, carbon dioxide, octafluoropropane, and inert gases.
- In one embodiment, the microbubble therapeutic compound wholly or partially comprises a suspension of perflutren lipid microspheres, such as that available under the brand name DEFINITY®, which is available from Bristol-Myers Squibb Medical Imaging, Inc. (New York, N.Y.). In such embodiments, the microbubbles comprise octafluoropropane (C3F8) encapsulated in an outer lipid shell. In one embodiment, the microbubble therapeutic compound is optionally diluted in a phosphate buffered saline solution.
- A hemacytometer, microscope and digital camera are usable to view consistent volumes of a microbubble therapeutic compound, thereby enabling quantitative determination of certain properties of the microbubbles in the therapeutic compound. Such properties include quantity of microbubbles per unit volume and microbubble size distribution. In certain applications, such properties are affected by factors such as (a) the temperature at which the microbubble therapeutic compound is stored; (b) the physical handling of the microbubble therapeutic compound by vibrating for a time period or allowing to settle for a time period; (c) the handling of the microbubble therapeutic compound with a syringe; (d) the exposure of the microbubble therapeutic compound to the atmosphere; and (e) the dilution of the microbubble therapeutic compound.
- The microbubble therapeutic compound preferably includes between approximately 4×106 and approximately 12×109 microbubbles per milliliter of liquid, more preferably between about 8×106 and about 10×109 microbubbles per milliliter of liquid, and most preferably approximately 4×107 microbubbles per milliliter of liquid. In one embodiment, the quantity of microbubbles per unit volume of carrier fluid is manipulated by diluting the microbubble therapeutic compound in a neutral solution, such as a phosphate buffered saline solution.
- The microbubbles preferably have an average diameter that is preferably between approximately 0.01 μm and approximately 100 μm and more preferably between approximately 0.4 μm and approximately 6 μm. The microbubble therapeutic compound is passed through the delivery lumen at a flow rate that is preferably between about 1 mL per hour and about 120 mL per hour, that is more preferably between about 10 mL per hour and about 100 mL per hour, and that is most preferably between about 18 mL per hour and about 22 mL per hour. Optionally, a syringe pump is used to regulate the infusion of microbubble therapeutic compound into the delivery lumen. Other microbubble and delivery parameters are used in other embodiments. For example, in one embodiment pulsed ultrasonic energy having a frequency between about 1 MHz and about 3 MHz (preferably about 1.7 MHz) delivered for between about 15 minutes and about 45 minutes (preferably about 30 minutes) advantageously provides a spatial peak negative pressure of between about 1 MPa and about 2 MPa (preferably between about 1.5 MPa and 2 MPa), which is sufficient to generate therapeutically beneficial cavitation at the treatment site.
- In some embodiments, the volume of microbubble therapeutic compound delivered to the catheter treatment zone (also referred to as the “bolus volume”) depends on the size of the treatment zone. Table A lists the approximate bolus volume for a treatment zone of a particular size. The values listed in the table are approximate and can be varied at the physician's discretion. For example, in some embodiments, the bolus volume corresponding to a treatment zone of approximately 6 cm is between approximately 0.5 and 2.5 mL; for a treatment zone of approximately 12 cm the bolus volume is between approximately 2 and 4 mL; for a treatment zone of approximately 18 cm the bolus volume is between approximately 3 and 5 mL; for a treatment zone of approximately 24 cm the bolus volume is between approximately 5 and 7 mL; for a treatment zone of approximately 30 cm the bolus volume is between approximately 6 and 8 mL; for a treatment zone of approximately 40 cm the bolus volume is between approximately 8 and 11 mL; and for a treatment zone of approximately 50 cm the bolus volume is between approximately 11 and 13 mL.
TABLE A Bolus Volume Bolus Volume Treatment Zone (example) (preferred range) 6 cm 1.4 mL 0.5 mL-2.5 mL 12 cm 2.9 mL 2.0 mL-4.0 mL 18 cm 4.3 mL 3.0 mL-5.0 mL 24 cm 5.8 mL 5.0 mL-7.0 mL 30 cm 7.2 mL 6.0 mL-8.0 mL 40 cm 9.6 mL 8.0 mL-11.0 mL 50 cm 12 mL 11.0 mL-13.0 mL - Optionally, the fluid in which the microbubbles are suspended does not have therapeutic properties itself, but is merely configured to deliver the microbubbles to the treatment site. Alternatively, the fluid in which the microbubbles are suspended has therapeutic properties, such as a solution containing rtPA that is diluted to a concentration of, for example, between about 2500 IU mL−1 and about 7500 IU mL−1. In other embodiments, some microbubbles can be infused with a drug with therapeutic properties. The drug infused microbubbles may also entrap a gas in addition to the drug. In some embodiments, the entrapped gas itself may be a drug with therapeutic properties, such as nitric oxide. These microbubbles can be delivered to the treatment site and be used to deliver drug to the treatment site when the bubble pops. Drug infused microbubbles can be mixed with non-drug infused microbubbles and be delivered as a mixture. Popping of the drug infused microbubbles, such as through a cavitation process, can be facilitated or enhanced with ultrasound treatment.
- In certain configurations, delivering a microbubble therapeutic compound through an optional syringe pump, through a catheter fluid delivery lumen, and past an activated ultrasound radiating member will reduce (a) the concentration of microbubbles delivered to the treatment site, and/or (b) the average size of the microbubbles delivered to the treatment site. Therefore, in an example embodiment the ultrasound radiating member is not activated until all or a portion of the microbubble therapeutic compound is delivered to the treatment site.
- In other embodiments, a first portion of the microbubble therapeutic compound is delivered to the treatment site before the ultrasound radiating member is activated, and a second portion of the microbubble therapeutic compound is delivered to the treatment site after the ultrasound radiating member is activated. In still other embodiments, the microbubble therapeutic compound is delivered to the treatment site only when the ultrasound radiating member is active. In embodiments wherein a microbubble therapeutic compound and ultrasonic energy are delivered to the treatment simultaneously, additional measures are taken to provide a sufficient density of microbubbles at the treatment site. Examples of such additional measures include using a microbubble therapeutic compound with an increased microbubble density, and providing an insulating chamber around the fluid delivery lumen, as described in greater detail below.
- In an example embodiment, the efficacy of an ultrasound-based vascular occlusion treatment is enhanced by the presence of microbubbles at the treatment site. In one embodiment, the microbubbles act as a nucleus for cavitation, thus allowing cavitation to be induced at lower levels of ultrasonic energy. Therefore, it is possible to increase the treatment efficacy as a result of cavitation without increasing the amount of ultrasonic energy delivered to the treatment site. In certain embodiments, cavitation also promotes more effective diffusion and penetration of the therapeutic compound into surrounding tissues, such as the clot material. This effect is often referred to as “microstreaming”. Furthermore, in some embodiments, the “microjet” mechanical agitation caused by motion of the microbubbles is effective in mechanically breaking up clot material.
- While certain vascular treatments are enhanced by the presence of microbubbles at the treatment site, certain intravascular catheter features have an adverse affect on the delivery of a microbubble therapeutic compound to an intravascular treatment site. For example, in certain configurations microbubbles have a tendency to accumulate in and clog the
fluid delivery ports 58 and thefluid delivery lumens 30, especially in embodiments wherein atemperature sensor 20 is positioned therein. For example, see the example embodiment illustrated inFIG. 8 . This effect is particularly problematic in embodiments wherein the size of the microbubbles are not significantly smaller than the size of thefluid delivery ports 58. For example, as described herein, in certain embodiments the microbubbles have an average diameter of between approximately 0.01 μm and approximately 100 μm, and thefluid delivery ports 58 have an average diameter between about 28 μm and about 48 μm. Additionally, in certain embodiments a portion of the microbubbles are destroyed as a result of the infusion pressure used to deliver the therapeutic compound through the delivery lumens and/the or shear stresses generated by fluid flow through the delivery lumens. The extent to which these structural catheter features affect the concentration of microbubbles that is ultimately delivered to the treatment site depends on several factors, including the flow rate of microbubble therapeutic compound through the delivery lumen and the concentration of the microbubble therapeutic compound delivered through the delivery lumen. - Furthermore, the microbubbles in a microbubble therapeutic compound occasionally cavitate and/or burst when exposed to ultrasonic energy, regardless of whether that exposure occurs inside or outside the fluid delivery lumens of the ultrasonic catheter. When such cavitation occurs within the fluid delivery lumens of the ultrasonic catheter, this not only reduces the quantity of microbubbles delivered to the treatment site, but it also increases the risk of damaging the fluid delivery lumens due to the energy released as a result of the cavitation. The extent to which cavitation occurs within the fluid delivery lumens of an ultrasonic catheter depends on factors such as the flow rate of microbubbles through the lumen (which is proportional to the time the microbubbles are exposed to ultrasonic energy), the concentration of microbubbles in the therapeutic compound (which is proportional to the amount of acoustic shielding for the microbubbles) and the number of active ultrasound radiating members in the catheter (which is proportional to the amount of ultrasonic energy delivered to the lumen). In an example embodiment, the ultrasonic catheter is configured such that the presence of a microbubble therapeutic compound in the delivery lumens does not substantially effect the operation of the ultrasound radiating members.
- Therefore, in certain embodiments, the catheter design and/or the treatment techniques are modified to reduce cavitation within the catheter fluid delivery lumens and/or to preserve the quantity of microbubbles delivered to the treatment site. Consequently, in certain embodiments, such modifications advantageously improve the efficacy of a microbubble-based vascular occlusion treatment.
- For example, in an embodiment that is particularly advantageous for use with an ultrasonic catheter having a cylindrical ultrasound radiating member (such as that illustrated in
FIGS. 12A and 12B ) an insulating chamber is used to reduce the amount of ultrasonic energy that is delivered into the catheter fluid delivery lumen. Specifically, an insulating chamber is positioned between the ultrasound radiating member and the delivery lumen. In such embodiments, the insulating chamber is filled with a material that does not efficiently transmit ultrasonic energy, thereby reducing the amount of ultrasonic energy reaching the fluid delivery lumen. Example materials that are put into the insulating chamber include, but are not limited to, air, nitrogen and oxygen. In a modified embodiment, an evacuated chamber is used. -
FIG. 13 illustrates an example embodiment of an ultrasound catheter having anultrasound radiating member 320 separated from a delivery lumen 338 by an insulatingchamber 330. Theultrasound radiating member 320 is offset from the delivery lumen 338 usingspacers 316 andsupport members 318. Other insulating chamber configurations are used in other embodiments. Additional information on using insulating chambers to spatially direct ultrasonic energy is provided in U.S. Pat. Nos. 6,582,392 and 6,676,626, the entire disclosure of which is incorporated herein by reference. - In another embodiment, a microbubble therapeutic compound is infused intra-arterially or intravenously to the treatment site before the ultrasound radiating members are activated. Therefore, once the ultrasound radiating members begin to generate ultrasonic energy, the microbubble therapeutic compound is already at the treatment site. The microbubble therapeutic compound is delivered using the same catheter that is used to the deliver the ultrasonic energy in some embodiments. The microbubble therapeutic compound is delivered using a different catheter than that used to deliver the ultrasonic energy in other embodiments. The microbubble therapeutic compound is delivered to the treatment site via the general vascular circulation in still other embodiments. Regardless of how the initial delivery of microbubbles to the treatment site is accomplished, ultrasonic energy is delivered to the treatment site after the delivery of microbubbles has occurred. A therapeutic compound or a cooling fluid is optionally delivered to the treatment site during ultrasonic energy delivery, thereby enhancing the treatment efficacy and/or helping to cool the ultrasound radiating members. In one embodiment, a microbubble therapeutic compound is delivered to the treatment site to supplement the concentration of microbubbles provided at the treatment site provided by the initial delivery of microbubbles. Optionally, a cooling element is used to help moderate the temperature of the treatment site.
- In a modified embodiment, a microbubble therapeutic compound is delivered to the treatment site intermittently with ultrasonic energy. In one such embodiment, the microbubble therapeutic compound is delivered without ultrasonic energy during a first treatment phase. Subsequently, delivery of the microbubble therapeutic compound is paused and ultrasonic energy is delivered to the treatment site during a second treatment phase. Optionally, the first and second treatment phases are alternately repeated several times. The duration of the first and second phases are each on the order of approximately a few minutes. For example, in one embodiment, the first and second phases each have a duration that is preferably between about 1 minute and about 20 minutes, that is more preferably between about 2 minutes and about 7 minutes, and that is most preferably between about 3 minutes and about 4 minutes. Optionally, the first and second treatment phases have different durations.
- Alternating the delivery of microbubble therapeutic compound and ultrasonic energy advantageously reduces the amount of cavitation that occurs within the catheter fluid delivery lumen or lumens. In other embodiments, the therapeutic compound delivered to the treatment site is alternated between a therapeutic compound that contains microbubbles and a therapeutic compound that does not contain microbubbles. In such embodiments, the phases wherein ultrasonic energy is delivered correspond to the phases during in which the therapeutic compound that does not contain microbubbles is delivered.
- In one embodiment, the microbubble therapeutic compound is injected directly into a vascular obstruction at the treatment site. A schematic illustration of this embodiment is provided in
FIG. 14 . Specifically,FIG. 14 illustrates acatheter 400 having a distal end that is positioned within anocclusion 410 in a patient'svasculature 420. A microbubbletherapeutic compound 430 has been infused into theocclusion 410 from thecatheter 400. Once the microbubble therapeutic compound has been sufficiently infused, one or moreultrasound radiating members 440 mounted within thecatheter 400 is energized, thereby delivering ultrasonic energy to theocclusion 410 and the infused microbubbletherapeutic compound 430. Thecatheter 400 is optionally repositioned during the treatment to direct additional ultrasonic energy into a larger portion of theocclusion 410 and the infused microbubbletherapeutic compound 430. In such embodiments, ultrasonic energy is applied to the microbubbles suspended within the occlusion, thereby causing mechanical agitation and/or cavitation of the microbubbles. The mechanical agitation and/or cavitation of the microbubbles assists faster enzyme mediated lysis of the clot and/or generates microholes that increase the clot surface area available to interact with lysing enzymes. - As described herein, in certain embodiments control circuitry is used to selectively activate certain ultrasound radiating members in the catheter. In certain embodiments, such control circuitry is also used to selectively activate an infusion pump that controls delivery of a microbubble therapeutic compound through the catheter fluid delivery lumens. Such embodiments advantageously allow the ultrasonic energy and the microbubble therapeutic compound to be separately delivered during distinct periods of the treatment. In an example embodiment, the control circuitry is capable of controlling a wide variety of infusion pump configurations, such as a rotating syringe pump, a peristaltic pump, or another pump that is capable of developing pressure differentials slowly. In a modified embodiment, the pump housing and/or the reservoir from which the microbubble therapeutic compound is drawn in agitated or rotated to prevent settling of the microbubbles during the course of the treatment.
- An example system that includes certain of these features is schematically illustrated in
FIG. 15 . Specifically,FIG. 15 illustrates anintravascular catheter 500 that is capable of receiving a fluid from afirst reservoir 502 that contains a microbubble therapeutic compound. Thecatheter 500 is also capable of receiving an ultrasound control signal from anultrasound signal generator 504.Controller 506 is configured to control theultrasound signal generator 504 and aninfusion pump 508 that is coupled to thefirst reservoir 502. Thecontroller 506 is also optionally configured to control anagitator 510 that is capable of vibrating, rotating, or otherwise agitating thefirst reservoir 502. As described herein, this configuration is advantageously capable of using asingle controller 506 to alternatively cause ultrasonic energy and a microbubble therapeutic compound to be delivered from thecatheter 500 to the treatment site. Thecontroller 506 is optionally configured to periodically agitate thefirst reservoir 502 to preserve the concentration of microbubbles in the microbubble therapeutic compound held therein. - In modified embodiments, the
intravascular catheter 500 is optionally also capable of receiving a fluid from asecond reservoir 512 that contains a therapeutic compound that does not include microbubbles. In such embodiments, theinfusion pump 508 is also coupled to the second reservoir, as is configured such that thecontroller 506 can be used to independently control delivery of fluids from thefirst reservoir 502 and thesecond reservoir 512 to thecatheter 500. This configuration advantageously allows thecontroller 506 to be used to alternate delivery of a microbubble therapeutic compound and a therapeutic compound that does not include microbubbles to thecatheter 500. - Regardless of the specific delivery techniques, use of a microbubble therapeutic compound provides enhanced clot weight reduction in certain circumstances. For example, in one application a 45±19% clot weight reduction enhancement was provided by supplementing an rtPa-containing therapeutic compound with ultrasonic energy. However, a 88±25% clot reduction enhancement was provided by supplementing an rtPA-containing therapeutic compound with ultrasonic energy and a microbubble-containing solution. As used herein, “clot reduction enhancement” is defined as the clot weight reduction as compared before and after treatment.
- Treatment of Vascular Occlusions Using Cavitation Promoting Surface.
- Disclosed herein are methods for enhancing the beneficial effect of ultrasonic energy at an intravascular treatment site by promoting cavitation at the treatment site. Aside from manipulating the acoustic parameters of the ultrasonic energy, other techniques for promoting cavitation at the treatment site include supplying an ultrasound contrast agent to the treatment site and/or using an ultrasound catheter that includes a cavitation promoting surface. Use of such techniques reduces the acoustic pressure amplitude required to initiate cavitation, and therefore allows lower levels of ultrasonic energy to be delivered to the treatment site from the ultrasound assembly. This provides several advantages, such as prolonging the life of an ultrasound radiating member and reducing the likelihood of causing thermal damage to the treatment site. While cavitation is used to enhance the delivery and/or effect of a therapeutic compound in certain embodiments, cavitation promotes clot dissolution even in the absence of a therapeutic compound. Indeed, in the context of treating a vascular occlusion, the beneficial effect of cavitation in the absence of a therapeutic compound is often greater than the beneficial effect of a therapeutic compound alone.
- Because cavitation promoting surfaces and ultrasound contrast agents are independently capable of inducing cavitation at an intravascular treatment site, in certain embodiments cavitation is induced at an intravascular treatment site using a cavitation promoting surface, but without using an ultrasound contrast agent. Such embodiments advantageously simplify the treatment procedure by eliminating the need to monitor the concentration of the ultrasound contrast agent at the treatment site, reduce the treatment cost, and reduce the risk of systemic complications caused by the ultrasound contrast agent. In other embodiments, cavitation is induced at an intravascular treatment site using a ultrasound contrast agent, but without using a cavitation promoting surface. Such embodiments advantageously are usable with conventional ultrasound catheters that have not been modified to include the cavitation promoting surface. In still other embodiments, both a cavitation promoting surface and an ultrasound contrast agent are used to enhance cavitation at the treatment site. Regardless of whether a ultrasound contrast agent, a cavitation promoting surface, or both, are used to promote cavitation, the generation of free microbubbles at the treatment site is optionally manipulated by adjusting the frequency, peak pressure and duration of ultrasonic energy delivered to the treatment site.
- Techniques for using a therapeutic compound that includes microbubbles (that is, a “microbubble therapeutic compound”) to enhance the effect of a vascular occlusion treatment have been disclosed herein. In one application a catheter with a cavitation promoting surface is used to deliver a microbubble therapeutic compound to an internal portion of a vascular occlusion, as opposed to the fluid medium surrounding the occlusion. This is particularly important in view of the observation that the viscoelastic properties of the surrounding medium affect how microbubbles respond to ultrasonic energy.
- In some embodiments, a cavitation promoting surface is obtained by patterning a catheter surface with an ablative laser. For example, an excimer laser with mask projection technique can be used to precisely pattern features onto the catheter surface. In some embodiments, the features are holes that are generally circular in shape. In other embodiments, the holes are oval, rectangular, triangular or another geometrical shape. In some embodiments, the features are approximately 15 μm in diameter and/or depth. In other embodiments, the features are between approximately 1 and 100 μm in diameter and/or depth. In some embodiments, the features can be separated by approximately 25 μm. In other embodiments, the features can be separately by a distance between approximately 1 and 100 μm.
FIGS. 16A and 16B illustrate an example of acatheter surface 3000 having a laser patternedcavitation promoting surface 3010. As illustrated inFIGS. 16A and 16B , thecavitation promoting surface 3010 comprisesholes 3020 that are formed on a portion of thecatheter surface 3000. In one embodiment, theholes 3020 do not extend through the catheter body, but instead are formed as surface features on theexterior catheter surface 3000. Thecavitation promoting surface 3010 can be formed on the portion of thecatheter surface 3000 that is proximate the ultrasound radiating members and/or the energy delivery section of the catheter. - In other embodiments, a cavitation promoting surface is obtained by grit blasting a catheter surface with an angular media. For example, one suitable angular media is a powder of aluminum oxide particles having an average diameter of approximately 25 μm. Aluminum oxide and other similar angular media are dry media, which advantageously facilitate cleaning of the catheter surface after the roughening treatment is performed. In other embodiments, the angular media has a diameter between approximately 1 and 100 μm.
- In other embodiments, a cavitation promoting surface is obtained by scoring a catheter surface. In some embodiments, the depth and/or width of the scoring is between approximately 1 and 100 μm. In some embodiments, the scoring is a single continuous spiral that winds around the catheter surface. In other embodiments, the scoring is formed from multiple intersecting spirals that form a cross-hatched pattern on the catheter surface. In other embodiments, the scoring is formed by parallel and non-intersecting scores.
- In other embodiments, a cavitation promoting surface is obtained by etching a catheter surface. In some embodiments, the etching is done with chemicals, plasma or laser. An etch mask can be applied to the catheter surface to limit etching to appropriate areas of the catheter surface. In some embodiments, the etching results in features similar to those produced by laser ablation, scoring or grit blasting.
- In some embodiments, a hydrophobic coating is applied to the catheter surface either before or after the cavitation promoting surface is formed as described herein. In some embodiments, the hydrophobic coating is formed, for example, from parylene. In some embodiments, application of the hydrophobic coating lowers the surface energy between blood and the cavitation promoting surface allowing for easier bubble liberation.
- In other embodiments, a cavitation promoting surface is obtained by coating a catheter surface with a superhydrophobic material with nanoscale porous structures. For example, one such coating material consists of polypropylene with an appropriate solvent, such as p-xylene, and the appropriate nonsolvent, such as methyl ethyl ketone, which is used to precipitate the dissolved polypropylene out of the solvent. After precipitation, the solvent and nonsolvent is removed by evaporation, leaving a film of porous material. In some embodiments, the porous structures provide gas entrapment sites for cavitation nuclei while the superhydrophobic properties reduce the surface energy allowing for easier bubble liberation.
- In other embodiments, a cavitation promoting surface is obtained by attaching a porous ceramic, resin, polymer or metal material to a catheter surface. The porous structure acts as a source of entrapped gas for cavitation nuclei.
- Treatment of Vascular Occlusions Using Stable and/or Inertial Cavitation.
- Although this disclosure is not limited by theory, it is believed that ultrasonic energy accelerates enzymatic fibrinolysis through non-thermal mechanisms by increasing transport of drug molecules into the clot. Mechanical effects of ultrasonic energy such as streaming, radiation force and cavitation have the ability to influence drug transport. Acoustic cavitation is generally acknowledged as playing a significant role in ultrasound-accelerated fibrinolysis. The addition of ultrasound contrast agents has been shown to increase the effectiveness of ultrasound-accelerated enzymatic fibrinolysis. Mechanisms related to both inertial cavitation (for example, intense localized stresses and micro-jets) and stable cavitation (for example, cavitation micro-streaming and bubble translation) are believed to be responsible for the enhanced drug transport and lysis.
- In certain embodiments, the type of cavitation activity occurring at the treatment site is determined by analyzing frequency components in the scattered acoustic emissions from the treatment site. For example subharmonic emission at half the driving frequency, which is a characteristic of stable nonlinear bubble oscillation, provides a general indicator for stable cavitation activity. Broadband noise, which is manifested as an elevation in the signal amplitude between the harmonic peaks in the fast Fourier transform (“FFT”) magnitude spectrum, provides a general indicator for inertial cavitation activity. In the absence of cavitation, only the fundamental ultrasound drive signal and its harmonics are present, aside from broadband electrical background noise.
- In certain embodiments, the broadband noise in a particular signal is quantified by integrating the “inter-peak” noise amplitude NA between 4 and 10 MHz. Other frequency spectra are used in other embodiments. To reference the noise amplitude to a non-cavitating “baseline” signal—such as that obtained in degassed (<36% of saturation), 0.2 μm filtered water-a relative noise enhancement RNE was calculated as the increase in noise amplitude relative to the average baseline noise amplitude <BNA> for n recorded baseline “bursts” of the hydrophone signal:
- A true rise in broadband noise over baseline due to inertial cavitation is identified by setting a detection threshold. For example, in one application the noise enhancement threshold NET is defined as the relative noise enhancement corresponding to 4 times the standard deviation of the baseline noise amplitude SD{BNA} for n recorded baseline bursts:
- By searching digitized “snapshots” of noise activity for instances in which the relative noise enhancement crossed the noise enhancement threshold, a total number of ultrasound bursts containing inertial cavitation (“IC count”) is determined. Additionally, the maximum relative noise enhancement detected in a snapshot max{RNE} compiled as an average from m independent snapshots is optionally compared between treatments, thereby enabling further statistical analysis.
- In certain embodiments, subharmonic emission in a particular signal is identified by the presence of a subharmonic peak in the FFT magnitude spectrum at one half of the fundamental frequency. To quantify the subharmonic content in a recorded burst, the FFT magnitude spectrum is computed and the magnitude at the subharmonic frequency was taken as the subharmonic amplitude SA. To reference the subharmonic amplitude to a non-cavitating baseline signal—such as that obtained in degassed (<36% of saturation), 0.2 μm filtered water—the relative subharmonic enhancement RSE is calculated as the increase in subharmonic amplitude relative to the average baseline subharmonic amplitude <BSA> for n recorded baseline bursts:
- Processed in this way, each digitized burst yields a single measure of the relative subharmonic enhancement, for which it is possible to plot as a function of time over the duration of the snapshot. For a given snapshot, the subharmonic quantities are averaged over the n bursts to yield the average subharmonic enhancement <RSE>. The average value of <RSE> is optionally compiled from m independent snapshots and compared between treatment groups, thereby enabling further statistical analysis.
- A plot illustrating RNE as a function of time during a 3.33-second snapshot for an example 30-minute ultrasound exposure within a clot is illustrated in
FIG. 17 . A plot illustrating RSE as a function of time during a 3.33-second snapshot for an example ultrasound exposure within a clot is illustrated inFIG. 18 . Data from four treatment protocols are illustrated inFIGS. 17 and 18 : therapeutic compound and ultrasonic energy (D+US); therapeutic compound, ultrasonic energy, and microbubbles (D+US+MB); therapeutic compound, ultrasonic energy, and microbubbles that were previously exposed to ultrasound (D+US+MB(pre)); and ultrasonic energy and microbubbles (US+MB). - As illustrated in
FIGS. 17 and 18 , in the absence of microbubbles (D+US), both RNE and RSE remained at baseline. When microbubbles were present, cavitation signals were high and were substantially identical for the two protocols in which the microbubbles were not pre-exposed to ultrasonic energy (D+US+MB and US+MB). RNE increased rapidly to a peak value within about 0.1 seconds, decreased toward baseline, crossed below the detection threshold (NET≈0.24) at about 0.4 seconds, and settled to baseline by about 1.0 seconds. Similarly, RSE increased to a peak value within about 0.1 seconds. However, RSE did not settle back to baseline, but instead remained at a slightly elevated value during the remainder of the snapshot. For the protocol in which microbubbles were pre-exposed to ultrasonic energy (D+US+MB(pre)), broadband noise and subharmonic activity were reduced compared to the other microbubble-based protocols. Specifically, elevation in RNE was observed in generally the first ultrasound burst, which immediately dropped to baseline by the next burst. On the other hand, RSE remained at a low, steady amplitude slightly above baseline. - The cavitation signal quantities per snapshot measured at various times throughout the 30-minute exposure are shown in
FIGS. 19A and 19B (max{RNE}) andFIGS. 20A and 20B (<RSE>). In the absence of microbubbles (D+US), max{RNE} remained below the detection threshold for the entire 30-minute exposure, and <RSE> remained at baseline. For the snapshot taken at time zero, max{RNE} for each of the microbubble-based protocols was significantly greater than that for the non-microbubble (D+US) protocol (p<0.033). The max{RNE} for both the (D+US+MB) and the (US+MB) protocols were significantly greater than that for the (D+US+MB(pre)) protocol (p<0.001). For the remainder of the 30-minute exposure, max{RNE} for the microbubble-based protocols showed no significant difference from the non-microbubble (D+US) protocol. For all microbubble-based protocols <RSE> was significantly greater than that for the non-microbubble (D+US) protocol during both the snapshot at time zero (p<0.001) and during the remainder of the 30-minute exposure (p<0.010). - Table B lists the total number of IC counts observed for the different treatment protocols. In accordance with the max{RNE} trends shown in
FIGS. 19A and 19B , IC counts were only observed during the initial snapshot in the 30-minute exposure. The number of counts was greatest for the two protocols in which microbubbles were not pre-exposed to ultrasound (D+US+MB and US+MB). In the absence of microbubbles (D+US), two IC counts were recorded.TABLE B Time D + D + US + D + US + US + Window US MB MB (pre) MB Total Number of 0 min 1000 1000 1000 1000 Bursts Analyzed 1-30 min 6000 6000 6000 6000 Total Number of 0 min 2 103 5 111 IC Counts 1-30 min 0 0 0 0 - In the absence of microbubbles, pulsed ultrasonic energy significantly accelerates rtPA-induced fibrinolysis in certain applications. In such applications, thermal mechanisms are not believed to have played a role in lysis enhancement. The minimal degree of heating observed is considered to be insufficient to account for the increased lysis. Cavitation signals were either not detected (subharmonic amplitude remained at baseline) or were negligible (only two IC counts) in the corresponding radiated acoustic signal, suggesting that the observed lysis enhancement in the absence of microbubbles was due to non-cavitation mechanical effects of the ultrasonic energy.
- In embodiments wherein microbubbles are dispersed within the clot, lysis enhancement due to ultrasonic energy increased significantly, confirming the synergistic effect of microbubbles and therapeutic compound. Inertial cavitation, observed as broadband noise in the acoustic signal, was present only at the start of the ultrasound exposure, and disappeared completely in less than one second. Subharmonic emission, an indicator for stable cavitation activity, was greatest at the start of the exposure, subsequently decreased in amplitude, yet persisted for the remainder of the 30-minute treatment. Without being limited by theory, the limited duration of inertial cavitation is explained by liberated microbubbles yielding sub-resonant bubbles (for example, bubbles smaller than resonance size at 1.7 MHz) that break up upon collapse, thereby forming very small bubbles that are quickly driven to dissolution by the compressive force of surface tension.
- In the presence of microbubbles alone, ultrasound exposure resulted in no measurable lysis, indicating that mechanical disruption (for example, fragmentation) of the clot was not a contributing mechanism for lysis. This lack of effect is not surprising because of the limited duration of inertial cavitation observed. Optionally, the microbubbles are replenished, or the acoustic parameters (such as acoustic pressure amplitude, pulse length, or duty cycle) are modified to increase the persistence and quantity of inertial cavitation to an extent where mechanical effects alone become important.
- In embodiments wherein microbubbles were pre-exposed to ultrasound prior to therapeutic compound delivery, the cavitation activity that occurred at the start of the treatment was significantly reduced compared to the other microbubble-based protocols. In particular, inertial cavitation was substantially eliminated: only the first ultrasound burst contained broadband noise. Without being limited by theory, a possible explanation for this result is that all of the candidate sub-resonant bubbles were “used up” in the pre-exposure and thus were not available to nucleate inertial cavitation when the therapeutic compound was present. The low-amplitude subharmonic emission, however, was still present during the 30-minute exposure and at the same magnitude as in the other protocols with microbubbles. Without being limited by theory, this result suggests the presence of super-resonant bubbles. Super-resonant bubbles are large bubbles that are less influenced by surface tension, that do not dissolve as quickly as smaller bubble, and that are held in place by the dense fibrin matrix of the clot. Lysis enhancement in such embodiments was substantially the same as that obtained for treatments in which microbubbles were not pre-exposed to ultrasound.
- Without being limited by theory, these results suggest that the increased lysis enhancement in the presence of microbubbles was correlated with the subharmonic emission that occurred throughout the 30-minute treatment, and that the brief inertial cavitation that occurred at the beginning of the exposure was inconsequential. This suggests that mechanisms related to stable cavitation (for example, steady micro-streaming) rather than inertial cavitation (for example, mechanical disruption and transient micro-jets) were responsible for the increased lysis in the presence of microbubbles. In embodiments wherein sustained inertial cavitation is achieved using modified acoustic parameters, it is possible to obtain an even greater degree of lysis enhancement.
- In certain embodiments the additional lysis enhancement due to microbubbles is correlated to the presence of the subharmonic emission, thus identifying an important role for stable cavitation in microbubble-enhanced ultrasound-accelerated fibrinolysis. Mechanisms related to stable cavitation, such as steady micro-streaming, enhance fibrinolysis by promoting local mass transfer and thus the rate of penetration of the therapeutic compound into the clot matrix. Thus, in certain embodiments inertial cavitation is optionally reduced or eliminated without adversely effecting the enhancement of ultrasound-accelerated fibrinolysis in the presence of microbubbles. Thus, in such embodiments it is possible to avoid the safety risks associated with inertial cavitation (for example, tissue hemorrhage and hemolysis) while still enjoying the lysis-enhancing effect of microbubbles by choosing ultrasound exposure parameters to promote stable cavitation while minimizing or eliminating inertial cavitation.
- As described herein, subharmonic emission was used as a general indicator for stable cavitation. In certain embodiments, other types of stable bubble activity, including oscillations that occur below the pressure threshold for subharmonic emission, occur simultaneously and are also responsible for lysis enhancement. However, surface waves on the bubble wall, which have been associated with subharmonic emissions, are effective in generating micro-streaming flows around bubbles undergoing repetitive large amplitude motion.
- While the foregoing detailed description discloses several embodiments of the present invention, it should be understood that this disclosure is illustrative only and is not limiting of the present invention. It should be appreciated that the specific configurations and operations disclosed can differ from those described above, and that the methods described herein can be used in contexts other than treatment of vascular occlusions.
Claims (46)
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US20210339055A1 (en) | 2021-11-04 |
EP2015846A2 (en) | 2009-01-21 |
US10232196B2 (en) | 2019-03-19 |
US20110264031A1 (en) | 2011-10-27 |
US11058901B2 (en) | 2021-07-13 |
US20240058627A1 (en) | 2024-02-22 |
WO2007127176A2 (en) | 2007-11-08 |
US20190269944A1 (en) | 2019-09-05 |
WO2007127176A3 (en) | 2008-12-24 |
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