CA2239116A1 - Apparatus and methods for ultrasonically enhanced intraluminal therapy - Google Patents
Apparatus and methods for ultrasonically enhanced intraluminal therapy Download PDFInfo
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- CA2239116A1 CA2239116A1 CA002239116A CA2239116A CA2239116A1 CA 2239116 A1 CA2239116 A1 CA 2239116A1 CA 002239116 A CA002239116 A CA 002239116A CA 2239116 A CA2239116 A CA 2239116A CA 2239116 A1 CA2239116 A1 CA 2239116A1
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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
-
- 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
- A61B2017/22021—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 electric leads passing through the catheter
-
- 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
- A61B2017/22038—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 with a guide wire
-
- 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
- A61B2017/22084—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 stone- or thrombus-dissolving
Abstract
An ultrasonic catheter comprises a catheter body having a resonantly vibrating assembly at its distal end. The resonantly vibrating assembly comprises a tail mass (42), an interface member (44), and a spring element (46) which connects the tail mass to the interface member (44). An interface surface is formed on the interface member and is forwardly disposed at the distal end of the catheter. A longitudinally oscillating drive (74) is disposed between the tail mass (42) and the interface member (44), and the catheter can be connected to a suitable power supply to induce oscillations in the driver. The driver is typically a piezoelectric device, such as a tubular piezoelectric transducer or a piezoelectric stack. The characteristics of the interface member (44), spring element (46), and longitudinally oscillating driver (74) are selected so that the interface (44) member may be resonantly vibrated at an ultrasonic frequency. The catheter is useful for treating luminal conditions, such as vascular clot and plaque. Optionally, a therapeutic agent may be delivered through the catheter simultaneously with the application of ultrasonic energy.
Description
CA 02239116 1998-0~-29 WO 97/19644 PCT~US96/19007 APPARATUS AND METHODS FOR ULTRASONICALLY ENHANCED
INTRALUMINAL THERAPY
OUND OF THE l~v~NllON
. Field o~ the I~vention The present invention relates generally to medical devices and methods. More particularly, the present invention relates to apparatus and methods for the localized delivery of therapeutic ultrasound energy within the vasculature and other body lumens.
Despite the growing sophistication o~ medical technology, vascular (blood vessel) diseases, such as acute myocardial infarction (heart attack) and peripheral arterial thrombosis (blood clots in leg arteries), remain a ~requent, costly, and very serious problem in health care. Current methods of treatment, often expensive, are not always e~fective. In the U.S. alone, the cost of treatment and support and the loss of productivity due to vascular diseases together exceed ~40 billion per year.
The core of the problem is that diseased sites within the blood vessels narrow and eventually become completely blocked as a result of the deposition of fatty materials, cellular debris, calcium, and/or blood clots, thereby blocking the vital flow of blood. Current treatments include drugs, interventional devices, and/or bypass surgery.
High doses o~ thrombolytics (clot-dissolving drugs) are frequently used in an ef~ort to dissolve the blood clots.
Even with such aggressive therapy, thrombolytics fail to restore blood flow in the affected vessel in about 30~ of patients. In addition, these drugs can also dissolve beneficial clots or in~ure healthy tissue causing potentially fatal bleeding complications.
While a variety of interventional devices are available, including angioplasty, atherectomy, and laser CA 02239116 1998-0~-29 WO97/19644 PCT~US96/19007 ablation catheters, the use o~ such devices to remove obstructing deposits may leave behind a wound that heals by ~orming a scar. The scar itsel~ may eventually become a serious obstruction in the blood vessel (a process known as restenosis). Also, diseased blood vessels being treated with interventional devices sometimes develop vasoconstriction (elastic recoil), a process by which spasms or abrupt reclosures o~ the vessel occur, thereby restricting the flow o~ blood and necessitating ~urther intervention.
Approximately 40~ o~ treated patients require additional treatment ~or restenosis resulting ~rom scar ~ormation occurring over a relatively long period, typically 4 to 12 months, while approximately 1-in-20 patients require treatment for vasoconstriction, which typically occurs ~rom 4 to 72 hours a~ter the initial treatment.
Bypass surgery can redirect blood around the obstructed artery resulting in improved blood ~low. However, the resulting bypass gra~ts can themselves develop scar tissue and new blood clots in ~ive to ten years resulting in blockage and the need ~or ~urther treatment. In summary, all current therapies have limited long term success.
The use o~ ultrasonic energy has been proposed both to mechanically disrupt clot and to enhance the intravascular delivery o~ drugs to dissolve clot and inhibit restenosis.
Ultrasonic energy may be delivered intravascularly using specialized catheters having an ultrasonically vibrating sur~ace at or near their distal ends. One type of ultrasonic catheter employs a wire or other axial transmission element to deliver energy ~rom an ultrasonic energy vibration source located outside the patient, through the catheter, and to the ultrasonically vibrating surface. While such systems can deliver relatively large amounts o~ energy, the need to transmit that energy through the entire length o~ the catheter presents a substantial risk to the patient.
Moreover, such catheters are typically rigid and cannot easily traverse narrow, tortuous arteries, such as the coronary arteries which ~requently need to be treated.
Because o~ their rigidity and inability to ~ollow the vascular -CA 02239ll6 l998-0~-29 WO97/19644 PCT~US96/19007 lumen, these catheters present a serious risk o~ vascular wall perforation.
In order to avoid the use o~ ultrasonic transmission members, catheters having ultrasonic transducers mounted directly on their distal ends have also been proposed. See, Eor example, U.S. Patent Nos. 5,362,309; 5,318,014; 5,315,998;
5,269,291; and 5,197,946. By providing the transducer within the catheter itself, there is no need to employ a transmission element along the entire length of the catheter. While such catheter designs o~er enhanced safety, they su~fer from a limited ability to generate large amounts o~ ultrasonic energy. Even though certain of these designs, such as that described in U.S. Patent No. 5,362,309, employ "amplii~iers"
which enhance the delivery of ultrasonic energy, such designs are still problematic. In particular, the catheters o~ the '309 patent have relatively long, rigid transducers and are not amenable to receiving guidewires, both o~ which ~eatures make it di~ficult to position the catheters within the vasculature, particularly the coronary vasculature.
For these reasons, it would be desirable to provide improved ultrasonic catheter designs overcoming at least some o~ the problems discussed above. In particular, it would be desirable to provide ultrasonic catheters having ultrasonic transducers at their distal ends, where the transducers are capable o~ driving interf~ace suri~aces with relatively high energy and amplitude. It would ~urther be desirable to provide transducer and driver designs which are highly e~icient and which minimize the production o~ heat within the vascular or other lllm; n~l environment. It would be still Eurther desirable to provide methods :Eor the intraluminal delivery o~ ultrasonic energy, where the ultrasonic energy is useful ~or a variety o~ purposes, including the direct ~ mechanical disruption o~ clot, the enhancement of thrombolytic activity o~ agents to dissolve clot, and the enhancement o~
pharmacologic agents to prevent restenosis oE vascular sites previously treated by angioplasty or other interventional methods.
CA 02239ll6 l998-0~-29 WO 97/19644 PCTnUS96/19007 2. Descri~tion of the Backaround Art Catheters having ultrasonic elements with the capability of delivering thrombolytic and other liquid agents are described in U.S. Patent Nos. 5,362,309; 5,318,014;
5,315,998; 5,197,946; 5,397,301; 5,380,273; 5,344,395;
5,342,292; 5,324,255; 5,304,115; 5,279,546; 5,269,297;
5,267,954; 4,870,953; 4,808,153; 4,692,139; and 3,565,062; in WO 90/01300; and in Tachibana (1992) JVIR 3:299-303. A rigid ultrasonic probe intended ~or treating vascular plaque and having fluid delivery means is described in U.S. Patent No. 3,433,226. An ultrasonic transmission wire intended for intravascular treatment is described in U.S. Patent No. 5,163,421 and Rosenschein et al. (1990) JACC 15:711-717.
Ultrasonically assisted atherectomy catheters are described in 15 _ U.S. Patent 5,085,662 and EP 189329. Ultrasonic enhancement o~ systemic and localized drug delivery is described in U.S. Patent Nos. 5,286,254; 5,282,785; 5,267,985; and 4,948,587; in WO 94/05361 and WO 91/19529; in JP 3-63041; and Yumita et al. (1990) JPN. J. CANCER RES. 81:304-308. An electrosurgical angioplasty catheter having ultrasonic enhancement is described in U.S. Patent No. 4,936,281. An infusion and drainage catheter having an ultrasonic cleaning mechanism is described in U.S. Patent No. 4,698,058. A drug delivery catheter having a pair of spaced-apart balloons to produce an isolated region around arterial plaque is described in U.S. Patent Mo. 4,636,195.
STTMMAT~Y OF THE I~v~llON
According to the present invention, a catheter for the intraluminal delivery of ultrasonic energy comprises a catheter body having a proximal end and a distal end. A tail mass is attached to the catheter body, typically at its distal end, and a longitudinally oscillating driver engages and extends distally from the tail mass. An inter~ace member is disposed to engage a distally forward sur:Eace of the oscillating driver, and the mass of the interface member is much less than that o~ the tail mass. The tail mass and inter~ace member are connected to each other by a spring CA 02239116 1998-0~-29 WO 97tl96~4 PCT~US96/19OU7 element so that a resonant system is formed for driving the inter~ace member. By employing a relatively large tail mass, the resonant ~requency o~ the interface member, spring element, and oscillating driver is independent of the tail mass and de~ined primarily by the mass o~ the interface member and the elastic modulus o~ the spring element, and the oscillating driver. By properly choosing the operating ~requency o~ the longitudinally oscillating driver, the resonant system defined by the interface member, the spring element, and the oscillating driver can be resonantly driven to enhance both the displacement amplitude o~ an interface sur~ace on the inter~ace member and increase the efficiency o~
operation, i.e., the conversion o~ electrical energy to mechanical energy.
The longitudinally oscillating member may take any conventional ~orm ~or an ultrasonic transducer, typically being a tubular piezoelectric transducer, a piezoelectric stack, or the like. An exemplary tubular piezoelectric transducer comprises a hollow piezoelectric cylinder having an inner cylindrical electrode and an outer cylindrical electrode. Application o~ a driving current to the electrodes causes axial and radial expansion and contraction o~ the piezoelectric transducer. The axial expansion and contraction allow the piezoelectric cylinder to resonantly drive the inter~ace member in the longitudinal direction. An exemplary piezoelectric stack comprises a plurality of ceramic disks having electrodes therebetween.
The spring element will comprise an axial member capable o~ mechanically coupling the inter~ace member to the tail mass with su~icient space therebetween to receive the longitudinal driver. Typically, the spring element will comprise at least one rod secured at a proximal end to the tail mass and at a distal end to the inter~ace member The rod may optionally be tubular to provide the path ~or a~ 35 guidewire, in~usion o~ therapeutic agent, or the like. A
single rod will usually be disposed coaxially within the catheter. Multiple rods may be disposed symmetrically about the axis of the catheter body. Alternatively, the spring CA 02239116 1998-0~-29 element may comprise a thin-walled cylindrical member secured to the tail mass and the inter~ace member and enclosing the longitudinally oscillating member in a concentric manner.
The inter~ace member will usually include a distally 5 ~ disposed inter~ace sur~ace which forwardly transmits longitudinal oscillations into the environment surrounding the distal end o~ the catheter. The inter~ace surface will typically be convex, although it could be ~lat, concave, or irregular.
A method according to the present invention ~or treating intraluminal lesions comprises providing a catheter having an inter~ace member at its distal end. A ~orwardly disposed sur~ace o~ the inter~ace member is advanced to a region near the intraluminal lesion, typically to a region o~
vascular stenosis within a patient's vasculature, and the inter~ace member is resonantly driven relative to a tail mass mounted proximally o~ the inter~ace member. In this way, ultrasonic energy is e~ficiently delivered into the regions surrounding the distal end o~ the catheter. The inter~ace member will usually have a mass in the range ~rom 0.005 gm to 1 gm, pre~erably from 0.01 gm to 0.3 gm, and is typically driven at a ~requency in the range ~rom 10 kHz to 300 kHz, and will have a longitudinal amplitude in the range from about 0.05 ~m to 40 ~m, pre~erably ~rom 10 ~m to 25 ~m, under typical mass loading conditions o~ a vascular lumen. The forwardly disposed sur~ace o~ the inter~ace member will typically have an area in the range ~rom 0.5 mm2 to 20 mm2, pre~erably ~rom 1 mm2 to 12 mm2, and the catheter may be used in a variety of speci~ic therapeutic protocols.
In a first such protocol, the inter~ace member will be engaged directly against a vascular obstruction and used to ablate the structure or optionally to dissolve the structure with the simultaneous delivery of a thrombolytic or ~ibrinolytic agent. Alternatively, the catheter can be used to deliver ultrasonic energy into an environment where a thrombolytic or ~ibrinolytic agent has been delivered, where the catheter need not be directly engaged against clot or other stenoses. In such cases, the ultrasonic energy will WO 97/19644 PCT~US96/19007 enhance the activity o~ the therapeutic agent, typically by improving penetration o~ the agent into the clot. ~n a third exemplary protocol, the catheter may be u~ed to deliver an anti-thrombotic agent to a previously treated vascular site to inhibit restenosis. Again, the ultrasonic energy will typically provide ~or enhanced delivery and penetration o~ the anti-thrombotic agent into the blood vessel wall. In a ~ourth exemplary protocol, the catheter may be used to dissolve the clot, without the adjunct bene~it o~ thrombolytic agents.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates an exemplary catheter and ultrasonic energy source constructed in accordance with the principles o~ the present invention.
Fig. 2 is a detailed view of the distal end o~ the catheter o~ Fig. 1, shown in partial section.
Fig. 3 is a perspective view o~ the tubular piezoelectric transducer which is incorporated in the catheter o~ Fig. 1.
Fig. 4 is a cross-sectional view taken along line 4-4 of Fig. 3.
Fig. 5 is a detailed view o~ the distal end o~ the catheter o~ Fig. 1, with the extent o~ longitudinal oscillation being shown in broken line.
Fig. 6 is an alternative detailed view o~ the distal end o~ the catheter o~ Fig. 1, shown in partial section.
Fig. 7 is a perspective view o~ the piezoelectric stack ultrasonic transducer incorporated in the design of Fig. 6.
Fig. 8 illustrates use o~ the catheter o~ Fig. 1 in a ~irst protocol ~or ultrasonically ablating clot by direct engagement with the clot.
Fig. 9 illustrates use o~ the catheter o~ Fig. 1 in a second protocol ~or ultrasonically enhancing the activity of a therapeutic agent released ~rom the distal end o~ the catheter.
CA 02239116 1998-0~-29 W O97/19644 PCT~US96/19007 DESCRIPTION OF THE SPECIFIC E ~ ODIME ~ S
The present invention provides a~paratus and methods for the treatment of l-lm; n~l conditions, particularly for the treatment of diseases of the coronary and peripheral vasculature. Specific conditions include coronary and peripheral arterial disease and thrombosis. The apparatus and methods are use~ul for primary treatment of such diseases, where the purpose is to ablate, dissolve, or otherwise disrupt the clot, plaque, or other stenotic lesions which are responsible for the disease. For example, catheters constructed according to the principles o~ the present invention can be used to directly engage and transmit ultrasonic energy into the stenotic material in order to mechanically disrupt the material to open the associated blood vessel lumen. Such mechanical disruption can be accomplished with or without the simultaneous administration of pharmacologic and therapeutic agents. The apparatus and methods of the present invention are also useful to enhance the administration o~ therapeutic agents, where the therapeutic agents are primarily responsible for the disruption o~ the stenotic material. In such cases, the catheter may be engaged against the stenotic material, or alternatively may be maintained a short distance away from the stenotic material. The ultrasonic energy will be relied on to agitate and promote the penetration of the therapeutic agent into the stenotic material. Suitable therapeutic agents include known thrombolytic and fibrinolytic drugs, such as heparin, tissue plasminogen activator (tPA), urokinase, streptokinase, and the like. The catheters and methods of the present invention are still further useful for the treatment of vascular sites which have been previously treated by other interventional techniques, such as angioplasty, atherectomy, laser ablation, and the like. In such cases, the catheters will be used to agitate and promote the penetration of anti-thrombogenic agents into the vascular or other luminal wall toinhibit restenosis. Suitable anti-thrombogenic agents include hirudin, hirulog, heparin, tPA, urokinase, streptokinase, and the like In addition to treatment of the vascular system, - CA 02239116 1998-0~-29 the present invention may also be used for systemic and localized delivery of drugs within other body lumens, such as the ureter, the urethra, fallopian tubes, and the like. The present invention may further be used for the systemic and localized delivery o:E drugs within the vascular system for treatment of non-vascular diseases, e.g., for the treatment of tumors by the localized delivery of drugs to the vasculature supporting the tumor.
The catheter of the present invention will comprise a cathete:E body having a proximal end and distal end. The catheter body will have dimensions and physical characteristics selected for the particular use. For vascular applications, the length of the catheter body will typically be from 50 cm to 200 cm, usually being from 75 cm to 150 cm, and the diameter will be from l mm to 5 mm, usually being from 2 mm to 4 mm. The diameter of the catheter body may vary over its length, and di:Eferent portions of the length may be formed from different materials. In the exemplary embodiment, the catheter body will comprise a single extrusion having at least one lumen therethrough. The lumen will usually be capable o~
receiving a guidewire, and may also be capable of delivering therapeutic agents and/or carrying electrical wires for connection from the proximal end of the catheter body to the distal end. Alternatively, the catheter body may include separate lumens for delivering therapeutic agent(s), routing electrical wires for connection to the ultrasonic transducer, or other purposes. The catheter body may be reinforced over all or a portion of its length. Conventional reinforcement materials include wire braids, wire meshes, wire coils, and the like. When employed with a guidewire for placement within the vasculature, the catheter body may have an "over-the-wire~
design or a "rapid exchange" design. In the former case, the guidewire lumen will extend substantially through the entire length of the catheter body. In the latter case, the guidewire lumen will terminate in a proximal guidewire port located relatively near the distal end of the catheter body, usually within 50 cm, more usually within 30 cm, and often within 25 cm or less. Usually, a proximal housing will be CA 02239116 1998-0~-29 secured to the pro~im~l end of the catheter body, where the housing includes a guidewire port, a therapeutic agent in~usion port, and the like.
A resonantly vibrating assembly is secured at or - near the distal end o~ the catheter body. The assembly will include an inter~ace member which is resonantly vibrated at the desired ultrasonic ~requency and which includes at least one inter~ace sur~ace ~or transmitting the ultrasonic vibrations to the ~luid environment surrounding the distal end o~ the catheter. The resonantly vibrating assembly will usually be attached directly to the distal end o~ the catheter body but also could be disposed partially or totally within the distal end o~ the catheter body. Usually, the resonantly vibrating assembly will have a relatively short length, usually being below 2 cm, preferably being below 1 cm, and typically being in the range from about 0.4 cm to 1.5 cm, more usuall~ in the range ~rom about 0.6 cm to 1 cm. The assembly will preferably have a low pro~ile to ~acilitate vascular or other intrall~ml n~l introductions, typically having a diameter below 6 mm, usually in the range ~rom 1 mm to 5 mm, more usually in the range ~rom 2 mm to 4 mm.
In the exemplary embodiment o~ the present invention, the inter~ace sur~ace will be ~orwardly disposed so that the sur:Eace may engage intral-lm; n~l obstructions as the catheter i8 advanced through the body lumen, such as a blood vessel. Such ~orwardly disposed vibrating sur~aces will also be use~ul ~or projecting ultrasonic energy ~orwardly to agitate and promote absorption o~ a li~uid therapeutic agent, which agent is usually delivered by the same catheter. In alternative embodiments, which are described in detail in copending application serial no. 08/566,739, the ~ull disclosure o~ which is incorporated herein by re~erence, the inter~ace sur~aces may be laterally disposed to radiate ultrasonic energy radially outward ~rom the catheter body.
The resonantly vibrating assembly o~ the present invention will ~urther comprise a tail mass, a spring element connecting the inter~ace member to the tail mass, and a longitudinally oscillating driver disposed between the tail CA 02239116 1998-0~-29 W O 97/19644 PCT~US96/19007 11 mass and the interface member. The mass o~ the tail mass will be substantially greater than that of the interface member, typically being at least four-fold greater, and usually being at least eight-fold greater. Usually, the mass o~ the tail mass will be in the range from about 0.1 gm to 10 gm, more usually in the range from about 0.2 gm to 4 gm. The mass of the interface member will be in the range from 0.005 gm to 1 gm, more usually in the range from 0.01 gm to 0.3 gm. In this way, the tail mass will remain substantially stationary or immobilized while the longitudinally oscillating driver imparts longitudinal (axial) movement to the inter~ace member.
The mass of the interface member and the spring constant of the spring element will be selected so that the resonantly vibrating assembly resonates at a particular ultrasonic frequency, typically in the range from 10 kHz to 300 kHz, preferably from 20 kHz to 80 kHz. The longitudinally oscillating driver will also be selected to operate (when electronically driven) at the same ultrasonic fre~uency. In this way, the longitudinally oscillating driver will drive the resonantly vibrating assembly at its resonant frequency, thus enhancing the efficiency of energy transfer and increasing the amplitude of vibration (displacement) of the interface member.
Pre~erably, the interface member will operate with a displacement (under loaded conditions) of at least about 0.5 ~m, preferably in the range from 0.5 ~m to 40 ~m, and more preferably in the range from 10 ~m to 20 ~m.
The tail mass will usually be formed separately from the catheter body and other components of the vibratory assembly, but optionally could be formed as part of the catheter body or alternatively as an integral unit with the spring element and/or interface member. The dimensions and shape of the tail mass will usually be selected to conform to - the dimensions of the catheter body, i.e., usually being a short cylinder having a diameter which is the same as or slightly smaller than that of the distal end of the catheter body.
The interface member will usually form the distal-most tip of the catheter, and will usually have a forwardly CA 02239116 1998-0~-29 WO 97/19644 PCT~US96/19007 disposed convex surface which defines the inter~ace surface.
The interface surface, however, need not be convex, and could alternatively be concave, flat, irregular, or have any other geometry capable of radiating ultrasonic energy forwardly as 5 = the interface member is vibrated. Typically, the interface sur~ace will have an area in the range from 0.5 mm2 to 20 mm2, pre~erably from 1 mm2 to 12 mm2.
The spring element may comprise a single rod or tube extending distally from the tail mass and attached to the proximal surface of the inter~ace member. Usually, the single spring element will be disposed coaxially within the catheter.
Alternatively, the spring element may comprise multiple rods or shafts, in which case they will usually be disposed symmetrically about the axis of the catheter.
One or more axial passages may be formed through the resonantly vibrating assembly, typically for passage o~ a guidewire, delivery of therapeutic agents, or the like. To provide such lumens, it will be necessary to form holes through both the tail mass and the inter~ace member. Such holes can be aligned and joined by one or more axial components o~ the spring element, typically in the ~orm of hollow tubes to provide a continuous lumen through the assembly.
The longitudinally oscillating driver can take any conventional form of ultrasonic transducer capable o~
converting electrical energy to mechanical ultrasonic vibrations. Exemplary transducers include piezoelectric elements, such as hollow piezoelectric cylinders, piezoelectric stacks, and the like. Suitable piezoelectric cylinders will be composed of a suitable piezoelectric material, such as a lead zirconate titinate (e.g., PZT-8), have a length in the range from 2 mm to 2 cm, an outer diameter in the range ~rom 1 mm to 4 mm, and a wall thickness in the range ~rom 0.1 mm to 0.5 mm. Piezoelectric stacks will comprise a plurality of ceramic disks, typically from 10 to 60 disks, having electrodes of alternate polarity disposed between the disks. Other suitable ultrasonic transducers include magnetostrictive elements, such as those described in CA 02239116 1998-0~-29 W O 97/19644 PCTrUS96/19007 copending application serial no. 08/566,740, the full disclosure o~ which is incorporated herein by reference.
The spring element which joins the inter~ace member to the tail mass may comprise a single component, e.g., a single solid rod or hollow tube disposed along the longitudinal axis of the catheter or a cylindrical shell either within or external to the longitudinally oscillating driver. Alternatively, the spring element may comprise a plurality of components, such as a plurality of rods or tubes disposed symmetrically about the longitudinal axis of the catheter. The spring element may be composed of any of a wide variety of materials, most typically being a stainless steel, such as a hardened stainless steel having a Rockwell stiffness of at least about 35. Other suitable materials include superelastic alloys, such as nickel-titanium alloys known as nitinols. The cross-sectional area of the spring element(s) shall be sufficient to provide a maximum tension of approximately 20~ of the tensile strength of the material, typically about 25,000 PSI, at the time when the spring experiences its maximum deformation, i.e., the time of maximum forward displacement of the interface member. The assembly of the tail mass, inter~ace member, and longitudinally oscillating driver is compressed by the spring mass with a static force sufficient to present continuing compressive forces at the time when the assembly shrinks to its minimum longitudinal displacement. The interface member and spring element shall have a mass and stiffness which together assure that the spring element retains compressive force on the interface member at the time o~ maximum reverse acceleration in order to prevent the interface member ~rom separating from the oscillating driver. The time o~ maximum reverse acceleration occurs at the time of maximum forward ~ displacement.
Re~erring now to Fig. 1, a catheter system 10 comprising a catheter 12 constructed in accordance with the principles of the present invention and an ultrasonic power supply 14 is illustrated. The catheter 12 includes a catheter body 16 having a distal end 18 and a proximal end 20, a CA 02239ll6 l998-0~-29 WO 97/~9644 PCT~US96/19007 proximal housing 22 having a ~luid in~usion port 24, and a guidewire port 26. The catheter 12 includes at least a single lumen 28 extending ~rom the proximal end 20 to the distal end 18 and connected to both the ~luid in~usion port 24 and the guidewire port 26. A cable 30 extends ~rom the proximal end 20 of the catheter body 16 (typically through the lumen 28) and includes a connector 32 which may be removably attached to the power supply 14. The power supply 14 may be selected to drive the ultrasonic transducer ~described below) at about a preselected ~requency. The power supply 14 will typically comprise a conventional signal generator, such as those that are commercially available from suppliers such as Hewlett-Packard, Palo Alto, Cali~ornia, and Tektronics, Portland, Oregon, and a power ampli~ier, such as those commercially 15~ available ~rom suppliers such as ENI, Rochester, New York, and Krohn-Hite, Avon, Massachusetts. Alternatively, the power supply may comprise custom signal generator and power ampli~ier circuits with tracking circuits to keep the driving frequency at the resonant ~requency o~ the ultrasonic driver in the catheter tip as this resonant ~requency dri~ts due to thermally induced material variations.
Usually, the longitudinally oscillating driver 50 will be energized by a continuou~ wave signal generator operating at a fixed ~requency selected to resonantly drive the assembly 40 under the expected operating load.
Alternatively, a tracking generator may be used which monitors the output current and voltage o~ the driver SO and adjusts it~ own operating ~requency to match any thermal or other dri~t in the system. As a ~urther alternative, the driver SO
may be energized by a ~unction generator which sweeps within a resonant energization band in order to control the duty cycle, with a more narrow bandwidth providing a higher duty cycle. A
~unction generator may also be con~igured or programmed to operate in an on-o~ or burst mode, with a duty cycle just su~icient to achieve the biological e~ect. By employing such discontinuous operation, heating o~ the resonantly vibrating assembly 40 can be minimized.
CA 02239116 1998-0~-29 WO97/19644 PCT~US96/19~07 Referring now to Figs. 2-4, a resonantly vibrating assembly 40 is mounted within the distal end o~ the catheter body 16. The resonantly vibrating assembly 40 comprises a tail mass 42, an interface member 44, and a spring element 46 in the form of a tube having a lumen 48 therethrough. The tubular spring element 46 is connected at its distal end to the interface member 44 and at its proximal end to the tail mass 42. Attachment of these components can be achieved in conventional ways, such as threaded attachment joints, the use of adhesives such as epoxy, solder joints, welded joints, and the like.
A longitudinally oscillating driver 50 is mounted between the tail mass 42 and the interface member 44. The driver 50 is a tubular piezoelectric transducer, as best illustrated in Figs. 3 and 4. The tubular transducer includes a piezoelectric tube 52 formed from a suitable material , as described above, sandwiched between an outer electrode 54 and inner electrode 56. Often, a small annular gap wlll be left between the driver 50 and the inner wall of the catheter body 16 and/or the outer wall of the spring element 46, although the gap is not shown in Fig. 2. Application of a suitable driving voltage to the electrodes 54 and 56 will cause the tubular transducer to oscillate both longitudinally and radially. A suitable continuous or variable (time dependent) wave driving voltage will be from 10 V to 200 V. The resulting axial displacement is best observed in Fig. 5, where displacements in the ranges set forth above may be achieved.
A lumen 60 is formed through the tail mass and a second lumen 62 is formed through the interface member. The lumens 60 and 62 are aligned with the lumen 48 through the driver 50. In this way, a continuous lumen is provided from the lumen 28 of the catheter body through the distal tip of - the catheter. This lumen is suitable ~or introducing the catheter over the guidewire and/or delivering therapeutic agents through the catheter and releasing said agents from the distal tip.
An alternative resonantly vibrating assembly 70 is illustrated in Figs. 6 and 7. Catheter body 12, tail mass 42, CA 02239116 1998-0~-29 WO 97/19644 PCT~US96/19007 and inter~ace member 44 may all be identical to those described in connection with Figs. 1-5. The spring element, however, comprises a pair o~ radially o~set shafts 72 which are disposed symmetrically about the axis o~ the catheter. A
longitudinally oscillating driver 74 comprise6 a stack of piezoelectric disks 76 which are sandwiched between electrode plates 78, as best illustrated in Fig. 7. The electrodes 78 will be connected to positive and negative terminals o~ the power supply 14 in order to induce longitudinal vibrations in the piezoelectric stack. The stack may be machined to include opposed channels 80 to accommodate the rods 72 as well as a central lumen 82 for accommodating a guidewire and/or the delivery of ~luids Re~erring now to Fig. 8, use o~ the catheter 12 ~or directly engaging a region o~ thrombus T in a diseased blood vessel BV having a region of plaque P is illustrated. The forwardly disposed interface surface o~ interface member 44 is advanced through the lumen of the blood vessel in a conventional manner until it engages the thrombus T. The resonantly vibrating assembly will then be activated to cause ultrasonic vibration o~ the interface member 44. The inter~ace sur~ace o~ the inter~ace member, in turn, will transmit the ultrasonic vibrations directly into the thrombus T, resulting in mechanical disruption of the thrombus and clot. Optionally, a thrombolytic or fibrlnolytic agent may be delivered through the catheter 12 and released into a region proximal to the thrombus T, either before, during or after the mechanical disruption. Pre~erably, the ultrasonic energy will be transmitted while the treatment agent is being released to enhance penetration o~ the agent into the thrombus T.
An alternative treatment method is illustrated in Fig. 9. There, a sleeve catheter 9o is disposed over the catheter 12 o~ the present invention. An anti-thrombogenic treatment agent is delivered through the sleeve catheter 90 to a target site TS within a blood vessel BV. The inter~ace member 44 is ultrasonically vibrated, as described previously.
The ultrasonic vibration will enhance penetration of the agent into the wall of the blood vessel BV. This method would be CA 02239116 1998-0~-29 W O 97/19644 PCT~US96/19007 17 equally suitable for delivering drugs into other body lumens.
Use of the sleeve catheter 90 for delivering drugs is illustrated as an alternative to delivering the drugs through the lumen of the catheter 12 itself. It will be appreciated that the sleeve catheter 90 could have been used in the method of Fig. 8. Conversely, the lumen of catheter 12 could have been used to deliver the anti-thrombogenic agent in the method of Fig. 9.
While the above is a complete description of the preferred embodlments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.
INTRALUMINAL THERAPY
OUND OF THE l~v~NllON
. Field o~ the I~vention The present invention relates generally to medical devices and methods. More particularly, the present invention relates to apparatus and methods for the localized delivery of therapeutic ultrasound energy within the vasculature and other body lumens.
Despite the growing sophistication o~ medical technology, vascular (blood vessel) diseases, such as acute myocardial infarction (heart attack) and peripheral arterial thrombosis (blood clots in leg arteries), remain a ~requent, costly, and very serious problem in health care. Current methods of treatment, often expensive, are not always e~fective. In the U.S. alone, the cost of treatment and support and the loss of productivity due to vascular diseases together exceed ~40 billion per year.
The core of the problem is that diseased sites within the blood vessels narrow and eventually become completely blocked as a result of the deposition of fatty materials, cellular debris, calcium, and/or blood clots, thereby blocking the vital flow of blood. Current treatments include drugs, interventional devices, and/or bypass surgery.
High doses o~ thrombolytics (clot-dissolving drugs) are frequently used in an ef~ort to dissolve the blood clots.
Even with such aggressive therapy, thrombolytics fail to restore blood flow in the affected vessel in about 30~ of patients. In addition, these drugs can also dissolve beneficial clots or in~ure healthy tissue causing potentially fatal bleeding complications.
While a variety of interventional devices are available, including angioplasty, atherectomy, and laser CA 02239116 1998-0~-29 WO97/19644 PCT~US96/19007 ablation catheters, the use o~ such devices to remove obstructing deposits may leave behind a wound that heals by ~orming a scar. The scar itsel~ may eventually become a serious obstruction in the blood vessel (a process known as restenosis). Also, diseased blood vessels being treated with interventional devices sometimes develop vasoconstriction (elastic recoil), a process by which spasms or abrupt reclosures o~ the vessel occur, thereby restricting the flow o~ blood and necessitating ~urther intervention.
Approximately 40~ o~ treated patients require additional treatment ~or restenosis resulting ~rom scar ~ormation occurring over a relatively long period, typically 4 to 12 months, while approximately 1-in-20 patients require treatment for vasoconstriction, which typically occurs ~rom 4 to 72 hours a~ter the initial treatment.
Bypass surgery can redirect blood around the obstructed artery resulting in improved blood ~low. However, the resulting bypass gra~ts can themselves develop scar tissue and new blood clots in ~ive to ten years resulting in blockage and the need ~or ~urther treatment. In summary, all current therapies have limited long term success.
The use o~ ultrasonic energy has been proposed both to mechanically disrupt clot and to enhance the intravascular delivery o~ drugs to dissolve clot and inhibit restenosis.
Ultrasonic energy may be delivered intravascularly using specialized catheters having an ultrasonically vibrating sur~ace at or near their distal ends. One type of ultrasonic catheter employs a wire or other axial transmission element to deliver energy ~rom an ultrasonic energy vibration source located outside the patient, through the catheter, and to the ultrasonically vibrating surface. While such systems can deliver relatively large amounts o~ energy, the need to transmit that energy through the entire length o~ the catheter presents a substantial risk to the patient.
Moreover, such catheters are typically rigid and cannot easily traverse narrow, tortuous arteries, such as the coronary arteries which ~requently need to be treated.
Because o~ their rigidity and inability to ~ollow the vascular -CA 02239ll6 l998-0~-29 WO97/19644 PCT~US96/19007 lumen, these catheters present a serious risk o~ vascular wall perforation.
In order to avoid the use o~ ultrasonic transmission members, catheters having ultrasonic transducers mounted directly on their distal ends have also been proposed. See, Eor example, U.S. Patent Nos. 5,362,309; 5,318,014; 5,315,998;
5,269,291; and 5,197,946. By providing the transducer within the catheter itself, there is no need to employ a transmission element along the entire length of the catheter. While such catheter designs o~er enhanced safety, they su~fer from a limited ability to generate large amounts o~ ultrasonic energy. Even though certain of these designs, such as that described in U.S. Patent No. 5,362,309, employ "amplii~iers"
which enhance the delivery of ultrasonic energy, such designs are still problematic. In particular, the catheters o~ the '309 patent have relatively long, rigid transducers and are not amenable to receiving guidewires, both o~ which ~eatures make it di~ficult to position the catheters within the vasculature, particularly the coronary vasculature.
For these reasons, it would be desirable to provide improved ultrasonic catheter designs overcoming at least some o~ the problems discussed above. In particular, it would be desirable to provide ultrasonic catheters having ultrasonic transducers at their distal ends, where the transducers are capable o~ driving interf~ace suri~aces with relatively high energy and amplitude. It would ~urther be desirable to provide transducer and driver designs which are highly e~icient and which minimize the production o~ heat within the vascular or other lllm; n~l environment. It would be still Eurther desirable to provide methods :Eor the intraluminal delivery o~ ultrasonic energy, where the ultrasonic energy is useful ~or a variety o~ purposes, including the direct ~ mechanical disruption o~ clot, the enhancement of thrombolytic activity o~ agents to dissolve clot, and the enhancement o~
pharmacologic agents to prevent restenosis oE vascular sites previously treated by angioplasty or other interventional methods.
CA 02239ll6 l998-0~-29 WO 97/19644 PCTnUS96/19007 2. Descri~tion of the Backaround Art Catheters having ultrasonic elements with the capability of delivering thrombolytic and other liquid agents are described in U.S. Patent Nos. 5,362,309; 5,318,014;
5,315,998; 5,197,946; 5,397,301; 5,380,273; 5,344,395;
5,342,292; 5,324,255; 5,304,115; 5,279,546; 5,269,297;
5,267,954; 4,870,953; 4,808,153; 4,692,139; and 3,565,062; in WO 90/01300; and in Tachibana (1992) JVIR 3:299-303. A rigid ultrasonic probe intended ~or treating vascular plaque and having fluid delivery means is described in U.S. Patent No. 3,433,226. An ultrasonic transmission wire intended for intravascular treatment is described in U.S. Patent No. 5,163,421 and Rosenschein et al. (1990) JACC 15:711-717.
Ultrasonically assisted atherectomy catheters are described in 15 _ U.S. Patent 5,085,662 and EP 189329. Ultrasonic enhancement o~ systemic and localized drug delivery is described in U.S. Patent Nos. 5,286,254; 5,282,785; 5,267,985; and 4,948,587; in WO 94/05361 and WO 91/19529; in JP 3-63041; and Yumita et al. (1990) JPN. J. CANCER RES. 81:304-308. An electrosurgical angioplasty catheter having ultrasonic enhancement is described in U.S. Patent No. 4,936,281. An infusion and drainage catheter having an ultrasonic cleaning mechanism is described in U.S. Patent No. 4,698,058. A drug delivery catheter having a pair of spaced-apart balloons to produce an isolated region around arterial plaque is described in U.S. Patent Mo. 4,636,195.
STTMMAT~Y OF THE I~v~llON
According to the present invention, a catheter for the intraluminal delivery of ultrasonic energy comprises a catheter body having a proximal end and a distal end. A tail mass is attached to the catheter body, typically at its distal end, and a longitudinally oscillating driver engages and extends distally from the tail mass. An inter~ace member is disposed to engage a distally forward sur:Eace of the oscillating driver, and the mass of the interface member is much less than that o~ the tail mass. The tail mass and inter~ace member are connected to each other by a spring CA 02239116 1998-0~-29 WO 97tl96~4 PCT~US96/19OU7 element so that a resonant system is formed for driving the inter~ace member. By employing a relatively large tail mass, the resonant ~requency o~ the interface member, spring element, and oscillating driver is independent of the tail mass and de~ined primarily by the mass o~ the interface member and the elastic modulus o~ the spring element, and the oscillating driver. By properly choosing the operating ~requency o~ the longitudinally oscillating driver, the resonant system defined by the interface member, the spring element, and the oscillating driver can be resonantly driven to enhance both the displacement amplitude o~ an interface sur~ace on the inter~ace member and increase the efficiency o~
operation, i.e., the conversion o~ electrical energy to mechanical energy.
The longitudinally oscillating member may take any conventional ~orm ~or an ultrasonic transducer, typically being a tubular piezoelectric transducer, a piezoelectric stack, or the like. An exemplary tubular piezoelectric transducer comprises a hollow piezoelectric cylinder having an inner cylindrical electrode and an outer cylindrical electrode. Application o~ a driving current to the electrodes causes axial and radial expansion and contraction o~ the piezoelectric transducer. The axial expansion and contraction allow the piezoelectric cylinder to resonantly drive the inter~ace member in the longitudinal direction. An exemplary piezoelectric stack comprises a plurality of ceramic disks having electrodes therebetween.
The spring element will comprise an axial member capable o~ mechanically coupling the inter~ace member to the tail mass with su~icient space therebetween to receive the longitudinal driver. Typically, the spring element will comprise at least one rod secured at a proximal end to the tail mass and at a distal end to the inter~ace member The rod may optionally be tubular to provide the path ~or a~ 35 guidewire, in~usion o~ therapeutic agent, or the like. A
single rod will usually be disposed coaxially within the catheter. Multiple rods may be disposed symmetrically about the axis of the catheter body. Alternatively, the spring CA 02239116 1998-0~-29 element may comprise a thin-walled cylindrical member secured to the tail mass and the inter~ace member and enclosing the longitudinally oscillating member in a concentric manner.
The inter~ace member will usually include a distally 5 ~ disposed inter~ace sur~ace which forwardly transmits longitudinal oscillations into the environment surrounding the distal end o~ the catheter. The inter~ace surface will typically be convex, although it could be ~lat, concave, or irregular.
A method according to the present invention ~or treating intraluminal lesions comprises providing a catheter having an inter~ace member at its distal end. A ~orwardly disposed sur~ace o~ the inter~ace member is advanced to a region near the intraluminal lesion, typically to a region o~
vascular stenosis within a patient's vasculature, and the inter~ace member is resonantly driven relative to a tail mass mounted proximally o~ the inter~ace member. In this way, ultrasonic energy is e~ficiently delivered into the regions surrounding the distal end o~ the catheter. The inter~ace member will usually have a mass in the range ~rom 0.005 gm to 1 gm, pre~erably from 0.01 gm to 0.3 gm, and is typically driven at a ~requency in the range ~rom 10 kHz to 300 kHz, and will have a longitudinal amplitude in the range from about 0.05 ~m to 40 ~m, pre~erably ~rom 10 ~m to 25 ~m, under typical mass loading conditions o~ a vascular lumen. The forwardly disposed sur~ace o~ the inter~ace member will typically have an area in the range ~rom 0.5 mm2 to 20 mm2, pre~erably ~rom 1 mm2 to 12 mm2, and the catheter may be used in a variety of speci~ic therapeutic protocols.
In a first such protocol, the inter~ace member will be engaged directly against a vascular obstruction and used to ablate the structure or optionally to dissolve the structure with the simultaneous delivery of a thrombolytic or ~ibrinolytic agent. Alternatively, the catheter can be used to deliver ultrasonic energy into an environment where a thrombolytic or ~ibrinolytic agent has been delivered, where the catheter need not be directly engaged against clot or other stenoses. In such cases, the ultrasonic energy will WO 97/19644 PCT~US96/19007 enhance the activity o~ the therapeutic agent, typically by improving penetration o~ the agent into the clot. ~n a third exemplary protocol, the catheter may be u~ed to deliver an anti-thrombotic agent to a previously treated vascular site to inhibit restenosis. Again, the ultrasonic energy will typically provide ~or enhanced delivery and penetration o~ the anti-thrombotic agent into the blood vessel wall. In a ~ourth exemplary protocol, the catheter may be used to dissolve the clot, without the adjunct bene~it o~ thrombolytic agents.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates an exemplary catheter and ultrasonic energy source constructed in accordance with the principles o~ the present invention.
Fig. 2 is a detailed view of the distal end o~ the catheter o~ Fig. 1, shown in partial section.
Fig. 3 is a perspective view o~ the tubular piezoelectric transducer which is incorporated in the catheter o~ Fig. 1.
Fig. 4 is a cross-sectional view taken along line 4-4 of Fig. 3.
Fig. 5 is a detailed view o~ the distal end o~ the catheter o~ Fig. 1, with the extent o~ longitudinal oscillation being shown in broken line.
Fig. 6 is an alternative detailed view o~ the distal end o~ the catheter o~ Fig. 1, shown in partial section.
Fig. 7 is a perspective view o~ the piezoelectric stack ultrasonic transducer incorporated in the design of Fig. 6.
Fig. 8 illustrates use o~ the catheter o~ Fig. 1 in a ~irst protocol ~or ultrasonically ablating clot by direct engagement with the clot.
Fig. 9 illustrates use o~ the catheter o~ Fig. 1 in a second protocol ~or ultrasonically enhancing the activity of a therapeutic agent released ~rom the distal end o~ the catheter.
CA 02239116 1998-0~-29 W O97/19644 PCT~US96/19007 DESCRIPTION OF THE SPECIFIC E ~ ODIME ~ S
The present invention provides a~paratus and methods for the treatment of l-lm; n~l conditions, particularly for the treatment of diseases of the coronary and peripheral vasculature. Specific conditions include coronary and peripheral arterial disease and thrombosis. The apparatus and methods are use~ul for primary treatment of such diseases, where the purpose is to ablate, dissolve, or otherwise disrupt the clot, plaque, or other stenotic lesions which are responsible for the disease. For example, catheters constructed according to the principles o~ the present invention can be used to directly engage and transmit ultrasonic energy into the stenotic material in order to mechanically disrupt the material to open the associated blood vessel lumen. Such mechanical disruption can be accomplished with or without the simultaneous administration of pharmacologic and therapeutic agents. The apparatus and methods of the present invention are also useful to enhance the administration o~ therapeutic agents, where the therapeutic agents are primarily responsible for the disruption o~ the stenotic material. In such cases, the catheter may be engaged against the stenotic material, or alternatively may be maintained a short distance away from the stenotic material. The ultrasonic energy will be relied on to agitate and promote the penetration of the therapeutic agent into the stenotic material. Suitable therapeutic agents include known thrombolytic and fibrinolytic drugs, such as heparin, tissue plasminogen activator (tPA), urokinase, streptokinase, and the like. The catheters and methods of the present invention are still further useful for the treatment of vascular sites which have been previously treated by other interventional techniques, such as angioplasty, atherectomy, laser ablation, and the like. In such cases, the catheters will be used to agitate and promote the penetration of anti-thrombogenic agents into the vascular or other luminal wall toinhibit restenosis. Suitable anti-thrombogenic agents include hirudin, hirulog, heparin, tPA, urokinase, streptokinase, and the like In addition to treatment of the vascular system, - CA 02239116 1998-0~-29 the present invention may also be used for systemic and localized delivery of drugs within other body lumens, such as the ureter, the urethra, fallopian tubes, and the like. The present invention may further be used for the systemic and localized delivery o:E drugs within the vascular system for treatment of non-vascular diseases, e.g., for the treatment of tumors by the localized delivery of drugs to the vasculature supporting the tumor.
The catheter of the present invention will comprise a cathete:E body having a proximal end and distal end. The catheter body will have dimensions and physical characteristics selected for the particular use. For vascular applications, the length of the catheter body will typically be from 50 cm to 200 cm, usually being from 75 cm to 150 cm, and the diameter will be from l mm to 5 mm, usually being from 2 mm to 4 mm. The diameter of the catheter body may vary over its length, and di:Eferent portions of the length may be formed from different materials. In the exemplary embodiment, the catheter body will comprise a single extrusion having at least one lumen therethrough. The lumen will usually be capable o~
receiving a guidewire, and may also be capable of delivering therapeutic agents and/or carrying electrical wires for connection from the proximal end of the catheter body to the distal end. Alternatively, the catheter body may include separate lumens for delivering therapeutic agent(s), routing electrical wires for connection to the ultrasonic transducer, or other purposes. The catheter body may be reinforced over all or a portion of its length. Conventional reinforcement materials include wire braids, wire meshes, wire coils, and the like. When employed with a guidewire for placement within the vasculature, the catheter body may have an "over-the-wire~
design or a "rapid exchange" design. In the former case, the guidewire lumen will extend substantially through the entire length of the catheter body. In the latter case, the guidewire lumen will terminate in a proximal guidewire port located relatively near the distal end of the catheter body, usually within 50 cm, more usually within 30 cm, and often within 25 cm or less. Usually, a proximal housing will be CA 02239116 1998-0~-29 secured to the pro~im~l end of the catheter body, where the housing includes a guidewire port, a therapeutic agent in~usion port, and the like.
A resonantly vibrating assembly is secured at or - near the distal end o~ the catheter body. The assembly will include an inter~ace member which is resonantly vibrated at the desired ultrasonic ~requency and which includes at least one inter~ace sur~ace ~or transmitting the ultrasonic vibrations to the ~luid environment surrounding the distal end o~ the catheter. The resonantly vibrating assembly will usually be attached directly to the distal end o~ the catheter body but also could be disposed partially or totally within the distal end o~ the catheter body. Usually, the resonantly vibrating assembly will have a relatively short length, usually being below 2 cm, preferably being below 1 cm, and typically being in the range from about 0.4 cm to 1.5 cm, more usuall~ in the range ~rom about 0.6 cm to 1 cm. The assembly will preferably have a low pro~ile to ~acilitate vascular or other intrall~ml n~l introductions, typically having a diameter below 6 mm, usually in the range ~rom 1 mm to 5 mm, more usually in the range ~rom 2 mm to 4 mm.
In the exemplary embodiment o~ the present invention, the inter~ace sur~ace will be ~orwardly disposed so that the sur:Eace may engage intral-lm; n~l obstructions as the catheter i8 advanced through the body lumen, such as a blood vessel. Such ~orwardly disposed vibrating sur~aces will also be use~ul ~or projecting ultrasonic energy ~orwardly to agitate and promote absorption o~ a li~uid therapeutic agent, which agent is usually delivered by the same catheter. In alternative embodiments, which are described in detail in copending application serial no. 08/566,739, the ~ull disclosure o~ which is incorporated herein by re~erence, the inter~ace sur~aces may be laterally disposed to radiate ultrasonic energy radially outward ~rom the catheter body.
The resonantly vibrating assembly o~ the present invention will ~urther comprise a tail mass, a spring element connecting the inter~ace member to the tail mass, and a longitudinally oscillating driver disposed between the tail CA 02239116 1998-0~-29 W O 97/19644 PCT~US96/19007 11 mass and the interface member. The mass o~ the tail mass will be substantially greater than that of the interface member, typically being at least four-fold greater, and usually being at least eight-fold greater. Usually, the mass o~ the tail mass will be in the range from about 0.1 gm to 10 gm, more usually in the range from about 0.2 gm to 4 gm. The mass of the interface member will be in the range from 0.005 gm to 1 gm, more usually in the range from 0.01 gm to 0.3 gm. In this way, the tail mass will remain substantially stationary or immobilized while the longitudinally oscillating driver imparts longitudinal (axial) movement to the inter~ace member.
The mass of the interface member and the spring constant of the spring element will be selected so that the resonantly vibrating assembly resonates at a particular ultrasonic frequency, typically in the range from 10 kHz to 300 kHz, preferably from 20 kHz to 80 kHz. The longitudinally oscillating driver will also be selected to operate (when electronically driven) at the same ultrasonic fre~uency. In this way, the longitudinally oscillating driver will drive the resonantly vibrating assembly at its resonant frequency, thus enhancing the efficiency of energy transfer and increasing the amplitude of vibration (displacement) of the interface member.
Pre~erably, the interface member will operate with a displacement (under loaded conditions) of at least about 0.5 ~m, preferably in the range from 0.5 ~m to 40 ~m, and more preferably in the range from 10 ~m to 20 ~m.
The tail mass will usually be formed separately from the catheter body and other components of the vibratory assembly, but optionally could be formed as part of the catheter body or alternatively as an integral unit with the spring element and/or interface member. The dimensions and shape of the tail mass will usually be selected to conform to - the dimensions of the catheter body, i.e., usually being a short cylinder having a diameter which is the same as or slightly smaller than that of the distal end of the catheter body.
The interface member will usually form the distal-most tip of the catheter, and will usually have a forwardly CA 02239116 1998-0~-29 WO 97/19644 PCT~US96/19007 disposed convex surface which defines the inter~ace surface.
The interface surface, however, need not be convex, and could alternatively be concave, flat, irregular, or have any other geometry capable of radiating ultrasonic energy forwardly as 5 = the interface member is vibrated. Typically, the interface sur~ace will have an area in the range from 0.5 mm2 to 20 mm2, pre~erably from 1 mm2 to 12 mm2.
The spring element may comprise a single rod or tube extending distally from the tail mass and attached to the proximal surface of the inter~ace member. Usually, the single spring element will be disposed coaxially within the catheter.
Alternatively, the spring element may comprise multiple rods or shafts, in which case they will usually be disposed symmetrically about the axis of the catheter.
One or more axial passages may be formed through the resonantly vibrating assembly, typically for passage o~ a guidewire, delivery of therapeutic agents, or the like. To provide such lumens, it will be necessary to form holes through both the tail mass and the inter~ace member. Such holes can be aligned and joined by one or more axial components o~ the spring element, typically in the ~orm of hollow tubes to provide a continuous lumen through the assembly.
The longitudinally oscillating driver can take any conventional form of ultrasonic transducer capable o~
converting electrical energy to mechanical ultrasonic vibrations. Exemplary transducers include piezoelectric elements, such as hollow piezoelectric cylinders, piezoelectric stacks, and the like. Suitable piezoelectric cylinders will be composed of a suitable piezoelectric material, such as a lead zirconate titinate (e.g., PZT-8), have a length in the range from 2 mm to 2 cm, an outer diameter in the range ~rom 1 mm to 4 mm, and a wall thickness in the range ~rom 0.1 mm to 0.5 mm. Piezoelectric stacks will comprise a plurality of ceramic disks, typically from 10 to 60 disks, having electrodes of alternate polarity disposed between the disks. Other suitable ultrasonic transducers include magnetostrictive elements, such as those described in CA 02239116 1998-0~-29 W O 97/19644 PCTrUS96/19007 copending application serial no. 08/566,740, the full disclosure o~ which is incorporated herein by reference.
The spring element which joins the inter~ace member to the tail mass may comprise a single component, e.g., a single solid rod or hollow tube disposed along the longitudinal axis of the catheter or a cylindrical shell either within or external to the longitudinally oscillating driver. Alternatively, the spring element may comprise a plurality of components, such as a plurality of rods or tubes disposed symmetrically about the longitudinal axis of the catheter. The spring element may be composed of any of a wide variety of materials, most typically being a stainless steel, such as a hardened stainless steel having a Rockwell stiffness of at least about 35. Other suitable materials include superelastic alloys, such as nickel-titanium alloys known as nitinols. The cross-sectional area of the spring element(s) shall be sufficient to provide a maximum tension of approximately 20~ of the tensile strength of the material, typically about 25,000 PSI, at the time when the spring experiences its maximum deformation, i.e., the time of maximum forward displacement of the interface member. The assembly of the tail mass, inter~ace member, and longitudinally oscillating driver is compressed by the spring mass with a static force sufficient to present continuing compressive forces at the time when the assembly shrinks to its minimum longitudinal displacement. The interface member and spring element shall have a mass and stiffness which together assure that the spring element retains compressive force on the interface member at the time o~ maximum reverse acceleration in order to prevent the interface member ~rom separating from the oscillating driver. The time o~ maximum reverse acceleration occurs at the time of maximum forward ~ displacement.
Re~erring now to Fig. 1, a catheter system 10 comprising a catheter 12 constructed in accordance with the principles of the present invention and an ultrasonic power supply 14 is illustrated. The catheter 12 includes a catheter body 16 having a distal end 18 and a proximal end 20, a CA 02239ll6 l998-0~-29 WO 97/~9644 PCT~US96/19007 proximal housing 22 having a ~luid in~usion port 24, and a guidewire port 26. The catheter 12 includes at least a single lumen 28 extending ~rom the proximal end 20 to the distal end 18 and connected to both the ~luid in~usion port 24 and the guidewire port 26. A cable 30 extends ~rom the proximal end 20 of the catheter body 16 (typically through the lumen 28) and includes a connector 32 which may be removably attached to the power supply 14. The power supply 14 may be selected to drive the ultrasonic transducer ~described below) at about a preselected ~requency. The power supply 14 will typically comprise a conventional signal generator, such as those that are commercially available from suppliers such as Hewlett-Packard, Palo Alto, Cali~ornia, and Tektronics, Portland, Oregon, and a power ampli~ier, such as those commercially 15~ available ~rom suppliers such as ENI, Rochester, New York, and Krohn-Hite, Avon, Massachusetts. Alternatively, the power supply may comprise custom signal generator and power ampli~ier circuits with tracking circuits to keep the driving frequency at the resonant ~requency o~ the ultrasonic driver in the catheter tip as this resonant ~requency dri~ts due to thermally induced material variations.
Usually, the longitudinally oscillating driver 50 will be energized by a continuou~ wave signal generator operating at a fixed ~requency selected to resonantly drive the assembly 40 under the expected operating load.
Alternatively, a tracking generator may be used which monitors the output current and voltage o~ the driver SO and adjusts it~ own operating ~requency to match any thermal or other dri~t in the system. As a ~urther alternative, the driver SO
may be energized by a ~unction generator which sweeps within a resonant energization band in order to control the duty cycle, with a more narrow bandwidth providing a higher duty cycle. A
~unction generator may also be con~igured or programmed to operate in an on-o~ or burst mode, with a duty cycle just su~icient to achieve the biological e~ect. By employing such discontinuous operation, heating o~ the resonantly vibrating assembly 40 can be minimized.
CA 02239116 1998-0~-29 WO97/19644 PCT~US96/19~07 Referring now to Figs. 2-4, a resonantly vibrating assembly 40 is mounted within the distal end o~ the catheter body 16. The resonantly vibrating assembly 40 comprises a tail mass 42, an interface member 44, and a spring element 46 in the form of a tube having a lumen 48 therethrough. The tubular spring element 46 is connected at its distal end to the interface member 44 and at its proximal end to the tail mass 42. Attachment of these components can be achieved in conventional ways, such as threaded attachment joints, the use of adhesives such as epoxy, solder joints, welded joints, and the like.
A longitudinally oscillating driver 50 is mounted between the tail mass 42 and the interface member 44. The driver 50 is a tubular piezoelectric transducer, as best illustrated in Figs. 3 and 4. The tubular transducer includes a piezoelectric tube 52 formed from a suitable material , as described above, sandwiched between an outer electrode 54 and inner electrode 56. Often, a small annular gap wlll be left between the driver 50 and the inner wall of the catheter body 16 and/or the outer wall of the spring element 46, although the gap is not shown in Fig. 2. Application of a suitable driving voltage to the electrodes 54 and 56 will cause the tubular transducer to oscillate both longitudinally and radially. A suitable continuous or variable (time dependent) wave driving voltage will be from 10 V to 200 V. The resulting axial displacement is best observed in Fig. 5, where displacements in the ranges set forth above may be achieved.
A lumen 60 is formed through the tail mass and a second lumen 62 is formed through the interface member. The lumens 60 and 62 are aligned with the lumen 48 through the driver 50. In this way, a continuous lumen is provided from the lumen 28 of the catheter body through the distal tip of - the catheter. This lumen is suitable ~or introducing the catheter over the guidewire and/or delivering therapeutic agents through the catheter and releasing said agents from the distal tip.
An alternative resonantly vibrating assembly 70 is illustrated in Figs. 6 and 7. Catheter body 12, tail mass 42, CA 02239116 1998-0~-29 WO 97/19644 PCT~US96/19007 and inter~ace member 44 may all be identical to those described in connection with Figs. 1-5. The spring element, however, comprises a pair o~ radially o~set shafts 72 which are disposed symmetrically about the axis o~ the catheter. A
longitudinally oscillating driver 74 comprise6 a stack of piezoelectric disks 76 which are sandwiched between electrode plates 78, as best illustrated in Fig. 7. The electrodes 78 will be connected to positive and negative terminals o~ the power supply 14 in order to induce longitudinal vibrations in the piezoelectric stack. The stack may be machined to include opposed channels 80 to accommodate the rods 72 as well as a central lumen 82 for accommodating a guidewire and/or the delivery of ~luids Re~erring now to Fig. 8, use o~ the catheter 12 ~or directly engaging a region o~ thrombus T in a diseased blood vessel BV having a region of plaque P is illustrated. The forwardly disposed interface surface o~ interface member 44 is advanced through the lumen of the blood vessel in a conventional manner until it engages the thrombus T. The resonantly vibrating assembly will then be activated to cause ultrasonic vibration o~ the interface member 44. The inter~ace sur~ace o~ the inter~ace member, in turn, will transmit the ultrasonic vibrations directly into the thrombus T, resulting in mechanical disruption of the thrombus and clot. Optionally, a thrombolytic or fibrlnolytic agent may be delivered through the catheter 12 and released into a region proximal to the thrombus T, either before, during or after the mechanical disruption. Pre~erably, the ultrasonic energy will be transmitted while the treatment agent is being released to enhance penetration o~ the agent into the thrombus T.
An alternative treatment method is illustrated in Fig. 9. There, a sleeve catheter 9o is disposed over the catheter 12 o~ the present invention. An anti-thrombogenic treatment agent is delivered through the sleeve catheter 90 to a target site TS within a blood vessel BV. The inter~ace member 44 is ultrasonically vibrated, as described previously.
The ultrasonic vibration will enhance penetration of the agent into the wall of the blood vessel BV. This method would be CA 02239116 1998-0~-29 W O 97/19644 PCT~US96/19007 17 equally suitable for delivering drugs into other body lumens.
Use of the sleeve catheter 90 for delivering drugs is illustrated as an alternative to delivering the drugs through the lumen of the catheter 12 itself. It will be appreciated that the sleeve catheter 90 could have been used in the method of Fig. 8. Conversely, the lumen of catheter 12 could have been used to deliver the anti-thrombogenic agent in the method of Fig. 9.
While the above is a complete description of the preferred embodlments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.
Claims (37)
1. A catheter comprising:
a catheter body having a proximal end and a distal end;
a tail mass attached to the catheter body;
a longitudinally oscillating driver engaging and extending distally from the tail mess;
an interface member engaging a distally forward surface of the oscillating driver, wherein the mass of the interface member is much less than that of the tail mass; and a spring element connecting the tail mass to the interface member, wherein the spring element has a spring force which is selected to permit resonant driving by the longitudinally oscillating driver.
a catheter body having a proximal end and a distal end;
a tail mass attached to the catheter body;
a longitudinally oscillating driver engaging and extending distally from the tail mess;
an interface member engaging a distally forward surface of the oscillating driver, wherein the mass of the interface member is much less than that of the tail mass; and a spring element connecting the tail mass to the interface member, wherein the spring element has a spring force which is selected to permit resonant driving by the longitudinally oscillating driver.
2. A catheter as in claim 1, wherein the longitudinally oscillating driver comprises a longitudinally oscillating member selected from the group consisting of piezoelectric elements and magnetostrictive elements.
3. A catheter as in claim 2, wherein the longitudinally oscillating member comprises a hollow piezoelectric cylinder having an inner cylindrical electrode and an outer cylindrical electrode.
4. A catheter as in claim 3, wherein piezoelectric cylinder has dimensions and is composed of a material which provide oscillation at a frequency in the range from 10 kHz to 300 kHz.
5. A catheter as in claim 4, wherein the piezoelectric cylinder is composed of a lead zirconate titinate, has a length in the range from 2 mm to 2 cm, an outer diameter in the range from 1 mm to 4 mm, and a wall thickness in the range from 0.1 mm to 0.5 mm.
6. A catheter as in claim 2, wherein the longitudinally oscillating member comprises a plurality of ceramic disks having electrodes therebetween.
7. A catheter as in claim 1, wherein the tail mass has a mass which is at least four times the mass of the interface member.
8. A catheter as in claim 7, wherein the tail mass has a mass in the range from 0.1 gm to 10 gm and the interface member has a mass in the range from 0.01 gm to 1 gm.
9. A catheter as in claim 1, wherein the spring element comprises at least one rod secured at a proximal end to the tail mass and at a distal end to the interface member.
10. A catheter as in claim 9, wherein the spring element consists of a single rod disposed coaxially within the catheter.
11. A catheter as in claim 9, wherein the spring element comprises at least two parallel rod members disposed symmetrically about the axis of the catheter body.
12. A catheter as in claim 1, wherein the interface member includes a distally disposed interface surface which forwardly transmits longitudinal oscillations into the environment surrounding the distal end of the catheter.
13. A catheter as in claim 12, wherein the interface surface has a generally convex shape.
14. A catheter as in claim 1, wherein the catheter body has at least one lumen for delivering a therapeutic agent therethrough.
15. An improved ultrasonic catheter of the type comprising a catheter body having an ultrasonic driver at a distal end thereof, wherein the improvement comprises an ultrasonic driver comprising:
a tail mass secured to the distal end of the catheter body;
an interface member distally spaced-apart from the tail mass;
a spring element connecting the interface member to the tail mass;
an ultrasonic driver disposed between the interface member and the tail mass, wherein said driver oscillates at or near a resonant frequency characteristic of the interface member, the spring element, and the ultrasonic driver.
a tail mass secured to the distal end of the catheter body;
an interface member distally spaced-apart from the tail mass;
a spring element connecting the interface member to the tail mass;
an ultrasonic driver disposed between the interface member and the tail mass, wherein said driver oscillates at or near a resonant frequency characteristic of the interface member, the spring element, and the ultrasonic driver.
16. A catheter as in claim 15, wherein the ultrasonic driver comprises a hollow piezoelectric cylinder having an inner cylindrical electrode and a outer cylindrical electrode.
17. A catheter as in claim 16, wherein the piezoelectric cylinder has dimensions and is composed of a material which provide oscillation at a frequency in the range from 10 kHz to 300 kHz.
18. A catheter as in claim 17, wherein the piezoelectric cylinder is composed of a lead zirconate titinate, has a length in the range from 2 mm to 2 cm, an outer diameter in the range from 1 mm to 4 mm, and a wall thickness in the range from 0.1 mm to 0.5 mm.
19. A catheter as in claim 15, wherein the ultrasonic driver comprises a plurality of ceramic disks having electrodes therebetween.
20. A catheter as in claim 15, wherein the tail mass has a mass which is at least four times the mass of the interface member.
21. A catheter as is claim 20, wherein the tail mass has a mass in the range from 0.1 gm to 10 gm and the interface member has a mass in the range from 0.01 gm to 1 gm.
22. A catheter as in claim 15, wherein the spring element comprises at least one rod secured at a proximal end to the tail mass and at a distal end to the interface member.
23. A catheter as in claim 22, wherein the spring element consists of a single rod disposed coaxially within the catheter.
24. A catheter as in claim 22, wherein the spring element comprises at least two parallel rod members disposed symmetrically about the axis of the catheter body.
25. A catheter as in claim 15, wherein the interface member includes a distally disposed interface surface which forwardly transmits longitudinal oscillations into the environment surrounding the distal end of the catheter.
26. A catheter as in claim 15, wherein the interface surface has a generally convex shape
27 A catheter as in claim 15, wherein the catheter body has at least one lumen for delivering a therapeutic agent therethrough.
28. A method for treating intraluminal lesions, said method comprising:
providing a catheter having an assembly comprising an interface member connected to a tail mass by a spring element disposed at its distal end, wherein the assembly has a resonant frequency;
advancing a forwardly disposed surface of the interface member to a region near the intraluminal lesion;
driving the interface member relative to the tail mass at the resonant frequency, wherein ultrasonic energy is amplified and radiated into the region.
providing a catheter having an assembly comprising an interface member connected to a tail mass by a spring element disposed at its distal end, wherein the assembly has a resonant frequency;
advancing a forwardly disposed surface of the interface member to a region near the intraluminal lesion;
driving the interface member relative to the tail mass at the resonant frequency, wherein ultrasonic energy is amplified and radiated into the region.
29. A method as in claim 28, wherein the intraluminal lesion contains a vascular stenosis.
30. A method as in claim 28, wherein the interface member is driven at a frequency in the range from about 10 kHz to 300 kHz.
31. A method as in claim 30, wherein the interface member is driven with a longitudinal amplitude in the range from 0.05 µm to 20 µm.
32. A method as in claim 28, wherein the forwardly disposed surface has an area in the range from 0.5 mm2 to 20 mm2.
33. A method as in claim 29, wherein the interface member surface is engaged against a vascular obstruction.
34. A method as in claim 28, further comprising delivering a therapeutic agent through the catheter to the intraluminal lesion.
35. A method as in claim 34, wherein the therapeutic agent is delivered while ultrasonic energy is being radiated into the region.
36. A method as in claim 35, wherein the therapeutic agent is a fibrinolytic agent delivered to a vascular stenosis to treat clot.
37. A method as in claim 35, wherein the therapeutic agent is delivered to a previously treated vascular site to inhibit restenosis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/565,575 US5725494A (en) | 1995-11-30 | 1995-11-30 | Apparatus and methods for ultrasonically enhanced intraluminal therapy |
| US08/565,575 | 1995-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2239116A1 true CA2239116A1 (en) | 1997-06-05 |
Family
ID=24259238
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002239116A Abandoned CA2239116A1 (en) | 1995-11-30 | 1996-11-27 | Apparatus and methods for ultrasonically enhanced intraluminal therapy |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5725494A (en) |
| EP (1) | EP0955910A4 (en) |
| JP (1) | JP2000502264A (en) |
| AU (1) | AU1142197A (en) |
| BR (1) | BR9611786A (en) |
| CA (1) | CA2239116A1 (en) |
| WO (1) | WO1997019644A1 (en) |
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| AU1142197A (en) | 1997-06-19 |
| JP2000502264A (en) | 2000-02-29 |
| EP0955910A1 (en) | 1999-11-17 |
| US5725494A (en) | 1998-03-10 |
| BR9611786A (en) | 1999-12-28 |
| WO1997019644A1 (en) | 1997-06-05 |
| EP0955910A4 (en) | 2001-02-14 |
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| EEER | Examination request | ||
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