Patent Grant
12064650
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.
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.
As illustrated in
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 the energy 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 body proximal 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 the tubular 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, 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.
In an example embodiment, the tubular body energy delivery section 18 comprises a material that is thinner than the material comprising the tubular body proximal region 14. In another example embodiment, 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. In certain modified embodiments, the energy delivery section 18 comprises the same material or a material of the same thickness as the proximal 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 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.
In certain embodiments, 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.
In an example embodiment, the central lumen 51 extends through the length of the tubular body 12. As illustrated in
The central lumen 51 is configured to receive an elongate inner core 34, an example embodiment of which is illustrated in
As shown in the cross-section illustrated in
Still referring to
In an example embodiment, the ultrasound assembly 42 includes a plurality of ultrasound radiating members 40 that are divided into one or more groups. For example,
Still referring to
Referring now to
In the example embodiment illustrated in
In a modified embodiment, such as illustrated in
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
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-shaped ultrasound radiating members 40 can be used in other embodiments. In an example embodiment, 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. In an example embodiment, 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.
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, the ultrasound radiating members 40 are operated with a frequency of about 2 MHz.
By spacing the fluid delivery lumens 30 around the circumference of the tubular body 12 substantially evenly, as illustrated in
For example, in one embodiment in which the fluid delivery ports 58 have similar sizes along the length of the tubular body 12, the fluid delivery ports 58 have a diameter between about 0.0005 inches to about 0.0050 inches. In another embodiment in which the size of the fluid delivery ports 58 changes along the length of the tubular body 12, 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.
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 the fluid delivery ports 58 can be selected to provide such nonuniform fluid flow.
Referring still to
In an example embodiment, 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. Additionally, in an example embodiment, 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.
In an example embodiment, 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. In a modified embodiment, 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. In either configuration, 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. In other embodiments, 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.
In other embodiments, the catheter 10 includes an occlusion device positioned at the distal 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 the central lumen 51. Thus, the inner core 34 is prevented from extending past the occlusion device and out the distal 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 the catheter 10, and instead recirculating to the tubular body proximal region 14. These and other cooling fluid flow configurations permit the power provided to the ultrasound 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
In other embodiments, 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.
In an example embodiment, 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.
In an example method of operation, 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.
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 the processing unit 78.
In such embodiments, 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. After each power adjustment, the processing unit 78 monitors the temperature sensors 20 and produces another temperature control signal which is received by the power circuits 72.
In an example embodiment, 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. In this case, 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.
Because, in certain embodiments, 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. For example, in a modified embodiment, 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.
As described above, the feedback control system 68 can be configured to maintain tissue adjacent to the energy 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 QC. As described above, the ultrasound radiating members 40 can be electrically connected such that each group of ultrasound radiating members 40 generates an independent output. In certain embodiments, the output from the power circuit maintains a selected energy for each group of ultrasound radiating members 40 fora selected length of time.
The processing unit 78 can comprise a digital or analog controller, such as a computer with software. In embodiments wherein the processing 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 and display 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 the processing 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 of ultrasound 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.
As illustrated in
As illustrated in
As illustrated in
In an example embodiment, the ultrasound assembly 42 includes sixty ultrasound radiating members 40 spaced over a length of approximately 30 to approximately 50 cm. In such embodiments, the catheter 10 can be used to treat an elongate clot 90 without requiring moving or repositioning the catheter 10 during the treatment. However, in modified embodiments, 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.
Still referring to
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
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.
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 a distal region 206. In such embodiments, the catheter tubular body 202 includes an outer sheath 208 that is positioned upon an inner core 210. In one embodiment, 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. In an example embodiment, 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.
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 the tubular body 202. For enhanced maneuverability, especially the ability to be pushed and rotated, 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.
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, the inner core 210 comprises polyamide or a similar material which can optionally be braided to increase the flexibility of the tubular body 202.
Still referring to
In the illustrated embodiment, 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.
In other embodiments, the ultrasound radiating member 224 can have a different shape. For example, the ultrasound radiating member 224 can take the form of a solid rod, a disk, a solid rectangle or a thin block. In still other embodiments, 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. For example, in one embodiment, 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. In another embodiment, 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.
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 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. In the illustrated configuration, the first wire 226 is connected to the hollow center of the ultrasound radiating member 224, while the second wire 228 is connected to the outer periphery of the ultrasound radiating member 224. In such embodiments, the ultrasound radiating member 224 comprises a transducer formed of a piezoelectric ceramic oscillator or a similar material.
Still referring to the example embodiment illustrated in
In a similar manner, the distal end of the sleeve 230 can be attached to a tip 234. As illustrated, the tip 234 is also attached to the distal end of the inner core 210. In an example embodiment, 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. In the illustrated example embodiment, 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.
Referring now to the example embodiment illustrated in
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 body distal 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 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. 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 DEFINITv®, which is available from Bristol-Myers Squibb Medical Imaging, Inc. (New York, NY). 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; fora 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.
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 the fluid delivery lumens 30, especially in embodiments wherein a temperature sensor 20 is positioned therein. For example, see the example embodiment illustrated in
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
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
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
In modified embodiments, 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. In such embodiments, 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.
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.
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 super hydrophobic 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> tor n recorded baseline “bursts” of the hydrophone signal:
RNE=[(NA−<BNA>)/<BNA>]
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} tor n recorded baseline bursts:
NET=[(4×SD{BNA})/<BNA>]
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:
RSE=[(SA−<BSA>)/<BSA>]
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
As illustrated in
The cavitation signal quantities per snapshot measured at various times throughout the 30-minute exposure are shown in
Table B lists the total number of IC counts observed for the different treatment protocols. In accordance with the max{RNE} trends shown in
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.
This application is a continuation of U.S. patent application Ser. No. 16/268,075, filed Feb. 5, 2019, now U.S. Pat. No. 11,058,901, which is a continuation of U.S. patent application Ser. No. 13/176,613, filed Jul. 5, 2011, now U.S. Pat. No. 10,232,196, which is a divisional of U.S. patent application Ser. No. 11/739,629, filed Apr. 24, 2007, which claims the benefit of U.S. Provisional Application No. 60/794,330, filed Apr. 24, 2006 and U.S. Provisional Application No. 60/799,119, filed May 9, 2006, the entire contents of these applications are hereby incorporated by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2961382 | Singher et al. | Nov 1960 | A |
| 3352303 | Delaney | Nov 1967 | A |
| 3430625 | Mcleod, Jr. | Mar 1969 | A |
| 3565062 | Kuris | Feb 1971 | A |
| 3827115 | Bom | Aug 1974 | A |
| 3861391 | Antonevich et al. | Jan 1975 | A |
| 3941122 | Jones | Mar 1976 | A |
| 4192294 | Vasilevsky et al. | Mar 1980 | A |
| 4309989 | Fahim | Jan 1982 | A |
| 4319580 | Colley et al. | Mar 1982 | A |
| 4354502 | Colley et al. | Oct 1982 | A |
| 4466442 | Hilmann et al. | Aug 1984 | A |
| 4657543 | Langer et al. | Apr 1987 | A |
| 4657756 | Rasor et al. | Apr 1987 | A |
| 4682596 | Bales et al. | Jul 1987 | A |
| 4692139 | Stiles | Sep 1987 | A |
| 4750902 | Wuchinich | Jun 1988 | A |
| 4762915 | Kung et al. | Aug 1988 | A |
| 4772594 | Hashimoto et al. | Sep 1988 | A |
| 4774958 | Einstein | Oct 1988 | A |
| 4797285 | Barenholz et al. | Jan 1989 | A |
| 4808153 | Parisi | Feb 1989 | A |
| 4821740 | Tachibana et al. | Apr 1989 | A |
| 4844882 | Widder et al. | Jul 1989 | A |
| 4870953 | DonMicheal et al. | Oct 1989 | A |
| 4900540 | Ryan et al. | Feb 1990 | A |
| 4920954 | Alliger | May 1990 | A |
| 4921478 | Solano et al. | May 1990 | A |
| 4936281 | Stasz | Jun 1990 | A |
| 4948587 | Kost et al. | Aug 1990 | A |
| 4953565 | Tachibana et al. | Sep 1990 | A |
| 4971991 | Umemura et al. | Nov 1990 | A |
| 5007438 | Tachibana et al. | Apr 1991 | A |
| 5040537 | Katakura | Aug 1991 | A |
| 5058570 | Idemoto et al. | Oct 1991 | A |
| 5069664 | Guess | Dec 1991 | A |
| 5076276 | Sakurai et al. | Dec 1991 | A |
| 5088499 | Unger | Feb 1992 | A |
| 5129883 | Black | Jul 1992 | A |
| 5149319 | Unger | Sep 1992 | A |
| 5156050 | Schmid et al. | Oct 1992 | A |
| 5158071 | Umemura et al. | Oct 1992 | A |
| 5163421 | Bernstein et al. | Nov 1992 | A |
| 5163436 | Saitoh et al. | Nov 1992 | A |
| 5197946 | Tachibana | Mar 1993 | A |
| 5209720 | Unger | May 1993 | A |
| 5215680 | D'Arrigo | Jun 1993 | A |
| 5216130 | Ine et al. | Jun 1993 | A |
| 5261291 | Schoch et al. | Nov 1993 | A |
| 5267954 | Nita | Dec 1993 | A |
| 5269291 | Carter | Dec 1993 | A |
| 5277913 | Thompson et al. | Jan 1994 | A |
| 5279546 | Mische et al. | Jan 1994 | A |
| 5289831 | Bosley | Mar 1994 | A |
| 5304115 | Pflueger | Apr 1994 | A |
| 5307816 | Hashimoto | May 1994 | A |
| 5315998 | Tachibana et al. | May 1994 | A |
| 5318014 | Carter | Jun 1994 | A |
| 5326342 | Pflueger | Jul 1994 | A |
| 5342292 | Nita et al. | Aug 1994 | A |
| 5342608 | Moriya et al. | Aug 1994 | A |
| 5344395 | Whalen et al. | Sep 1994 | A |
| 5345940 | Seward | Sep 1994 | A |
| 5362309 | Carter | Nov 1994 | A |
| 5368036 | Tanaka et al. | Nov 1994 | A |
| 5368557 | Nita | Nov 1994 | A |
| 5368558 | Nita | Nov 1994 | A |
| 5380273 | Dubrul et al. | Jan 1995 | A |
| 5401237 | Tachibana et al. | Mar 1995 | A |
| 5423797 | Adrian et al. | Jun 1995 | A |
| 5431663 | Carter | Jul 1995 | A |
| 5440914 | Tachibana et al. | Aug 1995 | A |
| 5447509 | Mills et al. | Sep 1995 | A |
| 5456259 | Barlow et al. | Oct 1995 | A |
| 5474530 | Passafaro | Dec 1995 | A |
| 5474531 | Carter | Dec 1995 | A |
| 5498236 | Dubrul et al. | Mar 1996 | A |
| 5509896 | Carter | Apr 1996 | A |
| 5542917 | Nita et al. | Aug 1996 | A |
| 5542935 | Unger et al. | Aug 1996 | A |
| 5558092 | Unger et al. | Sep 1996 | A |
| 5580575 | Unger et al. | Dec 1996 | A |
| 5582586 | Tachibana et al. | Dec 1996 | A |
| 5585112 | Unger et al. | Dec 1996 | A |
| 5603327 | Eberle | Feb 1997 | A |
| 5606974 | Castellano | Mar 1997 | A |
| 5620409 | Gans et al. | Apr 1997 | A |
| 5624382 | Oppelt | Apr 1997 | A |
| 5628728 | Tachibana et al. | May 1997 | A |
| 5630837 | Crowley | May 1997 | A |
| 5648098 | Porter | Jul 1997 | A |
| 5660909 | Tachibana et al. | Aug 1997 | A |
| 5681296 | Ishida | Oct 1997 | A |
| 5695460 | Siegel et al. | Dec 1997 | A |
| 5707608 | Liu | Jan 1998 | A |
| 5713848 | Dubrul et al. | Feb 1998 | A |
| 5718921 | Mathiowitz et al. | Feb 1998 | A |
| 5720710 | Tachibana et al. | Feb 1998 | A |
| 5724976 | Hirama et al. | Mar 1998 | A |
| 5725494 | Brisken | Mar 1998 | A |
| 5728062 | Brisken | Mar 1998 | A |
| 5733572 | Unger et al. | Mar 1998 | A |
| 5735811 | Brisken | Apr 1998 | A |
| 5752930 | Baudino et al. | May 1998 | A |
| 5776429 | Unger et al. | Jul 1998 | A |
| 5817048 | Lawandy | Oct 1998 | A |
| 5823962 | Lerch et al. | Oct 1998 | A |
| 5827203 | Nita | Oct 1998 | A |
| 5834880 | Tewandowski et al. | Nov 1998 | A |
| 5836896 | Rosenschein | Nov 1998 | A |
| 5840031 | Crowley | Nov 1998 | A |
| 5846218 | Brisken et al. | Dec 1998 | A |
| 5846517 | Unger | Dec 1998 | A |
| 5876345 | Eaton et al. | Mar 1999 | A |
| 5916192 | Nita et al. | Jun 1999 | A |
| 5925016 | Chornenky et al. | Jul 1999 | A |
| 5928186 | Homsma et al. | Jul 1999 | A |
| 5934284 | Plaia et al. | Aug 1999 | A |
| 5957851 | Hossack | Sep 1999 | A |
| 5957882 | Nita et al. | Sep 1999 | A |
| 5971949 | Levin et al. | Oct 1999 | A |
| 5976120 | Chow et al. | Nov 1999 | A |
| 5997497 | Nita et al. | Dec 1999 | A |
| 6001069 | Tachibana et al. | Dec 1999 | A |
| 6007514 | Nita | Dec 1999 | A |
| 6024718 | Chen et al. | Feb 2000 | A |
| 6063069 | Cragg et al. | May 2000 | A |
| 6066123 | Bednarski et al. | May 2000 | A |
| 6068857 | Weitschies et al. | May 2000 | A |
| 6088613 | Unger | Jul 2000 | A |
| 6089573 | Udagawa | Jul 2000 | A |
| 6096000 | Tachibana et al. | Aug 2000 | A |
| 6096070 | Ragheb et al. | Aug 2000 | A |
| 6113558 | Rosenschein et al. | Sep 2000 | A |
| 6113570 | Siegel et al. | Sep 2000 | A |
| 6117101 | Diederich et al. | Sep 2000 | A |
| RE36939 | Tachibana et al. | Oct 2000 | E |
| 6135976 | Tachibana | Oct 2000 | A |
| 6149596 | Bancroft | Nov 2000 | A |
| 6176842 | Tachibana et al. | Jan 2001 | B1 |
| 6206831 | Suorsa et al. | Mar 2001 | B1 |
| 6210356 | Anderson et al. | Apr 2001 | B1 |
| 6210393 | Brisken | Apr 2001 | B1 |
| 6221038 | Brisken | Apr 2001 | B1 |
| 6228046 | Brisken | May 2001 | B1 |
| 6235024 | Tu | May 2001 | B1 |
| 6238347 | Nix et al. | May 2001 | B1 |
| 6270460 | McCartan et al. | Aug 2001 | B1 |
| 6277077 | Brisken et al. | Aug 2001 | B1 |
| 6287271 | Dubrul et al. | Sep 2001 | B1 |
| 6296619 | Brisken et al. | Oct 2001 | B1 |
| 6312402 | Hansmann | Nov 2001 | B1 |
| 6361554 | Brisken | Mar 2002 | B1 |
| 6391042 | Cimino | May 2002 | B1 |
| 6394956 | Chandrasekaran et al. | May 2002 | B1 |
| 6398772 | Bond et al. | Jun 2002 | B1 |
| 6398792 | O'Connor | Jun 2002 | B1 |
| 6416740 | Unger | Jul 2002 | B1 |
| 6454737 | Nita et al. | Sep 2002 | B1 |
| 6454757 | Nita et al. | Sep 2002 | B1 |
| 6458118 | Lent et al. | Oct 2002 | B1 |
| 6464680 | Brisken et al. | Oct 2002 | B1 |
| 6471683 | Drasler et al. | Oct 2002 | B2 |
| 6478765 | Siegel et al. | Nov 2002 | B2 |
| 6494891 | Cornish et al. | Dec 2002 | B1 |
| 6506584 | Chandler et al. | Jan 2003 | B1 |
| 6508816 | Shadduck | Jan 2003 | B2 |
| 6524251 | Rabiner et al. | Feb 2003 | B2 |
| 6524271 | Brisken et al. | Feb 2003 | B2 |
| 6548047 | Unger | Apr 2003 | B1 |
| 6551337 | Rabiner et al. | Apr 2003 | B1 |
| 6558366 | Drasler et al. | May 2003 | B1 |
| 6562021 | Derbin et al. | May 2003 | B1 |
| 6565552 | Barbut | May 2003 | B1 |
| 6575956 | Brisken et al. | Jun 2003 | B1 |
| 6579277 | Rabiner et al. | Jun 2003 | B1 |
| 6582392 | Bennett et al. | Jun 2003 | B1 |
| 6585678 | Tachibana et al. | Jul 2003 | B1 |
| 6589253 | Cornish et al. | Jul 2003 | B1 |
| 6605084 | Acker et al. | Aug 2003 | B2 |
| 6623444 | Babaev | Sep 2003 | B2 |
| 6635046 | Barbut | Oct 2003 | B1 |
| 6645150 | Angelsen et al. | Nov 2003 | B2 |
| 6647755 | Rabiner et al. | Nov 2003 | B2 |
| 6652547 | Rabiner et al. | Nov 2003 | B2 |
| 6660013 | Rabiner et al. | Dec 2003 | B2 |
| 6663613 | Evans et al. | Dec 2003 | B1 |
| 6676626 | Bennett et al. | Jan 2004 | B1 |
| 6682502 | Bond et al. | Jan 2004 | B2 |
| 6689086 | Nita et al. | Feb 2004 | B1 |
| 6695781 | Rabiner et al. | Feb 2004 | B2 |
| 6695782 | Ranucci et al. | Feb 2004 | B2 |
| 6695785 | Brisken et al. | Feb 2004 | B2 |
| 6723063 | Zhang et al. | Apr 2004 | B1 |
| 6723064 | Babaev | Apr 2004 | B2 |
| 6726698 | Cimino | Apr 2004 | B2 |
| 6730048 | Hare et al. | May 2004 | B1 |
| 6733451 | Rabiner et al. | May 2004 | B2 |
| 6740040 | Mandrusov et al. | May 2004 | B1 |
| 6767345 | St. Germain et al. | Jul 2004 | B2 |
| 6824575 | Otomo et al. | Nov 2004 | B1 |
| 6830577 | Nash et al. | Dec 2004 | B2 |
| 6849062 | Kantor | Feb 2005 | B2 |
| 6855123 | Nita | Feb 2005 | B2 |
| 6866670 | Rabiner et al. | Mar 2005 | B2 |
| 6896659 | Conston et al. | May 2005 | B2 |
| 6905505 | Dodson, Jr. et al. | Jun 2005 | B2 |
| 6921371 | Wilson | Jul 2005 | B2 |
| 6929633 | Evans et al. | Aug 2005 | B2 |
| 6942620 | Nita et al. | Sep 2005 | B2 |
| 6942677 | Nita et al. | Sep 2005 | B2 |
| 6945937 | Culp et al. | Sep 2005 | B2 |
| 6958040 | Oliver | Oct 2005 | B2 |
| 6979293 | Hansmann et al. | Dec 2005 | B2 |
| 6985771 | Fischell et al. | Jan 2006 | B2 |
| 7137963 | Nita et al. | Nov 2006 | B2 |
| 7141044 | Gentsler | Nov 2006 | B2 |
| 7166098 | Steward et al. | Jan 2007 | B1 |
| 7186246 | Bennett et al. | Mar 2007 | B2 |
| 7220233 | Nita et al. | May 2007 | B2 |
| 7220239 | Wilson et al. | May 2007 | B2 |
| 7309334 | von Hoffmann | Dec 2007 | B2 |
| 7335180 | Nita et al. | Feb 2008 | B2 |
| 7341569 | Soltani et al. | Mar 2008 | B2 |
| 7384407 | Rodriguez et al. | Jun 2008 | B2 |
| 7503895 | Rabiner et al. | Mar 2009 | B2 |
| 7540852 | Nita et al. | Jun 2009 | B2 |
| 7567016 | Lu et al. | Jul 2009 | B2 |
| 7604608 | Nita et al. | Oct 2009 | B2 |
| 7621902 | Nita et al. | Nov 2009 | B2 |
| 7621929 | Nita et al. | Nov 2009 | B2 |
| 7648478 | Soltani et al. | Jan 2010 | B2 |
| 7727178 | Wilson | Jun 2010 | B2 |
| 7758509 | Angelsen et al. | Jul 2010 | B2 |
| 7771372 | Wilson | Aug 2010 | B2 |
| 7774933 | Wilson et al. | Aug 2010 | B2 |
| 7789830 | Fujita et al. | Sep 2010 | B2 |
| 7818854 | Wilson | Oct 2010 | B2 |
| 7828754 | Abe et al. | Nov 2010 | B2 |
| 7828762 | Wilson et al. | Nov 2010 | B2 |
| 7901359 | Mandrusov et al. | Mar 2011 | B2 |
| 7914509 | Bennett et al. | Mar 2011 | B2 |
| 8012092 | Powers et al. | Sep 2011 | B2 |
| 8062566 | Nita et al. | Nov 2011 | B2 |
| 8123789 | Khanna | Feb 2012 | B2 |
| 8152753 | Nita et al. | Apr 2012 | B2 |
| 8167831 | Wilson et al. | May 2012 | B2 |
| 8192363 | Soltani et al. | Jun 2012 | B2 |
| 8696612 | Wilson et al. | Apr 2014 | B2 |
| 8740835 | Soltani et al. | Jun 2014 | B2 |
| 9192566 | Soltani et al. | Nov 2015 | B2 |
| 10182833 | Soltani et al. | Jan 2019 | B2 |
| 10188410 | Soltani et al. | Jan 2019 | B2 |
| 10232196 | Soltani et al. | Mar 2019 | B2 |
| 20010003790 | Ben-Haim et al. | Jun 2001 | A1 |
| 20010053384 | Greenleaf et al. | Dec 2001 | A1 |
| 20020032394 | Brisken et al. | Mar 2002 | A1 |
| 20020041898 | Unger et al. | Apr 2002 | A1 |
| 20020045890 | Celliers et al. | Apr 2002 | A1 |
| 20020052620 | Barbut | May 2002 | A1 |
| 20020068869 | Brisken et al. | Jun 2002 | A1 |
| 20020077550 | Rabiner et al. | Jun 2002 | A1 |
| 20020082238 | Newman et al. | Jun 2002 | A1 |
| 20020123787 | Weiss | Sep 2002 | A1 |
| 20020151792 | Conston et al. | Oct 2002 | A1 |
| 20020193708 | Thompson et al. | Dec 2002 | A1 |
| 20030036705 | Hare et al. | Feb 2003 | A1 |
| 20030040501 | Newman et al. | Feb 2003 | A1 |
| 20030050662 | Don Michael | Mar 2003 | A1 |
| 20030065263 | Hare et al. | Apr 2003 | A1 |
| 20030069525 | Brisken et al. | Apr 2003 | A1 |
| 20030083608 | Evans et al. | May 2003 | A1 |
| 20030114869 | Nash | Jun 2003 | A1 |
| 20030139774 | Epstein et al. | Jul 2003 | A1 |
| 20030163147 | Hare et al. | Aug 2003 | A1 |
| 20030191446 | Tachibana et al. | Oct 2003 | A1 |
| 20030236539 | Rabiner et al. | Dec 2003 | A1 |
| 20040001809 | Brisken et al. | Jan 2004 | A1 |
| 20040010290 | Schroeppel et al. | Jan 2004 | A1 |
| 20040019318 | Wilson et al. | Jan 2004 | A1 |
| 20040024347 | Wilson et al. | Feb 2004 | A1 |
| 20040039311 | Nita et al. | Feb 2004 | A1 |
| 20040049148 | Rodriguez et al. | Mar 2004 | A1 |
| 20040054351 | Deniega et al. | Mar 2004 | A1 |
| 20040059313 | Anderson et al. | Mar 2004 | A1 |
| 20040068189 | Wilson et al. | Apr 2004 | A1 |
| 20040077976 | Wilson | Apr 2004 | A1 |
| 20040097996 | Hare et al. | May 2004 | A1 |
| 20040138570 | Nita et al. | Jul 2004 | A1 |
| 20040162571 | Rabiner et al. | Aug 2004 | A1 |
| 20040171981 | Buffen et al. | Sep 2004 | A1 |
| 20040220514 | Cafferata | Nov 2004 | A1 |
| 20040220544 | Heruth | Nov 2004 | A1 |
| 20040225318 | Eidenschink et al. | Nov 2004 | A1 |
| 20040236350 | Bolduc et al. | Nov 2004 | A1 |
| 20040255957 | Cafferata | Dec 2004 | A1 |
| 20040265393 | Unger et al. | Dec 2004 | A1 |
| 20050021063 | Hall et al. | Jan 2005 | A1 |
| 20050043629 | Rabiner et al. | Feb 2005 | A1 |
| 20050043753 | Rabiner et al. | Feb 2005 | A1 |
| 20050090818 | Pike et al. | Apr 2005 | A1 |
| 20050096669 | Rabiner et al. | May 2005 | A1 |
| 20050113688 | Nita et al. | May 2005 | A1 |
| 20050119679 | Rabiner et al. | Jun 2005 | A1 |
| 20050124877 | Nita et al. | Jun 2005 | A1 |
| 20050137520 | Rule et al. | Jun 2005 | A1 |
| 20050187513 | Rabiner et al. | Aug 2005 | A1 |
| 20050187514 | Rabiner et al. | Aug 2005 | A1 |
| 20050197619 | Rule et al. | Sep 2005 | A1 |
| 20050209578 | Christian Evans et al. | Sep 2005 | A1 |
| 20050215942 | Abrahamson et al. | Sep 2005 | A1 |
| 20050215946 | Hansmann et al. | Sep 2005 | A1 |
| 20050216044 | Hong | Sep 2005 | A1 |
| 20050256410 | Rabiner et al. | Nov 2005 | A1 |
| 20060069303 | Couvillon | Mar 2006 | A1 |
| 20060106308 | Hansmann et al. | May 2006 | A1 |
| 20060173387 | Hansmann et al. | Aug 2006 | A1 |
| 20060184070 | Hansmann et al. | Aug 2006 | A1 |
| 20060264809 | Hansmann et al. | Nov 2006 | A1 |
| 20070005051 | Kampa | Jan 2007 | A1 |
| 20070037119 | Pal et al. | Feb 2007 | A1 |
| 20070038158 | Nita et al. | Feb 2007 | A1 |
| 20070066978 | Schafer et al. | Mar 2007 | A1 |
| 20070083120 | Cain et al. | Apr 2007 | A1 |
| 20070207194 | Grayburn | Sep 2007 | A1 |
| 20070225619 | Rabiner et al. | Sep 2007 | A1 |
| 20070239027 | Nita | Oct 2007 | A1 |
| 20070265560 | Soltani et al. | Nov 2007 | A1 |
| 20080045865 | Kislev | Feb 2008 | A1 |
| 20080065014 | McCrystle et al. | Mar 2008 | A1 |
| 20080146918 | Magnin et al. | Jun 2008 | A1 |
| 20080154181 | Khanna | Jun 2008 | A1 |
| 20080167602 | Nita et al. | Jul 2008 | A1 |
| 20080171965 | Soltani et al. | Jul 2008 | A1 |
| 20080172067 | Nita et al. | Jul 2008 | A1 |
| 20080194954 | Matsunaga et al. | Aug 2008 | A1 |
| 20080221506 | Rodriguez et al. | Sep 2008 | A1 |
| 20080262350 | Unger | Oct 2008 | A1 |
| 20080306499 | Katoh et al. | Dec 2008 | A1 |
| 20080319355 | Nita | Dec 2008 | A1 |
| 20080319376 | Wilcox et al. | Dec 2008 | A1 |
| 20090018472 | Soltani et al. | Jan 2009 | A1 |
| 20090112150 | Unger et al. | Apr 2009 | A1 |
| 20090209900 | Carmeli et al. | Aug 2009 | A1 |
| 20090216246 | Nita et al. | Aug 2009 | A1 |
| 20100010393 | Duffy et al. | Jan 2010 | A1 |
| 20100022920 | Nita et al. | Jan 2010 | A1 |
| 20100022944 | Wilcox | Jan 2010 | A1 |
| 20100023036 | Nita et al. | Jan 2010 | A1 |
| 20100023037 | Nita et al. | Jan 2010 | A1 |
| 20100049209 | Nita et al. | Feb 2010 | A1 |
| 20100063413 | Volz | Mar 2010 | A1 |
| 20100063414 | Volz | Mar 2010 | A1 |
| 20100081934 | Hansmann et al. | Apr 2010 | A1 |
| 20100204582 | Lu | Aug 2010 | A1 |
| 20100210940 | Bradley et al. | Aug 2010 | A1 |
| 20100222715 | Nita | Sep 2010 | A1 |
| 20100256616 | Katoh et al. | Oct 2010 | A1 |
| 20100262215 | Gertner | Oct 2010 | A1 |
| 20100292685 | Katoh et al. | Nov 2010 | A1 |
| 20110160621 | Nita | Jun 2011 | A1 |
| 20110288449 | Schenkengel | Nov 2011 | A1 |
| 20110300078 | Borden et al. | Dec 2011 | A1 |
| 20110313328 | Nita | Dec 2011 | A1 |
| 20110319927 | Nita | Dec 2011 | A1 |
| 20120016272 | Nita et al. | Jan 2012 | A1 |
| 20120041307 | Patel et al. | Feb 2012 | A1 |
| 20120059285 | Soltani et al. | Mar 2012 | A1 |
| 20120078140 | Nita | Mar 2012 | A1 |
| 20120123273 | Okuno et al. | May 2012 | A1 |
| 20120179073 | Nita | Jul 2012 | A1 |
| 20120197277 | Stinis | Aug 2012 | A1 |
| 20130204166 | Villanueva et al. | Aug 2013 | A1 |
| 20130216593 | Borden et al. | Aug 2013 | A1 |
| 20130289398 | Borden et al. | Oct 2013 | A1 |
| 20130331738 | Borrelli | Dec 2013 | A1 |
| 20140236005 | Chen et al. | Aug 2014 | A1 |
| Number | Date | Country |
|---|---|---|
| 634470 | Mar 1989 | AU |
| 0224934 | Jun 1987 | EP |
| 0278074 | Aug 1988 | EP |
| 0327490 | Aug 1989 | EP |
| 0586875 | Jun 1994 | EP |
| 0744189 | Nov 1996 | EP |
| 1090658 | Apr 2001 | EP |
| 1252885 | Oct 2002 | EP |
| 1577551 | Oct 1980 | GB |
| 3S115591 | Sep 1977 | JP |
| H02180275 | Jul 1990 | JP |
| 80001365 | Jul 1980 | WO |
| 80002365 | Nov 1980 | WO |
| 89005159 | Jun 1989 | WO |
| 89005160 | Jun 1989 | WO |
| 89006978 | Aug 1989 | WO |
| 90001971 | Mar 1990 | WO |
| 95015118 | Jun 1995 | WO |
| 96015815 | May 1996 | WO |
| 96027341 | Sep 1996 | WO |
| 96029935 | Oct 1996 | WO |
| 96036286 | Nov 1996 | WO |
| 99033500 | Jul 1999 | WO |
| 99039647 | Aug 1999 | WO |
| 99039738 | Aug 1999 | WO |
| 00038580 | Jul 2000 | WO |
| 0213678 | Feb 2002 | WO |
| 02015803 | Feb 2002 | WO |
| 02015804 | Feb 2002 | WO |
| 03051208 | Jun 2003 | WO |
| 2005027756 | Mar 2005 | WO |
| 2005084552 | Sep 2005 | WO |
| 2005084553 | Sep 2005 | WO |
| 2007127176 | Nov 2007 | WO |
| Entry |
|---|
| Butler, “Production of Microbubbles for Use as Echo Contrast Agents”, Journal of Clinical Ultrasound, Jun. 1986, vol. 14, pp. 408-412. |
| Bao et al. “Transfection of a Reporter Plasmid into Cultured Cells by Sonoporation In Vitro,” Ultrasound in Medicine and Biology Journal, 1997, vol. 23, No. 6, pp. 953-959. |
| Bleeker et al., “On the Application of Ultrasonic Contrast Agents for Blood Flowmetry and Assessment of Cardiac Perfusion”, Journal of Ultrasound in Medicine, Aug. 1990, vol. 9, No. 8, pp. 461-471. |
| Chamsuddin et al., “Catheter-directed Thrombolysis with the Endowave System in the Treatment of Acute Massive Pulmonary Embolism: A Retrospective Multicenter Case Series,” Journal of Vascular and Interventional Radiology, Mar. 2008, vol. 19, No. 3, pp. 372-376. |
| Feinstein et al., “Two-dimensional Contrast Echocardiography. I. In Vitro Development and Quantitative Analysis of Echo Contrast Agents”, Journal of the American College of Cardiology, Jan. 1984, vol. 3, No. 1, pp. 14-20. |
| Greenleaf et al.; Artifical Cavitation Nuclei Significantly Enhance Acoustically Induced Cell Transfection. vol. 24, No. 4 pp. 587-595, 1998. |
| Holland et al., “Thresholds for Transient Cavitation Produced by Pulsed Ultrasound in a Controlled Nuclei Environment”, The Journal of the Acoustical Society of America, Nov. 1990, vol. 88, No. 5, pp. 2059-2069. |
| International Search Report and Written Opinion in Application No. PCT/US2007/009867, dated Sep. 30, 2008. |
| Jeffers et al.; Evaluation of the Effect of Cavitation Activity on Drug-Ultrasound Synergisms, 1993. |
| Jeffers et al. .; Dimethylformamide as an Enhancer of Cavitation-Induced Cell Lysis In Vitro, vol. 97, No. 1, Jan. 1995. |
| Keller et al., “Automated Production and Analysis of Echo Contrast Agents”, Journal of Ultrasound in Medicine, Sep. 1986, vol. 5, pp. 493-498. |
| Kim “Microbubbles Show Promise for Enhancing Ultrasound Signal, Image, Other Applications”, The Journal of the American Medical Association, Mar. 1989, vol. 281, No. 11, p. 1542. |
| Lang et al., “Contrast Ultrasonography of the Kidney: a New Method for Evaluation of Renal Perfusion in Vivo”, Circulation, 1987, vol. 75, No. 1, pp. 229-234. |
| Leong et al., “Polyanhydrides for Controlled Release of Bioactive Agents”, Biomaterials, Sep. 1986, vol. 7, pp. 364-371. |
| Lin et al., “Comparison of Percutaneous Ultrasound-Accelerated Thrombolysis versus Catheter-Directed Thrombolysis in Patients with Acute Massive Pulmonary Embolism,” Vascular, 2009, vol. 17, No. 3, pp. S137-S147. |
| Meltzer et al., “The Source of Ultrasound Contrast Effect”, Journal of Clinical Ultrasound, Apr. 1980, vol. 8, No. 2, pp. 121-127. |
| Miller et al.; Sonoporation of Cultured Cells in the Rotation Tube Exposure System, vol. 25, No. 1, 1999. |
| Porter et al., Thrombolytic Enhancement With Perfluorocarbom-Exposed Sonicated Dextrose Albumin Microbubbles, Nov. 1996. |
| Prat et al., “In Vivo Effects of Cavitation Alone or in Combination with Chemotherapy in a Peritoneal Carcinomatosis in the Rat,” 1993, vol. 68, pp. 13-17. |
| Price et al.; Delivery of Colloidal Particles and Red Blood Cells to Tissue Through Microvessel Ruptures Created By Targeted Microbubble Destruction With Ultrasound, Sep. 29, 1998. |
| Saletes et al., “Cavitation par Excitation Acoustique Bifréquentielle: Application á la Thrombolyse Ultrsonore,” N″ d'ordre 311, Universite de Lyon, Dec. 7, 2009, pp. 110. |
| Tachibana K.; Albumin Microbubble Echo-Contrast Materials as an Enhancer For Ultrasound Accelerated Thrombolysis, Sep. 1, 1995. |
| Unger et al., “Ultrasound Enhances Gene Expression of Liposomal Transfection,” Investigative Radiology, vol. 32, No. 12, pp. 723-727, 1997. |
| Unger et al., “Acoustically Active Liposheres Containing Paclitaxel,” vol. 11, No. 12, 1992. |
| Vandenburg et al., “Myocardial Risk Area and Peak Gray Level Measurement by Contrast Echocardiography: Effect of Microbubble Size and Concentration, Injection Rate, and Coronary Vasodilation,” American Heart Journal, Apr. 1988, vol. 115, No. 4, pp. 733-739. |
| Wheatly et al., “Contrast Agents for Diagnostic Ultrasound: Development and Evaluation of Polymer-Coated Microbubbles,” Biomaterials, Nov. 1990, vol. 11, No. 19, pp. 713-717. |
| Wu, Yunqiu et al., “Binding as Lysing of Blood Clots Using MRX-408,” Investigative Radiology, Dec. 1998, vol. 33, No. 12, pp. 880-885. |
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