WO2016061383A1

WO2016061383A1 - Ultrasound delivery system and method

Info

Publication number: WO2016061383A1
Application number: PCT/US2015/055788
Authority: WO
Inventors: Michael BENCHIMOL
Original assignee: Sonrgy, Inc.
Priority date: 2014-10-17
Filing date: 2015-10-15
Publication date: 2016-04-21

Abstract

An ultrasound system for delivering a substance to a target tissue using acoustically-responsive payload delivery vehicles includes a transducer system and controller. The controller is configured to focus acoustic energy on a first portion of the target tissue during a first period and focus acoustic energy on a different portion during a second period. The controller can change the location at which the energy is focused until the entire target tissue is treated. The controller can change the size of the location at which energy is focused, the intensity of the acoustic energy at the location, and/or the length of the time energy is focused on a particular portion of tissue. A thermal monitoring system can monitor tissue temperature as each portion of the tissue is being treated. An imaging system can be used to detect release of the payload in each portion of the tissue.

Description

ULTRASOUND DELIVERY SYSTEM AND METHOD

FIELD OF THE DISCLOSURE

[0001] The present invention relates generally to systems and methods for ultrasound treatment and more particularly to systems and methods for using focused acoustic energy to deliver a substance to a target tissue.

BACKGROUND OF THE DISCLOSURE

[0002] Ultrasound refers to sound waves at frequencies higher than that of the upper level of typical human hearing. Ultrasound acoustic energy can be used in a variety of biomedical and other applications for imaging and therapeutic purposes. For example, ultrasound imaging (also referred to as sonography) is a medical imaging technique that uses acoustic energy to observe internal structures of animals and humans. An image of the internal structures can be created and displayed by detecting reflections of the ultrasound energy by the internal structures.

[0003] Ultrasound technology can also be used as a mechanism to release therapeutic compounds from a larger structure or particle (referred to herein as a 'vehicle') for targeted and controlled delivery to a particular region or tissue of the body. Additional details about the use of ultrasound technology to deliver therapeutic compounds to specific tissues are provided in U.S. Pre-grant Patent Application Publication No. 2014/0046181 , the contents of which are hereby incorporated by reference.

[0004] The present inventors have developed improvements in the systems and methods for using ultrasound to deliver therapeutic agents to a desired organ or tissue, which will be described in detail below.

SUMMARY

[0005] One aspect of the invention is an ultrasound system for delivering a substance to a target tissue via acoustically responsive payload delivery vehicles. The ultrasound system includes an acoustic transducer system configured to deliver focused acoustic energy to a spatially adjustable payload delivery zone inside a body containing the target tissue. An acoustic transducer system controller is configured to control operation of the acoustic transducer system and to control the location of the payload delivery zone. The acoustic transducer system controller is further configured to: (i) operate the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time; (ii) change the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue, the second focal zone being different from the first focal zone and spaced apart from the first focal zone; and (iii) operate the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period. The ultrasound system is configured so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

[ 0006] Another aspect of the invention is an ultrasound system for delivering a substance to a target tissue via acoustically responsive payload delivery vehicles. The ultrasound system includes an acoustic transducer system configured to deliver focused acoustic energy to a spatially adjustable payload delivery zone inside a body containing the target tissue. An acoustic transducer system controller is configured to control operation of the acoustic transducer system and to control the location of the payload delivery zone. The acoustic transducer system controller is further configured to: (i) operate the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time; (ii) change the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue; and (iii) operate the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period. The acoustic transducer system controller is further configured to adjust the operation of the acoustic transducer system to change a size of the payload delivery zone. The focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

[ 0007 ] Still another aspect of the invention is an ultrasound system for delivering a substance to a target tissue via acoustically responsive payload delivery vehicles. The ultrasound system includes an acoustic transducer system configured to deliver focused acoustic energy to a spatially adjustable payload delivery zone inside a body containing the target tissue. A thermal monitoring system is configured to monitor local temperature changes within the target tissue. An acoustic transducer system controller is configured to control operation of the acoustic transducer system and to control the location of the payload delivery zone. The acoustic transducer system controller is further configured to: (i) operate the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time; (ii) change the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue; and (iii) operate the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period. The focused acoustic energy is sufficiently intense in the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone. The acoustic transducer system controller is further configured to monitor the local temperature changes detected by the thermal monitoring system during the first and second time periods and adjust at least one of the length of first and second time periods and the intensity of the focused acoustic energy to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones.

[ 0008 ] Another aspect of the invention is a computer-readable medium storing processor-executable instructions configured to be executed on a control processor to perform a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone. The method includes: (i) operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time; (ii) changing the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue, the second focal zone being different from the first focal zone and spaced apart from the first focal zone; and (iii)operating the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period. [0009] Yet another aspect of the invention is a computer-readable medium storing processor-executable instructions configured to be executed on a control processor to perform a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone. The method includes: (i) operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time; (ii) changing the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue; (iii) operating the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period; and (iv) adjusting the operation of the acoustic transducer system to change a size of the payload delivery zone.

[0010] Still another aspect of the invention is a computer-readable medium storing processor-executable instructions configured to be executed on a control processor to perform a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone. The method includes: (i) operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time; (ii) changing the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue; (iii) operating the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period; (iv) monitoring local temperature changes during the first and second time periods; and (v) adjusting a length of at least one of the first and second time periods to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones.

[ 0011 ] Another aspect of the invention is a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone. The method includes operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time. The location of the payload delivery zone is changed so that the payload delivery zone coincides with a second focal zone within the target tissue, the second focal zone being different from the first focal zone and spaced apart from the first focal zone. The acoustic transducer system is operated for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period.

[ 0012 ] Still another aspect of the invention is a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone. The method includes operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time. The location of the payload delivery zone is changed so that the payload delivery zone coincides with a second focal zone within the target tissue. The acoustic transducer system is operated for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period. The operation of the acoustic transducer system is adjusted to change a size of the payload delivery zone. [ 0013] Still another aspect of the invention is a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone. The method includes operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time. The location of the payload delivery zone is changed so that the payload delivery zone coincides with a second focal zone within the target tissue. The acoustic transducer system is operated for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period. Local temperature changes are monitored during the first and second time periods. The length of at least one of the first and second time periods is adjusted to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones

[ 0014 ] Other objects and features will be in part apparent and in part pointed out hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

[ 0015] FIG. 1 is a schematic diagram of one embodiment of a payload delivery vehicle;

[ 0016] FIG. 2 is a block diagram of one embodiment of an ultrasound system delivering focused acoustic energy to a target tissue, which is illustrated schematically;

[ 0017 ] FIG. 3 is a schematic diagram of a target tissue receiving focused acoustic energy at a payload delivery zone that substantially corresponds with the entire volume of the target tissue;

[ 0018 ] FIG. 4 is a schematic of one embodiment of a sequence in which a target tissue receives focused acoustic energy over multiple different time periods; and

[ 0019] FIG. 5 is a block diagram of one embodiment of a method of operating an acoustic transducer system to deliver a payload to a target tissue.

[ 0020 ] Corresponding reference characters indicate corresponding parts throughout the drawings. DETAILED DESCRIPTION

[0021] Referring to Fig. 1 , one embodiment of an acoustically-responsive payload delivery vehicle is indicated generally at reference number 10. The payload delivery vehicle 10 contains one or more payload substances 1 1 . The payload delivery vehicle 10 is configured to rupture when it encounters acoustic energy and to thereby release the payload substances 1 1 . Various different payload substances 1 1 can be delivered by the vehicle 10, including without limitation pharmaceuticals, imaging agents, enzymes, nucleic acids, viral vectors, or any other therapeutic or sensing substance. Moreover, the payload delivery vehicle 10 is configured to contain the payload substance 1 1 until such time as it encounters acoustic energy that is adapted to trigger release of the payload substance. This allows ultrasound energy to be used to control the time and/or location at which the payload substance is released to be controlled with high precision and accuracy. Though one preferred payload delivery vehicle 10 is described in detail, it is contemplated that the present invention can be practiced with any suitable payload delivery vehicle that is configured to deliver a payload substance in response to interaction of the payload delivery vehicle and acoustic energy.

[0022] The illustrated payload delivery vehicle 10 has an outer shell 12 that surrounds and contains an aqueous medium 13. One or more payload substances 1 1 and an acoustically-responsive nanoparticle 14 are suspended in the aqueous medium 13. The shell 12 can be made of a variety of different materials. For example, the vehicle 10 can be configured as a liposome-based carrier having a lipid bilayer shell 12. Alternatively, the vehicle 10 can be configured as a polymerosome-based carrier having a polymer material in the shell 12. Likewise, the vehicle 10 can be configured as a biological cell or any other suitable carrier for the payload to be delivered. The shell 12 suitably encapsulates the payload substances 1 1 in the internal volume of the vehicle 10 so the payload substances 1 1 are separated from the external environment by the shell 12 until release of the payload substances is triggered by ultrasound energy.

[0023] The payload delivery vehicle 10 is constructed to release the payload substances 1 1 upon encountering acoustic ultrasound energy. For example, the payload delivery vehicle 10 is suitably structured so interactions between the vehicle and ultrasound energy can rupture the outer shell 12. To illustrate one such interaction, the nanoparticle 14 of the payload delivery vehicle 10 in Fig. 1 is suitably configured to lower the threshold level of ultrasound intensity required to initiate cavitation within the payload delivery vehicle. In particular, the nanoparticle 14 is adapted to act as a nucleation site for acoustic cavitation when it encounters ultrasound energy. The nanoparticle 14 can be adapted to use any of various physical phenomena to facilitate acoustic cavitation, including surface effects that lead to gas cavity initiation at locations on the nanoparticle surface in response to ultrasound pressure, transient formation of a nano-bubble from an emulsion which may also serve as a nucleation site for further cavitation, or similar phenomena that lead to cavitation. Examples of particles that can serve as the nanoparticle 14 include liquid emulsion nanoparticles, metal

nanoparticles, oxide nanoparticles, polymer nanoparticles, biomolecule nanoparticles, a solid particle stabilizing nanoscale pockets of gas, and/or combinations thereof. The payload delivery vehicle 10 is suitably adapted, e.g., by inclusion of a suitable nanoparticle 14, to rupture or otherwise release the payload substances 1 1 in response to an intensity of ultrasound that is lower than an intensity that would result in significant cavitation in the tissue to which the payload substances are to be delivered. The ability to release the payload substances using only a relatively low ultrasound intensity can help limit unwanted damage to tissue.

[ 0024 ] Still referring to Fig. 1 , the outer shell 12 of the vehicle 10 suitably includes protruding molecules 15 that can be used to functionalize the vehicle so large numbers of such vehicles preferentially accumulate at a desired location within a broader target, such as within a tumor region of the body or an organ thereof. For example, the protruding molecules 15 are suitably tumor-targeting ligands that preferentially accumulate in a tumor region, rather than at other non-tumor tissues. The protruding molecules 15 can functionalize the vehicles 10 in other ways, such as by limiting or enhancing uptake from particular tissues, organs or systems, such as the immune system or the liver. Additional details concerning suitable payloads and payload delivery vehicles are provided in U.S. Pre-grant Patent Application Publication No.

2014/0046181 , the contents of which are incorporated by reference.

[ 0025 ] Referring to Fig. 2, an ultrasound system for delivering a payload substance to a target tissue T via acoustically-responsive payload delivery vehicles, such as, for example, the payload delivery vehicle 10 described above, is indicated generally at reference number 20. The ultrasound system 20 includes an acoustic transducer system 22 configured to deliver focused acoustic energy to a payload delivery zone 24 inside a body B containing the target tissue T. The ultrasound system 20 also has an acoustic transducer system controller 26 configured to control operation of the acoustic transducer system 22. In particular, the acoustic transducer system controller 26 is configured to operate the transducer system 22 so ultrasound energy is directed toward and focused within a focal zone 28 and also to control the position of the focal zone so it coincides with the payload delivery zone 24, as illustrated in Fig. 2.

[ 0026 ] The ultrasound system 20 is configured to deliver focused acoustic energy from the acoustic transducer system 22 into the focal zone 28, and therefore into the payload delivery zone 24, that is sufficiently intense to trigger release of the payload substances 1 1 from at least some of the payload delivery vehicles 10 inside the payload delivery zone. For example, the focused acoustic energy delivered by the acoustic transducer system 22 is suitably sufficiently intense to produce cavitation associated with the nanoparticles 14 and thereby rupture the outer shells 12 of payload delivery vehicles 10 located in the payload delivery zone 24 to release the payload substances 1 1 at the payload delivery zone 24. The ultrasound system 20 is also configured so the acoustic energy delivered by the acoustic transducer system 22 is sufficiently weak outside the payload delivery zone 24 to substantially avoid triggering release of the payload substances 1 1 from the payload delivery vehicles 10 outside the payload delivery zone. It is understood that there may be a gradual drop-off in the intensity of the acoustic energy and that this may result in a transition at the margin of the payload delivery zone 24 where a substantial fraction of the payload delivery vehicles 10 are triggered to release their payloads and another substantial fraction of the payload delivery vehicles are not triggered to release their payloads. It is also understood that the technology described herein can be successful at delivering a payload to the target T even if some of the payload delivery vehicles 10 that are inside the payload delivery zone 24 during delivery of the acoustic energy are not ruptured and/or if some of the payload delivery vehicles rupture outside the payload delivery zone, either because of exposure to weak acoustic energy or other reasons.

[ 0027 ] As illustrated in Fig. 2, the acoustic transducer system 22 includes an array of transducers 30 that are each configured to emit ultrasonic energy W. Examples of suitable ultrasonic transducers 30 include piezoelectric materials that convert electrical energy into acoustic energy W. Other transducers that convert electrical, mechanical, or other energy into acoustic energy can also be used. The transducers 30 are suitably configured to produce an ultrasonic beam or plurality of ultrasonic beams that direct focused acoustic energy to the focal zone 28 and the payload delivery zone 24. Preferably, the ultrasound system 20 is configured to change the size, shape, and/or focal distance of the beam(s) produced by the ultrasonic transducers 30 to spatially adjust the focal zone 28 (e.g., in size, shape, and/or location) and thereby allow corresponding adjustment(s) to the payload delivery zone 24.

[ 0028 ] As illustrated in Fig. 2, the ultrasonic transducers 30 are arranged in an array. For example, the array of transducers 30 is suitably a phased array. In a phased array the waves from different transducers 30 interfere with one another. The controller 26 is suitably configured to control the timing of acoustic wave generation by each individual transducer 30 to control where constructive and destructive interference of the acoustic waves occurs. In this way, the controller 26 is adapted to control the size, shape, and/or focal distance of the beam or beams of acoustic energy produced by the acoustic transducer system 22. Controlling the size, shape, and/or focal distance of the beam(s) produced by the transducer system 22 is generally known as "steering" the beam(s). Although the controller 26 in the illustrated embodiment uses beam steering to change the location of the focal zone 28, it is understood that the controller 26 could be configured to redirect ultrasound energy by moving the transducers (either in addition to or instead of beam steering) within the scope of the invention. Also, the size, shape, and/or focal distance of the beam(s) produced by the acoustic transducer system 22 can be controlled and/or adjusted in other ways without departing from the scope of the invention.

[ 0029 ] The ultrasound system 20 illustrated in Fig. 2 also includes a thermal monitoring system 34 and an imaging system 36. The thermal monitoring system 34 is configured to monitor a local temperature increase associated with the focused acoustic energy. For example, the thermal monitoring system 34 is suitably configured to monitor the local temperature of the tissue T and provide temperature data to the acoustic transducer system controller 26 when focused acoustic energy is directed into the focal zone 28. Suitable thermal monitoring systems include the MR-thermometry systems included in the ExAblate® system from InSightec and the Sonalleve® system from Philips Heathcare. Another example of a suitable thermal monitoring system is a backscatter temperature imaging system that detects heat-induced echo strain to assess temperature rise associated with application of ultrasound energy. The imaging system 36 is suitably configured to detect a phenomenon associated with release of the payload substances 1 1 from the payload delivery vehicles 10 that are in the target tissue T. For example, the imaging system 36 can be configured to detect cavitation associated with the release of the payload substances 1 1 (e.g., using passive cavitation detection). Likewise, the imaging system 36 can, in addition or in the alternative, be configured for imaging microbubbles generated by the cavitation. The imaging system 36 can detect still other phenomena associated with the release of the payload substances 1 1 from the payload delivery vehicles 10 without departing from the scope of the invention.

[ 0030 ] Referring to Fig. 3, the ultrasound system 20 can be configured to deliver focused acoustic energy to a payload delivery zone 24 and focal zone 28 that substantially correspond with the entire volume of the target tissue T. The focused acoustic energy heats the tissue T in the payload delivery zone 24 and thereby raises the temperature of the tissue T. The acoustic transducer system 22 is suitably switched on and off repeatedly such that acoustic energy is delivered for a period of time and then not delivered for a subsequent period of time to prevent damage to the tissue from the heating. Although this delivers the payload substances 1 1 to the payload delivery zone 24, the duty cycle (i.e., the percentage of time acoustic energy is being delivered to the payload delivery zone 24) must be kept very low to provide sufficient time for heat dissipation to avoid damaging the tissue T. This can lead to an undesirably long overall treatment time. Further, acoustic energy will often be delivered outside the volume of the tissue T or will not be delivered to the entire volume of the tissue T, as illustrated in Fig. 3. Moreover, as illustrated by the relative shading densities of Fig. 3, use of a single payload delivery zone 24 for the entire volume of tissue T can make it difficult to apply equal amounts of acoustic energy to all portions of the target tissue T. For example, the acoustic energy may be considerably stronger at the central region of the payload delivery zone 24 than at the marginal regions. This can cause different portions of a target tissue T to be treated at different levels of effectiveness.

[0031] The delivery mode illustrated in Fig. 3 is only one way the system 20 can be configured. The system 20 can be configured to focus acoustic energy into a smaller volume that is substantially smaller than the size of the target T and sequentially adjust the position of the focal zone to deliver focused acoustic energy to different locations in the tissue T at different times. Referring to Fig. 4, for instance, the acoustic transducer system controller 26 is suitably configured to control the acoustic transducer system 22 to focus acoustic energy into a first focal zone 28A to trigger release of the payloads 1 1 from vehicles 10 in a first payload delivery zone 24A within the target tissue T during a first period of time, then change the location of the focal zone, and direct focused acoustic energy into the second focal zone 28B to trigger release of the payloads 1 1 from vehicles 10 in a second payload delivery zone 24B within the target tissue T during a second period of time. The system 10 is suitably configured to repeat this process until the entire target T has been treated. Thus, in addition to the first and second time periods, Fig. 4 illustrates an n^th time period during which the acoustic transducer system 22 is directed by the controller to focus acoustic energy into a n^th focal zone 28N to trigger release of the payloads 1 1 from vehicles 10 in an n^th payload delivery zone 24N within the target tissue T. Figure 4 also illustrates how the acoustic transducer system 22 is directed to focus acoustic energy into several additional focal zones to release payloads from payload vehicles 10 in additional payload delivery zones between the first and second time periods (unlabeled zones on diagram for second period) and between the second and n^th time periods (unlabeled zones on diagram for third time period). Moreover, Fig. 4 illustrates how

substantially the entire target T is treated by the cumulative effects of this sequence.

[0032] As illustrated in Fig. 4, the second focal zone 28B is spaced apart from the first focal zone 28A. Although the spacing between the first focal zone 28A and the second focal zone 28B is illustrated schematically in two dimensions in Fig. 4, the tissue T is three- dimensional and the focal zones and payload delivery zones can be spaced in any of the three dimensions. Similarly, each subsequent focal zone and each subsequent payload delivery zone is suitably spaced apart from its immediate predecessor. The controller 26 is suitably configured to operate the transducer system 22 to cause the beam of focused acoustic energy to "hop" from one focal zone to the next. "Hopping" means that the focused acoustic energy is not swept across the tissue. Rather, the focused acoustic energy is delivered to one focal zone (comprising one or more focal regions) at one point in time and then the system 20 moves the beam of focused energy to another focal zone that is at least partially spaced apart from the first focal zone while substantially avoiding application of acoustic energy to areas between the two focal zones. Accordingly, the system 20 is suitably configured to move the beam of focused acoustic energy using this hopping technique to move the acoustic energy sequentially to different parts of the target T until treatment is complete. Although the technique described in detail above involves a single beam of focused acoustic energy at any particular time, it is understood that the controller 26 can be configured to produce multiple beams of focused acoustic energy at the same or during overlapping time periods (e.g., using multiple phased transducer arrays and/or by using subsets of transducers within a single phased array to generate multiple independently steerable beams). In such case, each beam can suitably hop from one focal zone to the next until the multiple beams have collectively treated the entire target T.

[ 0033 ] In addition to moving the focal zone, it can be desirable in some cases to change the size and/or shape of the focal zone (and therefore the size and/or shape of the payload delivery zone) as the beam hops from one location to the next. Thus, the controller 26 is suitably adapted to adjust the operation of the acoustic transducer system 22 to change a size and/or shape of the focal zone 28 and thereby change the size and/or shape of the payload delivery zone 24. Referring to Fig. 4, for example, the first focal zone 28A and the first payload delivery zone 24A are relatively larger while the second focal zone 28B and second payload delivery zone 24B are relatively smaller. For example, the acoustic transducer system controller 26 suitably uses a larger payload delivery zone 24 when the focal zone (e.g., the focal zone 28A) is at a central location in the target tissue T and uses a smaller payload delivery zone when the focal zone (e.g., the focal zone 28B) is located at a margin of the target tissue. In this way, focused acoustic energy can be quickly and accurately applied to the entire volume of an irregularly shaped tissue T without applying focused acoustic energy outside the volume of the target tissue T to limit delivery of payload to the body B except within the target tissue. This can be desirable, for instance, when the target tissue T is a tumor or other undesirable tissue that is in close proximity to non-target tissue such as a nerve.

[ 0034 ] Using different sizes of payload delivery zones 24 at different times can make it desirable to adjust the amount of acoustic energy generated by the transducer system to ensure the focused acoustic energy in the payload delivery zone is sufficiently intense throughout the zone to release a payload substance (e.g., payload substance 1 1 ) from at least some of the payload delivery vehicles (e.g., payload delivery vehicle 10) inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the payload substances from the payload delivery vehicles outside the payload delivery zone. Accordingly, the acoustic transducer system controller 26 is suitably configured to adjust the amount of acoustic energy generated by the acoustic transducer system 22 whenever the size of the payload delivery zone 24 is changed so that the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the payload substances from payload delivery vehicles inside the payload delivery zone. The energy adjustment also ensures the acoustic energy produced by the acoustic transducer system 22 is sufficiently weak outside the payload delivery zone to substantially avoid releasing the payload substances from the payload delivery vehicles outside the payload delivery zone. In addition, the acoustic transducer system controller 26 can change the amount of energy for other reasons (e.g., changes in the tissue density of successive focal zones, etc.).

[ 0035 ] When the ultrasound system 20 directs acoustic energy to any payload delivery zone in any of the focal zones (e.g., 28A, 28B, 28N), it heats the tissue in the zone, creating a respective heated zone (e.g., 32A, 32B, 32N). The heated zones 32A, 32B, 32N are located generally at the respective focal zones 28A, 28B, 28N. In the illustrated example, the heated zones 32A, 32B, 32N are slightly larger than the focal zones. Depending on the nature of the tissue T, amount of energy supplied thereto, etc., the heated zones 32A, 32B, 32N can also be the same size or smaller than the respective focal zones 28A, 28B, 28N. The heated zones 32A, 32B, 32N can remain and recede (e.g., in size or temperature) for a period of time after energy stops being delivered to a respective payload delivery zone 24. The ultrasound system 20 is suitably tuned so the focused acoustic energy does not increase the temperature of the target tissue T in any focal zone (e.g., 228A, 228B, 228N) by an amount sufficient to damage the target tissue. For example, the ultrasound system 20 is suitably tuned so the focused acoustic energy does not increase the temperature of the target tissue T in any focal zone 28A, 28B, 28N by more than about three degrees Celsius.

[ 0036 ] The acoustic transducer system controller 26 is suitably configured to change the location of the payload delivery zone 24 to the n^th focal zone 28N (for each value of n) so that the n^th heated zone 32N is spaced apart from the (n-1 )^th heated zone a sufficient distance so the n^th heated zone is not heated (or only negligibly heated) by the acoustic energy applied to the (n-1 )^th payload delivery zone and vice-versa. As a result, heating of each zone 32N is substantially isolated from heating of the preceding and subsequent zones. The acoustic transducer system controller 26 can also be configured to change the location of the payload delivery zone 24 to the n^th focal zone 28N (for each value of n) so the n^th heated zone 32N is spaced sufficiently apart from the (n-2)^th heated zone to isolate heating associated with each zone from heating of multiple preceding and subsequent zones. This can be extended to the (n- 3)^th heated zone, (n-4)^th heated zone, and so on to the extent necessary to prevent overheating any portion of the target tissue T..

[ 0037 ] The acoustic transducer system controller 26 is suitably configured to change the location of the payload delivery zone 24 to coincide with the n^th focal zone 28N to substantially avoid moving the location of the payload delivery zone to a location that results in the n^th heated zone 32N overlapping a previous heated zone until after heat added to the previous heated zone has substantially dissipated. For example, the acoustic transducer system controller 26 can be configured to change the location of the payload delivery zone 24 to coincide with the n^th focal zone 28N to substantially avoid moving the location of the payload delivery zone to a location that results in the n^th heated zone 32N overlapping a previous heated zone until after blood has perfused the previous heated zone causing the tissue to cool and/or the heat to be carried away from the heated zone by the blood.

[ 0038 ] The ultrasound system 20 can, for example, be configured to use the thermal monitoring system 34 to detect the boundaries of a heated zone (e.g., the (n-2)^th, (n-1 )^th, n^th heated zones, etc.). In addition or in the alternative, the acoustic transducer system controller 26 can be configured to calculate the size and location of a heated zone (e.g., the (n-2)^th, (n- 1 )^th, n^th heated zones, etc.) based on information about the boundaries of the respective payload delivery zone 24, the amount of acoustic energy delivered, the length of the period of time over which the energy was delivered, the passage of time since the acoustic transducer system 22 stopped delivering acoustic energy, the type of tissue constituting the target tissue T, etc. The acoustic transducer system controller 26 is suitably configured to use this information to determine a suitable location for the next focal zone (e.g., a location that does not overlap a previous heated zone in which the heat has not sufficiently dissipated sufficiently).

[ 0039 ] Although heating is generally undesirable in most cases, there are applications in which mild heating can facilitate treatment. Thus, the acoustic transducer system controller 26 is suitably configured to operate the acoustic transducer system 22 to heat the target tissue T in the payload delivery zone 24 by at least a threshold amount of heating. The threshold amount of heating can be effective, for example, to produce a change in the target tissue T that facilitates at least one of: uptake of the substance by the target tissue, diffusion of the substance into the target tissue, and stimulation of a local immune response. The system 20 is suitably configured to allow a user to selectively switch back and forth between a heating mode in which the controller 26 operates the transducer system 22 to heat the target tissue T and a non-heating mode in which the controller operates the transducer system 22 to substantially avoid or limit heating of the target tissue, as described above. However, it is understood the system can be configured to operate in only a single mode (heating or non- heating) within the scope of the invention.

[ 0040 ] In addition to the features discussed above, the acoustic transducer system controller 26 is suitably configured to adjust an acoustic energy flux generated by the acoustic transducer system 22 in the focal zone (i.e., the amount of acoustic energy per unit volume). For example, the energy flux may be increased in order to switch from a non-heating mode to a heating mode. Further, the controller 26 is suitably configured to receive feedback about operation of the system 20 and adjust the acoustic energy flux in response to the feedback. For example, the controller 26 is suitably configured to monitor a phenomenon associated with release of the payload (e.g., detection of cavitation by the imaging system 36) and adjust the acoustic energy flux in response thereto. Thus, if the controller 26 determines there is a relatively low amount of payload being released (e.g., because there is only a low level of cavitation being detected) it could increase the acoustic energy insensity in an attempt to increase the amount of payload being released. Likewise, if the controller 26 determines there is too much payload being released and/or that there is too much heating (e.g., using information from the thermal monitoring system it could decrease the acoustic intensity.

[0041] The system 20 is also suitably configured to adjust the length of at least one of the first and second time periods as needed. The first, second, and n^th time periods can vary depending on the size of the payload delivery zone 24, and/or the acoustic energy flux of the energy delivered to the payload delivery zone to ensure that an amount of energy is delivered to the payload delivery zone to cause at least some of the payload delivery vehicles (e.g., payload delivery vehicle 10) thereat to rupture and that does not cause the tissue T to overheat. By changing the location of the payload delivery zone 24 as discussed above, the acoustic transducer system controller 26 can operate the acoustic transducer system 22 at an improved duty cycle with respect to the duty cycle associated with the single-location payload delivery zone of Fig. 3.

[0042] The system 20 is suitably configured to display information from the imaging system 36 and/or thermal monitoring system 34 (e.g., on a computer monitor). For example, the system 20 is suitably configured to display an image of the tissue T along with an indicator (e.g., a color change) showing where the imaging system 36 has detected release of the payload substances to help track areas within the target tissue T that have received the payload. Additionally or alternatively, the system 20 is suitably configured to display an image of the tissue T along with an indicator indicating a current temperature distribution and/or distribution of accumulated heating of the tissue T associated with a procedure involving use of the system 20.

[0043] The acoustic transducer system controller 26 suitably includes a control processor and a computer-readable medium in communication with the processor. Control instructions are stored on the computer-readable medium and executed by the control processor of the system controller 26 to control the acoustic transducer system 22. The processor suitably communicates with the acoustic transducer system 22 (e.g., by selectively addressing the ultrasonic transducers 30) to execute the control instructions thereupon. It will be understood that the control processor can include one or more processing elements and that functions of the control processor can be executed on different processing elements. Likewise, it will be understood that the processor-executable control instructions can be stored on one or more storage mediums physically located at or remote from the control processor.

Although it is contemplated that the controller 26 is suitably programmed software to configure the system as described above and/or to perform the methods described below, it is understood that other options, including use of hardware, firmware, and/or other processing devices is within the scope of the invention.

[ 0044 ] Referring to Fig. 5, one embodiment of a method 200 of controlling an acoustic transducer system 22 of an ultrasound system 20 includes delivering focused acoustic energy from the acoustic transducer system 22 to a spatially adjustable payload delivery zone 24 inside a body containing target tissue T to deliver a payload substance (e.g., payload substance 1 1 ) from a payload delivery vehicle (e.g., payload delivery vehicle 10). The following description discusses the method 200 as being implemented in the acoustic transducer system controller 26. However, it should also be understood that the method can also be implemented other ways without departing from the scope of the invention.

[ 0045 ] In a first step 210 of the method 200, the acoustic transducer system controller 26 operates the acoustic transducer system 22 for a first period of time during which the payload delivery zone 24 is positioned coincident with a first focal zone 28A within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time. In a second step 220, the acoustic transducer system controller 26 changes the payload delivery zone 24 so that the payload delivery zone coincides with a second focal zone 28B within the target tissue. For example, the acoustic transducer system controller 26 can change the location of the payload delivery zone 24 so the second focal zone 28B is different from and spaced apart from the first focal zone 28A. The acoustic transducer system controller 26 can change the location of the payload delivery zone 24 by electronically steering the focused energy (e.g., by causing a focused beam of acoustic energy to "hop" from the first focal zone 28A to the second focal zone 28B)or by moving the acoustic transducer system 22 physically.

[ 0046 ] At step 220, the acoustic transducer system controller 26 changes the size of the payload delivery zone 24. For example, the acoustic transducer system controller 26 suitably uses a relatively larger payload delivery zone 24 when the focal zone is at a central location in the target tissue T and uses a relatively smaller payload delivery zone when the focal zone is located at a margin of the target tissue. In addition, the acoustic transducer system controller 26 suitably adjusts acoustic intensity generated by the acoustic transducer system 22 whenever the size of the payload delivery zone 24 is changed so that the focused acoustic intensity is sufficiently intense throughout the payload delivery zone to release the substance (e.g., the payload substance 1 1 ) from at least some of the payload delivery vehicles (e.g., the payload delivery vehicle 10) inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

[ 0047 ] At step 230, the acoustic transducer system controller 26 operates the acoustic transducer system 22 for a second period of time during which the payload delivery zone 24 is positioned coincident with the second focal zone 28B to deliver the focused acoustic energy to the second focal zone for the second time period.

[ 0048 ] At step 240, the acoustic transducer system controller 26 changes the location of the payload delivery zone 24 after the second time period so that the payload delivery zone coincides with an n^th focal zone 28N within the target tissue T. For example, the controller 26 suitably selects a focal zone 28N that is spaced apart from the previous focal zone. The controller 26 suitably uses beam steering (e.g., "hopping") to redirect the acoustic energy to the next focal zone 28N. At step 250, the acoustic transducer system controller 26 operates the acoustic transducer system 22 for an n^th period of time during which the payload delivery zone 24 is positioned coincident with the n^th focal zone 28N to deliver the focused acoustic energy to the n^th focal zone for the n^th period of time. At decision block 260, the acoustic transducer system controller 26 determines whether substantially the entire target tissue T has been within the payload delivery zone 24 while the focused acoustic energy is delivered to the payload delivery zone. If not, the acoustic transducer system controller 26 repeats steps 240 and 250 until substantially the entire target tissue T has been within the payload delivery zone 24 while the focused acoustic energy is delivered to the payload delivery zone.

[ 0049 ] Referring to steps 210, 230, and 250, when the acoustic transducer system controller 26 operates the acoustic transducer system 220 to deliver focused acoustic energy to the payload delivery zone 24, it can simultaneously perform any of several other optional steps 270. For example, the acoustic transducer system controller 26 can perform step 272 to monitor a local temperature increase associated with the focused acoustic energy (e.g., using a temperature measurement taken by the temperature monitoring system 34 or using information about the nature of target tissue T, the amount of acoustic energy supplied to the tissue, the length of the period of time over which the energy has been applied, etc.). Likewise, the acoustic transducer system controller 26 can perform step 274 to operate the acoustic transducer system 22 to heat the target tissue T in each of the payload delivery zones 24 by at least a threshold amount of heating. The threshold amount of heating can, for example, be effective to produce a change in the target tissue T that facilitates at least one of: uptake of the substance by the target tissue, diffusion of the substance into the target tissue, and stimulation of a local immune response. [0050] During steps 210, 230, and 250, the acoustic transducer system controller 26 can also perform step 276 to detect a phenomenon associated with release of a payload substance (e.g., the payload substance 1 1 ) from the payload delivery vehicles (e.g., the payload delivery vehicle 10). For example, the transducer system controller 26 can receive an indication of a phenomenon associated with release of a payload substance (e.g., the payload substance 1 1 ) from the payload delivery vehicles (e.g., the payload delivery vehicle 10) from the imaging system 36. The acoustic transducer system controller 26 can detect, for example, passive cavitation associated with the release of the substance from the payload delivery vehicles and/or micro bubbles generated from cavitation associated with the release of the substance from the payload delivery vehicles. The controller 26 can suitably track which portions of the target tissue T have produced the phenomenon to help ensure the entire target tissue receives the desired amount of payload 1 1. Also, if necessary the controller 26 suitably adjusts the acoustic energy intensity in response to the amount of the phenomenon detected.

[0051] When changing the location of the payload delivery zone 24 in either of steps 220, 240, the acoustic transducer system controller 26 can simultaneously perform one or more of the additional steps 280. For example, the acoustic transducer system controller 26 can perform the step 282 to change the location of the payload delivery zone 24 during step 240 so that the n^th heated zone (in Fig. 4, heated zone 32N) is spaced apart from the (n-1 )^th heated zone (in Fig. 4, the second heated zone 32B). In addition, the acoustic transducer system controller 26 can perform the step 284 to change the location of the payload delivery zone 24 during step 240 so that the n^th heated zone (in Fig. 4, heated zone 32N) is spaced from the (n- 2)^th heated zone (in Fig. 4, the first heated zone 32A). This can be extended to the (n-3)^th heated zone to the extent necessary to ensure heat has sufficiently dissipated from any previously heated zone before heat is applied to an adjacent part of the target tissue T. The acoustic transducer system controller 26 can also perform the step 286 during the changing step 240. At step 286, the acoustic transducer system controller 26 changes the location of the payload delivery zone 24 to substantially avoid moving the location of the payload delivery zone to a location that results in the n^th heated zone 232N overlapping a previous heated zone until after heat added to the previous heated zone has dissipated.

[0052] In addition to changing the location of the payload delivery zone 24, the acoustic transducer system controller 26 can also adjust other aspects of the delivery of focused acoustic energy in steps 220 and 240. For example, the acoustic transducer system controller 26 can execute a step 288 that adjusts an acoustic energy flux generated by the acoustic transducer system 22. Likewise, the acoustic transducer system controller 26 can perform a step 290 to adjust the length of one of the time periods over which acoustic transducer system 22 delivers focused acoustic energy to the payload delivery zone 24 (e.g., the first time period during which the acoustic transducer system controller operates the acoustic transducer system at step 210, the second time period during which the acoustic transducer system controller operates the acoustic transducer system at step 230, or the n^th time period during which the acoustic transducer system controller operates the acoustic transducer system at step 250). Further, the controller 26 suitably adjusts at least one of the acoustic intensity, the acoustic energy flux, and the length of the time period during which acoustic energy is applied to a payload delivery zone 24 in response to feedback including, for example, information about the amount of the phenomenon associated with release of the payload 1 1 (e.g., from the imaging system 36) and/or information about the amount of heating in the target tissue T (e.g., from the thermal monitoring system 34).

[ 0053 ] Having described some embodiments of the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention. Those skilled in the art will appreciate that the particular features of the examples discussed in detail herein can be omitted, altered, repeated, and/or combined with other techniques as needed or desired for a particular therapeutic application. Thus, depending on the nature and size of the tissue, characteristics of the payload delivery vehicles and payload substances, etc., various modifications to the use of the ultrasound system 20 can be made. The features illustrated in the examples herein are not to be understood to limit the capabilities of the ultrasound system. Rather, they should be understood to be exemplary of the capabilities of the ultrasound system 20 that can be adapted to suit a particular therapeutic application.

[ 0054 ] When introducing elements of the embodiments described herein, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[ 0055 ] As various changes could be made in the above systems and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

WHAT IS CLAIMED IS:

1 . An ultrasound system for delivering a substance to a target tissue via

acoustically responsive payload delivery vehicles, the ultrasound system comprising:

an acoustic transducer system configured to deliver focused acoustic energy to a spatially adjustable payload delivery zone inside a body containing the target tissue; and

an acoustic transducer system controller configured to control operation of the acoustic transducer system and to control the location of the payload delivery zone, wherein the acoustic transducer system controller is further configured to:

operate the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time;

change the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue, the second focal zone being different from the first focal zone and spaced apart from the first focal zone; and

operate the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period,

wherein the ultrasound system is configured so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

2. An ultrasound system for delivering a substance to a target tissue via

change the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue; and operate the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period,

wherein the acoustic transducer system controller is further configured to adjust the operation of the acoustic transducer system to change a size of the payload delivery zone, the focused acoustic energy being sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

3. An ultrasound system for delivering a substance to a target tissue via

an acoustic transducer system configured to deliver focused acoustic energy to a spatially adjustable payload delivery zone inside a body containing the target tissue;

a thermal monitoring system configured to monitor local temperature changes within the target tissue; and

change the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue; and

wherein the focused acoustic energy is sufficiently intense in the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone, and wherein the acoustic transducer system controller is further configured to monitor the local temperature changes detected by the thermal monitoring system during the first and second time periods and adjust length of at least one of the first and second time periods and the intensity of the focused acoustic energy to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones.

4. An ultrasound system as set forth in any one of claims 1 through 3 wherein the acoustic transducer system controller is further configured to:

(a) change the location of the payload delivery zone after the second time period so that the payload delivery zone coincides with an n^th focal zone within the target tissue; and

(b) operate the acoustic transducer system for an n^th period of time during which the payload delivery zone is positioned coincident with the n^th focal zone to deliver the focused acoustic energy to the n^th focal zone for the n^th period of time;

wherein the acoustic transducer system controller is further configured to repeat steps

(a) and (b) until substantially the entire target tissue has been within the payload delivery zone while the focused acoustic energy is delivered to the payload delivery zone.

5. An ultrasound system as set forth in any one of claims 1 through 4 wherein the ultrasound system is tuned so the focused acoustic energy does not increase the temperature of the tissue in any focal zone more than about three degrees Celsius.

6. An ultrasound system as set forth in either one of claims 4 and 5 wherein delivering the focused acoustic energy to the payload delivery zone when it is coincident with the n^th focal zone results in a temperature increase within an n^th heated zone of the target tissue and the acoustic transducer system controller is further configured to change the location of the payload delivery zone during step (a) so that the n^th heated zone is spaced apart from the (n- 1 )^th heated zone.

7. An ultrasound system as set forth in claim 6 wherein the acoustic transducer system controller is further configured to change the location of the payload delivery zone during step (a) so that the n^th heated zone is spaced from the (n-2)^th heated zone.

8. An ultrasound system as set forth in claim 7 wherein the acoustic transducer system controller is further configured to change the location of the payload delivery zone during step (a) to substantially avoid moving the location of the payload delivery zone to a location that results in the n^th heated zone overlapping a previous heated zone until after heat added to the previous heated zone has dissipated.

9. An ultrasound system as set forth in any one of claims 5 through 8 wherein the acoustic transducer system controller is configured to operate the acoustic transducer system at a duty cycle of at least about .01 % but less than about 10% without producing a temperature increase of more than about 3 degrees Celcius anywhere within the target tissue.

10. An ultrasound system as set forth in any one of claims 1 through 9 wherein the acoustic transducer system comprises a phased array of electrically addressable acoustic transducer elements.

1 1 . An ultrasound system as set forth in any one of claims 1 through 10 wherein the acoustic transducer system controller is configured to move the payload delivery zone by electronically steering the focused energy.

12. An ultrasound system as set forth in any one of claims 1 through 1 1 wherein the acoustic transducer system controller is configured to move the acoustic transducer system.

13. An ultrasound system as set forth in either one of claims 1 and 3 wherein the transducer system controller is configured to change the size of the payload delivery zone.

14. An ultrasound system as set forth in either one of claims 2 or 13 wherein the acoustic transducer system controller is configured to use a relatively larger payload delivery zone when the focal zone is at a central location in the target tissue and use a relatively smaller payload delivery zone when the focal zone is located at a margin of the target tissue.

15. An ultrasound system as set forth in any one of claims 2, 13, and 14 wherein the acoustic transducer system controller is configured to adjust the amount of acoustic energy generated by the acoustic transducer system whenever the size of the payload delivery zone is changed so that the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

16. An ultrasound system as set forth in any one of claims 2 and 13 through 15 wherein the acoustic transducer system controller is configured to change the size of the payload delivery zone by changing the way acoustic energy generated by the acoustic transducer system is focused.

17. An ultrasound system as set forth in any one of claims 1 through 16 wherein the acoustic transducer system controller is configured to adjust an acoustic intensity and/or acoustic energy flux generated by the acoustic transducer system.

18. An ultrasound system as set forth in any one of claims 1 through 17 wherein the acoustic transducer system controller is configured to adjust the length of at least one of the first and second time periods.

19. An ultrasound system as set forth in any one of claims 1 through 18 further comprising an imaging system configured to detect a phenomenon associated with release of the substance from the payload delivery vehicles.

20. An ultrasound system as set forth in claim 19 wherein the imaging system is configured for imaging cavitation associated with the release of the substance from the payload delivery vehicles using passive cavitation detection.

21 . An ultrasound system as set forth in either one of claims 19 and 20 wherein the imaging system is configured for imaging of microbubbles generated from cavitation associated with the release of the substance from the payload delivery vehicles.

22. An ultrasound system as set forth in either one of claims 1 and 2 wherein the acoustic transducer system controller is configured to operate the acoustic transducer system to heat the target tissue in the payload delivery zone by at least a threshold amount of heating, wherein the threshold amount of heating is effective to produce a change in the target tissue that facilitates at least one of: uptake of the substance by the target tissue, diffusion of the substance into the target tissue, and stimulation of a local immune response.

23. An ultrasound system as set forth in claim 22 further comprising a thermal monitoring system configured to monitor a local temperature increase associated with the focused acoustic energy.

24. A computer-readable medium storing processor-executable instructions configured to be executed on a control processor to perform a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone, the method comprising:

operating the acoustic transducer system for a first period of time during which the payload delivery zone is positioned coincident with a first focal zone within the target tissue to deliver the focused acoustic energy to the first focal zone for the first period of time;

changing the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue, the second focal zone being different from the first focal zone and spaced apart from the first focal zone; and

operating the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period.

25. A computer-readable medium storing processor-executable instructions configured to be executed on a control processor to perform a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone, the method comprising:

changing the location of the payload delivery zone so that the payload delivery zone coincides with a second focal zone within the target tissue;

operating the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period; and

adjusting the operation of the acoustic transducer system to change a size of the payload delivery zone.

26. A computer-readable medium storing processor-executable instructions configured to be executed on a control processor to perform a method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone, the method comprising:

operating the acoustic transducer system for a second period of time during which the payload delivery zone is positioned coincident with the second focal zone to deliver the focused acoustic energy to the second focal zone for the second time period;

monitoring local temperature changes during the first and second time periods; and adjusting a length of at least one of the first and second time periods to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones.

27. A computer readable medium as set forth in claim 26 wherein the method further comprises adjusting the intensity of the focused acoustic energy to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones.

28. A computer-readable medium as set forth in any one of claims 24 through 27 wherein the method further comprises:

(a) changing the location of the payload delivery zone after the second time period so that the payload delivery zone coincides with an n^th focal zone within the target tissue;

(b) operating the acoustic transducer system for an n^th period of time during which the payload delivery zone is positioned coincident with the n^th focal zone to deliver the focused acoustic energy to the n^th focal zone for the n^th period of time; and

repeating steps (a) and (b) until substantially the entire target tissue has been within the payload delivery zone while the focused acoustic energy is delivered to the payload delivery zone.

29. A computer-readable medium as set forth in any one of claims 24 through 28 wherein the ultrasound system is tuned so the focused acoustic energy does not increase the temperature of the tissue in any focal zone more than about three degrees Celsius.

30. A computer-readable medium as set forth in either one of claims 28 and 29 wherein delivering the focused acoustic energy to the payload delivery zone when it is coincident with the n^th focal zone results in a temperature increase within an n^th heated zone of the target tissue and the acoustic transducer system controller is further configured to change the location of the payload delivery zone during step (a) so that the n^th heated zone is spaced apart from the (n-1 )^th heated zone.

31 . A computer-readable medium as set forth in claim 30 wherein the method further comprises changing the location of the payload delivery zone during step (a) so that the n^th heated zone is spaced from the (n-2)^th heated zone.

32. A computer-readable medium as set forth in claim 31 wherein the method further comprises changing the location of the payload delivery zone during step (a) to substantially avoid moving the location of the payload delivery zone to a location that results in the n^th heated zone overlapping a previous heated zone until after heat added to the previous heated zone has dissipated.

33. A computer-readable medium as set forth in any one of claims 29 through 32 wherein the method further comprises operating the acoustic transducer system at a duty cycle of at least about .01 % but less than about 10% without producing a tempera increase of more than about 3 degrees Celsius anywhere within the target tissue.

34. A computer-readable medium as set forth in any one of claims 24 through 33 wherein the acoustic transducer system comprises a phased array of electrically addressable acoustic transducer elements.

35. A computer-readable medium as set forth in any one of claims 24 through 34 wherein the method further comprises moving the payload delivery zone by electronically steering the focused energy.

36. A computer-readable medium as set forth in any one of claims 24 through 35 wherein the method further comprises moving the acoustic transducer system.

37. A computer-readable medium as set forth in either one of claims 24 and 26 wherein the method further comprises changing the size of the payload delivery zone.

38. A computer-readable medium as set forth in either one of claims 25 and 37 wherein the method further comprises using a relatively larger payload delivery zone when the focal zone is at a central location in the target tissue and using a relatively smaller payload delivery zone when the focal zone is located at a margin of the target tissue.

39. A computer-readable medium as set forth in any one of claims 24, 37, and 38 wherein the method further comprises adjusting the acoustic intensity generated by the acoustic transducer system whenever the size of the payload delivery zone is changed so that the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

40. A computer-readable medium as set forth in any one of claims 25 and 37 through 39 wherein the method further comprises changing the size of the payload delivery zone by changing the way acoustic energy generated by the acoustic transducer system is focused.

41 . A computer-readable medium as set forth in any one of claims 24 through 40 wherein the method further comprises adjusting an acoustic energy flux generated by the acoustic transducer system.

42. A computer-readable medium as set forth in any one of claims 24 through 41 wherein the method further comprises adjusting the length of at least one of the first and second time period.

43. A computer-readable medium as set forth in any one of claims 24 through 42 wherein the method further comprises detecting a phenomenon associated with release of the substance from the payload delivery vehicles.

44. A computer-readable medium as set forth in claim 43 wherein the method further comprises detecting passive cavitation associated with the release of the substance from the payload delivery vehicles.

45. A computer-readable medium as set forth in either one of claims 43 and 44 wherein the method further comprises imaging micro bubbles generated from cavitation associated with the release of the substance from the payload delivery vehicles.

46. A computer-readable medium as set forth in either one of claims 24 and 25 wherein the method further comprises operating operate the acoustic transducer system to heat the target tissue in each of the payload delivery zones by at least a threshold amount of heating, wherein the threshold amount of heating is effective to produce a change in the target tissue that facilitates at least one of: uptake of the substance by the target tissue, diffusion of the substance into the target tissue, and stimulation of a local immune response.

47. A computer-readable medium as set forth in claim 46 further comprising monitoring a local temperature increase associated with the focused acoustic energy.

48. A method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone, the method comprising:

49. A method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone, the method comprising:

50. A method of controlling an acoustic transducer system of an ultrasound system to deliver a substance to a target tissue via acoustically responsive payload delivery vehicles by delivering focused acoustic energy from the acoustic transducer system to a spatially adjustable payload delivery zone inside a body containing the target tissue so the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery zone, the method comprising:

51 . A method as set forth in claim 50 further comprising adjusting the intensity of the focused acoustic energy to ensure a localized temperature increase that is above a preselected threshold amount is achieved in the first and second focal zones.

52. A method as set forth in any one of claims 48 through 51 further comprising:

53. A method as set forth in any one of claims 48 through 52 wherein the ultrasound system is tuned so the focused acoustic energy does not increase the temperature of the tissue in any focal zone more than about three degrees Celsius.

54. A method as set forth in any one of claims 51 through 53 wherein delivering the focused acoustic energy to the payload delivery zone when it is coincident with the n^th focal zone results in a temperature increase within an n^th heated zone of the target tissue and the acoustic transducer system controller is further configured to change the location of the payload delivery zone during step (a) so that the n^th heated zone is spaced apart from the (n-1 )^th heated zone.

55. A method as set forth in claim 54 further comprising changing the location of the payload delivery zone during step (a) so that the n^th heated zone is spaced from the (n-2)^th heated zone.

56. A method as set forth in claim 55 further comprising changing the location of the payload delivery zone during step (a) to substantially avoid moving the location of the payload delivery zone to a location that results in the n^th heated zone overlapping a previous heated zone until after heat added to the previous heated zone has dissipated.

57. A method as set forth in any one of claims 50 through 56 further comprising operating the acoustic transducer system at a duty cycle of at least about .01 % but less than about 10% without producing a tempera increase of more than about 3 degrees Celsius anywhere within the target tissue.

58. A method as set forth in any one of claims 48 through 57 wherein the acoustic transducer system comprises a phased array of electrically addressable acoustic transducer elements.

59. A method as set forth in any one of claims 48 through 58 further comprising moving the payload delivery zone by electronically steering the focused energy.

60. A method as set forth in any one of claims 48 through 59 further comprising moving the acoustic transducer system.

61 . A method as set forth in either one of claims 48 and 50 further comprising changing the size of the payload delivery zone.

62. A method as set forth in either one of claims 49 and 61 further comprising using a relatively larger payload delivery zone when the focal zone is at a central location in the target tissue and using a relatively smaller payload delivery zone when the focal zone is located at a margin of the target tissue.

63. A method as set forth in any one of claims 48, 50, and 62 further comprising adjusting the acoustic intensity generated by the acoustic transducer system whenever the size of the payload delivery zone is changed so that the focused acoustic energy is sufficiently intense throughout the payload delivery zone to release the substance from at least some of the payload delivery vehicles inside the payload delivery zone and sufficiently weak outside the payload delivery zone to substantially avoid releasing the substance from the payload delivery vehicles outside the payload delivery zone.

64. A method as set forth in any one of claims 48 and 62 through 63 further comprising changing the size of the payload delivery zone by changing the way acoustic energy generated by the acoustic transducer system is focused.

65. A method as set forth in any one of claims 48 through 64 further comprising adjusting an acoustic energy flux generated by the acoustic transducer system.

66. A method as set forth in any one of claims 48 through 65 further comprising adjusting the length of at least one of the first and second time period.

67. A computer-readable medium as set forth in any one of claims 48 through 66 further comprising detecting a phenomenon associated with release of the substance from the payload delivery vehicles.

68. A method as set forth in claim 67 further comprising detecting passive cavitation associated with the release of the substance from the payload delivery vehicles.

69. A method as set forth in either one of claims 67 and 68 further comprising imaging micro bubbles generated from cavitation associated with the release of the substance from the payload delivery vehicles.

70. A method as set forth in either one of claims 48 and 49 further comprising operating operate the acoustic transducer system to heat the target tissue in each of the payload delivery zones by at least a threshold amount of heating, wherein the threshold amount of heating is effective to produce a change in the target tissue that facilitates at least one of: uptake of the substance by the target tissue, diffusion of the substance into the target tissue, and stimulation of a local immune response.

71 . A method as set forth in claim 70 further comprising monitoring a local temperature increase associated with the focused acoustic energy.