Field of the Invention

[001] The present invention relates to the domain of tissue procedures. In particular, the invention provides systems, apparatuses and methods for performing a procedure on a subject using focused ultrasound energy, and even more particularly for dual mode activation in focused ultrasound based procedures.

Background

[002] Solid tumors are one of the most common causes of death in the world, with over a million deaths each year. Solid tumors are treated either with chemotherapy, surgery, or radiation. High intensity focused ultrasound (HIFU) is a new, non-invasive technology that is capable of treating solid tumors by thermal ablation without ionizing radiation.

[003] HIFU focuses ultrasound waves inside the tumor, increasing temperature to about 65°C, and causes ablative necrosis and immediate tissue death. However, HIFU thermal ablation can cause temperature rise in critical structures and tissues surrounding the tumors, potentially leading to iatrogenic effects, limiting its applicability in treating solid tumors in patients. In addition, thermal ablation denatures tumor associated antigens, and immediately leads to thermal fixation of tissue at the treated region with a reasonable margin. This prevents immediate (12-24 hrs) infiltration of immune cells including macrophages, NK cells, dendritic cells, and T-cells, further delaying the cascade of systemic immune events vital for tumor regression.

[004] There is accordingly a need for solutions that enable improved outcomes from implementation of HIFU procedures.

Summary

[005] The invention provides systems, apparatuses and methods for dual mode activation in focused ultrasound based procedures, wherein a transducer apparatus is configured to operate in a first mode, under parameters selected for implementing boiling histotripsy, followed by operation in a second mode, under parameters selected for implementing mild hyperthermia.

[006] In an embodiment the present invention provides a transducer apparatus for dual mode ultrasound based tissue intervention, comprising a probe assembly comprising a primary ultrasound transducer, a probe manipulation assembly, and a processor implemented transducer state controller. The transducer apparatus is configured for (i) receiving input identifying a target region for dual mode ultrasound, (ii) determining an external perimeter of the target region, and an inner area of the target region that is bounded by the determined external perimeter, and (ii) responsive to detection of an ultrasound session initiation event (a) manipulating the probe assembly to traverse a first set of identified locations within the inner area of the target region, and operating the primary ultrasound transducer under a first set of operating parameters at each location within the first set of identified locations, and (b) subsequently manipulating the probe assembly to traverse a second set of identified locations corresponding to the external perimeter of the target region, , and operating the primary ultrasound transducer under a second set of operating parameters at each location within the second set of identified locations - wherein the first set of operating parameters is distinct from the second set of operating parameters.

[007] The invention also provides a method for dual mode ultrasound based tissue intervention, implemented through a transducer apparatus comprising a probe assembly, a probe manipulation assembly, and a processor implemented transducer state controller. The probe assembly includes a primary ultrasound transducer, wherein the transducer apparatus is configured for (i) receiving input identifying a target region for dual mode ultrasound, (ii) determining an external perimeter of the target region, and an inner area of the target region that is bounded by the determined external perimeter, and (iii) responsive to detection of an ultrasound session initiation event (a) manipulating the probe assembly to traverse a first set of identified locations within the inner area of the target region, and operating the primary ultrasound transducer under a first set of operating parameters at each location within the first set of identified locations, and (b) subsequently manipulating the probe assembly to traverse a second set of identified locations corresponding to the external perimeter of the target region, , and operating the primary ultrasound transducer under a second set of operating parameters at each location within the second set of identified locations — wherein the first set of operating parameters is distinct from the second set of operating parameters.

[008] The invention additionally provides a computer program product for dual mode ultrasound based tissue intervention, implemented through a transducer apparatus, comprising a probe assembly, a probe manipulation assembly, and a processor implemented transducer state controller. The probe assembly includes a primary ultrasound transducer. The computer program product comprising a non-transitory computer usable medium having computer readable program code embodied therein, the computer readable program code comprising instructions for implementing at a processor, the steps of (i) receiving input identifying a target region for dual mode ultrasound, (ii) determining an external perimeter of the target region, and an inner area of the target region that is bounded by the determined external perimeter, and (iii) responsive to detection of an ultrasound session initiation event (a) manipulating the probe assembly to traverse a first set of identified locations within the inner area of the target region, and operating the primary ultrasound transducer under a first set of operating parameters at each location within the first set of identified locations, and (b) subsequently manipulating the probe assembly to traverse a second set of identified locations corresponding to the external perimeter of the target region, and operating the primary ultrasound transducer under a second set of operating parameters at each location within the second set of identified locations — wherein the first set of operating parameters is distinct from the second set of operating parameters.

Brief Description of the Accompanying Drawings

[009] Figure 1 illustrates a system configured for optimizing ultrasound based procedures in accordance with the teachings of the present invention.

[0010] Figure 2 illustrates a transducer apparatus configured for focused ultrasound therapy. [0011] Figures 3 to 6 illustrate components of a probe assembly configured in accordance with the teachings of the present invention.

[0012] Figure 7 illustrates a method for optimizing ultrasound based implementation of tissue diagnosis, tissue therapy, tissue perturbation, tissue fractionation, boiling histotripsy and / or mild hyperthermia, in accordance with the teachings of the present invention.

[0013] Figures 8A to 8D illustrate exemplary target regions corresponding to regions of a subject’ anatomy that can be defined or identified for dual mode therapy that is enabled by the present invention.

[0014] Figure 9 is a flowchart illustrating a method of implementing dual mode focused ultrasound therapy through an ultrasound transducer apparatus configured in accordance with the teachings of the present invention.

[0015] Figures 10A and 10B illustrate exemplary traversal patterns of an ultrasound transducer apparatus configured in accordance with the teachings of the present invention.

[0016] Figure 11 illustrates a transducer apparatus configured for implementation of dual mode ultrasound therapy in accordance with the teachings of the present invention.

[0017] Figure 12 illustrates an exemplary system for implementing the present invention.

Detailed Description

[0018] The invention provides systems, apparatuses and methods for implementation or delivery of dual mode focused ultrasound therapy. In particular, the invention provides systems, apparatuses and methods for dual mode activation of a focused ultrasound transducer so that in a first mode the ultrasound transducer is configured to implement boiling histotripsy, and in a second mode the focused ultrasound transducer is configured to implement mild hyperthermia.

[0019] Boiling histotripsy (BH) is a form of HIFU, that is capable of mechanically fractionating tumor tissues with high spatial precision, and minimal or no thermal effects to adjacent tissues. This enables the expansion and trafficking of tumor associated antigen population to draining lymph nodes for effective priming and activation of T-cell pathways leading to tumor regression. Improving blood flow into a treated tumor site for effect systemic immune response against the tumors, especially after an acute phase of BH therapy has been found to be important and effective in improving the effectiveness of boiling histotripsy therapy.

[0020] Mild hyperthermia is a technique using HIFU that can warm tissue/ solid tumors to about 41-45°C, causing reversible dilation in vessels, and lymph vessels, as well as other therapeutic benefits. Mild-hyperthermia helps increasing blood flow to the BH-treated site, increasing trafficking of immune cells to the treated region for enhanced anti-tumor effect.

[0021] The present invention is based on the discovery that a transducer apparatus configured for dual mode activation during ultrasound therapy can effectively combine delivery of boiling histotripsy and mild hyperthermia. [0022] The invention provides a transducer apparatus that is configured for safely and accurately directing focused ultrasound energy towards a tissue mass — for example, for perturbing, ablating, or fractionating the tissue mass, for implementing boiling histotripsy and for implementing mild hyperthermia.

[0023] The above systems, apparatuses and methods are described in more detail below.

[0024] Figure 1 illustrates a system 100 for delivery of focused ultrasound energy towards a tissue mass — for example, for perturbing or fractionating the tissue mass or for implementing boiling histotripsy or for implementing mild hyperthermia.

[0025] System 100 comprises a transducer apparatus 102. The transducer apparatus comprises an ultrasound transducer capable of directing focused ultrasound energy towards a tissue mass. The focused ultrasound energy may be delivered to tissue for any purpose including perturbing or ablating or fractionating the tissue mass or implementing boiling histotripsy or implementing mild hyperthermia. In an embodiment the ultrasound transducer is a focused ultrasound transducer. Transducer apparatus 102 may optionally include at least one additional ultrasound transducer. In one embodiment, the at least one additional ultrasound transducer is a second ultrasound transducer. In another embodiment, the at least one additional ultrasound transducer is a passive cavitation detector.

[0026] The ultrasound transducer is driven by a radio frequency (RF) amplifier 106, which is in turn controlled by a waveform generator 104. A waveform may be set or defined or input through one or more control parameters at waveform generator 104 — and this waveform is then amplified and used to drive the ultrasound transducer within transducer apparatus 102. The generated waveform may be viewed on digital oscilloscope 108. The waveform set or selected for generation by waveform generator will be selected based on the bioeffect desired to be produced in vivo at or on the region-of-interest or tissue-of-interest. Each of digital oscilloscope 108, waveform generator 104 and transducer apparatus may be controlled by a computer 110 configured for data acquisition and control, and may each be configured to transmit data signals back to computer 110 to enable a viewer or operator to view feedback from each such device.

[0027] Figure 2 illustrates an embodiment 200 of the transducer apparatus 102 that has been more generally described in connection with Figure 1.

[0028] Transducer apparatus 200 comprises a probe assembly 202. Probe assembly 202 comprises a primary ultrasound transducer capable of delivering ultrasound waves for perturbing or ablating or fractionating the tissue mass or for implementing boiling histotripsy or for implementing mild hyperthermia. In an embodiment the primary ultrasound transducer is a focused ultrasound transducer. Probe assembly 202 may optionally additionally include at least one additional ultrasound transducer. In one embodiment, the at least one additional ultrasound transducer is a second ultrasound transducer. In another embodiment, the at least one additional ultrasound transducer is a passive cavitation detector. In a particular embodiment, the additional ultrasound transducer is positioned coaxially relative to the primary ultrasound transducer, within probe assembly 202. In one embodiment, probe assembly 202 may include both of a second ultrasound transducer and a passive cavitation detector positioned coaxially relative to the primary ultrasound transducer. In an embodiment, probe assembly 202 may only include a primary ultrasound transducer without either of a second ultrasound transducer and a passive cavitation detector.

[0029] Transducer apparatus 200 additionally includes a probe assembly holder 204 — comprising a holder for, or an assembly for holding probe assembly 202. In an embodiment (illustrated in Figure 3), probe assembly holder 204 may comprise a casing or housing within which the primary ultrasound transducer and optionally the at least one additional ultrasound transducer are either partially or wholly housed coaxially relative to each other. In a particular embodiment the probe assembly holder 204 comprises a housing configured to house a primary ultrasound transducer 2022 (e.g. a first focused ultrasound transducer) and the additional ultrasound transducer 2024, such that the additional ultrasound transducer 2024 is disposed partially or wholly within a cavity or hole 2026 formed along the central axis of the primary ultrasound transducer 2022.

[0030] Probe assembly holder 204 is affixed to or coupled with probe manipulation assembly 206. Probe manipulation assembly 206 comprises an assembly configured to enable probe assembly 202 to be moved, positioned or manipulated along or about the x, y and / or z axes. In certain embodiments, probe manipulation assembly 206 comprises an assembly configured to confer on probe assembly 202, any of 3, 4, 5 or 6 degrees of freedom. In an embodiment, probe manipulation assembly 206 comprises any of (i) a linear stage exhibiting translation about a single axis, (ii) a motion stage configured for translation about two perpendicular axes, (iii) a motion stage configured for translation about three perpendicular axes, (iv) an articulated arm assembly comprising a plurality of interconnected arms, wherein one or more arms is / are pivotably interconnected to at least other arm in a manner that enables manipulation of probe assembly 202 along or about the x, y and / or z axes, or to confer on probe assembly 202, any of 3, 4, 5 or 6 degrees of freedom, (v) an articulated arm assembly comprising a first arm and a second arm that are pivotably interconnected, wherein the articulated arm assembly is configured to enable manipulation of probe assembly 202 along or about the x, y and / or z axes, or to confer on probe assembly 202, any of 3, 4, 5 or 6 degrees of freedom, and (vi) a robotic arm assembly configured to enable robotic manipulation of probe assembly 202 along or about the x, y and / or z axes, or to confer on probe assembly 202, any of 3, 4, 5 or 6 degrees of freedom. Probe manipulation assembly 206 may be controlled either manually or through a computer application program implemented through a computer 110. The probe manipulation assembly may be controlled either through wired or wireless controllers — enabling a physician or operator to perform gross positioning of probe assembly 202 (or the transducer(s) therewithin) optimally relative to a subject’s anatomy or relative to a region-of-interest / tissue-of-interest within a subject’s anatomy.

[0031] Transducer apparatus 200 may additionally include signal transmission infrastructure 208 comprising a bus or interconnections between one or more components of transducer apparatus 200 and / or between transducer apparatus 200 and one or more components of system 100 — to enable signalling or transmitting and receiving of signals therebetween.

[0032] Figure 3 illustrates an exemplary configuration for probe assembly 202 within transducer apparatus 200. As illustrated in Figure 3, probe assembly 202 comprises a primary ultrasound transducer 2022 having a cavity or hole 2026 extending therethrough along a central axis. At least one additional ultrasound transducer 2024 is positioned coaxially to primary ultrasound transducer 2022 about the central axis, such that primary ultrasound transducer 2022 can deliver ultrasound wavelengths onto a target region on a subject, for example for tissue perturbation / tissue fractionation purposes or ablation or boiling histotripsy or mild hyperthermia, while the additional ultrasound transducer can simultaneously transmit and/or receive image data signals (such as ultrasound wavelengths) through the cavity or hole 2026 that extends through primary ultrasound transducer 2022 — for implementing its imaging functionality without interfering with the therapy I perturbation / fractionation / boiling histotripsy / mild hyperthermia related functionality of primary ultrasound transducer 2022. In some embodiments imaging data from additional ultrasound transducer 2024 may be used for real time imaging purposes — to enable safe and accurate manipulation and positioning of probe assembly 202 and / or transducer apparatus 200 relative to a region-of-interest or a target region on or within a subject’s anatomy. In an embodiment, imaging signals generated by the additional ultrasound transducer 2024 generate images that are displayed on a display device for communicating position or orientation information corresponding to probe assembly 202. It would be understood that while the embodiment of the probe assembly 202 that is illustrated in Figure 3 is shown with both of a primary ultrasound transducer 2022 and an additional ultrasound transducer 2024, in other embodiments, the probe assembly 202 may only comprise a primary ultrasound transducer 2022 without any additional ultrasound transducer 2024.

[0033] Figure 4 illustrates a plan view of a probe assembly 202 having a primary ultrasound transducer 2022. In an embodiment, an additional ultrasound transducer 2024 is arranged coaxially relative to primary ultrasound transducer 2022 — wherein additional ultrasound transducer 2024 is positioned within or is aligned with a cavity 2026 extending through primary ultrasound transducer 2022. The plan view of Figure 4 may be understood as a view of probe assembly 202 showing a surface of primary ultrasound transducer 2022 that would be positioned proximal to a region-of- interest or tissue-of-interest during operation of primary ultrasound transducer 2022.

[0034] Figure 5 illustrates a second plan view of a probe assembly 202 wherein primary ultrasound transducer 2022 and the additional ultrasound transducer 2024 are arranged coaxially relative to each other — and wherein additional ultrasound transducer 2024 is positioned within or is aligned with a cavity 2026 extending through primary ultrasound transducer 2022. The plan view of Figure 5 may be understood as a view of probe assembly 202 showing a surface of primary ultrasound transducer 2022 that would be positioned distal to a region-of-interest or tissue-of-interest during operation of primary ultrasound transducer 2022. As shown, the primary ultrasound transducer 2022 may be provided with one or more fasteners, or affixing elements, or tapped holes 2028 for affixing primary ultrasound transducer 2022 to probe assembly holder 204. In an embodiment, the primary ultrasound transducer 2022 may be affixed to probe assembly holder 204 by engaging fasteners, affixing elements, or tapped holes 2028 with an adapter plate, which is in turn coupled with probe assembly holder 204.

[0035] Figure 6 illustrates various components of transducer apparatus 200. As shown in Figure 6, transducer apparatus may comprise probe assembly 202 — wherein probe assembly 202 comprises a primary ultrasound transducer 2022 and an additional ultrasound transducer 2024 arranged coaxially relative to each other. A contact surface 2030 may be provided on a surface of primary ultrasound transducer 2022 that is proximal to a region-of-interest or tissue-of-interest during operation of primary ultrasound transducer 2022 — for example a gel pad or other pad for contacting a surface 600 of a subject’s anatomy. Transducer apparatus 200 is additionally shown as having signal transmission infrastructure 208 comprising interconnections between one or more components of transducer apparatus 200 and / or between transducer apparatus 200 and one or more components of system 100 — to enable signalling or transmitting and receiving of signals therebetween.

[0036] In an embodiment of the invention, transducer apparatus 200 may be configured such that probe manipulation assembly 206 is only operatable when the primary ultrasound transducer 2022 (e.g. a focused ultrasound transducer) is in a deactivated state.

[0037] In another embodiment of the invention, transducer apparatus 200 may be configured such that the primary ultrasound transducer 2022 (e.g. a focused ultrasound transducer) is deactivated in response to detection of movement, repositioning or reorientation of probe manipulation assembly 206 or probe assembly 202, or in response to detection of a signal for implementing movement, repositioning or reorientation of probe manipulation assembly 206 or probe assembly 202.

[0038] In another embodiment of the invention, the transducer apparatus 200 may be configured such that (i) the primary ultrasound transducer 2022 (e.g. a focused ultrasound transducer) and the additional ultrasound transducer 2024 are activatable when the probe assembly is static, and (ii) only the additional ultrasound transducer 2024 is activatable when the probe assembly 202 or the probe manipulation assembly 206 is moving.

[0039] In an embodiment of the transducer apparatus 200, primary ultrasound transducer 2022 of the probe assembly is an ultrasound transducer capable of performing fractionation or ablation or perturbation or boiling histotripsy or mild hyperthermia of tissue cells or tumour cells in the range of a few hundred microns, at multiple spatial locations with each tumour/ cyst/ nodule/ etc.

[0040] In an embodiment of the invention, primary ultrasound transducer 2022 of the probe assembly is a focused ultrasound transducer configured for operation with, or controlled to operate at least within the below operating parameter ranges:

[0041] In an embodiment of the invention, where probe assembly 202 includes at least one additional ultrasound transducer 2024 — and wherein the at least one additional ultrasound transducer 2024 is a second ultrasound transducer, the second ultrasound transducer is configured to operate under a set of operating parameters that is different from the set of operating parameters under which the primary ultrasound transducer 2022 is configured to operate. In a specific embodiment, the second ultrasound transducer is configured to implement B-mode or pulsed Doppler or color Doppler or elastography imaging for positioning and localization of probe assembly 202 relative to a region-of-interest or tissue-of-interest, within the below set of operating parameters:

[0042] In an embodiment of the invention, where probe assembly 202 includes at least one additional ultrasound transducer 2024 — and wherein the at least one additional ultrasound transducer 2024 is a passive cavitation detector, the passive cavitation detector is configured to operate under a set of operating parameters that is different from the set of operating parameters under which the primary ultrasound transducer 2022 is configured to operate. In a specific embodiment, the passive cavitation detector can be spherical or cylindrical in shape and is configured to operate within the below set of operating parameters:

[0043] Figure 7 illustrates a method embodiment for optimizing ultrasound based implementation of tissue diagnosis, tissue therapy, tissue perturbation, tissue fractionation or boiling histotripsy and / or mild hyperthermia of tissue in accordance with the teachings of the present invention. In an embodiment, the method of Figure 7 may be implemented by operation of any of the embodiments of transducer apparatus 200 that has been described above.

[0044] Step 702 comprises activating a first transducer within probe assembly 202 for obtaining data representing a position of an ultrasound probe assembly relative to an anatomical object (for example a region-of-interest, tissue-of-interest, anatomical surface, tumour, cyst, nodule, etc.), wherein the first transducer operates under a first set of operating parameters. The first transducer activated at step 702 may comprise the imaging transducer 2024 of probe assembly 202 that has been described hereinabove, - wherein during an activated state said first transducer can simultaneously transmit or receive signals (such as audio wave signals or ultrasound wavelengths) through a cavity or hole 2026 that extends through a coaxially positioned primary ultrasound transducer 2022 — for implementing its imaging functionality without interfering with the therapy I perturbation / fractionation related functionality of the coaxially disposed primary ultrasound transducer 2022.

[0045] In an embodiment, where the first transducer is an ultrasound transducer, the ultrasound transducer is configured to operate under a first set of operating parameters In a specific embodiment, the first transducer is an ultrasound transducer that is configured to implement B- mode imaging for positioning and localization of probe assembly 202 relative to a region-of- interest or tissue-of-interest, within the below set of operating parameters:

[0046] In another embodiment where the first transducer is a passive cavitation detector, the passive cavitation detector is configured to operate under a first set of operating parameters. In a specific embodiment, the passive cavitation detector can be spherical or cylindrical in shape and is configured to operate within the below set of operating parameters:

[0047] Step 704 comprises generating and displaying on a display, one or more image (s) based on signals received from the first transducer. The images may be displayed on a display associated with a computer being operated by an operator or physician and provides positional / locational information concerning the position and / or orientation of the probe assembly 202 relative to a subject’s anatomy.

[0048] Step 706 comprises manipulating the probe assembly 202 to an intended position and / or orientation relative to the anatomical object — wherein said manipulation involves changing a position or orientation of the probe assembly 202 relative to the anatomical object by manipulating or manipulation of probe manipulation assembly 206. The manipulation of probe assembly at step 706 may continue until the operator or physician determines, based on images displayed on the display (i.e. images generated by data signals received from the first transducer), that the probe assembly has been moved to an appropriate or intended or desired position or orientation relative to the anatomical object.

[0049] Step 708 comprises activating a second transducer within probe assembly 202 to direct high intensity focused ultrasound waves onto a target region. In an embodiment, the second transducer operates under a second set of operating parameters that are (i) distinct from the first set of operating parameters and (ii) are selected for tissue perturbation, or tissue fractionation or boiling histotripsy. In an embodiment, the second transducer is a primary ultrasound transducer — and is configured such that during an activated state, the second transducer directs high intensity focused ultrasound wavelengths on a target region (such as the anatomical object) according to the below second set of operating parameters.

[0050] In a particular embodiment, the second transducer is a primary ultrasound transducer — and is configured to operate at a derated acoustic intensity (ISPTA) of 720 mW/cm ² or above (wherein ISPTA is intensity spatial peak temporal average), and either MI>1.9 (wherein MI is mechanical index) or derated ISPPA > 190 W/cm ² (wherein ISPPA is intensity spatial peak pulse average) .

[0051] The present invention enables implementation of dual mode focused ultrasound therapy through a transducer apparatus. In certain embodiments, the transducer apparatus may comprise solely of a primary ultrasound transducer. In other embodiments, the transducer apparatus may comprise an additional ultrasound transducer configured in accordance with the embodiments described in connection with Figures 3 to 6 above.

[0052] Implementation of dual mode ultrasound therapy in accordance with the present invention involves defining a target region on a patient’s anatomy at which ultrasound therapy requires to be provided — and thereafter initiating dual mode ultrasound therapy at the target region. A target region may be defined by providing operator inputs to the transducer apparatus — for example through a user interface or a computing device coupled with the transducer apparatus. Alternately, the target region may be marked with visible markings or with sensor detectable markings on the subject’s anatomy, and may be scanned by a scanner or sensor within the transducer apparatus, for the purposes of demarcating or defining the target region for delivery of dual mode ultrasound therapy.

[0053] Figures 8A to 8D illustrate exemplary target regions that can be defined for the purposes of delivery of dual mode ultrasound therapy to a subject’s anatomy. As shown in Figures 8A to 8C, the target region may comprise a regular or geometric region — for example a rectangular region 800A, a hexagonal region 800B, a circular region 800C etc. Alternately, the target region may comprise an irregular region that is defined keeping in mind the particular anatomical surface at which the ultrasound procedure requires to be delivered — for example, the irregular target region 800D. Each defined target region 800A, 800B, 800C, 800D comprises an external perimeter (or external perimeter region) 802A, 802B, 802C, 802D which defines an external boundary for the defined target region. Each external perimeter (or external perimeter region) 802A, 802B, 802C, 802D contains therewithin an inner area region 804A, 804B, 804C, 804D that is circumscribed or bounded by the corresponding external perimeter (or external perimeter region) 802A, 802B, 802C, 802D.

[0054] Figure 9 is a flowchart illustrating a method of implementing dual mode focused ultrasound therapy through an ultrasound transducer apparatus configured in accordance with the teachings of the present invention. The steps of the method may be implemented at an ultrasound transducer apparatus of the kind described in connection with any one of Figures 1 to 6 or 11.

[0055] Step 902 comprises receiving input identifying a target region on a subject’s anatomy for applying dual mode ultrasound therapy. The target region may be identified or defined by providing operator inputs to the transducer apparatus — for example through a user interface or a computing device coupled with the transducer apparatus. Alternately, the target region may be marked with visible markings or with sensor detectable markings on the subject’s anatomy, and may be scanned by a scanner or sensor on or within the transducer apparatus, for the purposes of demarcating or defining the target region for delivery of dual mode ultrasound therapy. [0056] Step 904 comprises analysis of the identified target region and determination of (i) an external perimeter of the target region and (ii) an inner area of the target region that is bounded by the determined external perimeter. It would be understood that analysis of the target region and determination of an external perimeter and / or an inner region of the target region may be implemented using any number of feature detection methods or algorithms known in the art, including without limitation any one or more of edge detection, corner detection, radius limits or detection, shape recognition etc.

[0057] Step 906 comprises detecting a dual mode therapy session initiation event (i.e. an ultrasound session initiation event). The dual mode therapy session initiation event may comprise any event or state change that signals initiation of a dual mode therapy session — and may include by way of example, an operator input through a user interface of a computing device, a voice command, image analysis and detection of a predefined gesture signaling session initiation, a predefined time based trigger event, or any other trigger event that the transducer apparatus is configured to recognize as a dual mode therapy session initiation event.

[0058] Responsive to detection of the dual mode therapy session trigger event, step 908 comprises initiating operation of the transducer apparatus in a first mode, wherein in said first mode of operation, a robotic arm is manipulated such that a probe assembly that is affixed to the robotic arm and that houses a primary ultrasound transducer traverses a first set of identified locations within the determined inner area of the target region, and wherein the primary ultrasound transducer is positioned and operated to emit and direct ultrasound waves at each location within the first set of identified locations under a first set of ultrasound transducer operating parameters.

[0059] The first set of identified locations within the inner area of the target region comprises a set of locations or positions within the inner area of the target region that are selected such that, by emitting and directing ultrasound waves when positioned at each location within the first set of locations, the entire inner area of the target region, or substantially the entire inner area of the target region, or at least a part of the inner area of the target region, is irradiated with ultrasound waves that are emitted from the primary ultrasound transducer. Stated differently, the first set of identified locations are selected to ensure full, or substantially full, or at least partial coverage of the entire inner area of the target region during delivery of ultrasound waves, under the first set of ultrasound transducer operating parameters.

[0060] In an embodiment, the transducer apparatus is configured such that the first set of ultrasound transducer operating parameters comprise operating parameters selected for implementing boiling histotripsy.

[0061] In an embodiment the first set of ultrasound transducer operating parameters comprise at least the below parameter ranges:

[0062] Implementation of step 908 may be understood with reference to the exemplary illustration in Figure 10A. Figure 10A illustrates an identified target region 1000, having an external perimeter 1002 and an inner area 1004. The inner area 1004 is sectored into a set of hexagonal sectors 1006, each comprising a center region 1008. Taken together the center regions 1008 corresponding to the set of hexagonal sectors 1006 comprises the first set of identified locations within inner area 1004. When implementing the first mode of operation at step 908 of the method of Figure 9, a robotic arm of the transducer apparatus is manipulated such that a probe assembly that is affixed to the robotic arm and that houses a primary ultrasound transducer traverses each of the hexagonal sectors 1006 within the inner area 1004. Traversal of a hexagonal sector 1006 by the probe assembly comprises positioning the primary ultrasound transducer at a center region 1008 of the corresponding hexagonal sector 1006, and operating the primary ultrasound transducer to emit and direct ultrasound waves onto the area covered by the hexagonal sector 1006. Each hexagonal sector 1006 may be sized so that by positioning the primary ultrasound transducer at the corresponding center region 1008 of said hexagonal sector 1006, the ultrasound beam footprint of the primary ultrasound transducer cover the area of said hexagonal sector 1006 (or substantially covers the area of hexagonal sector 1006). Stated differently, each hexagonal sector 1006 may be sized to substantially correspond (or substantially match, with a variance of +/-15 %) to the coverage area of the beam footprint of the primary ultrasound transducer, when the primary ultrasound transducer is positioned at a center region 1008 of said hexagonal sector 1006 and a contact surface of the probe assembly is in contact (i.e. direct or indirect contact) with a surface of the target region. While the illustration in Figure 10A shows the inner region being sectored into a plurality of hexagonal sectors, it would be understood that the sectoring of the inner region may be according to any geometric or irregular shape or pattern.

[0063] Subsequent to step 908, step 910 comprises initiating operation of the transducer apparatus in a second mode, wherein in said second mode of operation, the robotic arm is manipulated such that the probe assembly that is affixed to the robotic arm and that houses the primary ultrasound transducer traverses a second set of identified locations corresponding to the external perimeter of the target region. In the process of this traversal, the primary ultrasound transducer is positioned and operated to emit and direct ultrasound waves under a second set of ultrasound transducer operating parameters, at each location within the second set of identified locations.

[0064] The second set of identified locations corresponding to the external perimeter of the target region comprise a set of locations or positions on the determined external perimeter (or a set of locations or positions within a determined external perimeter region) that surrounds the inner area of the target region. The second set of identified locations are selected such that by traversing the primary ultrasound transducer across each location within the second set of identified locations, and by emitting and directing ultrasound waves from the primary ultrasound transducer onto the external perimeter region at each location within the second set of locations, the external perimeter I external perimeter region is entirely, substantially entirely, or at least partially, irradiated with ultrasound waves that are emitted from the primary ultrasound transducer. Stated differently, locations within the second set of identified locations are selected to ensure full, or substantially full, or at least partial, coverage of the external perimeter or external perimeter region of the target region, during delivery of ultrasound waves under the second set of ultrasound transducer operating parameters.

[0065] In an embodiment, the transducer apparatus is configured such that the second set of ultrasound transducer operating parameters comprise operating parameters selected for implementing mild hyperthermia at each of the locations within the second set of identified locations.

[0066] In an embodiment the second set of ultrasound transducer operating parameters comprise at least the below parameter ranges:

[0067] Implementation of step 910 may be understood with reference to the exemplary illustration in Figure 10B. As shown in Figure 10B the identified target region 1000, has an external perimeter 1002 and an inner area 1004. As in the case of Figure 10A, the inner area 1004 is sectored into a set of hexagonal sectors 1006, each comprising a center region 1008. When implementing the second mode of operation at step 910 of the method of Figure 9, the robotic arm of the ultrasound transducer apparatus is manipulated such that the probe assembly that is affixed to the robotic arm and that houses the primary ultrasound transducer traverses the full external perimeter 1002 of the target region 1000, wherein traversal of the external perimeter 1002 comprises positioning the primary ultrasound transducer at a second set of locations comprising one or more locations (and preferably comprising a plurality of locations) along the external perimeter 1002, and operating the primary ultrasound transducer to emit and direct ultrasound waves onto an area of the external perimeter 1002 or onto an area of an external perimeter region corresponding to external perimeter 1002, that is covered by the beam footprint of the primary ultrasound transducer when positioned at said location. In an embodiment, each location in the second set of locations may be selected such that by operating the primary ultrasound transducer under a second set of ultrasound transducer operating parameters to emit ultrasound waves at each location in the second set of locations, a portion of the external perimeter region that surrounds or corresponds to said location receives ultrasound waves emitted by the primary ultrasound transducer. By traversing the second set of locations along the external perimeter, and by emitting at each such location, ultrasound emissions under a second set of operating parameters that are selected for implementing mild hyperthermia, the transducer apparatus enables delivery of mild hyperthermia at least partially or fully across the perimeter of a target region to which boiling histotripsy has been previously delivered.

[0068] Figure 11 illustrates a transducer apparatus 1100 configured for dual mode ultrasound therapy in accordance with the teachings of the present invention.

[0069] Transducer apparatus 1100 comprises a probe assembly 1102. Probe assembly 1102 comprises one or more ultrasound transducer(s) 11022. In an embodiment, ultrasound transducer(s) 11022 comprises at least a primary ultrasound transducer and optionally one or more additional ultrasound transducers. At least one ultrasound transducer of the one or more ultrasound transducer(s) 11022 is capable of delivering ultrasound waves for perturbing or fractionating the tissue mass or for implementing boiling histotripsy or for implementing mild hyperthermia. In an embodiment the ultrasound transducer 11022 is a focused ultrasound transducer. Ultrasound trans ducer(s) 11022 may additionally include at least one additional ultrasound transducer. In one embodiment, the at least one additional ultrasound transducer is a second ultrasound transducer. In another embodiment, the at least one additional ultrasound transducer is a passive cavitation detector. In a particular embodiment, the additional ultrasound transducer is positioned coaxially relative to the primary ultrasound transducer, within probe assembly 1102. In one embodiment, probe assembly 1102 may include both of a second ultrasound transducer and a passive cavitation detector positioned coaxially relative to the primary ultrasound transducer. In an embodiment, probe assembly 1102 may only include a primary ultrasound transducer without either of a second ultrasound transducer and a passive cavitation detector.

[0070] Transducer apparatus 1100 additionally includes a probe assembly holder 1104 — comprising a holder for, or an assembly for, holding probe assembly 1102. In an embodiment, probe assembly holder 1104 may comprise a casing or housing within which the primary ultrasound transducer and optionally the at least one additional ultrasound transducer are either partially or wholly housed coaxially relative to each other. In a particular embodiment the probe assembly holder 1104 comprises a housing configured to house both of a primary ultrasound transducer(s) and an additional ultrasound transducer, in a manner wherein the additional ultrasound transducer is disposed partially or wholly within a cavity or hole formed along the central axis of the primary ultrasound transducer.

[0071] Probe assembly holder 1104 is affixed to or coupled with probe manipulation assembly 1106. Probe manipulation assembly 1106 comprises an assembly configured to enable probe assembly 1102 to be moved, positioned or manipulated along or about the x, y and / or z axes. In certain embodiments, probe manipulation assembly 1106 comprises an assembly configured to confer on probe assembly 1102, any of 3, 4, 5 or 6 degrees of freedom. In an embodiment, probe manipulation assembly 1106 comprises any of (i) a linear stage exhibiting translation about a single axis, (ii) a motion stage configured for translation about two perpendicular axes, (iii) a motion stage configured for translation about three perpendicular axes, (iv) an articulated arm assembly comprising a plurality of interconnected arms, wherein one or more arms is / are pivotably interconnected to at least other arm in a manner that enables manipulation of probe assembly 1102 along or about the x, y and / or z axes, or to confer on probe assembly 1102, any of 3, 4, 5 or 6 degrees of freedom, (v) an articulated arm assembly comprising a first arm and a second arm that are pivotably interconnected, wherein the articulated arm assembly is configured to enable manipulation of probe assembly 1102 along or about the x, y and / or z axes, or to confer on probe assembly 1102, any of 3, 4, 5 or 6 degrees of freedom, and (vi) a robotic arm assembly configured to enable robotic manipulation of probe assembly 1102 along or about the x, y and / or z axes, or to confer on probe assembly 1102, any of 3, 4, 5 or 6 degrees of freedom. Probe manipulation assembly 1106 may be controlled either manually or through a computer application program implemented through a computer or a processor, or through a specifically configured controller. The probe manipulation assembly 1106 may be controlled either through wired or wireless controllers — enabling a physician or operator to perform gross positioning of probe assembly 1102 (or the transducer(s) therewithin) optimally relative to a subject’s anatomy or relative to a region-of-interest / tissue-of-interest within a subject’s anatomy.

[0072] Transducer apparatus 1100 may additionally include signal transmission infrastructure 1108 comprising a bus or interconnections between one or more components of transducer apparatus 1100 and / or between transducer apparatus 1100 and one or more components of system 100 — to enable signalling or transmitting and receiving of signals therebetween.

[0073] Transducer apparatus 1100 also includes a processor 1110 configured to implement one of more method functionalities that have been previously described in connection with the methods of any of Figures 7 and 9.

[0074] Transducer apparatus 1100 includes a processor implemented target region analysis controller 1112 configured to implement the step of target region analysis as described in connection with step 904 of Figure 9, and for determining (i) an external perimeter of the target region and (ii) an inner area of the target region that is bounded by the determined external perimeter.

[0075] Transducer apparatus 1100 includes a processor implemented target region traversal controller 1114 configured to implement and control traversal of the probe assembly across the first set of identified locations and / or the second set of identified locations as described in connection with steps 908 and 910 of the method of Figure 9.

[0076] Transducer apparatus 1100 includes a processor implemented transducer state controller 1116 configured to control activation / deactivation states of a primary ultrasound transducer or of one or more ultrasound transducer elements or element arrays within the primary ultrasound transducer, and for emission of ultrasound waves under a first set of operating parameters or under a second set of operating parameters as described in connection with steps 908 and 910 respectively in the method of Figure 9.

[0077] The systems, apparatuses and methods described above enables delivery of boiling histotripsy followed by mild hyperthermia within a dual mode ultrasound therapy session. Implementation of boiling histotripsy serves to mechanically fractionate tumor tissues with high spatial precision, and minimal or no thermal effects to adjacent tissues, which enables the expansion and trafficking of tumor associated antigen population to draining lymph nodes for effective priming and activation of T-cell pathways leading to tumor regression. Subsequent implementation of mild hyperthermia at perimeter regions of the target region to which boiling histotripsy has been delivered improves blood flow into a treated tumor site for effect systemic immune response against the tumors, which results in significant improvements in the effectiveness of boiling histotripsy therapy.

[0078] In an embodiment the present invention provides a transducer apparatus for dual mode ultrasound based tissue intervention, comprising a probe assembly comprising a primary ultrasound transducer, a probe manipulation assembly, and a processor implemented transducer state controller. The transducer apparatus is configured for (i) receiving input identifying a target region for dual mode ultrasound, (ii) determining an external perimeter of the target region, and an inner area of the target region that is bounded by the determined external perimeter, and (ii) responsive to detection of an ultrasound session initiation event (a) manipulating the probe assembly to traverse a first set of identified locations within the inner area of the target region, and operating the primary ultrasound transducer under a first set of operating parameters at each location within the first set of identified locations, and (b) subsequently manipulating the probe assembly to traverse a second set of identified locations corresponding to the external perimeter of the target region, and operating the primary ultrasound transducer under a second set of operating parameters at each location within the second set of identified locations - wherein the first set of operating parameters is distinct from the second set of operating parameters.

[0079] In an embodiment of the transducer apparatus, the first set of operating parameters are configured for implementation of boiling histotripsy, and the second set of operating parameters are configured for implementation of mild hyperthermia.

[0080] In another embodiment of the transducer apparatus (i) the first set of operating parameters comprises one or more of acoustic pressure (positive pressure) between 4 to 100 MPa peak positive pressure, acoustic pressure (negative pressure) between 2 to 20 MPa peak negative pressure, pulse length between 5 to 20 milliseconds, pulse repetition frequency between 0.5 and 5 Hz, total sonication time per location between 10 and 600 seconds, and transmit frequency between 1 MHz and 3 MHz, and (ii) and the second set of operating parameters comprises one or more of acoustic pressure (positive pressure) between 1 to 5 MPa peak positive pressure, acoustic pressure (negative pressure) between 1 to 5 MPa peak negative pressure, duty cycle at 100%, total sonication time per location between 10 to 1800 seconds, and transmit frequency between 500 KHz and 2 MHz.

[0081] The transducer apparatus may be configured such that manipulation of the probe assembly to traverse the first set of identified locations and the second set of identified locations is implemented by manipulating a robotic arm to which the probe assembly is affixed.

[0082] In another embodiment of the transducer apparatus (i) the first set of identified locations are determined by sectoring the inner area of the target region into a set of sectors, and (ii) each sector within the set of sectors is sized to substantially match a coverage area of a beam footprint of the primary ultrasound transducer, when said primary ultrasound transducer is positioned at a center region of the sector and a contact surface of the probe assembly is in direct or indirect contact with a surface of the target region.

[0083] The invention also provides a method for dual mode ultrasound based tissue intervention, implemented through a transducer apparatus comprising a probe assembly, a probe manipulation assembly, and a processor implemented transducer state controller. The probe assembly includes a primary ultrasound transducer, wherein the transducer apparatus is configured for (i) receiving input identifying a target region for dual mode ultrasound, (ii) determining an external perimeter of the target region, and an inner area of the target region that is bounded by the determined external perimeter, and (iii) responsive to detection of an ultrasound session initiation event (a) manipulating the probe assembly to traverse a first set of identified locations within the inner area of the target region, and operating the primary ultrasound transducer under a first set of operating parameters at each location within the first set of identified locations, and (b) subsequently manipulating the probe assembly to traverse a second set of identified locations corresponding to the external perimeter of the target region, and operating the primary ultrasound transducer under a second set of operating parameters at each location within the second set of identified locations — wherein the first set of operating parameters is distinct from the second set of operating parameters.

[0084] In an embodiment of the method, the first set of operating parameters are configured for implementation of boiling histotripsy, and the second set of operating parameters are configured for implementation of mild hyperthermia.

[0085] In a further embodiment of the method (i) the first set of operating parameters comprises one or more of acoustic pressure (positive pressure) between 4 to 100 MPa peak positive pressure, acoustic pressure (negative pressure) between 2 to 20 MPa peak negative pressure, pulse length between 5 to 20 milliseconds, pulse repetition frequency between 0.5 and 5 Hz, total sonication time per location between 10 and 600 seconds, and transmit frequency between 1 MHz and 3 MHz, and (ii) the second set of operating parameters comprises one or more of acoustic pressure (positive pressure) between 1 to 5 MPa peak positive pressure, acoustic pressure (negative pressure) between 1 to 5 MPa peak negative pressure, duty cycle at 100%, total sonication time per location between 10 to 1800 seconds, and transmit frequency between 500 KHz and 2 MHz.

[0086] In a method embodiment, manipulation of the probe assembly to traverse the first set of identified locations and the second set of identified locations is implemented by manipulating a robotic arm to which the probe assembly is affixed.

[0087] In another method embodiment (i) the first set of identified locations are determined by sectoring the inner area of the target region into a set of sectors, and (ii) each sector within the set of sectors is sized to substantially match a coverage area of a beam footprint of the primary ultrasound transducer, when said primary ultrasound transducer is positioned at a center region of the sector and a contact surface of the probe assembly is in direct or indirect contact with a surface of the target region.

[0088] The invention additionally provides a computer program product for dual mode ultrasound based tissue intervention, implemented through a transducer apparatus, comprising a probe assembly, a probe manipulation assembly, and a processor implemented transducer state controller. The probe assembly includes a primary ultrasound transducer. The computer program product comprising a non-transitory computer usable medium having computer readable program code embodied therein, the computer readable program code comprising instructions for implementing at a processor, the steps of (i) receiving input identifying a target region for dual mode ultrasound, (ii) determining an external perimeter of the target region, and an inner area of the target region that is bounded by the determined external perimeter, and (iii) responsive to detection of an ultrasound session initiation event (a) manipulating the probe assembly to traverse a first set of identified locations within the inner area of the target region, and operating the primary ultrasound transducer under a first set of operating parameters at each location within the first set of identified locations, and (b) subsequently manipulating the probe assembly to traverse a second set of identified locations corresponding to the external perimeter of the target region, , and operating the primary ultrasound transducer under a second set of operating parameters at each location within the second set of identified locations — wherein the first set of operating parameters is distinct from the second set of operating parameters.

[0089] Figure 12 illustrates an exemplary system 1200 for implementing the present invention. The illustrated system 1200 comprises computer system 1202 which in turn comprises one or more processors 1204 and at least one memory 1206. Processor 1204 is configured to execute program instructions - and may be a real processor or a virtual processor. It will be understood that computer system 1202 does not suggest any limitation as to scope of use or functionality of described embodiments. The computer system 1202 may include, but is not be limited to, one or more of a general-purpose computer, a programmed microprocessor, a micro-controller, an integrated circuit, and other devices or arrangements of devices that are capable of implementing the steps that constitute the method of the present invention. Exemplary embodiments of a computer system 1202 in accordance with the present invention may include one or more servers, desktops, laptops, tablets, smart phones, mobile phones, mobile communication devices, tablets, phablets and personal digital assistants. In an embodiment of the present invention, the memory 1206 may store software for implementing various embodiments of the present invention. The computer system 1202 may have additional components. For example, the computer system 1202 may include one or more communication channels 1208, one or more input devices 1210, one or more output devices 1212, and storage 1214. An interconnection mechanism (not shown) such as a bus, controller, or network, interconnects the components of the computer system 1202. In various embodiments of the present invention, operating system software (not shown) provides an operating environment for various softwares executing in the computer system 1202 using a processor 1204, and manages different functionalities of the components of the computer system 1202.

[0090] The communication channel(s) 1208 allow communication over a communication medium to various other computing entities. The communication medium provides information such as program instructions, or other data in a communication media. The communication media includes, but is not limited to, wired or wireless methodologies implemented with an electrical, optical, RF, infrared, acoustic, microwave, Bluetooth or other transmission media.

[0091] The input device(s) 1210 may include, but is not limited to, a touch screen, a keyboard, mouse, pen, joystick, trackball, a voice device, a scanning device, or any another device that is capable of providing input to the computer system 1202. In an embodiment of the present invention, the input device (s) 1210 may be a sound card or similar device that accepts audio input in analog or digital form. The output device(s) 1212 may include, but not be limited to, a user interface on CRT, LCD, LED display, or any other display associated with any of servers, desktops, laptops, tablets, smart phones, mobile phones, mobile communication devices, tablets, phablets and personal digital assistants, printer, speaker, CD/DVD writer, or any other device that provides output from the computer system 1202.

[0092] The storage 1214 may include, but not be limited to, magnetic disks, magnetic tapes, CD- ROMs, CD-RWs, DVDs, any types of computer memory, magnetic stripes, smart cards, printed barcodes or any other transitory or non-transitory medium which can be used to store information and can be accessed by the computer system 1202. In various embodiments of the present invention, the storage 1214 may contain program instructions for implementing any of the described embodiments.

[0093] In an embodiment of the present invention, the computer system 1202 is part of a distributed network or a part of a set of available cloud resources.

[0094] The present invention may be implemented in numerous ways including as a system, a method, or a computer program product such as a computer readable storage medium or a computer network wherein programming instructions are communicated from a remote location.

[0095] The present invention may suitably be embodied as a computer program product for use with the computer system 1202. The method described herein is typically implemented as a computer program product, comprising a set of program instructions that is executed by the computer system 1202 or any other similar device. The set of program instructions may be a series of computer readable codes stored on a tangible medium, such as a computer readable storage medium (storage 1214), for example, diskette, CD-ROM, ROM, flash drives or hard disk, or transmittable to the computer system 1202, via a modem or other interface device, over either a tangible medium, including but not limited to optical or analogue communications channel(s) 1208. The implementation of the invention as a computer program product may be in an intangible form using wireless techniques, including but not limited to microwave, infrared, Bluetooth or other transmission techniques. These instructions can be preloaded into a system or recorded on a storage medium such as a CD-ROM, or made available for downloading over a network such as the Internet or a mobile telephone network. The series of computer readable instructions may embody all or part of the functionality previously described herein.

[0096] While the exemplary embodiments of the present invention are described and illustrated herein, it will be appreciated that they are merely illustrative. It will be understood by those skilled in the art that various modifications in form and detail may be made therein without departing from or offending the scope of the invention as defined by the appended claims. Additionally, the invention illustratively disclose herein suitably may be practiced in the absence of any element which is not specifically disclosed herein — and in a particular embodiment specifically contemplated, is intended to be practiced in the absence of any element which is not specifically disclosed herein.