CRYO-assisted irreversible electroporation (IRE) ablation system and method

Abstract

The cryo-assisted Irreversible Electroporation (IRE) ablation system includes an IRE ablation generator, a coolant supply, cryo-assisted IRE ablation stylet(s), and a cryo-assisted IRE ablation controller for controlling the IRE ablation generator and the cryo-assisted IRE ablation stylet(s). The ablation stylets include a stylet needle having longitudinally directed strip electrode(s) and a freezing module for cooling a longitudinal directed ice-forming surface for freezing a generally hemi-ellipsoidal volume of target tissue. The controller repeatedly switches the ablation stylets between an IRE ablation energy mode and a non-cryoablation freezing mode whereupon, in an absence of ice formation, each cryo-assisted IRE ablation stylet generates a pre-ice 3D electric field pattern in target tissue and, subsequent to a generally hemi-ellipsoidal ice formation, the ice formation modifies the pre-ice 3D electric field pattern to a post-ice 3D electric field pattern different from the pre-ice 3D electric field pattern.

Description

[0001] CRYO-ASSISTED IRREVERSIBLE ELECTROPORATION (IRE) ABLATION SYSTEM AND METHOD

[0002] Field of the Invention

[0003] The invention relates to Irreversible Electroporation (IRE) ablation system and method.

[0004] Background of the Invention

[0005] Irreversible Electroporation (IRE) ablation modality is a relatively recent tissue ablation modality originally introduced for treating tumors including malignant tumors, for example, prostate cancer, and more recently introduced for treating heart tissue. Instead of traditional temperature related ablation modalities using heat energy or cold energy respectively above and below physiological temperature, IRE ablation therapy uses short IRE energy bursts which enable tissue specific ablation at physiological temperatures while avoiding collateral damage to nearby structures.

[0006] IRE ablation typically employs monophase or bi-phase short IRE energy pulses in the region of upto 0.1 msec of 1.5kV-3kV electric energy compared to 30V - 60V RMS RF ablation. Tumorous cells are more prone to IRE ablation is based on the premise that healthy cells such as nerves and blood vessels have a much higher lethal electric field density than tumorous cells which have a lethal electric field density in the order of 400 V / cm to 800 V / cm, thereby enabling selective ablation. However, there is concern that, depending on the location of target tissue in a body organ or body tissue to be treated, and the required placement of IRE ablation needle electrodes to treat the target tissue, IRE ablation may not ablate all target tissue which may lead to undesirable high level of recurrence. One envisaged cause of high level of recurrence is that target tissue may be proximate to a large volume of fat tissue which leads to unablated “blind spots” due to its low electrical conductivity interfering with the IRE energy pulses. There is need for IRE ablation apparatus, system and method for effectively ablating lesions in a tumorous body organ or tissue.

[0007] Summary of the Invention

[0008] The present invention is to directed towards cryo-assisted Irreversible Electroporation (IRE) ablation systems and methods, cryo-assisted IRE ablation stylets and cryo-assisted IRE ablation controllers.

[0009] The cryo-assisted Irreversible Electroporation (IRE) ablation system includes an IRE ablation generator for providing at least one burst of IRE ablation energy wherein each at least one burst of IRE ablation energy includes at least one IRE ablation pulse and a coolant supply for providing coolant having a coolant temperature between from -5 °C to about 5 °C. The IRE ablation generator and the coolant supply are connected to one or more cryo- assisted IRE ablation stylets. The cryo-assisted IRE ablation stylets include an elongated flexible stylet catheter for connection with the cryo-assisted IRE ablation controller and the coolant supply, and an elongated rigid stylet needle mounted on the elongated flexible stylet catheter for introduction into target tissue in a tumorous body organ or body tissue. The elongated rigid stylet needle has a proximal stylet needle end and a distal stylet needle end. The distal stylet needle end has at least one longitudinally directed strip electrode for generating a 3D electric field pattern in target tissue and a freezing module including at least one thermoelectric device for cooling a longitudinal directed ice-forming surface circumferentially spaced apart from the at least one longitudinally directed strip electrode for freezing target tissue in the immediate vicinity of the longitudinally directed ice-forming surface. The cryo-assisted Irreversible Electroporation (IRE) ablation system includes a cryo-assisted IRE ablation controller for controlling the IRE ablation generator and the one or more cryo-assisted IRE ablation stylets for repeatedly switching a cryo-assisted IRE ablation stylet between two operation modes: an IRE ablation energy mode for energizing its at least one longitudinally directed strip electrode for delivering IRE ablation energy to target tissue and not operating its freezing module and a non-cryoablation freezing mode for freezing target tissue and not energizing its at least one longitudinally directed strip electrode whereupon, in an absence of ice formation in target tissue in the immediate vicinity of the cryo-assisted IRE ablation stylet, the cryo-assisted IRE ablation stylet generates a pre-ice 3D electric field pattern in target tissue and, subsequent to generation of a generally hemi-ellipsoidal volume of frozen target tissue in the immediate vicinity of the cryo-assisted IRE ablation stylet, the generally hemi-ellipsoidal volume of frozen target tissue modifies the preice 3D electric field pattern to a post-ice 3D electric field pattern different from the pre-ice 3D electric field pattern.

[0010] The present invention is based on the understanding that fat depots enclosing a body organ and ice have much lower electric conductivities than, for example, connective tissue, at physiological temperatures. Accordingly, fat depots can deform a 3D electric field pattern which can lead to certain locations within target tissue being subject to sub-lethal electric fields as required for IRE ablation. Such locations are in effect non-ablated volumes. Moreover, the present invention is based on the understanding that gradual ice formation in target tissue can be used to slowly modify a 3D electric field pattern from a pre-ice 3D electric field pattern to a post-ice 3D electric field pattern for subjecting previously non-ablated volumes to lethal electric fields thereby ensuring their IRE ablation. Such steering can enable a non-ablated volume to become an ablated lesion.

[0011] Operation of cryo-assisted IRE ablation stylets in their non-cryoablation freezing mode leads to rapid ice formation in target tissue from 37°C physiological temperature to about -30°C in a few seconds immediately adjacent their ice-forming surfaces. The frozen target tissue outwardly extends in a 3D maimer from by about 2 mm to about 5 mm from the longitudinally directed ice-forming surface, thereby assuming an about -10°C generally hemi- ellipsoidal volume of frozen target tissue in about 10 minutes. In comparison, US Publication No. 2024 / 005804 Al, to Babkin et al and assigned to Adagio Medical, Inc,. USA, describes a catheter which leads to a generally right cylindrical volume of frozen target tissue therearound at -40°C lethal cryoablation temperature. The right cylindrical volume has a typical radius of about 6 mm to about 7 mm. But such rapid ice formation may still lead to unintended highly limited cryoablation of a small volume of target tissue in their immediate vicinity similar to cryoablation. In comparison, typical temperatures of cryoablation technologies for destroying abnormal or diseased target tissue https: / / en.wikipedia.org / wiki / Cryoablation based on Joule- Thompson and liquid nitrogen are correspondingly about -120°C and -170°C.

[0012] Thereafter, the slow outward spreading of ice formation from the iceforming surfaces into target tissue takes considerably much longer. The slow outward spreading of ice formation can be considered as being similar to freezing biological matter, for example, sperm and oocytes, for preservation purposes. During the course of a cryo-assisted IRE ablation therapy, cryoassisted IRE ablation stylets are paradoxically almost entirely in their non- cryoablation freezing mode except for very short interruptions for delivering IRE ablation energy for forming an IRE ablation lesion in target tissue. The very short interruptions for switching to IRE ablation energy mode will not lead to any significant temperature increase in target tissue since target tissue has a large thermal capacitance.

[0013] Each freezing module intentionally gradually forms ice in target tissue so as to deliberately slowly modify a pre-ice 3D electric field pattern determining a pre-ice lethal 3D electric field contour to a post-ice lethal 3D electric field pattern determining a post-ice lethal 3D electric field contour. A post-ice lethal 3D electric field contour may be smaller than a pre-ice 3D lethal electric field contour, the same size as a pre-ice 3D lethal electric field contour, or larger than a pre-ice 3D lethal electric field contour. During the slow modification of a pre-ice 3D electric field pattern, target tissue is periodically subjected to IRE ablation energy such that previous non-ablated volumes become ablated lesions. Brief Description of Drawings

[0014] In order to understand the invention and to see how it can be carried out in practice, preferred embodiments will now be described, by way of nonlimiting examples only, with reference to the accompanying drawings in which similar parts are likewise numbered, and in which:

[0015] Fig. 1 is a combined pictorial view and block diagram of a commercially available Irreversible Electroporation (IRE) ablation system deployed for treating prostate cancer according to FDA approved Nanoknife™ protocol.

[0016] Fig. 2 is a transverse cross-section of a commercially available Irreversible Electroporation (IRE) ablation needle electrode along line 2-2 in Figure 1.

[0017] Fig. 3 is a schematic diagram of a 2D projection of a 3D electric field pattern on the Figure 1 cross-section A-A as generated by an IRE ablation needle electrode pair in accordance with the FDA approved Nanoknife™ protocol.

[0018] Fig. 4 is a combined pictorial view and block diagram of a cryo-assisted Irreversible Electroporation (IRE) ablation system including a cryo-assisted IRE ablation controller and multiple cryo-assisted IRE ablation stylets each having an elongated flexible stylet catheter and an elongated rigid stylet needle.

[0019] Fig. 5 is a close-up pictorial view of a cryo-assisted IRE ablation stylet’s elongated rigid stylet needle.

[0020] Fig. 6 is a close-up longitudinal cross-section of the cryo-assisted IRE ablation stylet’s elongated rigid stylet needle along Figure 5 line 6-6.

[0021] Fig. 7A is a close-up transverse cross-section of the cryo-assisted IRE ablation stylet’s elongated rigid stylet needle along Figure 6 line 7A-7A and a generally hemi-ellipsoidal shaped volume of frozen target tissue formed thereby.

[0022] Fig. 7B is a close-up front elevation of a cryo-assisted IRE ablation stylet’s elongated rigid stylet needle and a generally hemi-ellipsoidal shaped volume of frozen target tissue formed thereby. Fig. 8 is a schematic diagram of the cryo-assisted IRE ablation controller’s control logic.

[0023] Fig. 9 is a flow diagram of a cryo-assisted Irreversible Electroporation (IRE) ablation treatment method.

[0024] Fig. 10 is a schematic representation of a repeated switching between IRE ablation cycles and non-cryoablation freezing cycles.

[0025] Fig. 11 is a table showing parameter ranges of IRE ablation energy, IRE ablation bursts, and IRE ablation pulses of IRE ablation cycles, and non- cryoablation freezing cycles.

[0026] Fig. 12 is a close-up longitudinal cross-section of an alternative embodiment of a cryo-assisted IRE ablation stylet’s elongated rigid stylet needle.

[0027] Fig. 13 is a schematic diagram showing deployment of the cryo-assisted IRE ablation system for treating prostate cancer.

[0028] Fig. 14 is a schematic diagram of a 2D projection of the deployment of the cryo-assisted IRE ablation stylets on the Figure 13 cross-section A-A.

[0029] Fig. 15A is a table showing alternative 600 second cryo-assisted IRE ablation therapies.

[0030] FIG. 15B is a graphic representation of the first Figure 15A cryo- assisted IRE ablation therapy.

[0031] FIG. 15C is a graphic representation of the second Figure 15A cryo- assisted IRE ablation therapy.

[0032] Fig. 16 is a schematic diagram of a pre-ice 2D electric field pattern on the Figure 13 cross-section A-A as generated by Figure 4’s cryo-assisted IRE ablation system at T=10 seconds.

[0033] Fig. 17 is a schematic isotherm map on the Figure 13 cross-section A-A as generated by Figure 4’s cryo-assisted IRE ablation system at T=300 seconds.

[0034] Fig. 18 is a schematic diagram of a post-ice 2D electric field pattern on the Figure 13 cross-section A-A as generated by Figure 4’s cryo-assisted IRE ablation system at T=300 seconds. Fig. 19 is a schematic isotherm map on the Figure 13 cross-section A-A as generated by Figure 4’s cryo-assisted IRE ablation system at T=600 seconds.

[0035] Fig. 20 is a schematic diagram of a post-ice 2D electric field pattern on the Figure 13 cross-section A-A as generated by Figure 4’s cryo-assisted IRE ablation system at T=600 seconds.

[0036] Fig. 21 is a schematic diagram showing an oval shaped ablated lesion on the Figure 13 cross-section A-A at T=600 seconds.

[0037] Detailed Description of Drawings

[0038] The present description includes three sections

[0039] Section 1: Commercially Available Irreversible Electroporation (IRE) ablation system

[0040] Section 2: Cryo-assisted Irreversible Electroporation (IRE) ablation system Section 3: Cryo-assisted Irreversible Electroporation (IRE) ablation treatment method

[0041] Section 1: Commerciallv Available ablation svstem

[0042] Figure 1 shows an IRE ablation system 100 for treating a tumorous body organ or tissue, for example, a prostate, a kidney, etc, commercially available from inter alia Angiodynamics, Inc. under the brand name Nanoknife™. The IRE ablation system 100 include an IRE ablation generator 101 for providing IRE ablation energy, and an IRE ablation matrix 102 for assisting alignment and insertion of IRE ablation probes 103 into target tissue.

[0043] The IRE ablation generator 101 includes an operator interface 104 for setting an IRE ablation therapy and IRE ablation pulse parameters including inter alia the number of IRE ablation pulses, IRE ablation pulse duration, IRE ablation pulse voltage, IRE ablation pulse current, IRE ablation pulse repetition rate, and the like. Typical IRE ablation therapies include in the order of 200 to 300 IRE ablation pulses. Typical Nanoknife™ IRE ablation pulse specifications include: IRE ablation pulse duration of between about 40 -100 psec, IRE ablation pulse voltage 1.5 kV to 3 kV, and IRE ablation pulse current 10A to 50A. Each IRE ablation pulse delivers a considerable amount of electric energy in the order of 2 Joules to 7 Joules. The IRE ablation pulse repetition time between immediately consecutive IRE ablation pulses is several orders of magnitude longer than an IRE ablation pulse duration to enable electric energy to dissipate in surrounding tissue and limit raising its temperature above physiological temperatures. IRE ablation pulse repetition times are typically in the order of 0.5 sec to 1.0 sec.

[0044] IRE ablation probes 103 include an elongated flexible cable 106 terminating at an elongated rigid needle electrode 107. The cables 106 are typically about 1 m long and intended for connection to the IRE ablation generator 101. The needle electrodes 107 are typically cylindrical and have a length of about 10 cm to 15 cm and a diameter of about 1.5 mm to 2.5 mm (see Figure 2). Accordingly, the needle electrodes 107 generate a right cylindrical surrounding electric field.

[0045] Figure 1 shows a prostate 10, a rectum 11 and a bladder 12. The prostate 10 is surrounded by a specific fat depot called periprostatic adipose tissue (PPAT) 13. The prostate 10 and the PPAT 13 have an interface 14. The prostate 10 includes a target tissue 16 towards the interface 14 adjacent the rectum 11. Figure 1 also shows a cross-section A-A inclined at about 15° to a transverse plane and passing through the prostate 10, the rectum 11, the PPAT 13 and the interface 14.

[0046] For illustrative purposes, Figure 1 shows deployment of the IRE ablation system 100 for treating prostate cancer according to the FDA approved Nanoknife™ protocol employing three needle electrodes 107A-107C. The needle electrodes 107A-107C are deployed in a generally equilateral configuration with the needle electrode pair 107 A and 107B deployed towards the rectum 11 and the needle electrode 107C deployed more inwardly in the prostate 10. The needle electrode pair 107A and 107B define an inter needle electrode separation B therebetween from about 10 mm to about 15 mm and they are similarly spaced by a separation denoted A from the interface 13. On delivery of an IRE ablation pulse to the needle electrode pair 107A and 107B, the needle electrode pair 107A and 107B generate a 3D electric field pattern. Figure 3 shows a 2D projection of the 3D electric field pattern on the cross-section A-A as a 2D electric field pattern 20. The 2D electric field pattern 20 includes 2D electric field lines of decreasing electric field strength from a strongest 1750 V / cm 2D electric field line 21 immediately adjacent the needle electrode pair 107A and 107B via a 1000 V / cm 2D electric field line 22 to a 750 V / cm lethal 2D electric field line 23. The 750 V / cm lethal 2D electric field line 23 has a general triangular shape with a truncated apex 24 at the interface 14 due to the proximity of the needle electrode pair 107 A and 107B to the PPAT 13 and its low conductivity. The 750 V / cm lethal 2D electric field line 23 extends beyond the interface 14 into the rectum 11.

[0047] Each 2D electric field line is representative of a 3D electric field contour bounding a 3D volume. The general triangular shaped 750 V / cm lethal 2D electrical field line 22 corresponds to a mushroom shaped 750 V / cm lethal 3D electric field contour which bounds a 3D ablated lesion in which tumorous cells undergo IRE ablation. In other words, target tissue bounded by the 750 V / cm lethal 3D electric field contour undergoes IRE ablation and target tissue beyond the 750 V / cm lethal 3D electric field contour does not undergo IRE ablation. The mushroom shaped ablated lesion includes an ablated lesion cap and an ablated lesion stem. Tissue on opposite sides of the truncated apex 24 is not subject to the 750 V / cm lethal electric field contour, thereby leaving a toroidal shaped non-ablated volume surrounding the ablated lesion stem.

[0048] In this regard, reference is made to article “Comparison of ablation defect on MR imaging with computer simulation estimated treatment zone following IRE of patient prostate” by Srimathveeravalli et al., SpringerPlus (2016) 5:219 which is included herein by reference. The reference sets the lethal electrical field at a lower 700 V / cm than the present description’s more stringent 750 V / cm. The reference describes the toroidal-shaped non-ablated volume on page 2 of 9, Figure 4. Section 2: Cryo-assisted Irreversible Electroporation (IRE) ablation system

[0049] Figure 4 shows a cryo-assisted IRE ablation system 200 for treating a tumorous body organ or tissue, for example, a prostate, a kidney, etc. The cryo-assisted IRE ablation system 200 includes a cryo-assisted IRE ablation controller 201, an IRE ablation generator 202 for providing IRE ablation energy, a coolant circuit 203 for circulating coolant, and an IRE ablation matrix 204 similar to the IRE ablation matrix 102 for assisting alignment and insertion of cryo-assisted IRE ablation stylets 300 into target tissue. The IRE ablation generator 202 is a commercially available IRE ablation generator for providing IRE ablation energy. Suitable IRE ablation generators are commercially available from Vitave Tech, Czechia www.vitave.com. For example, the Omniporator generator.

[0050] The cryo-assisted IRE ablation stylets 300 include an elongated flexible stylet catheter 301 terminating at an elongated rigid stylet needle 302. The stylet catheters 301 are typically about 1 m long and intended for connection to the cryo-assisted IRE ablation controller 201 and the coolant circuit 203. The stylet needles 302 have a longitudinal stylet needle centerline 302CL and a length of about 10 cm to about 15 cm. The stylet needles 302 have truncated circular cross-section and a diameter of about 1.5 mm to about 2.5 mm cm (see Figure 7A).

[0051] The coolant circuit 203 includes a coolant source 206 for providing coolant, a pump 207 and a coolant drain 208 for receiving heated coolant after use. Suitable coolant sources 206 and coolant drains 208 can be a standard infusion bag with 0.9% saline and an empty standard infusion bag, respectively. The 0.9% saline can have an initial coolant temperature of between about -2°C to 5 °C and stays in a fluid phase during an entire IRE ablation therapy.

[0052] The cryo-assisted IRE ablation controller 201 includes an operator interface 209 for setting IRE ablation therapy protocols, namely, IRE ablation energy parameters and non-cryoablation freezing parameters. The operator interface 209 also provides operator information regarding coolant flow rate and the cryo-assisted IRE ablation stylets 300, for example, temperature measurements, and the like.

[0053] The cryo-assisted IRE ablation system 200 further includes a short circuit protection module 211 under the control of the cryo-assisted IRE ablation controller 201 for protecting the cryo-assisted IRE ablation stylets 300. As described hereinbelow, the cryo-assisted IRE ablation stylets 300 include Peltier thermoelectric devices which require protection from high local voltages induced from IRE ablation pulses. The short circuit protection module 211 can be implemented as a discrete module protecting all connected cryo- assisted IRE ablation stylets 300. Alternatively, each cryo-assisted IRE ablation stylet 300 can be provisioned with its individual short circuit protection module 211.

[0054] Figure 5, Figure 6, Figure 7 A and Figure 7B show a stylet needle 302 includes a proximal stylet needle end 303 and a distal stylet needle end 304 relative to the stylet catheter 301. The proximal stylet needle end 303 includes an elongated handheld grip 306 for assisting an operator’s manipulation of a cryo-assisted IRE ablation stylet 300. The distal stylet needle end 304 includes at least one longitudinally directed strip electrode 307 for delivering IRE ablation energy to target tissue for generating a 3D electric field therein. The stylet needle 302 includes a longitudinally spaced apart pair of longitudinally directed strip electrodes 307. Each longitudinally directed strip electrode 307 subtends an about 90° to about 180° arc angle a in the cryo-assisted IRE ablation stylet 300’s transverse cross-section. Alternatively, the at least one longitudinally directed strip electrode 307 can be circumferentially deployed adjacent to each other. In this case, the arc angle a bounds the side-by-side longitudinally directed strip electrodes 307.

[0055] The distal stylet needle end 304 includes a freezing module 308 for cooling a longitudinal directed ice-forming surface 309 for freezing at least some target tissue in its immediate vicinity. The longitudinally directed iceforming surface 309 similarly subtends an about 90° to about 150° arc angle 0 in the cryo-assisted IRE ablation stylet 300’s transverse cross-section. The longitudinally directed strip electrode(s) 307 and the longitudinally directed ice-forming surface 309 are necessarily circumferentially spaced apart.

[0056] The handheld grip 306 preferably includes a visual marker 311 for assisting an operator’s rotational orientation of the cryo-assisted IRE ablation stylet 300 in target tissue. The visual marker 311 preferably indicates either the longitudinally directed strip electrode 307 or the longitudinally directed iceforming surface 309. The distal stylet needle end 304 preferably includes an ultrasound marker 312 for assisting an operator’s rotational orientation of the cryo-assisted IRE ablation stylet 300 in target tissue. The ultrasound marker 312 preferably indicates either the longitudinally directed strip electrode 307 or the longitudinally directed ice-forming surface 309. The distal stylet needle end 304 includes a temperature sensor 313 for sensing target tissue’s temperature adjacent the longitudinal directed ice-forming surface 309 for input to the cryo-assisted IRE ablation controller 201.

[0057] Different manufacturing techniques can be employed for deploying the longitudinally directed strip electrode 307 along the distal stylet needle end 304. Such manufacturing techniques include inter alia pad printing with electrically conductive ink; a bonded flexible print circuit board, and the like. The longitudinally directed strip electrode 307 is in electrical connection with the cryo-assisted IRE ablation controller 201 and / or the IRE ablation generator 202.

[0058] The freezing module 308 can include an integral longitudinal directed ice-forming surface 309 or alternatively the freezing module 308 can be in high thermal connection with a longitudinal directed ice-forming surface 309. The longitudinal directed ice-forming surface 309 typically has an area of about 10 mm2to about 70 mm2. The freezing module 308 includes at least one thermoelectric device 314 connected to the cryo-assisted IRE ablation controller 201 for freezing the ice-forming surface 309. The freezing module 308 includes a series of, say, three to five, Peltier thermoelectric devices 314. The Peltier thermoelectric devices 314 each include an inwardly facing hot surface 316 and an outwardly facing cold surface 317 for freezing the ice- forming surface 309. Operation of the freezing module 308 can be reversed for thawing such that the inwardly facing hot surface 316 and the outwardly facing cold surface 317 are respectively an inwardly facing cold surface and an outwardly facing hot surface. The freezing module 308 preferably employs a jet impingement module 318 as described in US Patent No. 11,160,596 to Berger et al and assigned to Berger Thermal Research Ltd, Tel Aviv, Israel, the contents of which are included herein by reference.

[0059] The freezing module 308 is capable of freezing target tissue in immediate intimate contact with the ice-forming surface 309 from 37°C physiological temperature to about -30°C in a few seconds. The freezing module 308 freezes target tissue to form a generally hemi-ellipsoidal shaped volume of frozen target tissue 17. The freezing module 308 freezes transverse outwardly, upwardly and downwardly from its ice-forming surface 309 to generate an at about -10°C generally hemi-ellipsoidal volume of frozen target tissue 17 extending therefrom by about 2 mm to about 5 mm after about 10 minutes of operation. Figure 7A and Figure 7B show their respective cross sections of the generally hemi-ellipsoidal shaped volume of frozen target tissue 17.

[0060] The elongated flexible stylet catheter 301 includes a downstream coolant tube 319 for downstream flow of cold coolant from the coolant source 206 towards the freezing module 308 and an upstream coolant tube 321 for upstream flow of hot coolant from the freezing module 308 to the coolant source 206. Figure 7A shows coolant impinging from the downstream coolant tube 319 onto the Peltier thermoelectric device 314’s inwardly facing hot surface 316 before being returned to the coolant drain 208 via the upstream coolant tube 321. The circulating coolant maintains the longitudinally directed strip electrodes 307 above freezing temperature to prevent ice formation in target tissue in immediate intimate contact therewith.

[0061] Figure 8 shows the cryo-assisted IRE controller 201‘s control logic for operating a cryo-assisted IRE ablation stylet 300 and the short circuit protection module 211. For explanatory purposes, a cryo-assisted IRE ablation stylet 300’s freezing module 308 has an ON state and an OFF state, a cryoassisted IRE ablation stylet 300’s longitudinal directed strip electrode 307 has an ON state and an OFF state, and the short circuit protection module 211 has an ON state and an OFF state. The ON and OFF times are exemplary times to demonstrate orders of magnitude between the different ON and OFF states. The cryo-assisted IRE ablation controller 201 operates the short circuit protection module 211 for selectively short circuiting the freezing module 308 from before the IRE ablation energy mode until after the IRE ablation energy mode for protecting the freezing module 308 from high IRE energy bursts.

[0062] Figure 9 and Figure 10 show the cryo-assisted IRE controller 201 repeatedly switches a cryo-assisted IRE ablation stylet 300 between two operation modes as follows: a) an IRE ablation energy mode for delivering IRE ablation energy to target tissue and not operating its freezing module 308 and b) a non-cryoablation freezing mode for operating its freezing module 308 for freezing target tissue and not delivering IRE ablation energy. Each IRE ablation cycle includes at least one IRE ablation burst and each IRE ablation burst includes at least one IRE ablation pulse.

[0063] IRE ablation therapy protocols can include either monophasic or biphasic IRE ablation pulses or bipolar or unipolar ablation energy which affects their IRE ablation energy parameters and non-cryoablation freezing parameters. In the case of unipolar IRE ablation, an IRE ablation generator 202 ’s ground is connected to a return patch attached to a patient body. A return patch could be, for example, an IRE ablation matrix made from metallic material or having an electrically conductive coating. Bipolar IRE ablation pulses are activated between at least two cryo-assisted IRE ablation needles and the return patch. In the case of the bipolar IRE ablation, an IRE ablation generator 202 is connected to at least two cryo-assisted IRE ablation stylets needles and activates the IRE ablation pulses between them.

[0064] Figure 11 is a table showing parameter ranges of IRE ablation energy, IRE ablation bursts, and IRE ablation pulses of IRE ablation cycles, and of non-cryoablation freezing cycles. The FROM values and TO values are approximate values. During the course of a cryo-assisted IRE ablation therapy protocol, IRE ablation bursts can include the same number of IRE ablation pulses or different number of IRE ablation pulses. Similarly, other parameters may have the same or different values during the course of a cryo-assisted IRE ablation therapy protocol.

[0065] Figure 12 shows a cryo-assisted IRE ablation stylet 300 modified for enabling injection of liquid drugs to target tissue. The cryo-assisted IRE ablation stylet 300 includes an additional lumen 322 leading to a hollow stylet tip 323 provided with one or more injection apertures 324.

[0066] Section 3: Cryo-assisted Irreversible Electroporation (IRE) treatment method

[0067] The cryo-assisted IRE ablation system 200 can be employed for cryo- assisted IRE ablation therapy on a range of tumorous body organ or tissue to be treated. Cryo-assisted IRE ablation therapy depends on the tumorous body organ or tissue to be treated, the size and location of target tissue within a tumorous body organ or tissue to be treated, and the like.

[0068] Figure 13 shows the cryo-assisted IRE ablation system 200 deployed in a similar maimer as the IRE ablation system 100 for treating prostate cancer for enabling comparison of the present invention to FDA approved Nanoknife™ protocol. The cryo-assisted IRE ablation stylets 300A and 300B are deployed in the same positions as the IRE ablation probes 103A and 103B. Figure 13 shows the stylet needles 302A and 302B are deployed such their strip electrodes 307 A and 307B face away from the interface 14 and their iceforming surfaces 309A and 309B face toward the interface 14. Figure 14 shows the ice-forming surfaces 309A and 309B are not directly facing the interface 14 but rather are angled theretoward at an angle y where y ranges from 0° in which the ice-forming surfaces 309A and 309B directly face the interface 14 to about 60°.

[0069] For illustrative purposes only, the cryo-assisted IRE ablation system 200 is operated for a cryo-assisted IRE ablation therapy of T = 600 second. Cryo- assisted IRE ablation therapies can have shorter durations or longer durations. At the finish of a cryo-assisted IRE ablation therapy, frozen target tissue can be allowed to naturally thaw, thereby enabling removal of the cryo-assisted IRE ablation stylets 300A and 300B. Alternatively, operation of the cryo-assisted IRE ablation stylets 300 A and 300B can be temporarily reversed for heating frozen target tissue.

[0070] Figure 15A shows four 600 second cryo-assisted IRE ablation therapies demonstrating the ability to customize a cryo-assisted IRE ablation therapy to a particular medical instance. Figure 15B and Figure 15C show corresponding graphic representations of the first and second cryo-assisted IRE ablation therapies.

[0071] Figure 16 is similar to Figure 3 insofar as it shows 2D projections of 3D electric field patterns as 2D electric field patterns on the Figure 13 crosssection A- A, namely, a pre-ice 2D electric field pattern 30A at T=10 seconds. Similar to the 2D electric field pattern 20, the pre-ice 2D electric field pattern 30A includes 2D electric field lines decreasing from a strongest 1750 V / cm 2D electric field line 31 immediately adjacent the stylet needle pair 302A and 302B via a 1000 V / cm lethal 2D electric field line 32 to a 750 V / cm lethal 2D electric field line 33 displaced from the stylet needle pair 302 A and 302B. The pre-ice 2D electric field pattern 30A is highly similar to the 2D electric field pattern 20 insofar as it also has a general triangular shape with a truncated apex 34 at the interface 14.

[0072] The two major differences between the pre-ice 2D electric field pattern 30A and the 2D electric field pattern 20 by virtue of the cryo-assisted IRE ablation stylet pair 300A and 300B having strip electrodes 307A and 307B as opposed to the needle electrodes 107A and 107B are as follows: First, in the immediate vicinity of the cryo-assisted IRE ablation stylet needle pair 302 A and 302B themselves. And second, the pre-ice 2D electric field pattern 30A extends further beyond the interface 14 than the 2D electric field pattern 20. Notwithstanding the differences, at the outset of the cryo-assisted IRE ablation therapy, tissue on opposite sides of the truncated apex 34 is not subject to the 750 V / cm lethal electric field, thereby leaving a toroidal shaped non-ablated volume surrounding the ablated lesion stem.

[0073] Figure 17 is a schematic isotherm map on the Figure 13 cross-section A- A as generated by the cryo-assisted IRE ablation system 200 at T=300 seconds. Figure 17 shows that each cryo-assisted IRE ablation stylet 300 freezes its iceforming surface 309 to -30°C such that the cryo-assisted IRE ablation stylet needle pair 302 A and 302B generate outwardly facing generally hemi- ellipsoidal volumes of frozen target tissue reaching the interface 14.

[0074] Figure 18 is similar to Figure 3 insofar as it shows 2D projections of 3D electric field patterns as 2D electric field patterns on the Figure 13 crosssection A- A, namely, an intermediate 2D electric field pattern 30B at T=300 seconds. The intermediate 2D electric field pattern 30B includes 2D electric field lines decreasing from the strongest 1750 V / cm 2D electric field line 31 immediately adjacent the cryo-assisted IRE ablation stylet needle pair 302A and 302B via the 1000 V / cm 2D electric field 32 to the 750 V / cm lethal 2D electric field line 33. The intermediate 2D electric field pattern 30B has a smaller a toroidal shaped non-ablated volume surrounding the ablated lesion stem than the pre-ice 2D electric field pattern 30A.

[0075] Figure 19 is a schematic isotherm map on the Figure 13 cross-section A- A as generated by the cryo-assisted IRE ablation system 200 at T=600 seconds. Figure 19 shows that each cryo-assisted IRE ablation stylet 300 freezes its iceforming surface 309 to -30°C such that the cryo-assisted IRE ablation stylet needle pair 302 A and 302B generate outwardly facing generally hemi- ellipsoidal volumes of frozen tissue toward the interface 14 and beyond.

[0076] Figure 20 is similar to Figure 3 insofar as it shows 2D projections of 3D electric field patterns as 2D electric field patterns on the Figure 13 crosssection A-A, namely, a post-ice 2D electric field pattern 30C at T=600 seconds. The post-ice 2D electric field pattern 30C includes 2D electric field lines decreasing from the strongest 1750 V / cm 2D electric field line 31 immediately adjacent the cryo-assisted IRE ablation stylet needle pair 302A and 302B via the 1000 V / cm 2D electric field 32 to the 750 V / cm lethal 2D electric field line 33. The post-ice 2D electric field pattern 30C has a considerably different shape to the pre-ice 2D electric field pattern 30A insofar as the latter 30C has a general infinity shape compared to the former 30A’s general triangular shape with a truncated apex.

[0077] The two major differences between the post-ice 2D electric field pattern 30C and the 2D electric field pattern 20 due to the cryo-assisted IRE ablation stylet needle pair 302 A and 302B having strip electrodes 307 A and 307B as opposed to the needle electrodes 107A and 107B are as follows: First, the 750 V / cm lethal 2D electric field line 33 no longer encompasses the pre-ice 2D electric field pattern 30A’s truncated apex 34 which was previously ablated at the start of the cryo-assisted IRE ablation therapy. And second, the 750 V / cm lethal 2D electric field line 33 encompasses the opposite sides of the pre-ice 2D electric field pattern 30A’s truncated apex 34 such that towards the finish of the cryo-assisted IRE ablation therapy, target tissue on opposite sides of the previous truncated apex 34 is now subject to the 750 V / cm lethal electric field, thereby ablating the previous toroidal shaped 3D non-ablated volume.

[0078] Figure 21 shows an oval shaped ablated lesion 36 at T=600 seconds which shows the cryo-assisted IRE ablation has effectively enlarged the Figure 3’s mushroom shaped ablated lesion to include its toroidal shaped non-ablated volume such that the oval shaped ablated lesion 36 has a generally ellipsoidal shape.

[0079] While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications, and other applications of the invention can be made within the scope of the appended claims.

Claims

Claims:

1. A cryo-assisted Irreversible Electroporation (IRE) ablation system comprising: a) an IRE ablation generator for providing at least one burst of IRE ablation energy wherein each at least one burst of IRE ablation energy includes at least one IRE ablation pulse; b) a coolant supply for providing coolant having a coolant temperature between from -5 °C to about 5 °C; c) at least one cryo-assisted IRE ablation stylet including: i) an elongated flexible stylet catheter for connection with the cryo- assisted IRE ablation controller and the coolant supply, and ii) an elongated rigid stylet needle mounted on the elongated flexible stylet catheter for introduction into target tissue in a tumorous body organ or body tissue, the elongated rigid stylet needle having a proximal stylet needle end and a distal stylet needle end, the distal stylet needle end having at least one longitudinally directed strip electrode for generating a 3D electric field pattern in target tissue, and a freezing module including at least one thermoelectric device for cooling a longitudinal directed ice-forming surface circumferentially spaced apart from the at least one longitudinally directed strip electrode for freezing a generally hemi-ellipsoidal volume of target tissue in the immediate vicinity of the longitudinally directed ice-forming surface; and d) a cryo-assisted IRE ablation controller for controlling the IRE ablation generator and each at least one cryo-assisted IRE ablation stylet for repeatedly switching a cryo-assisted IRE ablation stylet between two operation modes: an IRE ablation energy mode for energizing its at least one longitudinally directed strip electrode for delivering IRE ablation energy to target tissue and not operating its freezing module, anda non-cryoablation freezing mode for operating its freezing module for freezing target tissue and not energizing its at least one longitudinally directed strip electrode, whereupon, in an absence of ice formation in target tissue in the immediate vicinity of the cryo-assisted IRE ablation stylet, the cryo-assisted IRE ablation stylet generates a pre-ice 3D electric field pattern therein and, subsequent to generation of a generally hemi-ellipsoidal volume of frozen target tissue in the immediate vicinity of the cryo-assisted IRE ablation stylet, the generally hemi-ellipsoidal volume of frozen target tissue modifies the preice 3D electric field pattern to a post-ice 3D electric field pattern different from the pre-ice 3D electric field pattern.

2. The system according to claim 1 wherein the cryo-assisted IRE ablation controller further controls a short circuit protection module for selectively short circuiting a cryo-assisted IRE ablation stylet’s freezing module from before the IRE ablation energy mode until after the IRE ablation energy mode.

3. The system according to claim 2 wherein a cryo-assisted IRE ablation stylet includes a short circuit protection module under the control of the cryo- assisted IRE ablation controller.

4. The system according to any one of claims 1 to 3 wherein a cryo- assisted IRE ablation stylet’s proximal stylet needle end includes a visual marker for assisting an operator’s rotational orientation of the cryo-assisted IRE ablation stylet in target tissue.

5. The system according to any one of claims 1 to 4 wherein a cryo- assisted IRE ablation stylet’s distal stylet needle end includes an ultra-sound marker for assisting an operator’s rotational orientation of the cryo-assisted IRE ablation stylet in target tissue.

6. The system according to any one of claims 1 to 5 wherein a cryoassisted IRE ablation stylet’s distal stylet needle end includes a temperature sensor for sensing the target tissue’s temperature adjacent the longitudinal directed ice-forming surface.

7. The system according to any one of claims 1 to 6 wherein a cryoassisted IRE ablation stylet’s each at least one longitudinally directed strip electrode subtends an about 90° to about 180° arc angle in a transverse crosssection of the cryo-assisted IRE ablation stylet.

8. The system according to any one of claims 1 to 7 wherein a cryoassisted IRE ablation stylet’s ice-forming surface subtends an about 90° to about 150° arc angle in a transverse cross-section of the cryo-assisted IRE ablation stylet.

9. The system according to any one of claims 1 to 8 for providing coolant to a cryo-assisted IRE ablation stylet at a flow rate of between about 20 ml / minute to 50 ml / minute to maintain its longitudinally directed strip electrode above freezing temperature.

10. A cryo-assisted Irreversible Electroporation (IRE) ablation stylet for use in the cryo-assisted Irreversible Electroporation (IRE) ablation system according to any one of claims 1 to 9.

11. A cryo-assisted IRE ablation controller for use in the cryo-assisted Irreversible Electroporation (IRE) ablation system according to any one of claims 1 to 9.

12. A cryo-assisted Irreversible Electroporation (IRE) ablation method comprising the steps of:a) providing an IRE ablation generator for providing IRE ablation energy at least one burst of IRE ablation energy wherein each at least one burst of IRE ablation energy includes at least one IRE ablation pulse; b) providing a coolant supply for providing coolant having a coolant temperature between from -5°C to about 5°C; c) providing at least one cryo-assisted IRE ablation stylet including: i) an elongated flexible stylet catheter for connection with the cryoassisted IRE ablation controller and the closed coolant circuit; and ii) an elongated rigid stylet needle mounted on the elongated flexible stylet catheter for introduction into target tissue in a tumorous body organ or body tissue, the elongated rigid stylet needle having a proximal stylet needle end and a distal stylet needle end, the distal stylet needle end having at least one longitudinally directed strip electrode for generating a 3D electric field pattern in target tissue, and a freezing module including at least one thermoelectric device for cooling a longitudinal directed ice-forming surface circumferentially spaced apart from the at least one longitudinally directed strip electrode for freezing a generally hemi-ellipsoidal volume of target tissue in the immediate vicinity of the longitudinally directed ice-forming surface; and d) providing a cryo-assisted IRE ablation controller for controlling the IRE ablation generator and each at least one cryo-assisted IRE ablation stylet, the cryo-assisted IRE ablation controller repeatedly switching a cryo- assisted IRE ablation stylet between two operation modes: an IRE ablation energy mode for energizing its at least one longitudinally directed strip electrode for delivering IRE ablation energy to target tissue and not operating its freezing module, and a non-cryoablation freezing mode for operating its freezing module for freezing target tissue and not energizing its at least one longitudinally directed strip electrode,whereupon, in an absence of ice formation in target tissue in the immediate vicinity of the cryo-assisted IRE ablation stylet, the cryo-assisted IRE ablation stylet generates a pre-ice 3D electric field pattern therein and, subsequent to generation of a generally hemi-ellipsoidal volume of frozen target tissue in the immediate vicinity of the cryo-assisted IRE ablation stylet, the generally hemi-ellipsoidal volume of frozen target tissue modifies the preice 3D electric field pattern to a post-ice 3D electric field pattern different from the pre-ice 3D electric field pattern.

13. The method according to claim 12 and further comprising the step of selectively short circuiting a cryo-assisted IRE ablation stylet’s freezing module from before the IRE ablation energy mode until after the IRE ablation energy mode.

14. The method according to either claim 12 or 13 and further comprising the step of providing coolant to a cryo-assisted IRE ablation stylet at a flow rate of between about 20 ml / minute to 50 ml / minute to maintain its longitudinally directed strip electrode above freezing temperature.

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