Pulsed-field electroporation system and method

Abstract

The improved systems described herein comprise one or more pulsed-field electroporation (PFE) electrodes configured to be localized in a target tissue, such as the ear, nose, or throat, and to produce a targeted PFE output.

Description

Technical Field

[0001] Cross - reference to related patent applications This application claims the benefit of U.S. Patent Application No. 18 / 630,653, filed April 9, 2024; U.S. Patent Application No. 18 / 623,681, filed April 1, 2024; U.S. Patent Application No. 18 / 616,916, filed March 26, 2024; U.S. Patent Application No. 18 / 613,827, filed March 22, 2024; U.S. Patent Application No. 63 / 536,339, filed September 1, 2023; and U.S. Patent Application No. 63 / 504,510, filed May 26, 2023. The entire contents of each of these related applications are incorporated herein by reference.

[0002] This disclosure relates to Pulsed Field Electroporation (PFE), such as a PFE system used in otolaryngology (ENT: Ear, Nose, and Throat) procedures.

Background Art

[0003] PFE is a type of electrostimulation therapy that involves delivering short high - amplitude electrical pulses to a patient's target tissue. These electrical pulses create temporary pores in the cell membranes of affected cells, causing membrane permeabilization without substantial damage to the cells. PFE can be used, for example, to treat unwanted or diseased tissue by triggering the regeneration of healthy and natural tissue at the site where the stimulation is applied.

[0004] Chronic rhinitis is a condition characterized by inflammation of the nasal mucosa, leading to persistent symptoms such as nasal congestion, runny nose, sneezing, and nasal itching. It can be triggered by a variety of factors, including allergies, infections, irritants, or structural abnormalities within the nose. Chronic rhinitis can affect several parts of the body, primarily the nasal cavity and adjacent structures. Inflammation of the nasal mucosa can lead to swelling and congestion of the nasal passages, making it difficult to breathe through the nose. Chronic rhinitis can even extend to the sinuses, which are air-filled cavities located around the nasal cavity.

[0005] When treating chronic rhinitis or other tissues within the nasal cavity, practitioners may assess factors such as time, patient comfort, and the risk of damage to healthy tissue and adjacent structures. The length of time required to perform such a procedure in the nasal cavity can vary significantly, especially if the procedure involves the delivery of thermal ablation energy, such as radiofrequency (RF), cryoablation (CA), or laser, to treat nasal symptoms. PFE therapy differs from these thermal ablation procedures, at least because each of RF, CA, and lasers uses thermal energy to intentionally induce cell death through a process called "necrosis." In doing so, the use of these thermal ablation techniques can cause significant temperature changes in the target tissue area (significantly higher or lower than normal body temperature, such as a tissue temperature rise of 10°C or more), which can cause inflammation (and often painful crusting) along the ablated tissue. In doing so, these thermal ablation techniques may also increase the risk of unintentional damage to healthy tissue in certain cases. For example, if RF ablation energy is delivered to a target tissue area, and then immediately afterward, further thermal energy is delivered so that the first and second lesions overlap, the overlapping ablation area may have a higher risk of severe crusting or scabbing compared to non-overlapping lesions. Furthermore, these thermal ablation devices (e.g., RF, CA, and lasers) may cause complications during nasal procedures, where the thermal profile may extend their ablation effect beyond the target tissue type to other types of tissue and adjacent structures. For instance, during such necrotic energy delivery, the expansion of the ablation effect beyond the target tissue may lead to unintended damage to critical structures such as arteries and nerves that are close to the active electrode or exposed to high temperatures for extended periods. [Overview of the project] [Means for solving the problem]

[0006] Some embodiments described herein may include improved systems configured to access, engage, and controllably deliver pulsed-field electroporation (PFE) to target tissues within the ear, nose, and throat, such as target locations in the posterior nasal nerve region, inferior turbinate region, posterior palatine region, posterior lingual region, hypopharyngeal region, pterygopalatine ganglion region, Eustachian tube, nasal cavity, paranasal sinuses, trigeminal nerve region, tonsils, or adenoid region. In certain embodiments, PFE can induce electroporation in the target tissue and stimulate one or more nerves adjacent to the target tissue. As will be described in more detail below, some embodiments of the system can induce localized PFE by using an electric field applied to the target tissue in a rapid burst to cause irreversible electroporation (IRE). This induces destabilization of the cell membrane, which leads to a specific type of cell death called "apoptosis." Therefore, these embodiments of PFE devices can treat target tissue to induce apoptosis, a cell death process similar to that of a natural and controllable part of anatomical growth or development, while avoiding the thermal ablation energy (e.g., from RF, CA, or laser ablation) that induces necrosis as described above. Optionally, the PFE systems described herein can be configured to output PFE that selectively targets a given tissue type to be treated, thereby reducing cellular inflammation and avoiding complications associated with conventional thermal ablation energy (e.g., from RF, CA, or laser ablation) that have ablation effects extending beyond the targeted therapeutic area.

[0007] According to several embodiments described herein, improved PFE systems may integrate PFE to more effectively treat target tissue while reducing the likelihood of damaging non-target tissue (which may occur with necrotic ablation devices such as RF ablation, CA ablation, or laser ablation systems). For example, the improved systems described herein may be configured to output PFE to selectively and non-thermally open cellular pores in target tissue to induce apoptosis, which can reduce the likelihood of damaging non-target tissue such as blood vessels and nerves. In many cases, the improved systems can perform such treatments without the use of general anesthesia on the patient, thereby providing additional convenience to both the user and the patient. For example, the improved systems can perform such treatments using local anesthetics at the treatment site. Optionally, some versions of the improved systems with integrated PFE may also be used to more efficiently deliver drugs such as steroids to target tissue compared to systems that treat tissue without PFE. Methods for tracking treated anatomical spaces and relating the treated spaces to outcomes are also disclosed.

[0008] In some of the options described herein, the system may be configured to deliver PFE to target tissue for one or both of two different effects. The first type relates to irreversible electroporation (IRE), which triggers cell death by the apoptotic process described above, as described above, and the second type is reversible electroporation (RE), in which the pores of the cell membrane are enlarged so that large molecule drugs such as steroids can permeate the cell membrane without inducing apoptosis. Both irreversible and reversible electroporation are non-thermal, meaning that these types of electroporation therapies do not deliver thermal ablation energy (e.g., heat from RF ablation instruments) that kills cells by necrosis.

[0009] In the various embodiments described below, the waveform of the PFE system can be controlled to stimulate nerves located in close proximity to the electroporation electrodes of the PFE device. For example, an electrical pulse can propagate an action potential through the patient's nerve, thus stimulating nerve activity. In some examples, the nerve stimulating effect of PFE is desired, resetting nerve activity and thus resulting in normal nerve signaling transmission. Optionally, this method of PFE can have the added advantage that nerve activity can be tuned in such a way to potentially alleviate neuralgia.

[0010] In some embodiments, a PFE device can deliver PFE having at least two different frequency components. For example, the PFE may include a sequence of bursts of electrical pulses occurring at a first frequency. Each of these bursts may include a train of high-frequency pulses at a second frequency significantly higher than the first frequency. The high-frequency bursts may induce irreversible electroperforation leading to apoptosis as described above. The gaps between the high-frequency bursts allow for nerve stimulation of nerves adjacent to the target tissue. This is because action potentials induced by electrical stimulation at the first frequency may not induce stimulation of nerves at the second frequency (high frequency). The gaps between individual pulses in a burst may be too small to allow stimulation in this manner.

[0011] In any embodiment detailed below, a machine learning model can be implemented with the PFE system to determine the dosage of PFE treatment based on a specific procedure to be performed and the type of tissue detected adjacent to the instrument for delivering PFE. For example, the machine learning model can receive endoscopic data indicating the position of the instrument relative to one or more anatomical features (e.g., tissue type). The machine learning model can independently determine the PFE dosage based on the endoscopic data without user input. Additionally or alternatively, the machine learning algorithm can enable PFE activation, readjust one or more PFE pulse parameters (e.g., frequency, amplitude), activate a neurostimulatory effect when a specific anatomical structure is detected in the endoscopic data, or any combination thereof. In one embodiment, if the machine learning model indicates that the PFE electrode is within the inferior turbinate region, it can deliver a PFE pulse to a PFE instrument configured to treat the inferior turbinate. By using a machine learning model to determine treatment based on endoscopic data, the system can improve the delivery of PFE treatment compared to a system that does not use a machine learning model to determine treatment.

[0012] Some embodiments described herein include systems comprising a PFE delivery device. The PFE delivery device may include a handle, an elongated shaft extending distally from the handle, and a treatment tip (having a PFE electrode) at the distal end of the elongated shaft. Optionally, the treatment tip may have an expandable PFE electrode for securing the PFE device in place so that the treatment tip is configured to deliver PFE from the PFE electrode into the nasal tissue.

[0013] Some embodiments described herein include methods for delivering PFE treatment. The method may include inserting the elongated shaft of a PFE delivery device into a site in the ear, nose, or throat such that the PFE electrode at the therapeutic tip of the PFE delivery device at its distal end is adjacent to the target tissue. The method may optionally include adjusting the PFE electrode relative to the elongated shaft. Additionally, the method may include activating a PFE generator on a control console connected to the PFE delivery device to output an electric field in a predefined pattern from the PFE electrode to induce at least one of irreversible electroporation (IRE) and reversible electroporation (IE) in the target tissue.

[0014] Some embodiments of this specification include a system comprising a pulsed-field electroporation (PFE) generator configured to output pulsed PFE. The system may also include a touchscreen interface coupled to the generator, configured to receive user input to control the PFE characteristics output from the generator. In some embodiments, the touchscreen interface may be connected to an endoscope system so that the touchscreen interface can display endoscope imaging data in real time. This imaging data may indicate the position of the PFE instrument relative to one or more anatomical features. Optionally, the system may include a PFE delivery instrument comprising an elongated shaft and a PFE electrode for delivering PFE from the PFE generator to at least one of the following locations: posterior nasal nerve region, inferior turbinate region, posterior palatine region, posterior lingual region, hypopharyngeal region, pterygopalatine ganglion region, Eustachian tube, nasal cavity, sinuses, trigeminal nerve region, tonsils, adenoid region, and other ear, nose, and throat regions.

[0015] Further embodiments described herein include methods for using a PFE instrument. The method may include advancing the treatment tip of the PFE instrument into a subject so that the PFE electrode along the treatment tip is in close proximity to the target site. Optionally, the method may include outputting a PFE waveform from the PFE electrode at the treatment tip to induce apoptosis at the target site and / or to stimulate nerves adjacent to the target site.

[0016] Additional embodiments described herein include PFE methods for treating target tissues of the ear, nose, or throat, preferably without the application of general anesthesia. The method may include the step of pressing a PFE electrode against the target tissue while emitting a PFE waveform from the PFE electrode.

[0017] Some embodiments described herein include methods for delivering pulse waveforms to target tissue in the ear, nose, or throat, preferably without raising the temperature of the target tissue above 5°C, and thus safely avoiding the necrosis associated with the thermal ablation techniques described above. The method may include advancing the treatment tip of a PFE instrument so that the PFE electrode along the treatment tip is in close proximity to the target tissue in the ear, nose, or throat. Optionally, the method may include outputting a PFE waveform from the PFE electrode at the treatment tip to induce apoptosis in the target tissue. Since the PFE waveform includes pulses for non-thermal treatment with little to no temperature change in the target tissue (preferably a change of 0-5°C), again to avoid the necrosis and associated side effects of the thermal ablation techniques described above, the PFE instrument can treat the target tissue via apoptosis, which triggers healthy and natural tissue regeneration at the treatment site.

[0018] Several implementations described herein include a PFE system configured to deliver PFE pulses to nasal tissue. The PFE system may include a handheld PFE tool and a PFE control console. The handheld PFE tool may optionally include a handle, an elongated shaft extending distally from the handle toward a bendable distal shaft portion, and a bulbous therapeutic tip extending distally from the bendable distal shaft portion. The bulbous therapeutic tip may include a PFE electrode configured to deliver PFE pulses to nasal tissue adjacent to the bulbous therapeutic tip, and the bulbous therapeutic tip may have a maximum lateral width of less than 5 mm and may be insertable into the nasal canal. Optionally, the PFE control console may be configured to accept a connector for the handheld PFE tool and may include a user interface display and a PFE generator. The PFE generator of the PFE control console may be optionally configured to output a pulsed field from the PFE electrode according to a predefined pulse pattern having a voltage in the range of 850V to 10,000V and a pulse duration of 0.05 microseconds (μs) to 3 μs in order to induce irreversible electroperforation in nasal tissue.

[0019] The specific implementation described herein includes a PFE system comprising an electrical stimulation tool. The electrical stimulation tool may include a handle, an elongated shaft extending distally from the handle, and one or more electrodes at the distal end of the elongated shaft. Optionally, the electrical stimulation tool of the PFE system may be configured to deliver electrical stimulation therapy to the patient's nasal tissue via one or more electrodes, the electrical stimulation therapy may induce electroperforation in the nasal tissue and stimulate one or more nerves adjacent to one or more electrodes.

[0020] Further implementations described herein include a PFE system comprising an electrical stimulation tool and an endoscope. The electrical stimulation tool may include a handle, an elongated shaft extending distally from the handle, and one or more electrodes at the distal end of the elongated shaft that can be inserted into the nasal passage. Preferably, the electrical stimulation tool is configured to induce electroperforation in the nasal tissue via one or more electrodes, while the endoscope is configured to capture the distal end portion within the patient's nasal passage.

[0021] Some implementations described herein include methods for providing PFE treatment in the ear, nose, or throat. The method may include the step of inserting the elongated shaft of a handheld PFE tool into the ear, nose, or throat such that one or more electrodes located at the distal end of the elongated shaft are adjacent to the target tissue. Optionally, the method may include the delivery of PFE pulses from one or more electrodes of the handheld PFE tool, following a computer-controlled decision to initiate electrical stimulation treatment to the target tissue.

[0022] Certain implementations described herein include a PFE system having a generator configured to deliver PFE therapy via an electrical stimulation tool to induce irreversible electroperforation in target tissue. The PFE system may optionally include a PFE console that includes at least one machine learning algorithm executable by the PFE console's processor to detect anatomical regions, determine whether to enable or disable PFE therapy delivery, superimpose graphics of the PFE field adjacent to the medical image of the electrical stimulation tool, or a combination thereof.

[0023] The implementations described herein may include any or all of the following features. Other features, embodiments, and potential advantages will become apparent from the accompanying description and figures. [Brief explanation of the drawing]

[0024] [Figure 1]Perspective view of a system for treating ear, nose, or throat tissue, according to some embodiments. [Figure 2] Perspective view of the PFE console, user interface, and instrument of the system of FIG. 1, according to some embodiments. [Figure 3] Perspective view of the instrument of FIG. 2, according to some embodiments. [Figure 4] Diagram showing an example of a PFE waveform output by the system of FIG. 1, according to some embodiments. [Figure 5] Side view of the distal portion of the PFE delivery instrument of the system of FIG. 1 and side view of the distal portion of an endoscope. [Figure 6A] Side view of the distal portion of a PFE delivery instrument for optional use with the system of FIG. 1, according to some alternative embodiments. [Figure 6B] Side view of the distal portion of a PFE delivery instrument for optional use with the system of FIG. 1, according to some alternative embodiments. [Figure 7] Side view of the distal portion of another PFE delivery instrument for optional use with the system of FIG. 1, according to some alternative embodiments. [Figure 8A] Side view of the distal portion of another PFE delivery instrument for optional use with the system of FIG. 1, according to some alternative embodiments. [Figure 8B] Side view of the distal portion of another PFE delivery instrument for optional use with the system of FIG. 1, according to some alternative embodiments. [Figure 9] Cross-sectional view of the nasal region having internally the PFE delivery instrument of the system of FIG. 1 and any return electrode, according to some embodiments. [Figure 10] Cross-sectional view of the nasal region having internally another PFE delivery instrument having a bipolar electrode configuration for optional use with the system of FIG. 1, according to some alternative embodiments. [Figure 11] Cross-sectional view of the nasal cavity having internally the PFE delivery instrument of the system of FIG. 1, according to some embodiments. [Figure 12] This is a cross-sectional view of the trigeminal nerve region containing a PFE delivery device within the system of Figure 1, according to several embodiments. [Figure 13] This is a cross-sectional view of the throat having a PFE delivery device inside the system of Figure 1, according to several embodiments. [Figure 14A] This figure shows endoscopic medical images of the instrument of the system in Figure 1, including a visual representation of the projected PFE field according to several embodiments. [Figure 14B] This figure shows endoscopic medical images of the instrument of the system in Figure 1, including a visual representation of the projected PFE field according to several embodiments. [Figure 14C] This figure shows endoscopic medical images of the instrument of the system in Figure 1, including a visual representation of the projected PFE field according to several embodiments. [Figure 14D] This figure shows endoscopic medical images of the instrument of the system in Figure 1, including a visual representation of the projected PFE field according to several embodiments. [Figure 14E] This figure shows endoscopic medical images of the instrument of the system in Figure 1, including a visual representation of the projected PFE field according to several embodiments. [Figure 14F] This figure shows endoscopic medical images of the instrument of the system in Figure 1, including a visual representation of the projected PFE field according to several embodiments. [Figure 15] This is a flowchart illustrating an exemplary method for generating a PFE field corresponding to a PFE delivery device and overlaying the PFE field onto image data. [Figure 16A] This figure shows endoscopic medical images of the instruments of the system shown in Figure 1 relative to anatomical landmarks, according to several embodiments. [Figure 16B] This figure shows endoscopic medical images of the instruments of the system shown in Figure 1 relative to anatomical landmarks, according to several embodiments. [Figure 16C] This figure shows endoscopic medical images of the instruments of the system shown in Figure 1 relative to anatomical landmarks, according to several embodiments. [Figure 16D] This figure shows endoscopic medical images of the instruments of the system shown in Figure 1 relative to anatomical landmarks, according to several embodiments. [Figure 17] This is a flowchart illustrating an exemplary method for processing endoscopic image data to automatically determine whether to initiate PFE output using a PFE delivery device. [Figure 18] This is a cross-sectional view of the tonsil and adenoid region having a PFE delivery device inside the system of Figure 1, according to several embodiments. [Figure 19] This is a side view of any device of the system shown in Figure 1, configured to stimulate neurons. [Figure 20] A side view of an arbitrary instrument of the system shown in Figure 1, configured to treat the synapses of neurons in goblet cells. [Modes for carrying out the invention]

[0025] Referring here to Figures 1-3, several embodiments of the system 10 for treating ear, nose, or pharyngeal tissue may include a pulsed-field electroporation (PFE) control console 100 and a PFE delivery device 200. The PFE delivery device 200 can be configured to access and engage target tissue in any of the following areas of the ear, nose, and throat: posterior nasal nerve region, inferior turbinate region, posterior palatine region, posterior lingual region, hypopharyngeal region, pterygopalatine ganglion region, Eustachian tube, nasal cavity, sinuses, trigeminal nerve region, tonsils, adenoid region, and other areas of the ear, nose, and throat, and simultaneously deliver PFE to the target tissue. For example, user 20 can guide the device 200 into the nose of patient 30 and activate the PFE control console 100 so that the PFE delivery device 200 can deliver PFE to treat swollen or diseased tissue. PFE therapy, controlled by a therapeutic waveform from the PFE control console 100, can induce apoptosis in cells of swollen or diseased tissue, thereby triggering healthy and natural tissue regeneration at the treatment site. The control console 100 includes a generator 130 configured to output PFE signals via PFE delivery devices 200. The control console 100 also includes a user interface device 110. The PFE delivery devices 200 can be detachably mounted to the control console 100 so that the control console 100 is configured to connect with multiple devices 200 over time. This means that the control console 100 can store and / or transmit information about these multiple devices, as will be described in more detail below.

[0026] The PFE delivery device 200 includes a distal tip 204 positioned along the distal end portion or the end of an elongated shaft 205 and configured to deliver PFE via one or more electrodes (such as mesh electrodes or needle electrodes, as detailed below). Optionally, the distal tip 204 may include expandable members, such as expandable stents, as described in the specific embodiments below. When in use, the distal tip 204 of the PFE device is inserted into an anatomical passage so that the PFE electrodes engage with target tissues in the sinus orifice, posterior nasal nerve region, inferior turbinate region, posterior palatine region, posterior lingual region, hypopharyngeal region, pterygopalatine ganglion region, Eustachian tube, nasal cavity, sinuses, trigeminal nerve region, tonsils, adenoid region, and other parts of the ear, nose, and throat. As will be described in more detail below, the system 10 may further include a foot switch 70 (for selective activation by the user 20 to initiate the output of PFE pulses from the instrument 200), a disposable grounding electrode pad 60 (for temporary adhesion to the patient 30), an endoscope system 80 (for delivery of the instrument 200 and medical imaging in use), and a cloud server 90 (for remote communication with the control console 100). The PFE delivery instrument may include a handle 260. An elongated shaft 205 may extend distally from the distal end of the handle.

[0027] During use, the PFE delivery device 200 is advanced to the lesion tissue that may need to be treated. In some examples, an expandable member of the distal tip 204 expands in the target tissue to fix the distal tip 204 to the target tissue and / or to spread the target tissue. The control console 210 can then activate the PFE electrode 206 (Figure 3) to deliver PFE to treat the target tissue via electroporation. The control console 100 (Figure 1) can control one or more embodiments of the delivered PFE to achieve a predetermined electric field applied to the target tissue in a rapid pattern to induce destabilization of the cell membrane in the target tissue and / or stimulate one or more nerves in or adjacent to the target tissue. Optionally, the PFE electrode 206 may work in conjunction with a grounding electrode 60, which is a grounding pad attached to the patient's body in the embodiment shown in Figure 1.

[0028] The PFE delivered by the PFE delivery device 200 can be configured to induce electroperforation (e.g., irreversible electroperforation and / or reversible electroperforation) in the target tissue and to stimulate one or more nerves within or adjacent to the target tissue. For example, biofilms can cause chronic sinusitis, and chronic sinusitis can be treated by destroying the biofilms. PFEs can destroy biofilms by inducing irreversible electroperforation, and thus destroy the biofilms via apoptosis. Therefore, in this embodiment, the PFE control console 100 and the PFE delivery device can work together to controllly induce apoptosis to destroy biofilms, thereby treating chronic sinusitis in a less invasive and less painful way compared to other treatments such as surgical removal of biofilms or thermal ablation of biofilms.

[0029] In some embodiments, the electrical stimulation from the PFE control console 100 that induces electroperforation may include pulses having a high frequency (e.g., in the range of 500 kHz to 10,000 kHz) and a high voltage (e.g., in the range of 850 volts to 10,000 V). Sustained delivery of high-frequency, high-voltage pulses can induce electroperforation, but this sustained delivery may sometimes not produce sufficient nerve stimulation if there is no interruption for nerve activity to take effect in the stimulation. In some embodiments, the PFE delivery device 200 may deliver a sequence of high-frequency bursts of high-voltage pulses with intervals between bursts during which no stimulation is delivered. This means that the high-frequency bursts induce electroperforation, and nerve activity can take effect during the isolation period.

[0030] Therefore, depending on the waveform output from the PFE control console 100, the system 10, including the PFE delivery device 200, can, in certain embodiments, realize an improved system for delivering PFE that induces electroperforation and stimulates nerves. Thus, the system 10 can treat target tissue by treating diseased cells and / or inducing apoptosis in diseased cells, and at the same time, nerve stimulation can also be used to reset nerve activity to a standard / natural activity level in a specific area of ​​the target tissue.

[0031] In some embodiments, the PFE delivery instrument 200 can be advanced into a target anatomical space under medical imaging using an endoscope system 80 (Figure 1) which includes, for example, a handheld endoscope instrument 50 configured to be operated by the user simultaneously with the use of the PFE delivery instrument 200. In some embodiments, the PFE generator 130 of the control console 100 can be activated by pressing a user interface button on the instrument 200 (Figure 3) or optionally by using a foot switch 70 (Figure 1). As detailed below, in some embodiments, the control console 100 can selectively enable the PFE output from the generator 130 in response to the connection of an approved instrument, for example, by capturing an identifier 235 (e.g., QR code® 203) at the connector 208 of the PFE delivery instrument 200. The control console 100 may communicate with the cloud server 90 (for example, via a wired or wireless connection to the Internet) to verify the instrument identifier 235, and at the same time, may transmit treatment data from the control console 100 to the cloud server indicating the use of that particular instrument (having the identifier 235) for a particular patient 30 on that day.

[0032] In some examples, the control console 100 and / or cloud server 90 are configured to store a machine learning model. This machine learning model can be trained to perform one or more actions to control the PFE based on input data. In some embodiments, the input data may include endoscopic data (medical image data) collected by the endoscopy system 80. For example, the endoscopic instrument 50 may collect endoscopic image data showing the position of the PFE delivery instrument 200 relative to one or more anatomical features of the patient 30 (e.g., location within the nasal cavity). In this example, the machine learning model can process the endoscopic image data to determine whether to enable the output of the PFE, whether to stop the delivery of the PFE, one or more parameters of the PFE pulse to be delivered, whether to deliver a PFE that achieves nerve stimulation, or any combination thereof.

[0033] Optionally, machine learning models stored in the control console 100 and / or cloud server 90 can also supplement or overlay information on images displayed by the endoscopy system 80 to assist clinicians when performing one or more procedures. For example, a machine learning model can process data corresponding to the parameters of the PFE delivered by the PFE delivery device 200 and the dimensions of the PFE delivery device 200 in order to determine one or more parameters of the PFE field of the PFE delivered by the PFE delivery device 200. For example, based on the size of the PFE electrode 206 of the PFE delivery device 200 and the frequency and magnitude of the PFE pulse, the machine learning model can determine the dimensions (e.g., radius) of the PFE field extending outward from the PFE electrode. Also, when endoscopic image data (as described above) is input, the machine learning model can automatically modify the medical image displayed in the endoscope to include an overlay of the PFE field in real time (the determined size is proportional to the size of the anatomical feature in the endoscopic image data), allowing clinicians to see how far the PFE field reaches the anatomical features of the patient 30. System 10 is not limited to using a machine learning model to determine the PFE field. In some embodiments, System 10 may use a computer-implemented software program to determine the PFE field without using a machine learning model.

[0034] In some embodiments, a machine learning model stored by the control console 100 and / or cloud server 90 can process endoscopic image data collected by the endoscopic system 80 to determine whether to deliver PFE. For example, the machine learning model can determine, based on the endoscopic image data, whether the PFE delivery device 200 is located within the target region. Based on whether the PFE delivery device 200 is located within the target region, the machine learning model can control the PFE delivery device 200 to deliver PFE or to not deliver PFE. Based on the endoscopic image data, the machine learning model can determine one or more parameters of the PFE pulse, whether to induce nerve stimulation by delivering PFE, whether to stop delivering PFE, or any combination thereof.

[0035] The PFE delivery device 200 can deliver PFE to target tissue by enabling the replacement of diseased cells with normal healthy cells, causing repair of healthy tissue, providing submucosal therapy, and delivering nerve stimulation to restore normal nerve electrical activity of nerves adjacent to the distal tip 204 of the PFE delivery device 200. The system 10, including the PFE delivery device 200, can access cavities such as the sinuses, as well as other areas of the ear, nose, and throat, to deliver PFE for the treatment of polyps, airway obstruction, mucus overdose, and other medical conditions. The PFE delivery device 200 is configured to communicate with the control console 100 so that the generator 130 can deliver PFE pulses based on the configuration of the PFE delivery device 200. The configuration of the PFE electrode along the distal tip 204 of the PFE delivery device 200 includes other forms of end-effector configurations such as a dome tip, basket, or expandable stent structure for outputting PFE therapy to target tissue.

[0036] Referring here to Figure 4, several embodiments of the PFE control console 100 are configured to output pulse field waveforms to a PFE delivery device 200 in order to deliver a plurality of PFE pulses 301A to 301D (collectively referred to as "PFE pulses 301"). The PFE delivery device 200 can be advanced to a target site having pathological tissue that may need to be treated. The generator 130 can output a plurality of PFE pulses via the PFE delivery device 200. In some embodiments, each PFE pulse of the plurality of PFE pulses can be defined by one or more parameters. For example, a PFE pulse may have amplitude and duration, and a sequence of PFE pulses may have frequency. In some embodiments, the shape of a PFE pulse can be defined. For example, a rectangular pulse may rapidly increase from a first amplitude to a second amplitude, remain at the second amplitude for the duration of the pulse, and rapidly decrease from the second amplitude to the first amplitude.

[0037] In some embodiments, the control console 100 can control the characteristics of a plurality of PFE pulses. For example, the control console 100 can control the amplitude of a plurality of PFE pulses, control the frequency of a plurality of PFE pulses, control one or more other parameters of a plurality of PFE pulses, and control whether the PFE delivery device 200 delivers PFE pulses. In some examples, the PFE delivery device 200 is configured to deliver PFE pulses 301 to induce electroporation (e.g., irreversible or reversible electroporation) in target tissue. To induce electroporation, the control console 100 can control the generator 130 to output pulses at very high frequencies over a specific time period.

[0038] The PFE delivery device 200 can induce electroperforation by applying an electric field to target tissue to increase the permeability of the target tissue's cell membrane. High-frequency electrical signals can induce electroperforation through a phenomenon called dielectric heating. When an electrical signal is applied to tissue, dielectric heating can occur. Rapid changes in the electric field cause water molecules within cells to rearrange themselves in response to the changing electric field. This rapid rearrangement of water molecules can generate heat due to molecular friction, causing a localized rise in temperature. This temperature rise can form transient pores in the cell membrane. High-frequency electrical signals can be effective in inducing electroperforation because high-frequency switching between voltages can excite water molecules to form pores.

[0039] As described above, there are at least two distinct types of electroporation that the PFE delivery device 200 can deliver, including irreversible and reversible electroporation. The PFE delivery device 200 can deliver PFE pulses 301 to induce irreversible electroporation via apoptosis through several mechanisms. For example, when delivered to a target tissue, PFE pulses 301 may disrupt cellular homeostasis by disrupting the balance of ions and molecules within the cells of the target tissue. This may lead to changes in intracellular pH and calcium concentration in the cells of the target tissue. These disruptions may trigger signaling pathways that ultimately lead to apoptosis. Exemplary signaling pathways include endogenous and extrinsic pathways. The formation of pores in the cell membrane associated with irreversible electroporation may also damage cellular structures such as organelles and the cytoskeleton. This damage may activate a cellular stress response that initiates the apoptotic pathway.

[0040] In some embodiments, the PFE delivery device 200 can deliver a PFE pulse 301 to induce reversible electroperforation by transiently forming pores in the cell membrane of a target tissue without ultimately killing cells through apoptosis. The control console 100 can determine whether the PFE delivery device 200 induces irreversible or reversible electroperforation by controlling the parameters of the PFE pulse 301. For example, a PFE pulse that induces reversible electroperforation is typically shorter and less intense than a PFE pulse that induces irreversible electroperforation. Other parameters, such as pulse frequency, may also affect whether a PFE pulse induces reversible or irreversible electroperforation.

[0041] Any heat associated with electroporation induced by the PFE pulse 301 is instantaneous and, as a result, there is little to no temperature change in the target tissue (i.e., a "non-ablation temperature change" of 0–5°C), thus safely avoiding the type of necrosis that results from thermal ablation techniques. This is because the PFE delivery device 200 can deliver the PFE pulse 301 such that the high-frequency electrical signal is delivered to the tissue within a threshold time. Limiting the time the tissue is exposed to the PFE signal limits the increase in heat associated with the electrical stimulation therapy technique. The PFE delivery device 200 can control the PFE pulse 301 based on the selected electroporation effect (e.g., selecting either reversible or irreversible electroporation) and further based on the procedure performed by the PFE delivery device 200. In some embodiments, the PFE delivery device 200 can control the PFE pulse 301 based on user input. Optionally, the PFE delivery device 200 can control the PFE pulse 301 based on a machine learning model or another type of model.

[0042] In the embodiment shown in Figure 4, each of the PFE pulses 301 represents a two-phase pulse having a positive phase followed by a negative phase. For example, PFE pulse 301A includes a positive phase 302A and a negative phase 304A, PFE pulse 301B includes a positive phase 302B and a negative phase 304BA, and so on. The magnitude of each negative phase of the PFE pulse 301 can be equal to the magnitude of the positive phase of the PFE pulse 301. For example, the amplitude 310 of each of the positive phases 302A to 302D can be +V, and the amplitude 312 of each of the negative phases 304A to 304D can be -V. This means that for each of the PFE pulses 301, the magnitude of the positive phase is the same as the magnitude of the negative phase, and preferably this magnitude is the magnitude of a high voltage of at least 850V. In some examples, the individual pulses may vary within the range of 850V to 10,000V for +V. In some examples, individual pulses may vary within a range of 850V to 10,000V for -V. As shown in Figure 4, a gap may exist between the positive and negative phases of a two-phase PFE pulse. This gap is not necessarily present in all embodiments. In some embodiments, two-phase and / or three-phase PFE pulses may not have a gap between the pulse phases. In some embodiments, the pulse width of each phase of the PFE pulse is less than 5 microseconds (μs), preferably in the range of 50 nanoseconds (ns) to 3 μs.

[0043] In some embodiments, the PFE pulse 301 preferably includes a two-phase pulse. This is because a single-phase pulse delivered to the target tissue may cause a greater muscle contraction compared to a two-phase pulse that causes muscle contraction. In some embodiments, the PFE delivery device 200 can deliver a two-phase PFE pulse without causing any muscle contraction. Delivering the PFE pulse 301 without causing muscle contraction can be beneficial, as muscle contraction can cause patient movement that interferes with the procedure. Another advantage of a two-phase pulse is that it has a balanced charge distribution, which prevents charge buildup at the interface between the PFE electrode 206 and the target tissue. Such charge buildup can damage tissue and / or cause discomfort to the patient.

[0044] The PFE delivery device 200 is not limited to delivering two-phase PFE pulses. In some embodiments, the PFE delivery device 200 can deliver one or more single-phase PFE pulses. In some cases, the PFE delivery device 200 can deliver one or more three-phase PFE pulses. In some cases, the PFE delivery device 200 can deliver any mixture of single-phase pulses, two-phase pulses, and three-phase pulses. The control console 100 can control the number of phases of the PFE pulses delivered by the PFE delivery device 200.

[0045] In some examples, the PFE pulse 301 includes a sequence of bursts of high-frequency pulses. Each burst of high-frequency pulses can contain a train of high-frequency pulses. For example, pulse train 330A includes PFE pulse 301A to PFE pulse 301B. Although Figure 4 shows pulse trains 330A and 330B each containing only two pulses, pulse trains 330A and 330B can each contain far more than two pulses. For example, pulse train 330A may contain one or more pulses in the gap 340 between pulse 301A and pulse 301B, and pulse train 330B may contain one or more pulses in the gap 342 between pulse 301C and pulse 301D. In some examples, each of pulse trains 330A and 330B can contain pulses ranging from 10 to 500 pulses. Preferably, each cycle of the PFE delivery 380, pulse train 330A, pulse train 330B, and any other train after 330B may preferably contain a total of about 2,500 pulses. Although Figure 4 shows only two pulse trains 330A and 330B, the PFE delivery device 200 can deliver three or more pulse trains (for example, one or more pulse trains between pulse train 330A and pulse train 330B).

[0046] In some embodiments, pulse trains 330A and 330B may each define pulse frequencies in the range of 500 kilohertz (kHz) to 10,000 kHz. Each pulse frequency of pulse trains 330A and 330B can induce electroperforation (e.g., irreversible electroperforation in this embodiment) in the target tissue. The control console 100 can, in some examples, control each frequency of pulse trains 330A and 330B to achieve a desired effect (e.g., perform a specific procedure). Gaps may exist in each of pulse trains 330A and 330B, such that the treatment method is primarily related to apoptosis and secondarily related to the delivered stimulus. Regarding the duration of the gaps, since pulse trains 330A and 330B feature high-frequency bursts of PFE pulses, the gaps between consecutive PFE pulses in the pulse train can be very short. This rapid transition between each pulse can induce electroperforation while also inducing several neurostimulatory effects.

[0047] The PFE delivery device 200 can deliver a sequence of pulse trains 380, which includes pulse trains 330A and 330B. In some examples, the sequence of pulse trains 380 may include pulse trains at pulse train frequencies. The pulse train frequencies can range from 1 Hz to 100 Hz. This means that the frequency at which the PFE delivery device 200 delivers the pulse trains of the sequence of pulse trains 380 may be orders of magnitude lower than the frequency at which the PFE delivery device 200 delivers the PFE pulses within a particular pulse train. As a result, there may be gaps between consecutive pulse trains in the sequence of pulse trains 380 that are significantly longer than the gaps between consecutive PFE pulses within a pulse train. In some examples, the duration of the gaps between consecutive pulse trains is in the range of 0.005 seconds to 1 second.

[0048] Therefore, in a specific implementation of the PFE console 100, by delivering a sequence of pulse trains 380 with gaps between pulse trains, the PFE delivery device 200 can be used in target tissue to induce electroperforation without changing the target tissue temperature by more than 5°C, thus safely avoiding the type of ablation necrosis / crusting caused by RF ablation and other thermal ablation techniques. For example, the PFE console 100 can control the sequence of pulse trains 380 (and the gaps between them) to avoid the sustained delivery of high-frequency electrical signals, which may excite intracellular water molecules to release a large amount of heat that would otherwise induce necrosis. Instead, the PFE console 100 can limit each of the pulse trains 380 to less than a threshold duration and provide gaps between consecutive pulse trains to induce electroperforation in the PFE delivery device 200 (which can induce apoptosis of cells and thus replace diseased / defective cells with healthy cells).

[0049] Continuing to refer to Figure 4, the PFE delivery device 200 can also stimulate one or more cells adjacent to the target tissue. By delivering a sequence of pulse trains 380 with gaps between pulse trains, the PFE delivery device 200 can generate action potentials within nerves and propagate them along nerves adjacent to the target tissue. This means that, in addition to inducing electroperforation in the patient's target tissue, the PFE delivery device 200 can optionally deliver nerve stimulation to the patient by delivering PFE pulses 301. In some cases, lower frequencies at which the PFE delivery device 200 delivers the sequence of pulse trains 380 are more effective in stimulating nerves compared to higher frequencies at which the PFE delivery device 200 delivers PFE pulses within each pulse train. This is because nerve stimulation involves inducing action potentials within the nerve that propagate after stimulation. A constant high-frequency stimulation does not necessarily allow for the establishment of action potentials.

[0050] Therefore, referring to Figures 1 to 4, the PFE control console 100 can set one or more PFE parameters, such as the number of PFE pulses per pulse train, pulse amplitude, pulse duration, frequency of PFE pulses occurring within the pulse train, and frequency of pulse train occurrence. The control console 100 can set the parameters of the PFE pulse 301 depending on the procedure performed by the PFE delivery device 200. In some embodiments, the control console 100 can deliver the PFE pulse 302 via the PFE electrode 206 to treat target tissue by inducing irreversible electroperforation and simultaneously delivering nerve stimulation. The PFE delivery device 200 does not need to induce irreversible electroperforation and simultaneously deliver nerve stimulation. In some cases, the PFE delivery device 200 can induce irreversible electroperforation without delivering nerve stimulation. In some cases, the PFE delivery device 200 can deliver nerve stimulation without inducing irreversible electroperforation.

[0051] In some embodiments, the control console 100 can apply a predetermined electric field to the target tissue in a rapid pattern that induces cell membrane destabilization in the target tissue. The PFE electrode 206 can operate in conjunction with a ground electrode pad 60 attached to the patient's body. For example, the PFE electrode 206 can deliver PFE pulses. The PFE pulses can travel from the PFE electrode 206 to the ground electrode pad 60, which acts as a return electrode. The system 10 does not need to use the ground electrode pad 60 as a return electrode. The PFE electrode 206 can deliver PFE pulses without a return electrode. The system 10 can alternatively use a return electrode other than the ground electrode pad 60. For example, the return electrode can be located on a separate shaft from the PFE delivery device 200, and that shaft can be advanced to a site close to the target tissue. When the PFE delivery device 200 delivers PFE pulses, the pulses can return via the return electrode on the separate shaft. As will be described in more detail below, the PFE delivery instrument 200 can be advanced to the target anatomical space under medical imaging using an endoscopic system 80, for example, a handheld endoscopic instrument 50 configured to be operated by the user simultaneously with the PFE delivery instrument 200.

[0052] As will be described in more detail below, in some embodiments, the control console 100 can selectively enable PFE output from the generator 130 in response to the detection of specific anatomical landmarks. For example, the control console 100 can detect anatomical landmarks corresponding to the target tissue to be treated and enable PFE in response to the detection of these landmarks. The control console 100 can communicate with the cloud server 90 (for example, via a wired or wireless connection to the Internet) in order to transmit data from the control console 100 to the cloud server 90.

[0053] The PFE generator 130 of the control console 100 can be configured to output various PFEs from the PFE electrode 206. In some embodiments, the PFE pulses output by the generator 130 and delivered by the PFE delivery device 200 provide an electric field applied to the target tissue in a series of rapid bursts to induce electroperforation in the target tissue, thereby inducing destabilization of the cell membrane to induce apoptosis, while simultaneously maintaining a state of virtually no temperature change (e.g., a temperature change of less than 5°C) in the target tissue. Optionally, the PFE pulses output by the generator 130 and delivered by the device 200 can provide highly efficient treatment in target tissues in the ear, nose, and throat, while simultaneously achieving improved convenience for both clinicians and patients. For example, the PFE delivery device 200 can deliver the therapy while the patient 30 is awake and using a local anesthetic rather than a general anesthetic.

[0054] Referring here to Figure 5, several embodiments of the PFE delivery device 200 can be used in combination with the use of an endoscope instrument 50. For example, when in use, the PFE delivery device 200 is advanced to the target tissue and the endoscope instrument 50 is also advanced so that the position of the target tissue relative to the distal tip 204 is within the field of view 570 of the endoscope instrument 50. In some embodiments, the endoscope instrument 50 includes an endoscope lens 572 positioned on the distal tip of the endoscope instrument 50. This means that the position of the target tissue relative to the distal tip 204 can be displayed in real time on the display screen of the endoscope system 80. As shown in Figure 5, some implementations of the PFE device include a distal tip 204 having a bulbous shape (having a rigid structure and fixed size) that provides a width greater than the outer diameter of the elongated shaft 205 extending from there.

[0055] The elongated shaft 205 of the PFE delivery device 200 includes, in some embodiments, a rigid straight shaft 552 and a bendable distal shaft portion 525 that is axially transverse to the rigid straight shaft 552. In the embodiment shown in Figure 5, the bendable distal shaft portion 525 extends distally from the distal end of the straight shaft 552. Optionally, the bendable distal shaft portion 525 can be pre-configured to a fixed bent shape so that the bent distal portion 525 does not deform from its bent shape. Alternatively, in the embodiment of Figure 5, the distal shaft portion 525 is manually bendable and can be repeatedly deformed in a user-selected bending direction relative to the rigid straight shaft 552. Thus, the angle of the bendable distal shaft portion 525 can be manually adjusted to customize the bendable distal shaft portion 525 to a selected relative position to the anatomical structure of a particular patient. In some optional embodiments, the PFE delivery device 200 may include an actuator along its proximal handle region (Figure 3) that allows the user 20 to adjust the angle of a bendable distal shaft portion 525 during a procedure to deliver PFE to target tissue. For example, the actuator may be slidable along the longitudinal axis of the handle. As the actuator slides, this adjusts the angle of the bendable distal shaft portion 425. As shown in Figure 5, the distal tip 204 may have a bulbous shape such that the outer diameter of the PFE electrode is greater than the maximum outer diameter of the shaft portion 525 extending toward the tip 204.

[0056] In some examples, a bendable distal shaft portion 525 having the angle shown in Figure 5 (lateral to the longitudinal axis of the rigid straight shaft 552) represents an improved system that ensures the distal tip 204 is within the field of view 570 of the endoscopic instrument 50. For example, the field of view 570 of the endoscopic instrument 50 can capture the distal tip 204 without capturing other parts of the PFE delivery instrument 200, which means an improved ability of the endoscopic instrument 50 to capture the bent distal shaft portion 525 within its field of view 570, since the distal shaft portion 525 is bent in a direction offset from the central axis of the straight shaft 552.

[0057] In the embodiment shown in Figure 5, the PFE delivery device 200 includes a single, fixed-size, unipolar PFE electrode 206 configured to deliver PFE therapy. In some cases, a system using a unipolar electrode also uses a separate return electrode (e.g., a grounding electrode pad 60 in Figure 1) positioned on or near the patient's body. The return electrode can, in some cases, prevent unwanted current from passing through sensitive tissue. The unipolar electrode 206 of the device 200 may be useful for delivering PFE therapy using high-voltage electrical signals (such as the PFE pulse 302 in Figure 4). For example, in some situations, the unipolar electrode 206 can be configured to avoid arc discharge in the output of such high-voltage electrical pulses that could potentially damage tissue adjacent to the device. Thus, as shown in Figure 1, the PFE delivery device 200 includes a unipolar PFE electrode 206 that can operate in conjunction with a grounding electrode 60 (sufficiently spaced from the distal tip of the PFE delivery device 200), thereby reducing the likelihood of arc discharge. In some alternative embodiments, the PFE delivery device 200 may include bipolar electrodes that work in conjunction with each other during treatment.

[0058] In some examples, the PFE electrode 206 has a conductive surface exposed along the outer surface of the distal tip 204 of the PFE delivery device 200. In some embodiments, the PFE electrode 206 does not extend outward from the housing of the PFE delivery device 200. The PFE electrode 206 can be connected to a conductor that extends through the lumen of the PFE delivery device 200. In some examples, the conductor can be connected to a control console 100 (for example, via a connector 208 in Figure 3). In some examples, the bendable distal shaft portion 525 and the elongated shaft 205 are sized to guide to target tissue in the patient (e.g., locations in the ear, nose, and throat). For example, the bendable distal shaft portion 525 may have a shaft outer diameter smaller than the outer diameter of the elongated shaft 205 and smaller than the maximum transverse width of the distal tip 204. In other words, in this example, the maximum lateral width of the distal tip 204 is greater than the outer diameter of both the bendable distal shaft portion 525 and the elongated shaft 205. In the embodiment shown in Figure 5, the bendable distal shaft portion 525 can have an outer diameter of 1 mm to 3 mm, preferably about 1.5 mm, and the elongated shaft 205 can have an outer diameter of 1.5 mm to 4 mm, preferably about 2 mm. Also, in the embodiment shown in Figure 5, the maximum lateral width of the distal tip 204 of the PFE delivery device 200 is less than 5 mm, preferably 2 mm to 4 mm, and in this embodiment it can be about 3 mm. Thus, the PFE delivery device 200 can be guided to the target tissue such that the PFE electrode 206 is close to the target tissue and the patient's anatomical structure does not hinder the advancement of the PFE electrode 206 of the PFE delivery device 200.

[0059] Referring here to Figures 6A to 8B, several alternative embodiments of the PFE delivery devices 600, 700, and 800 may include flexible PFE electrodes having a metal mesh or basket structure. For example, the embodiments of flexible PFE electrodes shown in Figures 6A to 8B can be compressed during delivery and then flexibly expand to have a larger radius to provide a compressed electrode shape against the target tissue, which may be useful in some implementations for fixing the distal tip of the PFE delivery device 600, 700, and 800 in place during PFE treatment. The flexible PFE electrode positioned on the treatment tip may conform to and match the inner wall of the anatomical passage of the target, such as the nasal cavity.

[0060] As shown in Figures 6A and 6B, the elongated shaft 689 of the PFE delivery device 600 may include a flexible PFE electrode 642 in the form of a metal basket electrode positioned at the distal end of the elongated shaft 689. In some embodiments, the basket electrode 642 can operate as a spring-biased PFE electrode having a maximum width greater than the maximum width of the elongated shaft 689. For example, the basket electrode 642 can be flexibly adjusted to compress toward the central axis of the elongated shaft 689 (e.g., during delivery into the nasal cavity), and further, the basket electrode 642 can be spring-biased to expand outward (at least in its central region) so as to press against the wall of the anatomical passage of a target, such as the nasal cavity. In some examples, the basket electrode 642 comprises a plurality of helical struts, the diameter of which is increased at the center of the struts. Each helical strut can be connected to other struts at connection points such that the struts of the basket electrode 642 form a single conductive material piece defining a plurality of open cells. In some embodiments, it is beneficial for the PFE delivery device 600 to include a basket electrode 642 in order to increase the overall electrode surface area and thereby distribute high-voltage pulses (e.g., Figure 4) over a larger tissue volume compared to a smaller fixed ring electrode. Thus, the basket electrode 642 can be advanced to the target tissue and deliver a large volume of PFE over a larger anatomical space, including the delivery of PFE therapy for the treatment of nasal valve collapse.

[0061] In some embodiments, the PFE device 600 may comprise two or more types of electrodes. For example, the PFE device 600 may include both a distal tip electrode 621 and a basket electrode 642, which can be used simultaneously or individually. Thus, the basket electrode 642 can be advanced to the target tissue, and the generator 130 (Figures 1-2) can initiate PFE delivery via the fixed ring of the distal tip electrode 621, the flexible basket electrode 642, or both. The device 600 may be configured such that a switch along the handle (not shown, see exemplary handle shown in Figure 3) is configured to allow the user to select which electrode or combination of electrodes will deliver the PFE therapy.

[0062] Continuing to refer to Figures 6A-6B, the flexible PFE electrode 642 comprises a conductive flexible material such as stainless steel, titanium, iridium, aluminum, gold, silver, nitinol, nickel, or any alloy, composition, or combination of these materials. In some embodiments, the basket electrode 642 is shaped to deliver PFE to target tissue in a manner that improves patient safety and reduces the risk of tissue damage. For example, the basket electrode 642 can be spring-biased toward a shape having a wider central portion that tapers toward a smaller end (along a curved circumferential region) (see Figures 6A-6B), thereby ensuring that the flexible basket electrode 642 is biased outward to conform to and compress the target tissue and then rapidly deliver PFE pulses dispersed across all areas of the basket electrode 642 in contact with the tissue.

[0063] In some embodiments, the elongated shaft 689 may include a steerable or malleable region 655 that can extend distally from the straight portion of the elongated shaft 689 at a lateral angle from the central axis of the straight portion of the elongated shaft 689. For example, a portion of the elongated shaft 689 including a basket electrode 642 and a distal tip 621 may be manually bent by the user around the malleable region 655 such that the portion including the basket electrode 642 forms an angle with the straight portion of the elongated shaft 689. In some examples, the PFE delivery device 600 includes a steering actuator along a handle (not shown, see an exemplary handle shown in Figure 3) configured to selectively adjust the angle of the steerable or malleable region 655. Thus, the user 20 (Figure 1) can controllably steer the elongated shaft 689 within the patient's anatomical passage.

[0064] Referring here to Figure 7, several embodiments of the PFE delivery device 700 may include a flexible PFE electrode 642 partially insulated by an insulating cover 701. In some embodiments, the insulating cover 701 includes a non-conductive element that prevents electrical pulses from passing through the insulating cover 701. This means that the PFE pulses output from the partially insulated basket electrode 642 (Figure 7) can be directed toward adjacent tissue close to the exposed portion of the basket electrode 642 (on the opposite side of the insulating cover 701) in a direction selected relative to the elongated shaft 689. In some examples, the partially insulated basket electrode 642 with the insulating cover 701 can improve the basket electrode 642's ability to treat a specific target tissue region without delivering treatment around the entire circumference of the electrode 642's central axis, thereby allowing the user to protect non-target tissue regions from PFE pulses. For example, if the elongated shaft 689 is positioned such that the insulating cover 701 is positioned toward the non-target tissue area (as can be seen through the endoscope 50 in Figure 1) and the flexible basket electrode 642 is positioned opposite to the target tissue, the user sends a signal to the PFE control console 100 to initiate a PFE pulse for treating the target tissue and simultaneously protect the non-target tissue.

[0065] The insulating cover 701 may comprise a non-conductive material such as polyamide, polytetrafluoroethylene (PTEE), glass, ceramic, plastic, rubber, or any composition or combination thereof. Optionally, the cover 701 may be detachably fitted onto an elongated shaft 689 to provide a shield covering a portion of the basket electrode 642. An exemplary procedure in which a partially insulated basket electrode 642 (having the insulating cover 701) may be particularly useful includes PFE therapy delivered to the palate of patients suffering from obstructive sleep apnea (OSA). In these procedures, it may be preferable to treat the soft palate tissue by delivering PFE pulses without delivering PFE pulses to the tongue region (shielded using the insulating cover 701).

[0066] Referring here to Figures 8A and 8B, some embodiments of the PFE delivery device 800 may include an expandable stent PFE electrode 815 that can be manually operated between a compressed state (Figure 8A) and an expanded state (Figure 8B). For example, the expandable stent PFE electrode can be advanced toward a narrow anatomical passage in the ear, nose, or throat while the electrode 815 is in a compressed state (Figure 8A), and then the user can adjust the electrode 815 to an expanded state using a slider actuator 812 when the stent electrode 815 is close to the target tissue (thereby conforming the flexible PFE electrode 815 outward to the target tissue and increasing surface contact between the electrode and the tissue). In some examples, the PFE delivery device 800 may include a distal portion 810 having a smaller diameter, sized to allow the device to reach narrow anatomical passages such as the Eustachian tube, via the middle ear, otio medial nerve plexus, and other areas consisting of narrow anatomical structures.

[0067] Optionally, the distal portion 810 may include a bent tip 825 that can be manually bent by the user before the procedure and / or bent during the procedure. As seen in Figures 8A–8B, the expandable stent PFE stent electrode 815 can be positioned on the straight portion of the distal portion 810, and the bent tip 825 extends distally from the distal end of the expandable stent PFE electrode 815. In some embodiments, it may be preferable to manually bend the bent tip 825 to a selected deformation / orientation before advancing the distal portion 810 to the target tissue. This may allow the user 20 to guide the instrument as it advances by rotating the distal portion 810 so that the bent tip 825 engages with a narrow anatomical passage containing the target tissue. Once the passage is engaged, the distal portion 810 can be advanced until the stent electrode 815 is positioned within the area in which the PFE can be delivered. The initially flattened stent electrode 815 can be expanded using the actuation slider 812 when the stent electrode 815 is in close proximity to the target tissue. The bent tip 825 can be bent by mechanically deforming the distal end of the tip in the manufacturing facility by a design in which the tip is pre-bent, or by having an automated motorized or mechanical retraction actuator on the handle.

[0068] Referring here to Figures 9-10, several embodiments of the PFE delivery device 200 (or 600, 700, or 800) can be configured to operate in conjunction with a ground electrode 1288 mounted on a shaft. In such cases, the ground electrode 1288 can be directed towards a selected portion of the anatomical cavity (rather than the external ground pad 670 as shown in Figure 1). Thus, the PFE delivery device 200 can deliver PFE pulses via the PFE electrode 206 (as described above in Figures 3-4), while simultaneously, a lead 1299 including a return electrode 1288 (having a flexible mesh structure in the illustrated embodiment) is positioned in the body in close proximity to the target tissue. In this embodiment, the electrode mesh 1288 provides a return electrode with a surface area significantly larger than the surface area of ​​the PFE electrode 206. This larger surface area can reduce the likelihood of arc discharge between the PFE electrode 206 and the mesh 1288.

[0069] In the example shown in Figure 9, both the PFE electrode 206 and the passive electrode mesh 1288 can be placed in the body. For example, the PFE electrode 206 can be placed in a first nasal region 1222, and the return electrode 1288 can be placed in a second nasal region 1244. Although the embodiment in Figure 9 includes two electrodes 206 and 1288, the system may include three or more electrodes in some embodiments. For example, there may be two or more circuits between the therapy delivery electrode and the return electrode.

[0070] Referring here to Figure 10, several embodiments of the system may include a first active electrode 1387 attached to a first lead 1300 and a second active electrode 1303 attached to a second lead 1333. Both the first active electrode 1387 and the second active electrode 1303 can deliver PFE pulses, and both the first active electrode 1387 and the second active electrode 1303 can be configured as flexible metal mesh electrodes. Both the first active electrode 1387 and the second active electrode 1303 can be used to deliver PFE pulses in a unipolar or bipolar configuration. A unipolar configuration is implemented for the output of PFE pulses from the first and second active electrodes 1387 and 1303, for example, when the PFE output is accompanied by a uniform electric field instead of a directional current. In procedures where nerves are at least partially the cause of conditions such as chronic rhinitis, tympani plexus neurectomy for intractable ear pain, trigeminal nerve treatment for migraines, and other diseases, PFE may be useful because PFE can replace defective cells through apoptosis and restore nerves to normal function through nerve stimulation.

[0071] Referring here to Figures 11-13, several embodiments of System 10 may include PFE delivery devices 200 (Figures 1-3) sized and configured for ENT procedures to treat conditions such as chronic rhinitis, migraines, sleep apnea, snoring, and other medical conditions. In the illustrated example, the elongated shaft 205 may include a distal tip 904 that can be bent relative to the elongated shaft 205. For example, as shown in Figure 11, the PFE delivery device 200 can be used in the nasal cavity 914 to treat chronic rhinitis. The PFE delivery device 200 can be advanced through the nasal cavity 914 to the target tissue. The PFE delivery device 200 can deliver PFE pulses via an electrode at the distal tip 214.

[0072] In the example shown in Figure 12, the distal tip 904 can be bent so that the PFE electrode located at the distal tip 904 is directed towards the posterior side of the inferior turbinate. Bending the distal tip 904 brings it closer to the inferior turbinate compared to the example where the distal tip 904 is not bent. The distal tip 204 of the instrument 200 can deliver the PFE treatment to the tissue to trigger apoptosis of cells when the generator 130 is activated, thereby replacing defective cells with healthy cells. In some embodiments, the area of ​​the nasal cavity containing defective cells that may contribute to abnormal mucus secretion also includes nerves 1009 involved in mucus secretion resulting from either neurodegeneration or environmental triggers, which may include strong odors, exposure to cold air, alcohol consumption, and / or spicy foods. These signals generated by neural networks within the nasal cavity may result in chronic rhinitis (allergic or non-allergic), migraines, and / or other medical conditions. This means that PFE can be delivered to both the distal tip 204 for cell replacement and regeneration through apoptosis, and for stimulating nerve 1009. In some cases, nerve 1009 may include the pterygopalatine ganglion (SPG). This may result in nerve improvement and restoration of the nerve to its normal function.

[0073] In the example shown in Figure 13, the PFE delivery device 200 can treat the pharynx 1101 by inducing apoptosis in the target tissue using PFE pulses (as described above in relation to Figures 1-4). Apoptosis can replace unhealthy cells with healthy cells and thus improve airflow during sleep in patients with OSA. The PFE delivery device can deliver PFE pulses via the PFE electrode at its distal tip 204. The PFE pulses can induce irreversible electroperforation to destroy unhealthy cells through apoptosis and can also stimulate one or more nerves to restore normal nerve function. Replacing unhealthy cells with healthy cells and improving nerve function by stimulating nerves in the pharynx 1101 ensures that the upper airway remains open during sleep and airflow is not obstructed. This type of treatment can improve breathing in patients suffering from nasal valve collapse. During nasal valve collapse, the nasal valve, or other anatomical structures within the upper respiratory system, can collapse due to rapid breathing through the nose.

[0074] Therefore, as described above in relation to Figures 1 to 5, and by further exemplary use shown in Figures 11 to 13, it should be understood from this description that the PFE control console 100 and PFE delivery device 200 can be used in various ENT procedures to deliver PFE therapy for stimulation of any one or a combination thereof of the pterygopalatine ganglion (SPG), posterior nasal nerve, pterygoid canal nerve, and all branches of the optic nerve, trigeminal nerve, or other nerves in the ear, nose, or throat. Such nerve stimulation provided by the PFE system 10 detailed above can treat migraines, rhinitis, and other medical conditions by restoring normal nerve activity by eliminating nerve stressors triggered by signals resulting from odor, allergic and non-allergic rhinitis, chronic rhinitis, or other nerve damage.

[0075] Furthermore, as described in detail above, it should be understood from the description herein that the PFE control console 100 and the PFE delivery device 200 are capable of delivering PFE pulses 301 having a high voltage (e.g., over 1,000 volts). This ensures that the PFE pulses 301 stimulate the submucosal nerves that are the cause of triggering migraines, trigeminal neuralgia, and other forms of pain. The high amplitude of the PFE pulses 301 ensures that the pulses result in a long-lasting nerve recovery, thus reducing or eliminating the need for repeated nerve stimulation. When treating certain conditions such as the soft palate in relation to obstructive sleep apnea (OSA), the PFE delivery device 200 may include a basket electrode 642 (see Figures 6-7) that compresses and holds the tissue in place while the PFE delivery device 200 delivers PFE. By holding the tissue in place, the basket electrode 642 can result in more efficient delivery of the PFE pulses to adjacent tissues. Mechanically compressing the soft palate with the basket electrode 642 while delivering PFE can significantly improve the outcome of the procedure. For example, by compressing the tissue, the basket electrode 642 can ensure that it is in contact with all parts of the tissue that can benefit from the treatment. The basket electrode 642 can deliver the PFE pulse 301 so that the regeneration of healthy cells occurs uniformly throughout the tissue.

[0076] Additionally, as described above in relation to Figures 1-5, and by further exemplary use shown in Figures 11-13, from this description, the PFE control console 100 and PFE delivery device 200 can deliver PFE pulses 301 that improve the patient's safety profile. For example, the PFE pulses 301 can restore healthy tissue via apoptosis by killing unhealthy cells and protecting the extracellular matrix. Healthy cells can regenerate within this extracellular matrix. For example, the PFE delivery device 200 can deliver PFE treatment to the otitis median plexus, trigeminal nerve, pterygopalatine ganglion, Eustachian tube (ET), and other locations. The PFE delivery device 200 can deliver PFE in a manner that does not cause damage to healthy ligaments, tissues, nerves, and other anatomical structures located within the area being treated by the PFE delivery device 200, thus avoiding unintended damage that may occur from systems using RF treatment or ablation. The PFE delivery device 200 can also treat soft tissue with little to no damage to important structures such as nerves and blood vessels, even when these structures are located within the area of ​​PFE delivery.

[0077] Optionally, as described above in relation to Figures 1 to 5, and by further exemplary use shown in Figures 11 to 13, it should be understood from this description that the PFE control console 100 and the PFE delivery device 200 can deliver PFE pulses 301 to treat asthma. Asthma affects the lungs by causing recurrent attacks of wheezing, shortness of breath, and coughing. One way to control asthma is to avoid triggers that may cause bronchospasm. The PFE delivery device 200 can treat asthma by delivering PFE pulses to stimulate nerves in the upper and lower respiratory tracts, including nerves located in the nasal cavity, pharynx, larynx, trachea, and lungs. The application of pulsed-field electroporation to the entire respiratory system or within a specific area can make the anatomical area of ​​application less susceptible to allergens or other irritants in the respiratory system, thus reducing or eliminating asthma attacks.

[0078] Within the upper airway, the PFE delivery device 200 can treat tissues that may obstruct airflow in the respiratory system, such as inferior turbinates, polyps, and other tissues that may obstruct normal airflow. For example, the PFE delivery device 200 can induce a tissue contraction process. This tissue-inducing process occurs when the PFE delivery device 200 induces irreversible electroporation in unhealthy cells, which ultimately kills the unhealthy cells. As the cells regenerate, their volume may be smaller than the volume of the cells before treatment with PFE. This means that the PFE delivery device 200 can expand the patient's airway by delivering PFE to replace unhealthy cells with healthy cells. The PFE delivery device 200 can open spaces that were previously closed by diseased tissue, allowing airflow to move through the patient's airway.

[0079] Referring here to Figures 14A to 14F, in some embodiments, the display screen of the PFE control console 100 (Figure 1, or optionally the display screen of the endoscope system 80 connected to the console 100 in Figure 1) can display image data showing the calculated PFE field size relative to the distal tip 204 of the PFE delivery instrument 200. In some cases, the endoscope instrument 50 can collect this image data displayed by the control console 100. During use, in some embodiments, the endoscope instrument 50 and the PFE delivery instrument 200 can be advanced to the target site. The endoscope instrument 50 can capture the position of the PFE delivery instrument 200 relative to the anatomical structure of the patient 30 at the target site. Medical images 1402 to 1404 show the distal tip 204 and the respective PFE field corresponding to the distal tip 204, respectively. In this embodiment, the PFE control console 100 is configured to calculate the estimated size of the PFE field output from the PFE electrode (described below) and overlay the calculated PFE field, which is a graphic on the medical image of the distal tip 204, onto the display screen of the user interface device 110 (Figure 1, or optionally, the display screen of the endoscope system 80 connected to the console 100 in Figure 1). The control console 100 can overlay a graphic of the calculated PFE field scaled to an appropriate size relative to the distal tip 204 and anatomical features shown in the medical images 1402-1404. For example, the graphic of the calculated PFE field can be overlaid on the electrode of the distal tip 204 according to the appropriate size / scale shown in the medical images 1402-1404, in order to quickly communicate to the user the actual physical location of the PFE therapy relative to the distal tip 204 shown on the display screen of the user interface device 110.

[0080] For example, in Figure 14A, the graphic 1442 of the calculated PFE field output by the distal tip 204 is sized based on the calculated size of the field (described below) and the size of the distal tip 204 of the instrument, thereby displaying the location reached by the PFE field as a graphic of translucent white bubbles overlaid on the distal tip 204. Similarly, in Figure 14B, the graphic 1444 of the calculated PFE field output by the distal tip 204 reaches a point covered by a white bubble overlaid on the distal tip 204, and so on. Figure 14A shows an image 1402 of the distal tip 204 and the graphic 1442 of the calculated PFE field, the distal tip 204 including a 1 mm tip electrode configured to output a 10 kilovolt (kV) PFE signal. Figure 14B shows an image 1404 of the distal tip 204 and a graphic 1444 of the calculated PFE field, where the distal tip 204 includes a 5 mm tip electrode configured to output a 10 kV PFE signal. Figure 14C shows an image 1406 of the distal tip 204 and a graphic 1446 of the calculated PFE field, where the distal tip 204 includes a 10 mm tip electrode configured to output a 10 kV PFE signal. Figure 14D shows an image 1408 of the distal tip 204 and a graphic 1448 of the calculated PFE field, where the distal tip 204 includes a 1 mm tip electrode configured to output a 1 kV PFE signal. Figure 14E shows an image 1410 of the distal tip 204 and a graphic 1450 of the calculated PFE field, where the distal tip 204 includes a 5 mm tip electrode configured to output a 1 kV PFE signal. Figure 14F shows an image 1412 of the distal tip 204 and a graphic 1452 of the calculated PFE field, the distal tip 204 including a 10 mm tip electrode configured to output a 1 kV PFE signal.

[0081] Referring here to Figure 15, several implementations of the computer implementation method (e.g., performed by the PFE control console 100) can accurately generate a graphic of the calculated PFE field corresponding to the PFE delivery instrument 200 and overlay the graphic of the calculated PFE field onto the endoscopic image data. In some embodiments, the control module 1502 is configured to receive endoscopic image data from the endoscopic instrument 50 showing at least the distal tip 204 of the PFE delivery instrument 200 and one or more anatomical features of the patient 30 (1502). In some examples, both the PFE delivery instrument 200 and the endoscopic instrument 50 are inserted into a region within the ear, nose, or pharynx of the patient 30. The endoscope can be advanced so that the distal tip 204 of the PFE delivery instrument 200 is within the field of view of the endoscopic instrument 50. This allows the endoscopic instrument 50 to capture the distal tip 204 relative to one or more anatomical features of the patient 30. The user interface device 110 can display the endoscopic data in real time.

[0082] The PFE control console 100 is configured to detect the position of the PFE delivery device 200 relative to the anatomical structure of the patient 30 based on endoscopic image data (1504). In some embodiments, this involves determining whether the PFE delivery device 200 is close to a target tissue site. The control console 100 may optionally apply a machine learning model to detect the position of the PFE delivery device 200 corresponding to the anatomical structure of the patient 30. The user 20 can move the endoscopic instrument 50 and the PFE delivery device 200 independently of each other, so that the lens of the endoscopic instrument 50 can move relative to the distal tip 204. The further the endoscopic instrument 50 is from the distal tip 204, the smaller the distal tip 204 appears on the display screen of the user interface device 110, and the closer the endoscopic instrument 50 is to the distal tip 204, the larger the distal tip 204 appears on the display screen of the user interface device 110. The machine learning model can process endoscopic image data to determine the position of the distal tip 204 relative to anatomical structures, taking into account the distance between the distal tip 204 and the lens of the endoscopic instrument 50.

[0083] For example, a machine learning model can be trained using training data that includes multiple training images. Each of these training images can be associated with the distance between objects in the image and the distance between the image capture device and the objects in the image. The machine learning model can be trained to recognize patterns that allow it to determine the position of the distal tip 204 relative to one or more anatomical features based on endoscopic image data, when the distance between the endoscopic lens and the distal tip 204 is unknown. In some examples, the machine learning model can estimate the depth of the distal tip 204 in the endoscopic image data. One type of machine learning model that can estimate depth is a convolutional neural network (CNN).

[0084] Continuing to refer to Figure 15, the PFE control console 100 can determine one or more PFE settings corresponding to the PFE delivered by the PFE delivery device 200 (1506). These PFE settings may include, for example, one or a combination of the PFE pulse amplitude, PFE pulse duration, PFE pulse frequency in a pulse burst, the number of PFE pulses in each pulse burst, and the frequency at which the pulse burst is delivered. The control console 100 can obtain one or more physical parameters of the PFE delivery device 200, such as the size of the PFE electrode on the distal tip 204 (1508). Based on the detected position of the PFE delivery device 200, the determined PFE settings, and the obtained physical parameters, the control console 100 can determine the size of the PFE field (1510). For example, the control console 100 can determine the size and dimensions of the space to which the PFE pulse can reach, relative to the position of the PFE electrode on the distal tip 204.

[0085] In some examples of this computer implementation method shown in Figure 15, the PFE control console 100 can apply a machine learning model to estimate the depth of the distal tip 204 in the endoscopic image data in order to determine the size of the PFE field displayed on the display screen of the user interface device 110 (for example, for the calculated PFE field graphics shown in Figures 14A to 14F). The depth can indicate how large the PFE field will appear on the display screen. For example, the PFE field will appear larger on the screen as the endoscopic lens approaches the distal tip 204, and smaller as the endoscopic lens moves away from the distal tip 204. The control console 100 can display the PFE field in real time on the display screen of the user interface device 110 so that the PFE field is overlaid on the electrode at the distal tip 204 (1512).

[0086] Referring here to Figures 16A–16D, the endoscopic image data displayed by the user interface device 110 of the PFE control console (Figure 1) can show the position of the distal tip 204 of the PFE delivery instrument 200 relative to a computer-identified anatomical landmark 1669 (e.g., the inferior turbinate in this embodiment). Optionally, as will be described in more detail below (Figure 17), the PFE control console may be equipped with enhanced safety devices to prevent the output of a PFE pulse if the distal tip 204 is not in close proximity to a specific (approved) anatomical region. Turning to the exemplary images in Figures 16A–16D, image 1602 in Figure 16A shows the distal tip 204 relative to the anatomical landmark 1669 in a first position. Figure 16B shows image 1604 of the distal tip 204 relative to the anatomical landmark 1669 in a second position. Figure 16C shows image 1606 of the anatomical landmark 1669 in a first position, outlined in white. Figure 16D shows an image 1608 of the anatomical landmark 1669 at a second location, outlined in white. In some cases, the control console 100 includes a machine learning model configured to recognize the distal tip 204 and identify the anatomical landmark 1669. In some embodiments, the machine learning model can distinguish the anatomical landmark 1669 from other anatomical landmarks. The machine learning model can determine the distance between the distal tip 204 and the anatomical landmark 1669. Examples of anatomical landmarks include the inferior turbinate, septum, pharynx, and posterior nasal nerve. By determining the identity of the anatomical landmarks and the position of the distal tip 204 relative to those landmarks in real time, the control console 100 can determine whether to deliver PFE via the PFE delivery device 200.

[0087] Referring here to Figure 17, several implementations of the computer implementation method (e.g., performed by the PFE control console 100) can process endoscopic data during ENT procedures to automatically determine whether to output a PFE using the PFE delivery instrument 200. For example, the PFE control console 100 implements a method to achieve enhanced safety by preventing the output of a PFE pulse if the distal tip 204 is not in close proximity to a specific (approved) anatomical area. For example, as shown in operation 1701, the PFE control console 100 can receive endoscopic image data collected by the endoscopic instrument 50 in real time. This endoscopic data may show the distal tip 204 and one or more anatomical features of the patient 30. Also, in operation 1703, the PFE control console 100 can apply a machine learning model to detect the position of the distal tip 204 relative to one or more anatomical features. This operation may include determining the depth of the distal tip 204 relative to one or more anatomical features relative to the endoscopic lens.

[0088] In operation 1705, the PFE control console 100 can segment the anatomical structures that are the target of treatment using the PFE delivery device 200. Preferably, the control console 100 uses a machine learning model to segment the anatomical structures. The machine learning model can segment the image by assigning a label or category to each pixel in the image, effectively dividing the image into regions corresponding to different objects or classes. For example, the target anatomical structure may be in one segment of the image, and that segment can be divided into subsegments.

[0089] In some cases, to train a machine learning model to segment endoscopic image data, the control console 100 can collect a dataset of image frames of endoscopic image data, each image frame annotated with pixel-level labels. These labels may indicate the object or class to which each pixel belongs (e.g., PFE delivery tool, inferior turbinate). This is called labeled training data. The control console 100 can use the labeled training data to train a machine learning model to recognize patterns corresponding to labels that the trained machine learning model can apply to segment unlabeled image data. Convolutional Neural Networks (CNNs) are a type of machine learning model that is useful for segmenting image data. In some embodiments, the machine learning model is trained by applying a loss function to the labeled training data that penalizes discrepancies between predicted segmentation and true labels. For example, the machine learning model predicts segmentation based on labeled frames and learns to minimize discrepancies between the predicted segmentation and true labels. During training, the machine learning model can learn to identify features in the images related to segmentation and make accurate predictions. Therefore, the trained machine learning model can capture in real time and accurately identify objects such as the distal tip 204 and one or more anatomical features in the endoscopic data displayed on the user interface device 110.

[0090] Continuing to refer to Figure 17, in operation 1707, the PFE control console 100 can determine the position of the distal tip 204 of the PFE delivery instrument 200 relative to the segmented anatomical structure. This may involve determining the depth of the delivery instrument 200 and the segmented anatomical structure in order to determine the distance between the delivery instrument 200 and the segmented anatomical structure. A machine learning model such as a CNN can be used to estimate the depth of objects in the image. In operation 1709, the PFE control console 100 can detect that PFE delivery has been activated. In operation 1711, based on the fact that PFE delivery has been activated, the control console 100 can determine whether the PFE delivery instrument 200 is within the segmented anatomical region for PFE delivery. As shown in operation 1713, based on the fact that the PFE delivery device 200 is not within a segmented anatomical region for delivering PFE ("No" in block 1711), the control console 100 prevents the output of a PFE pulse using the PFE delivery device 200 (even if the user activates the foot switch 70 in Figure 1). As shown in operation 1715, based on the fact that the PFE delivery device 200 is within a segmented anatomical structure for delivering PFE ("YES" in block 1711), the control console 100 can activate the output of a PFE pulse using the PFE delivery device 200 (for example, because a machine learning model has accurately identified that the distal tip 204 is within the safe range of the segmented anatomical region).

[0091] Referring here to Figure 18, several embodiments of System 10 include using a PFE delivery device 200, which includes an elongated shaft 205 and a distal tip 204 (as shown in Figures 1-5), to treat the tonsils 1808 and adenoids 1888. For example, the device 200 can be advanced to the tonsils 1808 or adenoids 1888. When the distal tip 204 is close to the target tissue in the tonsils 1808 or adenoids 1888, the PFE delivery device 200 can deliver PFE to treat the target tissue. System 10 is not limited to using the PFE delivery tool shown in Figure 17 to treat the tonsils 1808 and adenoids 1888. Other delivery tools can be used, such as delivery tools that include a basket electrode (e.g., basket electrode 642) or a stent (e.g., stent electrode 815). The PFE delivery device 200 can treat areas within the oral cavity 1833, such as the tongue 1818, tonsils 1808, soft palate 1858, adenoids 1888, and other structures in the oral cavity. The PFE delivery device 200 can sometimes treat malignant or benign cancer cells within the oral cavity 1833. The PFE delivery device 200 can deliver PFE to target tissue to induce apoptosis and trigger lymphocytes to rush to the target tissue, thus releasing T cells and B cells that can fight carcinogenic tissue.

[0092] Referring here to Figures 19-20, several embodiments of System 10 include using a PFE delivery device 200 (described in Figures 1-5) to provide both apoptosis-inducing PFE pulses (for tissue therapy) and nerve stimulation (for restoring healthy nerve function). For example, the PFE delivery device 200 can stimulate neuron 1942, treat the synaptic junction 1911, restore the vesicle 1921 to a healthy state, and trigger an apoptotic event in the cell body 1930 and receptor 1910, as shown in Figure 19. For example, the cell body 1930 containing receptor 1910 may be a diseased cell that disrupts the function of neuron 1942. By delivering PFE, the PFE delivery device 200 can induce apoptosis in the cell body 1930 so that the cell dies and is replaced by a healthy cell. PFE can also restore normal function in neuron 1942 by restoring normal communication between neuron 1942 and receptor 1910. In some embodiments, the PFE electrode 206 of the PFE delivery device 200 can deliver an irreversible electroporation field 1991.

[0093] For example, the PFE delivery device 200 can stimulate bundles of goblet cells 2066 such that the mucus glands 2069 and / or goblet cells 2075 deplete mucus located deep within or within the tissue 2021. This ensures that the tissue is completely or partially cleared of excess mucus. This can also ensure that the tissue is completely or partially cleared of mucus trapped within it. PFE can also repair vesicles 1921 so that they do not produce excess mucus 2020 by irregularly signaling goblet cells 2075 to produce mucus. This can be achieved using PFE to stimulate nerve 1942 such that vesicles 1921 overwork until the channel depletes neurotransmitter 1901. In some embodiments, the vesicle 1921, synaptic junction 1911, and cell body 1930 do not communicate with each other because the synapse 1911 is deprived of neurotransmitter 1901, and the PFE delivered by the PFE delivery device 200 can encapsulate the vesicle 1921 and receptor 1910.

[0094] Some embodiments of system 10 include using a PFE delivery device 200 to stimulate neurons 1942, treat synaptic junctions 1911, restore vesicles 1921 to a healthy state, and trigger an apoptotic event in the cell body 1930 and receptor 1910, as shown in Figure 19. Furthermore, the PFE delivery device 200 can deliver PFE to induce apoptosis in cells constituting cilia 2050, as shown in Figure 20, thus causing those cells to transform into goblet cells 2075 that produce mucus.

[0095] The PFE delivery device 200 can induce electroperforation in the cell body 1930, neurotransmitter 1901, vesicles 1921, and synaptic junction 1911 so that the cell body 1930 dies through apoptosis. The PFE delivery device 200 can restore the neurotransmitter 1901 and synaptic junction 1911 to a normal state by removing and replacing the neurotransmitter 1901 over time. The PFE delivery device 200 can restore the vesicles 1921 and release neurotransmitter 1901 so that the synaptic junction 1911 carries signals transmitted from nerve 1942 to cell receptor 1910.

[0096] It should be understood that one or more of the teachings, expressions, embodiments, examples, etc., described herein may be combined with one or more of the other teachings, expressions, embodiments, examples, etc., described herein. Therefore, the teachings, expressions, embodiments, examples, etc., described below should not be considered separately from each other. Various appropriate ways in which the teachings herein may be combined will be readily apparent to those skilled in the art, given the teachings herein. Such modifications and variations are intended to be included within the claims.

[0097] While various embodiments of the present invention have been shown and described, further adaptations of the methods and systems described herein can be achieved by appropriate modifications by those skilled in the art without departing from the scope of the invention. Some of such potential modifications have been mentioned, while others will be obvious to those skilled in the art. For example, the examples, embodiments, geometric shapes, materials, dimensions, proportions, steps, etc., discussed above are illustrative and not essential. Accordingly, the scope of the invention should be considered with respect to the following claims and is not limited to the details of the structure and operation shown and described herein and in the drawings. [Explanation of Symbols]

[0098] 10 Systems, PFE Systems 20 users 30 patients 50 Handheld Endoscope Instruments, Endoscope Instruments 60 disposable grounding electrode pads, grounding electrode pads, grounding electrodes 70 Footswitches 80 Endoscopy Systems 90 Cloud Servers 100 Pulse-field electroporation (PFE) control console, PFE control console, control console, PFE console, console 110 User Interface Devices 130 Generator, PFE Generator 200 PFE delivery devices, devices 203 QR code 204 Distal tip, tip 205 Long and slender shaft 206 PFE electrodes, single fixed-size monopolar PFE electrode, monopolar electrode, monopolar PFE electrode, electrode 208 connectors 210 Control Console 235 Identifiers 260 Handle 301 PFE pulse 301A~301D PFE pulse, pulse 302A~302D Positive phase 304A~304D Negative phase 310 amplitude 312 Amplitude 330A pulse train 330B pulse train 340 Gap 342 Gap 350 pulse width 380 PFE delivery, pulse train sequence, pulse train 525 Flexible distal shaft section, bent distal section, distal shaft section, shaft section 552 rigid straight shaft, straight shaft 570 field of view 572 Endoscope Lens 600 PFE Delivery Devices, PFE Devices, Instruments 621 Distal tip electrode 642 Flexible PFE electrode, basket electrode, flexible basket electrode, electrode 655 steerable or malleable region, malleable region 670 External grounding pad 689 Long and slender shaft 700 PFE Delivery Device 701 Insulating cover, cover 800 PFE Delivery Device 810 Distal portion 812 Slider Actuator, Actuator Slider 815 Expandable stent PFE electrode, electrode, stent electrode, expandable stent PFE stent electrode 825 Bent tip 904 Distal tip 914 Nasal cavity 1009 Nerves 1101 Throat 1222 First nasal region 1244 Second nasal region 1288 return electrode, electrode mesh, mesh, passive electrode mesh, electrode 1299 Reeds 1300 First lead 1303 Second active electrode 1333 Second lead 1387 First active electrode 1402 Medical images, images 1404 Medical images, images 1406 images 1408 images 1410 images 1412 images 1442 Graphics of the calculated PFE field 1444 Graphics of the calculated PFE field 1446 Graphics of the calculated PFE field 1448 Graphics of the calculated PFE field 1450 Calculated PFE Field Graphics 1452 Graphics of the calculated PFE field 1502 Control Module 1602 images 1604 images 1606 images 1608 images 1669 Computer-identified anatomical landmarks, anatomical landmarks 1808 Tonsils 1818 Tongue 1822 Grounding electrode attached to the shaft, grounding electrode 1833 oral cavity 1858 soft palate 1888 Adenoids 1901 Neurotransmitters 1910 Receptor, Cell Receptor 1911 Synaptic junction, synapse 1921 vesicles 1930 cell body 1942 Neuron, nerve 1991 Irreversible electroporation field 2020 Tissue, mucus 2021 Organization 2050 cilia 2066 bunch 2069 Mucus gland 2075 Goblet Cell

Claims

1. A PFE system configured to deliver pulsed-field electroporation (PFE) pulses to nasal tissue, A handheld PFE tool comprising a handle, an elongated shaft extending from the handle toward a bendable distal shaft portion, and a bulbous treatment tip extending distally from the bendable distal shaft portion, having a PFE electrode configured to deliver PFE pulses to nasal tissue adjacent to the bulbous treatment tip, wherein the bulbous treatment tip has a maximum width of less than 5 mm and is insertable into the nasal canal. A PFE control console configured to accept the connector of the handheld PFE tool, wherein the PFE control console includes a user interface display and A PFE control console includes a PFE generator configured to output a pulsed field from the PFE electrode according to a predefined pulse pattern having a voltage in the range of 850 V to 10,000 V and a pulse duration of 0.05 microseconds (μs) to 3 μs, in order to induce irreversible electroperforation in the nasal tissue, A PFE system equipped with [this feature].

2. The PFE system according to claim 1, wherein the PFE generator is configured to output the pulsed field from the PFE electrode for inducing apoptosis in the nasal tissue without changing the therapeutic temperature of the target tissue by more than 5°C.

3. The PFE system according to claim 2, wherein the PFE control console is connectable to the endoscope system to receive medical image data from the endoscope system such that an endoscopic image of the bulbous treatment tip of the handheld PFE tool is displayed on the user interface display of the PFE control console.

4. The PFE system according to claim 3, wherein the bulbous treatment tip has a rigid shape having a single PFE electrode exposed along the outside of the bulbous treatment tip, and the maximum width of the bulbous treatment tip is from 2 mm to 4 mm.

5. The PFE system according to claim 1, wherein the PFE control console is connectable to a return electrode pad configured to adhere to the patient's skin, and the PFE generator is configured to output the pulse field from the PFE electrode to induce irreversible electroperforation in the patient's nasal tissue such that the pulse field returns to the PFE control console via the return electrode pad on the patient's skin.

6. The PFE system according to claim 5, wherein the PFE control console is connectable to a foot switch, and the PFE control console is configured to activate the PFE generator for outputting the pulse field in response to receiving user input via the foot switch.

7. The PFE system according to claim 1, wherein the predefined pulse pattern comprises a sequence of bursts of electrical pulses, and each burst of electrical pulses comprises a train of high-frequency pulses.

8. The PFE system according to claim 7, wherein the burst of the electrical pulse occurs at a first frequency, and the electrical pulses of each high-frequency pulse train occur at a second frequency lower than the first frequency.

9. The PFE system according to claim 8, wherein the first frequency is in the range of 1 Hertz (Hz) to 100 Hz, and the second frequency is in the range of 500 KiHertz (kHz) to 10,000 kHz.

10. The PFE system according to claim 7, wherein a separation gap occurs between each pair of consecutive bursts of electrical pulses in the sequence of electrical pulse bursts, and a separation gap shorter than the separation gap that occurs between pairs of consecutive bursts of electrical pulses in the sequence of electrical pulse bursts occurs between each pair of consecutive electrical pulses in the high-frequency pulse train.

11. The PFE system according to claim 10, wherein the duration of the separation gap that occurs between each pair of consecutive bursts of electrical pulses in the sequence of electrical pulse bursts is in the range of 0.005 seconds to 1 second, and the duration of the separation gap that occurs between each pair of consecutive electrical pulses in the high-frequency pulse train is in the range of 0.05 μs to 3 μs.

12. The PFE system according to claim 10, wherein each high-frequency pulse train is configured to induce the irreversible electroperforation in the nasal tissue, and the separation gap that occurs between each pair of consecutive bursts of electrical pulses in the sequence of bursts of electrical pulses prevents the handheld PFE tool from delivering thermal ablation energy.

13. The PFE system according to claim 12, wherein the isolation gap between each burst of electrical pulses in the sequence of bursts of electrical pulses allows the handheld PFE tool to stimulate one or more nerves by delivering the sequence of bursts of electrical pulses.

14. The PFE system according to claim 13, wherein the high-frequency pulse train of each burst of electrical pulses in the sequence of bursts of electrical pulses includes several electrical pulses ranging from 10 to 500 electrical pulses.

15. The PFE system according to claim 7, wherein each electrical pulse in the high-frequency pulse train has a single-phase waveform.

16. The PFE system according to claim 7, wherein each electrical pulse in the high-frequency pulse train has a two-phase waveform.

17. The PFE system according to claim 7, wherein the electrical pulses of the high-frequency pulse train alternately have a positive amplitude and a negative amplitude.

18. The PFE system according to claim 1, wherein the pulse field comprises a sequence of bursts of electrical pulses, and each burst of electrical pulses in the sequence of bursts of electrical pulses comprises a plurality of pulse groups.

19. The PFE system according to claim 18, wherein each pulse group of the plurality of pulse groups comprises a first pulse of positive polarity followed by a second pulse of negative polarity.

20. The PFE system according to claim 18, wherein each pulse group of the plurality of pulse groups comprises a first pulse of positive polarity, followed by a second pulse of negative polarity, and followed by a third pulse of positive polarity.

21. The PFE system according to claim 18, wherein each pulse group of the plurality of pulse groups comprises a first pulse of negative polarity, followed by a second pulse of positive polarity, and followed by a third pulse of negative polarity.

22. The PFE system according to claim 1, wherein the angle of the bendable distal shaft portion is adjustable.

23. The PFE system according to claim 22, wherein the angle of the bendable distal shaft portion is adjustable in accordance with the pressure applied to the bendable distal shaft portion.

24. The PFE system according to claim 22, wherein the handheld PFE tool includes an actuator on the handle, the actuator is configured to receive user input for adjusting the angle of the bendable distal shaft portion during the procedure of delivering the PFE pulse to the nasal tissue.

25. The PFE system according to claim 24, wherein the actuator is slidable relative to the handle along the longitudinal axis of the handle, and the angle of the bendable distal shaft portion is adjusted based on the actuator sliding along the longitudinal axis of the handle.

26. A PFE system configured to deliver pulsed-field electroporation (PFE) pulses to target nasal tissue, A handheld PFE tool having a handle, an elongated shaft extending distally from the handle, and a PFE electrode positioned along the tip of the nasal treatment attached to the distal portion of the elongated shaft and configured to be inserted into the nasal passage toward the target nasal tissue, A PFE control console comprising a PFE generator configured to detachably mate with a connector of the handheld PFE tool and to output a sequence of bursts of PFE pulses separated from the PFE electrode by a predefined gap, wherein each burst of PFE pulses in the sequence comprises a train of high-frequency pulses configured to induce irreversible electroperforation in the target nasal tissue, and the predefined gap is configured to stimulate one or more nerves adjacent to the target nasal tissue, A PFE system equipped with [this feature].

27. The PFE system according to claim 26, wherein the burst of the PFE pulse occurs at a first frequency within the sequence, and the electrical pulses within each high-frequency pulse train occur at a second frequency higher than the first frequency.

28. The PFE system according to claim 27, wherein the first frequency is in the range of 1 Hertz (Hz) to 100 Hz, and the second frequency is in the range of 500 KiHertz (kHz) to 10,000 kHz.

29. The PFE system according to claim 26, wherein the predefined gap occurs within the sequence between consecutive high-frequency pulse trains, and a pulse gap occurs between consecutive PFE pulses within each of the high-frequency pulse trains, and the pulse gap is shorter than the predefined gap that occurs between consecutive high-frequency pulse trains.

30. The PFE system according to claim 29, wherein the PFE generator is configured to output a sequence of bursts of the PFE pulses from the PFE electrode so that the handheld PFE tool can deliver PFE therapy without changing the temperature of the target nasal tissue by more than 5°C.

31. The PFE system according to claim 29, wherein the PFE generator is configured to output a sequence of bursts of the PFE pulses from the PFE electrode so that the handheld PFE tool delivers a PFE therapy with a non-ablation temperature change in the target nasal tissue.

32. The PFE system according to claim 31, wherein the PFE control console is configured to prevent the PFE electrodes from delivering electrical stimulation to the target nasal tissue during the predefined gaps occurring between the consecutive high-frequency pulse trains, so that during the predefined gaps, one or more action potentials induced by the sequence of bursts of the PFE pulses propagate through one or more nerves adjacent to the target nasal tissue without interference from the PFE pulses.

33. The PFE system according to claim 29, wherein the duration of the predefined gap that occurs between the consecutive high-frequency pulse trains of the sequence is in the range of 0.005 seconds to 1 second, and the duration of the pulse gap that occurs between the consecutive PFE pulses in each of the high-frequency pulse trains is in the range of 0.05 μs to 3 μs.

34. The PFE system according to claim 26, wherein the PFE control console is configured to activate a nerve stimulation mode such that the predefined gap and the sequence of bursts of the PFE pulses are selected for output to the handheld PFE tool to provide nerve stimulation to one or more nerves adjacent to the target nasal tissue.

35. The PFE system according to claim 26, wherein the PFE generator is configured to output the pulsed field from the PFE electrode for inducing apoptosis in the target nasal tissue without changing the temperature of the target nasal tissue by more than 5°C.

36. The PFE system according to claim 26, wherein the distal portion of the elongated shaft comprises a bendable distal shaft portion that can be selectively adjusted to a direction selected by the user.

37. The PFE system according to claim 36, wherein the handheld PFE tool comprises a bulbous therapeutic tip extending distally from the bendable distal shaft portion, the PFE electrode is exposed along the fixed outer surface of the bulbous therapeutic tip, and the bulbous therapeutic tip defines a maximum width of less than 5 millimeters (mm).

38. The PFE system according to claim 37, wherein the bulbous treatment tip has a rigid shape having the PFE electrode exposed along the fixed outer surface of the bulbous treatment tip, and the maximum width of the bulbous treatment tip is in the range of 2 mm to 4 mm.

39. The PFE system according to claim 36, wherein the PFE electrode comprises a basket electrode extending distally from the bendable distal shaft portion, the basket electrode comprises a plurality of flexible metal supports, each of the plurality of flexible metal supports is connected to one or more of the plurality of flexible metal supports such that the plurality of flexible metal supports form a single conductive PFE electrode.

40. The PFE system according to claim 36, wherein the angle of the bendable distal shaft portion is adjustable to be lateral with respect to the central axis of the proximal portion of the elongated shaft extending from the handle.

41. The PFE system according to claim 40, wherein the bendable distal shaft portion is malleable in response to a bending force applied by the user such that the bendable distal shaft portion maintains a position nonparallel to the proximal portion of the elongated shaft extending from the handle.

42. The PFE system according to claim 40, wherein the handheld PFE tool includes an actuator on the handle configured to receive user input to adjust the bendable distal shaft portion to a position non-parallel to the proximal portion of the elongated shaft extending from the handle.

43. The PFE system according to claim 42, wherein the maximum outer diameter of the bendable distal shaft portion is smaller than the maximum outer diameter of the proximal portion of the elongated shaft extending from the handle.

44. The PFE system according to claim 26, wherein each PFE pulse in the burst sequence of PFE pulses has a magnitude in the range of 850 volts (V) to 10,000 V.

45. The PFE system according to claim 44, wherein each PFE pulse in the burst sequence of PFE pulses has a duration in the range of 0.05 μs to 3 μs.

46. The PFE system according to claim 45, wherein each electrical pulse in the high-frequency pulse train has a single-phase waveform.

47. The PFE system according to claim 45, wherein each electrical pulse in the high-frequency pulse train has a two-phase waveform.

48. The PFE system according to claim 26, wherein the PFE control console is connectable to the endoscope system to receive medical image data from the endoscope system so that the endoscopic image of the handheld PFE tool is displayed on the user interface display of the PFE control console.

49. The PFE system according to claim 26, wherein the PFE control console is connectable to a return electrode pad configured to adhere to the patient's skin, and the PFE generator is configured to output a sequence of bursts of PFE pulses from the PFE electrode to induce irreversible electroperforation in the patient's nasal tissue such that the sequence of bursts of PFE pulses returns to the PFE control console via the return electrode pad on the patient's skin.

50. The PFE system according to claim 49, wherein the PFE control console is connectable to a foot switch, and the PFE control console is configured to activate the PFE generator for outputting a sequence of bursts of the PFE pulses in response to receiving user input via the foot switch.

51. A step of inserting a handheld PFE tool into a patient's nasal canal, wherein the handheld PFE tool comprises a handle, an elongated shaft extending distally from the handle toward a bendable distal shaft portion, and a bulbous therapeutic tip extending distally from the bendable distal shaft portion, having a PFE electrode configured to deliver PFE pulses to the nasal tissue in the patient's nasal canal adjacent to the bulbous therapeutic tip, and the bulbous therapeutic tip having a maximum width of less than 5 mm, The steps include: outputting a pulsed field from the PFE electrode according to a predefined pulse pattern having a voltage in the range of 850 V to 10,000 V and a pulse duration of 0.05 microseconds (μs) to 3 μs in order to induce irreversible electroperforation in the nasal tissue; A method that includes this.

52. The step further includes mating the detachable connector of the handheld PFE tool to the PFE control console, The step of outputting the pulse field includes the step of outputting the pulse field via the PFE electrode in accordance with the predefined pulse pattern by the PFE generator of the PFE control console. The method according to claim 51.

53. The method according to claim 52, further comprising the step of activating the PFE generator to output the pulse field via the PFE electrode according to the predefined pulse pattern in order to induce irreversible electroperforation in the nasal tissue.

54. The method according to claim 53, further comprising the step of initiating a nerve stimulation mode such that the PFE generator delivers the pulse field, which includes a sequence of bursts of PFE pulses, via the PFE electrode in order to provide nerve stimulation to one or more nerves adjacent to the bulbous therapeutic tip.

55. The steps include connecting the PFE control console to a return electrode pad configured to adhere to the patient's skin, The steps include: outputting the pulse field from the PFE electrode according to the predefined pulse pattern in order to induce irreversible electroperforation in the patient's nasal tissue, such that the pulse field returns to the PFE control console via the return electrode pad on the patient's skin; The method according to claim 52, further comprising:

56. The method of claim 55, further comprising the step of activating a PFE generator to output the pulse field via the PFE electrodes according to a predefined pulse pattern, based on the receipt of a user input to a foot switch connected to the PFE console.

57. The method according to claim 51, further comprising the step of inserting the endoscopic instrument into the nasal passage of the patient so that the endoscopic system, including the endoscopic instrument, captures medical image data, including an endoscopic image of the bulbous therapeutic tip of the handheld PFE tool in the nasal passage.

58. The method according to claim 57, further comprising the step of outputting the medical image data for real-time display on the user interface display of the PFE control console.

59. The method according to claim 51, further comprising the step of inserting the handheld PFE tool into the nasal passage of a patient such that the PFE electrode at the bulbous treatment tip is adjacent to the nasal tissue representing the target treatment tissue.

60. The method according to claim 59, further comprising the step of inserting the endoscopic instrument into the nasal passage of the patient so that the endoscopic system, including the endoscopic instrument, captures an endoscopic image showing the position of the bulbous therapeutic tip in the nasal passage relative to the location of the target therapeutic tissue.

61. The method according to claim 60, further comprising the step of outputting the endoscopic image for real-time display on the user interface display of the PFE control console.

62. The PFE control console generates a PFE field range corresponding to the PFE pulse output by the PFE electrode, based on the endoscopic image. The steps include: overlaying a graphic of the PFE field range on the endoscopic image in real time so that the PFE field range for the target therapeutic tissue is visible on the user interface display of the PFE control console; The method according to claim 61, further comprising:

63. The method according to claim 51, wherein the angle of the bendable distal shaft portion is adjustable so as to be lateral to the central axis of the proximal portion of the elongated shaft extending from the handle, and the method further includes the step of adjusting the angle of the bendable distal shaft portion so that the bulbous treatment tip can be inserted into the nasal passage.

64. The method according to claim 63, further comprising the step of adjusting the angle of the bendable distal shaft portion in response to a bending force applied by the user, such that the bendable distal shaft portion maintains a non-parallel position with respect to the proximal portion of the elongated shaft extending from the handle.

65. The method according to claim 63, wherein the handheld PFE tool includes an actuator on the handle, and the method further includes the step of adjusting the angle of the bendable distal shaft portion based on receiving user input to the actuator during the procedure of delivering the PFE pulse to the nasal tissue.

66. The method according to claim 65, wherein the actuator is slidable relative to the handle along the longitudinal axis of the handle, and the method further includes the step of adjusting the angle of the bendable distal shaft portion by sliding the actuator along the longitudinal axis of the handle.

67. The method according to claim 51, further comprising the step of outputting the pulsed field from the PFE electrode for inducing apoptosis in the nasal tissue without changing the target tissue treatment temperature of the nasal tissue by more than 5°C.

68. The method according to claim 51, further comprising the step of outputting the pulse field such that the predefined pulse pattern comprises a sequence of bursts of electrical pulses, each burst of electrical pulses comprising a high-frequency pulse train.

69. The method according to claim 68, wherein the burst of the electrical pulse occurs at a first frequency, and the electrical pulses of each high-frequency pulse train occur at a second frequency higher than the first frequency.

70. The method according to claim 69, wherein the first frequency is in the range of 1 Hertz (Hz) to 100 Hz, and the second frequency is in the range of 500 KiHertz (kHz) to 10,000 kHz.

71. The step of outputting the sequence of the aforementioned electrical pulse bursts is The steps include defining a predefined gap within the sequence between consecutive high-frequency pulse trains, A step of defining a pulse gap between consecutive PFE pulses in each of the aforementioned high-frequency pulse trains, wherein the pulse gap is shorter than the predefined gap occurring between consecutive high-frequency pulse trains. The method according to claim 68, including the method described in claim 68.

72. The steps include receiving medical image data showing the position of the bulbous treatment tip relative to the position of the nasal tissue, A step of determining whether to deliver the pulse field according to the predefined pulse pattern based on the medical image data showing the position of the bulbous treatment tip relative to the position of the nasal tissue, The method according to claim 51, further comprising:

73. The method of claim 72, further comprising the step of delivering the pulse field according to the predefined pulse pattern, based on the decision to deliver the pulse field according to the predefined pulse pattern.

74. The method of claim 72, further comprising the step of refraining from delivering the pulse field according to the predefined pulse pattern, based on the decision not to deliver the pulse field according to the predefined pulse pattern.

75. The method according to claim 51, wherein each electrical pulse in the predefined pulse pattern has a two-phase waveform.

76. A pulsed-field electroporation (PFE) method, The steps include: inserting the elongated shaft of the handheld PFE tool into the patient's nasal canal toward the target nasal tissue, while the handle of the handheld PFE tool, located at the proximal end of the elongated shaft, remains outside the nasal canal; and inserting the elongated shaft of the handheld PFE tool toward the target nasal tissue, such that the PFE electrode located along the nasal treatment tip of the handheld PFE tool at the distal end of the elongated shaft is in close proximity to the target nasal tissue; Steps of outputting a sequence of bursts of PFE pulses from the PFE electrode of a handheld PFE tool, wherein each pair of consecutive bursts of PFE pulses in the sequence is separated by a predefined gap, and each burst of PFE pulses in the sequence comprises a high-frequency pulse train configured to induce irreversible electroperforation in the target nasal tissue, and the predefined gap separating each pair of consecutive bursts of PFE pulses is configured to stimulate one or more nerves adjacent to the PFE electrode; A method that includes this.

77. The method according to claim 76, wherein the burst of PFE pulses occurs at a first frequency within the sequence, and the PFE pulses within each burst of PFE pulses occur at a second frequency higher than the first frequency.

78. The method according to claim 77, wherein the first frequency is in the range of 1 Hertz (Hz) to 100 Hz, and the second frequency is in the range of 500 KiHertz (kHz) to 10,000 kHz.

79. The step further includes mating the detachable connector of the handheld PFE tool to the PFE control console, The step of outputting the burst sequence of PFE pulses includes the step of activating the PFE control console to output the burst sequence of PFE pulses to the handheld PFE tool. The method according to claim 76.

80. The method according to claim 79, wherein the PFE generator of the PFE control console is controlled to output a sequence of bursts of the PFE pulses via the PFE electrode to induce irreversible electroperforation in the target nasal tissue.

81. The method according to claim 80, further comprising the step of activating a nerve stimulation mode of the PFE control console such that the PFE generator delivers a sequence of bursts of the PFE pulses through the PFE electrode to stimulate one or more nerves adjacent to the PFE electrode.

82. The method according to claim 4, further comprising the step of connecting the PFE control console to a return electrode pad configured to adhere to the patient's skin, wherein a sequence of bursts of PFE pulses output from the PFE electrode to induce irreversible electroperforation in the target nasal tissue of the patient is returned to the PFE control console via the return electrode pad on the patient's skin.

83. The method according to claim 72, further comprising the step of connecting a foot switch to the PFE control console, wherein the step of activating the PFE control console to output a sequence of bursts of the PFE pulses includes the step of activating the foot switch connected to the PFE console.

84. The method according to claim 76, wherein a pulse gap occurs between consecutive PFE pulses in each high-frequency pulse train of the sequence of high-frequency pulse trains, and the pulse gap is shorter than the predefined gap that occurs between consecutive high-frequency pulse trains of the sequence of high-frequency pulse trains.

85. The method according to claim 84, wherein the step of outputting a sequence of bursts of PFE pulses from the PFE electrode of the handheld PFE tool induces irreversible electroperforation in the target nasal tissue without changing the temperature of the target nasal tissue by more than 5°C.

86. The method according to claim 84, wherein the step of outputting a sequence of bursts of PFE pulses from the PFE electrode of the handheld PFE tool induces irreversible electroperforation in the target nasal tissue during a non-ablation temperature change in the target nasal tissue.

87. The method according to claim 84, wherein the duration of the predefined gap occurring between consecutive bursts of PFE pulses is in the range of 0.005 seconds to 1 second, and the duration of the pulse gap occurring between consecutive PFE pulses within each burst of PFE pulses is in the range of 0.05 μs to 3 μs.

88. The method according to claim 76, wherein the step of outputting a sequence of bursts of PFE pulses from the PFE electrode of the handheld PFE tool further includes the step of preventing the PFE electrode from delivering electrical stimulation to the target nasal tissue during the predefined gap that separates each pair of consecutive bursts of PFE pulses, so that one or more action potentials induced by the sequence of bursts of PFE pulses propagate through the one or more nerves adjacent to the PFE electrode without interference from the sequence of bursts of PFE pulses.

89. The method according to claim 76, further comprising the step of inserting the endoscopic instrument into the nasal canal of the patient so that the endoscopic system, including the endoscopic instrument, captures medical image data, including an endoscopic image of the nasal treatment tip of the handheld PFE tool in the nasal canal.

90. The method according to claim 89, further comprising the step of displaying medical imaging data captured by the endoscopic instrument in real time on the user interface display of the PFE control console.

91. The method according to claim 76, wherein the insertion step includes engaging the PFE electrode at the nasal treatment tip of the handheld PFE tool with the target nasal tissue.

92. The method according to claim 91, further comprising the step of inserting an endoscopic instrument into the nasal passage of the patient in order to capture an endoscopic image showing the position of the tip of the nasal treatment within the nasal passage relative to the position of the target nasal tissue.

93. The method according to claim 92, further comprising the step of displaying the endoscopic image in real time on a user interface display of a PFE control console, wherein the endoscopic image shows the position of the tip of the nasal treatment in the nasal passage relative to the position of the target nasal tissue.

94. The PFE control console generates a PFE field range corresponding to the sequence of bursts of PFE pulses output by the PFE electrode, based on the endoscopic image. The steps include overlaying a graphic of the PFE field range on the endoscopic image so that the PFE field range for the target nasal tissue is visible on the user interface display of the PFE control console, and The method according to claim 93, further comprising:

95. The method according to claim 76, wherein each PFE pulse in the burst sequence of PFE pulses has a magnitude in the range of 850 volts (V) to 10,000 V.

96. The method according to claim 95, wherein each PFE pulse in the burst sequence of PFE pulses has a duration in the range of 0.05 μs to 3 μs.

97. The method according to claim 96, wherein each PFE pulse in the burst sequence of the PFE pulses has a single-phase waveform.

98. The method according to claim 96, wherein each PFE pulse in the burst sequence of the PFE pulses has a two-phase waveform.

99. The method according to claim 76, wherein the distal portion of the elongated shaft comprises a bendable distal shaft portion, and the method further includes the step of selectively adjusting the angle of the bendable distal shaft portion such that the nasal treatment tip of the handheld PFE tool extends laterally with respect to the elongated shaft of the handheld PFE tool.

100. The method according to claim 99, wherein the nasal treatment tip of the handheld PFE tool comprises a bulbous treatment tip extending distally from the bendable distal shaft portion, the PFE electrode is exposed along the fixed outer surface of the bulbous treatment tip, and the bulbous treatment tip defines a maximum width of less than 5 millimeters (mm).

101. An electrical stimulation tool comprising a handle, an elongated shaft extending distally from the handle, and one or more electrodes at the distal end of the elongated shaft. A pulsed-field electroporation (PFE) system comprising: The electrical stimulation tool is configured to deliver electrical stimulation therapy to the patient's nasal tissue via one or more electrodes, and the electrical stimulation therapy induces electroperforation in the nasal tissue and stimulates one or more nerves adjacent to the one or more electrodes. PFE system.

102. The PFE system according to claim 101, further comprising a PFE control console configured to receive a connector for the electrical stimulation tool, wherein the PFE control console includes a PFE generator configured to generate the electrical stimulation therapy for delivery via the one or more electrodes.

103. The PFE system according to claim 101, wherein the electroporation includes one of irreversible electroporation (IRE) and reversible electroporation (RE).

104. The PFE system according to claim 101, wherein the electrical stimulation therapy comprises a sequence of bursts of electrical pulses occurring at a first frequency, and each burst of electrical pulses occurs at a second frequency higher than the first frequency.

105. The PFE system according to claim 104, wherein the first frequency is in the range of 1 Hertz (Hz) to 100 Hz, and the second frequency is in the range of 500 KiHertz (kHz) to 10,000 kHz.

106. The PFE system according to claim 101, wherein the electrical stimulation therapy comprises a sequence of bursts of electrical pulses, wherein a separation gap occurs between each pair of consecutive bursts of electrical pulses in the sequence of bursts of electrical pulses, and each burst of electrical pulses in the sequence of bursts of electrical pulses is configured to stimulate one or more nerves such that one or more nerves adjacent to one or more electrodes are activated during the separation gap that follows the burst of electrical pulses.

107. The PFE system according to claim 101, wherein the electrical stimulation therapy comprises a sequence of bursts of electrical pulses, each burst of electrical pulses comprising a train of high-frequency pulses that induces the electroperforation in the nasal tissue.

108. The PFE system according to claim 107, wherein the amplitude of each electrical pulse in the high-frequency pulse train is within the range of 850 volts (V) to 5,000 V.

109. The PFE system according to claim 107, wherein the duration of each electrical pulse in the high-frequency pulse train is in the range of 0.05 microseconds (μs) to 3 μs.

110. The PFE system according to claim 7, wherein each electrical pulse in the high-frequency pulse train has a single-phase waveform.

111. The PFE system according to claim 107, wherein each electrical pulse in the high-frequency pulse train has a two-phase waveform.

112. The PFE system according to claim 107, wherein the electrical pulses of the high-frequency pulse train alternately have a positive amplitude and a negative amplitude.

113. The PFE system according to claim 101, wherein the electrical stimulation therapy comprises a sequence of bursts of electrical pulses, and each burst of electrical pulses comprises a plurality of pulse groups.

114. The PFE system according to claim 113, wherein each pulse group of the plurality of pulse groups comprises a first pulse of positive polarity followed by a second pulse of negative polarity.

115. The PFE system according to claim 113, wherein each pulse group of the plurality of pulse groups comprises a first pulse of positive polarity, followed by a second pulse of negative polarity, and followed by a third pulse of positive polarity.

116. The PFE system according to claim 113, wherein each pulse group of the plurality of pulse groups comprises a first pulse of negative polarity, followed by a second pulse of positive polarity, and followed by a third pulse of negative polarity.

117. An electrical stimulation tool comprising a handle, an elongated shaft extending distally from the handle, and one or more electrodes at the distal end of the elongated shaft, wherein the electrical stimulation tool is configured to induce electroperforation in the patient's nasal tissue via the one or more electrodes, An endoscope configured to capture the distal portion inside the nose of the patient, A pulsed-field electroporation (PFE) system equipped with [specific feature].

118. The PFE control console is further configured to accept the connector of the PFE delivery device and the connector of the endoscope, and the PFE control console is Image data is received from the endoscope showing the position of the distal end portion of the electrical stimulation tool relative to the position of one or more anatomical features of the patient's nose. A machine learning model is applied to generate one or more instructions based on the position of the distal end portion of the electrical stimulation tool relative to the location of one or more anatomical features of the patient's nose. A controller configured as follows: The PFE system according to claim 117.

119. The PFE system according to claim 118, wherein the one or more instructions include instructions for controlling electrical stimulation therapy for delivery via the one or more electrodes.

120. The steps include inserting the elongated shaft of the electrical stimulation tool into the patient's nose such that one or more electrodes located at the distal end of the elongated shaft are adjacent to the target tissue, A step of determining whether to deliver electrical stimulation therapy to the patient's nasal tissue in the target tissue via one or more electrodes in order to induce electroperforation in the nasal tissue, A method that includes this.

121. A generator configured to deliver pulsed-field electroporation (PFE) therapy via an electrical stimulation tool in order to induce irreversible electroporation in target tissue and cause electrical stimulation, A computing system comprising one or more machine learning algorithms for detecting anatomical regions, determining whether to enable or disable the delivery of PFE therapy, and projecting areas of irreversible electroporation adjacent to the electrical stimulation tool. A PFE system equipped with [this feature].

122. The PFE system according to claim 121, wherein the PFE delivered by the generator is configured to treat at least one of chronic rhinitis, sleep apnea, migraine, nasal airway obstruction, and intractable ear pain.

123. The PFE system according to claim 121, wherein the generator is configured to deliver a plurality of PFEs to replace defective cells in the target tissue with healthy cells.

124. The PFE system according to claim 121, wherein the generator is configured to deliver a plurality of PFE pulses to trigger the regeneration of healthy tissue in the target tissue.

125. The PFE system according to claim 121, wherein the generator is configured to kill abnormal lesion cells via apoptosis in order to promote replacement with healthy cells, while leaving the extracellular matrix intact.

126. The PFE system according to claim 121, wherein the generator is configured to deliver high-frequency bursts of non-thermal PFE pulses to induce apoptosis.

127. The PFE system according to claim 126, wherein the high-frequency burst PFE pulse is generated at a frequency within the range of 500 kilohertz (kHz) to 10,000 kHz.

128. The PFE system according to claim 121, wherein the generator is configured to deliver a low-frequency group of PFE pulses to stimulate the nerve cells in order to regulate mucus secretion by restoring electrical activity in the nerve cells.

129. The PFE system according to claim 121, wherein the generator is configured to deliver a low-frequency group of PFE pulses to stimulate nerve cells in order to remove mucus from the target tissue.

130. The PFE system according to claim 129, wherein the group of low-frequency PFE pulses is generated at a frequency in the range of 1 Hertz (Hz) to 100 Hz.

131. The PFE system according to claim 121, wherein the generator is configured to deliver a plurality of PFE pulses, and the amplitude of each PFE pulse is greater than 850V to induce irreversible electroporation.

132. The PFE system according to claim 130, wherein the duration of each pulse is less than 3 microseconds in order to minimize muscle contraction in the target tissue.

133. The PFE system according to claim 121, wherein the generator is configured to deliver a plurality of PFE pulses, each pulse being either a single-phase pulse or a two-phase pulse to reduce muscle stimulation.

134. The generator is configured to deliver a plurality of PFE pulse groups, and each pulse group follows the following pattern: A positive polarity pulse is followed by a negative polarity pulse. A first positive pulse is followed by a negative pulse, and then a second positive pulse, and The first negative pulse is followed by a positive pulse, and then a second negative pulse. The PFE system according to claim 121, comprising one of the above.

135. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured for middle ear treatment for treating intractable ear pain.

136. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat the soft palate, posterior lingual space, or hypopharyngeal region that causes airflow obstruction associated with sleep apnea or snoring.

137. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are optimized to treat airway stenosis causing airflow obstruction.

138. The PFE system according to claim 21, wherein the PFE therapy and the electrical stimulation tool are configured to treat dynamic and static nasal valve collapse.

139. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat chronic rhinitis by non-thermally treating the distribution of the posterior nasal nerve through apoptosis.

140. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat chronic rhinitis by stimulating the posterior nasal nerve.

141. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat upper airway obstruction, including the nose, by non-thermally treating the anatomical tissue causing the obstruction.

142. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat upper airway obstruction, including the nose, by displacing tissues such as the tongue, nasal turbinates, and soft palate that cause obstruction, and by stimulating nerves so that nerve activity is restored in order to improve airflow.

143. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat the tonsils.

144. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat the tonsils by stimulating nerves so that nerve activity is restored in order to replace, contract, and / or regenerate tonsil tissue with healthy tissue.

145. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat adenoids.

146. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat adenoids by stimulating nerves so that nerve activity is restored in order to replace, contract, and regenerate adenoid tissue with healthy tissue.

147. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat migraines by non-thermally treating the trigeminal nerve region and the pterygopalatine ganglion region.

148. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat migraines by inducing nerve stimulation in the trigeminal nerve region and the pterygopalatine ganglion region.

149. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat chronic rhinitis via apoptosis.

150. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat cancer by non-thermally inducing lymphocyte proliferation in the region to which the PFE is delivered.

151. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat cancer by inducing lymphocyte proliferation in a region to which the PFE is delivered by nerve stimulation.

152. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat the synaptic junction between the nerve and the cell body so that signal activity is restored to a healthy state.

153. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat neuronal vesicles such that the rate of neurotransmitters is regulated by nerves and restored to a healthy state.

154. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat and / or reduce cell body receptors so that neurotransmitters signaling cell mucus production are restored to a healthy state.

155. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to remove trapped or excess mucus from the tissue by stimulating nerves so that cells remove mucus from the tissue.

156. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to reduce or remove mucus glands so that mucus production is restored to a healthy state.

157. The PFE system according to claim 121, wherein the computing system is configured to generate the PDF therapy based on applying one or more machine learning algorithms to process image data from an endoscope, the image data showing an anatomical structure and the electrical stimulation tool.

158. The PFE system according to claim 121, wherein the electrical stimulation tool is configured to detect tissue contact by monitoring the impedance of the system.

159. The PFE system according to claim 121, wherein the computing system is configured to monitor nerve stimulation signals to determine an anatomical configuration including one or more of the following: excessive mucous glands, nerves, blood vessels, infected tissue, and mucosal thickening.

160. The PFE system according to claim 121, wherein the PFE therapy is configured to treat nasal tissue without disrupting the nasal cycle.

161. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to treat turbinate hypertrophy.

162. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to induce polyp reduction.

163. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to induce the removal of cancer cells via apoptosis.

164. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to induce the removal of cancer cells via nerve stimulation.

165. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to restore normal nerve activity using PFE.

166. The PFE system according to claim 121, wherein the PFE therapy and the electrical stimulation tool are configured to induce inflammation reduction for the treatment of allergic rhinitis.

167. The PFE system according to claim 121, wherein the tip of the electrical stimulation tool is configured to bend between 0 and 150 degrees via a knob located on the handle in response to a mechanical force applied to the tip.

168. The PFE system according to claim 121, wherein the PFE therapy comprises a plurality of PFE pulses that begin at a fixed amplitude, and the computing system is configured to change settings during PFE therapy delivery based on impedance.

169. The PFE system according to claim 121, wherein one or more components in a larger conductive region represent a return electrode, and one or more components in a smaller conductive region represent an active electrode.

170. The PFE system according to claim 169, wherein both the return electrode and the active electrode are used as active electrodes for delivering PFE pulses for tissue treatment in a bipolar configuration.

171. The PFE system according to claim 121, wherein the PFE therapy is configured to treat the upper and lower respiratory systems, including the lungs, in order to avoid triggers that may cause bronchospasm in patients with asthma.

172. The PFE system according to claim 121, wherein the PFE therapy is configured to treat the upper and lower respiratory systems, including the lungs, in order to make the anatomical region less susceptible to allergens or other irritants in the respiratory system, and thus reduce or eliminate asthma attacks.

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