Lung treatment

Abstract

The present invention relates to methods and systems for topical treatment of a wound (e.g., ARDS) or a mediastinal disorder of lung tissue, comprising selecting a target in the tissue in need of treatment; inserting a transbronchial catheter with a miniature ultrasonic treatment transducer at a position as close as possible to the target; calibrating the contact; calibrating the position and irradiating the target with therapeutic ultrasound. Optionally, treatments using sonotrophy and iontotrophy are also provided for topical application of a drug into a wound.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 395,380, filed on August 5, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] Technical Field and Background Art

[0004] In some embodiments of the invention, the invention relates to systems and methods for localized lung treatment, and more particularly, but not exclusively, to systems and methods for transbronchial therapeutic ultrasound, for example, for the treatment of ARDS and thromboembolic complications of mediastinum (mediastinal disorders).

[0005] Local, non-invasive treatment of lung tissue pathologies ranging from inflammatory processes to ARDS, including tumor pathologies, remains a very relevant and virtually unsolved problem.

[0006] Additionally, the potential benefits of therapeutic ultrasound are the ability to mechanically clean wounds, accelerate angiogenesis and vasomotion, and speed up tissue regeneration processes, which meet the necessary criteria for localized treatment of a wide variety of tissues, from diabetic legs to reproductive organs.

[0007] For many years, the lungs have been considered a forbidden zone for ultrasound. Characteristics of the lung anatomy, namely the presence of air in the alveoli, which completely reflects ultrasound waves, and the rib-muscle corset of the chest where the lungs are located, make this organ virtually impenetrable to the use of external therapeutic ultrasound.

[0008] However, it has recently been shown that lung diagnostic ultrasound (LUS) may represent a useful tool for the evaluation of many lung conditions, as mentioned in a review by Laura Gargani entitled "Lung ultrasound: a new tool for the cardiologist." The most clear diagnostic vs. therapeutic definition of ultrasound is that diagnostic ultrasound is used to evaluate medical conditions, while therapeutic ultrasound is used to treat medical conditions.

[0009] Additional background technology for diagnostic ultrasound includes U.S. Pat. No. 8,961,508, which discloses systems, assemblies, and methods for treating lung disease, the systems, assemblies, and methods being used to reduce nervous system input to distal regions of the bronchial tree in the lungs. The treatment system damages nervous tissue to temporarily or permanently reduce nervous system input. The treatment system can heat the nervous tissue, cool the nervous tissue, deliver a flowable substance that causes trauma to the nervous tissue, puncture the nervous tissue, tear the nervous tissue, cut the nervous tissue, apply pressure to the nervous tissue, apply ultrasound to the nervous tissue, apply ionizing radiation to the nervous tissue, damage the cell membranes of the nervous tissue with electrical energy, or deliver a long-acting nerve blocking chemical to the nervous tissue.

[0010] U.S. Patent No. US10307580B2 discloses methods, devices and systems suitable for applying drugs or therapeutic agents to biological conduits (e.g., vascular lumens). More specifically, it discloses combining with ultrasound energy to enhance the uptake of drugs or therapeutic agents encapsulated in microbubbles, and applying drugs or therapeutic agents in a cyclic manner using a pulse generator whose frequency can be matched to the patient's blood pulsation.

[0011] US patent application No. US20180193078A1 discloses a system, method and device for treating tissue. The system includes an elongate tube having a distal portion. A treatment element is positioned on the distal portion of the elongate tube, and the treatment element is constructed and arranged to treat the target tissue.

[0012] The scientific article "Endobronchial high-intensity ultrasound for thermal therapy of pulmonary malignancies: simulations with patient-specific lung models" by Liu et al discloses a study of the feasibility of using an endobronchial ultrasound applicator for thermal ablation of lung tumors using acoustic and biothermal simulations. The study showed that simulations demonstrated the feasibility of an endobronchial ultrasound applicator to deliver thermal coagulation to 2 to 3 cm diameter tumors adjacent to or accessible from the major and deep lung airways.

[0013] The scientific article "Endobronchial ultrasound: A new innovation in bronchoscopy" by Bakamugesh et al discloses the use of an EBUS microprobe for analyzing the multilayer structure of the tracheobronchial wall and for performing biopsies of peripheral lesions.

[0014] The scientific article "Pushing the boundaries: transesophagealendoscopic ultrasound-guided fine-needle aspiration for the diagnosis of intraparenchymal pulmonary micronodules" by Donghi et al discloses the use of transesophageal intracavitary ultrasound (EBUS) electronic bronchoscope for transesophageal exploration (EUS-B-FNA).

[0015] Therefore, to date, for the lungs, only diagnostic ultrasound has been used.

[0016] Treatment of mediastinal thromboembolic complications, especially pulmonary embolism, remains associated with high mortality. The current state-of-the-art technique is the introduction of a catheter with an ultrasound transducer into the pulmonary artery and the concurrent administration of thrombolytic agents, as described in the article “The Role of EkoSonic Endovascular System or It should be noted that despite the high invasiveness of this procedure, it has become state-of-the-art technology for many categories of patients. Summary of the invention

[0017] The following is a non-exclusive list of some examples of embodiments of the present invention. The present invention also includes embodiments containing fewer features than all the features in one example, and embodiments using features from multiple examples (if not explicitly listed below, also included in the present invention).

[0018] Example 1. A catheter system for treating a wound, the catheter system comprising:

[0019] a. At least one catheter comprising a proximal end and a distal end; the distal end comprising:

[0020] i. one or more ultrasonic transmitters;

[0021] ii. an expandable balloon covering the one or more ultrasound transmitters; the expandable balloon comprising a first electrode located at a proximal end of the expandable balloon and a second electrode located at a distal end of the expandable balloon;

[0022] iii. a plurality of first type openings located on the surface of the balloon; the positions of the first type openings being co-located with the positions of the one or more ultrasound transmitters on the catheter;

[0023] iv. a plurality of second type openings located on the surface of the balloon; the locations of the second type openings being co-located with the locations of the first electrodes.

[0024] Example 2. The catheter system of Example 1, further comprising at least one liquid configured to inflate the inflatable balloon.

[0025] Example 3. The catheter system of Example 2, wherein the at least one liquid comprises at least one drug.

[0026] Example 4. The catheter system of Example 2, wherein the at least one liquid is saline.

[0027] Example 5. The catheter system of any one of Examples 1 to 4, further comprising one or more controllers located at the proximal end of the catheter device and configured to control movement of the distal end of the catheter device.

[0028] Example 6. The catheter system of any one of Examples 1 to 5, further comprising a camera located at a distal end of the catheter device.

[0029] Example 7. The catheter system of any of Examples 1 to 6, wherein the at least one catheter is configured to provide phonophoresis therapy.

[0030] Example 8. The catheter system of any one of Examples 1 to 6, wherein the at least one catheter is configured to provide iontophoresis therapy.

[0031] Example 9. The catheter system according to any one of Examples 1 to 8, further comprising an external unit, wherein the at least one catheter is connected to the external unit, and the external unit comprises:

[0032] a. A video unit comprising a navigation system, configured to manipulate the at least one catheter and provide visualization means to the user by the camera;

[0033] b. an electric field unit configured to generate an interference field;

[0034] c. an ultrasound unit configured to generate ultrasound waves of about 0.5 MHz to about 3 MHz with a power of up to 2 watts / cm2;

[0035] d. a calibration unit configured to indicate the attenuation coefficients at different positions and further configured to determine the ideal positioning of the one or more ultrasound transmitters;

[0036] e. a pressure unit configured to maintain and monitor the pressure in the balloon;

[0037] f. a phonophoresis medication unit configured to monitor and administer the at least one drug during phonophoresis therapy;

[0038] g. An iontophoresis medication unit configured to monitor and administer the at least one drug during iontophoresis therapy.

[0039] Example 10. The catheter system of Example 9, wherein the electric field unit is configured to provide current to the first catheter at a first frequency and to provide current to the second catheter at a second frequency.

[0040] Example 11. The catheter system of Example 10, wherein the first frequency is about 4000 Hz and the second frequency is about 4100 Hz to about 4500 Hz.

[0041] Example 12. The catheter system of Example 9, wherein the electric field unit is configured to provide a current of no more than 13 milliamperes.

[0042] Example 13. A method for treating a lung tissue disorder, a pulmonary embolism, and / or a mediastinal thromboembolic disorder, comprising:

[0043] a. selecting a target in the tissue in need of treatment;

[0044] b. advancing at least one catheter device according to Example 1 toward a position near the target;

[0045] c. Perform contact calibration;

[0046] d. Perform position calibration;

[0047] e. Provide ultrasound treatment.

[0048] Example 14. The method of example 13, wherein performing contact calibration comprises:

[0049] a. Inflating the expandable balloon;

[0050] b. receiving a signal from the first electrode and the second electrode;

[0051] c. Stop inflating the balloon.

[0052] Example 15. The method of example 13 or example 14, wherein performing position calibration comprises:

[0053] a. delivering a first amount of ultrasonic energy;

[0054] b. Determine the attenuation coefficient;

[0055] c. Based on the result of the determination, evaluating whether the position near the target is an ideal position.

[0056] Example 16. The method of Example 15, wherein the ideal position is a position where the attenuation coefficient is a low attenuation coefficient.

[0057] Example 17. The method of Example 16, wherein the low attenuation coefficient is about 0.18 dB / mHz*cm.

[0058] Example 18. The method of any one of Examples 13 to 17, further comprising repositioning the catheter device toward a new position near the target if the position calibration fails.

[0059] Example 19. The method of any one of Examples 13 to 17, wherein providing ultrasound treatment comprises irradiating the target with ultrasound waves, wherein the irradiation is characterized by time, force, and amount of radiation field.

[0060] Example 20. The method of Example 19, wherein the irradiation is characterized in order to obtain maximum therapeutic effect and minimum side effects and / or avoid inducing cell death in the target.

[0061] Example 21. The method of Example 19, wherein the irradiating comprises irradiating at a force of about 1 MHz to about 3 MHz.

[0062] Example 22. The method of Example 19, wherein the irradiating comprises irradiating for a time period of about 10 seconds to about 15 minutes.

[0063] Example 23. The method of Example 19, wherein the irradiating comprises irradiating with a focused beam.

[0064] Example 24. A method according to any one of Examples 13 to 23, further comprising monitoring the temperature of the target being treated.

[0065] Example 25. The method of any one of Examples 13 to 24, further comprising avoiding raising the temperature of the treated target above a predetermined temperature.

[0066] Example 26. The method of Example 25, wherein the predetermined temperature is about 40 degrees Celsius to about 45 degrees Celsius.

[0067] Example 27. A method according to any one of Examples 13 to 26, further comprising actively controlling the temperature of the target being treated.

[0068] Example 28. A method according to Example 27, wherein the controlling includes changing the temperature of the target being treated.

[0069] Example 29. The method of Example 27, wherein the controlling comprises causing a cold liquid to flow into the target when the target reaches a predetermined temperature.

[0070] Example 30. A method according to any one of Examples 13 to 29, further comprising visually monitoring the target tissue.

[0071] Example 31. The method of Example 19, wherein the irradiating is performed by two different catheter devices operating simultaneously.

[0072] Example 32. The method of any one of Examples 13 to 31, further comprising providing sonophoresis therapy.

[0073] Example 33. The method of Example 32, wherein providing the phonophoresis treatment comprises further expanding the inflatable balloon to a second inflated state; the second inflated state causing the plurality of first type openings to open.

[0074] Example 34. The method of Example 32, wherein providing the phonophoresis treatment comprises delivering at least one drug while providing the phonophoresis treatment.

[0075] Example 35. The method of any one of Examples 13 to 34, further comprising providing iontophoresis.

[0076] Example 36. The method of Example 35, wherein providing iontophoresis treatment comprises further expanding the expandable balloon to a third expanded state; the third expanded state causes the plurality of second type openings to open.

[0077] Example 37. The method of Example 35, wherein said providing iontophoresis comprises delivering at least one drug while said providing iontophoresis.

[0078] Example 38. The method of any one of Examples 13 to 37, further comprising generating an interfering current by activating two different catheter devices for the location.

[0079] Example 39. The method of any one of Examples 13 to 38, wherein the treatment is for treating one or more of ARDS, a lung parenchymal disorder, and a mediastinal disorder.

[0080] Example 40. A method according to any one of Examples 13 to 39, wherein the advancing is performed via the esophagus and / or via the trachea.

[0081] Example 1a. A method for treating a wound in tissue in a lung, the method comprising:

[0082] a. selecting a target in the tissue in need of treatment;

[0083] b. advancing a catheter having an ultrasonic transducer at the distal end of the catheter toward the target;

[0084] The target is irradiated with ultrasound, the irradiation being characterized by a time and force configured to avoid inducing cell death in the target.

[0085] Example 2a. The method of example 1a, wherein the irradiating comprises irradiating at a force of about 1 MHz to about 3 MHz.

[0086] Example 3a. The method of example 1a or example 2a, wherein the irradiating comprises irradiating for a time period of about 10 seconds to about 15 minutes.

[0087] Example 4a. The method of any one of Examples 1a to 3a, wherein the irradiating comprises irradiating with a focused beam.

[0088] Example 5a. The method of any one of Examples 1a to 4a, further comprising monitoring the temperature of the target being treated.

[0089] Example 6a. The method of any one of Examples 1a to 5a, further comprising avoiding raising the temperature of the treated target above a predetermined temperature.

[0090] Example 7a. The method of example 6a, wherein the predetermined temperature is about 40 degrees Celsius to about 45 degrees Celsius.

[0091] Example 8a. The method of any one of Examples 1a to 7a, further comprising actively controlling the temperature of the target being treated.

[0092] Example 9a. The method of Example 8a, wherein the controlling comprises changing the temperature of the target being treated.

[0093] Example 10a. The method of example 8a, wherein the controlling comprises flowing a cold liquid into the target when the target reaches a predetermined temperature.

[0094] Example 11a. The method of any one of Examples 1a to 10a, further comprising visually monitoring the target tissue.

[0095] Example 12a. The method of any one of Examples 1a to 11a, further comprising actively searching for new targets while performing the irradiating.

[0096] Example 13a The method according to example 12a, wherein the searching and the irradiating are performed by the same device.

[0097] Example 14a. A method according to Example 12a, wherein the searching is performed by a diagnostic ultrasound device introduced through an additional catheter, the diagnostic ultrasound device being configured to transmit coordinates to the therapeutic ultrasound device.

[0098] Example 15a. The method of example 12a, wherein the searching and the irradiating are performed simultaneously.

[0099] Example 16a. The method of example 12a, wherein the searching and the irradiating are performed by two different devices.

[0100] Example 17a. The method of any one of Examples 1a to 16a, further comprising irradiating the target with a laser.

[0101] Example 18a. The method of example 17a, wherein the irradiating with laser light is performed at a different time than the irradiating with ultrasound waves.

[0102] Example 19a. The method of Example 17a, wherein the irradiating with laser is performed for one third of the total irradiation treatment time, and the irradiating with ultrasound is performed for two thirds of the total irradiation treatment time.

[0103] Example 20a. The method of any one of Examples 1a to 19a, further comprising, prior to the irradiating, selecting one or more locations proximal to the target from which the irradiation is to be performed.

[0104] Example 21a. The method of Example 20a, further comprising dividing the irradiating between the one or more locations.

[0105] Example 22a. The method of any one of Examples 1a to 21a, further comprising, prior to the irradiating, selecting at least three locations proximal to the target from which the irradiation is to be performed.

[0106] Example 23a. The method of Example 22a, further comprising dividing the irradiating between the at least three locations.

[0107] Example 24a. The method of any one of Examples 1a to 23a, further comprising topically providing one or more drugs during said treatment.

[0108] Example 25a. A method of treating pulmonary embolism (PE) in a patient, comprising:

[0109] a. selecting at least one target to be treated;

[0110] b. inserting a bronchoscope into the patient and positioning the distal end of the bronchoscope as close as possible to the at least one target;

[0111] c. inserting a catheter including a distal end having a therapeutic ultrasound transmitter into the bronchoscope;

[0112] d. irradiating the at least one target according to a predetermined effective irradiation program.

[0113] Example 26a. The method of Example 25a, wherein the predetermined effective irradiation program includes irradiating at a frequency of about 1 MHz to about 3 MHz.

[0114] Example 27a. The method of example 25a or 26a, wherein the predetermined effective irradiation program includes irradiating the target with three irradiation fields.

[0115] Example 28a. The method of Example 27a, wherein the predetermined effective irradiation program includes irradiating at least 10 points within the three irradiation fields.

[0116] Example 29a. The method of example 28a, wherein the predetermined effective irradiation program comprises an irradiation duration of at least 10 seconds per point.

[0117] Example 30a. The method of any one of Examples 25a to 29a, wherein the predetermined effective irradiation program comprises irradiation for a total duration of at least 5 minutes.

[0118] Example 31a. The method of any one of Examples 25a to 30a, wherein the predetermined effective irradiation program comprises irradiating to achieve a temperature of about 42 degrees Celsius in the target.

[0119] Example 32a. The method of any one of Examples 25a to 31a, wherein the selecting comprises locating and visualizing the affected area.

[0120] Example 33a. The method of any one of Examples 25a to 32a, wherein the irradiating comprises irradiating for a time period of about 10 seconds to about 15 minutes.

[0121] Example 34a. The method of any one of Examples 25a to 33a, wherein the irradiating comprises irradiating with a focused beam.

[0122] Example 35a. The method of any one of Examples 25a to 34a, further comprising monitoring the temperature of the target being treated.

[0123] Example 36a. The method of any one of Examples 25a to 35a, further comprising avoiding raising the temperature of the treated target above a predetermined temperature.

[0124] Example 37a. The method of Example 36a, wherein the predetermined temperature is about 40 degrees Celsius to about 45 degrees Celsius.

[0125] Example 38a. The method of any one of Examples 25a to 37a, further comprising actively controlling the temperature of the target being treated.

[0126] Example 39a. The method of Example 38a, wherein the controlling comprises changing the temperature of the target being treated.

[0127] Example 40a. A method according to Example 38a, wherein the controlling includes causing a cold liquid to flow into the target when the target reaches a predetermined temperature.

[0128] Example 41a. The method of any one of Examples 25a to 40a, further comprising visually monitoring the target tissue.

[0129] Example 42a. The method of any one of Examples 25a to 41a, further comprising actively searching for new targets while performing the irradiating.

[0130] Example 43a. The method of example 42a, wherein the searching and the irradiating are performed by the same device.

[0131] Example 44a. A method according to Example 42a, wherein the searching is performed by a diagnostic ultrasound device introduced through an additional catheter, wherein the diagnostic ultrasound device is configured to transmit coordinates to the therapeutic ultrasound device.

[0132] Example 45a. The method of Example 42a, wherein the searching and the irradiating are performed simultaneously.

[0133] Example 46a. The method of example 42a, wherein the searching and the irradiating are performed by two different devices.

[0134] Example 47a. The method of any one of Examples 25a to 46a, further comprising irradiating the target with a laser.

[0135] Example 48a. The method of Example 47a, wherein the irradiating with laser light is performed at a different time than the irradiating with ultrasound waves.

[0136] Example 49a. The method of Example 47a, wherein the irradiating with laser is performed for one third of the total irradiation treatment time, and the irradiating with ultrasound is performed for two thirds of the total irradiation treatment time.

[0137] Example 50a. The method of any one of Examples 25a to 49a, further comprising, prior to the irradiating, selecting one or more locations proximal to the target from which the irradiation is to be performed.

[0138] Example 51a. The method of Example 50a, further comprising dividing the irradiating between the one or more locations.

[0139] Example 52a. The method of any one of Examples 25a to 51a, further comprising, prior to the irradiating, selecting at least three locations proximal to the target from which the irradiation is to be performed.

[0140] Example 53a. The method of Example 52a, further comprising dividing the irradiating between the at least three locations.

[0141] Example 54a. The method of any one of Examples 25a to 53a, further comprising locally providing one or more drugs during said treatment.

[0142] Example 55a. A method for treating a lung parenchymal and mediastinal disorder in a patient, the method comprising:

[0143] a. selecting at least one target to be treated;

[0144] b. inserting a bronchoscope or a gastroscope into the esophagus or stomach of the patient and positioning the distal end of the bronchoscope as close as possible to the at least one target;

[0145] c. inserting a catheter including a distal end having a therapeutic ultrasound transmitter into the bronchoscope;

[0146] d. irradiating the at least one target according to a predetermined maximum irradiation schedule.

[0147] Example 56a. The method of Example 55a, wherein the predetermined maximum irradiation program includes irradiating at a frequency of about 5 MHz to about 50 MHz.

[0148] Example 57a. The method of example 55a or 56a, wherein the predetermined maximum irradiation program includes irradiating the target with five irradiation fields.

[0149] Example 58a. The method of Example 57a, wherein the predetermined maximum irradiation program includes irradiating at least 20 points within the three irradiation fields.

[0150] Example 59a. A method according to Example 58a, wherein the predetermined maximum irradiation program includes irradiation for a duration of at least 30 seconds per point.

[0151] Example 60a. The method of any one of Examples 55a to 59a, wherein the predetermined maximum irradiation program comprises irradiation for a total duration of at least 30 minutes.

[0152] Example 61a. The method of any one of Examples 55a to 60a, wherein the predetermined maximum irradiation program comprises irradiating to achieve a temperature of about 45 degrees Celsius in the target.

[0153] Example 62a. A method according to any one of Examples 55a to 61a, wherein the selecting includes locating and visualizing the affected area.

[0154] Example 63a. The method of any one of Examples 55a to 62a, wherein the irradiating comprises irradiating for a time period of about 10 seconds to about 15 minutes.

[0155] Example 64a. A method according to any one of Examples 55a to 63a, wherein the irradiating includes irradiating using a focused beam.

[0156] Example 65a. The method of any one of Examples 55a to 64a, further comprising monitoring the temperature of the target being treated.

[0157] Example 66a. The method of any one of Examples 55a to 65a, further comprising avoiding raising the temperature of the target being treated above a predetermined temperature.

[0158] Example 67a. The method of Example 66a, wherein the predetermined temperature is about 40 degrees Celsius to about 45 degrees Celsius.

[0159] Example 68a. The method of any one of Examples 55a to 67a, further comprising actively controlling the temperature of the target being treated.

[0160] Example 69a. A method according to Example 68a, wherein the controlling includes changing the temperature of the target being treated.

[0161] Example 70a. A method according to Example 68a, wherein the controlling includes causing a cold liquid to flow into the target when the target reaches a predetermined temperature.

[0162] Example 71a. The method of any one of Examples 55a to 70a, further comprising visually monitoring the target tissue.

[0163] Example 72a. The method of any one of Examples 55a to 71a, further comprising actively searching for new targets while performing the irradiating.

[0164] Example 73a. The method of example 72a, wherein the searching and the irradiating are performed by the same device.

[0165] Example 74a. A method according to Example 72a, wherein the searching is performed by a diagnostic ultrasound device introduced through an additional catheter, wherein the diagnostic ultrasound device is configured to transmit coordinates to the therapeutic ultrasound device.

[0166] Example 75a. A method according to Example 72a, wherein the searching and the irradiating are performed simultaneously.

[0167] Example 76a. The method of example 72a, wherein the searching and the irradiating are performed by two different devices.

[0168] Example 77a. The method of any one of Examples 55a to 76a, further comprising irradiating the target with a laser.

[0169] Example 78a. The method of Example 77a, wherein the irradiating with laser light is performed at a different time than the irradiating with ultrasound.

[0170] Example 79a. The method of Example 77a, wherein the irradiating with laser is performed for one third of the total irradiation treatment time, and the irradiating with ultrasound is performed for two thirds of the total irradiation treatment time.

[0171] Example 80a. The method of any one of Examples 55a to 79a, further comprising, prior to the irradiating, selecting one or more locations proximal to the target from which the irradiation is to be performed.

[0172] Example 81a. The method of Example 80, further comprising dividing the irradiating between the one or more locations.

[0173] Example 82a. The method of any one of Examples 55a to 81a, further comprising, prior to the irradiating, selecting at least three locations proximal to the target from which the irradiation is to be performed.

[0174] Example 83a. The method of Example 82a, further comprising dividing the irradiating between the at least three locations.

[0175] Example 84a. The method of any one of Examples 55 to 83a, further comprising locally providing one or more drugs during said treatment.

[0176] Example 85a. The method of Example 55a, wherein the selecting includes locating and visualizing the affected area.

[0177] Example 86a. A method of treating a wound in lung and / or parenchymal tissue in a patient, the method comprising:

[0178] a. selecting at least one target in the tissue in need of treatment;

[0179] b. introducing a bronchoscope into the patient and positioning the bronchoscope in the vicinity of the target;

[0180] c. inserting a catheter including a distal end having a therapeutic ultrasound transmitter into the bronchoscope;

[0181] d. irradiating the at least one target according to a predetermined effective pattern program.

[0182] Example 87a. The method of Example 86a, wherein the predetermined effective mode program includes irradiating at a frequency of about 1 MHz to about 3 MHz.

[0183] Example 88a. A method according to Example 86a or 87a, wherein the predetermined effective mode program includes irradiating the target with three irradiation fields.

[0184] Example 89a. A method according to Example 88a, wherein the predetermined effective mode program includes irradiating at least 10 points within the three irradiation fields.

[0185] Example 90a. A method according to Example 89a, wherein the predetermined effective mode program includes irradiation for a duration of at least 10 seconds per point.

[0186] Example 91a. The method of any one of Examples 86a to 90a, wherein the predetermined effective mode program comprises irradiation for a total duration of at least 5 minutes.

[0187] Example 92a. A method according to any one of Examples 86a to 91a, wherein the predetermined effective mode program includes irradiating to achieve a temperature of about 42 degrees Celsius in the target.

[0188] Example 93a. A method according to any one of Examples 86a to 92a, wherein the selecting includes locating and visualizing the affected area.

[0189] Example 94a. The method of any one of Examples 86a to 93a, wherein the irradiating comprises irradiating for a time period of about 10 seconds to about 15 minutes.

[0190] Example 95a. A method according to any one of Examples 86a to 94a, wherein the irradiating includes irradiating using a focused beam.

[0191] Example 96a. A method according to any one of Examples 86a to 95a, further comprising monitoring the temperature of the target being treated.

[0192] Example 97a. The method of any one of Examples 86a to 96a, further comprising avoiding raising the temperature of the target being treated above a predetermined temperature.

[0193] Example 98a. The method of Example 97a, wherein the predetermined temperature is about 40 degrees Celsius to about 45 degrees Celsius.

[0194] Example 99a. The method of any one of Examples 86a to 98a, further comprising actively controlling the temperature of the target being treated.

[0195] Example 100a. A method according to Example 99a, wherein the controlling includes changing the temperature of the target being treated.

[0196] Example 101a. A method according to Example 99a, wherein the controlling includes causing a cold liquid to flow into the target when the target reaches a predetermined temperature.

[0197] Example 102a. A method according to any one of Examples 86aa to 101, further comprising visually monitoring the target tissue.

[0198] Example 103a. The method of any one of Examples 86a to 102a, further comprising actively searching for new targets while performing the irradiating.

[0199] Example 104a. The method of Example 103a, wherein the searching and the irradiating are performed by the same device.

[0200] Example 105a. A method according to Example 103a, wherein the searching is performed by a diagnostic ultrasound device introduced through an additional catheter, wherein the diagnostic ultrasound device is configured to transmit coordinates to the therapeutic ultrasound device.

[0201] Example 106a. The method of Example 103a, wherein the searching and the irradiating are performed simultaneously.

[0202] Example 107a. The method of Example 103a, wherein the searching and the irradiating are performed by two different devices.

[0203] Example 108a. The method of any one of Examples 86a to 107a, further comprising irradiating the target with a laser.

[0204] Example 109a. The method of Example 108a, wherein the irradiating with laser light is performed at a different time than the irradiating with ultrasound.

[0205] Example 110a. The method of Example 108a, wherein the irradiating with laser is performed for one third of the total irradiation treatment time, and the irradiating with ultrasound is performed for two thirds of the total irradiation treatment time.

[0206] Example 111a. The method of any one of Examples 86a to 110a, further comprising, prior to the irradiating, selecting one or more locations proximal to the target from which the irradiation is to be performed.

[0207] Example 112a. The method of Example 111a, further comprising dividing the irradiating between the one or more locations.

[0208] Example 113a. The method of any one of Examples 86a to 112a, further comprising, prior to the irradiating, selecting at least three locations adjacent to the target from which the irradiation is to be performed.

[0209] Example 114a. The method of Example 113a, further comprising dividing the irradiating between the at least three locations.

[0210] Example 115a. The method of any one of Examples 86a to 114a, further comprising locally providing one or more drugs during said treatment.

[0211] Example 116a. A method according to Example 115a, wherein the selection is made based on one or more of R-ray, CT, MRI and US.

[0212] Unless otherwise defined, all technical terms and / or scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to the methods and materials described herein can be used for the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In the event of a conflict, this patent specification (including definitions) shall prevail. In addition, materials, methods and examples are only illustrative and are not intended to be necessarily restrictive.

[0213] As will be appreciated by those skilled in the art, some embodiments of the present invention may be embodied as systems, methods or computer program products. Therefore, some embodiments of the present invention may take the form of a complete hardware embodiment, a complete software embodiment (including firmware, resident software, microcode, etc.) or the form of an embodiment in which software and hardware aspects are combined, all of which are generally referred to herein as "circuit", "module" or "system". In addition, some embodiments of the present invention may take the form of a computer program product embodied in one or more computer-readable media, and the one or more computer-readable media have a computer-readable program code embodied thereon. The implementation of the method and / or system of some embodiments of the present invention may involve performing and / or completing selected tasks manually, automatically or in combination thereof. In addition, according to the actual instruments and equipment of some embodiments of the method and / or system of the present invention, several selected tasks may be implemented by hardware, software or firmware and / or a combination thereof, for example, using an operating system.

[0214] For example, according to some embodiments of the present invention, the hardware for performing selected tasks can be implemented as a chip or circuit. As software, the selected tasks according to some embodiments of the present invention can be implemented as multiple software instructions performed by a computer using any suitable operating system. In an exemplary embodiment of the present invention, one or more tasks according to some exemplary embodiments of the method and / or system as described herein are performed by a data processor (e.g., a computing platform for performing multiple instructions). Optionally, the data processor includes a volatile memory for storing instructions and / or data and / or a non-volatile memory for storing instructions and / or data, such as a magnetic hard disk and / or a removable medium. Optionally, a network connection is also provided. A display and / or a user input device, such as a keyboard or a mouse, are also optionally provided.

[0215] Any combination of one or more computer-readable media can be used for some embodiments of the present invention.Computer-readable media can be computer-readable signal media or computer-readable storage media.Computer-readable storage media can be, for example, but not limited to, electronic, magnetic, optical, electromagnetic, infrared or semiconductor systems, devices or equipment, or any suitable combination of the foregoing.More specific examples (non-exhaustive list) of computer-readable storage media will include the following: electrical connection with one or more wires, portable computer floppy disks, hard disks, random access memory (random access memory, RAM), read-only memory (read-only memory, ROM), erasable programmable read-only memory (EPROM (erasable programmable read-only memory) or flash memory), optical fiber, portable compact disc read-only memory (compact disc read-only memory, CD-ROM), optical storage device, magnetic storage device or any suitable combination of the foregoing.In the context of this document, computer-readable storage media can be any tangible medium that can contain or store a program, and the program is used by an instruction execution system, device or device or is used in combination with an instruction execution system, device or device.

[0216] A computer readable signal medium may include a propagated data signal in which a computer readable program code is embodied, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including but not limited to electromagnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can convey, propagate, or transmit a program for use by or in conjunction with an instruction execution system, device, or apparatus.

[0217] Program code embodied on a computer readable medium and / or data used thereby may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.

[0218] The computer program code for performing the operation of some embodiments of the present invention can be written in any combination of one or more programming languages, including object-oriented programming languages, such as Java, Smalltalk, C++, etc., and conventional procedural programming languages, such as "C" programming language or similar programming languages. The program code can be executed completely on the user's computer, partially on the user's computer, as an independent software package, partially on the user's computer and partially on a remote computer, or completely on a remote computer or server. In the latter case, the remote computer can be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or can be connected to an external computer (e.g., by using the Internet of an Internet service provider).

[0219] Some embodiments of the present invention may be described below with reference to the flow chart and / or block diagram of the method, device (system) and computer program product according to embodiments of the present invention. It will be appreciated that the combination of each frame in the flow chart and / or block diagram and the frame in the flow chart and / or block diagram may be implemented by computer program instructions. These computer program instructions may be provided to the processor of a general-purpose computer, a special-purpose computer or other programmable data processing device to produce a machine, so that the instruction executed via the processor of a computer or other programmable data processing device creates a means for implementing the function / action specified in one or more frames of a flow chart and / or block diagram.

[0220] These computer program instructions may also be stored in a computer-readable medium, which may direct a computer, other programmable data processing device, or other apparatus to function in a specific manner, so that the instructions stored in the computer-readable medium produce an article of manufacture including the following instructions: implementing the functions / actions specified in one or more boxes of the flowchart and / or block diagram.

[0221] The computer program instructions may also be loaded onto a computer, other programmable data processing device or other apparatus to cause a series of operational steps to be performed on the computer, other programmable device or other apparatus to produce a computer-implemented process, so that the instructions executed on the computer or other programmable device provide a process for implementing the functions / actions specified in one or more boxes of the flowchart and / or block diagram.

[0222] Some of the methods described herein are generally designed to be used only by computers and may not be feasible or practical for full manual execution by a human expert. A human expert who would like to perform a similar task manually (e.g., providing the correct ultrasound intensity for the tissue to be treated) may be expected to use an entirely different approach (e.g., utilizing expertise and / or the pattern recognition capabilities of the human brain) that would be much more efficient than manually performing the steps of the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0223] With reference to the accompanying drawings, some embodiments of the present invention are described herein by way of example only. With specific reference now to the accompanying drawings in detail, it is emphasized that the details shown are by way of example and for the purpose of illustrative discussion of embodiments of the present invention. In this regard, the description in conjunction with the accompanying drawings makes it clear to those skilled in the art how embodiments of the present invention can be practiced.

[0224] In the attached picture:

[0225] Figure 1 is a flow chart of an exemplary treatment method according to some embodiments of the present invention;

[0226] Figure 2 is a schematic diagram of positioning a treatment area according to some embodiments of the present invention;

[0227] Figure 3 is a schematic diagram of inserting a device into a lung for diagnostic and / or therapeutic purposes according to some embodiments of the present invention; and

[0228] Figure 4 is a schematic diagram of selected locations for therapeutic US according to some embodiments of the present invention.

[0229] Figure 5 is a schematic diagram of an interfering electric field generated by two CTCats according to some embodiments of the present invention;

[0230] Figure 6 is a schematic diagram of an exemplary calibration / treating Catheter (CTCat) 600 according to some embodiments of the present invention;

[0231] Figure 7 is a flow chart of an exemplary general method of using CTCat according to some embodiments of the present invention;

[0232] Figure 8 is a flow chart of an exemplary contact calibration method according to some embodiments of the present invention;

[0233] Fig. 9 is a flow chart of an exemplary position calibration method according to some embodiments of the present invention;

[0234] Fig.10 is a schematic diagram of an interference current generated by two CTCats according to some embodiments of the present invention;

[0235] Fig.11 is a schematic diagram of a catheter system according to some embodiments of the present invention. DETAILED DESCRIPTION

[0236] In some embodiments of the invention, the present invention relates to systems and methods for local lung treatment, and more specifically, but not exclusively, to transbronchial therapeutic ultrasound systems and methods for local lung treatment also in patients with ARDS and mediastinal thromboembolic complications (mediastinal disorders).

[0237] Overview

[0238] One aspect of some embodiments of the present invention relates to local non-invasive treatment of lung tissue lesions ranging from inflammatory processes to ARDS and tumor pathology. In some embodiments, therapeutic ultrasound, due to its nature (i.e., invasiveness), includes the ability to mechanically clean wounds, accelerate angiogenesis and vasomotion, and tissue regeneration processes, and has all the necessary criteria for local treatment of a wide range of tissues from diabetic legs to reproductive organs. More than 70% of patients with COVID 19 die from pulmonary complications. Without being bound by theory, it has been shown that damage to the lung parenchyma in a variety of diseases is a special type of "bed healing wound". This is particularly evident in ARDS, where the main biomarkers leading to poor wound healing are the same as those in poorly healing wounds (pressure wounds, venous wounds, diabetic wounds) of completely different etiology. Therefore, the inventors are dealing with poorly healing vascular wounds in the lungs, which, like any wound, primarily require local treatment. Currently, such treatment is not performed, which explains the very high mortality rate of such patients, greater than 40%. In some embodiments, the present invention relates to transbronchial therapeutic ultrasound (minimally invasive) alone or in combination with phonophoresis / iontophoresis and optionally laser for local treatment of lung diseases and mediastinal disorders. In some embodiments, in order for the therapeutic ultrasound to reach the affected area in the lung / mediastinum, a calibration is performed, which allows the determination of a location as close as possible to the lesion focus but with the least aeration and the easiest passage of ultrasound.

[0239] One aspect of some embodiments of the present invention relates to the use of ultrasound to treat the lung. In some embodiments, ultrasound is delivered using a transbronchial therapeutic ultrasound method, alone or in combination with one or more of sonophoresis, iontophoresis, and laser, for local treatment of lung disease and mediastinal disorders. In some embodiments, before applying a therapeutic amount of ultrasound radiation, a calibration process is performed to evaluate one or more positions that meet one or more of the following requirements: as close as possible to the position of the lesion to be treated and the position where ventilation is the least and ultrasound is most easily passed. In some embodiments, calibration and positioning are performed by determining the attenuation coefficient, that is, identifying the area where ultrasound is most easily passed, the area being as close as possible to the lesion. In some embodiments, other methods can be used for calibration. In some embodiments, the target irradiated with ultrasound is characterized by time, force, and the number of radiation fields to obtain maximum therapeutic effect and minimum side effects, and to avoid inducing cell death in the target. In some embodiments, treatment includes providing one or more drugs locally during treatment by using a special catheter, which is a calibration therapeutic catheter (CTCat) with a transducer covered by a balloon, wherein there is a micropore in front of the transducer, and the micropore opens under a certain pressure in the balloon. In some embodiments, the micropores can allow the medicinal substance in the balloon to pass through them. In some embodiments, at the same time, ultrasound mechanically introduces the drug into the adjacent tissue and delivers it to the lesion lesion (sonopenetration). The size range of the catheter depends on their resistance and has different contact pressures (minimum pressure is generated in the balloon to achieve complete contact with the bronchial wall and the perforation remains closed). The use of contact pressure prevents overgrowth and ischemia of the bronchial wall (common complications caused by excessive balloon expansion). For example, the contact pressure of the catheter with resistance R1 is 10mm / H2O, R 2-15mm / H2O, R3-20mm / H2O, etc. In some embodiments, the treatment method includes providing an interferential current. In some embodiments, two medium frequency currents are used for this purpose. In some embodiments, they are called carrier waves because they do not produce muscle or nerve stimulation and are only used to obtain greater penetration depth and generate interference currents. In some embodiments, iontophoresis, in which the electric field is used as a drug promoter, at this time, the drug ions move the drug toward the other pole into the tissue according to their charge. It is based on the following principle: in a given electric field, positively charged drug ions (cations) are repelled by the positive electrode (anode) and are directed to the cathode. For example, ketoprofen is repelled by the negative electrode (cathode) and moves along the anode. In some embodiments, interference currents are used for iontophoresis.

[0240] One aspect of some embodiments of the present invention relates to a system comprising an external unit to which one or more dedicated catheters are connected. In some embodiments, the external unit includes all dedicated controllers for actuating all different mechanical devices of different catheters. In some embodiments, the external unit includes one or more of the following: 1. A video unit with a navigation system. 2. An electric field unit configured to generate an interference field, for example, the first pair receives 4000 Hz and the second pair receives 4100 to 4500 Hz. In some embodiments, at the same time, the current intensity does not exceed 13 mA. 3. An ultrasound unit configured to generate waves of 0.5 to 3 MHz with a power of up to 2 watts / cm2. In some embodiments, it also monitors the ambient temperature of the probe. In some embodiments, the ultrasound generator generates an ultrasonic pulse / non-pulse waveform. 4. A calibration unit configured to indicate the attenuation coefficient in different positioning and determine the ideal positioning of the transducer. 5. A unit for monitoring and maintaining the pressure in the balloon. 6. Unit for medicine administration and dose monitoring - used to inject drugs into the catheter and monitor the dose for phonophoresis. 7. Unit for medicine administration and dose monitoring - used to inject drugs into the catheter and monitor the dose for iontophoresis.

[0241] Example 25. A method of treating pulmonary embolism (PE) or other thromboembolic mediastinal complications in a patient, comprising:

[0242] One aspect of some embodiments of the present invention relates to using ultrasound to treat the lung. In some embodiments, treatment is provided to the relevant tissue in need of treatment from a very short distance. In some embodiments, treatment is provided from within the body, for example, from within the lung. In some embodiments, a preliminary calibration process is performed before treatment to determine one or more areas of the lung characterized by a high level of ultrasound openness and / or being located as close to the lesion as possible. In some embodiments, the potential advantage of performing a preliminary calibration is that it potentially avoids transmitting ultrasound energy to a ventilated area, which will reflect ultrasound energy and thus fail to provide appropriate treatment. In some embodiments, therapeutic ultrasound is delivered while delivering or not delivering drugs and / or medications to the lung. In some embodiments, the calibration process includes selecting an ideal position for the ultrasound probe. In some embodiments, the ideal position is characterized by being a position where there is no air between the probe and the position where treatment is required. In some embodiments, the ideal position is characterized by being the position closest to the position where treatment is required. In some embodiments, the ideal position is characterized by having both of the following: being a position where there is no air between the probe and the position where treatment is required, and being the position closest to the position where treatment is required. In some embodiments, the calibration process utilizes the attenuation of the transmitted ultrasound energy to select the position where the probe will be positioned. In some embodiments, the preliminary calibration process includes ensuring continuous contact between the ultrasound probe and the bronchial wall. In some embodiments, the electrode includes a mechanical device configured to assess that both distal and proximal ends of the region including the ultrasound transmitter are in continuous contact with the bronchial wall.

[0243] In some embodiments, ultrasound action is configured to provide a therapeutic effect while avoiding inducing cell death. In some embodiments, the treatment is characterized by a relatively narrow and / or focused ultrasound beam. In some embodiments, optionally, imaging is used in conjunction with treatment. In some embodiments, imaging is used to identify (optionally identify in real time) the relevant position that needs treatment, for example, the position with increased fluid volume or other signs of lung tissue dysfunction. In some embodiments, the potential advantage of combining transbronchial diagnostic and therapeutic ultrasound is that it potentially allows a better understanding of the dynamics and effectiveness of treatment, and potentially eliminates the need to increase the number of x-rays (otherwise these patients will need to undergo an increased number of x-rays), and therefore alleviates the radiation load of the patient.

[0244] In some embodiments, as described above, during treatment, an ultrasound (US) probe is brought as close as possible to the tissue to be treated from within the body (intubation, bronchoscopy, endoscopy, laparoscopy, robotic), for example, via the esophagus and / or via the trachea, for example, at a distance of about 1 mm to about 1 cm; optionally, at a distance of about 0.5 mm to about 3 cm; optionally, at a distance of about 0.1 mm to about 5 cm. In some embodiments, a potential advantage of bringing the US probe close to the tissue is that it potentially avoids problems caused by interfering with the tissue when treatment is applied from outside the body. In addition, another potential advantage is that it potentially allows a reduction in treatment session time compared to external treatment, for example, reducing the treatment session time to about 3 minutes to about 5 minutes; optionally, about 2 minutes to about 10 minutes; optionally, about 1 minute to about 15 minutes. In addition, another potential advantage is that it potentially allows the use of a focused US beam, which potentially improves the specificity of the treatment area. Additionally, another potential advantage is that it potentially allows treatment to be provided to patients regardless of their body constitution, for example, in overweight patients it is not possible to use external ultrasound from the chest source because the penetration is almost zero due to the bone and added weight.

[0245] In some embodiments, treatment allows monitoring of temperature changes (increases or decreases) in the lungs, and more specifically, in the parenchymal wound, which increases due to the hyperthermic effect of therapeutic ultrasound (about 40 degrees Celsius to about 45 degrees Celsius) and decreases after cessation of treatment. In some embodiments, ultrasound emissions are monitored and controlled to ensure that the therapeutic effect is provided while potentially avoiding cell damage. In some embodiments, a potential advantage of the system and method is that, since the US probe is brought very close to the desired lung tissue, the temperature of the wound itself can be controlled and the hyperthermic effect of ultrasound is actively used without side effects, which has a potential positive effect on improving blood circulation in the lung wound within the above range; this is in contrast to external ultrasound, in which only the temperature of the transducer and skin can be monitored, while the temperature of the wound area is not controlled.

[0246] One aspect of some embodiments of the present invention relates to the treatment of lung wounds, which are optionally caused by COVID19 with refractory ARDS, and the treatment is combined with mechanical ventilation or ECMO. In some embodiments, the treatment is a local treatment of wounds in the lungs. In some embodiments, the treatment is a local treatment provided from within the lungs rather than from outside the patient's body. In some embodiments, the treatment is a treatment of the lung parenchyma, blood vessels, and alveolar-vascular complexes. In some embodiments, the identification of candidates for treatment includes evaluating the level of one or more of IL6, MMP-9, TNF-α, D-dimer, TGF-β1, which is independent of the cause of the wound and determines the final severity of the lesion healing. In some embodiments, the candidate will present one or more of the following parameters: high serum levels of IL-6; high serum levels of TNF-α; high serum levels of matrix metalloproteinases (MMP-9); high serum levels of D-dimers (where those who require intubation have a higher risk of pulmonary embolism (PE)); and high serum levels of TGF-β. It should be understood that these are exemplary parameters and that treatment may be provided to patients who do not meet the exact parameter criteria.

[0247] In some embodiments, after and / or during treatment is provided, the blood / serum level of the parameters disclosed above (one or more of IL6, MMP-9, TNF-α, D-dimer, TGF-β1) is evaluated to assess the level of progress of the treatment, for example, relative to the value found before the start of treatment, the reduction of the above molecular parameters may indicate an improvement in the state of the lesion / wound. In some embodiments, the monitored values ​​of one or more of IL6, MMP-9, TNF-α, D-dimer, TGF-β1 are compared with the initial values ​​before treatment is provided. In some embodiments, monitoring is performed after each treatment. In some embodiments, monitoring is performed one or two days after each treatment. In some embodiments, monitoring is performed at a determined time after treatment is provided according to the instructions of medical staff.

[0248] In some embodiments, treatment includes therapeutic, high frequency, low power ultrasound configured to locally treat wounds in the lungs. In some embodiments, despite the fact that the lungs are filled with air, which does not allow ultrasound to be performed, locations in the lungs that have wounds and / or inflammation are affected by therapeutic ultrasound because these locations are filled not only with air, but also with fluid produced by the inflammatory process.

[0249] In some embodiments, in order to optimize the delivery of therapeutic ultrasound, the therapeutic ultrasound probe is brought close to the focus of the lesion in the lung, which is the bronchial tree. In some embodiments, treatment includes inserting the thinnest catheter with a therapeutic ultrasound probe, which is configured to reach almost any part in the lung, thus avoiding any obstacles (except the thin walls of the bronchus) in the path of the ultrasound to the lesion in the lung tissue. In some embodiments, the potential advantage of doing so is that it potentially allows all the positive qualities (cleaning, anti-inflammatory, high fever, angiogenesis and vasomotion and other local qualities of ultrasound in the repair process) important for the local treatment of wounds of therapeutic ultrasound. In some embodiments, the method is relatively non-invasive and can be optionally combined with diagnostic ultrasound, which can also be inserted through the bronchi and can be used to locate the lesions of the lung parenchyma and can be used to convert coordinates into therapeutic ultrasound, which can potentially allow the accuracy of positioning the catheter with therapeutic ultrasound to be improved. In some embodiments, treatment includes providing treatment that does not cause side effects. In addition, in some embodiments, a catheter with therapeutic ultrasound can be used in the esophagus or stomach under endoscopic control, and the closest distance to the lung lesion can also be subsequently accurately experienced. In some embodiments, considering the anti-thrombotic effect of therapeutic ultrasound, the calibrated / therapeutic catheter is maintained transbronchyally or endoscopically, independently or in combination with local anticoagulants, which can treat mediastinal thromboembolic complications, including pulmonary embolism. In some embodiments, a potential advantage of the treatment of the present invention is that it is a much less invasive procedure for treating pulmonary embolism compared to pulmonary artery cauterization performed in EKOS. In addition, in the case of the treatment disclosed herein, the mechanical effect of ultrasound will manifest itself, which will additionally recruit 12% to 15% of the alveoli in the atelectasis state, and these alveoli can be opened because the micro-massage of ultrasound is almost very close to the alveoli. Another potential advantage of the treatment method of the present invention is that it overcomes the disadvantages of using external ultrasound to the lung area in the chest, which is not effective due to the presence of tissue and bone that do not actually allow ultrasound to pass through, due to the high acoustic morphology (ecogenography) of the bone. In addition, the penetration ability of therapeutic ultrasound is about 5 cm. It should be clear to those skilled in the art that due to the thickness of the chest wall and the diversity of tissues with different impedances along the beam path: such as skin, subcutaneous layer, fat, bone, muscle, fascia, etc., it is virtually impossible for ultrasound waves to reach the lung tissue.

[0250] Additionally, in some embodiments, laser is used concomitantly with therapeutic US. In some embodiments, laser is used in the same manner, by inserting the laser probe with an endobronchial catheter or via an endoscope, and combined with therapeutic ultrasound as described above.

[0251] An aspect of some embodiments of the present invention relates to a method for treating wounds in tissue in the lung, comprising: 1. selecting a target in the tissue to be treated; 2. advancing one or more tracheobronchial tubes toward the target, the tracheobronchial tubes having an ultrasonic transducer at the distal end of the tube; the advancement is performed, for example, via the esophagus and / or via the trachea; 3. calibrating and positioning by determining the attenuation coefficient, i.e. identifying the area as close to the lesion as possible through which ultrasound can pass most easily; irradiating the target with ultrasound, the irradiation being characterized by time, force and amount of radiation field, which is suitable for obtaining maximum therapeutic effect and minimum side effects and avoiding inducing cell death in the target.

[0252] In addition, in some embodiments, the above methods using therapeutic ultrasound provide for local administration of drugs (anticoagulants, anti-inflammatory agents, etc.). A potential advantage is that ultrasound accelerates the introduction of drugs into tissues. In addition, in some embodiments, local administration of drugs is provided using sonophoresis and / or using iontophoresis.

[0253] Before explaining at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited in its application to the details of construction and arrangement of components and / or methods, and / or the examples shown in the following description and / or shown in the drawings and / or examples. The invention is capable of other embodiments or can be practiced or implemented in various ways.

[0254] In the following paragraphs, treatment methods will be disclosed. Although the inventive concept of the present invention will be explained using an exemplary lung treatment method, it should be understood that the same or similar methods can be performed on different locations, for example, the method can be used for colon treatment.

[0255] Exemplary Methods

[0256] Reference Figure 1 , which shows a flow chart of an exemplary treatment method according to some embodiments of the present invention.

[0257] In some embodiments, general exemplary treatment methods include one or more of the following actions:

[0258] Locate the treatment area 102. In some embodiments, a visual assessment of the organ in question (e.g., lung) is performed to locate the relevant treatment area. For example, a lung CT is performed to assess locations 202 in the lungs 204 that require or may require US treatment, such as in Figure 2In some embodiments, a US diagnostic catheter is inserted and the location and / or diagnosis of the problem is performed. In some embodiments, an exemplary method for evaluating the location in need of treatment may be X-ray, MRI, CT, and US.

[0259] The coordinates are provided to the device 104. In some embodiments, optionally, a computerized navigation system is used to navigate the bronchoscope. Thus, in some embodiments, the coordinates of the intrapulmonary location are provided to the computerized navigation system. In some embodiments, a potential advantage of using a computerized navigation system is that the navigation accuracy of such a device potentially allows reaching distant and thin bronchi in the lungs.

[0260] The device is inserted into the patient and brought to the desired coordinates 106. In some embodiments, the device is inserted into the patient and the distal end of the device comprising the ultrasound transmitter is brought into proximity with the location where treatment is desired, e.g., at a distance of about 1 mm to about 1 cm from the location; optionally, at a distance of about 0.5 mm to about 3 cm from the location; optionally, at a distance of about 0.1 mm to about 5 cm from the location. Figure 3 A schematic diagram of an exemplary bronchoscope brought to a position within a lung is shown. In some embodiments, a diagnostic ultrasound transducer is inserted, depending on the diameter of the duct. In some embodiments, the diagnostic ultrasound transducer is activated using, for example, a frequency of about 20 MHz and a 360° field of view.

[0261] Evaluate treatment parameters 108. In some embodiments, once the position is reached, the user evaluates treatment parameters, which include one or more of the following:

[0262] 1. Select one or more (optionally three) locations around the tissue to be treated where the echoes are strongest. Figure 4 Schematically shown are a right lung 402 and a left lung 404. In the right lung 402 there is a small area 406 that needs treatment, while in the left lung 404 there is a large area 408. Figure 4In addition, three positions 410a, 410b, 410c are shown (they are selected as such positions, and treatment will be delivered from this position to position 406 in the right lung 402); and three positions 412a, 412b, 412c (they are selected as such positions, and treatment will be delivered from this position to position 408 in the right lung 404). The arrows indicate the general direction in which the ultrasound treatment will be delivered. In some embodiments, the ideal echo parameters are selected as follows, for example: based on CT or X-ray, the user brings a bronchoscope and evaluates 3 to 5 positions that are ideally visualized by diagnostic ultrasound in one session. In some embodiments, these are positions where lung tissue is heavily destroyed. Therefore, in some embodiments, due to their increased echo reflection, these positions will be ideal positions for inserting and using therapeutic US, and treatment should start from these positions. In some embodiments, if uniformly increased echo reflection is detected in the lesion area, the user selects the most adjacent lesions and treats them according to the protocol.

[0263] In some embodiments, the choice of location is optionally based on the greatest proximity of the transducer to the desired location, and optionally should be a location around the desired location.

[0264] In some embodiments, optionally, the choice of transducer depends on the location to be treated and the diameter of the bronchoscope channel. In some embodiments, the transducer diameter is typically 2.5 mm to 0.7 mm.

[0265] In some embodiments, the treatment plan takes into account the depth of the location where treatment is needed relative to the location from which treatment will be delivered, as well as the size of the location where treatment is needed. In some embodiments, the type of transducer is selected accordingly, for example, based on the location and size of the lung tissue lesion. In some embodiments, a radial probe, a linear probe, or a spot probe may be used.

[0266] In some embodiments, the probe can be both combined therapeutic US and laser, or only laser or only US. In some embodiments, the size of the probe is selected according to the location of the tissue in the lung that needs to be treated and the corresponding diameter of the bronchoscopy. In some embodiments, the smallest is approximately 2 mm.

[0267] In some embodiments, the probe may include, for example, one or more of the following combinations: laser and ultrasound in one probe; one to ten or more therapeutic ultrasound probes in one catheter; laser and ultrasound performed separately; a laser with an ultrasound receiver; and ultrasound diagnostic and ultrasound therapeutic probes, which are separated or combined into one probe. In some embodiments, if the treatment is performed only by therapeutic US, the operation is performed, for example, twice a day for five minutes. In some embodiments, in the case of combined laser and ultrasound treatment, they are optionally performed alternately, depending on the condition of the tissue and the patient. In addition, in some embodiments, the above-mentioned probe can be used at certain locations closer to the mediastinum, and the probe is inserted through the esophagus or gastroscope. In some embodiments, in this case, a bronchoscope can be used for transesophageal treatment of tissue in the lungs.

[0268] In some embodiments, the treatment spectrum (meaning the activation of the transducer) is also affected by the location where treatment is needed relative to the location from which treatment will be delivered and the size of the location where treatment is needed. For example, for a location where treatment is needed that is deeper in the tissue, the transducer is activated at, for example, 1 MHz, while for a closer location, the transducer is activated at, for example, 3 MHz.

[0269] In some embodiments, the location from which treatment is delivered is selected among different locations of the bronchial tree, and optionally, as close as possible to the location where treatment is needed. In some embodiments, at each location having a size, for example, a size up to 2 cm, that is part of the bronchial tree, up to 10 points are selected for treatment. For example, in some embodiments, each point is treated for 10 seconds by forward and backward and / or circular motions. Thus, in some embodiments, about 30 points are treated in one session, so the treatment time will constitute 5 minutes.

[0270] In some embodiments, during the treatment session, the temperature is dynamically measured by a thermal sensor. In some embodiments, when the sensed temperature reaches a certain value, treatment is reduced or stopped, and / or active cooling action is performed, for example, cold liquid is delivered to the treatment area. For example, when the sensed temperature is greater than 41 degrees Celsius, treatment is temporarily stopped (until the sensed temperature reaches a certain value), or the ultrasonic force transmitted is reduced. For example, in some embodiments, when a certain temperature value is sensed, cold liquid is delivered using a separate bronchoscope / endoscope channel, optionally automatically. In some embodiments, the potential advantage of actively monitoring temperature is that it allows active and specific control of temperature, as explained above, which is important for the success of treatment on the one hand, and also important for the safety of the patient on the other hand.

[0271] Treatment is provided 110. In some embodiments, once the treatment plan is prepared, the catheter with the diagnostic ultrasound transducer is removed from the bronchoscope and replaced with a therapeutic ultrasound transducer. In some embodiments, an ultrasound or laser treatment device is inserted endobronchially, and depending on the location of the tissue to be treated, the device is brought in so that the probe is located as close to the desired location as possible.

[0272] In some embodiments, a treatment session includes one or more of the following parameters:

[0273] - Frequency of treatment: In some embodiments, treatment sessions are performed once a day, optionally twice a day, optionally several times a day. In some embodiments, treatment sessions are performed every day, optionally every other day, optionally at any interval selected by the medical practitioner.

[0274] - In some embodiments, the site selected from which treatment is delivered is alternated during the first seven to ten days of treatment, depending on the size of the lesion. In some embodiments, a potential advantage of alternating the site from which treatment is delivered is that it allows the site to be treated from different sides while allowing tissue death processes to occur at those previously treated sites. Another potential advantage is that it allows the largest possible area to be treated. In some embodiments, the area to be treated is treated at least three times from each selected site during the first seven to ten days of treatment.

[0275] In some embodiments, the US beam is not uniform and its properties vary with distance from the transducer. In some embodiments, the US beam closest to the treatment head is called the NEAR field, INTERFERENCE field, or Fresnel zone. In some embodiments, in the case of areas with significant interference, the behavior of the US in this field is far from regular. In some embodiments, the size (length) of the near field can be calculated using r2 / l, where r = radius of the transducer crystal and l = US wavelength according to the frequency used (e.g., 0.5 mm for 3 MHz and 1.5 mm for 1.0 MHz).

[0276] Evaluate whether to repeat or stop treatment 112. In some embodiments, after seven to ten days of treatment, a new CT scan is performed for comparison. In some embodiments, treatment can be stopped after three weeks when medical staff concludes that there are positive clinical results (optionally based on imaging results). In some embodiments, during the convalescent period, it begins immediately after the patient is out of critical condition and continues until respiratory function is restored. In some embodiments, for example, treatment is performed once or twice a week. It should be noted that the fibrotic changes in the lungs after ARDS are very severe and strongly affect respiratory function. However, in about 40% of patients, they are eventually replaced by normal lung tissue. In some embodiments, the convalescent period can be, for example, up to 6 months, or until the scars in the treatment position in the lungs are completely removed.

[0277] In some embodiments, after 7 to 10 days, if medical personnel conclude that there are no positive clinical findings (optionally based on imaging results), treatment is stopped and treatment is subsequently administered to a different lung or a different point in the same lung based on existing echogenic zones opportunities.

[0278] In some embodiments, where laser is used with US therapy, the exposure time is divided, for example, 2 / 3 exposure to US and 1 / 3 exposure to laser. In this case, a catheter with a laser probe is inserted instead of a catheter with a therapeutic ultrasound probe.

[0279] In some embodiments, the same principles apply to the treatment of other malady, for example, when treating pulmonary embolism or other mediastinal vascular complications, or when using therapeutic ultrasound for transesophageal therapy.

[0280] In some embodiments, the same principles apply to treatments using topical agents that penetrate the affected areas of the lungs via ultrasound.

[0281] In some embodiments, during treatment, the patient is provided with one or more medications, such as anti-inflammatory drugs, anticoagulants, and the like.

[0282] Reference Figure 6 , which shows a schematic diagram of an exemplary calibration / therapy catheter (CTCat) 600 according to some embodiments of the present invention.

[0283] In some embodiments, the CTCat is a catheter that includes a dedicated distal end 602 that is configured to allow both calibration and treatment. In some embodiments, a potential advantage of the CTCat is that it potentially avoids the need to perform a two-step operation, one step is to locate the appropriate position for providing treatment, and another step is to bring the device that actually provides the treatment. In some embodiments, two different devices are used, one for calibration and one for treatment.

[0284] In some embodiments, the distal end 602 includes one or more ultrasonic transducers 604. In some embodiments, the distal end 602 is covered by a balloon 606. In some embodiments, the balloon 606 can be inflated with a liquid 608 (e.g., saline and / or a drug or medication). In some embodiments, the balloon 606 includes a first electrode 610 located at a distal portion of the balloon 606 and a second electrode 612 located at a proximal portion of the balloon 606. In some embodiments, in the region of the second electrode 612, the balloon 606 includes a plurality of orifices 614 configured to be actuated when performing iontophoresis treatment (see below). In some embodiments, the positions of the first electrode 610 and the second electrode 612 are set so that the position of the first electrode 610 is away from the position of the farthest transducer 604 among all possible transducers, and the second electrode 612 is close to the position of the closest transducer 604 among all possible transducers. In other words, all possible transducers 604 are located between the first electrode 610 and the second electrode 612. In some embodiments, optionally, the balloon 606 further comprises an additional aperture 616 configured to be actuated when performing phonophoresis treatment (see below) and located at a position that matches the position of the transducer 604. In some embodiments, optionally, the distal end 602 comprises a camera 618 configured to assist the user when navigating the CTCat 600 within the patient's body.

[0285] In some embodiments, CTCat 600 has a range of sizes depending on their resistance and differs from each other in their contact pressure (i.e., the minimum pressure generated in the balloon to achieve complete contact with the bronchial wall and the perforation remains closed). In some embodiments, a potential advantage of using contact pressure is that it potentially prevents overgrowth and / or bronchial wall ischemia, which are common complications from over-expansion of the balloon. In some embodiments, for example, the contact pressure of a catheter with resistance R1 is 10 mmH2O, the contact pressure of a catheter with resistance R2 is 15 mmH2O, and the contact pressure of a catheter with resistance R3 is 20 mmH2O, and so on.

[0286] Example Methods When Using the Example CTCat

[0287] Reference Figure 7 , which shows a flowchart of an exemplary general method of using CTCat according to some embodiments of the present invention.

[0288] In the following paragraphs, a general overview of the method will be explained, followed by a more detailed description of specific actions.

[0289] In some embodiments, the method includes inserting a CTCat into a patient, optionally using a camera 618 (702). In some embodiments, the insertion is performed, for example, via the esophagus and / or via the trachea.

[0290] In some embodiments, the method includes performing a contact calibration (704).

[0291] In some embodiments, the method includes performing a position calibration (706).

[0292] In some embodiments, optionally, the method includes repositioning the CTCat device to a new position and performing actions 704 and 706 again (708). In some embodiments, the reason for repositioning the CTCat is a contact calibration failure or a position calibration failure.

[0293] In some embodiments, the method includes providing ultrasound therapy (710).

[0294] In some embodiments, the method includes optionally providing phonophoresis therapy (712).

[0295] In some embodiments, the method includes optionally providing iontophoresis (714).

[0296] Exemplary Method of Contact Calibration 704

[0297] Reference Figure 8 , which shows a flow chart of an exemplary contact calibration method according to some embodiments of the present invention. In some embodiments, once the CTCat is brought to a potential position (optionally selected based on an X-ray image and / or a CT image), a contact calibration is performed.

[0298] In some embodiments, contact calibration is performed to ensure that ultrasound waves will pass through the bronchial wall by ensuring that the distal end of the device is actually in continuous contact with the bronchial wall.

[0299] In some embodiments, contact calibration is performed by inflating the balloon, optionally slowly inflating the balloon (802) until both the first electrode and the second electrode are in contact with the bronchial wall. In some embodiments, contacting both the first electrode and the second electrode with the bronchial wall will result in a circuit between the first electrode and the second electrode being closed, which will result in a signal to the user that the circuit has been closed (and thus the user will receive a signal 804). In some embodiments, the user then stops inflating the balloon 806.

[0300] In some embodiments, the method provides the minimum pressure required to inflate the balloon to achieve maximum contact with the bronchial wall - hereinafter referred to as the contact pressure or Pcont. In some embodiments, at Pcont, the balloon is in contact with the bronchial wall without overstretching the bronchial wall and without causing tissue ischemia (or other complications).

[0301] In some embodiments, at Pcont, the balloon is in contact with the bronchial wall without opening either orifice 616 (for phonophoresis) or orifice 614 (for iontophoresis).

[0302] Example Position Calibration 706

[0303] Reference Fig. 9 , which shows a flow chart of an exemplary position calibration method according to some embodiments of the present invention. In some embodiments, position calibration is performed to evaluate the ideal position for positioning the CTCat device relative to the position where treatment is required for delivery of treatment. In some embodiments, the ideal position is characterized by being a position where there is no air between the distal end of the device and the position where treatment is required. In some embodiments, the ideal position is characterized by being a position that is closest to the position where treatment is required. In some embodiments, the ideal position is characterized by having both of the following: a position where there is no air between the probe and the position where treatment is required and it is a position that is closest to the position where treatment is required. In some embodiments, the calibration process utilizes the attenuation of the transmitted ultrasonic energy to select the position where the probe will be positioned.

[0304] Without being bound by theory, attenuation is the result of several characteristics of the interaction of sound waves with tissues and tissue boundaries, including, for example: reflection, refraction, scattering, absorption, interference. The conversion of transmitted energy into another form of energy, such as heat (absorption), is the primary way in which ultrasound attenuation occurs in biological tissues, while scattering constitutes another important contributing factor. The inherent tendency of a medium, such as tissue, to attenuate sound waves of a given frequency can be represented by its attenuation coefficient (represented by the Greek letter alpha (α) and measured in dB / [mHz×cm]). The following are examples of attenuation coefficients and properties of some common tissues, which are provided merely as examples to enable those skilled in the art to understand the present invention:

[0305] Maximum attenuation coefficient

[0306] Ventilated lung (α>34.0) presents a nearly impermeable barrier to ultrasound, as does cortical bone (α is approximately 20.0)

[0307] Loss of lung ventilation will change the degree to which it attenuates ultrasound

[0308] Minimum attenuation coefficient

[0309] Water and blood attenuate ultrasound waves to an almost imperceptible degree (α is about 0.18)

[0310] Other soft tissues (such as organs or skeletal muscle) have attenuation coefficients between these extremes.

[0311] Therefore, by determining the attenuation coefficient, not only is it possible to understand how open the lung tissue is to ultrasound, but it also allows the value of this coefficient to be used to hypothesize what processes will occur in the treatment area at the tissue level and therefore relate the composition and dosage of the drug used (when a drug is needed).

[0312] Thus, in some embodiments, position calibration includes:

[0313] a. delivering a certain amount of ultrasonic energy (902);

[0314] b. Determine the attenuation coefficient (904);

[0315] c. Evaluate whether the position is an ideal position by using the attenuation coefficient (906).

[0316] In some embodiments, optionally, other indicators can be used for calibration, for example, X-rays, CT scans, etc.

[0317] Exemplary Ultrasound Treatment

[0318] In some embodiments, as described above, the treatment spectrum (meaning the activation of the transducer) is affected by the location where treatment is desired relative to the location from which treatment will be delivered and the size of the location where treatment is desired. For example, for a location where treatment is desired that is deeper within the tissue, the transducer is activated at, for example, 1 MHz, while for a location that is closer, the transducer is activated at, for example, 3 MHz.

[0319] In some embodiments, a treatment session includes one or more of the following parameters:

[0320] - Frequency of treatment: In some embodiments, treatment sessions are performed once a day, optionally twice a day, optionally several times a day. In some embodiments, treatment sessions are performed every day, optionally every other day, optionally at any interval selected by the medical practitioner.

[0321] - In some embodiments, the site selected from which treatment is delivered is alternated during the first seven to ten days of treatment, depending on the size of the lesion. In some embodiments, a potential advantage of alternating the site from which treatment is delivered is that it allows treatment of sites from different sides while allowing tissue death processes to occur at those previously treated sites. Another potential advantage is that it allows the largest possible area to be treated. In some embodiments, the area to be treated is treated at least three times from each selected site during the first seven to ten days of treatment.

[0322] In some embodiments, the US beam is not uniform and its properties vary with distance from the transducer. In some embodiments, the US beam closest to the treatment head is called the NEAR field, INTERFERENCE field, or Fresnel zone. In some embodiments, in the case of areas with significant interference, the behavior of the US in this field is far from regular. In some embodiments, the size (length) of the near field can be calculated using r2 / l, where r = radius of the transducer crystal and l = US wavelength according to the frequency used (e.g., 0.5 mm for 3 MHz and 1.5 mm for 1.0 MHz).

[0323] In some embodiments, providing ultrasound therapy includes providing ultrasound therapy with interferential current. In some embodiments, two medium frequency currents are used. In some embodiments, the frequency currents act as carrier waves, and they do not produce muscle or nerve stimulation. In some embodiments, the frequency currents are used to obtain greater penetration depth and / or produce interferential currents.

[0324] Reference Figure 5, which shows a schematic diagram of an interfering electric field generated by two CTCat according to some embodiments of the present invention. In some embodiments, as described above, an interfering electric field is used during treatment. In some embodiments, in order to generate an interfering current, two intermediate frequency currents are used. For example, current A: f1-this current is set on the machine, so it is called the "natural / carrier frequency", for example at 4000Hz (2000Hz and 6000Hz are also available); then, current B: f2-the same amplitude, but slightly higher frequency; set by the user. For example, in some embodiments, f2 can vary from 4001Hz to 4150Hz. In some embodiments, f2 will move within a certain frequency range. In some embodiments, the potential advantage of doing so is that it potentially limits the regulation and adaptation of the current. In some embodiments, F=f2-f1, where the amplitude of F (current C) is not constant. In some embodiments, this is called a beat frequency current C. In some embodiments, F=f2-f1 ranges from 1Hz to 150Hz (frequency swing is also called spectrum or sweep). In some embodiments, the area where the interfering current is set remains stationary. In some embodiments, the region of the static interference takes on a cloverleaf appearance (eg, Fig.10 ), and it is at a 45° angle to the vertical line of each electrode. In some embodiments, during treatment, 1, 2, 3, 4 or more electrodes are used.

[0325] In some embodiments, the field is used for one or more of the following:

[0326] 1. To determine the contact pressure, i.e. the minimum pressure at which there is complete contact between the balloon and the bronchial wall, which is important for ultrasound therapy. In some embodiments, the contact pressure allows to control the pressure in the balloon and avoid damage and ischemia of the bronchial mucosa, which can occur in the case of excessive pressure. In some embodiments, the same principle can be applied to all types of catheters at any location.

[0327] 2. Used to perform iontophoresis (see below), during which drugs are introduced deep into the tissue as a means of local drug application. In some embodiments, the balloon is inflated to a pressure level, i.e., to Pion (pressure for iontophoresis), an opening is opened in the proximal electrode, and the drug is introduced into the lung wound by iontophoresis. In some embodiments, a potential advantage of having the ability to provide iontophoresis treatment is that iontophoresis can be used as a treatment alone in cases where calibration does not identify the characteristics (accessible sites) for ultrasound treatment.

[0328] Reference Fig.10, which shows a schematic diagram of an exemplary generation of an interfering current by two CTCats according to some embodiments of the present invention. In some embodiments, when obtaining an interfering current, for example, four fabric electrodes are fixed to a pair of catheters, fixed to the end of each balloon. In some embodiments, if there is a positive charge at the distal end of the balloon, there will be a negative charge at the proximal end of the second balloon. In some embodiments, the electrodes are annular and mounted on the outside of the balloon, as explained above, at both ends thereof.

[0329] Evaluate whether to repeat or stop treatment. In some embodiments, after seven to ten days of treatment, a new CT scan is performed for comparison. In some embodiments, treatment can be stopped after three weeks when medical staff concludes that there are positive clinical results (optionally based on imaging results). In some embodiments, during the convalescent period, it starts immediately after the patient is out of critical condition, and continues until respiratory function is restored. In some embodiments, for example, treatment is performed once or twice a week. It should be noted that the fibrotic changes in the lungs after ARDS are very serious and strongly affect respiratory function. However, in about 40% of patients, they are eventually replaced by normal lung tissue. In some embodiments, the convalescent period can be, for example, up to 6 months, or until the scar in the treatment position in the lung is completely removed.

[0330] Exemplary Provision of Therapeutic Agents During Treatment

[0331] In some embodiments, treatment optionally includes providing one or more drugs / medicines locally during treatment. In some embodiments, as explained above, ultrasound treatment is provided by using a CTCat with a transducer, which is covered with a balloon in which there are micropores in front of the transducer, which open at a certain pressure in the balloon. In some embodiments, these micropores allow drugs / medicines to pass through them. In some embodiments, this is performed when ultrasound treatment is provided. In some embodiments, ultrasound mechanically introduces drugs / medicines into adjacent tissues and facilitates their delivery into lesions (see below—phonophoresis therapy).

[0332] Exemplary Phonophoresis Treatment

[0333] In some embodiments, optionally, in addition to providing ultrasound therapy, sonophoresis therapy is also provided. In some embodiments, as a supplement or alternative to saline, the drug / medication is provided in the liquid that inflates the balloon. In some embodiments, ultrasound therapy is used to deliver drugs to tissues using the sonophoresis principle. In some embodiments, when sonophoresis therapy is provided, the balloon is further inflated to open the orifice 616 located in the transducer 604 area. For example, under Pcont (found during contact calibration), it is found that the amount of 20mmH2O is the amount required to reach Pcont. Then, for example, an additional 5mmH2O (a total of 25mmH2O in the balloon) is inserted into the balloon to open only the orifice 616 located in the transducer 604 area (without opening the orifice 614 located in the second electrode 612 area). In some embodiments, the pressure is hereinafter referred to as sonophoresis pressure (Pressure Phonophoresis) or Pphon, so Pphon=Pcon+5mmH2O.

[0334] Exemplary Iontophoresis Therapy

[0335] In some embodiments, optionally, in addition to providing ultrasound therapy and / or sonophoresis, iontophoresis is also provided. In some embodiments, as a supplement or alternative to saline, the drug / medication is provided in the liquid that inflates the balloon. In some embodiments, iontophoresis is used to deliver the drug to the tissue by interfering with the electric field. In some embodiments, when iontophoresis is provided, the balloon is further inflated to open the orifice 614 located in the second electrode 612 area. For example, at Pcont (found during contact calibration), it is found that the amount of 20mmH2O is the amount required to reach Pcont. Then, for example, an additional 5mmH2O (a total of 25mmH2O in the balloon) is inserted into the balloon to open only the orifice 616 located in the transducer 604 area (without opening the orifice 614 located in the second electrode 612 area), thereby achieving Pphon. Then, additionally, an additional 5 mmH2O (total 30 mmH2O in the balloon) is inserted into the balloon to additionally open the orifice 614 located in the region of the second electrode 612. In some embodiments, this pressure is referred to hereinafter as iontophoresis pressure (Pressure Iontophoresis) or Pion, so Pion = Pcon + Pphon + 5 mmH2O. Thus, by inflating the balloon to 10 mmH2O, the opening in the proximal electrode of the balloon is opened, wherein the polarity of the injected substance in the liquid corresponds to iontophoresis, and the process begins.

[0336] In some embodiments, when iontophoresis is performed, an electric field is used as a drug facilitator. Without being bound by theory, iontophoresis allows the movement of drugs by using drug ions, which, depending on their charge, move into tissues. It is based on the following principle: in a given electric field, positively charged drug ions (cations) are repelled by the positive electrode (anode) and are directed toward the cathode. For example, ketoprofen is repelled by the negative electrode (cathode) and moves along the anode. In some embodiments, an interfering current is used for iontophoresis.

[0337] Exemplary Catheter Systems

[0338] Reference Fig.11 , which shows a schematic diagram of an exemplary catheter system according to some embodiments of the present invention. In some embodiments, the system includes at least one CTCat. Optionally, the system includes more than one CTCat, such as two, three, four or more CTCats.

[0339] In some embodiments, all CTCats 1104 are connected to a central external unit 1102, which includes all the hardware required for the operation of the CTCats.

[0340] In some embodiments, the external unit includes one or more of the following:

[0341] a. A video unit 1106 comprising a navigation system, which is configured to manipulate the at least one catheter and provide visualization means to the user by the camera;

[0342] b. an electric field unit 1108 configured to generate an interference field; in some embodiments, the electric field unit is configured to provide a current to the first conduit at a first frequency and to the second conduit at a second frequency. In some embodiments, the first frequency is about 4000 Hz, and the second frequency is about 4100 Hz to about 4500 Hz. In some embodiments, the electric field unit is configured to provide a current of no more than 13 mA;

[0343] c. Ultrasonic unit 1110, which is configured to generate ultrasonic waves of about 0.5 MHZ to about 3 MHz, with a power of up to 2 watts / cm 2 ;

[0344] d. a calibration unit 1112 configured to indicate attenuation coefficients at different locations and further configured to determine an ideal positioning of the one or more ultrasound transmitters;

[0345] e. a pressure unit 1114 configured to maintain and monitor the pressure in the balloon;

[0346] f. a phonophoresis medication unit 1116 configured to monitor and administer the at least one drug during phonophoresis therapy;

[0347] g. An iontophoresis drug unit 1118 configured to monitor and administer the at least one drug during iontophoresis therapy.

[0348] Exemplary additional information

[0349] In some embodiments, the balloon can be characterized by having different values ​​of Pcont, Pphon, and Pion. In some embodiments, the maximum amount of liquid that can be inserted into the balloon is about 20 mmH2O to about 40 mmH2O, optionally about 15 mmH2O to about 50 mmH2O, optionally greater than 50 mmH2O.

[0350] In some embodiments, the resistance and polarity of CTCat are different. In some embodiments, different people have different broncho-alveolar tree resistances, and therefore, there are CTCat with different balloon resistances so that mechanical damage is not caused to the walls of the broncho-alveolar tree.

[0351] As used herein, the term "about" with respect to an amount or value means "within ±20% thereof."

[0352] The terms "including", "comprising", "having" and variations thereof mean "including but not limited to".

[0353] The term "consisting of" means "including and limited to."

[0354] The term "consisting essentially of" means that a composition, method, or structure may include additional ingredients, steps, and / or parts, but only if the additional ingredients, steps, and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0355] Unless the context clearly indicates otherwise, nouns used herein include plural referents. For example, the term "compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0356] Throughout this application, some embodiments of the present invention may be presented with reference to a range format. It should be understood that the description of the range format is only for convenience and brevity, and should not be construed as an unchangeable limitation on the scope of the present invention. Therefore, it should be considered that the description of a range has specifically disclosed all possible subranges within the range as well as a single numerical value. For example, it should be considered that the description of a range such as "1 to 6" has specifically disclosed subranges within the range, such as "1 to 3", "1 to 4", "1 to 5", "2 to 4", "2 to 6", "3 to 6", etc.; as well as single numbers, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0357] Unless the context clearly indicates otherwise, whenever a numerical range is indicated herein (e.g., "10-15," "10 to 15," or any pair of numbers connected by these additional such range indications), it is meant to include any number (fractional or integer) within the indicated range limits, including the range limits. The phrases "range and variations thereof" between a first indicator and a second indicator and "range and variations thereof" from a first indicator "to," "up to," "up to," or "until" (or other such range indicating terms) to a second indicator are used interchangeably herein and are meant to include the first and second indicators and all fractions and integers therebetween.

[0358] Unless otherwise indicated, the numbers used herein and any numerical ranges based thereon are approximations within a reasonable degree of accuracy of measurement and rounding errors as understood by one skilled in the art.

[0359] The term "method" as used herein refers to ways, means, techniques and procedures for accomplishing a given task, including but not limited to those ways, means, techniques and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine or readily developed by such practitioners from known ways, means, techniques and procedures.

[0360] As used herein, the term "treating" includes abrogating the disorder, substantially inhibiting, slowing or reversing the progression of the disorder, substantially ameliorating the clinical or aesthetic symptoms of the disorder, or substantially arresting the appearance of the clinical or aesthetic symptoms of the disorder.

[0361] It should be understood that, for the sake of clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, multiple features of the invention described in the context of a single embodiment may also be provided separately, or in any suitable sub-combination, or as appropriate in any other described embodiment of the invention. Certain features described in the context of multiple embodiments should not be considered essential features of those embodiments, unless the embodiment is inoperative without these elements.

[0362] Although the present invention has been described in conjunction with specific embodiments of the present invention, it is apparent that many substitutions, modifications and variations will be apparent to those skilled in the art. Therefore, it is intended to cover all such substitutions, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0363] The applicant's intention is that all publications, patents and patent applications mentioned in this specification are incorporated into this specification by reference in their entirety, just as each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference when quoted. In addition, the citation or identification of any reference in this application should not be interpreted as admitting that such reference can be obtained as the prior art of the present invention. With regard to the section titles used, they should not be interpreted as necessary restrictions. In addition, any priority document of the application is hereby incorporated herein by reference in its entirety.

Claims

1. A catheter system for treating a wound, the catheter system comprising: a. At least one catheter comprising a proximal end and a distal end; the distal end comprising: i. one or more ultrasonic transmitters; ii. an expandable balloon covering the one or more ultrasound transmitters; the expandable balloon comprising a first electrode located at a proximal end of the expandable balloon and a second electrode located at a distal end of the expandable balloon; iii. a plurality of first type openings located on the surface of the balloon; the positions of the first type openings being co-located with the positions of the one or more ultrasound transmitters on the catheter; iv. a plurality of second type openings located on the surface of the balloon; the locations of the second type openings being co-located with the locations of the first electrodes.

2. The catheter system of claim 1, further comprising at least one liquid configured to inflate the inflatable balloon.

3. The catheter system of claim 2, wherein the at least one liquid comprises at least one drug.

4. The catheter system of claim 2, wherein the at least one liquid is saline.

5. The catheter system of any one of claims 1 to 4, further comprising one or more controllers located at the proximal end of the catheter device and configured to control movement of the distal end of the catheter device.

6. The catheter system according to any one of claims 1 to 5, further comprising a camera located at a distal-most end of the catheter device.

7. The catheter system of any one of claims 1 to 6, wherein the at least one catheter is configured to provide phonophoresis therapy.

8. The catheter system of any one of claims 1 to 6, wherein the at least one catheter is configured to provide iontophoresis therapy.

9. The catheter system according to any one of claims 1 to 8, further comprising an external unit, the at least one catheter being connected to the external unit, the external unit comprising: a. A video unit comprising a navigation system, configured to manipulate the at least one catheter and provide visualization means to the user by the camera; b. an electric field unit configured to generate an interference field; c. an ultrasound unit configured to generate ultrasound waves of about 0.5 MHz to about 3 MHz with a power of up to 2 watts / cm 2 ; d. a calibration unit configured to indicate the attenuation coefficients at different positions and further configured to determine the ideal positioning of the one or more ultrasound transmitters; e. a pressure unit configured to maintain and monitor the pressure in the balloon; f. a phonophoresis medication unit configured to monitor and administer the at least one drug during phonophoresis therapy; g. An iontophoresis medication unit configured to monitor and administer the at least one drug during iontophoresis therapy.

10. The catheter system of claim 9, wherein the electric field unit is configured to provide current to the first catheter at a first frequency and to provide current to the second catheter at a second frequency.

11. The catheter system of claim 10, wherein the first frequency is about 4000 Hz and the second frequency is about 4100 Hz to about 4500 Hz.

12. The catheter system of claim 9, wherein the electric field unit is configured to provide a current of no more than 13 milliamperes.

13. A method for treating a lung tissue disorder, a pulmonary embolism and / or a mediastinal thromboembolic disorder, comprising: a. selecting a target in the tissue in need of treatment; b. advancing at least one catheter device according to claim 1 toward a position near the target; c. Perform contact calibration; d. Perform position calibration; e. Provide ultrasound treatment.

14. The method according to claim 13, wherein the performing contact calibration comprises: a. Inflating the expandable balloon; b. receiving a signal from the first electrode and the second electrode; c. Stop inflating the balloon.

15. The method according to claim 13 or claim 14, wherein the performing position calibration comprises: a. delivering a first amount of ultrasonic energy; b. Determine the attenuation coefficient; c. Based on the result of the determination, evaluating whether the position near the target is an ideal position.

16. The method of claim 15, wherein the ideal position is a position where the attenuation coefficient is a low attenuation coefficient. The method of claim 16 , wherein the low attenuation coefficient is about 0.18 dB / mHz*cm.

18. The method of any one of claims 13 to 17, further comprising repositioning the catheter device towards a new position proximate the target if the position calibration fails.

19. The method of any one of claims 13 to 17, wherein providing ultrasound therapy comprises irradiating the target with ultrasound waves, the irradiation being characterized by time, force, and amount of radiation field.

20. The method of claim 19, wherein the irradiation is characterized in order to obtain maximum therapeutic effect and minimum side effects and / or to avoid inducing cell death in the target.

21. The method of claim 19, wherein the irradiating comprises irradiating at a force of about 1 MHz to about 3 MHz.

22. The method of claim 19, wherein the irradiating comprises irradiating for a period of time from about 10 seconds to about 15 minutes.

23. The method of claim 19, wherein the irradiating comprises irradiating with a focused beam.

24. The method of any one of claims 13 to 23, further comprising monitoring the temperature of the target being treated.

25. The method of any one of claims 13 to 24, further comprising avoiding raising the temperature of the treated target above a predetermined temperature.

26. The method of claim 25, wherein the predetermined temperature is about 40 degrees Celsius to about 45 degrees Celsius.

27. The method of any one of claims 13 to 26, further comprising actively controlling the temperature of the target being treated.

28. The method of claim 27, wherein the controlling comprises changing the temperature of the target being treated.

29. The method of claim 27, wherein the controlling comprises flowing a cold liquid into the target when the target reaches a predetermined temperature.

30. The method of any one of claims 13 to 29, further comprising visually monitoring the target tissue.

31. The method of claim 19, wherein the irradiating is performed by two different catheter devices operating simultaneously.

32. The method of any one of claims 13 to 31 further comprising providing phonophoresis treatment.

33. The method of claim 32, wherein providing phonophoresis therapy comprises further expanding the inflatable balloon to a second inflated state; the second inflated state causing the plurality of first type openings to open.

34. The method of claim 32, wherein said providing phonophoresis therapy comprises delivering at least one drug while said providing phonophoresis therapy.

35. The method of any one of claims 13 to 34, further comprising providing iontophoresis treatment.

36. The method of claim 35, wherein providing iontophoresis treatment comprises further expanding the expandable balloon to a third expanded state; the third expanded state causing the plurality of second type openings to open.

37. The method of claim 35, wherein said providing iontophoresis comprises delivering at least one drug while said providing iontophoresis.

38. The method of any one of claims 13 to 37, further comprising generating an interfering current by activating two different catheter devices for the location.

39. The method of any one of claims 13 to 38, wherein the treatment is for treating one or more of ARDS, a lung parenchymal disorder, and a mediastinal disorder.

40. The method according to any one of claims 13 to 39, wherein the advancing is performed via the esophagus and / or via the trachea.

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