A wearable device for applying ultrasound pulses to a subject's blood vessels or tissues.

Abstract

This disclosure provides a system and method for non-invasively delivering ultrasound (US) pulses to a target site in a subject. The target site is either a blood vessel or blood-flowing tissue. By delivering US pulses to the target site, a therapeutic process in the body is facilitated. This therapeutic process is typically associated with the production of nitric oxide molecules induced by ultrasound irradiation. This disclosure provides a solution combining a US transducer with one or more sensors. The sensors can detect parameters indicating whether the US transducer is properly coupled and positioned to the subject's body site, enabling safe application of US pulses, or whether the subject and / or target area are in a state to tolerate ultrasound irradiation.

Description

Technical Field

[0001] The present invention generally relates to a wearable device for supplying therapeutic energy to a patient. More specifically, it relates to an ultrasonic device configured to act on the vascular endothelium to induce the release of nitric oxide (NO). Further, the present disclosure generally relates to the treatment of various diseases such as pulmonary hypertension, peripheral arterial disease (PAD), arteriovenous fistula (AVF) maturation, asthma, etc. by promoting local perfusion to a specific target organ.

Background Art

[0002] The emergence of the highly reactive inorganic radical gas nitric oxide (NO) as a molecule contributing to important physiological and pathological processes is one of the major discoveries in recent biology.

[0003] This molecule is produced by cells mediating important biological functions under various physiological and pathological conditions. An example is the endothelial cells of blood vessels. Nitric oxide produced from these cells not only relaxes smooth muscle and regulates blood pressure, but also has an important influence on the functions of circulating blood cells such as platelets and neutrophils, and the smooth muscle of other organs such as the airways as well as blood vessels. In the brain and other sites, nitric oxide functions as a neurotransmitter in non-adrenergic non-cholinergic neurons. In these cases, nitric oxide is thought to be produced intermittently in small amounts in response to various endogenous molecular signals. In the immune system, nitric oxide is synthesized in large amounts over a longer period of time. The production of nitric oxide is induced by endotoxins and cytokines produced by cells of the host defense system in response to exogenous or endogenous inflammatory stimuli, particularly infectious and inflammatory stimuli. This induction of production results in the continuous release of nitric oxide, which is involved not only in host defense processes such as killing bacteria and viruses, but also in the pathological conditions associated with acute and chronic inflammation in various diseases (Non-Patent Documents 1 and 2).

[0004] In the field of vascular function, it has been reported that NO production is physiologically stimulated when the endothelium is exposed to shear stress and changes in blood flow induced by blood flow (Non-patent documents 3-7).

[0005] Recent reports suggest that the application of ultrasound can induce vasodilation, increased blood flow, and pH changes in a frequency and amplitude-dependent manner by mimicking the necessary shear force against the backdrop of NO production from blood vessels (Non-Patent Documents 8-11).

[0006] The vasodilatory effects of nitric oxide (NO), its beneficial effects on perfusion, and the release of NO from the vascular endothelium (inner layer) are major natural mechanisms that regulate local and systemic blood pressure. It is also known that extracorporeal NO administration induces local vasodilation. However, the systemic therapeutic use of NO is limited by its short half-life (less than 1 second) and the potential for adverse effects on systemic blood pressure at high doses.

[0007] One of the most prominent applications of NO induction is the treatment of ischemic tissue in peripheral artery disease (PAD). PAD refers to narrowing or occlusion of arteries due to atherosclerosis (accumulation of fatty plaque), with or without calcification.

[0008] Another use of NO induction is primary pulmonary hypertension. Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) refers to elevated blood pressure in the pulmonary arteries and / or pulmonary capillaries (collectively known as the pulmonary vascular system).

[0009] NO induction is sometimes used in the treatment of Raynaud's disease. Raynaud's disease is a rare vascular disorder that usually affects the fingers and toes. Blood vessels constrict under cold stress. In this condition, blood cannot reach the skin surface, causing the affected area to turn white and blue. When blood flow is restored, the skin turns red and a throbbing or tingling sensation occurs. In severe cases, loss of blood flow can lead to ulcers or tissue necrosis.

[0010] Another application of NO induction is in the maturation of arteriovenous fistulas (AVFs) in patients with end-stage renal disease (ESRD). In ESRD, kidney function declines, and the kidneys cease to function independently. Patients with ESRD require hemodialysis or a kidney transplant to survive for more than a few weeks. As preparation for hemodialysis, these patients undergo surgery to create an arteriovenous fistula in their arm. In this surgery, a nutrient artery, such as the radial artery, is connected to a vein to form the fistula. It takes about 2-3 weeks for the fistula to mature. Unfortunately, 25-50% of fistulas do not mature.

[0011] Thus, given that nitric oxide is a powerful vasodilator and has proven to have very high therapeutic potential, there remains a need to locally enhance the availability of nitric oxide in target tissues (e.g., by using ultrasound energy) to treat the various clinical symptoms disclosed above. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Furchgott and Zawadzki 1980. [Non-Patent Document 2] Palmer et al. 1987. [Non-Patent Document 3] Taso et al. 1995. [Non-Patent Document 4] Uematsu et al. 1995. [Non-Patent Document 5] Ayajiki et al. 1996. [Non-Patent Document 6] Corson et al. 1996. [Non-Patent Document 7] Fleming et al. 1998. [Non-Patent Document 8] O'Neil R Mason, Brian P Davidson, Paul Sheeran, Matthew Muller, James M Hodovan, Jonathan Sutton, Jeffry Powers, Jonathan R Lindner “Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation”, JACC Cardiovasc Imaging. 2020 Mar;13(3):641-651.

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

[0013] The long-standing challenges disclosed above can be solved by providing a skin-worn device for delivering directional therapeutic energy to a patient, and more specifically, by providing an ultrasound device configured to act particularly on the vascular endothelium to induce the release of nitric oxide (NO). [Means for solving the problem]

[0014] The present invention relates to improving NO release in ischemic tissue (for example, in the treatment of tissues affected by ischemic limbs or peripheral artery disease) by applying ultrasound to the tissue under conditions that are effective in increasing blood flow to ischemic tissue.

[0015] To increase NO levels through the application of ultrasound energy via skin-worn and / or wearable devices, a substantial amount of energy must be concentrated on the blood vessels. Furthermore, it has been found that continuous irradiation of such energy may reduce the effectiveness due to mechanisms such as physiological adaptation. Therefore, to maintain high efficacy, it is beneficial to minimize energy irradiation to a duration consistent with natural physiological demands and to limit the duration of stimulation to an optimal level where the limiting increase in NO production and vasodilation decreases.

[0016] Thus, in certain embodiments of the present disclosure, at least one sensor embedded within a device, a sensor disposed outside the body (e.g., a wearable sensor), or a sensor disposed at another location within the body is used to detect a period during which a patient's physiological state causes an increase in the demand for oxygenated blood and promotes perfusion, and then energy (e.g., ultrasound) is applied during that period to initiate stimulation of NO production. In some embodiments, the period optimal for NO production is investigated, and the stimulation time is limited to these periods.

[0017] A first form of one aspect of the present disclosure provides a wearable device configured to couple ultrasonic energy through a patient's skin in the vicinity of, adjacent to, or within at least one blood vessel or tissue containing flowing blood. The device comprises means for applying ultrasonic energy to the at least one blood vessel or tissue containing flowing blood, the ultrasonic energy applying means being configured to cause a physiological effect on the at least one blood vessel or tissue upon application. The device is disposed outside the patient's body and is communicable with at least one remote control device configured to control the ultrasonic energy applying means. The device is communicable with at least one sensor configured to monitor at least one physiological state of the patient, and when that state changes, at least one of the following is performed: (a) the ultrasonic energy is delivered to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one treatment parameter of the supply of ultrasonic energy to the at least one blood vessel or tissue is modified to provide treatment as needed; (c) the change is notified; (d) these are optionally combined.

[0018] Another form of one aspect of the present disclosure provides a non-invasive system for applying ultrasonic (US) pulses or waves to, or towards, blood vessels or tissues containing flowing blood of a subject. In other words, the system is configured to perform ultrasonic irradiation on the tissues or blood vessels of the subject.

[0019] This system includes at least one US transducer configured to transmit ultrasonic pulses; a fixation assembly for fixing / holding the at least one US transducer to a body part of a subject including the blood vessel or tissue; and at least one sensor configured to monitor at least one physiological parameter or state of the subject, for example, a parameter indicating insufficient blood flow in a blood vessel that can be monitored by reflection or echo of a US pulse, or a parameter indicating whether the subject is sitting, walking, or in other body postures or states, thereby recognizing whether the subject is in a suitable state for receiving US treatment by this system and generating detection data based thereon.

[0020] This system further includes at least one processing circuit, that is, a control device or control unit. This processing circuit is configured to communicate with the at least one US transducer and the at least one sensor, receive the detection data, and operably control the at least one US transducer according to the detection data to transmit US pulses towards the blood vessel or tissue. The operable control of the at least one US transducer includes controlling parameters such as intensity, direction, duty cycle, frequency, phase, or any combination thereof.

[0021] It should be noted that any of the following embodiments or objects may refer to any one of the above configurations. Further, any of the following embodiments or objects can be arbitrarily combined with other objects or embodiments in any form or aspect of this disclosure and applied to any of the above configurations.

[0022] In some embodiments, this system further includes an operating device for operably controlling the at least one US transducer with respect to the blood vessel or tissue.

[0023] The term "operation" should be understood to encompass both physical operations, i.e., operations that physically change the position and / or orientation of the transducer and align the transducer's principal axis in different directions under different operating conditions, and digital operations, i.e., operations that change the direction of the US beam to reach different locations regardless of physical changes in the transducer's position and / or orientation. It should be noted that transducer operations may consist of either physical or digital operations alone, or a combination of both.

[0024] In one embodiment of the system, the operating device comprises an operating element and a chamber filled with a fluid material, i.e., a liquid or gel. The chamber may have flexible walls to conform to the shape of the subject's skin surface. At least a portion of the at least one US transducer is positioned within the chamber so as to float in the fluid material within the chamber. The operating element is configured to controllably move the at least one US transducer, thereby controllingly operating the at least one US transducer and applying a US pulse to a desired location along a blood vessel.

[0025] In one embodiment of this system, the fluid material is a non-conductive liquid such as oil.

[0026] In one embodiment of the system, at least one processing circuit is configured to perform a periodic operation control loop. This control loop includes controlling the operating device using different sets of operating parameters and analyzing sensing data associated with the operating timeframes of each set of operating parameters to identify the optimal set of operating parameters that yields the best results for at least one physiological parameter. In other words, each timeframe analyzed is associated with a specific set of operating parameters, which includes angles to at least two orthogonal planes, each plane being perpendicular to the plane defined by the skin of the subject's body part. Once the optimal set of operating parameters is identified, the at least one processing circuit is configured to operate the operating device in a controllable manner with the optimal set of operating parameters until the next periodic operation control loop. In other words, within each periodic control loop, the operating arrangement will be different in different timeframes. For example, the operating device may be in a first position in one timeframe and in a second position in another. It should be noted that at each position, the operating parameters may also include different operating parameters such as the intensity, phase, or duty cycle of the US transducer. The detection data includes sensing the pulse wave of blood flow within the vessels and identifying the optimal time frame for blood flow within those vessels. The set of operational parameters associated with that time frame is selected to operate until the next cyclical operational control loop.

[0027] In one embodiment of this system, the fluid material functions as an impedance transmission medium. That is, the fluid material has an impedance that is relatively compatible with the impedance of skin tissue.

[0028] In one embodiment of this system, the operating elements may include, for example, MEMS-based elements, electromagnetic-based elements, electrostatic-based elements, piezoelectric-based elements, magnetic-based elements, mechanical-based elements, or other suitable elements.

[0029] In one embodiment of the system, the at least one processing circuit is configured to control the at least one US transducer and apply an examination US pulse toward the subject's skin or blood vessels to detect the reflected echoes resulting from the examination pulses. The at least one processing circuit is configured to analyze the detected reflected echoes and determine whether they meet predetermined conditions, thereby determining whether the at least one US transducer is in proper contact with the subject's skin portion. The reflected echoes convey information indicating the coupling state between the transducer and the skin portion. The application of the US pulse from the transducer to the blood vessel is performed through the skin portion. If the detected reflected echoes do not meet the predetermined conditions, the at least one processing circuit is configured to generate an output alarm. The alarm may be auditory, visual, and / or tactile. For example, the output alarm may be a sound heard from the device, an alarm displayed on a mobile device or remote control of the system, and / or vibration of the mobile device or remote control of the system, or other appropriate output method. Furthermore, if the detected reflected echo does not meet predetermined conditions, at least one processing circuit may be configured to disable the operation of at least one US transducer, rendering it inoperable.

[0030] In one embodiment of this system, the predetermined conditions are at least one of the range of time delay from the application of the inspection pulse to the detection of reflection, the range of intensity, or a combination thereof.

[0031] In some embodiments, the system further comprises a first electrode and a second electrode, and at least one US transducer is positioned between the first and second electrodes when the US transducer and the two electrodes come into contact with a portion of the subject's skin. That is, when a current is applied from the first electrode to the second electrode, the current passes through the portion of skin in contact with the US transducer. At least one processing circuit is configured to apply a current from the first electrode to the second electrode in order to measure an electrical parameter. The electrical parameter may be current, impedance, voltage, or any combination thereof. The electrical parameter indicates the quality of contact between the portion of the subject's skin and at least one US transducer. If the quality of contact, as identified by the electrical parameter, falls below a selected threshold, at least one processing circuit is configured to generate an output alarm. The alarm may be audible and / or visual. For example, the output alarm may be a sound heard from the device and / or an alarm displayed on a mobile device or remote control of the system, or other appropriate output method.

[0032] In some embodiments, the system further includes a first temperature sensor configured to sense skin temperature in the vicinity of at least one US transducer and generate first skin temperature data thereon. At least one processing circuit is configured to analyze the first skin temperature data and the electrical parameters to determine the subcutaneous temperature of the body region through which the US pulse passes. At least one operating device is configured to analyze the temporal profile of the subcutaneous temperature and to control the operation of at least one transducer based on the identified behavior or characteristics of the temporal profile of the subcutaneous temperature. For example, the behavior of the temporal profile is the average value above a specific temperature threshold over a selected period, which requires stopping the application of the US pulse to the subject or reducing the intensity or duty cycle of the applied US pulse. In another example, if the average temperature over a period falls below a specific threshold, the operation of at least one US transducer is adjusted to provide a higher intensity pulse or operate at a higher duty cycle. It should be understood that the operation of at least one US transducer is adjusted based on the determined temporal profile of subcutaneous temperature.

[0033] In some embodiments, multiple conductive electrodes may be placed on the skin around the ultrasonic transducer. For example, an AC high frequency of approximately 500 kHz is applied. This high frequency is required for at least two reasons: (1) it is far from the 50-60 Hz noise coupled from the grid to the skin, thus easily eliminating grid noise; and (2) it couples the current to the tissue via the capacitive dielectric barrier of the stratum corneum connected in series with the equivalent tissue impedance, so that the skin contact impedance of the electrodes becomes the dominant impedance in the overall equivalent impedance perceived by the AC power supply. The high-frequency AC power supply is connected between the electrodes forming a bipolar or multipolar arrangement (i.e., limited to local paths between electrodes rather than systemic current). If the electrodes are properly positioned on the skin and a gel, i.e., a transfer medium, is pre-applied to the skin, a closed electrical circuit is formed and an AC current (~1 mA) flows between the electrodes and the tissue beneath the skin surface. If one of the electrodes is not in contact, or if the electrodes are not in full contact with the skin surface, such as when the skin contact surface of the device is tilted, the current will fall below the current threshold for good contact. As a result, measuring the current between electrodes reveals the quality of contact between the skin and the electrodes, and therefore the quality of contact between the skin and the transducer.

[0034] Furthermore, sweeping the frequency of the AC power supply can improve measurement sensitivity. By sensing current at multiple frequencies, it becomes possible to estimate the temperature of the underlying tissue based on the temperature dependence of the impedance structure.

[0035] In some embodiments, the system further includes at least one force sensor configured to measure the tightening force of the device generated around a body part by a fixed assembly. At least one processing circuit is configured to generate a tightening alarm if the tightening force is outside the acceptable range, i.e., overtightened or too loose.

[0036] In one embodiment of this system, the force sensor is selected from a force-sensing resistor or a strain gauge.

[0037] In some embodiments of this system, the body part is selected from the limbs (e.g., arms, legs) and the neck.

[0038] In some embodiments, the system further includes an accelerometer configured to sense the subject's acceleration and generate acceleration data thereunder, and at least one processing circuit configured to analyze the acceleration data and determine whether the subject is moving. If subject movement is determined, at least one processing circuit may be configured to disable the operation of at least one US transducer, thereby avoiding the application of US pulses when the subject is moving. This prevents inappropriate contact between at least one transducer and the subject's skin. When the subject's movement stops, at least one US transducer resumes operation (e.g., automatically). That is, the operation of the US transducer occurs only during the period when subject movement is detected.

[0039] In some embodiments, at least one sensor further comprises a second temperature sensor, which may be the same as or different from the first temperature sensor, and is configured to sense skin temperature in the vicinity of at least one US transducer and generate second skin temperature data thereon. At least one processing circuit is configured to analyze the second temperature data to determine whether the skin temperature exceeds an acceptable temperature threshold, and if it identifies that the acceptable temperature threshold has been exceeded, it stops the operation of at least one US transducer.

[0040] In one embodiment of the system, the response to the detection data includes identifying a change in the at least one physiological parameter, or identifying that at least one US transducer is in a suitable state for applying a US pulse. This suitable state is, for example, an indication that the at least one US transducer is in proper contact with a body part; once the change, the suitable state, or a combination thereof is identified, at least one of the following is performed: (a) the US pulse is transmitted to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one treatment parameter of the transmission of the US pulse to the at least one blood vessel or tissue is changed to provide treatment as needed; (c) a notification output regarding the change is output; (d) any combination thereof.

[0041] In one embodiment of the system, the at least one sensor includes an acoustic sensor, which may be part of or independent of the US transducer, and is configured to detect acoustic signals from a portion of the subject's skin and generate acoustic sensing data. The acoustic sensing data indicates blood flow within the blood vessels or tissues. Sensing data may include the acoustic sensing data. That is, the US transducer operates based on a blood flow profile interpreted from the acoustic sensing data.

[0042] In one embodiment of the system, at least one sensor is configured to sense at least one pulse wave characteristic and to determine the subject's heart rate from the at least one pulse wave characteristic. Analysis of the at least one pulse wave characteristic facilitates the adjustment of the relative position of the US transducer to the at least one blood vessel or tissue. That is, the pulse wave characteristic affects the operation of the operating assembly, so that the operating element moves the US transducer in response to the analysis of the pulse wave characteristic. Here, facilitating the adjustment includes either outputting instructions for the desired alignment of the US transducer or directly controlling the operating assembly, specifically the operating element.

[0043] In one embodiment of the system, the at least one sensor is an ultrasonic sensor configured to sense an ultrasonic signal. The ultrasonic sensor may consist of at least one US transducer, that is, at least one US transducer may be configured for applying US pulses and sensing US signals.

[0044] In one embodiment of the system, the at least one sensor is configured to sense the US Doppler parameter of the applied US pulse. The US Doppler parameter indicates blood flow in tissue or blood vessels. In other words, the US Doppler parameter is indirectly the at least one physiological parameter.

[0045] In one embodiment of this system, at least one sensor comprises an ECG sensor and a US transducer. That is, in this embodiment, the system is configured to sense an ECG signal by the ECG sensor and an acoustic signal by at least one US transducer. The acoustic signal is generated by the pulse of blood flowing through a blood vessel or tissue. At least one processing circuit is configured to determine the time delay between the ECG signal and the generation of the blood pulse wave sensed by at least one US transducer. The time-delay variation profile over time indicates changes in blood flow within the tissue or blood vessel. At least one processing circuit is configured to controllably operate at least one US transducer based on the variation profile. In other words, the variation profile provides an indicator of whether the ultrasound irradiation is efficient, and the parameters of the ultrasound irradiation are controlled based on the identified variation profile.

[0046] In one embodiment of this system, at least one sensor is at least one US transducer configured to sense an acoustic signal generated by the pulse of blood flowing through a blood vessel or tissue. At least one processing circuit is configured to determine the variation profile of the acoustic signal and to operate at least one US transducer to apply a pulse according to the variation profile. In other words, changes in the shape of the acoustic pulse wave indicate the effectiveness of ultrasonic irradiation, and the operation of at least one US transducer is performed in response to the identification of characteristic changes over time in the shape of these acoustic signals.

[0047] In one embodiment of this system, at least one sensor is at least one US transducer configured to sense an acoustic signal generated by the pulse of blood flowing through a blood vessel or tissue. At least one processing circuit is configured to synchronize the application of a US pulse by the processing circuit with the generation or appearance of the acoustic pulse wave. This is useful, for example, to enhance the shear effect.

[0048] In one embodiment of this system, at least one sensor includes one or more temperature sensors and infrared (IR) sensors to measure skin perfusion parameters indicating skin perfusion in tissues related to blood vessels or tissues. This relevance lies in the fact that the skin portion is located downstream of the blood flow pathway to the tissue or blood vessel being treated. This can be done by direct temperature measurement or by IR measurement of radiation from the skin portion. Skin perfusion represents microcirculation blood flow that depends on the blood flow of the nutrient arteries, while arterial blood flow depends on ultrasound irradiation. Therefore, at least one US transducer operates in response to sensing the skin perfusion parameters. It should be noted that skin perfusion parameters can also be determined by indirect measurement using an arterial pulse oximeter (Pleth plethysmograph: pulse wave measuring instrument).

[0049] In some embodiments, the system comprises an array of US sensors / transducers, where at least one processing circuit is configured to controllably operate the array of US transducers to direct US pulses in a desired direction.

[0050] In one embodiment of this system, the array of US sensors / transducers operates as a phase array for the direction control.

[0051] In one embodiment of the system, at least one processing circuit is configured to execute a periodic control loop, which includes controlling the US transducer array using various sets of operating parameters, analyzing sensing data associated with the operating time frame of each set of operating parameters, and identifying the optimal set of operating parameters that yields the best results for at least one physiological parameter; where, once the optimal set of operating parameters is identified, at least one processing circuit is configured to control the multiple US transducers using the optimal set of operating parameters until the next periodic control loop. In other words, in each periodic control loop, the US transducer array operates differently in different time frames. For example, in one time frame, only some US transducers may operate while others do not, and in another time frame, other combinations of US transducers may operate. Furthermore, in each operation of a combination of US transducers, the operating parameters of the US transducers may be changed over time to identify the optimal operating parameters for a particular combination of US transducers. The detection data includes sensing the pulse wave of blood flow within the blood vessels and identifying the optimal time window for blood flow within the vessels. A set of operating parameters associated with that time window is then selected for operation until the next periodic control loop.

[0052] In one embodiment of this system, the set of changing operating parameters includes one or more changes in the intensity, phase, or duty cycle of each US transducer in the transducer array.

[0053] In some embodiments, the device automatically activates when at least one physiological parameter / state changes.

[0054] In some embodiments, when the at least one physiological parameter / state changes, the user (e.g., patient, caregiver) can activate the ultrasound energy or modify the at least one therapeutic parameter.

[0055] In some embodiments, the at least one sensor configured to monitor at least one physiological parameter / state of a subject may be, for example, an accelerometer, acoustic impedance meter, electrical impedance meter, photoelectric volume plethysmography sensor, PPG sensor, pH sensor, ultrasound sensor, echocardiogram, ultrasound echo, thermometer, trunk temperature, heart rate, blood pulse wave characteristics, glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating blood pressure, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof.

[0056] In some embodiments, at least one sensor may be configured to detect / monitor, for example, patient movement, impedance, PPG signal, pH, acoustic signal, pressure, temperature, heart rate, pulse wave characteristics, blood glucose level, blood pressure, and any combination thereof.

[0057] In some embodiments, the at least one sensor may be a patient-worn sensor, a remote sensor outside the patient's body, a sensor incorporated in at least one control device, or any combination thereof, if incorporated within the device.

[0058] In some embodiments, the physiological parameters / states or changes thereof monitored are, for example, the patient's position, the patient's involvement in physical activity, a decrease in NO levels in the at least one blood vessel or tissue, tissue perfusion, the initiation of physical activity, a change in at least one parameter related to the physical activity, the patient's position relative to the ground, a change in the patient's position relative to the ground, the application of at least one medical procedure to the patient, a change in the application of at least one medical procedure to the patient, and any combination thereof.

[0059] In some embodiments, at least one treatment parameter is, for example, the phase, center of motion frequency, output, intensity, amplitude, timing, duration, direction of the ultrasonic energy, and any combination thereof.

[0060] In some embodiments, if the at least one physiological condition changes, at least one notification is sent to the patient or their caregiver.

[0061] In some embodiments, the device can communicate with at least one battery. The at least one battery may be located outside the patient's body. The at least one battery may be configured to be wirelessly rechargeable.

[0062] In some embodiments, physiological effects include, for example, vasodilation, increased local nitric oxide, enhanced nitric oxide release from vascular endothelium, prolonged local nitric oxide effect, altered erythrocyte function, modified oxygen release from hemoglobin, increased blood temperature, altered blood pH, modulation of the immune response of blood leukocytes, modulation of coagulation and / or platelet function, altered function of heme catalytic enzymes in the blood, improved bioavailability of the drug, improved efficiency of hemodialysis sessions, arterial dilation, increased hemoperfusion, and any combination thereof.

[0063] In some embodiments, ultrasonic energy is supplied at a center frequency in the range of about 10 kHz to about 10 MHz.

[0064] In some embodiments, ultrasonic energy is supplied by, for example, at least one of the following: at least one piezoelectric transducer that generates ultrasonic energy, at least one passive ferromagnetic element, at least one capacitive micro-ultrasonic transducer (CMUT), a concave transducer, a convex transducer, and any combination thereof.

[0065] In some embodiments, the piezoelectric transducer is made from at least one of the following: lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composite materials, and any combination thereof.

[0066] In some embodiments, the piezoelectric transducer is shielded by apodization, such as Gaussian apodization. This Gaussian apodization may be provided by material polarization.

[0067] In some embodiments, the piezoelectric transducer generates ultrasonic energy pulses having multiple center frequencies.

[0068] In some embodiments, at least one of the control devices is configured to charge the device.

[0069] In some embodiments, the at least one sensor is configured to detect at least one pulse wave characteristic.

[0070] In some embodiments, the at least one sensor is configured to detect at least one pulse wave characteristic reflected from the device, for example, by acoustic sensing, echo, or any combination thereof.

[0071] In some embodiments, the device is configured to sense the heart rate from the at least one pulse wave characteristic.

[0072] In some embodiments, the analysis of the at least one pulse wave characteristics facilitates the relative position and / or orientation alignment of the device with respect to the at least one blood vessel or tissue containing flowing blood.

[0073] In some embodiments, the alignment is indicated to the patient or their caregiver. The alignment may be indicated by at least one indicator, such as an auditory means, a visual means, a tactile means, a vibrating means, or any combination thereof.

[0074] In some embodiments, the analysis of at least one pulse wave characteristic indicates the cause of the physiological effect.

[0075] In some embodiments, ultrasonic energy is supplied by an array of piezoelectric transducers, each of which generates ultrasonic energy. The array of piezoelectric transducers may be a phase array.

[0076] In some embodiments, activating at least one of the transducers according to a predetermined procedure fine-tunes the direction of the ultrasonic energy to the at least one blood vessel and aligns the device with the blood vessel.

[0077] In some embodiments, the ultrasonic energy may be supplied continuously or, alternatively, in a pulsed manner.

[0078] In some embodiments, at least one of the control devices is adapted to collect data from the at least one sensor and to perform, for example, (a) monitoring the data; (b) modifying at least one treatment parameter of a treatment procedure; (c) maintaining the treatment provided to the patient as is; and at least one of any combination thereof.

[0079] In some embodiments, at least one of the control devices is wearable by the patient. The control device can be incorporated, for example, into socks, shoes, gloves, sleeves, clothing, hats, and any combination thereof.

[0080] In some embodiments, at least one of the control devices is integrated into the patient's environment.

[0081] In some embodiments, at least one of the control devices is capable of communicating with a processing device such as a CPU, a smartphone, or any combination thereof.

[0082] In some embodiments, the disclosed devices and systems can be used to treat a variety of clinical conditions, including: pulmonary denervation, pulmonary hypertension, ischemic tissue, peripheral artery disease (PAD), critical limb ischemia (CLI), pulmonary hypertension, maturation of arteriovenous fistula (AVF), Raynaud's disease, severe asthma, improvement of cerebral blood flow during stroke, increased blood flow to the penis for maintaining erection, improved bioavailability of drugs, enhanced absorption of local chemotherapeutic agents to solid tumors by increasing blood flow to specific arteries supplying nutrients to the tumor, and any combination thereof.

[0083] In some embodiments, the ischemic tissue may be, for example, an upper limb, lower limb, arm, leg, or any combination thereof.

[0084] In some embodiments, the purpose of applying the ultrasonic energy is to increase blood flow to the target tissue.

[0085] In some embodiments, the ultrasonic energy is supplied at at least two different center frequencies. The first center frequency may be in the range of about 10 kHz to about 10 MHz. The second center frequency may be in the range of about 100 kHz to about 10 MHz.

[0086] In some embodiments, the device comprises at least one piezoelectric transducer adapted to generate the ultrasonic energy at one of the at least two different center frequencies.

[0087] In some embodiments, the device further comprises at least one electromagnetic acoustic transducer mechanically coupled to the at least one piezoelectric transducer and adapted to generate the ultrasonic energy at one of the at least two different center frequencies. The at least one electromagnetic acoustic transducer may be at least one ferromagnetic sheet.

[0088] In some embodiments, the device includes at least one processing unit configured to control at least one operating / therapeutic parameter, the phase of the ultrasonic energy, the operating center frequency, output, intensity, operating amplitude, timing, duration, direction, and any combination thereof.

[0089] In some embodiments, the at least one processing device is capable of communicating with the at least one sensor.

[0090] In some embodiments, the at least one processing unit is configured to collect data from the at least one sensor and to perform at least one of the following actions: (a) monitoring the data; (b) modifying the treatment provided to the patient; (c) maintaining the treatment provided to the patient as is; and any combination thereof.

[0091] Another aspect of the present invention provides a first method definition. The first method definition provides a method for treating a patient and includes the following steps: a. A step to provide at least one device adapted to be positioned on the skin in a patient near, adjacent to, or within at least one blood vessel or tissue including blood flow, comprising means for applying ultrasonic energy to the at least one blood vessel or tissue including blood flow, wherein the ultrasonic energy application means is adapted to produce a physiological effect on the at least one blood vessel or tissue when applied, and the device is positioned outside the patient's body and is capable of communicating with at least one remote control device adapted to control the ultrasonic energy application means; b. The step of positioning the at least one device adjacent to, or inside, at least one blood vessel or tissue containing blood flow; c. The device communicates with at least one sensor adapted to monitor at least one physiological state of a patient, and when the physiological state changes, at least one of the following steps is performed: (a) the ultrasonic energy is delivered to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one therapeutic parameter of the ultrasonic energy delivery to the at least one blood vessel or tissue is modified to provide treatment as needed; (c) the change is notified; (d) the patient is treated by any combination thereof.

[0092] A further method definition in this embodiment provides a method for non-invasively applying ultrasound (US) pulses or waves to or toward the blood vessels or tissues of a subject, i.e., performing ultrasound irradiation. The method comprises: fixing or attaching at least one ultrasound (US) transducer to a body part of the subject including the blood vessels or tissues; monitoring at least one physiological parameter and generating detection data therefrom; and operating the at least one US transducer in response to the detection data to transmit US pulses toward the blood vessels or tissues. The operation of the at least one US transducer includes controlling parameters selected from intensity, direction, duty cycle, frequency, phase, or any combination thereof.

[0093] In one embodiment of this method, the operation includes manipulating the at least one US transducer toward the blood vessel or tissue.

[0094] In some embodiments, the method further includes placing at least a portion of the at least one US transducer in a chamber filled with a fluid material, i.e., a liquid or gel, and controllingly moving the at least one US transducer to thereby controllably operate it.

[0095] In one embodiment of the present method, the controllable movement is performed by an operating element, which is selected from among a MEMS-based element, an electromagnetic-based element, a magnetic-based element, or a mechanical-based element.

[0096] In one embodiment of this method, the fluid material is a non-conductive liquid (e.g., oil).

[0097] In one embodiment of this method, the fluid material functions as an impedance transmission medium. That is, the fluid material has an impedance that is relatively matched to the impedance of skin tissue.

[0098] In some embodiments, the method further includes operating at least one US transducer with a changing set of operating parameters and performing a periodic operation control loop which includes analyzing sensing data associated with the operating time frame of each set of operating parameters to identify the optimal set of operating parameters that yields the best result for at least one physiological parameter; the method further includes, once the optimal set of operating parameters has been identified, operating the at least one US transducer with the optimal set of operating parameters until the next periodic operation control loop.

[0099] In some embodiments, the method further includes applying an examination US pulse to the skin or blood vessels of a subject using at least one US transducer and detecting the reflected echoes resulting from the examination pulses; determining whether at least one US transducer is in proper contact with a portion of the subject's skin by analyzing the detected reflected echoes and determining whether the reflected echoes meet predetermined conditions. The application of the US pulse from the transducer to the blood vessels is performed via the skin portion; here, if the detected reflected echoes do not meet the predetermined conditions, the method further includes generating an output alarm. The output alarm may be a sound heard from the device, an alarm displayed on a mobile device or remote control of the system, or other suitable method for such output. Also, if the detected reflected echoes do not meet the predetermined conditions, the method further includes disabling and rendering inoperable at least one US transducer.

[0100] In one embodiment of this method, the predetermined conditions are at least one of the range of time delay from the application of the inspection pulse to the detection of reflection, the range of intensity, or a combination thereof.

[0101] In some embodiments, the method further includes attaching a first electrode and a second electrode to a portion of the subject's skin, wherein at least one US transducer is positioned between the first and second electrodes when the US transducer and the two electrodes are in contact with the subject's skin. That is, when a current is applied from the first electrode to the second electrode, the current passes through the skin portion in contact with the US transducer; the method further includes applying a current from the first electrode to the second electrode to measure an electrical parameter, the electrical parameter being selected from current, impedance, voltage, or any combination thereof. The electrical impedance indicates the quality of contact between the subject's skin and at least one US transducer, wherein the method includes generating an output alarm if the quality of contact falls below a selected threshold. The output alarm can be a sound heard from the device, an alarm displayed on a mobile device or remote control of the system, or other suitable method for such output.

[0102] In some embodiments, at least one physiological parameter includes skin temperature near at least one US transducer, and based on this skin temperature, first skin temperature data is generated; the method further includes analyzing the first skin temperature data and the electrical impedance to determine the subcutaneous temperature. The method further includes analyzing the temporal profile of the subcutaneous temperature and controlling the operation of the at least one transducer based on the behavior of the temporal profile identified from the temporal profile of the subcutaneous temperature.

[0103] In some embodiments, the method further includes measuring the tightening force of the device around a body part resulting from the fastening; the method includes generating a tightening alarm if the tightening force is outside the range of permissible tightening force, i.e., overtightened or too loose.

[0104] In one embodiment of this method, the measurement is performed by at least one force sensor selected from a force sensing resistor or a strain gauge.

[0105] In some embodiments of this method, the body part is selected from the limbs and the neck.

[0106] In some embodiments, the method further includes sensing the subject's acceleration and generating acceleration data based thereon; the method includes analyzing the acceleration data and determining whether the subject is moving; if subject movement is determined, the method includes disabling the operation of at least one US transducer and thus avoiding the application of US pulses if the subject is moving and there is a possibility of inappropriate contact between at least one transducer and the subject's skin. When the subject's movement stops, at least one US transducer resumes operation; that is, the US transducers operate only during the period when subject movement is detected.

[0107] In some embodiments, the method further includes sensing skin temperature in the vicinity of at least one US transducer and generating second skin temperature data thereon, wherein the method includes analyzing the second temperature data to determine whether the skin temperature exceeds an acceptable temperature threshold, and if an excess of the acceptable temperature threshold is identified, stopping the operation of the at least one US transducer.

[0108] In one embodiment of the Method, the response to the sensing data includes the identification of a change in the at least one physiological parameter, or the identification of a suitable state for the at least one US transducer to apply a US pulse, for example, if there is indication of suitable contact between the at least one US transducer and a body part, upon identification of the change, the suitable state, or a combination thereof, at least one of the following is performed: (a) the US pulse is transmitted to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one therapeutic parameter of the transmission of the US pulse to the at least one blood vessel or tissue is changed to provide treatment as needed; (c) a notification output regarding the change is output; (d) any combination thereof.

[0109] In some embodiments, the method further includes detecting acoustic signals from a portion of the subject's skin and generating acoustic sensing data. The acoustic sensing data indicates blood flow within the blood vessels or tissues, and the sensing data includes the acoustic sensing data. That is, the US transducer operates based on the blood flow profile interpreted from the acoustic sensing data.

[0110] In one embodiment of the present method, at least one physiological parameter is monitored by the at least one US transducer, which is configured to apply a US pulse and detect a US signal.

[0111] In one embodiment of this method, at least one physiological parameter is a US Doppler parameter of a US pulse applied by at least one US transducer.

[0112] In one embodiment of this method, at least one physiological parameter includes an ECG signal and an acoustic signal. The acoustic signal is generated by the pulsation of blood flowing through a blood vessel or tissue. The method further includes determining the time delay between the ECG signal and the generation of the blood pulse wave sensed by the acoustic signal. The time-delayed variation profile over time indicates changes in blood flow in the tissue or blood vessel. The method further includes operating at least one US transducer based on the variation profile.

[0113] In one embodiment of the method, at least one physiological parameter includes an acoustic signal generated by the pulsation of blood flowing through a blood vessel or tissue. The method further includes determining the variation profile of the acoustic signal and operating at least one US transducer to apply a pulse according to the variation profile.

[0114] In one embodiment of this method, at least one physiological parameter includes an acoustic signal generated by the pulsation of blood flowing through a blood vessel or tissue. The method further includes synchronizing the application of a US pulse by at least one processing circuit with the generation or appearance of an acoustic pulse wave.

[0115] In one embodiment of this method, at least one physiological parameter includes a skin perfusion parameter indicating skin perfusion in a tissue related to blood vessels or tissue. The skin perfusion parameter can be obtained by IR or temperature measurement. Skin perfusion represents microcirculation blood flow dependent on nutrient arterial blood flow, and arterial blood flow depends on ultrasound irradiation. Therefore, at least one US transducer operates in response to the detection of the skin perfusion parameter. It should be noted that the skin perfusion parameter can also be determined by indirect measurement using an arterial pulse oximeter (Pleth plethysmograph: pulse wave measuring instrument).

[0116] In one embodiment of the method, the at least one US transducer includes an array of US transducers, and the method further includes controlling the operation of the array of US transducers to manipulate a US pulse in a desired direction.

[0117] In one embodiment of this method, the array of US transducers operates as a phase array for the aforementioned operation.

[0118] In some embodiments, the method further includes executing a periodic control loop. This control loop includes controlling an array of US transducers using various sets of operating parameters, analyzing sensing data associated with the operating timeframe of each set of operating parameters, and identifying an optimal set of operating parameters that yields the best results for at least one physiological parameter. Once the optimal set of operating parameters is identified, the method further includes controlling a plurality of US transducers using the optimal set of operating parameters until the next periodic control loop.

[0119] In one embodiment of this method, the blood vessel is an arteriovenous fistula (AVF), and the method includes irradiating the AVF with ultrasound to promote its maturation.

[0120] In some embodiments, the method includes positioning at least two devices at the same location relative to the at least one blood vessel or tissue containing flowing blood.

[0121] In some embodiments, the method involves positioning at least two devices at substantially different locations relative to the at least one blood vessel or tissue containing flowing blood.

[0122] In some embodiments, the method includes enabling the ultrasonic energy to be concentrated on the at least one blood vessel or tissue by positioning the at least two devices.

[0123] In some embodiments, the method includes enabling communication between the at least two devices.

[0124] In some system embodiments, at least two of a group of devices communicate with each other.

[0125] A further aspect of the present disclosure provides a system for treating a patient's blood vessels. The system includes a vascular sleeve configured to be fitted outside at least a portion of a blood vessel, comprising at least one ultrasound (US) transducer configured to deliver ultrasound energy to at least a portion of the blood vessel, and a first sensor configured to monitor at least one physiological parameter of the patient and generate detection data therefrom; and a remote control located outside the patient's body, capable of communicating with the at least one ultrasound transducer and the first sensor, and capable of controllingly operating the at least one ultrasound transducer and receiving detection data from the sensor.

[0126] In some embodiments, the system further comprises an energy transmitting unit intended to be located outside the patient's body and an energy receiving unit coupled to or integrated with a vascular sleeve, wherein the energy transmitting unit is configured to send energy from outside the patient's body to the energy receiving unit in order to supply energy to a US transducer, thereby enabling the US transducer to operate in a desired operating mode according to controlled operation by a remote control device.

[0127] In one embodiment of this system, the remote control device includes the energy transmission unit.

[0128] In one embodiment of this system, the energy receiving unit is a first inductor, and the energy transmitting unit is a second inductor.

[0129] In one embodiment of this system, the energy receiving unit is connected to the vascular sleeve by a pigtail connection.

[0130] A further aspect of the present disclosure provides a method for treating a patient's blood vessel. The method includes fitting a vascular sleeve outside at least a portion of the blood vessel. The sleeve comprises at least one ultrasound (US) transducer configured to deliver ultrasound energy to at least a portion of the blood vessel, and a first sensor configured to monitor at least one physiological parameter of the patient and generate detection data thereon, thereby controllingly operating the at least one ultrasound transducer and receiving detection data from the sensor.

[0131] In one embodiment of this method, the blood vessel is a bypass vessel that goes around the narrowed portion of the artery.

[0132] Various other purposes, aspects, and advantages of the disclosure of the present invention can be obtained by examining this specification, the drawings, and the appended claims. Embodiments

[0133] The following are any embodiments and combinations thereof according to aspects of this disclosure.

[0134] 1. A non-invasive system for applying ultrasound (US) pulses to blood vessels or tissues, including the blood flow of a subject, and: With at least one US transducer configured to transmit ultrasonic pulses; The at least one US transducer is configured to be fixed or held in place by a fixation assembly which includes the blood vessel or tissue of the subject; A system comprising at least one sensor configured to monitor at least one physiological parameter or state of a subject and generate detection data based thereon; The at least one US transducer and the at least one sensor are configured to communicate with each other, receive the detection data, and in response to the detection data, controllably operate the at least one US transducer to transmit US pulses toward the blood vessel or tissue; A system equipped with these features.

[0135] 2. A system according to Embodiment 1, comprising an operating device configured to controllably operate the at least one US transducer toward the blood vessel or tissue.

[0136] 3. The system according to Embodiment 2, wherein the operating device comprises an operating element and a chamber filled with a fluid material, at least a portion of the at least one US transducer is located in the chamber, and the operating element is configured to controllably move the at least one US transducer, thereby controllingly operating the at least one US transducer.

[0137] 4. The system according to Embodiment 3, wherein the fluid material is a non-conductive liquid.

[0138] 5. A system according to Embodiment 3 or 4, wherein the fluid material functions as an impedance transmission medium.

[0139] 6. A system according to any one of Embodiments 3 to 5, wherein the operating element is selected from any one of MEMS-based elements, electromagnetic-based elements, electrostatic-based elements, piezoelectric-based elements, magnetic-based elements, or mechanical-based elements.

[0140] 7. A system according to any one of embodiments 2 to 6, wherein the at least one processing circuit is configured to perform a periodic operation control loop, the operation control loop includes controlling an operating device using different sets of operating parameters and analyzing sensing data related to the operating time frame of each set of operating parameters to identify an optimal set of operating parameters that yields an optimal result for at least one physiological parameter, and once the optimal set of operating parameters is identified, the at least one processing circuit is configured to operate the operating device in a controllable manner with the optimal set of operating parameters until the next periodic operation control loop.

[0141] 8. A system according to any one of embodiments 1 to 7, wherein the at least one processing circuit is configured to control the at least one US transducer and apply an inspection US pulse to detect a reflected echo generated from the inspection pulse; the at least one processing circuit is configured to analyze the detected reflected echo and determine whether the detected reflected echo satisfies predetermined conditions, thereby determining whether the at least one US transducer is in proper contact with a portion of the subject's skin; and if the detected reflected echo does not satisfy the predetermined conditions, the at least one processing circuit is configured to generate an output alarm.

[0142] 9. A system according to Embodiment 8, wherein the predetermined condition is at least one of a range of time delay from the application of the inspection pulse to the detection of reflection, a range of intensity, or a combination thereof.

[0143] 10. A system according to any one of embodiments 1 to 9, comprising a first electrode and a second electrode, wherein at least one US transducer is positioned between the first electrode and the second electrode; at least one processing circuit is configured to apply current from the first electrode to the second electrode to measure an electrical parameter selected from impedance, current, and voltage; the electrical parameter indicates the quality of contact between a portion of the subject's skin and the at least one US transducer; and the at least one processing circuit is configured to generate an output alarm if the quality of contact falls below a selected threshold.

[0144] 11. The system according to Embodiment 10, comprising a first temperature sensor configured to sense skin temperature in the vicinity of the at least one US transducer and generate first skin temperature data thereon; the at least one processing circuit configured to analyze the first skin temperature data and the electrical parameters to determine subcutaneous temperature; and the at least one operating device configured to analyze the temporal profile of the subcutaneous temperature and to control the at least one transducer based on the behavior of the identified temporal profile of the subcutaneous temperature.

[0145] 12. A system according to any one of embodiments 1 to 11, comprising at least one force sensor configured to measure the tightening force of a device generated around a body part by a fixed assembly; the at least one processing circuit configured to generate a tightening alarm when the tightening force is outside the range of an allowable tightening force.

[0146] 13. The system according to Embodiment 12, wherein the at least one force sensor is selected from a force sensing resistor or a strain gauge.

[0147] 14. A system according to any one of embodiments 1 to 13, comprising an accelerometer configured such that at least one sensor senses the acceleration of a subject and generates acceleration data therefrom; the at least one processing circuit configured to analyze the acceleration data and determine whether the subject is moving; and if the subject is moving, the at least one processing circuit configured to disable the operation of the at least one US transducer.

[0148] 15. A system according to any one of embodiments 1 to 14, comprising a second temperature sensor configured to sense skin temperature in the vicinity of the at least one US transducer and generate second skin temperature data thereon; and the at least one processing circuit configured to analyze the second temperature data to determine whether the skin temperature exceeds an acceptable temperature threshold, and to stop the operation of the at least one US transducer if it identifies that the acceptable temperature threshold has been exceeded.

[0149] 16. A system according to any one of embodiments 1 to 15, wherein the at least one sensor includes an acoustic sensor configured to detect an acoustic signal from a portion of the subject's skin and generate acoustic detection data, the acoustic detection data indicating blood flow in the blood vessel or tissue; and the detection data includes the acoustic detection data.

[0150] 17. A system according to any one of embodiments 1 to 16, wherein the response to the detection data includes the identification of a change in the at least one physiological parameter; and when the change is identified, at least one of the following is performed: (a) the US pulse is transmitted to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one therapeutic parameter of the US pulse transmission to the at least one blood vessel or tissue is changed to provide treatment as needed; (c) a notification regarding the change is output; (d) any combination thereof.

[0151] 18. A system according to any one of Embodiments 1 to 17, wherein the at least one sensor is selected from the group consisting of an accelerometer, an impedance meter, a photoelectric volume pulse wave recording sensor, a PPG sensor, a pH sensor, an ultrasonic sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a trunk temperature sensor, a heart rate sensor, a pulse wave characteristic sensor, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating blood pressure, any sensor indicating the start of a dialysis session, any sensor related to a dialysis machine, and any combination thereof.

[0152] 19. A system according to Embodiment 18, wherein the sensor is configured to detect at least one parameter selected from the group consisting of the patient's movement, impedance, PPG signal, acoustic signal, pressure, temperature, heart rate, pulse wave characteristics, blood glucose level, blood pressure, and any combination thereof.

[0153] 20. A system according to any one of Embodiments 1 to 19, wherein the physiological parameters or states or changes thereof are selected from the group consisting of the patient's position, involvement in physical activity, decrease in NO levels in the at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, change in at least one parameter related to the physical activity, the patient's position relative to the ground, change in the patient's position relative to the ground, application of at least one medical procedure to the patient, change in the application of at least one medical procedure to the patient, and any combination thereof.

[0154] 21. A system according to any one of embodiments 1 to 20, wherein controlling the operation of the at least one US transducer includes controlling at least one therapeutic parameter selected from the group consisting of the phase, operating frequency, output, intensity, operating amplitude, timing, duration, direction relative to a blood vessel, and any combination thereof of the ultrasonic energy.

[0155] 22. A system according to any one of Embodiments 1 to 21, wherein by controlling the operation of at least one US transducer, a physiological effect is produced selected from the group consisting of vasodilation, increased local nitric oxide, enhanced nitric oxide release from vascular endothelium, sustained local nitric oxide effect, altered erythrocyte function, modified oxygen release from hemoglobin, increased blood temperature, altered blood pH, regulated immune response of blood leukocytes, regulated coagulation and / or platelet function, altered function of heme catalytic enzymes in the blood, improved bioavailability of drugs, improved efficiency of hemodialysis sessions, arterial dilation, increased hemoperfusion, and any combination thereof.

[0156] 23. A system according to any one of embodiments 1 to 22, wherein the at least one sensor is configured to sense at least one pulse wave characteristic and to determine the heart rate of a subject from the at least one pulse wave characteristic, and the analysis of the at least one pulse wave characteristic facilitates the adjustment of the relative position of the US transducer to the at least one blood vessel or tissue.

[0157] 24. A system according to any one of embodiments 1 to 23, wherein the ultrasonic sensor is configured such that at least one sensor senses an ultrasonic signal, and the ultrasonic sensor comprises at least one US transducer.

[0158] 25. A system according to any one of embodiments 1 to 24, comprising an array of US transducers, wherein at least one processing circuit is configured to controllably operate the array of US transducers to direct US pulses in a desired direction.

[0159] 26. A system according to Embodiment 25, wherein an array of US transducers operates as a phase array for the direction control.

[0160] 27. A system according to Embodiment 25 or 26, wherein the at least one processing circuit is configured to perform a periodic control loop, the periodic control loop comprising controlling the US transducer array using various sets of operating parameters, analyzing sensing data associated with the operating time frame of each set of operating parameters, and identifying an optimal set of operating parameters that yields the best results for the at least one physiological parameter; and once the optimal set of operating parameters is identified, the at least one processing circuit is configured to control the plurality of US transducers using the optimal set of operating parameters until the next periodic control loop.

[0161] 28. A system according to Embodiment 27, wherein the set of changing operating parameters includes changes in the intensity, phase, or duty cycle of each US transducer in the transducer array.

[0162] 29. A method for non-invasively applying ultrasound (US) pulses to or toward the blood vessels or tissues of a subject: Immobilizing at least one ultrasound (US) transducer on the body part of the subject, including the blood vessels or tissues; Monitoring at least one physiological parameter and generating detection data based on it; and Activating the at least one US transducer in response to the detection data to transmit a US pulse toward the blood vessel or tissue; A method that includes this.

[0163] 30. A method according to Embodiment 29, wherein the operation comprises manipulating the at least one US transducer toward the blood vessel or tissue.

[0164] 31. A method according to Embodiment 30, comprising placing at least a portion of the at least one US transducer in a chamber filled with a fluid material, and controllingly moving the at least one US transducer to thereby controllably operate it.

[0165] 32. A method according to Embodiment 31, wherein the controllable movement is performed by an operating element, the operating element being selected from one of MEMS-based elements, electromagnetic-based elements, magnetic-based elements, or mechanical-based elements.

[0166] 33. A method according to Embodiment 31 or 32, wherein the fluid material is a non-conductive liquid.

[0167] 34. A method according to any one of embodiments 29 to 33, wherein the fluid material functions as an impedance transmission medium.

[0168] 35. A method according to any one of embodiments 29 to 34, comprising performing a periodic operation control loop which includes analyzing sensing data associated with the operating time frame of each operation parameter set to identify an optimal operation parameter set that yields an optimal result for at least one physiological parameter; further comprising, once the optimal operation parameter set is identified, operating the at least one US transducer with the optimal operation parameter set until the next periodic operation control loop.

[0169] 36. A method according to any one of embodiments 29 to 35, Apply the test US pulse using at least one US transducer; To detect reflected echoes generated from the aforementioned test pulse; Determining whether the reflected echo meets predetermined conditions to determine whether at least one US transducer is in proper contact with the subject's skin; and If the detected reflected echo does not meet the predetermined conditions, an output alarm is generated; A method that includes this.

[0170] 37. A method according to Embodiment 36, wherein the predetermined condition is at least one of a range of time delay from the application of the inspection pulse to the detection of reflection, a range of intensity, or a combination thereof.

[0171] 38. A method according to any one of embodiments 29 to 37, A first electrode and a second electrode are attached to the skin portion of the subject, and at least one US transducer is positioned between the first electrode and the second electrode; Applying current from the first electrode to the second electrode to measure an electrical parameter selected from current, impedance, or voltage, the electrical parameter indicating the quality of contact between the subject's skin portion and at least one US transducer; and If the quality of contact falls below a selected threshold, generate an output alarm; A method that includes this.

[0172] 39. The method described in Embodiment 38, Sensing skin temperature in the vicinity of at least one US transducer and generating first skin temperature data based on that; Analyzing the first skin temperature data and the electrical parameters to determine the subcutaneous temperature; and Analyze the temporal profile of the subcutaneous temperature and control the operation of at least one transducer based on the behavior of the temporal profile identified from the temporal profile of the subcutaneous temperature; A method that includes this.

[0173] 40. A method according to any one of embodiments 29 to 39, comprising measuring the tightening force of a device around a body part resulting from the fixation, and generating a tightening alarm if the tightening force is outside the range of an allowable tightening force.

[0174] 41. A method according to Embodiment 40, wherein the measurement is performed by at least one force sensor selected from a force sensing resistor or a strain gauge.

[0175] 42. A method according to any one of embodiments 29 to 41: Sensing the subject's acceleration and generating acceleration data based on that; Analyzing the acceleration data to determine whether the subject is moving; and If subject movement is detected, disable the operation of at least one US transducer; A method that includes this.

[0176] 43. A method according to any one of embodiments 29 to 42: Sensing skin temperature near at least one US transducer and generating second skin temperature data based on that; Analyzing the second temperature data to determine whether the skin temperature exceeds the acceptable temperature threshold; and If the excess of the aforementioned permissible temperature threshold is detected, the operation of at least one US transducer shall be stopped; A method that includes this.

[0177] 44. A method according to any one of embodiments 29 to 43: Detecting acoustic signals from the skin of the subject; and Including generating acoustic sensing data; The aforementioned acoustic sensing data indicates blood flow within the blood vessels or tissues; The aforementioned sensing data includes the aforementioned acoustic sensing data.

[0178] 45. A method according to any one of embodiments 29 to 44, wherein the response to the sensing data includes the identification of a change in the at least one physiological parameter; and upon identification of the change, at least one of the following is performed: (a) the US pulse is transmitted to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one therapeutic parameter of the US pulse transmission to the at least one blood vessel or tissue is modified to provide treatment as needed; (c) a notification regarding the change is output; (d) any combination thereof.

[0179] 46. ​​A method according to any one of embodiments 29 to 45, wherein the at least one sensor includes one or more of the following: an accelerometer, an impedance meter, a photoelectric volume pulse wave recording sensor, a PPG sensor, a pH sensor, an ultrasonic sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a trunk temperature sensor, a heart rate sensor, a pulse wave characteristic sensor, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating blood pressure, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof.

[0180] 47. A method according to Embodiment 46, wherein the sensor is configured to detect at least one parameter selected from the group consisting of the patient's movement, impedance, PPG signal, acoustic signal, pressure, temperature, heart rate, pulse wave characteristics, blood glucose level, blood pressure, and any combination thereof.

[0181] 48. The method according to Embodiments 29 to 47, wherein the physiological parameters or states or changes thereof are selected from one or more of the following: patient's position, involvement in physical activity, decrease in NO levels in the at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, change in at least one parameter related to the physical activity, patient's position relative to the ground, change in the patient's position relative to the ground, application of at least one medical procedure to the patient, change in the application of at least one medical procedure to the patient, and any combination thereof.

[0182] 49. A method according to any one of embodiments 29 to 48, wherein the operation includes controlling at least one therapeutic parameter selected from the group consisting of the phase, operating frequency, output, intensity, operating amplitude, timing, duration, direction, alignment, and any combination thereof of the ultrasonic energy.

[0183] 50. A method according to any one of embodiments 29 to 49, wherein at least one notification is sent to the patient or their caregiver when the at least one physiological parameter or condition changes.

[0184] 51. A method according to any one of embodiments 29 to 50, wherein the action results in a physiological effect selected from one or more of the following: vasodilation, increased local nitric oxide, enhanced nitric oxide release from vascular endothelium, sustained local nitric oxide effect, altered erythrocyte function, modified oxygen release from hemoglobin, increased blood temperature, altered blood pH, regulated immune response of blood leukocytes, regulated coagulation and / or platelet function, altered function of heme catalytic enzymes in the blood, improved bioavailability of drugs, improved efficiency of hemodialysis sessions, arterial dilation, increased hemoperfusion, and any combination thereof.

[0185] 52. A method according to any one of embodiments 29 to 51, wherein the non-invasive application of ultrasound (US) pulses to or directed to the blood vessels or tissues of a subject is for the treatment of one or more of the following: pulmonary deneurosis, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary artery hypertension, maturation of arteriovenous fistula (AVF), Raynaud's disease, severe asthma, improvement of cerebral blood flow in stroke, increased blood flow to the penis for maintaining erection, improved bioavailability of drugs, enhanced absorption of local chemotherapeutic agents to solid tumors by enhancing blood flow to specific arteries supplying nutrients to the tumor, and any combination thereof.

[0186] 53. The method according to Embodiment 52, wherein the ischemic tissue is selected from the group consisting of the upper limb, lower limb, arm, leg, and any combination thereof.

[0187] 54. A method according to any one of embodiments 29 to 53, wherein the action increases blood flow.

[0188] 55. A method according to any one of embodiments 29 to 54, wherein the at least one US transducer comprises an array of US transducers, and further comprises controlling the array of US transducers to manipulate a US pulse in a desired direction.

[0189] 56. The method according to Embodiment 55, wherein the array of US transducers operates as a phase array for the operation.

[0190] 57. A method according to Embodiment 55 or 56, comprising performing a periodic control loop, the periodic control loop comprising controlling an array of US transducers using various sets of operating parameters, analyzing sensing data associated with the operating time frame of each set of operating parameters, and identifying an optimal set of operating parameters that yields an optimal result for at least one physiological parameter, and once the optimal set of operating parameters is identified, controlling a plurality of US transducers using the optimal set of operating parameters until the next periodic control loop.

[0191] 58. A method according to Embodiment 57, wherein the set of changing operating parameters includes changes in intensity, phase, or duty cycle of each US transducer in the transducer array.

[0192] 59. A system for treating a patient's blood vessels: A vascular sleeve configured to be fitted outside at least a portion of a blood vessel, comprising at least one ultrasound (US) transducer configured to supply ultrasonic energy to at least a portion of the blood vessel, and a first sensor configured to monitor at least one physiological parameter of a patient and generate detection data therefrom; and A remote control device positioned outside the patient's body, capable of data communication with the at least one ultrasonic transducer and the first sensor, capable of controlling the operation of the at least one ultrasonic transducer, and capable of receiving detection data from the sensor; A system equipped with these features.

[0193] 60. A system according to Embodiment 59, comprising an energy transmitting unit configured to be located outside the patient's body and an energy receiving unit coupled to or integrated with a vascular sleeve; the energy transmitting unit is configured to transmit energy from outside the patient's body to the energy receiving unit in order to supply energy to a US transducer.

[0194] 61. A system according to Embodiment 60, wherein the remote control device comprises the energy transmission unit.

[0195] 62. A system according to embodiment 60 or 61, wherein the energy receiving unit is a first inductor and the energy transmitting unit is a second inductor.

[0196] 63. A system according to any one of embodiments 59 to 62, wherein the energy receiving unit is connected to a vascular sleeve by a pigtail connection.

[0197] 64. A system according to any one of embodiments 59 to 63, wherein the vascular sleeve comprises a light-emitting unit configured to emit light toward the blood vessel.

[0198] 65. A method for treating a patient's blood vessels, A vascular sleeve is fitted outside at least a portion of a blood vessel, the sleeve comprising at least one ultrasound (US) transducer configured to supply ultrasonic energy to at least a portion of the blood vessel, and a first sensor configured to monitor at least one physiological parameter of a patient and generate detection data therefrom; Controllably operate at least one ultrasonic transducer to receive detection data from the sensor; A method that includes this.

[0199] 66. The method according to Embodiment 65, wherein the blood vessel is a bypass vessel that bypasses an arterial stenosis.

[0200] 67. A method according to embodiment 65 or 66, wherein light is irradiated from the sleeve toward the blood vessel. [Brief explanation of the drawing]

[0201] To keep the diagrams concise and clear, the elements shown are not necessarily drawn to scale. For example, the dimensions of some elements may be exaggerated relative to others for clarity. Furthermore, reference numbers may be duplicated between diagrams to indicate corresponding or similar elements. The diagram is as follows.

[0202] Figure 1 schematically shows a wearable device that applies ultrasonic energy to an artery according to one aspect of the present disclosure.

[0203] Figure 2 schematically shows another wearable device that applies ultrasonic energy to an artery, according to one aspect of the present disclosure.

[0204] Figure 3a shows an example of pulse-mode ultrasound generation by a wearable device according to one aspect of the present disclosure.

[0205] Figure 3b shows an exemplary operating protocol for a device according to one aspect of the present disclosure.

[0206] Figure 4a shows an example of a piezoelectric transducer having two center frequencies according to one aspect of the present disclosure.

[0207] Figure 4b shows an example of the geometric arrangement of the piezoelectric element array in a piezoelectric transducer.

[0208] Figure 5 shows an example of a skin-mounted piezoelectric transducer used as an acoustic sensor according to one aspect of the present disclosure.

[0209] Figure 6 shows an example of ECG and pulse wave signal analysis according to one aspect of this disclosure.

[0210] Figure 7 shows an example of the charge / discharge current waveform of a piezoelectric terminal according to one aspect of the present disclosure.

[0211] Figure 8 shows an exemplary waveform generated by a piezoelectric transducer and its associated circuitry in response to the movement of a leg, according to one aspect of the present disclosure.

[0212] Figure 9 is a schematic diagram of a system according to one aspect of this disclosure.

[0213] Figures 10 and 11 are schematic diagrams of different solutions for supplying energy to a system according to one aspect of this disclosure.

[0214] Figure 12 is a schematic cross-sectional view of a non-limiting example of a system according to one aspect of the present disclosure. Detailed description of specific embodiments of the present invention

[0215] In this specification, the term “approximately” as used in relation to quantity or value means “within a range of ±10%.” “Comprises,” “comprising,” “includes,” “including,” “has,” “having,” and their conjugations mean “including, but not limited to.”

[0216] Throughout this application, embodiments of the invention may be presented by reference to a range form. It should be understood that such range forms are for convenience and brevity only and should not be interpreted as a rigid limitation on the scope of the invention. Therefore, a range description should be considered to specifically disclose all possible subranges, not just the individual numerical values ​​within that range.

[0217] In this specification, the term “method” means methods, means, techniques and procedures for achieving a given task, including but not limited to methods, means, techniques and procedures that are known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine, or that can be readily developed from known methods, means, techniques and procedures.

[0218] The present invention discloses a device comprising at least one transducer (e.g., piezoelectric) that generates either ultrasonic or vibrational energy to mimic the application of shear force to endothelial cells and induce NO production and release.

[0219] This device is placed near ischemic tissue (specifically, the upper and lower extremities, i.e., the arms and legs).

[0220] The operation of a device that supplies vibration or ultrasonic energy may primarily affect local NO release from endothelial cells. Furthermore, such a device may induce ATP release. The scope of the present invention also includes providing devices configured and positioned to produce other physiological effects. These physiological effects include, for example, increased blood temperature, vasodilation, sustained local nitric oxide effect, altered red blood cell function, regulation of oxygen release from hemoglobin, regulation of blood pH, regulation of the immune response of blood leukocytes, regulation of coagulation and / or platelet function, altered function of heme catalytic enzymes in the blood, improved bioavailability of drugs, improved efficiency of hemodialysis sessions, and combinations thereof.

[0221] According to another embodiment, the device is operated from outside the patient's body. Thus, according to this embodiment, a remote control device equipped with an electronic communication device installed outside the patient's body is capable of communicating with the device and configured to operate the device, and can be used by a “healthcare” provider to program and control an energy source and thereby manipulate the treatment protocol provided to the patient (e.g., increasing or decreasing the amount of energy, time, level, energy source, etc.).

[0222] Referring to Figure 1, a device 100 is shown that is placed on the patient's skin surface 102 and in contact with an artery 107. A binding gel 101 may be used between the radiating surface of the device and the skin surface. The direction of blood flow is indicated by 109. A narrowing 110 may be present in the artery. When the transducer is activated, mechanical vibrations 106 are induced in a portion 108 of the blood vessel 107. Those skilled in the art will understand that the device 100 can utilize any number of transducers. The device 100 can communicate with an external unit 104, such as a smartphone, via a wireless link such as Bluetooth 103. The device can communicate with a cloud-based program 105 directly or via the external unit 104.

[0223] Furthermore, by providing multiple transducers, the position and orientation of each transducer can be controlled. Additionally, by controlling the position and orientation of each transducer, the ability to focus on the desired blood is achieved.

[0224] According to another embodiment, since there are multiple transducers, each transducer can be operated at different center frequencies within a range (for example, 10 kHz to about 10 MHz as a first range and 100 kHz to about 10 MHz as a second range). According to another embodiment, all transducers operate within the same center frequency range.

[0225] The device controls at least one parameter, such as the amplitude (and therefore intensity or output) of the sound wave transmitted by the transducer, timing (e.g., start and period), refractory period (i.e., not starting a new session until at least X minutes have elapsed since the previous session), signal directionality (one transmitter can stimulate multiple blood vessels located slightly apart from each other, and a phase array can direct stimulation to different blood vessels each time), and any combination thereof. In other embodiments, if the device includes multiple transducers, such as piezoelectric transducers, the shape or size of the focal region generated by the transducer elements can be controlled, for example, by controlling the phase component of the drive signal to each transducer element of the transducer device, and / or the focal region can be moved to a desired position. For example, the control device can control the phase shift of the drive signal to adjust the focal length (i.e., the distance from the surface of the transducer to the center of the focal region). In yet another embodiment, the device can operate the transducer for a predetermined time. Alternatively, or additionally, the control unit of this device may be configured to automatically shut down the transducer if the transducer usage time exceeds a predetermined period.

[0226] As described above, according to one embodiment, the device can communicate with at least one sensor. Examples of such sensors include accelerometers, impedance sensors, photoplethysmography sensors, PPG sensors, pH sensors, ultrasonic sensors, hydrophones, thermometers, trunk temperature sensors, heart rate sensors, pulse wave characteristics sensors, glucose sensors, manual activation sensors, any sensors indicating changes in cardiac output, any sensors indicating blood pressure, any sensors indicating the start of a dialysis session, any sensors associated with a dialysis machine, and combinations thereof. In such embodiments, the device is an "on-demand" device. In other words, the "on-demand" device is activated only when needed (on an "on-demand" basis). According to this embodiment, the sensor monitors the patient's physiological state, and when a change in the physiological state is detected, the control device signals the transducer to emit an acoustic signal (or modify one of the parameters of the acoustic signal).

[0227] As specified, each sensor is adapted to monitor the patient's physiological state, and treatment is provided accordingly. For example, an accelerometer is used to indicate changes in the patient's posture (e.g., the patient lies down, stands, walks). When a change is detected (e.g., when the patient starts walking), the device activates. In other words, the device is activated "on demand" (when the patient engages in physical activity, e.g., walking) to induce NO release (which increases oxidative levels / tissue perfusion in the tissues, reducing pain associated with physical activity).

[0228] In one embodiment, the target tissue to be treated is tissue affected by peripheral artery disease (tissue located within the patient's upper or lower limb). In other embodiments, the target tissue may be related to other diseases or conditions (such as pain caused by exercise) and may be located in other parts of the patient's body.

[0229] Once the device is positioned, the transducer (receiving a signal from the device control unit) delivers ultrasonic energy to the target tissue. The transducer may emit acoustic energy continuously or in pulses. In some embodiments, the device control unit may also control, for example, the phase, the operating center frequency, the tissue temperature (to prevent tissue overheating), and / or the operating amplitude of the transducer.

[0230] According to another embodiment, the device may include a tissue electrical impedance sensor.

[0231] Referring to Figure 2, Figure 2 shows an ultrasonic transducer 200 (e.g., a piezoelectric transducer) attached to the skin surface 201 relative to an artery 202. Conductive electrodes 203 and 204 are used and can be attached to the skin surface 201. These electrodes can be excited with a high center frequency AC signal (e.g., 100 kHz). This excitation causes an AC current 205 to flow through the subcutaneous tissue. The induced AC current can be measured and the equivalent electrical impedance can be calculated. If the device is not properly attached to the skin surface, the electrical impedance changes, and the device control unit can stop ultrasonic emission to prevent overheating of the skin surface.

[0232] According to another embodiment, the temperature of subcutaneous tissue exposed to ultrasonic radiation can be more accurately estimated by sweeping the center frequency of electrode excitation.

[0233] According to another embodiment, the tissue surface temperature can be measured using thermal sensors 206, 207 such as thermistors. The thermal sensors can be attached to the skin surface or to electrodes.

[0234] In another embodiment, the electrode can also be used as an ECG electrode.

[0235] In another embodiment, at least one acoustic sensor 208 can be used to detect the pulse wave of blood flowing through the artery 202. Since the pulse wave measurement by the acoustic sensor can reveal the blood flow profile within the artery, the effect of ultrasound irradiation can be evaluated. Optionally, the ultrasound irradiation parameters can be adjusted based on the blood flow profile determined by the acoustic sensor measurement.

[0236] It should be noted that the system in Figure 2 can incorporate various types of sensors in addition to acoustic and thermal sensors. For example, an ECG sensor can be incorporated into this system.

[0237] The processing circuit controlling the operation of the system in Figure 2, i.e., the transducer and sensor, can be configured to perform at least one of the following: (1) determine the quality of contact between the transducer and the subject's skin by analyzing the detected echo of the examination US pulse; (2) perform electrical measurements between two electrodes positioned on either side of the transducer to determine electrical parameters indicating the quality of contact between the transducer and the subject's skin; (3) use a periodic operation control loop to change the angle of the transducer relative to the subject's skin and / or the beam angle of the US pulse, and select the optimal operating state based on the measured physiological parameters, for example, based on the measured pulse wave by an acoustic sensor. Note that (1), (2), and (3) can be performed independently or simultaneously. For example, performing verification of the examination US pulse and electrical measurements can increase confidence in the quality of contact between the transducer and the skin.

[0238] Referring to Figure 3a, which shows an example of ultrasound emitted by the device toward an artery, the ultrasound takes the form of pulses 300 having a PRP 301. Each pulse contains pressure cycles ranging from a few to several thousand cycles, with a constant center frequency 302 and a peak negative pressure below the cavitation threshold 303. In another embodiment, the center frequency and / or peak negative pressure amplitude may vary with each pulse.

[0239] In another embodiment, open-loop or closed-loop transducer resonance frequency tracking can be utilized.

[0240] Referring to Figure 3b, the operating protocol is based on a pulse repetition period 306. This period includes a first detection phase 304 followed by an ultrasonic irradiation pulse 305. During the detection phase, the device control unit verifies the correct positioning and attachment of the device to the skin, and that the tissue temperature is below a safety threshold level, before exciting the piezoelectric transducer.

[0241] According to another embodiment, a piezoelectric transducer can generate ultrasound at multiple center frequencies. Ultrasound containing multiple center frequencies is known to enhance the effect on the target: Schoellhammer CM, Polat BE, Mendenhall J, Maa R, Jones B, Hart DP, Langer R, Blankschtein D. Rapid skin permeabilization by the simultaneous application of dual-frequency, high-intensity ultrasound. J Control Release. 2012 Oct 28;163(2):154-60.

[0242] Referring to Figure 4a, an example of a piezoelectric transducer is shown. This transducer is based on an array of piezoelectric elements such as bar 400. The piezoelectric elements can be arranged such that each element alternately has different resonant frequencies, for example, f1 401, f2 402, where f1 and f2 are the vibrational resonances of the piezoelectric elements.

[0243] Referring to Figure 4b, the piezoelectric array may be arranged in the shape of a concave / bowl 403, or in any other geometric shape that focuses energy longitudinally 406 to a focal region 404 on the artery 405 and increases the shear force on the arterial wall transversely 407.

[0244] According to another embodiment, by measuring pulse wave characteristics and pulse wave velocity, arterial dilation and increased blood perfusion can be demonstrated.

[0245] Referring to Figure 5, Figure 5 shows acoustic detection of pulse wave characteristics. As can be seen from Figure 5, the incident and reflected waves 503 of blood flowing through the artery 502 generate vibrations 504 that also propagate toward the skin surface 501. The skin-mounted unit 500 includes an acoustic sensor 505 that senses the vibrations 504 and converts them into electrical signals at its electrical terminals. In another embodiment, an ultrasonic generating transducer can also be used as the acoustic sensor 505. A protective switch 506 can be used to protect the electronic tuning circuit 507 from high-voltage pulses used to excite the ultrasonic transducer. The output signal of the electronic tuning circuit 508 can be digitized by a device control unit. Analysis of this signal can provide indicators of vasodilation and increased tissue perfusion, as well as the optimal position and / or orientation of the transducer relative to the blood vessel. Thus, this analysis facilitates the alignment of the device transducer relative to the blood vessel or tissue containing flowing blood.

[0246] According to another embodiment, alignment is indicated (to the patient or caregiver) by at least one indicating means. This indicating means may be an acoustic means, a visual means, a tactile means, or any combination thereof.

[0247] According to another embodiment, analysis of pulse wave characteristics indicates whether the desired physiological effects (vasodilation and increased blood perfusion) were actually achieved.

[0248] Referring to Figure 6, exemplary ECG signals 600 and pulse wave signals 601 are shown. A time delay 604 exists between the R portion 602 of the ECG signal 600 and the start of the systolic rise stroke 603 of the pulse wave signal 601. This delay varies depending on the stiffness of the downstream vessel (Kwon Y, Jacobs DR Jr, Lutsey PL, Brumback L, Chirinos JA, Mariani S, Redline S, Duprez DA. "Sleep disordered breathing and ECG R-wave to radial artery pulse delay, The Multi-Ethnic Study of Atherosclerosis". Sleep Med. 2018 Aug; 48:172-179. doi: 10.1016 / j.sleep.2018.05.005. Epub 2018 May 21). Maximum systolic phase 605, overlapping rise 606, and pulse pressure 607 are also shown. All of this contains valuable information regarding arteriosclerosis and downstream blood flow resistance. By detecting pulse wave waveforms, clinical conditions such as the progression of PAD can be tracked over the long term, and the ultrasound dose can be appropriately adjusted in a closed-loop manner.

[0249] According to one embodiment, the skin-mounted unit acoustically senses at least one pulse wave characteristic reflected from an artery with blood flow.

[0250] The scope of this disclosure includes cases where pulse wave analysis facilitates the alignment of at least one of several devices with respect to a blood-flowing blood vessel or tissue being treated. It should also be understood that the scope of this disclosure includes cases where pulse wave analysis indicates whether a desired physiological effect (e.g., arterial dilation and increased blood flow) has been induced.

[0251] Maintaining good adhesion between the transducer's radiating surface and the tissue surface is crucial. If the patient is moving, this movement can affect the adhesion. If the adhesion is insufficient, ultrasonic energy will not be transmitted to the skin and tissue, and most of the electrical energy supplied from the drive unit to the transducer will be converted into heat. This heat can rise rapidly and reach levels that cause burns and damage to the tissue. To ensure that the adhesion between the transducer and the skin is appropriate and well maintained, the equivalent electrical impedance of the transducer at the operating vibration resonance frequency may be detected. The resistive component of the electrical impedance depends on the mechanical load as seen from the transducer's radiating surface.

[0252] Referring to Figure 7, to detect impedance, the drive unit can excite the transducer using a low-voltage AC signal, for example, 1 volt, at a frequency "f-excitation" 702 that is sufficiently close to the operating vibration frequency of the transducer. After several dozen excitation cycles in the excitation phase 700, the drive unit stops the excitation phase and transitions to the discharge phase, forcibly short-circuiting the electrical terminals of the transducer. Under the short-circuit state of the discharge phase 701, the vibration energy of the transducer is discharged, and a discharge current flows through the electrical terminals that remain short-circuited. The frequency of the discharge current "f-discharge" 703 is at its natural vibration frequency. The current decay envelope 704 depends on the quality of the coupling between the transducer and the skin.

[0253] Due to the piezoelectric properties of the ultrasonic transducer in this device, the transducer can be used as a sensor to detect patient movement even when it is not excited.

[0254] Referring to Figure 8, an example of an electrical voltage signal measured at the electrical terminals of an ultrasonic transducer while the patient is moving (for example, in response to leg movement) is shown.

[0255] In another embodiment, the components of the device (battery, electronic circuitry, etc.) can be distributed among multiple subunits. Distribution among multiple subunits allows for a more even distribution of weight and minimizes the height of each component from the skin, thereby enabling a thinner device.

[0256] In another embodiment, connections between various components of the device are achieved by flexible, inflatable sleeves.

[0257] In another embodiment, the device (skin-mounted unit) 100 shown in Figure 1 can communicate with an external sensor, such as an ECG sensor. The external sensor may be a wearable sensor. The external ECG sensor, for example, sends a synchronous pulse indicating the R portion of the signal. In one embodiment, the wearable ECG sensor can be used continuously, or the ECG sensor can be used intermittently (i.e., occasionally).

[0258] Furthermore, according to this embodiment, during a treatment session, the energy intensity or dose supplied by the transducer to the tissue is maintained below a predetermined threshold (for example, by using an appropriate driving method and / or by selecting appropriate operating parameters such as the operating center frequency and operating amplitude). This protects the tissue from damage caused by acoustic energy.

[0259] In other embodiments, the transducer can be moved relative to the patient. In such embodiments, the position of at least one transducer can be optimized with respect to the tissue or blood vessel being treated.

[0260] In another embodiment, multiple skin-worn devices are used. In such embodiments, multiple treatment points are provided along the blood vessels (resulting in a wide-ranging effect). Furthermore, pulse wave characteristics are analyzed to determine treatment parameters and The positioning (e.g., alignment) of at least one device relative to blood vessels or tissues can be optimized.

[0261] According to another embodiment, the piezoelectric transducer of a skin-worn ultrasonic device can be suspended in a partially soft material chamber filled with an electrically non-conductive fluid such as silicone oil. Thus, the suspended transducer is better protected from mechanical shock.

[0262] According to another embodiment, the piezoelectric transducer chamber is inflatable, thereby maintaining sufficient acoustic coupling of acoustics / ultrasound to the skin.

[0263] According to another embodiment, the levitating piezoelectric transducer is tilted to improve alignment and orientation with respect to the blood vessel. In another embodiment, the piezoelectric transducer can be moved within the chamber to change its relative position with respect to the blood vessel. Alignment is achieved by (a) electromagnetic mechanisms (but not limited to) such as magnetic bearings used in flywheel energy storage or magnetic levitation, (b) piezoelectric mechanisms, (c) electrostatic mechanisms, and any combination thereof.

[0264] According to another embodiment, the device comprises a gel holder, which has an opening near the ultrasonic emitting or receiving surface. The gel contained in the gel holder is automatically or semi-automatically ejected from the gel holder through the opening on the ultrasonic emitting surface, maintaining proper ultrasonic coupling between the device's emitting surface and the skin. According to another embodiment, the gel holder is made of a flexible material, and the gel is released from the holder through the opening when the patient presses on the gel holder.

[0265] In another embodiment, the device may be embedded in a stretchable sleeve. This sleeve is automatically stretched before ultrasound irradiation to ensure good ultrasound coupling to the skin.

[0266] In another embodiment, the device may be embedded in an inflatable sleeve. In another embodiment, only the subunit containing the piezoelectric transducer inflates. The device's control unit can automatically inflate the sleeve before ultrasonic irradiation to ensure proper ultrasonic coupling to the skin. In another embodiment, the control unit inflates the sleeve to a predetermined pressure level. The pressure can be detected using a pressure sensor or force sensor, or using the device's piezoelectric transducer as a coupling detection mechanism using a charge-discharge method, as illustrated in Figure 7.

[0267] It should be noted that this system can be configured in any arrangement, and its components can be positioned along the limbs of the subject according to any design. There are no restrictions on the arrangement of the components of this system.

[0268] Figure 9 is a schematic diagram illustrating a non-limiting example of a system according to one aspect of the present disclosure. The system comprises a vascular sleeve 905 fitted to the outside of a bypass vessel 902 (e.g., an arteriovenous fistula (AVF)). In the figure, the artery 900 has a stenosis 901 that restricts blood flow. The bypass vessel 902 is connected to the artery 900 at connection points 903 and 904, allowing blood flow to bypass the arterial stenosis 901. The device 905 comprises an ultrasonic transducer that applies ultrasonic energy to the bypass vessel. The ultrasonic energy is administered, for example, several times a day, for short periods each time, with a low duty cycle, for example, a few minutes. The operation of the device 905 is controlled by an external control device 906 connected to the skin surface 907. The vascular sleeve 905 can provide external mechanical support to the bypass vessel by limiting the possibility of expansion of the bypass vessel. Furthermore, it may induce shear forces in arterial endothelial cells and red blood cells flowing through the bypass vessel, resulting in the release of nitric oxide (NO), which leads to vasodilation and increased blood flow. The vascular sleeve 905 can also minimize the abnormal proliferation of vascular smooth muscle cells (VSMCs), which are known to be a major factor in the development of vascular restenosis. The vascular sleeve 905 may be equipped with a light source, such as a laser diode, to irradiate the vessel with light in order to promote the maturation of arteriovenous fistulas (AVFs). The light emitted from the light source may be in the IR spectrum, more specifically in the far-infrared spectral region.

[0269] The vascular sleeve 905 may be equipped with a blood flow measurement sensor and / or a temperature sensor for detecting physiological parameters indicating blood flow and condition of the bypass vessel.

[0270] The vascular sleeve 905 may be equipped with a heat source, such as a resistive heat source, a light energy source, or an ultrasonic source. This heat source transfers heat to the vascular portion. To facilitate the measurement of intravascular blood flow velocity, the heat source may be operated in pulse mode. This can also promote the maturation of the AVF or an increase in intravascular blood flow.

[0271] The vascular sleeve 905 may be equipped with its own battery to supply energy, or may be supplied with energy by wireless energy transmission from an external control device 906.

[0272] Figures 10 and 11 show different solutions for supplying energy to the vascular sleeve.

[0273] Figure 10 shows a vascular sleeve 1003 disposed on a bypass vessel 1002 to bypass a stenosis 1001. The sleeve 1003 includes electrical wiring in the form of a pigtail 1004 connected to an inductor 1005, for example in the shape of a flat spiral inductor. The inductor 1005 may be disposed subcutaneously. A skin unit 1007 connected to the external skin surface 1008 can incorporate an inductor 1006 disposed opposite the subcutaneous inductor 1005 to form a wireless power and data transfer inductive link.

[0274] In another embodiment, the wireless link at the end of the pigtail 1004 can be utilized as an ultrasonic wireless link or a capacitive wireless link, or a combination thereof.

[0275] Figure 11 shows another embodiment of wireless power and data transfer of a bypass device. In the figure, a vascular sleeve 1101 is disposed around a bypass vessel 1100. An inductor 1102 is disposed inside the sleeve 1101 to form a wireless link for power and data with an external antenna 1103 included in an external device 1104. The external device 1104 may be connected to the external skin surface 1105.

[0276] In another embodiment, the sleeve 1101 can incorporate an ultrasonic transducer such as a flat disk-shaped piezoelectric element. This forms a wireless power and data transfer with an external ultrasonic transducer on the skin.

[0277] Refer to Figure 12. Figure 12 is a schematic diagram showing a cross-section of a system for non-invasively applying ultrasound pulses to a subject's blood vessels or tissues. It should be noted that while System 1200 comprises multiple US transducers 1202, the system may also comprise only one transducer. The transducer 1202 is housed in a chamber 1204 filled with a fluid suitable for functioning as an acoustic couplant. The transducer 1202 is operable by an operating element 1206 that can be actuated by mechanical, electrical, magnetic or other known techniques. System 1200 further comprises a restraint assembly for fixing / holding the transducer to a body part of the subject (e.g., the subject's limbs). In one embodiment, the restraint assembly consists of one or more straps 1208. The straps 1208 can be attached to the subject's body (e.g., limbs) using a buckle, hook and loop mechanism (e.g., Velcro®). By employing this configuration, the transducer 1202 can be easily manipulated towards a desired location identified as the location of a blood vessel. Furthermore, by fixing the system to the subject's limbs, good acoustic coupling is ensured between the transducer 1202 and the subject's body, and the US pulse is transmitted to the blood vessels or tissues. The operating state of the transducer can be optimized by a processing circuit that controls the operation of the operating element 1206. For example, the angle of the operating element 1206 can be optimized by executing an operating control loop. During the control loop, ultrasound irradiation can be performed using various combinations of angles. During the control loop, at least one physiological parameter is monitored, for example, a parameter indicating blood flow in a blood vessel. By the end of the control loop, the processing circuit analyzes at least one physiological parameter over multiple time frames. Each time frame is associated with a specific combination of angles of the operating element 1206. The combination of angles that yields the optimal parameter for at least one physiological parameter is selected for the next ultrasound irradiation period. It should be noted that the disclosed device can be used to treat a variety of clinical conditions, including several non-limiting examples included in the following list. • CLI / PAD - Accelerates healing in patients after vascular reconstruction surgery. In this application, the device operates continuously or intermittently after vascular reconstruction surgery. • Arteriovenous fistula (AVF) maturation in patients with end-stage renal disease (ESRD). The disclosed device and method can be used to improve the success rate of fistula formation and to maintain fistula patency for extended periods. It is also effective for long-term monitoring of blood flow through the fistula. • Improve wound healing in PAD patients and prevent lower limb amputation. • Local and continuous treatment for pulmonary arterial hypertension. • By acting on the bronchial arteries, this device is used to treat patients with severe asthma (severe asthma that does not respond to standard asthma inhalers). In such applications, it should be noted that any respiratory or vocal parameters indicating an asthma attack can trigger the device to relieve bronchospasm. • By generating NO within the carotid artery, blood flow to the brain during a stroke is improved (using an external ultrasound device). • "Local Viagra®" - Maintains erection by increasing blood flow to the penis without the systemic side effects of sildenafil (Viagra® tablets). • Improving the bioavailability of drugs - In this application, the timing of drug administration (oral, intravenous, or pump-operated) can be synchronized with the operation of an ultrasound device to promote local absorption of the drug in the target organ. It should be noted that the device should be positioned near the arteries supplying nutrients to the target organ. For example, it can be used to promote the inflow of chemotherapy drugs into solid tumors during a chemotherapy session. • Raynaud's disease - By using the solution of the present invention, it is possible to increase blood flow to the fingers by irradiating the nutrient arteries of the hand with ultrasound.

[0278] While specific embodiments have been illustrated and described herein, those skilled in the art will understand that a wide variety of alternative or equivalent embodiments or implementations designed to achieve the same or similar objectives may be used in place of the embodiments illustrated and described herein without departing from the scope of the present invention. Those skilled in the art will readily understand that embodiments of the present invention can be implemented in a wide variety of ways. This application is intended to encompass all modifications and / or variations of the embodiments discussed herein.

[0279] The terms and expressions used herein are for illustrative purposes only and not for limitation. Furthermore, the use of these terms and expressions is not intended to exclude equivalents or parts of any of the illustrated and / or described features. It is recognized that the scope of the present invention is defined and limited solely by the claims.

[0280] Those skilled in the art will see that, based on the teachings of this disclosure, numerous modifications and variations are possible to the examples and embodiments described herein. The disclosed examples and embodiments are presented for illustrative purposes only. Other alternative embodiments may include some or all of the features disclosed herein. Therefore, it is intended to cover all modifications and alternative embodiments that may fall within the true scope of the invention, and the scope therein shall be the entire scope of the invention. Furthermore, disclosure of a range of values ​​is a disclosure of all numerical values ​​within that range.

Claims

1. A non-invasive system for applying ultrasound (US) pulses to blood vessels or tissues, including the blood flow of a subject, and: With at least one US transducer configured to transmit ultrasonic pulses; The at least one US transducer is configured to be fixed or held in place by a fixation assembly which includes the blood vessel or tissue of the subject; A system comprising at least one sensor configured to monitor at least one physiological parameter or state of a subject and generate detection data based thereon; The system includes at least one US transducer and at least one processing circuit configured to communicate with the at least one sensor, receive the detection data, and in response to the detection data, controllably operate the at least one US transducer to transmit a US pulse toward the blood vessel or tissue; A system equipped with these features.

2. A system according to claim 1, comprising an operating device configured to controllably operate the at least one US transducer toward the blood vessel or tissue.

3. The system according to claim 2, wherein the operating device comprises an operating element and a chamber filled with a fluid material, at least a portion of the at least one US transducer is located in the chamber, and the operating element is configured to controllably move the at least one US transducer, thereby controllingly operating the at least one US transducer.

4. The system according to claim 3, wherein the fluid material is a non-conductive liquid.

5. A system according to claim 3 or 4, wherein the fluid material functions as an impedance transmission medium.

6. A system according to any one of claims 3 to 5, wherein the operating element is selected from one of the following: an element based on MEMS, an element based on electromagnetics, an element based on electrostatics, an element based on piezoelectricity, an element based on magnetism, or a mechanical element.

7. A system according to any one of claims 2 to 6, wherein the at least one processing circuit is configured to perform a periodic operation control loop, the operation control loop includes controlling an operating device using different sets of operation parameters and analyzing sensing data related to the operating time frame of each set of operation parameters to identify an optimal set of operation parameters that yields an optimal result for at least one physiological parameter, and once the optimal set of operation parameters is identified, the at least one processing circuit is configured to operate the operating device in a controllable manner with the optimal set of operation parameters until the next periodic operation control loop.

8. A system according to any one of claims 1 to 7, wherein the at least one processing circuit is configured to control the at least one US transducer and apply a test US pulse to detect a reflected echo generated from the test pulse; the at least one processing circuit is configured to analyze the detected reflected echo and determine whether the detected reflected echo satisfies predetermined conditions, thereby determining whether the at least one US transducer is in proper contact with a portion of the subject's skin; and if the detected reflected echo does not satisfy the predetermined conditions, the at least one processing circuit is configured to generate an output alarm.

9. The system according to claim 8, wherein the predetermined condition is at least one of a range of time delay from the application of the inspection pulse to the detection of reflection, a range of intensity, or a combination thereof.

10. A system according to any one of claims 1 to 9, comprising a first electrode and a second electrode, wherein at least one US transducer is positioned between the first electrode and the second electrode; at least one processing circuit is configured to apply current from the first electrode to the second electrode to measure an electrical parameter selected from impedance, current, and voltage; the electrical parameter indicates the quality of contact between a portion of the subject's skin and the at least one US transducer; and the at least one processing circuit is configured to generate an output alarm if the quality of contact falls below a selected threshold.

11. The system according to claim 10, comprising a first temperature sensor configured to sense skin temperature in the vicinity of the at least one US transducer and generate first skin temperature data thereon; the at least one processing circuit configured to analyze the first skin temperature data and the electrical parameters to determine subcutaneous temperature; and the at least one operating device configured to analyze the temporal profile of the subcutaneous temperature and to control the operation of the at least one transducer based on the behavior of the identified temporal profile of the subcutaneous temperature.

12. A system according to any one of claims 1 to 11, comprising at least one force sensor configured to measure the tightening force of a device generated around a body part by a fixed assembly; and the at least one processing circuit configured to generate a tightening alarm when the tightening force is outside the range of an allowable tightening force.

13. A system according to any one of claims 1 to 12, comprising an accelerometer configured such that at least one sensor senses the acceleration of a subject and generates acceleration data therefrom; the at least one processing circuit configured to analyze the acceleration data and determine whether the subject is moving; and if the subject is moving, the at least one processing circuit configured to disable the operation of the at least one US transducer.

14. A system according to any one of claims 1 to 13, comprising a second temperature sensor configured to sense skin temperature in the vicinity of the at least one US transducer and generate second skin temperature data therefrom; and a system configured to analyze the second temperature data to determine whether the skin temperature exceeds an acceptable temperature threshold, and to stop the operation of the at least one US transducer if it identifies that the acceptable temperature threshold has been exceeded.

15. A system according to any one of claims 1 to 14, wherein at least one sensor includes an acoustic sensor configured to detect an acoustic signal from a portion of the subject's skin and generate acoustic detection data, wherein the acoustic detection data indicates blood flow in the blood vessel or tissue; and the detection data includes the acoustic detection data.

16. A system according to any one of claims 1 to 15, wherein the response to the detection data includes the identification of a change in the at least one physiological parameter; and when the change is identified, at least one of the following is performed: (a) the US pulse is transmitted to the at least one blood vessel or tissue to provide on-demand treatment; (b) at least one therapeutic parameter of the US pulse transmission to the at least one blood vessel or tissue is changed to provide treatment as needed; (c) a notification regarding the change is output; (d) any combination thereof.

17. A system according to any one of claims 1 to 16, wherein the at least one sensor is configured to sense at least one pulse wave characteristic and to determine the heart rate of a subject from the at least one pulse wave characteristic, and the analysis of the at least one pulse wave characteristic facilitates the adjustment of the relative position of the US transducer with respect to the at least one blood vessel or tissue.

18. A system according to any one of claims 1 to 17, wherein the ultrasonic sensor is configured such that at least one sensor senses an ultrasonic signal, and the ultrasonic sensor is comprised of at least one US transducer.

19. A system according to any one of claims 1 to 18, comprising an array of US transducers, wherein at least one processing circuit is configured to controllably operate the array of US transducers in order to direct US pulses in a desired direction.

20. The system according to claim 19, wherein the at least one processing circuit is configured to perform a periodic control loop, the periodic control loop includes controlling the operation of a US transducer array using various sets of operating parameters, analyzing sensing data related to the operating time frame of each set of operating parameters, and identifying an optimal set of operating parameters that yields the optimal result for the at least one physiological parameter; and once the optimal set of operating parameters is identified, the at least one processing circuit is configured to control the operation of a plurality of US transducers using the optimal set of operating parameters until the next periodic control loop.

21. A system according to claim 20, wherein the set of changing operating parameters includes changes in the intensity, phase, or duty cycle of each US transducer in the transducer array.

22. A method for non-invasively applying ultrasound (US) pulses to or toward the blood vessels or tissues of a subject, the following: Immobilizing at least one ultrasound (US) transducer on the body part of the subject, including the blood vessels or tissues; Monitoring at least one physiological parameter and generating detection data based on it; and Activating the at least one US transducer in response to the detection data and transmitting a US pulse toward the blood vessel or tissue; A method that includes this.

23. A method according to claim 22, wherein the operation includes manipulating the at least one US transducer toward the blood vessel or tissue; Furthermore, the method includes placing at least a portion of the at least one US transducer in a chamber filled with a fluid material, and controllingly moving the at least one US transducer so as to be controllable; the fluid material is a non-conductive liquid; and the fluid material functions as an impedance transfer medium.

24. A method according to claim 22 or 23, comprising performing a periodic operation control loop which includes analyzing detection data associated with the operating time frame of each operation parameter set to identify an optimal operation parameter set that yields an optimal result for at least one physiological parameter; further comprising, once the optimal operation parameter set is identified, operating the at least one US transducer with the optimal operation parameter set until the next periodic operation control loop.

25. A method according to any one of claims 22 to 24, Apply a test US pulse using at least one US transducer; To detect reflected echoes generated from the aforementioned test pulse; Determining whether the reflected echo meets predetermined conditions to determine whether at least one US transducer is in proper contact with the subject's skin; and If the detected reflected echo does not meet the predetermined conditions, an output alarm is generated; A method that includes this.

26. A method according to any one of claims 22 to 25, A first electrode and a second electrode are attached to the skin portion of the subject, and at least one US transducer is positioned between the first electrode and the second electrode; An electric current is applied from the first electrode to the second electrode to measure an electrical parameter selected from current, impedance, or voltage, the electrical parameter indicating the quality of contact between the subject's skin portion and at least one US transducer; If the quality of contact falls below a selected threshold, generate an output alarm; To sense skin temperature in the vicinity of at least one US transducer and generate first skin temperature data based on that; Analyzing the first skin temperature data and the electrical parameters to determine the subcutaneous temperature; and Analyzing the temporal profile of the subcutaneous temperature and controlling the operation of at least one transducer based on the behavior of the temporal profile identified from the temporal profile of the subcutaneous temperature; A method that includes this.

27. A method according to any one of claims 22 to 26, wherein the action produces a physiological effect, the physiological effect being one or more of the following: vasodilation, increased local nitric oxide, enhanced nitric oxide release from vascular endothelium, sustained local nitric oxide effect, altered red blood cell function, modified oxygen release from hemoglobin, increased blood temperature, altered blood pH, regulated immune response of blood leukocytes, regulated coagulation and / or platelet function, altered function of heme catalytic enzymes in the blood, improved bioavailability of a drug, improved efficiency of a hemodialysis session, arterial dilation, increased hemoperfusion, and any combination thereof.

28. A method according to any one of claims 22 to 27, wherein the non-invasive application of ultrasound (US) pulses to or directed to the blood vessels or tissues of a subject is for the treatment of one or more of the following: pulmonary deneurosis, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary artery hypertension, maturation of arteriovenous fistula (AVF), Raynaud's disease, severe asthma, improvement of cerebral blood flow in stroke, increased blood flow to the penis for maintaining erection, improved bioavailability of drugs, enhanced absorption of local chemotherapeutic agents to solid tumors by enhancing blood flow to specific arteries supplying nutrients to the tumor, and any combination thereof.

29. A method according to any one of claims 22 to 28, wherein the at least one US transducer comprises an array of US transducers, and further comprises controlling the array of US transducers to manipulate a US pulse in a desired direction; the array of US transducers operates as a phase array for the operation.

30. A method according to claim 28 or 29, comprising performing a periodic control loop, the periodic control loop comprising controlling an array of US transducers using various sets of operating parameters, analyzing sensing data associated with the operating time frame of each set of operating parameters, and identifying an optimal set of operating parameters that yields an optimal result for at least one physiological parameter; once the optimal set of operating parameters is identified, the periodic control loop comprises controlling a plurality of US transducers using the optimal set of operating parameters until the next periodic control loop; A method in which a set of changing operating parameters includes changes in the intensity, phase, or duty cycle of each US transducer in a transducer array.

31. A system for treating a patient's blood vessels: A vascular sleeve configured to be fitted outside at least a portion of a blood vessel, comprising at least one ultrasound (US) transducer configured to supply ultrasonic energy to at least a portion of the blood vessel, and a first sensor configured to monitor at least one physiological parameter of a patient and generate detection data therefrom; and A remote control device positioned outside the patient's body, capable of data communication with the at least one ultrasonic transducer and the first sensor, capable of controlling the operation of the at least one ultrasonic transducer, and capable of receiving detection data from the sensor; A system equipped with these features.

32. A method for treating a patient's blood vessels, A vascular sleeve is fitted outside at least a portion of a blood vessel, the sleeve comprising at least one ultrasound (US) transducer configured to supply ultrasonic energy to at least a portion of the blood vessel, and a first sensor configured to monitor at least one physiological parameter of a patient and generate detection data therefrom; To controllably operate at least one ultrasonic transducer and receive detection data from the sensor; A method that includes this.

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