Device and method for influencing vascular blood flow

Abstract

The present disclosure relates to an implantable device for delivering therapeutic energy to a patient. More specifically, the present disclosure relates to an implantable ultrasound device adapted to affect vascular endothelium to induce the release of at least one substance selected from nitric oxide, NO, and / or adenosine triphosphate (ATP) release. Furthermore, the present disclosure relates to the treatment of various medical conditions, such as pulmonary hypertension, peripheral arterial disease (PAD), and asthma, by enhancing local perfusion to specific target organs.

Description

[Technical field]

[0001] The present invention relates generally to an implantable device for delivering therapeutic energy to a patient. More specifically, the present disclosure relates to an implantable ultrasound device adapted to affect vascular endothelium to induce the release of at least one substance selected from nitric oxide, NO, and / or adenosine triphosphate (ATP). Furthermore, the present disclosure relates generally to the treatment of various medical conditions, such as pulmonary hypertension, peripheral arterial disease (PAD), and asthma, by enhancing local perfusion to specific target organs. [Background technology]

[0002] The emergence of the reactive inorganic radical gas nitric oxide (NO) as a molecule that contributes to important physiological and pathological processes represents one of the major biological breakthroughs of recent years.

[0003] This molecule is produced under various physiological and pathological conditions by cells that mediate important biological functions. Examples include endothelial cells that line blood vessels, where nitric oxide derived from these cells relaxes smooth muscle, regulates blood pressure, and has profound effects on the function of circulating blood cells such as platelets and neutrophils, as well as on the smooth muscle of both blood vessels and other organs such as the airways. In the brain and elsewhere, nitric oxide functions as a neurotransmitter for non-adrenergic, non-cholinergic neurons. In these examples, nitric oxide appears to be produced intermittently in small amounts in response to various endogenous molecular signals. In the immune system, nitric oxide can be synthesized in much larger amounts on a prolonged basis. Its production is induced by exogenous or endogenous inflammatory stimuli, particularly endotoxins and cytokines produced by cells of the host defense system in response to infectious and inflammatory stimuli. This induced production results in the prolonged release of nitric oxide, which contributes to both host defense processes, such as bacterial and viral killing, and to pathologies associated with acute and chronic inflammation in a wide variety of diseases (Furchgott and Zawadzki 1980; Palmer et al. 1987).

[0004] In the field of vascular function, it has been reported that NO production as well as ATP release from endothelial cells (see Matthew A. Muller et al., Augmentation of Tissue Perfusion with Contrast Ultrasound: Influence of Three-Dimensional Beam Geometry and Conducted Vasodilation, Journal of the American Society of Echocardiography, doi:10.1016 / j.echo.2021.02.018) is physiologically stimulated when the endothelium is exposed to blood flow and shear stress induced by changes in blood flow (Taso et al. 1995; Uematsu et al. 1995; Ayajiki et al. 1996; Corson et al. 1996; Fleming et al. 1998). There are two possible mechanisms of endothelial NO production in response to fluid shear stress. Previous studies (Ando et al. 1988; Geiger et al. 1992; James et al. 1995) have shown that when the endothelium is exposed to increased fluid shear stress, it releases Ca from intracellular stores. 2+ release of Ca may be stimulated, resulting in intracellular free Ca 2+ It has been established that increased concentrations lead to increased enzymatic activity of endothelial NO synthase (eNOS) leading to the production of NO.

[0005] However, recently, several studies (Ayajiki et al. 1996; Corson et al. 1996; Fleming et al. 1998) have demonstrated that eNOS upregulates Ca in response to fluid shear stress. 2+ It has been suggested that tyrosine phosphorylation and intracellular pH (Ayajiki et al. 1996), phosphorylation of eNOS (Corson et al. 1996), and tyrosine kinase inhibitor-sensitive pathways (Fleming et al. 1998) play important roles in NO production.

[0006] In addition to this physiological stimulus, recent reports have noted that ultrasound application mimics the shear forces required for induced vasodilation, increased blood flow, and pH changes, depending on frequency and amplitude, in the context of NO production from blood vessels (Mason et al., Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation, JACC Cardiovasc Imaging 2020 Mar;13(3):641-651; Belcik et al., Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation, Circ.Cardiovasc Imaging.2015Apr;8(4):e002979; Kiyoshi Iida et al. Noninvasive low-frequency ultrasound energy causes vasodilation in humans; J Am Coll Cardiol.2006 Aug1;48(3):532-7; Muller et al., Treatment of Limb Ischemia with Conducted Effects of Catheter-Based Endovascular Ultrasound,Ultrasound Med Biol.2021Aug;47(8):2277-2285;).

[0007] One of the most prominent potential uses of NO induction and release of adenosine triphosphate is in the treatment of ischemic tissue with peripheral arterial disease (PAD), which is the narrowing or blockage of arteries due to atherosclerosis (buildup of fatty plaque), with or without calcification.

[0008] Stenosis or PAD can occur in any blood vessel, but is more common in the legs or lower extremities. PAD is a chronic disease. In its moderate form, it presents as claudication. In its severe form, PAD presents as critical limb ischemia (CLI). CLI is a severe blockage in the arteries of the lower extremities, significantly reducing blood flow. Peripheral arterial disease (PAD) and ischemic tissue is the most common form of atherosclerosis affecting many people worldwide. As a result of such disease, patients' mobility is limited (claudication) and their quality of life is significantly affected. In the early stages, such disease may progress to more severe stages and ultimately present a risk of amputation requiring revascularization treatment (e.g., arterial bypass surgery, stenting, angioplasty, opening the artery and placing a stent in an angiography room), but in the severe stages, many people experience pain during physical activity (e.g., walking) and in severe cases, patients experience pain in their feet and toes even at rest. Complications of poor circulation may include sores on the legs and feet, as well as wounds that do not heal. Left untreated, complications of CLI may result in amputation of the affected limb. Such conditions may be medically treated with exercise and drugs such as cilostazol, which moderately improve walking ability by inhibiting platelet aggregation. However, patients often do not comply with the prescribed exercise regimen due to the pain associated with the disease.

[0009] Medical interventions such as balloon angioplasty, stenting, and surgery are options for treating patients suffering from peripheral arterial disease and critical limb ischemia. However, many such procedures can fail. Consequences of graft failure include continued ischemia, delayed wound healing, gangrene, or amputation of the patient's limb.

[0010] The vasodilatory effects of nitric oxide (NO) and adenosine triphosphate (ATP), positive effects on perfusion, and release of NO from the endothelium (inner lining) of blood vessels are the major natural mechanisms for controlling local and systemic blood pressure. It is also known that administration of exogenous NO can induce local vasodilation, but the therapeutic use of systemic NO is limited because NO has a short half-life (<1 s) and high dose administration can have deleterious effects on systemic blood pressure.

[0011] Another use of NO and ATP induction is for primary pulmonary hypertension. Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is an increase in blood pressure in the pulmonary arteries and / or capillaries, collectively known as the pulmonary vasculature.

[0012] PH is a disease phenomenon of multifactorial etiology with a high mortality rate. The disease increases the work of the right side of the heart, eventually leading to hypertrophy and dysfunction of both the right and left sides of the heart in many cases. Despite improvements in treatment, the prognosis of pulmonary hypertension is poor, with a median survival of approximately 5 years.

[0013] Typically, patients with PH are treated with medications that are very expensive and not completely effective. Moreover, treatment outcomes among patients with PH are highly variable, due primarily to variability in underlying factors.

[0014] Therefore, the present invention also relates to improving NO release in ischemic tissues by applying ultrasound to the tissues under conditions effective to increase blood flow to said ischemic tissues (e.g., treating ischemic limbs or tissues affected by peripheral arterial disease). In other words, although nitric oxide has been proven to be a potent vasodilator with great therapeutic potential, there is still a long felt need to locally increase the availability of nitric oxide in target tissues (by utilizing ultrasound energy) to treat the above disclosed tissues.

[0015] It has further been found that application of ultrasound energy to increase the release of NO and ATP by implantable and / or wearable devices requires significant energy to be concentrated in the blood vessels, and furthermore, that continuous application of such energy may result in reduced efficacy due to physiological adaptation mechanisms or other mechanisms. Therefore, in order to maintain high efficacy, it is beneficial to minimize the application of energy to periods consistent with natural physiological demands and to limit the duration of such stimulation to optimal levels at which the slight increase in NO production and vasodilation diminishes.

[0016] Several devices are known in the art. One of them is described in PCT Publication No. WO2018071908 to VIBRATO MEDICAL INC, which discloses a wearable, non-invasive ultrasound modality for treating various medical conditions, including but not limited to peripheral vascular disease. The modality may be therapeutic ultrasound (TUS), which may be configured to promote angiogenesis in a patient through the stimulation of cavitation and shear stress, among other mechanisms. However, the aforementioned devices are wearable and are limited in their effectiveness (depth of penetration). It is further noted that such devices are bulky devices (adapted to be wearable) and require the presence of an acoustic gel between the transducer and the skin surface. Thus, patient acceptance is low and not suitable for long-term use (due to the low acceptance and the need for gel).

[0017] Thus, it is an object of the present invention to use sensors embedded in an implantable device, sensors external to the body (e.g., wearable sensors), and / or sensors implantable elsewhere in the body to detect periods during which the patient's physiology creates an increased demand for oxygenated blood and enhanced perfusion, and then to apply energy (e.g., ultrasound) to initiate stimulation of NO and ATP production during those periods. It is also an object of the present invention to test optimal periods for NO and ATP production and to limit the time of stimulation to these periods. Summary of the Invention

[0018] The long-standing needs disclosed above can be addressed by providing at least one implantable device for delivering therapeutic energy to a patient. More specifically, it relates to an implantable ultrasound device adapted to affect vascular endothelium to induce nitric oxide, NO and ATP release having the features of the independent claims. Further features of advantageous embodiments of the present disclosure are the subject matter of the dependent claims.

[0019] One object of the present invention is to provide a device adapted to be implanted adjacent to at least one blood vessel or tissue containing flowing blood, said device comprising at least one ultrasonic transducer configured to provide ultrasonic energy to said at least one blood vessel or tissue containing flowing blood, whereby said ultrasonic energy, when applied, is adapted to cause a physiological effect in said at least one blood vessel or tissue, said device being in communication with at least one on-skin remote controller positioned external to the patient and adapted to control said ultrasonic energy; The device is in communication with at least one sensor adapted to monitor at least one physiological condition of the patient.

[0020] Another object of the invention is to provide a device as defined above, wherein said device is self-activating upon a change in said at least one physiological condition.

[0021] Another object of the present invention is to provide a device as defined above, wherein said patient activates said ultrasound energy or modifies said at least one treatment parameter upon change in said at least one physiological condition.

[0022] Another object of the present invention is to provide a device as defined above which is adapted for the treatment of pulmonary artery denervation, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary arterial hypertension, severe asthmatics, improving blood flow to the brain during stroke, increasing blood flow to the penis to maintain erection, enhancing drug bioavailability, enhancing local chemotherapy absorption in solid tumors by enhancing flow in certain arteries that feed the tumor, and any combination thereof.

[0023] Another object of the invention is to provide a device as defined above, wherein said sensor is selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave properties, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, an acoustic blood pulse wave sensor, an electrocardiogram sensor, an ultrasound sensor or a vibration sensor, any sensor associated with a dialysis machine, and any combination thereof, and further wherein said sensor is adapted to sense at least one parameter selected from the group consisting of patient movement, impedance, a PPG signal, pH, an acoustic signal, pressure, temperature, heart rate, pulse wave properties, glucose level, blood pressure, and any combination thereof.

[0024] Another object of the invention is to provide a device as defined above, in which said ultrasound transducer is an array of transducers.

[0025] Another object of the invention is to provide a device as defined above, in which the position and orientation of each of said transducers is controllable.

[0026] Another object of the present invention is to provide a device as defined above, wherein said array of ultrasound transducers facilitates a focused ultrasound beam being directed towards said at least one vessel or tissue containing flowing blood.

[0027] Another object of the present invention is to provide a device as defined above, in which said array of ultrasonic transducers facilitates beam steering of said ultrasonic energy.

[0028] Another object of the present invention is to provide a device as defined above, wherein said array of ultrasonic transducers facilitates positioning of ultrasonic energy to said at least one blood vessel or tissue containing flowing blood.

[0029] Another object of the present invention is to provide a device as defined above, wherein said array is generating said ultrasonic energy at at least one ultrasonic carrier frequency.

[0030] Another object of the present invention is to provide a device as defined above, wherein at least one selected from the group consisting of said at least one on-skin remote controller, said device, and any combination thereof, comprises at least one coil for forming an inductive link and for transcutaneously transmitting said ultrasonic energy from said at least one on-skin remote controller to said at least one ultrasonic transducer.

[0031] Another object of the present invention is to provide a device as defined above, wherein said at least one on-skin remote controller is adapted to drive said device by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof.

[0032] Another object of the present invention is to provide a device as defined above, wherein said at least one on-skin remote controller is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) adjusting the treatment provided to said patient; (c) maintaining the treatment provided to said patient; and any combination thereof.

[0033] Another object of the invention is to provide a device as defined above, in which said data is the shape of the pulse wave signal.

[0034] Another object of the invention is to provide a device as defined above, in which said data is the time delay between the ECG signal and the pulse wave signal.

[0035] Another object of the present invention is to provide a device as defined above, wherein said device is encapsulated in at least one layer of polyetheretherketone (PEEK), the emitting surface of the PEEK being the acoustic matching layer, and further wherein the emitting surface of the PEEK is of quarter lambda, lambda being the ultrasonic energy wavelength of the PEEK.

[0036] Another object of the invention is to provide a device as defined above, in which said implant envelope is coated with parylene.

[0037] Another object of the present invention is to provide a device as defined above, wherein said at least one transducer is a piezoelectric transducer made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, PZT with non-uniform polarization, PZT with uniform polarization, and any combination thereof.

[0038] Another object of the present invention is to provide a device as defined above, in which said ultrasonic energy can be provided continuously or, alternatively, in pulses.

[0039] Another object of the present invention is to provide a device as defined above, wherein said at least one on-skin remote controller is adapted to measure a heart rate from said at least two pulse wave pulses.

[0040] Another object of the present invention is to provide a device as defined above, wherein analysis of said at least two pulse wave characteristics facilitates alignment of the position of said implant relative to said at least one vessel or tissue containing flowing blood.

[0041] Another object of the present invention is to provide a device as defined above, wherein at least one of the following applies: (a) said ultrasonic frequency is within 10 kHz to 10 MHz; (b) said ultrasonic energy has a peak negative pressure of about 0.1 MPa to about 2 MPa; and any combination thereof.

[0042] Another object of the present invention is to provide a device as defined above, in which said ultrasound energy is synchronized to a pulse wave signal.

[0043] Another object of the present invention is to provide a device as defined above, wherein said physiological condition or change therein is selected from the group consisting of patient position, engagement in physical activity, a decrease in NO level in said at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with said physical activity, patient position relative to the ground, a change in said position of the patient relative to the ground, application of at least one medical treatment to said patient, a change in the application of at least one medical treatment to said patient, and any combination thereof.

[0044] Another object of the present invention is to provide a device as defined above, wherein upon a change in said at least one physiological condition, at least one notification is sent to said patient or to any caregiver of said patient.

[0045] Another object of the present invention is to provide a device as defined above, wherein said physiological effects are selected from the group consisting of vasodilation, increase in local ATP, enhanced ATP release, increase in local nitric oxide, enhanced nitric oxide release from vascular endothelium, prolonged local nitric oxide effect, enhanced nitric oxide release from red blood cells, altered erythrocyte function, modified oxygen release from hemoglobin, increased blood temperature, vasodilation, prolonged local nitric oxide effect, altered erythrocyte function, modified oxygen release from hemoglobin, modified blood pH, regulating the immune response of blood leukocytes, regulating coagulation and / or blood globule function, modifying the function of heme-catalyzing enzymes in the blood, improving the bioavailability of drugs, improving the efficiency of arterial dilation of hemodialysis sessions, increased blood perfusion, and combinations thereof.

[0046] Another object of the present invention is to provide a device as defined above, wherein at least one of said at least one on-skin remote controller is wearable by said patient, and further wherein said at least one on-skin remote controller wearable by said patient is selected from the group consisting of: integrated into wearable socks, shoes, gloves, clothing, hats, and any combination thereof.

[0047] Another object of the present invention is to provide a device as defined above, wherein said ischemic tissue is selected from the group consisting of upper and lower extremities, arms, legs, and any combination thereof.

[0048] Another object of the present invention is to provide a device as defined above, wherein said at least one on-skin remote controller is adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof, of said ultrasound energy.

[0049] Another object of the invention is to provide a device as defined above, wherein said at least one on-skin remote controller is in communication with said at least one sensor.

[0050] Another object of the present invention is to provide a device as defined above, wherein upon a change in said at least one physiological condition of the patient, (a) said device is activated and ultrasound energy is delivered to said at least one blood vessel or tissue such that on-demand treatment is provided, (b) at least one treatment parameter of said ultrasound energy to said at least one blood vessel or tissue is modified such that treatment is provided as needed, (c) said changes are notified, and (d) at least one of any combination thereof is performed.

[0051] Another object of the present invention is to provide a device as defined above, wherein said sensor is selected from the group consisting of a sensor implanted in said patient and integrated within said device, a sensor worn by said patient, a remote sensor outside the patient's body integrated within said at least one on-skin remote controller, and any combination thereof.

[0052] Another object of the present invention is to provide a device as defined above, wherein said at least one ultrasound transducer functions as an acoustic sensor and is adapted to sense at least one acoustic wave generated by said at least one blood vessel or tissue containing flowing blood.

[0053] Another object of the invention is to provide a device as defined above, wherein said device is implanted subcutaneously.

[0054] Another object of the present invention is to provide a device as defined above adapted to be implanted adjacent to at least one blood vessel or tissue containing flowing blood, the device comprising at least one pulse wave sensor and adapted to sense at least one acoustic wave generated by said at least one blood vessel or tissue containing flowing blood and thereby to monitor at least one physiological condition of a patient.

[0055] Another object of the present invention is to provide a device as defined above, wherein said at least one pulse wave sensor is at least one transducer, and further wherein said transducer is selected from the group consisting of a capacitive element, an accelerometer, a piezoelectric element, an electro-acoustic element, an electrostatic element, and any combination thereof.

[0056] Another object of the invention is to provide a device as defined above, wherein said device is in communication with or additionally comprises at least one sensor selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave properties, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, an acoustic blood pulse wave sensor, an electrocardiogram sensor, an ultrasound sensor or a vibration sensor, any sensor associated with a dialysis machine, and any combination thereof, and further wherein said sensor is adapted to sense at least one parameter selected from the group consisting of movement of the patient, impedance, a PPG signal, pH, an acoustic signal, pressure, temperature, heart rate, pulse wave properties, glucose level, blood pressure, and any combination thereof.

[0057] Another object of the invention is to provide a device as defined above, in which said ultrasound transducer is an array of transducers.

[0058] Another object of the present invention is to provide a device as defined above, wherein said device is encapsulated in at least one layer of polyetheretherketone (PEEK), the emitting surface of the PEEK being the acoustic matching layer.

[0059] Another object of the invention is to provide a device as defined above, in which said implant envelope is coated with parylene.

[0060] Another object of the present invention is to provide a device as defined above, wherein said at least one transducer is a piezoelectric transducer made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, PZT with non-uniform polarization, PZT with uniform polarization, and any combination thereof.

[0061] Another object of the present invention is to provide a device as defined above, wherein said physiological condition or change therein is selected from the group consisting of patient position, engagement in physical activity, a decrease in NO level in said at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with said physical activity, patient position relative to the ground, a change in said position of the patient relative to the ground, application of at least one medical treatment to said patient, a change in the application of at least one medical treatment to said patient, and any combination thereof.

[0062] Another object of the present invention is to provide a device as defined above, wherein upon a change in said at least one physiological condition, at least one notification is sent to said patient or to any caregiver of said patient.

[0063] Another object of the invention is to provide a device as defined above, wherein said device is implanted subcutaneously.

[0064] Another object of the invention is an implant adjacent to or within at least one vessel or tissue containing flowing blood, comprising: i. at least one casing including at least one coil for forming an inductive link and for transcutaneously transmitting said ultrasonic energy from said at least one on-skin remote controller to said at least one ultrasonic transducer; ii. at least one sealed pigtail connected by wire or wirelessly to said at least one casing, said at least one ultrasonic transducer configured to couple ultrasonic energy to said at least one blood vessel or tissue containing flowing blood, whereby said ultrasonic energy, when applied, is adapted to cause a physiological effect in said at least one blood vessel or tissue; The objective is to provide an implant, wherein the casing is positioned external to the patient and is in communication with the at least one on-skin remote controller adapted to control the ultrasonic energy.

[0065] Another object of the present invention is to provide an implant as defined above, wherein at least one selected from the group consisting of said at least one casing, said at least one sealed pigtail, and any combination thereof, is in communication with at least one sensor adapted to monitor at least one physiological condition of the patient.

[0066] Another object of the present invention is to provide an implant as defined above, wherein said implant is self-activating upon a change in at least one of said physiological conditions.

[0067] Another object of the present invention is to provide an implant as defined above, wherein said patient activates said ultrasound energy or modifies said at least one treatment parameter upon change in said at least one physiological condition.

[0068] Another object of the present invention is to provide an implant as defined above which is adapted for the treatment of pulmonary artery denervation, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary arterial hypertension, severe asthma patients, improving blood flow to the brain during stroke, increasing blood flow to the penis to maintain an erection, enhancing the bioavailability of drugs, enhancing local chemotherapy absorption in solid tumors by enhancing flow in certain arteries that feed the tumor, and any combination thereof.

[0069] Another object of the invention is to provide an implant as defined above, wherein said sensor is selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave quality, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, an acoustic blood pulse wave sensor, an electrocardiogram sensor, an ultrasound sensor or a vibration sensor, any sensor associated with a dialysis machine, and any combination thereof, and further wherein said sensor is adapted to sense at least one parameter selected from the group consisting of patient movement, impedance, a PPG signal, pH, an acoustic signal, pressure, temperature, heart rate, pulse wave quality, glucose level, blood pressure, and any combination thereof.

[0070] Another object of the invention is to provide an implant as defined above, wherein said ultrasound transducer is an array of transducers.

[0071] Another object of the invention is to provide an implant as defined above, wherein said array is generating said ultrasonic energy at at least one ultrasonic carrier frequency.

[0072] Another object of the present invention is to provide an implant as defined above, wherein said at least one on-skin remote controller comprises at least one coil for forming an inductive link and for the transcutaneous transmission of said ultrasonic energy from said at least one on-skin remote controller to said at least one ultrasonic transducer.

[0073] Another object of the present invention is to provide an implant as defined above, wherein said at least one on-skin remote controller is adapted to drive said implant by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof.

[0074] Another object of the present invention is to provide an implant as defined above, wherein said at least one on-skin remote controller is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) adjusting the treatment provided to said patient; (c) maintaining the treatment provided to said patient intact; and any combination thereof.

[0075] Another object of the invention is to provide an implant as defined above, in which said data is the shape of a pulse wave signal.

[0076] Another object of the invention is to provide an implant as defined above, in which said data is the time delay between the ECG signal and the pulse wave signal.

[0077] Another object of the present invention is to provide an implant as defined above, wherein said implant is implanted subcutaneously.

[0078] Another object of the invention is to provide an implant as defined above, wherein said implant envelope is coated with parylene.

[0079] Another object of the invention is to provide an implant as defined above, wherein said at least one transducer is a piezoelectric transducer made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, PZT with non-uniform polarization, PZT with uniform polarization, and any combination thereof.

[0080] Another object of the present invention is to provide an implant as defined above, in which said ultrasonic energy can be provided continuously or, alternatively, in pulses.

[0081] Another object of the invention is to provide an implant as defined above, wherein said at least one on-skin remote controller is adapted to measure a heart rate from said at least two pulse wave pulses.

[0082] Another object of the present invention is to provide an implant as defined above, wherein analysis of said at least two pulse wave characteristics facilitates alignment of the position of said implant relative to said at least one blood vessel or tissue containing flowing blood.

[0083] Another object of the present invention is to provide an implant as defined above, wherein at least one of the following applies: (a) said ultrasonic frequency is within 10 kHz to 10 MHz; (b) said ultrasonic energy has a peak negative pressure of about 0.1 MPa to about 2 MPa; and any combination thereof.

[0084] Another object of the present invention is to provide an implant as defined above, wherein said ultrasound energy is synchronized to a pulse wave signal.

[0085] Another object of the present invention is to provide an implant as defined above, wherein said physiological condition or change thereof is selected from the group consisting of patient position, engagement in physical activity, a decrease in NO level in said at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with said physical activity, patient position relative to the ground, a change in said position of the patient relative to the ground, application of at least one medical treatment to said patient, a change in the application of at least one medical treatment to said patient, and any combination thereof.

[0086] Another object of the present invention is to provide an implant as defined above, wherein upon change of said at least one physiological condition, at least one notification is sent to said patient or to any caregiver of said patient.

[0087] Another object of the present invention is to provide an implant as defined above, wherein said physiological effects are selected from the group consisting of vasodilation, increase in local ATP, enhanced ATP release, increase in local nitric oxide, enhanced nitric oxide release from vascular endothelium, prolonged local nitric oxide effect, enhanced nitric oxide release from red blood cells, altered erythrocyte function, modified oxygen release from hemoglobin, increased blood temperature, vasodilation, prolonged local nitric oxide effect, altered erythrocyte function, modified oxygen release from hemoglobin, modified blood pH, regulating the immune response of blood leukocytes, regulating coagulation and / or blood globule function, modifying the function of heme-catalyzing enzymes in the blood, improving the bioavailability of drugs, improving the efficiency of arterial dilation of hemodialysis sessions, increased blood perfusion, and combinations thereof.

[0088] Another object of the present invention is to provide an implant as defined above, wherein at least one of said at least one on-skin remote controller is wearable by said patient, and further wherein said at least one on-skin remote controller wearable by said patient is selected from the group consisting of: integrated into a wearable sock, a shoe, a glove, a garment, a hat, and any combination thereof.

[0089] Another object of the present invention is to provide an implant as defined above, wherein said ischemic tissue is selected from the group consisting of upper and lower extremities, arms, legs, and any combination thereof.

[0090] Another object of the present invention is to provide an implant as defined above, wherein said at least one on-skin remote controller is adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof, of said ultrasound energy.

[0091] Another object of the invention is to provide an implant as defined above, wherein said at least one on-skin remote controller is in communication with said at least one sensor.

[0092] Another object of the present invention is to provide an implant as defined above, wherein upon a change in said at least one physiological condition of the patient, (a) said ultrasonic energy is delivered to said at least one blood vessel or tissue such that an on-demand treatment is provided, (b) at least one treatment parameter of said ultrasonic energy delivery to said at least one blood vessel or tissue is modified such that treatment is provided as needed, (c) said changes are notified, and (d) at least one of any combination thereof is performed.

[0093] Another object of the present invention is to provide an implant as defined above, wherein said sensor is selected from the group consisting of a sensor implanted in said patient and integrated within said at least one casing, a sensor integrated within said at least one pigtail, a sensor worn by said patient, a remote sensor outside the patient's body integrated within said at least one on-skin remote controller, and any combination thereof.

[0094] Another object of the present invention is to provide an implant as defined above, wherein said at least one ultrasonic transducer functions as an acoustic sensor and is adapted to sense at least one acoustic wave generated by said at least one blood vessel or tissue containing flowing blood.

[0095] Another object of the present invention is to provide an implant as defined above, wherein said at least one ultrasonic transducer functions as an acoustic sensor and is adapted to sense at least one acoustic wave generated by said at least one blood vessel or tissue containing flowing blood.

[0096] Another object of the present invention is a method for treating a patient, comprising the steps of: providing at least one device adapted to be implanted in a patient adjacent to at least one blood vessel or tissue containing flowing blood, said device comprising at least one ultrasonic transducer configured to provide ultrasonic energy to said at least one blood vessel or tissue containing flowing blood, whereby said ultrasonic energy, when applied, is adapted to cause a physiological effect in said at least one blood vessel or tissue; b. placing said device in communication with at least one on-skin remote controller positioned external to the patient and adapted to control said means for applying said ultrasound energy; c. implanting at least one of the devices described above adjacent to at least one blood vessel or tissue containing flowing blood; and d. causing the device to communicate with at least one sensor adapted to monitor at least one physiological condition of the patient.

[0097] Another object of the present invention is a method for treating a patient, comprising the steps of: a. providing at least one implant adjacent to or within at least one vessel or tissue containing flowing blood, said implant comprising: (i) at least one casing comprising at least one coil for forming an inductive link and for transcutaneously transmitting said ultrasonic energy from at least one on-skin remote controller to at least one ultrasonic transducer; and (ii) at least one sealed pigtail connected by wire or wirelessly to said at least one casing, said at least one ultrasonic transducer configured to couple ultrasonic energy to said at least one vessel or tissue containing flowing blood, whereby said ultrasonic energy, when applied, is adapted to cause a physiological effect in said at least one vessel or tissue; b. placing said implant in communication with at least one on-skin remote controller positioned external to the patient and adapted to control said means for applying said ultrasonic energy; c. implanting said at least one implant adjacent to or within at least one blood vessel or tissue that contains flowing blood; and d. placing said implant in communication with at least one sensor adapted to monitor at least one physiological condition of the patient.

[0098] Another object of the present invention is to provide a method for monitoring at least one physiological condition of a patient, comprising the steps of: a. providing at least one implant adjacent to at least one vessel or tissue containing flowing blood, said implant comprising at least one pulse wave sensor adapted to sense at least one acoustic wave generated by said at least one vessel or tissue containing flowing blood, thereby monitoring said at least one physiological condition of the patient; b. implanting said at least one implant adjacent to at least one blood vessel or tissue containing flowing blood; and c. sensing at least one acoustic wave generated by said at least one blood vessel or tissue containing flowing blood, thereby monitoring at least one physiological condition of the patient.

[0099] One object of the present invention is a device adapted to be implanted near, adjacent to or within at least one blood vessel or tissue containing flowing blood, comprising means (e.g. a transducer) for applying ultrasonic energy to said at least one blood vessel or tissue containing flowing blood, whereby said means for applying ultrasonic energy is adapted to cause a physiological effect in said at least one blood vessel or tissue when applied; and providing a device in communication with at least one sensor adapted to monitor at least one physiological condition of the patient such that, upon a change in the at least one physiological condition of the patient, (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 ultrasonic energy delivery to the at least one blood vessel or tissue is modified to provide treatment as needed, (c) the change is notified, and (d) any combination thereof is performed.

[0100] Another object of the invention is to provide a device as defined above, wherein said device is self-activating upon a change in said at least one physiological condition.

[0101] Another object of the present invention is to provide a device as defined above, wherein said patient activates said ultrasound energy or modifies said at least one treatment parameter upon change in said at least one physiological condition.

[0102] Another object of the present invention is to provide a device as defined above, wherein said sensor is selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave properties, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof.

[0103] Another object of the present invention is to provide a device as defined above, wherein said sensor is adapted to sense at least one parameter selected from the group consisting of movement of said patient, impedance, PPG signal, pH, acoustic signal, pressure, temperature, heart rate, pulse wave properties, glucose level, blood pressure, and any combination thereof.

[0104] Another object of the present invention is to provide a device as defined above, wherein said device is in communication with at least one remote controller positioned external to the patient and adapted to control said means for applying said ultrasonic energy.

[0105] Another object of the present invention is to provide a device as defined above, wherein said sensor is selected from the group consisting of a sensor implanted in said patient and integrated within said device, a sensor worn by said patient, a remote sensor outside the patient's body integrated within said at least one remote controller, and any combination thereof.

[0106] Another object of the present invention is to provide a device as defined above, wherein said physiological condition or change therein is selected from the group consisting of patient position, engagement in physical activity, a decrease in NO level in said at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with said physical activity, patient position relative to the ground, a change in said position of the patient relative to the ground, application of at least one medical treatment to said patient, a change in the application of at least one medical treatment to said patient, and any combination thereof.

[0107] Another object of the present invention is to provide a device as defined above, wherein at least one treatment parameter is selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof of said ultrasound energy.

[0108] Another object of the present invention is to provide a device as defined above, wherein upon a change in said at least one physiological condition, at least one notification is sent to said patient or to any caregiver of said patient.

[0109] Another object of the invention is to provide a device as defined above, wherein said device is in communication with at least one battery, said at least one battery being implanted in the patient or positioned external to the patient.

[0110] Another object of the invention is to provide a device as defined above, in which said at least one battery is adapted to be charged wirelessly.

[0111] Another object of the present invention is to provide a device as defined above, wherein said physiological effects are selected from the group consisting of vasodilation, increase in local nitric oxide, enhanced nitric oxide release from vascular endothelium, prolonged local nitric oxide effect, altered function of red blood cells, modified oxygen release from hemoglobin, increased blood temperature, vasodilation, prolonged local nitric oxide effect, altered function of red blood cells, modified oxygen release from hemoglobin, modified blood pH, modulation of immune response of blood leukocytes, modulation of coagulation and / or blood globule function, modification of function of heme catalytic enzymes in blood, improved bioavailability of drugs, improved efficiency of arterial dilation of hemodialysis sessions, increased blood perfusion, and combinations thereof.

[0112] It is another object of the present invention to provide a device as described above, wherein the ultrasonic energy is provided at a frequency in the range of about 20 kHz to about 10 MHz.

[0113] Another object of the present invention is to provide a device as defined above, wherein the ultrasonic energy is provided by at least one selected from the group consisting of at least one piezoelectric transducer generating ultrasonic energy, at least one passive ferromagnetic element, at least one capacitive micromachined ultrasonic transducer, a CMUT, a concave transducer, a convex transducer, and any combination thereof.

[0114] Another object of the present invention is to provide a device as defined above, wherein said piezoelectric transducer is made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, and any combination thereof.

[0115] Another object of the invention is to provide a device as defined above, in which said piezoelectric transducer is shaded by a Gaussian distribution apodization.

[0116] Another object of the invention is to provide a device as defined above, in which the aforementioned Gaussian distribution apodization is provided by the polarization of the material.

[0117] Another object of the invention is to provide a device as defined above, in which at least one of said controllers is adapted to charge said device.

[0118] Another object of the present invention is to provide a device as defined above, wherein at least one of said controllers is adapted to charge said device by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof.

[0119] Another object of the invention is to provide a device as defined above, in which at least one of the aforementioned controllers comprises at least one coil.

[0120] Another object of the present invention is to provide a device as defined above, wherein said at least one sensor is adapted to sense at least one pulse wave characteristic reflected from said device by at least one method selected from the group consisting of: (a) passive acoustic sensing of at least one signal reflected from said at least one blood vessel or tissue; (b) active transmission of at least one acoustic signal; (c) echo; and any combination thereof.

[0121] Another object of the invention is to provide a device as defined above, wherein the device is adapted to sense the heart rate from at least one pulse wave characteristic as mentioned above.

[0122] Another object of the present invention is to provide a device as defined above, wherein analysis of said at least one pulse wave characteristic facilitates alignment of the position of said device relative to said at least one vessel or tissue containing flowing blood.

[0123] Another object of the present invention is to provide a device as defined above, in which said alignment is indicated either to the patient or to the patient's caregiver.

[0124] Another object of the present invention is to provide a device as defined above, wherein said alignment is indicated by at least one indication means selected from the group consisting of audio means, visual means, tactile means, and any combination thereof.

[0125] Another object of the invention is to provide a device as defined above, wherein analysis of said at least one pulse wave characteristic indicates said causing of said physiological effect.

[0126] Another object of the invention is to provide a device as defined above, in which the ultrasonic energy is provided by an array of piezoelectric transducers, each of which generates ultrasonic energy.

[0127] Another object of the invention is to provide a device as defined above, in which said array of piezoelectric transducers is a phased array.

[0128] Another object of the present invention is to provide a device as defined above, wherein activation of at least one of said transducers according to a predefined protocol fine-tunes the position of said implant relative to said at least one blood vessel and aligns said implant therewith.

[0129] Another object of the present invention is to provide a device as defined above, in which said ultrasonic energy can be provided continuously or, alternatively, in pulses.

[0130] Another object of the present invention is to provide a device as defined above, wherein at least one of said controllers is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) modifying at least one treatment parameter of a treatment protocol; (c) maintaining intact the treatment provided to said patient; and any combination thereof.

[0131] Another object of the invention is to provide a device as defined above, in which at least one of said controllers is wearable by said patient.

[0132] Another object of the present invention is to provide a device as defined above, wherein at least one of said controllers wearable by said patient is selected from the group consisting of: integrated into a wearable sock, a shoe, a glove, a garment, a hat, and any combination thereof.

[0133] Another object of the invention is to provide a device as defined above, in which at least one of said controllers is integrated in the environment of said patient.

[0134] Another object of the present invention is to provide a device as defined above, wherein at least one of said controllers is in communication with at least one selected from the group consisting of a CPU, a smartphone, and any combination thereof.

[0135] Another object of the present invention is to provide a device as defined above which is adapted for the treatment of pulmonary artery denervation, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary arterial hypertension, severe asthmatics, improving blood flow to the brain during stroke, increasing blood flow to the penis to maintain erection, enhancing drug bioavailability, enhancing local chemotherapy absorption in solid tumors by enhancing flow in certain arteries that feed the tumor, and any combination thereof.

[0136] Another object of the present invention is to provide a device as defined above, wherein said ischemic tissue is selected from the group consisting of upper and lower extremities, arms, legs, and any combination thereof.

[0137] Another object of the invention is to provide a device as defined above, adapted to provide said ultrasonic energy so as to increase blood flow.

[0138] Another object of the invention is to provide a device as defined above, in which said ultrasonic energy is provided at least two substantially different frequencies of a carrier signal.

[0139] Another object of the present invention is to provide a device as defined above, wherein said device comprises at least one piezoelectric transducer adapted to generate said ultrasonic energy at one of said at least two substantially different frequencies of said carrier signal.

[0140] Another object of the present invention is to provide a device as defined above, wherein said device additionally comprises at least one electromagnetic acoustic transducer mechanically coupled to said at least one piezoelectric transducer adapted to generate said ultrasonic energy at one of said at least substantially different frequencies of said carrier signal.

[0141] Another object of the invention is to provide a device as defined above, in which said at least one electromagnetic acoustic transducer is at least one ferromagnetic sheet.

[0142] Another object of the invention is to provide a device as defined above, in which the frequency of one of the carrier signals is in the range from approximately 20 kHz to approximately 10 MHz.

[0143] Another object of the invention is to provide a device as defined above, in which the second frequency of the carrier signal is in the range of approximately 20 kHz to approximately 10 MHz.

[0144] Another object of the invention is to provide a device as defined above, wherein said device is encapsulated in at least one layer of polyetheretherketone (PEEK).

[0145] Another object of the present invention is to provide a device as defined above, wherein said device comprises at least one processor adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof, of said ultrasonic energy.

[0146] Another object of the invention is to provide a device as defined above, in which said at least one processor is in communication with said at least one sensor.

[0147] Another object of the present invention is to provide a device as defined above, wherein said at least one processor is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) modifying the therapy provided to said patient; (c) maintaining the therapy provided to said patient intact; and any combination thereof.

[0148] Another object of the present invention is a method for treating a patient, comprising the steps of: providing at least one implantable device adapted to be implanted near, adjacent to, or within at least one blood vessel or tissue containing flowing blood, said device comprising means for applying ultrasonic energy to said at least one blood vessel or tissue containing flowing blood, whereby said means for applying ultrasonic energy is adapted to cause a physiological effect in said at least one blood vessel or tissue when applied; b. implanting said at least one device adjacent to or within at least one blood vessel or tissue that contains flowing blood; and c. providing a method comprising: upon a change in said at least one physiological condition of the patient, (a) delivering said ultrasonic energy to said at least one blood vessel or tissue to provide on-demand treatment; (b) modifying at least one treatment parameter of said ultrasonic energy delivery to said at least one blood vessel or tissue to provide treatment as needed; (c) notifying said change; and (d) causing said device to communicate with at least one sensor adapted to monitor said at least one physiological condition of the patient such that at least one of any combination thereof is performed, thereby treating said patient.

[0149] Another object of the invention is to provide a method as defined above, wherein said device is self-activating upon a change in said at least one physiological condition.

[0150] Another object of the present invention is to provide a method as defined above, wherein said patient activates said ultrasound energy or modifies said at least one treatment parameter upon change in said at least one physiological condition.

[0151] Another object of the present invention is to provide a method as defined above, wherein said sensor is selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave quality, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof.

[0152] Another object of the present invention is to provide a method as defined above, wherein said sensor is adapted to sense at least one parameter selected from the group consisting of movement, impedance, PPG signal, pH, acoustic signal, pressure, temperature, heart rate, pulse wave properties, glucose level, blood pressure, and any combination thereof of said patient.

[0153] Another object of the invention is to provide a method as defined above, wherein said device is in communication with at least one remote controller positioned external to the patient and adapted to control said means for applying said ultrasonic energy.

[0154] Another object of the present invention is to provide a method as defined above, wherein said sensor is selected from the group consisting of a sensor implanted in said patient and integrated within said device, a sensor worn by said patient, a remote sensor outside the patient's body integrated within said at least one remote controller, and any combination thereof.

[0155] Another object of the present invention is to provide a method as defined above, wherein said physiological condition or a change therein is selected from the group consisting of a patient's position, engagement in physical activity, a decrease in NO level in said at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with said physical activity, a patient's position relative to the ground, a change in said position of the patient relative to the ground, application of at least one medical treatment to said patient, a change in the application of at least one medical treatment to said patient, and any combination thereof.

[0156] Another object of the present invention is to provide a method as defined above, wherein at least one treatment parameter is selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof of said ultrasound energy.

[0157] Another object of the present invention is to provide a method as defined above, wherein upon a change in said at least one physiological condition, at least one notification is sent to said patient or to any caregiver of the patient.

[0158] Another object of the invention is to provide a method as defined above, wherein said device is in communication with at least one battery, said at least one battery being implanted in the patient or positioned external to the patient.

[0159] Another object of the invention is to provide a method as defined above, in which said at least one battery is adapted to be wirelessly charged.

[0160] Another object of the present invention is to provide a method as defined above, wherein said physiological effect is selected from the group consisting of vasodilation, increase in local nitric oxide, enhanced release of nitric oxide from vascular endothelium, prolonged local nitric oxide effect, altered function of red blood cells, modified oxygen release from hemoglobin, increased blood temperature, vasodilation, prolonged local nitric oxide effect, altered function of red blood cells, modified oxygen release from hemoglobin, modified blood pH, modulation of immune response of blood leukocytes, modulation of coagulation and / or blood globule function, modification of the function of heme catalytic enzymes in blood, improved bioavailability of drugs, improved efficiency of arterial dilation of hemodialysis sessions, increased blood perfusion, and combinations thereof.

[0161] It is another object of the present invention to provide a method as described above, wherein the ultrasonic energy is provided at a frequency in the range of about 20 kHz to about 10 MHz.

[0162] Another object of the present invention is to provide a method as defined above, wherein the ultrasonic energy is provided by at least one selected from the group consisting of at least one piezoelectric transducer generating ultrasonic energy, at least one passive ferromagnetic element, at least one capacitive micromachined ultrasonic transducer, a CMUT, a concave transducer, a convex transducer, and any combination thereof.

[0163] Another object of the present invention is to provide a method as defined above, wherein said piezoelectric transducer is made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, and any combination thereof.

[0164] Another object of the invention is to provide a method as defined above, in which said piezoelectric transducer is shaded by a Gaussian distribution apodization.

[0165] Another object of the invention is to provide a method as defined above, in which said Gaussian distribution apodization is provided by the polarization of the material.

[0166] Another object of the invention is to provide a method as defined above, in which at least one of said controllers is adapted to charge said device.

[0167] Another object of the present invention is to provide a method as defined above, wherein at least one of said controllers is adapted to charge said device by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof.

[0168] Another object of the invention is to provide a method as defined above, in which at least one of said controllers comprises at least one coil.

[0169] Another object of the present invention is to provide a method as defined above, wherein said at least one sensor is adapted to sense at least one pulse wave characteristic reflected from said device by at least one method selected from the group consisting of: (a) passive acoustic sensing of at least one signal reflected from said at least one blood vessel or tissue; (b) active transmission of at least one acoustic signal; (c) echo; and any combination thereof.

[0170] Another object of the invention is to provide a method as defined above, in which the device is adapted to sense the heart rate from at least one of the aforementioned pulse wave characteristics.

[0171] Another object of the present invention is to provide a method as defined above, wherein analysis of said at least one pulse wave characteristic facilitates alignment of the position of said device relative to said at least one vessel or tissue containing flowing blood.

[0172] Another object of the invention is to provide a method as defined above, in which said alignment is indicated either to the patient or to the patient's caregiver.

[0173] Another object of the present invention is to provide a method as defined above, wherein said alignment is indicated by at least one indication means selected from the group consisting of audio means, visual means, tactile means, and any combination thereof.

[0174] Another object of the present invention is to provide a method as defined above, wherein analysis of said at least one pulse wave characteristic indicates said cause of said physiological effect.

[0175] Another object of the invention is to provide a method as defined above, in which the ultrasonic energy is provided by an array of piezoelectric transducers, each of which generates ultrasonic energy.

[0176] Another object of the invention is to provide a method as defined above, in which said array of piezoelectric transducers is a phased array.

[0177] Another object of the present invention is to provide a method as defined above, wherein activation of at least one of said transducers according to a predefined protocol fine-tunes the position of said implant relative to said at least one blood vessel and aligns said implant therewith.

[0178] Another object of the present invention is to provide a method as defined above, in which said ultrasonic energy can be provided continuously or, alternatively, in pulses.

[0179] Another object of the present invention is to provide a method as defined above, wherein at least one of said controllers is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) modifying at least one treatment parameter of a treatment protocol; (c) maintaining intact the treatment provided to said patient; and any combination thereof.

[0180] Another object of the present invention is to provide a method as defined above, wherein at least one of said controllers is wearable by said patient.

[0181] Another object of the present invention is to provide a method as defined above, wherein at least one of said controllers wearable by said patient is selected from the group consisting of: integrated into wearable socks, shoes, gloves, clothing, hats, and any combination thereof.

[0182] Another object of the invention is to provide a method as defined above, in which at least one of said controllers is integrated in the environment of said patient.

[0183] Another object of the present invention is to provide a method as defined above, wherein at least one of said controllers is in communication with at least one selected from the group consisting of a CPU, a smartphone, and any combination thereof.

[0184] Another object of the present invention is to provide a method as defined above which is adapted for the treatment of pulmonary artery denervation, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary arterial hypertension, severe asthmatics, improving blood flow to the brain during stroke, increasing blood flow to the penis to maintain erection, enhancing drug bioavailability, enhancing local chemotherapy absorption in solid tumors by enhancing flow in certain arteries that feed the tumor, and any combination thereof.

[0185] Another object of the present invention is to provide a method as defined above, wherein said ischemic tissue is selected from the group consisting of upper and lower limbs, arms, legs, and any combination thereof.

[0186] Another object of the invention is to provide a method as defined above, adapted to provide said ultrasound energy so as to increase blood flow.

[0187] Another object of the invention is to provide a method as defined above, in which said ultrasonic energy is provided at least two substantially different frequencies of a carrier signal.

[0188] Another object of the present invention is to provide a method as defined above, wherein said device comprises at least one piezoelectric transducer adapted to generate said ultrasonic energy at one of said at least two substantially different frequencies of said carrier signal.

[0189] Another object of the present invention is to provide a method as defined above, wherein said device additionally comprises at least one electromagnetic acoustic transducer mechanically coupled to said at least one piezoelectric transducer adapted to generate said ultrasonic energy at one of said at least substantially different frequencies of said carrier signal.

[0190] Another object of the present invention is to provide a method as defined above, in which said at least one electromagnetic acoustic transducer is at least one ferromagnetic sheet.

[0191] Another object of the invention is to provide a method as defined above, in which the frequency of one of the carrier signals is in the range of approximately 20 kHz to approximately 10 MHz.

[0192] Another object of the invention is to provide a method as defined above, wherein the second frequency of the carrier signal is in the range of about 20 kHz to about 10 MHz.

[0193] Another object of the invention is to provide a method as defined above, in which said device is encapsulated in at least one layer of polyetheretherketone (PEEK).

[0194] Another object of the present invention is to provide a method as defined above, wherein said device comprises at least one processor adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof, of said ultrasonic energy.

[0195] Another object of the invention is to provide a method as defined above, in which said at least one processor is in communication with said at least one sensor.

[0196] Another object of the present invention is to provide a method as defined above, wherein said at least one processor is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) modifying the therapy provided to said patient; (c) maintaining the therapy provided to said patient intact; and any combination thereof.

[0197] Another object of the present invention is to provide a method as defined above, additionally comprising the step of orienting at least two devices in the same position relative to said at least one vessel or tissue containing flowing blood.

[0198] Another object of the present invention is to provide a method as defined above, additionally comprising a step of orienting at least two devices in substantially different positions relative to said at least one vessel or tissue containing flowing blood.

[0199] Another object of the present invention is to provide a method as defined above, additionally comprising the step of enabling said ultrasonic energy to be focused on said at least one blood vessel or tissue by said positioning of said at least two devices.

[0200] Another object of the invention is to provide a method as defined above, which additionally comprises the step of enabling communication between at least two of the devices.

[0201] Another object of the present invention is to provide a system comprising a plurality of implantable ultrasound devices, at least one of which is implanted near, adjacent to, or within at least one blood vessel or tissue containing flowing blood, and comprising means for applying ultrasonic energy to said at least one blood vessel or tissue containing flowing blood, whereby said means for applying ultrasonic energy is adapted to cause a physiological effect in said at least one blood vessel or tissue when applied, and at least one of said devices is in communication with at least one sensor adapted to monitor at least one physiological condition of the patient, such that upon a change in at least one physiological condition of the patient, (a) said ultrasonic energy is delivered to said at least one blood vessel or tissue such that an on-demand treatment is provided, (b) at least one treatment parameter of said ultrasonic energy provision to said at least one blood vessel or tissue is modified such that a treatment is provided as needed, (c) said change is notified, and (d) at least one of any combination thereof is performed.

[0202] Another object of the invention is to provide a system as defined above, in which at least one of said devices is self-activating upon a change in at least one of said physiological conditions.

[0203] Another object of the present invention is to provide a system as defined above, wherein said patient activates said ultrasound energy or modifies said at least one treatment parameter upon change in said at least one physiological condition.

[0204] Another object of the present invention is to provide a system as defined above, wherein said sensor is selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, an echocardiogram, an ultrasound echo, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave quality, a glucose sensor, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof.

[0205] Another object of the present invention is to provide a system as defined above, wherein said sensor is adapted to sense at least one parameter selected from the group consisting of movement of said patient, impedance, PPG signal, pH, acoustic signal, pressure, temperature, heart rate, pulse wave properties, glucose level, blood pressure, and any combination thereof.

[0206] Another object of the invention is to provide a system as defined above, wherein at least one said device is positioned external to the patient and in communication with at least one remote controller adapted to control said means for applying said ultrasound energy.

[0207] Another object of the present invention is to provide a system as defined above, wherein said sensor is selected from the group consisting of a sensor implanted in said patient and integrated within at least one of said devices, a sensor worn by said patient, a remote sensor outside the patient's body integrated within said at least one remote controller, and any combination thereof.

[0208] Another object of the present invention is to provide a system as defined above, wherein said physiological condition or change therein is selected from the group consisting of a patient's position, engagement in physical activity, a decrease in NO level in said at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with said physical activity, a patient's position relative to the ground, a change in a patient's position relative to the ground, application of at least one medical treatment to said patient, a change in the application of at least one medical treatment to said patient, and any combination thereof.

[0209] Another object of the present invention is to provide a system as defined above, wherein at least one treatment parameter is selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof of said ultrasound energy.

[0210] Another object of the present invention is to provide a system as defined above, wherein upon a change in said at least one physiological condition, at least one notification is sent to said patient or to any caregiver of the patient.

[0211] Another object of the present invention is to provide a system as defined above, wherein at least one of said devices is in communication with at least one battery, said at least one battery being implanted in the patient or positioned external to the patient.

[0212] Another object of the invention is to provide a system as defined above, in which said at least one battery is adapted to be wirelessly charged.

[0213] Another object of the present invention is to provide a system as defined above, wherein said physiological effect is selected from the group consisting of vasodilation, increase in local nitric oxide, enhanced release of nitric oxide from vascular endothelium, prolonged local nitric oxide effect, altered function of red blood cells, modified oxygen release from hemoglobin, increased blood temperature, vasodilation, prolonged local nitric oxide effect, altered function of red blood cells, modified oxygen release from hemoglobin, modified blood pH, modulation of immune response of blood leukocytes, modulation of coagulation and / or blood globule function, modification of function of heme catalytic enzymes in blood, improved bioavailability of drugs, improved efficiency of arterial dilation of hemodialysis sessions, increased blood perfusion, and combinations thereof.

[0214] It is another object of the present invention to provide a system as described above, wherein the ultrasonic energy is provided at a frequency in the range of about 20 kHz to about 10 MHz.

[0215] Another object of the present invention is to provide a system as defined above, wherein the ultrasonic energy is provided by at least one selected from the group consisting of at least one piezoelectric transducer generating an ultrasonic system, at least one passive ferromagnetic element, at least one capacitive micromachined ultrasonic transducer, a CMUT, a concave transducer, a convex transducer, and any combination thereof.

[0216] Another object of the present invention is to provide a system as defined above, wherein said piezoelectric transducer is made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, and any combination thereof.

[0217] Another object of the invention is to provide a system as defined above, in which said piezoelectric transducer is shaded by a Gaussian distribution apodization.

[0218] Another object of the invention is to provide a system as defined above, in which said Gaussian distribution apodization is provided by the polarization of the material.

[0219] Another object of the invention is to provide a system as defined above, in which at least one of said controllers is adapted to charge at least one of said devices.

[0220] Another object of the present invention is to provide a system as defined above, wherein at least one of said controllers is adapted to charge at least one of said devices by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof.

[0221] Another object of the invention is to provide a system as defined above, in which at least one of said controllers comprises at least one coil.

[0222] Another object of the present invention is to provide a system as defined above, wherein said at least one sensor is adapted to sense at least one pulse wave characteristic reflected from at least one of said devices by at least one method selected from the group consisting of: (a) acoustic sensing; (b) echo; and any combination thereof.

[0223] Another object of the present invention is to provide a system as defined above, wherein at least one of said devices is adapted to sense heart rate from said at least one pulse wave characteristic.

[0224] Another object of the present invention is to provide a system as defined above, wherein analysis of said at least one pulse wave characteristic facilitates alignment of the position of at least one of said devices relative to said at least one vessel or tissue containing flowing blood.

[0225] Another object of the invention is to provide a system as defined above, in which said alignment is indicated either to the patient or to the patient's caregiver.

[0226] Another object of the present invention is to provide a system as defined above, wherein said alignment is indicated by at least one indication means selected from the group consisting of audio means, visual means, tactile means, and any combination thereof.

[0227] Another object of the invention is to provide a system as defined above, wherein analysis of said at least one pulse wave characteristic indicates said cause of said physiological effect.

[0228] Another object of the invention is to provide a system as defined above, in which the ultrasonic energy is provided by an array of piezoelectric transducers, each of which generates ultrasonic energy.

[0229] Another object of the invention is to provide a system as defined above, in which said array of piezoelectric transducers is a phased array.

[0230] Another object of the present invention is to provide a system as defined above, wherein activation of at least one of said transducers according to a predefined protocol fine-tunes the position of said implant relative to said at least one blood vessel and aligns said implant therewith.

[0231] Another object of the present invention is to provide a system as defined above, in which said ultrasonic energy can be provided continuously or, alternatively, in pulses.

[0232] Another object of the present invention is to provide a system as defined above, wherein at least one of said controllers is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) modifying at least one treatment parameter of a treatment protocol; (c) maintaining intact the treatment provided to said patient; and any combination thereof.

[0233] Another object of the present invention is to provide a system as defined above, wherein at least one of said controllers is wearable by said patient.

[0234] Another object of the present invention is to provide a system as defined above, wherein at least one of said controllers wearable by said patient is selected from the group consisting of: integrated into wearable socks, shoes, gloves, clothing, hats, and any combination thereof.

[0235] Another object of the invention is to provide a system as defined above, in which at least one of said controllers is integrated in the environment of said patient.

[0236] Another object of the present invention is to provide a system as defined above, wherein at least one of said controllers is in communication with at least one selected from the group consisting of a CPU, a smartphone, and any combination thereof.

[0237] Another object of the present invention is to provide a system as defined above that is adapted for the treatment of pulmonary artery denervation, pulmonary hypertension, ischemic tissue, PAD, CLI, pulmonary arterial hypertension, severe asthma patients, improving blood flow to the brain during stroke, increasing blood flow to the penis to maintain erection, enhancing drug bioavailability, enhancing local chemotherapy absorption in solid tumors by enhancing flow in certain arteries that feed the tumor, and any combination thereof.

[0238] Another object of the present invention is to provide a system as defined above, wherein said ischemic tissue is selected from the group consisting of upper and lower extremities, arms, legs, and any combination thereof.

[0239] Another object of the invention is to provide a system as defined above, adapted to provide said ultrasound energy so as to increase blood flow.

[0240] Another object of the invention is to provide a system as defined above, in which said ultrasonic energy is provided at least two substantially different frequencies of a carrier signal.

[0241] Another object of the present invention is to provide a system as defined above, wherein at least one of said devices comprises at least one piezoelectric transducer adapted to generate said ultrasonic energy at one of said at least two substantially different frequencies of a carrier signal.

[0242] Another object of the present invention is to provide a system as defined above, wherein at least one of said devices additionally comprises at least one electromagnetic acoustic transducer mechanically coupled to said at least one piezoelectric transducer adapted to generate said ultrasonic energy at one of said at least substantially different frequencies of a carrier signal.

[0243] Another object of the invention is to provide a system as defined above, in which said at least one electromagnetic acoustic transducer is at least one ferromagnetic sheet.

[0244] Another object of the invention is to provide a system as defined above, in which the frequency of one of the carrier signals is in the range from approximately 20 kHz to approximately 10 MHz.

[0245] Another object of the invention is to provide a system as defined above, in which the second frequency of the carrier signal is in the range of approximately 20 kHz to approximately 10 MHz.

[0246] Another object of the invention is to provide a system as defined above, in which at least one of the aforementioned devices is encapsulated in at least one layer of polyetheretherketone (PEEK).

[0247] Another object of the present invention is to provide a system as defined above, wherein at least one of said devices comprises at least one processor adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof, of said ultrasonic energy.

[0248] Another object of the invention is to provide a system as defined above, in which said at least one processor is in communication with said at least one sensor.

[0249] Another object of the present invention is to provide a system as defined above, wherein said at least one processor is adapted to collect data from said at least one sensor and perform at least one selected from the group consisting of: (a) monitoring said data; (b) modifying the therapy provided to said patient; (c) maintaining the therapy provided to said patient intact; and any combination thereof.

[0250] Another object of the present invention is to provide a system as defined above, wherein all of said plurality of implants are oriented in the same position relative to said at least one vessel or tissue containing flowing blood.

[0251] Another object of the present invention is to provide a system as defined above, wherein each of said plurality of implants is oriented in a substantially different position relative to said at least one blood vessel or tissue containing flowing blood relative to another one of said plurality of implants.

[0252] It is a further object of the present invention to provide a system as defined above, wherein said locations of said plurality of implants are adapted to enable focusing of said energy on said at least one vessel or tissue containing flowing blood.

[0253] Finally, it is an object of the present invention to provide a system as defined above, in which at least two of said plurality of implantable devices are in communication with each other.

[0254] Various other objects, aspects and advantages of the present disclosure can be obtained from a study of the specification, the drawings and the appended claims.

[0255] For simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity of presentation. Further, reference numerals may be repeated among the figures to indicate corresponding or similar elements. The figures are listed below. [Brief description of the drawings]

[0256] [Figure 1A] 1 illustrates an external view of the system in which an ultrasound transducer is located within the implant, the system including various sensors, such as a protective thermal sensor, making it possible to limit the temperature of the implant envelope below a given safe level. [Figure 1B]1 illustrates an external view of the system in which an ultrasound transducer is located within the implant, the system including various sensors, such as a protective thermal sensor, making it possible to limit the temperature of the implant envelope below a given safe level. [Diagram 2] 1 illustrates an external view of the system in which the ultrasound transducer is located on a pigtail cable exiting the implant case, positioned near the artery. [Diagram 3] Illustrating typical pulsed mode ultrasound energy coupled into tissue, ultrasound parameters such as peak negative pressure, carrier frequency, pulse duration, and pulse repetition frequency may be altered according to data collected from the sensors. [Figure 4] 1 illustrates a general implementation of an ultrasound implant of the system. [Diagram 5] Illustrates blood pulse wave sensing by an implant. A pulse wave induces an acoustic signal. When passing within an artery relative to the implant, the acoustic signal is detected by the implant. [Figure 6] 1 illustrates an exemplary implementation of an on-skin control unit. The on-skin unit may be in the form of a sleeve, a wearable device, etc. [Figure 7] Illustrates a possible transmission method for the implant using load key modulation. [Figure 8] Illustrates the measurement of the time delay between ECG and pulse wave signals. [Figure 9] 1 illustrates generally different embodiments of the present invention; [Figure 10] 1 illustrates generally different embodiments of the present invention; [Figure 11] 1 illustrates generally different embodiments of the present invention; [Figure 12] 1 illustrates an embodiment in which multi-layer acoustic matching is implemented. [Figure 13] Illustrates an embodiment in which a passive implant is provided. [Figure 14]Illustrates an embodiment in which NO induction is provided by utilizing an already implanted stent. [Figure 15] Illustrates an embodiment in which ultrasonic energy is provided at least two substantially different frequencies of a carrier signal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0257] The present invention, in some embodiments thereof, relates to a subcutaneously implantable device for delivering therapeutic energy to a patient. More specifically, the present invention relates to an implantable ultrasound device adapted to affect vascular endothelium to induce nitric oxide, NO, and ATP release. Thus, by applying ultrasound energy to blood vessels or tissues, stimulate cavitation and shear stress to promote angiogenesis in the patient. Furthermore, the present disclosure generally relates to the field of pulmonary artery denervation in the treatment of pulmonary hypertension and ischemic tissue.

[0258] Several cardiovascular diseases still lack effective treatments with significant improvement in prognosis. One of the most prominent is primary pulmonary hypertension, PH, a disease in which elevated vascular resistance in the lungs often leads to right heart failure and premature death. Treatment with endothelin receptor antagonists has raised hopes for clinicians and patients. The main pathophysiological mechanism of pulmonary hypertension is the lack of nitric oxide in the pulmonary vasculature. Therefore, the present invention discloses a number of implants adapted to apply either ultrasound or vibration energy to induce NO release for the treatment of pulmonary hypertension, PH.

[0259] Another prominent application of the induction of NO and ATP is ischemic tissue. Therefore, the present invention also relates to improving the release of NO and ATP in said ischemic tissue by applying ultrasound to the tissue under conditions effective to increase NO and ATP release to the ischemic tissue (e.g., treating an ischemic limb or tissue affected by peripheral arterial disease). Peripheral arterial disease is the most common form of atherosclerosis that affects many people around the world. As a result of such diseases, many people experience pain during physical activity (e.g., walking). Therefore, the present invention discloses a subcutaneous implantable device adapted to apply either ultrasound or vibration energy to induce NO and ATP release for the treatment of ischemic tissue.

[0260] One object of the present invention is to provide an ultrasonic subcutaneous implant that can locally dilate a target artery and increase downstream perfusion.Another object of the present invention is to provide a system comprising a plurality of implantable devices that are implanted near, adjacent to, or in at least one blood vessel or tissue that contains flowing blood, each of said plurality of implantable devices comprising means for applying at least one energy source (e.g., ultrasonic transducer) in said at least one blood vessel or tissue that contains flowing blood, whereby said energy source is adapted to cause a physiological effect in said at least one blood vessel or tissue when applied, and at least one of said implantable devices is positioned outside the patient, adapted to communicate with at least one remote controller (e.g., worn by the patient) and program and control said means for applying said at least one energy source.

[0261] Such wearable controllers may be integrated into wearable socks, shoes, gloves, clothing, hats, or may be integrated into the patient's environment (e.g., furniture such as chairs, sofas, beds, etc.) and any combination thereof.

[0262] Therefore, each of the implants can locally dilate the target artery and increase perfusion downstream. The mechanism of action involves acoustic energy being absorbed by endothelial cells and red blood cells resulting in the release of adenosine triphosphate (ATP) and nitric oxide (NO) into the bloodstream. NO dilates the artery and increases local blood flow and perfusion. In PAD / CLI patients suffering from claudication, the implants are placed several centimeters (e.g., 2-3 cm) upstream from the ischemic area to locally increase tissue perfusion with the goal of reducing hypoxic pain during walking, exercise, or rest. Note that the positioning of the implant can be initially calculated by the half-life and flow rate of NO in the specific blood vessel required so that customized positioning can be provided to ensure that the most effective vasodilatory effect is achieved for the desired distance.

[0263] According to one embodiment, at least one of the plurality of implantable devices is in communication with at least one battery either implanted in the patient or positioned externally.

[0264] According to one embodiment, the implant comprises or communicates with at least one sensor adapted to monitor at least one physiological condition of the patient. When a change is detected, the device applies said energy (thus inducing NO release) or is self-activated to inform the patient or any designated caregiver of said change, either of whom activates the device.

[0265] According to one embodiment, the sensor is selected from the group consisting of a sensor implanted in said patient, a sensor worn by said patient, a remote sensor outside the patient's body, and any combination thereof. For example, the sensor can also be external (e.g., wearable) that transmits to the implant, or it can be implanted elsewhere in the body. For example, a pacemaker that senses activity can also send a signal to the implant, so that both devices work in coordination and the heart rate increases while NO is being released. Another example can be other sensors used in cardiology (e.g., heart failure implantable sensors such as BSC HeartLogic and Abbot CardioMems).

[0266] According to another embodiment of the invention, the implant is in communication with at least one controller, said controller adapted to receive information associated with at least one physiological condition of the patient. According to another embodiment, the controller is in communication with at least one sensor, adapted to sense information associated with at least one physiological condition of the patient.

[0267] As used herein in reference to an amount or value, the term "about" means "within ±10% of."

[0268] The words "comprises," "comprising," "includes," "including," "has," "having," and their cognates mean "including but not limited to."

[0269] Throughout this application, embodiments of the invention may be presented with reference to a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual values ​​within that range.

[0270] As used herein, the term "method" refers to manners, means, techniques, and procedures for accomplishing a given task, including, but not limited to, manners, means, techniques, and procedures that are known or readily developed from known manners, means, techniques, and procedures by practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0271] The present invention discloses an implant device comprising at least one transducer (e.g., piezoelectric) that generates either ultrasonic or vibrational energy to mimic the application of shear forces to endothelial cells to induce the production and release of NO and ATP.

[0272] The implants may be implanted in proximity to ischemic tissue (ie, the upper and lower extremities, ie, the arms and legs).

[0273] Activation of the aforementioned implant device to provide vibration or ultrasonic energy may primarily affect the release of local NO from endothelial cells. In addition, such devices may induce ATP release. It is noted that it is within the scope of the present invention to provide a device constructed and arranged to cause any other physiological effect selected from the group consisting of blood temperature increase, vasodilation, prolonged local nitric oxide effect, altered red blood cell function, modified oxygen release from hemoglobin, modified blood pH, regulating immune response of blood white blood cells, regulating coagulation and / or blood globule function, modifying the function of heme-catalyzing enzymes in blood, improving drug bioavailability, improved efficiency of hemodialysis sessions, and combinations thereof.

[0274] According to another embodiment, the device is activated from outside the patient's body. Thus, according to this embodiment, a remote controller located outside the patient is adapted to communicate with the device and activate same, and can be used by the patient himself or a "healthcare" provider to program and control the energy source and therefore the treatment protocol (e.g., increase / decrease in intensity of energy, time, energy level, energy source, etc.) delivered to the patient.

[0275] According to one embodiment, an "on-demand" device / system is provided. Note that an "on-demand" device is activated only when needed (on an "on-demand" basis). According to this embodiment, the device is integrated / not in communication with at least one sensor that monitors the patient's physiological condition, such that changes to the device activate the device or modify the device's treatment protocol.

[0276] According to this embodiment, the sensors of the "on-demand" device may be selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasonic sensor, a hydrophone, a thermometer, manual activation, 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.

[0277] Each of the sensors is adapted to monitor the patient's physiological state and provide therapy accordingly. For example, the accelerometer is used to indicate the patient's position (e.g., when the patient is lying down, standing, walking, etc.). Upon sensing a change (e.g., when the patient starts walking), the device is activated. In other words, the device is activated "on demand" (when the patient engages in physical activity, e.g., walking) and induces the release of NO (thus increasing oxidation levels and increasing tissue perfusion in the tissue and reducing any associated pain).

[0278] It is therefore another object of the present invention to provide an implantable device as defined above, in which said sensors are selected such that an indication of the level of physical activity or a change therein can be deduced, for example from the initiation of walking, or a change in gait parameters such as speed, stride length, cadence, or a movement from a sitting or lying position to a standing position, or from walking to running.

[0279] It is within the scope of the present invention that the aforementioned sensors are selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasonic sensor, a hydrophone, a thermometer, manual activation, 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.

[0280] Another example is the integration of an impedance measuring sensor. According to this embodiment, vasodilation reduces the local impedance around the blood vessels due to the high fluid volume compared to solid tissue. Such an impedance sensor would therefore provide an indication on the NO / oxidation levels in the tissue or blood vessels, from which input can be obtained on the necessary activation of the device or any necessary modifications to the device's treatment protocol (increased US intensity, duration of treatment, etc.).

[0281] According to another embodiment, a subcutaneous implant or wearable device comprises an ultrasound transducer (and, optionally, at least one ultrasound receiver), a rechargeable battery, and an array of sensors to measure physiological parameters (e.g., patient activity or local tissue perfusion) and enable "on-demand" treatment. For example, the device can sense ambulation and apply treatment at the appropriate time to minimize pain. It is noted that local tissue perfusion and oxygenation levels can be measured by impedance, PPG, ultrasound echo, and any combination thereof.

[0282] As mentioned above, according to one embodiment of the invention the device is in communication with an external charging unit for wirelessly charging the implant, according to another embodiment the external unit allows for the downloading of data collected by the sensors.

[0283] The charging unit can be designed as a wearable unit on the patient. According to one embodiment, the charging unit is worn once per predetermined time (e.g., once per day). According to another embodiment, the charging unit is placed in a fixed location or integrated in the patient's natural environment (e.g., under a piece of furniture, e.g., a bed cover).

[0284] According to another embodiment of the invention, a data controller is provided (e.g., in the form of a cellular application) that allows both the clinician and the patient to control device activity. The controller connects data for monitoring and based thereon modifies / maintains its treatment protocol.

[0285] It should be noted that it is within the scope of the present invention to disclose a system comprising a plurality of such devices, at least partially in communication with one another, at least one of which comprises at least one piezoelectric transducer or passive ferromagnetic element that generates either ultrasonic or vibrational energy to mimic the application of shear forces to endothelial cells to induce NO production and release.

[0286] According to one embodiment, the piezoelectric transducer is made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, and any combination thereof.

[0287] The implant is implanted subcutaneously in proximity to the ischemic tissue (i.e., upper and lower extremities, i.e., arms and legs). Alternatively, a wearable device may be worn in proximity to the ischemic tissue.

[0288] Activation of the aforementioned implants to provide vibration or ultrasonic energy may primarily affect the release of local NO from endothelial cells. In addition, such implants may induce ATP release. It is noted that it is within the scope of the present invention to provide a device constructed and arranged to cause any other physiological effect selected from the group consisting of blood temperature increase, vasodilation, prolonged local nitric oxide effect, altered red blood cell function, modified oxygen release from hemoglobin, modified blood pH, regulating immune response of blood white blood cells, regulating coagulation and / or blood globule function, modifying the function of heme-catalyzing enzymes in blood, improving drug bioavailability, improved efficiency of hemodialysis sessions, and combinations thereof.

[0289] According to one embodiment of the present invention, the increased bioavailability of drugs may be utilized, for example, in chemotherapy. According to this embodiment, the device may be positioned near a solid tumor. Its activation during a systemic chemotherapy session will result in enhanced blood flow to the tumor as chemotherapy is delivered.

[0290] According to another embodiment, the device is activated from outside the patient's body. Thus, according to this embodiment, a remote controller comprising an electronic communication device external to the patient in communication with at least one of the implants is adapted to activate it and can be used by a "healthcare" provider to program and control (e.g., increase / decrease amount, time, energy level, energy source, etc.) the energy source and hence the treatment protocol delivered to the patient.

[0291] Reference is now made to FIG. 1A, which illustrates an external view of a system including an implant 101 and an on-skin unit 100 (implant and on-skin controller).

[0292] 1A, the implant 101 has a coil attached to its rear surface 113 and forms an inductive link 112 with an on-skin inductor 114. The inductive link can be used both for power transfer from the on-skin unit 108 to the implant 101 through the skin 102 and as a communication channel for data exchange and control between the on-skin unit 100 and the implant 101.

[0293] In some embodiments, the on-skin unit 100 may communicate with an external host via a wireless link 111, such as Bluetooth Low Energy, BLE, etc.

[0294] As can be seen, a blood pulse 105 flows through a blood vessel (e.g., an artery) 104. A stenosis 109 restricts flow downstream 110 of the blood vessel. To increase blood flow, the implant 101 generates ultrasonic energy 107 that is directed toward the blood vessel 104. The system can be programmed to emit ultrasonic energy automatically or on command from the patient. As a result, a blood vessel section 108 (which may be proximate to the stenosis section 109) is exposed to the ultrasonic energy 107.

[0295] It is within the scope of the present invention that the ultrasonic energy may be in the form of a continuous wave or a pulsed wave.

[0296] According to one embodiment, ultrasonic energy is emitted from the implant surface 106. Additionally, the surface 106 is also exposed to acoustic waves generated by, for example, pulse waves as they flow through the blood vessel 104.

[0297] According to one embodiment, a smartphone application 102 may be utilized to communicate with the on-skin unit 100. In some embodiments, the application may be executed on an external computer.

[0298] In some embodiments, the smartphone application 115 may communicate with the cloud-based program 103 for continuous monitoring and analysis.

[0299] Reference is now made to FIG. 1B, which illustrates substantially the same embodiment illustrated in FIG. 1a, with the addition of at least one transducer 116.

[0300] As mentioned above, according to one embodiment, the implant includes or communicates with at least one sensor. Said sensor is adapted to monitor at least one physiological condition of the patient. When a change is detected, the device applies said energy (thus inducing NO release) or is self-activated to notify the patient or any designated caregiver of said change, either of whom activates the device.

[0301] According to one embodiment, the sensor is selected from the group consisting of a sensor implanted in said patient, a sensor worn by said patient, a remote sensor outside the patient's body, and any combination thereof. For example, the sensor can also be external (e.g., wearable) that transmits to the implant, or it can be implanted elsewhere in the body. For example, a pacemaker that senses activity can also send a signal to the implant, so that both devices work in coordination and the heart rate increases while NO is being released. Another example can be other sensors used in cardiology (e.g., heart failure implantable sensors such as BSC HeartLogic and Abbot CardioMems).

[0302] According to another embodiment of the present invention, the implant is in communication with at least one on-skin controller, said controller adapted to receive information associated with at least one physiological condition of the patient. According to another embodiment, the controller is in communication with at least one sensor, adapted to sense information associated with at least one physiological condition of the patient. Furthermore, according to said physiological condition of the patient, the controller can modify the treatment protocol of the applied ultrasound energy.

[0303] According to one embodiment, an "on-demand" device / system is provided. Note that an "on-demand" device is activated only when needed (on an "on-demand" basis). According to this embodiment, the device is integrated / communicates with at least one sensor that monitors the patient's physiological condition, such that changes to the device activate the device or modify the device's treatment protocol.

[0304] According to this embodiment, the sensors of the "on-demand" device may be selected from the group consisting of an accelerometer, an impedance measurement, a photoplethysmography, a PPG sensor, a pH sensor, an ultrasonic sensor, a hydrophone, a thermometer, manual activation, 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.

[0305] Each of the sensors is adapted to monitor the patient's physiological state and provide therapy accordingly. For example, the accelerometer is used to indicate the patient's position (e.g., when the patient is lying down, standing, walking, etc.). Upon sensing a change (e.g., when the patient starts walking), the device is activated. In other words, the device is activated "on demand" (when the patient engages in physical activity, e.g., walking) and induces the release of NO (thus increasing oxidation levels and increasing tissue perfusion in the tissue and reducing any associated pain).

[0306] It is therefore another object of the present invention to provide an implantable device as defined above, in which said sensors are selected such that an indication of the level of physical activity or a change therein can be deduced, for example from the initiation of walking, or a change in gait parameters such as speed, stride length, cadence, or a movement from a sitting or lying position to a standing position, or from walking to running.

[0307] Reference is now made to Figure 2, which illustrates another embodiment of the present invention. According to this embodiment, the blood vessel 204 to be exposed to ultrasonic energy is located deep or in a position where there is no direct line of sight of the ultrasonic waves between the implant 200 and the vessel section 203 to be treated.

[0308] According to this embodiment, the ultrasonic transducer 202 may be located within a sealed pigtail cable 201 coupled to the implant 200 .

[0309] According to this embodiment, the implant 200 is controlled percutaneously by an on-skin unit 205 through an inductive link 206 (ie, at least one coil).

[0310] The on-skin unit may communicate with the smartphone 211 using a wireless link such as BLE 210.

[0311] In another embodiment, the aforementioned smartphone 211 may communicate with an externally hosted program, such as cloud-based software 212 .

[0312] According to this embodiment, the end of the pigtail is located near the blood vessel 204. Therefore, one or more blood vessel sections 203 are exposed to the ultrasound waves generated by the ultrasound transducer 202.

[0313] The ultrasonic transducer 202 may be a piezoelectric transducer, an electrostatic transducer, or any type of ultrasonic transducer capable of generating a peak negative pressure sufficient to induce a shear force on the vessel wall.

[0314] According to another embodiment, the ultrasonic transducer 202 may be used as a feedback sensor to allow monitoring of the ultrasonic energy generated by the ultrasonic transducer.

[0315] In another embodiment, the ultrasonic transducer 202 may be employed to sense the blood pulse wave 213 as it flows within the artery 204 proximate to the pigtail 201 .

[0316] In another embodiment, a dedicated acoustic sensor may be employed in the pigtail 201 for sensing.

[0317] In another embodiment, the aforementioned acoustic sensor may sense downstream 208 the pulse wave 213 flowing through the artery 204 . In another embodiment, a thermal sensor, such as a thermistor, may be employed in the pigtail 201 for sensing.

[0318] In another embodiment, two or more acoustic sensors may be employed within the pigtail 201 to sense the pulse wave velocity within the blood vessel 204.

[0319] Reference is now made to FIG. 3, which illustrates pulsed mode ultrasonic energy.

[0320] The pulse wave duration PW 300 may be as short as 10 cycles. The pulse repetition frequency 301 may be such that the duty cycle may be as low as 10%. The ultrasonic energy pulses may have a peak negative pressure 303 of up to 5 MPa.

[0321] In another embodiment, the ultrasonic carrier frequency may be between 10 kHz and 2 MHz.

[0322] In some embodiments, the ultrasonic carrier frequency 302 may be modulated.

[0323] In some embodiments, the pulse wave may be composed of two or more carrier frequencies to increase the shear forces exerted on the blood vessel.

[0324] In some embodiments, the ultrasound pulse amplitude may be amplitude modulated.

[0325] In some embodiments, the pool repetition rate, PRF, 301, and the length and amplitude 303 of the PW 300 may be adjusted according to the patient's requirements.

[0326] In some embodiments, the PRF 301, PW 300 length and amplitude 303 may be adjusted automatically without patient intervention.

[0327] Reference is now made to FIG. 4, which illustrates an overview of an implementation of an implant 400 .

[0328] According to this embodiment, the implant may have a non-metallic envelope, such as PEEK401.

[0329] In some embodiments, the PEEK may be coated with parylene.

[0330] The front surface 403, in which the ultrasonic transducer is mounted, may function as an acoustic matching layer if its width has a thickness, for example, about one-quarter of lambda, where lambda is the ultrasonic wavelength in PEEK.

[0331] The front surface 403 is oriented towards the blood vessel to be treated to allow the ultrasonic energy to impinge on the intended blood vessel. The emitting surface 403 is also used as a pressure wave receiving surface to sense pulsed wave acoustic signals or to detect ultrasonic reflections.

[0332] According to one embodiment, the back of the implant employs a coil 402 as part of an inductive link with the on-skin unit. Energy collected by the coil 402 may directly drive the ultrasound transducer 404. In such a case, rectification and filtering by the power collection unit 407 is primarily required for the auxiliary power source 409.

[0333] Alternatively or additionally, the AC electrical energy collected by the coil 402 can be converted to a direct current voltage DC by a power collection unit 407. The DC voltage is stored in a capacitive storage 406. The energy collected in the capacitive storage 406 is used to drive the internal ultrasonic driver 405. The DC voltage is also used by an auxiliary power supply 409 to power the implant circuitry.

[0334] According to one embodiment, an analog conditioning stage 412 may be used to amplify and filter the pulse wave signal. A T / R switch 411 may be employed to protect the analog circuitry from the higher voltages used to drive the ultrasound transducer 404. The T / R switch may be controlled by the microcontroller stage 408, for example by a GPIO 410. The microcontroller may sample the pulse wave analog signal and transmit it to the on-skin unit through an inductive channel.

[0335] The ultrasonic transducer 404 may be, but is not limited to, a PZT element, preferably a hard lead zirconate titanate PZT, to reduce internal power losses.

[0336] In some embodiments, the piezoelectric may have a non-uniform transverse polarization, such as a Gaussian polarization, to reduce side lobes of the ultrasonic energy.

[0337] In some embodiments, the ultrasonic transducer 404 may include an array of PZTs.

[0338] In some embodiments, the array of PZTs may be driven as a phased array.

[0339] According to one embodiment, the ultrasound includes two or more carrier frequencies that can create higher shear forces in the vessel wall. Thus, in some embodiments, the array of PZTs 404 can be driven by two or more carrier frequencies. For example, some of the array are driven by one carrier frequency and others are driven by a second carrier frequency.

[0340] In some embodiments, an embedded microcontroller 408 may be employed. The microcontroller may control the transmit / receive protection switch 411, collect sensor information, control the ultrasonic driver 405, and communicate with the on-skin unit via a communication block 415.

[0341] In some embodiments, an acceleration sensor 414 may be employed to sense patient movement.

[0342] In some embodiments, the thermal sensor 413 may be employed as a safeguard against overheating of the implant circuitry and its envelope.

[0343] The blood pulse wave contains valuable information about blood flow, such as blood flow velocity, pulse pressure level, augmentation index, etc. Therefore, it may be beneficial to sense it for long-term monitoring of blood flow in the treated vessel and downstream trees.

[0344] Reference is now made to FIG. 5, which illustrates another embodiment of the present invention showing a pulse wave sensing arrangement with an implant 500 .

[0345] A blood pulse wave 502 flowing within an intended blood vessel (eg, an artery) 503 radially expands 504 the walls of the vessel due to the vessel's elasticity.

[0346] The momentary expansion and retraction of the vessel wall generates acoustic waves 501 that also propagate through the tissue towards the acoustic receptive surface 509 of the implant. Therefore, the ultrasonic transducer 505 can also function as an acoustic sensor.

[0347] Alternatively, dedicated acoustic sensors such as piezoelectric lead zirconate titanate (PZT) or piezoelectric elements made from polyvinylidene fluoride or polyvinylidene difluoride (PVDF) membranes may be employed. A protection circuit in the form of a T / R switch 506 may be employed to protect the analog conditioning circuit 507 from high driving voltages. The amplified analog signal 508 may be sampled by the implant microcontroller and sent to the on-skin unit for further processing.

[0348] Reference is now made to Figure 6, which illustrates an external view of an on-skin controller 600 that may be positioned on the skin 601. According to this embodiment, the controller employs a coil 602 that forms an inductive power and communication link with the implant coil.

[0349] A coil driver 611 is employed to drive a desired current to the coil. The driver 611 is powered by a power stage 610 that may be employed to boost the voltage of the electrical energy source 609 to a desired level.

[0350] The energy source may be a non-rechargeable or rechargeable battery that may be charged through port 612.

[0351] The on-skin controller 600 may employ a microcontroller 604 to facilitate a communication channel with the implant through the induction coil 602 and may also incorporate a communication front-end 606 to communicate with external systems through a wireless link such as Bluetooth 607.

[0352] According to another embodiment, the aforementioned microcontroller 604 may protect the receive chain 605 by employing a transmit / receive electronic switch 603 .

[0353] According to another embodiment, the on-skin unit may also employ several sensors 608, such as an accelerometer to allow detection of patient movement, a thermal sensor such as a thermistor for temperature protection, and an electrocardiogram (ECG) sensor. The ECG sensor facilitates sensing of propagation delay variations of the pulse wave in the treated artery compared to the ECG pulse.

[0354] Various sensor outputs such as heart rate, pulse waveform, pulse wave velocity, core body temperature, and the delay between ECG and pulse wave signals in the treated artery may be analyzed locally by an on-skin controller to adjust ultrasound energy parameters or may be transmitted upwards for further processing and long-term data collection, for example by cloud-based software.

[0355] Reference is now made to Figure 7, which illustrates a possible mechanism for facilitating data extraction through an inductive link. Bitstream data 700 modulates an electronic switch 701, such as a silicon switch, to connect / disconnect an impedance 702 across an implant coil 703. The switched load impedance 702 elicits switched current pulses that can be sensed by the on-skin coil.

[0356] Reference is now made to FIG. 8, which illustrates a time delay 802 between an ECG signal 800 and a pulse wave signal 801.

[0357] The time delay 802 may vary depending on the variations in the treated vessel and downstream blood flow resistance. Typically, the time delay is measured between the R wave 803 of the ECG signal and the onset of the leading edge of the pulse wave signal 804.

[0358] Furthermore, according to another embodiment, from the pulse wave signal the pulse pressure 807 is measured, which is the difference between the systolic peak 805 and the end diastolic pressure. The systolic rise time 804 is another possible parameter that depends on the downstream resistance of the blood flow. The overall information that can be extracted from the pulse wave and the ECG can also be used for automatic adjustment of the ultrasound energy parameters generated by the implant or by the pigtail, as well as for long-term monitoring of the patient's blood flow quality in the artery and downstream.

[0359] Reference is now made to Figure 9, which illustrates an array 100 of two implants 10 in communication with one external device (in this case a coil) 20 located on the patient's skin 30. Upon activation of the transducers, mechanical vibrations 40 are induced in the blood vessels 50. Those skilled in the art will appreciate that although only two implants are illustrated in the figure, any number of implants may be utilized.

[0360] This embodiment facilitates the use of smaller implants by utilizing multiple implants.

[0361] Additionally, by providing multiple implants, the position and orientation of each of the implants may be controlled. Additionally, by controlling the position and orientation of each of the implants, the ability to focus on a desired vessel may be achieved.

[0362] According to another embodiment of the invention, there may be multiple implanted transducers, each operating in a different frequency range (e.g., a first range of 20 kHz to about 10 MHz and a second range of 20 kHz to about 10 MHz). According to another embodiment of the invention, all of the transducers operate in the same frequency range.

[0363] The controller (external unit), which may be an electrical oscillator, may generate a signal in the ultrasonic frequency spectrum, for example at frequencies as low as 20 kilohertz, or as high as 10 MHz.

[0364] According to another embodiment, the external controller is adapted to charge the implant. According to another embodiment, the charging is performed by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof.

[0365] According to one embodiment, the controller comprises at least one coil.

[0366] When a controller signal is provided to the transducer, the transducer emits acoustic energy from its surface, as is known to those skilled in the art.

[0367] The controller may control at least one selected from the group consisting of the amplitude and therefore the intensity or power of the acoustic waves transmitted by the transducer, the timing (start and duration), possibly the refractory period (i.e., not starting a new session before at least X minutes have passed since the last session), the directivity of the signal (one transmitter can stimulate multiple blood vessels located slightly away from each other, and a phased array can direct the stimulation to a different blood vessel each time), and any combination thereof. In other embodiments, if the transducer includes multiple transducer elements, the controller may also control the phase components of the drive signals to each transducer element of the transducer device, for example, to control the shape or size of the focal zone generated by the transducer elements and / or to move the focal zone to a desired location. For example, the controller may control the phase shift of the drive signal to adjust the focal length (i.e., the distance from the face of the transducer to the center of the focal zone). In further embodiments, the controller may be configured to operate the transducer for a predetermined period of time. Alternatively or additionally, the controller may be configured to automatically turn off the transducer when the use of the transducer exceeds the aforementioned predetermined time.

[0368] It should be noted that the controller may be external to the patient or integrated within the implant, thus when multiple implants are utilized and implanted, one implant (within which the controller is integrated) may control the remaining implants.

[0369] As disclosed above, according to one embodiment of the present invention, the controller may communicate with at least one sensor selected from the group consisting of an accelerometer, an impedance measurement, photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave properties, a glucose sensor, a manual activation, any sensor indicating a change in cardiac output, any sensor indicating a blood pressure, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof. In such an embodiment, the device is an "on-demand" device. In other words, an "on-demand" device is a device that is activated when needed. only ("on-demand basis") According to this embodiment, a sensor monitoring a patient's physiological condition causes the controller to signal the transducer to emit an acoustic signal (or to modify one of the parameters of the acoustic signal) in response to a change therein.

[0370] As specified, each of the sensors is adapted to monitor the patient's physiological state and provide therapy accordingly. For example, the accelerometer is used to indicate the patient's position (e.g., when the patient is lying down, standing, walking, etc.). Upon sensing a change (e.g., when the patient begins to walk), the device is activated. In other words, the device is activated "on demand" (when the patient engages in physical activity, e.g., walking) and induces the release of NO (thus increasing oxidation levels and increasing tissue perfusion in the tissue and reducing any associated pain).

[0371] According to one embodiment of the invention, the treated target tissue is tissue affected by peripheral arterial disease (and located within the upper or lower extremities of the patient). In other embodiments, the target tissue may be associated with other diseases or medical conditions (such as pain with movement) and may be located elsewhere in the patient.

[0372] Once the device is positioned at its predefined location, the transducer (per a signal from the controller) delivers ultrasonic energy to the target tissue. The transducer may emit acoustic energy continuously or, alternatively, in pulses. In some embodiments, the controller may also control the phase, operating frequency, tissue temperature (to prevent overheating of the same), and / or operating amplitude of the transducer.

[0373] According to another embodiment of the present invention, pulse wave characteristics and pulse wave velocity measurements can be measured to indicate arterial dilation and increased blood flow perfusion. Reference is now made to FIG. 10, which illustrates such acoustic sensing of pulse wave characteristics. As seen in the figure, incident and reflected waves (11 and 12, respectively) result in vibrations 60 through blood vessel 50 and can be sensed by either an external controller (or a microcontroller integrated within the implant). Analysis of said waves can provide indications of dilation and increased blood perfusion, as well as instructions for optimizing the orientation of the implant relative to the blood vessel. Thus, said analysis can facilitate alignment of the position of at least one of said plurality of implants relative to said at least one blood vessel or tissue containing flowing blood.

[0374] According to another embodiment, the alignment is indicated (to either the patient or the caregiver) by at least one indication means selected from the group consisting of audio means, visual means, tactile means, and any combination thereof.

[0375] According to another embodiment, the analysis of at least one of the aforementioned pulse wave characteristics indicates whether the desired physiological effect (vasodilation and increased blood perfusion) is in fact achieved.

[0376] According to another embodiment of the present invention, a second instantaneous wearable controller is utilized to facilitate pulse wave velocity flow measurement. Reference is now made to Figure 11 which illustrates such an embodiment.

[0377] According to this embodiment, the implant 10 is in communication with a main external unit (controller) 20. The main external unit 20 is wired connected via wires 70 (it may however be wirelessly connected) to at least one second wearable unit 80. Said second wearable unit 80 facilitates intermittent pulse wave flow sensing. According to one embodiment, the second wearable unit 80 may not be used continuously, but only occasionally.

[0378] Alternatively, the second wearable unit 80 can be used as a battery holder due to the thickness and weight of the main external unit (controller) 20.

[0379] According to one embodiment, an "on-demand" device is provided. It should be noted that an "on-demand" device is activated only when necessary (on an "on-demand" basis). According to this embodiment, the device is integrated with at least one sensor that monitors the physiological state of the patient, such that changes to the device activate the device or modify the device's treatment protocol.

[0380] According to this embodiment, the sensors of the "on-demand" device may be selected from the group consisting of an accelerometer, an impedance measurement, photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave profile, a glucose sensor, manual activation, 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.

[0381] Each of the sensors is adapted to monitor the patient's physiological state and provide therapy accordingly. For example, the accelerometer is used to indicate the patient's position (e.g., when the patient is lying down, standing, walking, etc.). Upon sensing a change (e.g., when the patient starts walking), the device is activated. In other words, the device is activated "on demand" (when the patient engages in physical activity, e.g., walking) and induces the release of NO (thus increasing oxidation levels and increasing tissue perfusion in the tissue and reducing any associated pain).

[0382] It is therefore another object of the present invention to select a sensor such that an indication of the level of physical activity or a change therein can be inferred, for example, from the initiation of walking or a change in a walking parameter such as speed, stride length, cadence, or a movement from a sitting or lying position to a standing position, or from walking to running.

[0383] It is within the scope of the present invention that the aforementioned sensors are selected from the group consisting of an accelerometer, an impedance measurement, photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave profile, a glucose sensor, manual activation, 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, any sensor indicating the start of a dialysis session, any sensor associated with a dialysis machine, and any combination thereof.

[0384] Another example is the integration of an impedance measuring sensor. According to this embodiment, vasodilation reduces the local impedance around the blood vessels due to the high fluid volume compared to solid tissue. Such an impedance sensor would therefore provide an indication on the NO / oxidation levels in the tissue or blood vessels, from which input can be obtained on the necessary activation of the device or any necessary modifications to the device's treatment protocol (increased US intensity, duration of treatment, etc.).

[0385] According to another embodiment of the present invention, the impulse utilizes multiple piezoelectric transducers. According to another embodiment, the multiple piezoelectric transducers are arranged in a phased array. Such an array allows fine adjustment of the position of the device relative to the treated vessel. According to this embodiment, each transducer is activated / deactivated to allow for relative alignment of the device position relative to the vessel to maximize NO induction.

[0386] According to another embodiment, at least one of the aforementioned piezoelectric transducers is shaded by Gaussian distribution apodization and material polarization.

[0387] According to another embodiment, the piezoelectric transducer is made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, and any combination thereof.

[0388] According to another embodiment, a multi-layer acoustic matching is implemented to reduce the overall implant thickness. According to this embodiment, the implant encapsulation is part of the acoustic matching layer. Reference is now made to FIG. 12, which illustrates such an embodiment.

[0389] According to this embodiment, the implant is encapsulated in an envelope made of a layer of acoustic impedance matching, in particular polyetheretherketone (PEEK) 15 .

[0390] As can be seen, a first acoustic impedance matching layer 16 is provided at the most distal and most proximal ends of the blood vessel. According to this embodiment, this first acoustic impedance matching layer 16 is sandwiched between at least two layers of adhesive (e.g., penloc GTI) 14, after which a transducer (e.g., piezoelectric element) 13 is positioned.

[0391] According to this embodiment, various piezoelectric materials may be employed selected from lead zirconate titanate, PZT such as PZT8, lead magnesium niobate-lead titanate, PMN-PT, composite materials, and any combination thereof.

[0392] According to another embodiment, at least one of the implants comprises an ultrasound transducer (and, optionally, at least one ultrasound receiver), a rechargeable battery, and an array of sensors for measuring physiological parameters (e.g., patient activity or local tissue perfusion).

[0393] Another embodiment enables "on-demand" therapy: for example, the device can sense walking and apply therapy at the right time to minimize pain.

[0394] It should be noted that local tissue perfusion and oxygenation levels can be measured by impedance, PPG, ultrasound echo, and any combination thereof.

[0395] As mentioned above, according to one embodiment of the present invention, the implant is in communication with an external charging unit for wirelessly charging the implant.

[0396] According to some embodiments, the charging unit can be designed as a wearable unit to be worn by the patient. According to one embodiment, the charging unit is worn once per predetermined time (e.g., once per day). According to another embodiment, the charging unit is placed in a fixed location or integrated in the patient's natural environment (e.g., under a piece of furniture, e.g., a bed cover).

[0397] According to some embodiments, the charging unit is performed by at least one method selected from the group consisting of electromagnetic, ultrasonic, capacitive, inductive, and any combination thereof. According to one embodiment, the charging unit (i.e., the external controller) comprises at least one coil.

[0398] According to another embodiment, the external controller acoustically senses at least one pulse wave characteristic reflected from at least one of the plurality of implants. It is within the scope of the present invention that analysis of said at least one pulse wave characteristic facilitates alignment of the position of at least one of the plurality of implants relative to the treated vessel or tissue containing the flowing blood. It should also be understood that it is within the scope of the present invention that analysis of said at least one pulse wave characteristic indicates whether a desired physiological effect (e.g., arterial dilation and increased blood perfusion) has been induced.

[0399] According to one embodiment, such alignment is indicated (to the caregiver user) by audio means, visual means, tactile means, and any combination thereof.

[0400] According to other embodiments, at least one of the implants comprises at least one processor (or controller). According to one embodiment, such processor is capable of acoustically sensing at least one pulse wave characteristic reflected from at least one of the plurality of implants. It is within the scope of the present invention that analysis of said at least one pulse wave characteristic facilitates alignment of the position of at least one of the plurality of implants relative to the treated vessel or tissue containing the flowing blood.

[0401] It should also be understood that within the scope of the present invention, analysis of at least one of the aforementioned pulse wave characteristics indicates whether a desired physiological effect (e.g., arterial dilation and increased blood perfusion) has been induced.

[0402] According to one embodiment, such alignment is indicated (to the caregiver user) by audio means, visual means, tactile means, and any combination thereof.

[0403] According to other embodiments, at least one of the implants comprises at least one processor adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, tissue temperature, timing, duration of the aforementioned energy sources, and any combination thereof, and according to such embodiments, the aforementioned implants are in communication with each other such that based on the parameters, the treatment protocol can be adjusted accordingly.

[0404] According to another embodiment, the processor is adapted to communicate with at least one sensor to sense information associated with at least one physiological condition of the patient, the sensor may be selected from the group consisting of a sensor implanted in said patient, a sensor worn by said patient, a remote sensor outside the patient's body, and any combination thereof.

[0405] According to another embodiment, the processor is adapted to collect data from the at least one sensor and perform at least one selected from the group consisting of: (a) monitoring the data; (b) modifying the therapy provided to the patient; and (c) maintaining the therapy provided to the patient unchanged; and any combination thereof.

[0406] According to another embodiment, the external unit, in addition to having the ability to charge the implant, allows for the downloading of data collected by the sensors, according to some embodiments of the invention, data downloading is possible by means known in the art, for example similar to RFID reading methods.

[0407] According to another embodiment of the invention, a data controller is provided (e.g., in the form of a cellular application) that allows both the clinician and the patient to control device activity. The controller connects data for monitoring and based thereon modifies / maintains its treatment protocol.

[0408] According to some embodiments, the ultrasound implant is positioned a few centimeters (e.g., 2-3 cm) from an intermittently or chronically ischemic or stenosed (reduced perfusion) region, or in an area where permanent or intermittent local enhancement of perfusion is desired. Initial target arteries can be the lilac artery and the superficial femoral artery (SFA). After positioning the implant, the treating physician sets the operating parameters, activates it, and verifies the increase in perfusion in the ischemic or stenosed (reduced perfusion) area.

[0409] If the patient proves to be unresponsive (e.g., calcification in the artery is too advanced to permit dilation), additional implants can be considered. Furthermore, the patient's physiological response to localized NO release can be tested using external ultrasound and verified if critical areas prove to be unresponsive (e.g., because arteries are too advanced in calcification to permit dilation).

[0410] It should be noted, therefore, that the patient's physiological response to local NO release is tested using external ultrasound to verify that the device is effective and to estimate the effective NO dosage (which is later used to set the device's operating parameters) and its response.

[0411] According to another embodiment of the present invention, the compliance of the tissue or endothelial response to US application is examined prior to using the device. According to this embodiment, a secondary system (e.g., Doppler ultrasound, ultrasound, MRI, CT) is utilized. According to this embodiment, a Doppler ultrasound device can be utilized to measure the degree of perfusion, which provides a qualitative measurement of the increase in blood flow resulting from the ultrasound therapy provided by the device.

[0412] According to another embodiment of the invention, before implantation, the compliance of the tissue or endothelium response to US application is examined. According to this embodiment, a secondary system (e.g. Doppler ultrasound, ultrasound, MRI, CT) is utilized. According to one embodiment, the secondary system is Doppler ultrasound, ultrasound, MRI, CT, etc. According to this embodiment, Doppler ultrasound is applied to the required location (where the implant is supposed to be implanted), and then at least one parameter selected from the group consisting of increased blood flow (by analyzing the reflected sound waves from red blood cells), NO level, oxygen level, tissue perfusion, verification of the optimal position of the aforementioned device, and any combination thereof is monitored and verified whether there has been an improvement. Indeed, if one of the parameters, e.g. blood flow, is improved, it will indicate that the patient responds to the effect of the device and is therefore suitable for such use. Hence, a method of fitting the patient to such a treatment is provided. Alternatively, the use of such a method may result in verification of the optimal position of the implant as well as optimization of the treatment parameters and protocols to achieve the best treatment.

[0413] Therefore, according to this embodiment, at least one parameter of the device selected from the group consisting of the intensity or power of the applied US energy, its duration, its frequency, and any combination thereof is varied (other parameters are kept constant) and their effect on the treated tissue or vessel is studied via a secondary system (Doppler ultrasound, ultrasound, MRI, CT). In this way, a customized and optimized treatment protocol for the patient can be established.

[0414] According to one embodiment, the implant according to the invention comprises at least one transducer. According to another embodiment, the transducer is either a piezoelectric transducer for generating ultrasonic energy, at least one passive ferromagnetic element, or any combination thereof.

[0415] According to other embodiments, the transducer may be provided on a platform capable of supporting it. The platform may be substantially rigid, semi-rigid, or substantially flexible and may be made from a variety of materials such as plastics, polymers, metals, and alloys. Electrodes and leads may also be provided in known manner for coupling the transducer to a control unit.

[0416] According to an embodiment of the present invention, the transducer includes one or more transducer elements. Each of the transducer elements may be a monolithic piezoelectric ceramic component or alternatively may be composed of a mosaic arrangement (e.g., a phased array) of multiple small piezoelectric ceramic elements. The piezoelectric ceramic components or elements may have various geometric shapes, such as hexagons, triangles, squares, and the like. The material used to construct the transducer elements may be composites, piezoelectric ceramics, or any other material capable of converting electrical signals into acoustic waves. The transducer elements are coupled to a controller to generate and / or control the acoustic energy emitted by the transducer elements.

[0417] According to another embodiment, the piezoelectric material is made from at least one material selected from the group consisting of lead zirconate titanate, lead magnesium niobate-lead titanate, hard PZT, composites, and any combination thereof.

[0418] According to another embodiment of the present invention, a passive implant is provided that includes an electromagnetic acoustic transducer, EMAT, for inducing ultrasonic vibrations. Reference is now made to Figure 13, which illustrates such an embodiment.

[0419] As can be seen, the implant 10 is made of EMAT (a ferromagnetic material) for inducing ultrasonic vibrations 19 in a blood vessel 50 .

[0420] An external control 20 (illustrated as a coil in the figure) generates an alternating electromagnetic flux 21 that induces mechanical vibration from the EMAT to the blood vessel 50 .

[0421] According to another embodiment of the present invention, NO induction is provided by utilizing an already implanted stent. Reference is now made to FIG. 14 which illustrates such an embodiment. As seen in the figure, a ferromagnetic stent 10 previously implanted in the patient is utilized to induce ultrasonic vibrations. As previously mentioned, an external unit (external controller (shown as a coil in the figure) 20 generates an alternating magnetic flux which induces a current in the ferromagnetic surface of the stent 10. This in turn produces mechanical vibrations on the blood vessel 50.

[0422] As indicated above, the controller may control at least one selected from the group consisting of the amplitude and therefore the intensity or power of the acoustic waves transmitted by the transducer, the timing (start and duration), possibly the refractory period (i.e., not starting a new session before at least X minutes have passed since the last session), the directivity of the signal (one transmitter can stimulate multiple blood vessels located slightly away from each other, and a phased array can direct the stimulation to a different blood vessel each time), and any combination thereof. In other embodiments, if the transducer includes multiple transducer elements, the controller may also control the phase components of the drive signals to each transducer element of the transducer device, for example, to control the shape or size of the focal zone generated by the transducer elements and / or to move the focal zone to a desired location. For example, the controller may control the phase shift of the drive signal to adjust the focal length (i.e., the distance from the face of the transducer to the center of the focal zone). In further embodiments, the controller may be configured to operate the transducer for a predetermined period of time. Alternatively or additionally, the controller may be configured to automatically turn off the transducer when the use of the transducer exceeds the aforementioned predetermined time.

[0423] It should be noted that the controller may be external to the patient or integrated within the implant, thus when multiple implants are utilized and implanted, one implant (within which the controller is integrated) may control the remaining implants.

[0424] As disclosed above, according to one embodiment of the present invention, the controller may communicate with at least one sensor selected from the group consisting of an accelerometer, an impedance measurement, photoplethysmography, a PPG sensor, a pH sensor, an ultrasound sensor, a hydrophone, a thermometer, a core body temperature, a heart rate, a pulse wave properties, a glucose sensor, a manual activation, 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. In such an embodiment, the implant device is an "on-demand" device. In other words, an "on-demand" device is capable of communicating with at least one sensor selected from the group consisting of an accelerometer, an impedance measurement, a ... pulse wave properties, a glucose sensor, a manual activation, 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. In such an embodiment, the implant device is an "on-demand" device. In other words, an "on-demand" device is capable of communicating with at least one sensor selected from the group consisting of an accelerometer, an impedance measurement, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties, a pulse wave properties only ("on-demand basis") According to this embodiment, a sensor monitoring a patient's physiological condition causes the controller to signal the transducer to emit an acoustic signal (or to modify one of the parameters of the acoustic signal) in response to a change therein.

[0425] As specified, each of the sensors is adapted to monitor the patient's physiological state and provide therapy accordingly. For example, the accelerometer is used to indicate the patient's position (e.g., when the patient is lying down, standing, walking, etc.). Upon sensing a change (e.g., when the patient begins to walk), the device is activated. In other words, the device is activated "on demand" (when the patient engages in physical activity, e.g., walking) and induces the release of NO (thus increasing oxidation levels and increasing tissue perfusion in the tissue and reducing any associated pain).

[0426] According to one embodiment of the invention, the treated target tissue is tissue affected by peripheral arterial disease (and located within the upper or lower extremities of the patient). In other embodiments, the target tissue may be associated with other diseases or medical conditions (such as pain with movement) and may be located elsewhere in the patient.

[0427] Once the device is positioned at its predefined location, the transducer (per a signal from the controller) delivers ultrasonic energy to the target tissue. The transducer may emit acoustic energy continuously or, alternatively, in pulses. In some embodiments, the controller may also control the phase, operating frequency, tissue temperature (to prevent overheating of the same), and / or operating amplitude of the transducer.

[0428] As mentioned above, the acoustic energy delivered by the transducer is at least partially absorbed by the tissue, causing mechanical stimulation of endothelial cells by compression and wall shear stress in the blood vessel, which stimulates the production of endothelial nitric oxide synthesis (eNO). Elevated levels of nitric oxide are believed to have many effects on tissues, including inhibition of leukocyte and platelet adhesion, control of vascular tone, and maintenance of a thrombophilic interface between the blood flow and the vessel wall, increasing capillary perimeter (vasodilation), and / or increasing blood flow (perfusion), and thus treat pulmonary HP. Such effects, in turn, help relieve pain in the tissue and allow the patient to rehabilitate through exercise.

[0429] According to another embodiment of the present invention, a secondary system is utilized. According to this embodiment, the secondary system is at least one selected from Doppler ultrasound, ultrasound, MRI, CT, and any combination thereof. According to this embodiment, Doppler ultrasound is applied to the required location, and then at least one parameter selected from the group consisting of blood flow (by analyzing the reflected sound waves from red blood cells), NO level, oxygen level, tissue perfusion, verification of the optimal position of the aforementioned device, and any combination thereof is monitored and verified whether there has been an improvement. Indeed, if one of the parameters, for example blood flow, is improved, it will indicate that the patient is responding to the effect of the device and therefore is suitable for such use. Therefore, a method of fitting a patient to such a treatment is provided.

[0430] According to another embodiment of the present invention, a secondary system (e.g., Doppler ultrasound, ultrasound, MRI, CT) is utilized for an optimized treatment protocol. According to this embodiment, Doppler ultrasound (or ultrasound, MRI, CT) is applied at the required location, and then at least one parameter selected from the group consisting of blood flow (by analyzing the reflected sound waves from red blood cells), NO levels, oxygen levels, tissue perfusion, verification of the optimal position of the aforementioned device, and any combination thereof, is monitored to establish the optimized treatment parameters. Therefore, according to this embodiment, at least one parameter of the implant device selected from the group consisting of the intensity or power of the applied US energy, timing, the temperature of the treated tissue (to ensure that it is not overheated), its duration, its frequency, and any combination thereof is changed (while other parameters are kept constant) and their effect on the treated tissue or vessel is examined via a secondary system (Doppler ultrasound or ultrasound, MRI, CT). In this way, a customized and optimized treatment protocol for the patient can be established.

[0431] It should be noted that according to this embodiment, during a treatment session, the energy intensity or dosage delivered by the transducer at the tissue is maintained below a predetermined threshold (e.g., by using an appropriate driving scheme and / or by selecting appropriate operating parameters such as operating frequency, operating amplitude, etc.), thereby protecting the tissue from being damaged by the acoustic energy.

[0432] As mentioned above, in any of the embodiments described herein, the implant can further include one or more additional ultrasound transducers. The transducers can be positioned in a parallel configuration to form a line. For example, in some embodiments, the system includes several transducers, each of which operates with a different delivered acoustic wave. It is noted that providing multiple transducers allows multiple target areas to be treated simultaneously or at different treatment protocols (e.g., each transducer operates with a different power, intensity, timing, duration, etc.).

[0433] In some cases, the controller can be configured to control the transducers so that the acoustic waves emitted by each transducer interact in a desired manner. For example, in some embodiments, the relative phase between the transducers can be changed. In one implementation, adjacent transducers are alternately driven in phase and out of phase. Because the acoustic fields from adjacent transducers may overlap and resonance occurs, the intensity distribution within the patient's body may form a series of interference maxima and minima. By changing the phase relationship between the transducers, the location of these pecks and nulls may be reversed, thereby providing an overall uniform (or substantially uniform) irradiation of the target tissue or vessel. In other embodiments, the operating frequency of one or more transducers may be changed to shift the interference pattern of the acoustic field.

[0434] In other embodiments, the transducers can be moved relative to the patient, in which case the position of at least one of the transducers can be optimized relative to the desired treated tissue or vessel.

[0435] In another embodiment, at least one of the implants is adapted to apply ultrasonic energy at at least two substantially different frequencies of a carrier signal. Reference is now made to FIG. 15 illustrating such an embodiment. In such an embodiment, the implant 10 comprises at least one piezoelectric transducer 23 adapted to generate said ultrasonic energy at one of said two substantially different frequencies of a carrier signal, and at least one electromagnetic acoustic transducer EMAT, 24 mechanically coupled to said at least one piezoelectric transducer 24 adapted to generate said ultrasonic energy in a second different frequency range. As described above, mechanical vibrations (acoustic waves) 19 are induced on the blood vessel 50 in response to activation of the external controller 20.

[0436] In one embodiment, the first range is selected from about 20 kHz to about 10 MHz, and the second range is selected from about 20 kHz to about 10 MHz.

[0437] In another embodiment, the at least one electromagnetic acoustic transducer is at least one ferromagnetic sheet.

[0438] In other embodiments, the implant is encapsulated in at least one layer of polyetheretherketone (PEEK) 22 .

[0439] According to another embodiment of the invention, multiple implants are utilized; one of them is very thin, comprises at least one coil and is positioned close to the skin, while at least one second implant comprises a transducer (piezoelectric element) positioned close to the blood vessel. Both implants are wired to each other. According to another embodiment, the thin implant (comprising at least one coil and positioned close to the skin) is wired to multiple implants, each of which is positioned at a different position and orientation relative to the blood vessel. Such an embodiment provides multiple treatment points along the blood vessel (leading to a wide range of effects) and may analyze the pulse wave characteristics to optimize the treatment parameters and the positioning (e.g., alignment) of at least one of the implants relative to the blood vessel, as described above. It is noted that the implant device can be used for the following treatments: Improved patient healing after CLI / PAD-revascularization procedures. In such applications, the implant is activated either permanently or intermittently after the revascularization procedure. · Improved wound healing in PAD patients, including preventing leg amputations. ·Local and chronic treatment of pulmonary arterial hypertension. Treatment of severe asthma patients (those for whom standard asthma inhalation does not work) by acting on the bronchial arteries. It should be noted that in such applications, any parameter associated with breathing or phonation that can provide an indication of an asthma attack can trigger activation of the implant device to relieve bronchospasm. Improving blood flow to the brain during stroke by generating NO in the carotid arteries (using an external ultrasound device). · "Topical Viagra" - Increases blood flow to the penis to maintain an erection without the systemic side effects of sildenafil (Viagra tablets). Improved drug bioavailability - in this application, the time of drug administration (oral, intravenous, or pump activation) can be synchronized with the activation of the ultrasound implant to enhance the local absorption of the drug in the target organ, note that the location of the implant is in the vicinity of the artery that supplies said target organ. For example, the flow of chemotherapy to a solid tumor can be enhanced during a chemotherapy session.

[0440] While certain embodiments have been illustrated and described herein, those skilled in the art will appreciate that a wide variety of alternative or equivalent embodiments or implementations calculated to accomplish the same or similar purpose may be substituted for the embodiments illustrated and described herein without departing from the scope of the invention. Those skilled in the art will readily appreciate that embodiments in accordance with the present invention may be implemented in a wide variety of ways. This application is intended to cover any and all adaptations and / or variations of the embodiments discussed herein.

[0441] It is recognized that the terms and expressions employed in the foregoing specification are used therein as terms of description and not of limitation, and that in the use of such terms and expressions there is no intention of excluding equivalents of the features shown and / or described or portions thereof, and that the scope of the invention is defined and limited only by the claims which follow.

[0442] In light of the above teachings of the present disclosure, it will be apparent to those skilled in the art that numerous modifications and variations of the described examples and embodiments are possible. 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 such modifications and alternative embodiments as may fall within the true scope of the present invention given its full breadth. Additionally, the disclosure of a range of values ​​is a disclosure of all numerical values ​​within that range.

Claims

1. 1. A device adapted to be implanted adjacent to at least one blood vessel or tissue containing flowing blood, said device comprising: at least one ultrasound transducer configured to provide ultrasound energy to the at least one blood vessel or tissue containing flowing blood, whereby the ultrasound energy is adapted to cause a physiological effect in the at least one blood vessel or tissue when applied; the device is positioned external to the patient and in communication with at least one on-skin remote controller adapted to control the ultrasound energy; and The device is in communication with at least one sensor adapted to monitor at least one physiological condition of the patient.

2. The device of claim 1 , wherein the device is self-activating upon a change in the at least one physiological condition.

3. The device of claim 1 , wherein at least one of the ultrasonic transducers is an array of ultrasonic transducers.

4. The device of claim 3 , wherein the array of ultrasonic transducers facilitates alignment of the ultrasonic energy with the at least one blood vessel or tissue containing flowing blood.

5. 10. The device of claim 1, wherein the at least one on-skin remote controller is adapted to collect data from the at least one sensor and perform at least one selected from the group consisting of: (a) monitoring the data; (b) adjusting the treatment provided to the patient; and (c) maintaining the treatment provided to the patient; and any combination thereof.

6. The device of claim 5 , wherein the data is the shape of a pulse wave signal.

7. The device of claim 5 , wherein the data is the time delay between the ECG signal and the pulse wave signal.

8. The device of claim 6 , wherein the ultrasound energy is synchronized to the pulse wave signal.

9. 2. The device of claim 1, wherein the physiological condition or change therein is selected from the group consisting of the patient's position, engagement in physical activity, a decrease in NO levels in the at least one blood vessel or tissue, tissue perfusion, initiation of physical activity, a change in at least one parameter associated with the physical activity, the patient's position relative to the ground, a change in the patient's position relative to the ground, application of at least one medical treatment to the patient, a change in application of at least one medical treatment to the patient, and any combination thereof.

10. 10. The device of claim 1, wherein the physiological effect is selected from the group consisting of vasodilation, an increase in local ATP, enhanced ATP release, an increase in local nitric oxide, enhanced nitric oxide release from vascular endothelium, prolonged local nitric oxide effects, enhanced nitric oxide release from red blood cells, altered erythrocyte function, modified oxygen release from hemoglobin, increased blood temperature, modified blood pH, modulation of the immune response of blood leukocytes, modulation of coagulation and / or blood microglobule function, modification of the function of heme-catalyzing enzymes in the blood, improved drug bioavailability, improved efficiency of hemodialysis sessions, arterial dilation, increased blood perfusion, and combinations thereof.

11. 10. The device of claim 1, wherein the at least one on-skin remote controller is adapted to control at least one parameter selected from the group consisting of phase, operating frequency, power, intensity, operating amplitude, timing, duration, and any combination thereof of the ultrasound energy.

12. 10. The device of claim 1, wherein upon a change in the at least one physiological condition of the patient, the device is activated and ultrasound energy is delivered to the at least one vessel or tissue to provide on-demand therapy; (b) at least one treatment parameter of the ultrasound energy for the at least one vessel or tissue is modified to provide therapy as needed; (c) the change is notified; and (d) any combination thereof is performed.

13. 10. The device of claim 1, wherein the sensor is selected from the group consisting of a sensor implanted in the patient, a sensor integrated within the device, a sensor worn by the patient, a remote sensor outside the patient's body, a sensor integrated within the at least one on-skin remote controller, and any combination thereof.

14. 14. The device of any one of claims 1 to 13, wherein the at least one ultrasound transducer functions as an acoustic sensor and is adapted to sense at least one acoustic wave generated by the at least one blood vessel or tissue containing flowing blood.

15. A system comprising: a device adapted to be implanted adjacent to at least one blood vessel or tissue containing flowing blood, the device comprising at least one ultrasound transducer configured to emit ultrasound energy toward the at least one blood vessel or tissue, whereby the ultrasound energy, when applied, is adapted to cause a physiological effect in the at least one blood vessel or tissue; an on-skin remote controller positioned external to the patient and configured to control the ultrasound energy; the device is configured to be in communication with the at least one on-skin remote controller; the device comprises or is configured to communicate with at least one sensor adapted to monitor a physiological condition of the patient; system.

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