Non-invasive central venous pressure monitoring device

Abstract

The present invention relates to methods and systems for non-invasive monitoring of central venous pressure using a set of microneedles and microelectromechanical systems, such as for heart failure. Herein, a microneedle-based sensor is attached to the skin at the neck of the subject to monitor central venous pressure because the central venous pressure is a direct indicator reflecting the filling pressure resulting in subsurface strain of the skin.

Description

Technical Field

[0001] This invention relates to methods and systems for non-invasive monitoring of central venous pressure. Background Technology

[0002] Heart failure (HF) is a common clinical syndrome with adverse effects on both individuals and society. The prevalence of heart failure in adults in the United States is 2.2%, affecting nearly 6.2 million people and imposing a heavy annual financial burden. Related economic expenditures were estimated at $30.7 billion in 2012, and this figure is projected to more than double by 2030. Due to medical and social advancements, the prevalence of heart failure is expected to continue to rise. Recent advances in heart failure medications and device-based therapies have brought significant progress to the field; however, even with optimal medical care, one in four patients still faces persistent severe symptoms, hospitalization, and even death. Therefore, employing diverse approaches to manage heart failure is crucial.

[0003] Heart failure is characterized by its progressive development and recurrent acute exacerbations, leading to high hospitalization and readmission rates, which constitute a significant part of the disease burden. Due to its high morbidity and financial incentives, reducing hospitalization and readmission rates for acute decompensated heart failure (ADH) has become a top priority for healthcare systems. The pathophysiological process of ADH begins days or even weeks before the onset of obvious signs and symptoms. Given our understanding of the timeline of ADH progression, it is hypothesized that intervention to achieve normal blood volume before the appearance of obvious clinical manifestations can prevent disease progression.

[0004] Elevated filling pressure in both the left and right ventricles is a key trigger for acute heart failure decompensation. Therefore, real-time monitoring and tracking of elevated cardiovascular pressure can provide early warning of impending decompensation and the risk of hospitalization for heart failure, and guide treatment, thereby improving the quality of life and prolonging survival for patients with heart failure.

[0005] Central venous pressure (CVP) is the traditional site for assessing intracardiac pressure in the right heart (which also reflects the left heart). Right atrial pressure measurement (RAP), also known as central venous pressure (CVP), is typically performed via invasive surgery, which carries serious complications such as damage to blood vessels, the heart, or the lungs. Furthermore, specialized surgical procedures, tools, and intensive care environments are required. Clearly, dynamic and home-based measurement is impractical. The jugular vein (internal jugular vein) is an acceptable alternative for CVP measurement; dilation of the jugular vein usually presupposes elevated pressure. Nevertheless, there is currently no objective, let alone dynamic, method for measuring this pressure.

[0006] Therefore, there is a need for non-invasive methods and systems for monitoring central venous pressure. Summary of the Invention

[0007] The present invention relates to methods and systems for non-invasive monitoring of central venous pressure.

[0008] Some embodiments relate to a device for substantially non-invasive monitoring of a subject's vascular pressure (e.g., central vascular pressure, more specifically, central venous pressure), which can include: a microneedle structure comprising a first surface, a second surface opposite the first surface, and a plurality of microneedles attached to or as an integral part of the first surface, wherein the plurality of microneedles are configured to pierce a skin surface at a target region located above and / or in the vicinity of the subject's vascular pressure (e.g., central vascular pressure, more specifically, central venous pressure); and at least one force sensor associated with or incorporated within the microneedle structure, wherein the at least one sensor is configured to provide a signal indicative of the central venous pressure.

[0009] Provided herein is a system for substantially non-invasive monitoring of a subject's central venous pressure according to some embodiments, which comprises:

[0010] a microneedle structure comprising a first surface and a second surface opposite the first surface, wherein the microneedle structure further comprises: a plurality of microneedles attached to or integrated within the first surface of the microneedle structure, and wherein the plurality of microneedles are configured to pierce a skin surface at a region above and / or in the vicinity of the subject's central vein; at least one sensor associated with or incorporated within the microneedles and / or the microneedle structure, wherein the at least one sensor is configured to provide a pressure-indicative signal; and

[0011] a patient data acquisition and processing system configured to receive data from the at least one sensor and apply a trained algorithm (e.g., an artificial intelligence (e.g., machine learning) based algorithm) to the received pressure signal and provide a value indicative of the subject's central venous pressure.

[0012] According to some embodiments, the patient data acquisition and processing system is directly or remotely (e.g., cloud-based) connected to the at least one sensor.

[0013] As used herein, the term "substantially non-invasive" can refer to not involving a procedure in which a depth of penetration of a device (e.g., a needle) beyond the skin, according to some embodiments.

[0014] According to some embodiments, the device can include a flexible pad configured to conform the microneedle structure to a contour of the subject's target region. According to some embodiments, the flexible pad can be adhered to the second surface of the microneedle structure and / or positioned in the proximal side of the second surface of the microneedle structure.

[0015] According to some embodiments, the device can include an adhesive layer. According to some embodiments, the adhesive layer can be a double-sided tape layer positioned between the second surface of the microneedle structure and the first surface of the flexible pad. According to some embodiments, the adhesive layer can extend over the second surface of the flexible pad and beyond the second surface and can be configured to attach the device to the skin of the subject.

[0016] According to some embodiments, the device can include a rigid substrate positioned at the base of the device. According to some embodiments, the rigid substrate can be configured to generate a counter pressure to the venous pressure and to increase the sensitivity of the sensor.

[0017] According to some embodiments, the device can be associated with a patient data acquisition processing system configured to receive data from the at least one sensor. According to some embodiments, the patient data acquisition processing system can be directly or remotely connected to the at least one sensor. According to some embodiments, the patient data acquisition processing system can include a processor.

[0018] According to some embodiments, the at least one force sensor can be a force sensor, a pressure sensor, or a strain gauge. Optionally, the sensor can be a force resistive sensor. According to some embodiments, the at least one sensor can be configured to detect: a strain under the skin surface, a skin fluctuation due to a change in the diameter of a blood vessel caused by a change in internal pressure, a skin stretch, or a combination thereof.

[0019] According to some embodiments, the at least one force sensor can be a polymer-based sensor, in particular an electroactive flexible polymer. According to some embodiments, such polymers are tailored as needed to enhance performance. Examples of such polymers can include poly(3,4-ethylenedioxythiophene) (PEDOT), polypyrrole (PPy), polyaniline (PANI), polythiophene (PTh), poly(3-hexylthiophene) (P3HT), or any combination thereof. Each possibility constitutes a separate embodiment.

[0020] According to some embodiments, the polymer can include a copolymer, such as poly(3,4-ethylenedioxythiophene):p-toluenesulfonate (PEDOT:TOS), PEDOT-co-polyurethane (PEDOT-co-PU), PEDOT-co-poly(lactic acid) (PEDOT-co-PLA), polyaniline-co-pyrrole (PANI-co-PPy), PEDOT-co-polycaprolactone (PEDOT-co-PCL), PEDOT-co-polyethylene glycol (PEDOT-co-PEG), or any combination thereof. Each possibility constitutes a separate embodiment.

[0021] According to some embodiments, the device can include a housing configured to house the microneedle structure and the at least one sensor. According to some embodiments, the housing can include a flexible pad, a rigid substrate, a connector to connect with a patient data acquisition processing system, or any combination thereof.

[0022] According to some embodiments, the density of microneedles on the first surface of the microneedle structure is between about 5 microneedles / cm2to about 150 microneedles / cm2(e.g., about 5 to 20, about 10 to 50, about 20 to 80). According to some embodiments, at least one member of the microneedle, the microneedle structure, and the at least one sensor is 3D printed. According to some embodiments, the at least one force sensor can be integrated within the microneedle to provide a combined microneedle-mechanical sensor.

[0023] According to some embodiments, the central vessel can include a central vein, such as (left and / or right jugular vein), femoral vein, superior vena cava, inferior vena cava, or other monitoring site. According to some embodiments, the device can be used to monitor a patient for a condition characterized by a change in central venous pressure. According to some embodiments, the condition characterized by a change in central venous pressure is selected from the group consisting of right heart failure, heart failure, pulmonary embolism, pulmonary hypertension, cardiac tamponade, pericardial tamponade, hemodynamic shock, and valvular lesion. Each possibility constitutes a separate embodiment.

[0024] According to some embodiments, the at least one force sensor can be a pressure sensor, a strain gauge sensor, a piezoelectric sensor, a tactile sensor, or any other suitable sensor. Each possibility constitutes a separate embodiment.

[0025] According to some embodiments, provided herein is a method of substantially non-invasive monitoring of central venous pressure of a subject, the method comprising: placing a central venous pressure monitoring device onto a skin surface of the subject at a region above and / or adjacent to a central vein of the subject, wherein the device comprises: a microneedle structure comprising: a first surface, a second surface opposite to the first surface, and a plurality of microneedles attached to the first surface of the microneedle structure or as an integral part of the first surface of the microneedle structure; and at least one force sensor associated with or incorporated within the microneedle and / or the microneedle structure; piercing the skin surface with the microneedle; measuring skin deformation with the at least one sensor; obtaining a signal related to the skin deformation using a data acquisition processing system; applying a trained algorithm to the received signal using the data acquisition processing system; and providing a value indicative of the central venous pressure of the subject based on the obtained signal and the trained algorithm.

[0026] Without being bound by any theory, according to some embodiments, the skin deformation can be due to a change in venous pressure, which is caused by a change in vessel diameter and strain in the adjacent skin.

[0027] According to some embodiments, the signal can be transmitted to a patient data acquisition processing system. According to some embodiments, the transmission to the patient data acquisition processing system can be by way of a direct or indirect connection with the at least one sensor.

[0028] According to some embodiments, the method can provide a pressure profile of the subject. According to some embodiments, the pressure profile can be provided to a medical professional for real-time monitoring and / or periodic assessment.

[0029] According to some embodiments, the system can alert a user, caregiver, or medical professional when the central venous pressure monitoring device detects a predefined change in one or more measured and / or calculated parameters. According to some embodiments, the change in one or more measured and / or calculated parameters is above and / or below a predefined threshold for the parameter. According to some embodiments, the device can be placed by self-application (e.g., by taping) or by application by a caregiver or medical professional.

[0030] According to some embodiments, the monitoring can be configured for one-time monitoring, short-term monitoring, or long-term monitoring. According to some embodiments, the monitoring can monitor any one fluctuation in venous pressure as well as specific pressure waveforms from the central blood vessels that reflect intracardiac pressure. According to some embodiments, the non-invasive monitoring can detect arterial pressure waves, monitor blood pressure, and / or integrate arterial and venous data.

[0031] According to some embodiments, the method can further comprise predicting central venous pressure based on the measured sub-surface skin deformation and a trained algorithmic model (e.g., an artificial intelligence-based machine learning algorithmic model).

[0032] According to some embodiments, the method can further comprise predicting central venous pressure based on the measured sub-surface skin deformation and a time series regression algorithmic model.

[0033] It is noted that while particular mention can be made of monitoring of central venous pressure, the scope of the present disclosure encompasses devices, systems, or methods for monitoring any type of blood vessel (e.g., arteries, veins, central arteries, and central veins).

[0034] Certain embodiments of the present disclosure can include some, all or none of the advantages described above. One or more of the technical advantages can be readily apparent to one skilled in the art from the figures, descriptions and claims included herein. Moreover, while one or more advantages are identified above, various embodiments can include all, some or none of the advantages.

[0035] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent from the following detailed description, claims, and drawings. BRIEF DESCRIPTION OF DRAWINGS

[0036] Exemplary embodiments are described below with reference to the accompanying drawings. In the drawings, like reference numerals indicate like structure, elements or components in the various figures. Alternatively, elements or components in the figures can be marked with a different reference numeral in different figures where they appear. The sizes of the components and features shown in the figures are chosen for convenience and clarity of presentation and are not necessarily to scale. The figures are listed as follows:

[0037] Figure 1A and Figure 1B A preferred target area for pressure sensing using a central venous pressure monitoring device is schematically illustrated in accordance with some embodiments;

[0038] Figure 2 A side view of a central venous pressure monitoring device is schematically illustrated in accordance with some embodiments;

[0039] Figure 3A and Figure 3B A side view, perspective view and cutaway view of a central venous pressure monitoring device are schematically illustrated in accordance with some embodiments, respectively;

[0040] Figure 4 is a schematic illustration of a central venous pressure monitoring device in accordance with some embodiments;

[0041] Figure 5A and Figure 5B is a schematic illustration of a cross-sectional view of a central venous pressure monitoring device in accordance with some embodiments;

[0042] Figure 5C is a schematic illustration of an isometric partial view of a central venous pressure monitoring device in accordance with some embodiments;

[0043] Figure 6 is a schematic illustration of an isometric partial view of a central venous pressure monitoring device in accordance with some embodiments;

[0044] Figure 7is an exemplary block diagram of a central venous pressure monitoring device according to some embodiments;

[0045] Figure 8 is an exemplary block diagram of a central venous pressure monitoring system according to some embodiments;

[0046] Figure 9A and Figure 9B is an exemplary photograph of an artificial jugular vein model according to some embodiments;

[0047] Figure 10 is a top view schematically showing a vein model with different test positions of a monitor according to some embodiments;

[0048] Figure 11 is a pressure distribution of a central test position of a model flow system using a central venous pressure monitoring device according to some embodiments;

[0049] Figure 12 is a pressure distribution of a posterior test position of a model flow system using a central venous pressure monitoring device according to some embodiments;

[0050] Figure 13 is a pressure distribution of a right test position of a model flow system using a central venous pressure monitoring device according to some embodiments;

[0051] Figure 14 is a pressure distribution of a left anterior lateral test position of a model flow system using a central venous pressure monitoring device according to some embodiments;

[0052] Figure 15A shows the construction of a time series regression model for predicting central venous pressure according to some embodiments;

[0053] Figure 15B shows a comparison between real venous pressure readings and algorithmic predictions derived from sensor readings using a simulator of an integrated carotid and jugular vein vessel model; and

[0054] Figure 16 is a flowchart of a method for monitoring a central venous pressure monitoring device according to some embodiments. DETAILED DESCRIPTION

[0055] In the following description, various aspects of the present disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the present disclosure. However, it will also be apparent to one skilled in the art that the present disclosure can be practiced without specific details given herein. Furthermore, to avoid obscuring the present disclosure, well-known features can be omitted or simplified.

[0056] Some embodiments relate to methods and systems for non-invasive monitoring of central venous pressure. According to some embodiments, the system can include a non-invasive cardiac filling pressure measurement device. According to some embodiments, the device can be used to monitor conditions characterized by changes in central venous pressure (CVP), including: heart failure, pulmonary embolism, pericardial tamponade, hemodynamic shock, right heart failure, and valvular pathology or disease. Furthermore, central venous pressure monitoring can aid in the management of these conditions.

[0057] According to some embodiments, a device for monitoring central venous pressure can include one or more microneedles and a microelectromechanical system including one or more sensors, such as a force sensor. According to some embodiments, the device can aid in non-invasive direct monitoring of central venous pressure (e.g., at the jugular vein). Advantageously, the device can aid in more sensitive and convenient monitoring of central venous pressure. Furthermore, advantageously, the microneedles can be substantially minimally invasive, as the microneedles create micron-sized holes in the skin, thereby circumventing areas of the deep dermis with higher density of nerves. Thus, the microneedles can be used for transdermal sensing and can be used as long-term wearable health monitoring devices. Further advantageously, the device can facilitate application, such as for self-application, application by a simply trained caregiver (e.g., family member, etc.), application by medical personnel, etc. Additionally and / or alternatively, such a medical device can also include additional functionality to enable seamless transfer of data between patient and physician, such as with modern technology such as a smartphone, etc.

[0058] According to some embodiments, the device can be small, with an active sensor surface of about 0.5 cm to 7 cm in diameter and about 0.3 cm to about 2 cm in height, surrounded by a medical grade bandage, adhesive pad, surgical tape, etc.

[0059] According to some embodiments, the height of the microneedle can be between about 50 pm and about 2,500 pm, between about 100 pm and about 2,000 pm, between about 150 pm and about 1,500 pm, or between about 200 pm and about 1,000 pm. Each possibility represents a separate embodiment.

[0060] According to some embodiments, the base width of the microneedle can be between about 15 pm and about 750 pm, between about 25 pm and about 500 pm, between about 50 pm and about 250 pm, or between about 75 pm and about 200 pm. Each possibility represents a separate embodiment.

[0061] According to some embodiments, the base diameter of the microneedle can be between about 50 pm to about 300 pm, between about 50 pm to about 100 pm, between about 50 pm to about 200 pm, or between about 100 pm to about 300 pm. Each possibility constitutes a separate embodiment.

[0062] According to some embodiments, the density of microneedles on the microneedle structure can be between about 1 microneedle / cm2to about 10 microneedles / cm2, between about 10 microneedles / cm2to about 50 microneedles / cm2, between about 50 microneedles / cm2to about 100 microneedles / cm2, between about 50 microneedles / cm2to about 150 microneedles / cm2, between about 100 microneedles / cm2to about 250 microneedles / cm2, or between about 250 microneedles / cm2to 500 microneedles / cm2. Each possibility constitutes a separate embodiment.

[0063] According to some embodiments, the microneedles can be fabricated using a variety of different methods, such as 3D printing techniques, photolithography techniques, droplet-born air blowing (DAB), micro-molding, solvent casting, one-step or two-step casting in a negative mold, hot-melt, etc., and / or combinations thereof. Each possibility constitutes a separate embodiment.

[0064] According to some embodiments, the microneedles can be hollow. According to some embodiments, the microneedles can be at least partially composed of hollow metal needles. According to some embodiments, the microneedles can be fabricated using common fabrication techniques, such as photochemical etching, electroplating, laser cutting, micro-computer numerical control (CNC) cutting, etc.

[0065] According to some embodiments, the microneedles can be at least partially composed of one or more biocompatible polymers. According to some embodiments, the biocompatible polymers can be electrically conductive. According to some embodiments, the electrically conductive polymers can have electromechanical sensing properties. According to some embodiments, the biocompatible polymers can be synthetic polymers, such as polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polystyrene, etc., or natural polymers, such as cross-linked chitosan, alginate, hyaluronic acid, etc., and / or any combination thereof. Each possibility constitutes a separate embodiment.

[0066] According to some embodiments, the microneedles can be composed of one or more polymers whose electrical resistance changes with mechanical strain, and / or can be modified by cutting the base of the microneedle. According to some embodiments, if the microneedles are composed of a polymer, the polymer is a biocompatible polymer.

[0067] According to some embodiments, the microneedles and / or their support structure can be advantageously adapted for use on curved skin and / or can react to skin curvature in a uniaxial, planar or 3D manner.

[0068] According to some embodiments, the microneedles themselves can be used as high resolution 2D or 3D mechanical sensors. According to some embodiments, the microneedles can be incorporated into a flexible matrix material to provide a flexible microneedle array. According to some embodiments, the flexible microneedles can be integrated with one or more strain sensing elements whose resistance or capacitance changes when subjected to bending, stretching, compressive forces and / or combinations thereof.

[0069] According to some embodiments, the microneedles can be configured to provide one or more therapeutic agents. According to some embodiments, the microneedles can be configured for injection of one or more therapeutic agents. According to some embodiments, the microneedles can be configured for controlled release of one or more therapeutic agents. According to some embodiments, the microneedles can implement a complete closed loop system in which one or more therapeutic agents can be released upon detection of a signal.

[0070] According to some embodiments, one or more of the mechanical and / or support members of the monitoring device can be designed and / or printed using a 3D printer, cast into a negative mold, fabricated using micro-lithography, laser machining processes, extrusion molding, injection molding and / or combinations thereof and / or the like. Each possibility constitutes a separate embodiment.

[0071] According to some embodiments, the microneedles can be attached at a first surface of the microneedle structure. According to some embodiments, the microneedle structure can include and / or be associated with one or more additional members. According to some embodiments, the members can be arranged in any order.

[0072] According to some embodiments, a second surface of the microneedle structure can include and / or be associated with an adhesive layer. Optionally, the adhesive layer can include an adhesive, such as a polyurethane adhesive, an acrylic resin, a silicone resin and / or the like. Optionally, the adhesive can be hypoallergenic. Optionally, the adhesive layer can be a double-sided adhesive layer. Optionally, a first surface of the adhesive layer can be associated with the skin of the subject.

[0073] According to some embodiments, the adhesive layer can be the outermost layer (the layer furthest from the skin) associated with the device, such as a patch, which can be placed on top of the device. According to some embodiments, the adhesive layer can extend over and beyond the second surface of the flexible pad. According to some embodiments, the adhesive layer can be configured to attach the device to the skin of the subject.

[0074] According to some embodiments, the device can include an adhesive associated with the second surface of the microneedle structure and an outer adhesive layer. According to some embodiments, the adhesive layer can be configured to prevent and / or reduce infection. According to some embodiments, the adhesive layer can be configured to improve and / or maintain adhesion of the device to the skin of the user. According to some embodiments, the adhesive layer can be configured to reduce and / or prevent movement of the device after application to the skin of the subject. Optionally, a flexible pad can be associated with the second surface of the adhesive layer, e.g., extending over and beyond the second surface and configured to attach the device to the skin of the subject.

[0075] According to some embodiments, the adhesive layer can be a patch. Optionally, the patch and / or a portion of the patch can be water resistant and / or waterproof. Optionally, the patch and / or a portion of the patch can be hypoallergenic. Optionally, the patch and / or a portion of the patch can include a polyurethane adhesive, an acrylic resin, a silicone resin, etc. Optionally, the patch can be configured to provide a measurable counter response to stretching and / or straining of the skin.

[0076] According to some embodiments, the second surface of the microneedle structure can be associated with a flexible pad (e.g., silicone, etc.). According to some embodiments, the flexible pad can include a plasticizer, e.g., a polyol (e.g., glycerol, polyethylene glycol) or an organic ester (e.g., diethyl phthalate (DEP) and triethyl citrate (TEC)), etc. According to some embodiments, the flexible pad can be configured to conform to the contours of the skin of the user. According to some embodiments, the first surface of the flexible pad can be associated with the adhesive layer and / or the microneedle support. According to some embodiments, the second surface of the flexible pad can be associated with the rigid base and / or one or more sensors (e.g., force sensors).

[0077] According to some embodiments, the device can include a rigid base. Optionally, the rigid base can be made by 3D printing or cast into a negative mold. According to some embodiments, the rigid base can serve as a counter support on the side away from the force sensors, e.g., as a base of the device.

[0078] According to some embodiments, the rigid base can be configured to create a counter pressure to venous pressure. According to some embodiments, the rigid base can be configured to boost sensitivity of the sensors.

[0079] According to some embodiments, the device can include a housing. Optionally, the housing can be 3D printed. Optionally, the housing can be water resistant and / or waterproof. Optionally, the housing can include one or more mechanical and / or electronic components, e.g., a processor, a Wi-Fi connector, a Bluetooth connector, a cable, a sensor, a printed circuit board (PCB), a flexible printed circuit board, an optical component, etc., and / or any combination thereof. Each possibility constitutes a separate embodiment.

[0080] According to some embodiments, the device can be associated with and / or can include one or more sensors. According to some embodiments, the sensor can be a pressure sensor, a force sensor, a strain gauge, a flexible sensor, a bend sensor, an optical sensor, and / or the like, and / or combinations thereof. Each possibility represents a separate embodiment. According to some embodiments, the sensor can be a force sensitive resistor (FSR). According to some embodiments, the sensor can be configured to have sufficient sensitivity to measure changes in venous pressure. According to some embodiments, the sensor can be configured to measure small changes in strain under the skin surface.

[0081] According to some embodiments, the sensor can be integrated with the plurality of microneedles to provide a combined microneedle-mechanical sensor.

[0082] According to some embodiments, the monitoring device can be attached to the skin at the neck of the subject. According to some embodiments, the monitoring device can be configured to measure the central venous pressure of the jugular vein, as the central venous pressure of the jugular vein is a direct indicator of the filling pressure. Optionally, the monitoring device can measure the strain under the skin surface. According to some embodiments, the microneedles can pierce the stratum corneum to better detect the deformation under the skin surface due to changes in the jugular vein pressure.

[0083] According to some embodiments, the pressure change profile can be processed by and / or transmitted to a patient data acquisition processing system. According to some embodiments, the monitoring device can be connected to the patient data acquisition processing system directly (e.g., by a cable, and / or the like) and / or indirectly (e.g., wirelessly, such as by Wi-Fi, Bluetooth, and / or the like). According to some embodiments, the patient data acquisition processing system can be a processor within the monitoring device. According to some embodiments, the patient data acquisition system can include a remote processor.

[0084] According to some embodiments, the patient data acquisition processing system can provide the acquired data to a visualization device, such as a screen, a printer, and / or the like, visually and / or electronically. Optionally, the patient data acquisition processing system can provide the acquired data to an on-site visualization device. Optionally, the patient data acquisition processing system can provide the acquired data to an off-site medical professional for real-time monitoring and / or periodic evaluation (e.g., every hour, twice a day, every day, every week, every two weeks, every month, and / or the like). Optionally, the patient data acquisition processing system can save the acquired data, such as in a memory storage device, in the cloud, and / or the like. Optionally, the memory storage device can be incorporated within the housing of the device. Optionally, the memory storage device can be remotely connected to the device.

[0085] According to some embodiments, the patient data acquisition and processing system can alert the user, caregiver, and / or medical professional when the monitoring device detects a predefined change in one or more measured and / or calculated parameters (e.g., central venous pressure (CVP) profile, blood pressure changes, CVP waveform morphology changes, etc.). For example, an elevated CVP can indicate that a heart failure patient is volume overloaded, requiring an increased dose of diuretics. Conversely, a decreased CVP pressure can indicate that the blood volume is insufficient, possibly requiring a decreased dose of diuretics. In addition, CVP monitoring can aid in the diagnosis of the diseases described above, follow-up of patients with the diseases described above, assist in risk stratification, and / or adjust treatment regimens. Alternatively, the patient data acquisition and processing system can alert the user, caregiver, and / or medical professional when one or more measured and / or calculated parameters are above and / or below a pre-set threshold. Alternatively, the medical professional can also pre-define one or more parameters and / or thresholds based on the user's medical history and / or condition.

[0086] According to some embodiments, the monitoring device can be applied by the user, by the caregiver, and / or by the medical professional. According to some embodiments, the monitoring device can be applied for immediate monitoring, short-term monitoring (e.g., hours, days, etc.), and / or long-term monitoring (e.g., days, weeks, etc.).

[0087] Advantageously, the monitoring device can be easily applied and / or removed without the need for special procedures, specialized tools, and / or intensive care environments. According to some embodiments, the monitoring device can allow for clinical, ambulatory, and / or home care applications. According to some embodiments, the monitoring device can allow for dynamic use.

[0088] According to some embodiments, the monitoring device can be attached to the skin at the jugular venous region, preferably aligned with the internal jugular vein. According to some embodiments, the monitoring device can monitor the fluctuations induced by the pressure wave amplitude and / or the height at which the pressure wave is perceptible in the neck skin and / or specific pressure waveforms generated by the jugular vein that reflect the intracardiac pressure. Alternatively, the signal monitoring can provide real-time indications of absolute pressure values and / or relative readings over a defined time period. According to some embodiments, the monitoring device can be able to detect specific pressure waveforms (a, x, v, y) that reflect the venous pressure profile of the right atrial pressure and / or central venous pressure throughout the cardiac cycle. Alternatively, the monitoring device can provide additional information about the clinical status of various cardiac conditions (e.g., severity of mitral regurgitation indicated by the V wave, right ventricular failure and pressure, follow-up of patients with pulmonary embolism, etc.).

[0089] According to some embodiments, the monitoring device can detect arterial pressure waves, monitor blood pressure, and / or integrate arterial and venous data. According to some embodiments, this can facilitate relative or absolute measurement of arterial blood pressure. According to some embodiments, this can facilitate analysis of arterial pressure waves, providing clinical insights related to and / or complementary to venous readings. According to some embodiments, monitoring venous pressure can enable monitoring of other clinical conditions, such as volume status, cardiac tamponade, pulmonary embolism, right heart failure, pulmonary hypertension, valvular pathology, and / or disease, among others.

[0090] According to some embodiments, the device can be provided as part of a kit. Optionally, the kit can include: the monitoring device, instructions for use, and / or a patient data acquisition processing system and / or access to a patient data acquisition processing system (e.g., cable, password, etc.) and / or one or more spare parts (e.g., additional patch, etc.). Optionally, the instructions for use can include information regarding use, positioning, and / or activation of the monitoring device, and / or connection to a patient data acquisition processing system.

[0091] Reference is now made to Figure 1A and Figure 1B which schematically illustrate preferred target regions for pressure sensing using a central venous pressure monitoring device, according to some embodiments. The target locations 106, 108 of the monitoring device can be on the right internal jugular vein of the user's neck 104 skin, below the head 102 and above the collarbone 110. Additionally and / or alternatively, the left jugular vein and / or other vascular sites can also be monitored, as clinically indicated.

[0092] According to some embodiments, the monitoring device can measure sub-skin surface strain, skin fluctuations due to changes in internal pressure, and / or skin stretch (pulse / heartbeat) and / or the inverse response of the adhesive patch and the height of the detected changes in the patient's skin at the neck where the signal is detected. According to some embodiments, the microneedles can pierce the stratum corneum to better detect sub-skin surface deformations due to changes in jugular vein pressure.

[0093] According to some embodiments, the device can be used to monitor conditions characterized by central venous pressure changes, including heart failure, pulmonary embolism, cardiac tamponade, hemodynamic shock, right heart failure, valvular pathology, and / or disease.

[0094] Reference is now made to Figure 2FIG. 1 schematically illustrates a side view of a central venous pressure monitoring device 100, according to some embodiments. As shown herein, the monitoring device 100 includes a microneedle structure 112 including a plurality of microneedles 116 attached to or integrally formed with a first surface of the microneedle structure. The microneedles 116 are configured to penetrate a target region 114 of a subject's skin, for example, in order to better detect sub-skin surface deformations due to pressure changes. The monitoring device 100 further includes a force sensor 104 associated with a second surface of the microneedle structure (opposite the first surface). The force sensor can be in contact with the microneedles, and / or can be placed within the microneedles themselves, and / or embedded into a base of the microneedles.

[0095] According to some embodiments, the monitoring device 100 further includes a patch 102 configured to adhere the monitoring device 100 to the target region 114 of the subject's skin. Thus, the monitoring device 100 is configured to monitor the fluctuations 108 and / or skin stretch (pulsations) 110 and / or the inverse response 106 of the patch and / or the height in the skin at the neck where the signal is detected.

[0096] Reference is now made to Figures 3A-3B FIG. 2 schematically illustrates a perspective view and a cross-sectional view, respectively, of a central venous pressure monitoring device 200, according to some embodiments. The monitoring device 200 includes a microneedle structure 212 for a plurality of microneedles 216. The microneedle structure 212 includes a first surface to which the plurality of microneedles 216 are attached or integrally formed, and a second surface that is optionally attached to an adhesive layer 214. Optionally, the adhesive layer 214 can include a polyurethane adhesive. The adhesive layer can be a double-sided tape - where a first surface can adhere to the subject's skin, and a second surface that can adhere to a first surface of a flexible pad 210. Optionally, the flexible pad 210 can include a silicone material. A second surface of the flexible pad 210 is associated with a force sensor 208 and / or a rigid substrate 206. Optionally, all or part of the components described herein can be incorporated into a housing 202. Optionally, the rigid substrate 206 and / or the housing 202 can be at least partially composed of a 3D printed material. Optionally, the microneedles 216 can be at least partially composed of PCL, PLGA, and / or combinations thereof. The force sensor 208 is connected to a patient data acquisition processing system by a cable and / or wirelessly.

[0097] According to some embodiments, the sensor can be a force sensor, a pressure sensor, or a strain gauge, or any combination thereof. Optionally, the sensor can be off-the-shelf or specifically designed for the monitor. According to some embodiments, the sensor can be integrated within a backing layer of the microneedles, for example, to enhance sensitivity. According to some embodiments, the sensor can be attached from the outside of the device.

[0098] According to some embodiments, the sensor may be made of a conductive, stretch-sensitive material, such as graphene (and / or other carbon-based materials), silver, silicon, and any combination thereof. According to some embodiments, the sensor may be manufactured using inkjet printing, screen printing, photolithography, other methods, or any combination thereof. Additionally and / or alternatively, the sensor may also include optical fibers and / or conductive polymers.

[0099] According to some embodiments, sensor components can be integrated into the microneedle structure that pierces the skin, thereby facilitating the monitoring of strain changes at higher resolution. According to some embodiments, multilayer and / or multi-component sensors can provide high spatial resolution readings, especially when integrated with microneedles.

[0100] Now for reference Figure 4 This is a schematic diagram of a central venous pressure monitoring device 400 according to some embodiments. The monitoring device 400 includes a sensor 410 (e.g., but not limited to a polymer sensor) integrating multiple microneedles 412 to provide a combined microneedle-mechanical sensor. The combined microneedles 404 include a sensor membrane 402, a resistor / capacitor 406, one or more strain elements 408, and one or more nanoparticles embedded in the microneedles, which change their electrical properties (e.g., resistance, capacitance, etc.) under deformation due to pressure changes. Detecting this deformation and performing appropriate calibration can help to accurately determine changes in pressure distribution.

[0101] Figure 5A and Figure 5B This is a schematic cross-sectional view of a central venous pressure monitoring device 500 according to some embodiments. Figure 5C This is a schematic isometric partial view of a central venous pressure monitoring device 500 according to some embodiments. The monitoring device 500 includes a plurality of microneedles 506 supported on a microneedle structure 508, the microneedle structure including one or more sensors 510, a housing 512, and optional cables 502. Optionally, the cables 502 may be connected to one or more sensors 510 via one or more resistors / capacitors 514. Optionally, the microneedle structure 508 is associated with a flexible pad 516 and / or a rigid substrate 504.

[0102] Now for reference Figure 6 This is a schematic isometric partial view of a central venous pressure monitoring device 600 according to some embodiments. The monitoring device 600 includes a backing layer 602 composed of protrusions 604 that isolate mechanical effects associated with strain, compression, or movement of one or more microneedles 606.

[0103] Now for reference Figure 7which is an exemplary block diagram of a central venous pressure monitoring device according to some embodiments. According to some embodiments, monitoring device 700 can optionally include a housing 702, a microneedle structure 706, wherein microneedles 704 are on a first surface and a force sensor 708 is associated with a second surface. The device can optionally include a rigid substrate 712, a flexible pad 710, and an adhesive layer 714. Optionally, the adhesive layer can be adjacent to the first surface and / or the second surface of the microneedle structure.

[0104] Reference is now made to Figure 8 which is an exemplary block diagram of a central venous pressure monitoring system according to some embodiments. According to some embodiments, system 800 can include a monitoring device and a patient data acquisition processing system 816. Monitoring device 802 can optionally include a housing. Monitoring device 802 can include a microneedle structure 806, wherein microneedles 804 are on a first surface and a force sensor 808 is associated with a second surface. The device can optionally include a rigid substrate 812, a flexible pad 810, and an adhesive layer 814. Optionally, the adhesive layer can be adjacent to the first surface and / or the second surface of the microneedle structure. Force sensor 808 can transmit data directly, indirectly, or both directly and indirectly to patient data acquisition processing system 816. Optionally, patient data acquisition processing system 816 can receive data via a cable or wirelessly (e.g., short-range wireless communication, such as Bluetooth®, Wi-Fi, local area network, etc.).

[0105] Examples

[0106] 1. Proof of concept model

[0107] An artificial jugular vein model was designed and manufactured from materials that mimic as closely as possible the mechanical properties of human anatomy and venous blood flow. The artificial jugular vein model includes: casted silicone, a pulsatile pump, a dedicated tube, and a gel.

[0108] According to some embodiments, the artificial neck model can be an artificial carotid- jugular model that mimics as closely as possible the mechanical properties of human anatomy and arterial and venous blood flow.

[0109] Reference is now made to Figure 9A and Figure 9B which is an exemplary photograph of an artificial jugular vein model 900 according to some embodiments. According to some embodiments, artificial jugular vein model 900 includes a housing 904, one or more tubes 908, and a gel 906, wherein the tubes are connected to an inlet 902 and an outlet 901. Housing 904 can be covered by one or more layers 910 (e.g., soft elastomer, etc.) to mimic skin through which monitoring device 912 can measure the pressure profile of the system.

[0110] The pressure monitors, microneedles, and pressure sensors (e.g., force sensitive resistors) were positioned to face the artificial jugular vein model “skin”, which was mounted on a custom test bench that allowed for the application of a constant vertical force to the artificial jugular vein model 900 to neutralize and standardize the effect of the skin attachment means.

[0111] For the simulation, another artificial neck model was also made (not shown in the figures), which included a carotid artery and a jugular vein with associated pulses.

[0112] According to some embodiments, the algorithms and device designs were tuned and trained on such a simulator (particularly one with both arterial and venous pulses), as the pulse in the jugular vein region is mainly related to the arterial pulse. Thus, embodiments of the present disclosure are further directed to extracting the tiny venous pulse from the combined signal (see Figure 15A and Figure 15B for results).

[0113] Reference is now made to Figure 10 , which schematically illustrates a top view of a vein model with different test positions of the monitor, according to some embodiments. The target position of the monitoring device is the jugular vein. Even if the monitoring device is positioned slightly off-center (e.g., during self-application, application by an inexperienced caregiver, etc.), the pressure distribution can be measured as long as the monitoring device is within a certain distance from the jugular vein. Optionally, the off-center device can be positioned within a range of about 1 cm radius from the vein.

[0114] Experimental setup

[0115] The device was mounted on a vertical moving stage of the test bench, which was moved downwards at a speed of 0.8 mm / s, which resulted in a gradual increase in the normal force until a value of 20 N was reached. Then, the system remained in this loaded state for a dwell time of 30 s, after which the moving stage was withdrawn upwards at a speed of 0.5 mm / s until a preload force of 0.5 N was reached, and the system remained in this loaded state for the remainder of the test.

[0116] The neck model was attached to an external pulsatile pump to simulate venous blood flow (pulse amplitude range of 2-6 mmHg), while the pressure monitors were attached to the skin model and data (pressure distribution) were recorded. To evaluate the sensitivity and accuracy of the pressure monitor prototypes, the test was performed at four different positions relative to the artificial blood vessel, namely, center, back, right, and left front (e.g., Figure 10 ).

[0117] Results

[0118] Figure 11 , Figure 12, Figure 13 and Figure 14 show pressure profiles for the center, back, right, and left front test positions of a model flow system using the central venous pressure monitoring device. In Figure 11 , the lower curve 1100 represents the actual pressure in the model flow system delivered by the pump in millimeters of mercury (mmHg) (right axis), while the upper curve 1200 represents the force recorded by the new pressure monitor prototype in volts (left axis). In Figure 12 , the lower curve 1102 represents the actual pressure in the model flow system delivered by the pump in millimeters of mercury (mmHg) (right axis), while the upper curve 1202 represents the force recorded by the new pressure monitor prototype in volts (left axis). In Figure 13 , the lower curve 1103 represents the actual pressure in the model flow system delivered by the pump in millimeters of mercury (mmHg) (right axis), while the upper curve 1203 represents the force recorded by the new pressure monitor prototype in volts (left axis). In Figure 14 , the lower curve 1104 represents the actual pressure in the model flow system delivered by the pump in millimeters of mercury (mmHg) (right axis), while the upper curve 1204 represents the force recorded by the new pressure monitor prototype in volts (left axis). The device clearly detected the pulsatile wave pressure changes of the mock model and successfully recorded the pressure signal in all positions with good sensitivity.

[0119] To optimize the patient data acquisition processing system (or processor) of the pressure monitoring device described above, a data analysis algorithm has been constructed. The data used to construct the data analysis algorithm was generated in two stages. The first stage was performed on a simulator that simulated a neck in which the blood vessels were designed to represent the carotid artery and jugular vein and incorporated the mechanical properties of the relevant blood vessels and tissue (similar to the neck model described above). Blood flow simulations were performed on the simulator while measuring the pressure within the vein and simultaneously performing pressure measurements using the central venous pressure monitoring device disclosed herein. The integration of these data was used to construct the first stage algorithm (e.g., an artificial intelligence (AI)-based algorithm). Subsequently, data from an approved clinical trial with a similar design was collected, which was performed on a population of people who underwent a right heart catheterization as part of a clinical evaluation. Data was simultaneously acquired from an invasive catheter (Swan-Ganz catheter) and the central venous pressure monitoring device (sensor) disclosed herein.

[0120] Reference is now made to Figure 15AFIG. 15 shows a graphical representation of a comparison of actual central venous pressure readings 1502 (using Swan-Ganz) and algorithm predicted values 1504 using a simulator based on sensor readings 1556 using a model integrating carotid and jugular vessels. Good correlation is observed between actual central venous pressure readings 1502 and algorithm predicted values 1504.

[0121] Reference is now made to Figure 15B FIG. 16 shows a graphical representation of a comparison of actual central venous pressure readings 1552 (using Swan-Ganz) and algorithm predicted values 1554 using a simulator based on sensor readings 1556 using a model integrating carotid and jugular vessels. Good correlation is observed between actual central venous pressure readings 1552 and algorithm predicted values 1554.

[0122] Advantageously, as shown by the results disclosed above, the pressure values obtained by monitoring the central venous pressure of a subject using the device / system disclosed herein using the algorithm indicate the actual central venous pressure. According to some embodiments, the pressure values generated by the trained algorithm eliminate the effect of arterial or other undesired factors on the measured values (signals).

[0123] Reference is now made to Figure 16 FIG. 17 is an exemplary flowchart of a method of monitoring central venous pressure using a monitoring device, according to some embodiments. According to some embodiments, the method 1600 can comprise placing a monitoring device adjacent to a central vein (e.g., jugular vein) (1602). Puncturing the stratum corneum of the skin using the microneedle structure of the device (1604). Obtaining, using a data acquisition and processing system, signals related to deformation of the skin provided by the sensor(s) (1606). Applying, using the data acquisition and processing system, a trained algorithm to the received signals (1608), and providing a value indicative of the central venous pressure of the subject based on the obtained signals and the trained algorithm (1610).

[0124] Thus, having described several embodiments of methods for practicing the present application, its advantages and purposes can be readily understood. Modifications can be made to the above-described description without departing from the scope of the present application.

[0125] Thus, the present application is not limited to the embodiments described above, which are merely given as examples.

[0126] It is expected that many related construction technologies, artificial intelligence methods, computer user interfaces, image capture devices, and design elements, analysis programs, user devices will be constructed during the patent life of this application, and the scope of the terms range of user devices is intended to pre-emptively include all such new technologies.

[0127] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the application, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples provided are illustrative only and are not intended to be limiting.

[0128] The terms "comprise," "comprising," "include," "including," "contain," "containing," "have," "having," and variants thereof, mean "including but not limited to."

[0129] The term "consisting of means "including and limited to."

[0130] The term "consisting essentially of means that the composition, method or structure can include additional ingredients, steps and / or components, but only if the additional ingredients, steps and / or components do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0131] As used herein, the term "about" can be used in reference to a value (e.g., a length of an element) to indicate that the value is within a continuous range of values (including the value) around the given (recited) value. According to some embodiments, "about" can indicate that the value of a parameter is between 80% and 120% of the given value.

[0132] In this application, various embodiments of the application can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and is to be interpreted -in the context of the specification as a whole. Therefore, this description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.

[0133] Herein, any numerical values recited herein include all values from the lower limit to the upper limit of that range. The phrase "between," as used herein in the context of a range should be interpreted to also mean "from" and "to." For example, the phrase "between 1 and 5" should be interpreted to mean "from 1 to 5."

[0134] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. If there is a conflict between the definitions of terms in this disclosure and the patent specification, the definitions set forth in this specification control. As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise.

[0135] It should be understood that, for clarity purposes, some of the features of the present disclosure are described in the context of separate embodiments, but these features can also be provided in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of separate embodiments, can also be provided separately or in any suitable subcombination, or in as many suitable embodiments as desired, or in any other suitable embodiment as is described in the present disclosure. No feature described in the context of a certain embodiment is to be taken as essential to that embodiment unless explicitly so specified.

[0136] Although the method steps according to certain embodiments can be described in a particular order, the methods of the present disclosure can include some or all of the described steps performed in a different order. The methods of the present disclosure can include several of the described steps or all of the described steps. No particular step in the disclosed methods should be considered essential to that method unless explicitly so specified.

[0137] Although the present disclosure has been described in connection with certain embodiments, it will be understood that the application is capable of further modifications and variations. Accordingly, the application is intended to cover all such modifications and variations as fall within the spirit and broad scope of the appended claims. It is to be understood that the application is not limited to particular examples described, as such may, of course, vary. The application can be practiced according to the claims and

[0138] The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The reference in this application of any priority documents or other documents, or of anything on any Web site or elsewhere, is not intended to be an admission that this can constitute prior art under the patent law or laws of any country. Section headings are used herein for ease of reference only and are not to be construed as limiting law.

[0139] Although the present application has been described in connection with specific embodiments thereof, it will be understood that the application is capable of further modifications and variations. Accordingly, the application is intended to cover all such modifications and variations as fall within the spirit and broad scope of the appended claims.

[0140] The examples presented are intended to provide a more complete understanding of the application. The particular ingredients, conditions, materials, proportions and reported data set forth in the examples are not to be construed as limiting the scope of the application.

Claims

1. A device for substantially non-invasively monitoring central venous pressure in a subject, the device comprising: A microneedle structure comprising: a first surface, a second surface opposite to the first surface, and a plurality of microneedles attached to or integrally formed with the first surface, wherein the plurality of microneedles are configured to puncture the skin surface at a target area above and / or near a central vein of the subject; and at least one force sensor associated with or integrated within the microneedle structure. The at least one force sensor is configured to provide a signal indicating the central venous pressure.

2. The device of claim 1 further includes a flexible pad configured to conform the microneedle structure to the contour of the target region of the subject.

3. The apparatus according to claim 2, wherein, The flexible pad is positioned in the proximal side of the second surface of the microneedle structure.

4. The apparatus according to any one of claims 1 to 3, further comprising an adhesive layer.

5. The apparatus according to claim 4, wherein, The adhesive layer is a double-sided adhesive layer located between the second surface of the microneedle structure and the first surface of the flexible pad.

6. The apparatus according to claim 4, wherein, The adhesive layer extends on and beyond the second surface of the flexible pad and is configured to attach the device to the subject's skin.

7. The device according to any one of claims 1 to 6, further comprising a rigid base positioned at the base of the device.

8. The apparatus according to claim 7, wherein, The rigid substrate is configured to generate contralateral pressure to the central venous pressure and to improve the sensitivity of the force sensor.

9. The apparatus according to any one of claims 1 to 8, wherein, The device is associated with a patient data acquisition and processing system configured to receive data from the at least one force sensor.

10. The apparatus according to claim 9, wherein, The patient data acquisition and processing system is directly or remotely connected to the at least one force sensor.

11. The apparatus according to claim 9 or 10, wherein, The patient data acquisition and processing system includes a processor.

12. The apparatus according to any one of claims 1 to 11, wherein, The at least one force sensor is a force sensor, a pressure sensor, or a strain gauge.

13. The apparatus according to any one of claims 1 to 12, wherein, The at least one force sensor is configured to detect: subsurface strain, skin fluctuations caused by changes in blood vessel diameter due to internal pressure variations, skin stretching, or a combination thereof.

14. The device according to any one of claims 1 to 13, further comprising a housing configured to accommodate the microneedle structure and the at least one force sensor.

15. The apparatus according to claim 14, wherein, The housing also includes: a flexible pad, a rigid base, a connector for connecting to the patient data acquisition and processing system, or any combination thereof.

16. The apparatus according to any one of claims 1 to 15, wherein, The microneedle density on the first surface of the microneedle structure is between about 5 microneedles / cm² and about 150 microneedles / cm².

17. The apparatus according to any one of claims 1 to 16, wherein, The microneedle, the microneedle structure, and at least one component of the at least one force sensor are 3D printed.

18. The apparatus according to any one of claims 1 to 17, wherein, The at least one force sensor is integrated within the microneedle to provide a combined microneedle-mechanical sensor.

19. The apparatus according to any one of claims 1 to 18, wherein, The central cardiovascular vessel mentioned is the jugular vein.

20. The device according to any one of claims 1 to 19, for monitoring the patient's volume status and / or symptoms characterized by changes in central venous pressure.

21. The apparatus according to any one of claims 1 to 20, wherein, The condition characterized by changes in central venous pressure is selected from the group consisting of: right heart failure, heart failure, pulmonary embolism, pulmonary hypertension, cardiac tamponade, cardiac tamponade, hemodynamic shock, and valvular disease.

22. A system for substantially non-invasively monitoring central venous pressure in a subject, the system comprising: A microneedle structure, the microneedle structure including a first surface and a second surface opposite to the first surface, wherein the microneedle structure further includes a plurality of microneedles attached to the first surface of the microneedle structure or integrated within the first surface of the microneedle structure, and wherein the plurality of microneedles are configured to puncture the skin surface in an area above and / or near the central vein of the subject; At least one sensor, said at least one sensor being associated with or incorporated within said microneedle and / or said microneedle structure, said at least one sensor being configured to provide a signal indicating pressure; and A patient data acquisition and processing system configured to receive data from the at least one sensor and apply a trained algorithm to the received pressure signal, and provide a value indicating the central venous pressure of the subject.

23. The system according to claim 22, wherein, The patient data acquisition and processing system is directly or remotely connected to the at least one sensor.

24. The system according to any one of claims 22 to 23, wherein, The at least one force sensor is a pressure sensor or a strain gauge sensor.

25. The system according to any one of claims 22 to 24, wherein, The at least one sensor is configured to detect: subsurface skin strain, blood vessel diameter fluctuations, skin stretching, or any combination thereof.

26. A method for substantially non-invasively monitoring central venous pressure in a subject, the method comprising: A central venous pressure monitoring device is placed on the skin surface of the subject in an area above and / or near the central vein, wherein the central venous pressure monitoring device comprises: A microneedle structure, comprising: a first surface, a second surface opposite to the first surface, and a plurality of microneedles attached to the first surface of the microneedle structure or forming an integral part of the first surface of the microneedle structure; and At least one force sensor, said at least one force sensor being connected to or integrated within the microneedle and / or the microneedle structure; The microneedles are used to pierce the skin surface; Skin deformation is measured using the at least one force sensor; Use a data acquisition and processing system to obtain signals related to skin deformation; The data acquisition and processing system is used to apply a trained algorithm to the received signals; and Based on the obtained signals and the trained algorithm, a value indicating the central venous pressure of the subject is provided.

27. The method of claim 26 further includes transmitting the signal to a patient data acquisition and processing system.

28. The method according to any one of claims 26 to 27, wherein, The data is transmitted to the patient data acquisition and processing system via a direct or indirect connection to the at least one force sensor.

29. The method according to any one of claims 26 to 28, further comprising providing a pressure distribution of the central venous pressure of the subject.

30. The method of claim 29, further comprising providing the pressure distribution to a medical professional for real-time monitoring and / or periodic assessment.

31. The method according to any one of claims 26 to 30, further comprising issuing an alarm to a user, caregiver, or medical professional when the central venous pressure monitoring device detects a change in one or more measured and / or calculated parameters.

32. The method according to any one of claims 26 to 31, wherein, The change in one or more measured and / or calculated parameters is higher than and / or lower than a predefined threshold for the parameter.

33. The method according to any one of claims 26 to 32, wherein, The placement is performed by self-application or by application by caregivers or medical professionals.

34. The method according to any one of claims 26 to 33, wherein, The monitoring can be a one-time monitoring, short-term monitoring, or long-term monitoring.

35. The method according to any one of claims 26 to 34, wherein, The monitoring monitors either venous pressure fluctuations or a specific pressure waveform generated by the central vein.

36. The method according to any one of claims 26 to 35, wherein, The device is essentially non-invasive, detecting arterial pressure waves, monitoring blood pressure, and / or integrating arterial and venous data.

37. The method according to any one of claims 26 to 36, further comprising predicting central venous pressure based on measured subcutaneous skin deformation and a trained algorithmic model.

38. The method according to any one of claims 26 to 37, further comprising predicting central venous pressure based on measured subsurface skin deformation and a time-series regression algorithm model.

Images