Device, system and method for measuring vasculature hemodynamics

Abstract

A device, method, and system for measuring vasculature hemodynamics are disclosed. The device includes a pressurizing member that applies force to a tested body region to stop blood flow to the tested body region for a predetermined duration, data acquisition means comprising a plethysmograph configured to measure and receive one or more signals associated with one or more hemodynamic parameters in the tested body region, and a processor configured to analyze the one or more measured signals and provide an output of the hemodynamic parameters indicative of the hemodynamic status of the subject.

Description

[0001] DEVICE, SYSTEM AND METHOD FOR MEASURING VASCULATURE HEMODYNAMICS

[0002] FIELD OF THE INVENTION

[0003] The present invention is in the field of measuring physiological variables and more specifically measuring a vasculature hemodynamic parameter in a subject.

[0004] BACKGROUND OF THE INVENTION

[0005] Capillary Filling is a well-known clinical test used to assess the hemodynamic status of patients (H. K. BEECHER et. al.. Surgery, 1947 Oct;22(4):672-711; The internal state of the severely wounded man on entry to the most forward hospital). Capillary filling rate is an observational clinical test. It is done by a trained healthcare professional by manually compressing the tested region such as the distal phalanx of a finger or a skin surface elsewhere and then abruptly releasing the compression and observing the time it takes for the color of the tested area to return to its normal pink / red color.

[0006] The normal capillary refill time in an individual is 2-3 seconds. If it exceeds this duration, it is considered delayed capillary filling. (Duncan McGuire et. al., 2024; Capillary Refill Time; National Institutes of Health. StatPearls. Treasure Island (FL): StatPearls Publishing).

[0007] The rate of capillary filling depends on three parameters that control the flow of blood to the tested area: (a) the arterial blood pressure, acting as the driving force; (b) the resistance to flow of the blood vessels leading into the tested region (primarily, but not exclusively the arterioles); and (c) the compliance or capacitance of the blood vessels in the tested region and their ability to distend and increase the volume of blood in this region.

[0008] Figure 1 illustrates the steady-state vascular system in a body region such as the distal phalanx of a finger. Under steady state conditions Pin is the mean arterial blood pressure, R represents the resistance of the arterial blood vessels leading into the tested region, Vblood is the volume of blood in the tested region and C is its compliance. Pout is the pressure of the venous vessels leading out of the tested region. In a living person, the pressure Pin oscillates, being higher than the mean during systole and lower than the mean during diastole. These pressure pulsations are well known and represent the physiological foundation of the measurement of pulse oximetry. Venous Occlusion Plethysmography (VOP) is another widely recognized hemodynamic method for measuring blood flow into a specific region, such as a limb or finger (F Kleinberg et. al., Mayo Clin Proc. 1976 Jul;51(7):430-2; A volume-displacement plethysmograph to measure limb blood flow in the newborn infant). In this method, the veins leading blood out of the tested area are blocked by inflating a circumferential cuff to a pressure that is higher than the venous pressure, but lower than the arterial pressure. The blocking of the blood outflow causes the tested region to further fill up with blood beyond the steady state volume. It is stipulated that the initial rate of increasing blood volume in the tested region is a representation of the blood flow into it. If the rate of increase of volume of blood in the tested region is slower than normal, it is indicative of narrowing of the arterial vessels leading into it (vasoconstriction) which may be caused by elevated sympathetic nerve activity. Figure 2a is a schematic diagram of the hemodynamics during VOP and Figure 2b shows the blood volume (represented as light transmission) in the tested region during a VOP test.

[0009] VOP is a quick, non-invasive procedure that requires only basic equipment to perform. Tools used to measure the volume of the test region include photoplethysmography, mercury-in- silastic devices, electromagnetic inductive sensors, or air displacement methods. However, VOP suffers from an inherent significant drawback - the cuff that occludes the venous outflow of the blood also impedes and partially block the arterial inflow into the tested area. Figure 3 shows examples of three different VOP measurements in a single subject with the same arterial pressure, but with three different venous occlusion pressures. It is showing that higher venous occlusion pressure causes the initial slope of the blood filling of the test region to be slower.

[0010] In view of the drawback of VOP, the capillary filling test is considered superior. However, to date there are no devices for accurate, consistent and quantitative documentation of capillary filling time. Liu et. al., pertains to an integrated optical sensor probe, combining monitoring of the capillary refilling process with the blanching pressure applied. The sensor consists of an optical fibre-based reflectance photoplethysmography (PPG) sensor to measure the reflected light signal, as well as a fibre Bragg grating (FBG) to measure the applied blanching pressure and to indicate the time when pressure is released. (Chong Liu. et. al., Optical Fibre Sensor for Simultaneous Measurement of Capillary Refill Time and Contact Pressure. Sensors 2020, 20(5), 1388). The described method involves the subject manually pressing their finger against a plate and then releasing the pressure. This approach cannot be considered as a standardized and reliable device or method and is unsuitable for non- cooperative patients, such as those in severe shock. US 11,089,966 discloses devices and methods for non-invasive capillary blood pressure measurement. The device comprises a front end in contact with the body to compress and decompress the capillaries in the tissue, a pressure control module for regulating the contact pressure between the front end and the tissue, a pressure transducer coupled to the front end for measuring the contact pressure, a capillary sensing module for detecting the capillaries pulsations under the contact pressure modulation, and an algorithm for determining the capillaries pressures from the traces of capillary pulsation signals and the contact pressure signal. The methods include an oscillometric method for intermittent arterial and capillary blood pressure measurement and a volume-clamp method for continuous capillary blood pressure measurement.

[0011] US 9,474,459 pertains to a non-invasively measuring a physiological parameter by applying to a subject's body part a venous occlusion plethysmographic device and intermittently raising and lowering the pressure to a pressure below the arterial blood pressure. The pressure applied allows blood flow from the arteries.

[0012] US 2019 / 0069785A pertains to a combined sensor adapted to measure at least one medical or clinical sign. The combined sensor comprises a textile sensor configured to determine pressure applied to the combined sensor, and an optical sensor. This reference also involves a manual, non-standardized process for the pressure application stage.

[0013] Masayoshi Shinozaki et. al., describe electronically monitoring the return of the blood to the compressed area of a finger (Artificial Life and Robotics (2024) 29:334-339; Feasibility study of wearable capillary refill time measurement device and Artificial Life and Robotics (2022) 27: 48-57; Portable measurement device to quantitatively measure capillary refilling time). Here, again, the disclosed device relies on manually pressing the finger by the person performing the test.

[0014] There is thus a need for devices and systems for measuring capillary filling in a standardized and controllable manner. The present invention provides such a device and system.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention pertains to a device, a method, and a system for measuring the hemodynamic parameters such as capillary filling rate of a subject. The device and system comprise (a) a pressurizing member configured to compress and pressurize a tested body region for a pre-determined duration to squeeze blood out of the tested body region; (b) a data acquisition means comprising a blood volume tracking member configured to track and measure blood volume in the tested body region during the procedure; and (c) a processor comprising a capillary filling rate analyzer configured to extract numerical values that characterize capillary filling rate from the blood volume measurements.

[0017] The method comprises applying a controlled force (pressure) on a tested body region for a predetermined duration. This compression squeezes the blood out and away from the tested region. After the elapsed time of compression, the force (pressure) is removed and the blood returns to the tested region with no impediment, i.e., freely. The volume of blood may be monitored and recorded during the method procedure to thereby provide a blood refilling rate.

[0018] Thus, an aspect of the invention pertains to a non-invasive device for monitoring vasculature hemodynamics in a subject, the device comprising means configured to controllably apply force to a tested body region to completely stop blood flow in the tested body region and temporarily empty it from blood for a predetermined duration; data acquisition means configured to measure one or more signals associated with blood volume in the tested body region; and a processor configured to analyze said one or more measured signals and provide an output of the vasculature hemodynamic status of the subject.

[0019] Another aspect of the invention pertains to a device for non-invasive monitoring of vasculature hemodynamics in a subject, the device comprising means configured to controllably apply to a tested body region a pressure that exceeds a systolic blood pressure of the subject and abruptly release said pressure after a predetermined duration to permit blood to freely flow into said tested body region; data acquisition means configured for measuring one or more signals associated with vasculature hemodynamics (e.g., blood volume) in the tested body region; and a processor operatively coupled to the data acquisition means configured to analyze the one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject.

[0020] Another aspect of the invention pertains to a device for non-invasive monitoring of capillary filing rate in a subject, the device comprising a mechanical pressurizing mechanism configured to controllably and mechanically pressurize the body region to compress the blood vessels in said body region of said subject to apply a pressure that exceeds a systolic blood pressure of the subject and abruptly release said pressure after a predetermined duration to permit blood to freely flow into said tested body region; data acquisition means configured for measuring one or more signals associated with vasculature hemodynamics (e.g., blood volume) in the tested body region; and a processor operatively coupled to the data acquisition means configured to analyze the one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject.

[0021] Another aspect of the invention pertains to a device for non-invasive monitoring of capillary filing rate in a subject, the device comprising a mechanical pressurizing mechanism comprising one or more nozzles for emitting gas jets directed toward the tested body region, configured to be blown toward the tested body region to controllably and mechanically pressurize the body region to thereby compress the blood vessels in said body region of said subject to thereby apply a pressure that exceeds a systolic blood pressure of the subject and abruptly release said pressure after a predetermined duration to permit blood to freely flow into said tested body region; data acquisition means configured for measuring one or more signals associated with vasculature hemodynamics (e.g., blood volume) in the tested body region; and a processor operatively coupled to the data acquisition means configured to analyze the one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject.

[0022] Another aspect of the invention pertains to a device for non-invasive monitoring of capillary filing rate in a subject, the device comprising a mechanical pressurizing mechanism comprising a closed chamber with a pressure source for increasing pressure within the chamber accommodating the tested body region to controllably compress the blood vessels in said body region of said subject to thereby apply a pressure that exceeds a systolic blood pressure of the subject and abruptly release said pressure after a predetermined duration to permit blood to freely flow into said tested body region; data acquisition means configured for measuring one or more signals associated with vasculature hemodynamics (e.g., blood volume) in the tested body region; and a processor operatively coupled to the data acquisition means configured to analyze the one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject. In one or more embodiments, the hemodynamic status comprises one or more hemodynamic parameters selected from the group consisting of blood pressure, blood flow, blood volume change, blood filling rate, oxygen saturation parameter, and blood vessels capacitance (vasculature compliance).

[0023] In one or more embodiments, the means to apply pressure to the tested body region comprise at least one member selected from the group consisting of a mechanical pressurizing mechanism configured to mechanically compress the blood vessels in said body region of said subject, gas jets configured to be blown toward the tested body region, and means for increasing pressure within a closed chamber accommodating the tested body region. In one or more embodiments, the mechanical pressurizing mechanism comprises a pressurizing plate, surface, or piston actuated via an electromagnetic linear actuator to squeeze the tested body region. In one or more embodiments, the pressurizing mechanism comprises a circumferential inflatable member configured to apply supra-systolic pressure on the tested body region.

[0024] In one or more embodiments, wherein the means configured to controllably apply pressure comprise one or more nozzles for emitting gas jets directed toward the tested body region and configured to be blown toward the tested body region.

[0025] In one or more embodiments, the means to apply pressure to the tested body region comprise a closed chamber with a pressure source for increasing pressure within the chamber accommodating the tested body region.

[0026] In one or more embodiments, wherein the data acquisition means comprise at least one member selected from the group consisting of an optical plethysmograph, a strain gauge plethysmograph, a mercury-in-silastic strain gauge, an electromagnetic inductive sensor, a gamma camera, an air displacement plethysmograph, a photoresistor, a complementary metal- oxide-semiconductor (CMOS) image sensor, and a photoelectric diode.

[0027] In one or more embodiments, wherein the device is configured for determining the capillary filling rate of the subject.

[0028] In one or more embodiments, the processor is adapted to calculate a numerical best-fit single exponent of said measured signal to find the timeconstant of the rate of return of blood to the tested body region; calculate a numerical best-fit two exponents of said measured signal to find the timeconstants of the fast and slow rates of return of blood to the tested body region; and / or provide a derivative of the measured signal and measure the amplitude and duration of the derivative of said signal.

[0029] In one or more embodiments, the pressure applied to the tested body region is sufficient to stop the arterial blood flow to the tested body region.

[0030] In one or more embodiments, the applied pressure comprises applying a force of at least 400 g per square cm. In one or more embodiments, the applied pressure comprises applying a force of at least 500 g per square cm. In one or more embodiments, the applied pressure comprises applying a force of at least 600 g per square cm. In one or more embodiments, the applied force is at least 700 g per square cm. In one or more embodiments, the applied force is at least 800 g per square cm.

[0031] In one or more embodiments, the tested body region is a flat part of the body. In one or more embodiments, the tested body region is a finger or a toe. In one or more embodiments, the tested body region is the distal phalanx of a finger.

[0032] In one or more embodiments, the predetermined duration is in the range of 1 to 10 seconds. In one or more embodiments, the device further comprises a heating member to maintain the temperature of the tested body region at 38°C to 43°C.

[0033] In one or more embodiments, the data acquisition means comprises a light source emitting in the visible wavelength. In one or more embodiments, the light source comprises a near infrared wavelength light source, an infrared wavelength light source, and / or a light emitting diode.

[0034] In one or more embodiments, the analysis is performed by curve fitting to a single exponent or multiple exponents.

[0035] In one or more embodiments, the device further comprises a display screen configured to show the output indicative of the measured hemodynamic status of the subject.

[0036] In one or more embodiments, the measured hemodynamic status is a blood filling rate, and the display screen is configured to show at least one of the amplitudes of the signal derivative, and / or a measured time constant.

[0037] In one or more embodiments, the device is configured to conduct multiple measurements over time.

[0038] In one or more embodiments, the processor is configured to calculate averages, trends and / or standard deviations of the signals. In one or more embodiments, the device further comprises a controller configured to initiate, control the duration of, and / or stop the pressure applied on the tested body region.

[0039] In one or more embodiments, the device further comprises a housing configured to accommodate the means configured to controllably apply pressure to a tested body region, the data acquisition means, and optionally, the processor.

[0040] In one or more embodiments, the device further comprises a platform for positioning the tested body region.

[0041] In one or more embodiments, the means configured to controllably apply pressure to a tested body region, and the data acquisition means are positioned in close proximity to each other.

[0042] An aspect of the invention pertains to a method for monitoring hemodynamic status of a subject, the method comprising: applying force to a tested body region to empty and stop blood flow to the tested body region for a predetermined duration; removing the force applied onto the tested body region to allow a free flow of blood in the vasculature of the tested body region; measuring one or more signals associated with blood volume in the tested body region using a data acquisition means; and analyzing the one or more measured signals using a processor to provide an output indicative of the hemodynamic status of the subject.

[0043] Another aspect of the invention pertains to a non-invasive method for monitoring hemodynamic status of a subject, the method comprising: applying to a tested body region a pressure that exceeds a systolic blood pressure of the subject for a predetermined duration; abruptly releasing the pressure to permit blood to freely flow into the tested body region; measuring one or more signals associated with blood volume in the tested body region using a data acquisition means; and analyzing the one or more measured signals to provide an output indicative of the hemodynamic status of the subject.

[0044] In one or more embodiments, blood pressure of the subject is measured prior to the step of applying pressure or force to the tested body region to thereby determine the subject’s systolic blood pressure. In one or more embodiments, the step of measuring one or more signals associated with blood volume in the tested body region is performed before the step of pressurizing the tested body region. In one or more embodiments, the step of measuring one or more signals associated with blood volume in the tested body region is performed after the step of pressurizing the tested body region. In one or more embodiments, the step of measuring one or more signals associated with blood volume in the tested body region is performed before and after the step of pressurizing the tested body region.

[0045] In one or more embodiments, removing the pressure applied onto the tested body region comprises abrupt removal of said pressure. In one or more embodiments, abrupt is immediate without delay or not in a continuous or gradual manner.

[0046] In one or more embodiments, the measuring step is conducted immediately after the step of releasing the pressure applied onto the tested body region.

[0047] In one or more embodiments, applying pressure comprises pressing the tested body region, blowing one or more gas jets toward the tested body region or increasing the pressure surrounding the tested body region.

[0048] In one or more embodiments, the method further comprises initiating and controlling the testing process using a controller.

[0049] In one or more embodiments, the method further comprises accommodating the tested body region in a device comprising a housing.

[0050] In one or more embodiments, the method further comprises positioning the tested body region onto a platform within the housing.

[0051] An aspect of the invention pertains to a device for monitoring capillary hemodynamics in a subject, the device comprising a mechanism configured for applying one or more gas jets imposing a compression force to a tested body region to stop blood flow in the tested body region and empty it from blood for a predetermined duration; data acquisition means configured to measure one or more signals associated with blood volume in the tested body region; and a processor configured to analyze said one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject.

[0052] In one or more embodiments, the gas jets are a plurality of jets. In one or more embodiments, the gas is air. In one or more embodiments, the gas is selected from the group consisting of CO2, N2, O2, a noble gas, and a combination thereof. In one or more embodiments, the noble gas is selected from He, Ar, and a combination thereof.

[0053] BRIEF DESCRIPTION OF THE FIGURES

[0054] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0055] Figure l is a schematic diagram illustrating the steady-state vascular hemodynamics in a body region such as the distal phalanx of a finger.

[0056] Figure 2a is a schematic diagram of vascular hemodynamics during VOP.

[0057] Figure 2b is a plethysmograph illustrating the blood volume (represented as light transmission) in a tested body region during a VOP test.

[0058] Figure 3 is a line graph showing examples of three different VOP measurements of a single subject with the same arterial pressure, but with three different venous occlusion pressures.

[0059] Figures 4a and 4b are a side view (fig. 4a) and a top view (fig. 4b) of an exemplary device for measuring capillary hemodynamics comprising a piston for pressurizing a tested body region, according to some embodiments of the invention.

[0060] Figures 5a and 5b are a side view (fig. 5a) and a wheatstone bridge scheme (fig. 5b) of an exemplary device for measuring capillary hemodynamics comprising a housing with means for elevating internal pressure for compressing the vasculature of a tested body region, according to some embodiments of the invention.

[0061] Figures 6a, 6b and 6c are a perspective view (fig. 6a) and side views of an exemplary device in an opened (fig. 6b) and closed (fig. 6c) configurations for measuring capillary hemodynamics, the device comprising a housing with means for pressing the vasculature of a tested body region, according to some embodiments of the invention. Figure 7a is a side view of an exemplary device for measuring capillary hemodynamics comprising gas jet means for pressing the vasculature of a tested body region, according to some embodiments of the invention.

[0062] Figures 7b and 7c are images that show the effect of gas jet forces applied on a finger of a subject when the jet is turned off (fig. 7b) and on (fig. 7c), according to some embodiments of the invention.

[0063] Figure 8 shows data analysis modelled by a single exponent.

[0064] Figures 9a and 9b show data analysis modelled by two exponents of measured signals to calculate the time-constants of the fast and slow rates of blood return to the tested body region.

[0065] Figures 10a and 10b show data analysis performed by derivatizing the measured signal and measuring the amplitude and duration of the derivative.

[0066] Figure 11 shows the effect of load (pressure) applied to a tested body region (upper panel a) and the light transmission through the tested region when photoplethysmography is used to measure and monitor the blood volume (bottom panel b).

[0067] Figure 12 shows a validation test of the herein method. Load (pressure) is applied to a tested body region (upper panel). The light transmission (bottom panel) is specific and sensitive to blood flow to the tested body region.

[0068] Figure 13 are evaluations of the sensitivity of the herein device in vasoconstriction conditions of low temperature.

[0069] Figure 14 shows linearly increasing signals over time while the temperature is rising. The lower panel shows signals at normal conditions, and the upper panel shows signals under cool temperature.

[0070] Figure 15 shows blood filling measured by Free Flow Pleythysmograph (FFP) (top) and by VOP (bottom).

[0071] Figure 16 shows an exponential curve fitted to the FFP signal.

[0072] DETAILED DESCRIPTION OF THE INVENTION

[0073] The following detailed description provides illustrative embodiments of the present technology, which pertains to devices, systems, and methods for measuring vasculature hemodynamics, including capillary filling rates, in a subject. The described technology is presented in the context of applications to physiological monitoring and clinical diagnostics, particularly in assessing hemodynamic parameters such as blood flow, blood volume, and vascular compliance. While specific examples and configurations are provided to facilitate understanding, these are not intended to limit the scope of the described technology. Instead, the described technology encompasses variations, modifications, and equivalents that fall within the scope of the claims.

[0074] Certain details, commonly recognized by those skilled in the art, may be omitted to enhance clarity and conciseness. The embodiments described herein are presented for illustrative purposes and do not encompass all possible variations. Various components, configurations, and methods may be rearranged, substituted, or combined in ways that align with the principles and scope of the described subject matter. The described subject matter is designed to accommodate a broad range of applications and implementations, as will be evident to those skilled in the relevant field.

[0075] The challenge of accurately and consistently measuring capillary filling time, an important hemodynamic parameter, has persisted in clinical settings. The present disclosure addresses these limitations by introducing a novel device, system, and method for measuring vasculature hemodynamics, including capillary filling rates, in a standardized, automated, and accurate manner. The described solution incorporates a pressurizing mechanism to apply a controlled force to a tested body region, such as a finger or toe, to temporarily stop blood flow and empty the region of blood. This is followed by the abrupt removal of pressure, allowing blood to flow freely back into the region. The device employs data acquisition means, such as optical plethysmography or other suitable sensors, to monitor and measure blood volume changes in real time. A processor analyzes the acquired data, optionally using specialized algorithms, including curve-fitting techniques and derivative analysis, to extract precise numerical values that characterize the capillary filling rate. This approach eliminates the subjectivity and variability associated with manual methods while addressing the limitations of VOP. The herein invention offers a non-invasive device that facilitates consistent, reproducible, and quantitative assessments of capillary filling rates, making the system highly applicable in clinical environments, including urgent care and patient monitoring scenarios requiring close attention.

[0076] The present invention pertains to a system that comprises (a) means configured to controllably apply force to a tested body region to stop blood flow to the tested body region for a predetermined duration; (b) data acquisition means configured to measure and receive one or more signals associated with one or more hemodynamic parameters in the tested body region; and (c) a processor configured to analyze the one or more measured signals and provide an output of the hemodynamic parameters indicative of the hemodynamic status of the subject (e.g., capillary filling rate).

[0077] Standardization of the duration of compression applied onto a tested body region during capillary filling procedure is important due to the physiological phenomenon of reactive hyperemia (Ryan Rosenberry et al., Am J Physiol. Regul. Integr. Comp. Physiol. 2020 Mar 1 ;318(3): R605-R618), which is vasodilatation in response to transient ischemia.

[0078] The herein device is configured to measure and monitor vasculature hemodynamics. In some embodiments, the herein device is regarded as a Free Flow Plethysmography (FFP) configured to measure capillary filling rate once blood flow blockage is removed and the blood can freely flow and fill the vasculature in the tested body region. The blood flow removal may be regarded as an “abrupt removal”, i.e., an immediate and non-gradual cessation of applied force or pressure on a tested body region, allowing unimpeded blood flow to resume.

[0079] As used herein the term “Capillary Filling Rate” refers to the rate at which blood returns to a tested body region after the removal of applied pressure, typically measured in seconds.

[0080] The means configured to apply force to the body region tested include mechanical devices capable of at least partially or completely stopping blood flow to the tested body region and at least partially or completely empty it from blood. In some embodiments, the force applied by the herein device to the tested body region is supra (i.e., above)-systolic pressure. In some embodiments, the force applied by the herein device to the tested body region comprises a pressure greater than the arterial blood pressure. In some embodiments, the pressure applied by the herein device to the body region comprises pressure greater than the systolic blood pressure of the tested person. In one or more embodiments, the pressure applied is above about 200 mm Hg. In one or more embodiments, the pressure is above about 60, 80, 90, 100, 110, 120, 150, 200, 210, 220, 230, 240 or 250 millimeters of mercury (mmHg). Each possibility represents a separate embodiment of the invention. In one or more embodiments, the pressure applied in terms of load is above about 200 grams per square centimeter (g / cm2). In one or more embodiments, the pressure is above about 250 g / cm2. In one or more embodiments, the pressure applied onto the tested body region is up to about 800 g / cm2. In an exemplary embodiment, the pressure applied onto the tested body region is up to about 760 g / cm2. The pressure is applied for a pre-determined and standardized duration “T”. The predetermined time may be about 10 seconds. In other embodiments, the pressure is applied for a standard duration of time of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or 20 seconds or any value in between. Each possibility represents a separate embodiment of the invention. The pressure may be applied for up to about 60 seconds. For example, the presume may be applied for up to about 50, 40, or 30 seconds or any value in between. Each possibility represents a separate embodiment of the invention.

[0081] Application of the load, force or compression on the tested body region can be done by various mechanisms. For example, the application of force may be done mechanically by applying a pressurizing mechanism onto the tested body region, using, for example, a pressurizing platform that may feature a piston structure, or using clamping members or the like. The piston structure may be maneuvered or actuated to move using various mechanisms including a motor driven system, an electromagnetic force, a pneumatic pressure, a voice coil actuator, or a linear motor.

[0082] Application of the load can be done by inflating an elastic sealed compartment in touch with the tested body region. In another embodiment, compression of the body region may be achieved by pressing a cushioned plate to the tested body region. The plate may be moveable using various mechanisms including an electromagnetic linear actuator, a solenoid, a piezoelectric actuator element, or a screw driven linear motor.

[0083] In yet another embodiment, the compression or load may be applied by blowing one or more jets of gas (e.g., air) onto the surface of the body region at sufficient force and speed to pressurize the tissue.

[0084] The jets may be one jet, or a plurality of jets. In one or more embodiments, the plurality of jets may comprise at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more jets. Each possibility represents a separate embodiment of the invention.

[0085] The gas of the jets is safe to the skin and preferably stale. Exemplary suitable gases may include air (-21% Oxygen, -78% Nitrogen, - 0.93% Argon, and - 0.04% Carbon Dioxide -CO2). Further applicable gases may include carbon dioxide (CO2), nitrogen (N2), oxygen (O2), helium (He), argon (Ar), or a combination thereof, or any of the known noble gases.

[0086] Alternative methods for applying pressure may be utilized, as will be readily recognized by those skilled in the art. In one or more embodiments, the herein device may further include a heating member utilized to maintain the skin temperature of the tested body region. The heating member may be used for ensuring accurate measurements of hemodynamic parameters, thereby enhancing the reliability of the data acquired. Therefore, the heating member may serve as a supportive component that contributes to the overall functionality of the device by maintaining optimal and standardized conditions for data acquisition. Alternatively, the heating member may be used to evaluate the hemodynamics response of the tested body region at various temperatures.

[0087] Various heating members may be utilized and are contemplated within the scope of this invention. Exemplary heating members include, but are not limited to, heating coils, heating plates, and other suitable technologies, such as resistive heating elements, infrared heaters, Peltier elements, or ceramic heating components.

[0088] In some embodiments, the tested body region may be heated prior to and / or during the test to body temperature or higher temperature such as 36°C, 37°C, 38°C, 39°C, or 40°C, or 45°C or any value in between. Each possibility represents a separate embodiment of the invention. This is also part of the standardization of the test and is used to avoid cold-induced vasoconstriction.

[0089] The data acquisition means may comprise a plethysmograph configured to detect, measure and / or receive one or more signals associated with one or more hemodynamic parameters in the tested body region, such as blood volume, blood flow, or vascular compliance, in the tested body region.

[0090] As used herein, the term Capacitance (Compliance) refers to the ability of blood vessels to distend and increase their volume in response to changes in pressure.

[0091] The data acquisition means may comprise plethysmograph.

[0092] As used herein when referring to “plethysmograph” it is meant to refer to a device that measures changes in blood volume within an organ, or body part. This measurement may be achieved through various methods, such as the detection of pressure changes, light transmission or reflection, impedance variations, or other suitable techniques for monitoring physiological volume changes. The plethysmograph may comprise an optical plethysmograph, strain gauge plethysmograph, or other types, and may utilize components like a photoresistor, photodiode, or CMOS image sensor.

[0093] The data acquisition means comprises monitoring the volume of blood in the tested region by measuring light transmission or reflection from the region (photoplethysmography) using broad-spectrum light source or light-emitting diodes (LED) at specific wavelengths in the visible spectrum or infrared spectrum that are more specific for blood. The detection of the light transmission or reflection may be done by photoelectric sensors such as photoresistors. In another embodiment, phototransistors or photodiodes are used or any other light detectors known.

[0094] In yet another embodiment, a complementary metal-oxide-semiconductor (CMOS) image sensor can be used to video-record the tested area, optionally at a typical throughput of 30 or 60 frames per second. Other methods and embodiments of measuring the volume of blood in the tested body region comprise sensors that directly measure the volume of the tested region. One embodiment is based on measuring the circumference of a body member such as a finger by using a mercury-in-silastic strain gauge device. This is an elastic tubular element containing a conductive liquid such as Mercury. It is wrapped around the body part and when stretched it becomes narrower due to the Poisson ratio, and its electrical conductivity is reduced. This conductivity can be measured by using a Wheatstone bridge or a similar resistance measuring device. For measuring the return of blood to a flat surface of the body a proximity probe consisting of a capacitance measurement, or an ultrasonic distance probe may be used.

[0095] In another embodiment the circumference of the body region can be detected by a magnetic field plethysmograph or magnetometer. In another embodiment, the volume of blood in the tested area can be monitored by linking a radioactive substance such as Technetium" to the red blood cells and using a Gamma Camera to monitor the quantity of blood in the test region as function of time. In another embodiment, a radio-opaque contrast material such as Iodine may be injected into the bloodstream. The latter can be monitored by using cineradiography of the tested region. It is obvious to those skilled in the art that it is possible to use other methods to monitor the volume of blood in the tested body region over time.

[0096] In one or more embodiments, the processor comprises a non-transitory or non-volatile computer readable medium comprising stored instructions that when executed cause at least one processor to determine the hemodynamic parameters indicative of the hemodynamic status of the subject.

[0097] The processor may comprise an electronic component or system, such as a microprocessor or computer configured to analyze signals recorded by the data acquisitions means and to provide an output indicative of the hemodynamic status of the subject. This analysis may involve calculating numerical best-fit exponents to assess blood return rates. The processor may calculate a numerical best-fit single exponent to determine the time-constant of blood return, or a numerical best-fit two exponents for fast and slow blood return rates. The processor may also determine the derivative of the measured signal to assess amplitude and duration. The analysis may be performed by curve fitting to single or multiple exponents. The processor may calculate averages, trends, and standard deviations of the signals.

[0098] The device may also include a display screen to show the measured hemodynamic parameters, such as blood filling rate of a single measurement or a succession of measurements over time.

[0099] The device may further comprise a controller configured to initiate, control, and stop the duration of pressure applied.

[0100] The device may further comprise a housing to accommodate the components, and a platform for positioning the tested body region. The force / pressure application mechanism and data acquisition means may be positioned in close proximity to each other.

[0101] Turning now to the drawings, Figure 4a is a side view of an exemplary device 10 for measuring capillary filling rate and Figure 4b is a top view of device 10. The device 10 is designed to apply a controlled pressure to a tested body region, such as a finger or toe, to temporarily and at least partially stop blood flow and subsequently measure the capillary filling rate upon the release of pressure. Device 10 comprises means configured to controllably apply force to a tested body region to at least partially or completely stop blood flow to the tested body region for a predetermined duration. The means configured to controllably apply force to a tested body region comprise a mechanical pressurizing member 12. Device 10 further comprises a data acquisition means comprising a plethysmograph 14 and a processor 16. The mechanical pressurizing member 12 comprises a piston 30. Device 10 comprises a housing 6 accommodating piston 30. Piston 30 is actuated by an external inductive coil 17 and an internal inductive coil 26. These coils, when supplied with an electric current, generate a magnetic field that creates a downward force to move the piston 30 towards the tested body region. The direction of the current determines whether the piston 30 is pushed downward to apply pressure or lifted upward to release pressure. The piston 30 is pressed down to the surface 20 of a skin of a subject by pushing button 2 in a sufficient load to activate microswitches 4 and 11 in sufficient force to activate them. The pressing of button 2 may be against an elastic cushion 28 which keeps the button 2 normally elevated when not pressed. Once the microswitches 4 and 11 are activated, the electric current through the coils 17 and 26 is initiated and the piston 30 is pushed toward the surface 20 of the skin of a subject in a pre-determined force which may be within the range of 200 - 600 grams per square cm. The piston 30 may be pressed toward the skin for a pre-set standard duration of about 1-10 seconds.

[0102] The device 10 is equipped with a button 2, which is pressed to initiate the operation. The button 2 may be positioned on top of an elastic cushion 28, which keeps the button 2 elevated when not in use. Pressing the button 2 activates microswitches 4 and 11, which in turn allow the electric current to flow through the inductive coils 17 and 26, initiating the movement of the piston 30.

[0103] Device 10 also includes data acquisition means 14 which may comprise components, such as LEDs 18 and / or a CMOS imager and / or a photoelectric cell and / or photoresistor 22. These components are used to monitor and measure blood volume changes in the tested body region. The data acquisition means 14 may be positioned in close proximity to the piston 30 to ensure accurate and real-time measurements. The signals collected by the data acquisition means 14 may be transmitted to a processor 16, which may be housed within device 10. Processor 16 analyzes the data optionally using specialized algorithms to calculate the capillary filling rate. The results of the analysis are optionally displayed on a digital or analog display 8, providing a clear and immediate output of the measured hemodynamic parameters. Once the duration of pressurizing force has elapsed, LEDs 18 and / or CMOS imager and / or the photoelectric cell and / or photoresistor 22 are turned on and signals from the CMOS imager and / or the photoelectric cell and / or photoresistor 22 are received and transmitted to the processor 16 where the data is processed and analyzed to show a digital or analogue display 8 of the capillary filling rate. At this point or slightly after (e.g., after 1-10 second), the current in the coils 17 and 26 is reversed and the piston 30 is lifted from the surface 20. At this point, there is no more force applied to the skin surface 20 and the blood, previously displaced from the area beneath the piston 30, is allowed to freely flow back. The device 10 is optionally powered by a battery 24, which may also be housed within the housing 6 of device 10. This allows for portable operation, making device 10 suitable for use in various clinical and non-clinical settings. The entire system 10 can be operated by a battery 24 or by an external power supply.

[0104] The design of the device 10 ensures that the pressure applied to the tested body region is sufficient to stop blood flow without causing discomfort. The abrupt release of pressure allows blood to flow freely back into the tested region, enabling device 10 to measure the capillary filling rate accurately and consistently. Figures 5a and 5b illustrate yet another exemplary device 100 for measuring capillary hemodynamics in a subject. Device 10 is designed to regulate blood flow in a tested body region, such as a finger F, by employing an enclosed pressurized chamber. In device 100 blood flow is controlled utilizing injection of air 112 so as to form a cell enclosure with high pressure that compresses the blood vessels within the finger F of a subject for a predetermined duration of time T. Device 100 comprises a rigid housing 106 which is essentially closed forming a cell enclosure that includes an opening 110 through which a finger F of a subject can be inserted therein. The device housing 106 forms a closed enclosure to accommodate the tested body region. The finger F of the examined person may be inserted into a housing 106 of the device 100 via a flexible shutter (not shown) which may constrain a transparent membrane 119 and prevent it from bulging out of the opening 110 through which the finger F was inserted, thereby preserving the integrity of the pressurized environment. The pressure inside housing 106 accommodating the transparent membrane 119 is elevated. The pressure within the housing 106 may be elevated to a level sufficient to compress the blood vessels in the tested body region. This may be achieved by a pressure source capable of injecting air 112 into the housing through one or more tubes 107. The pressure may be elevated to a level above the systolic pressure of the subject, such as 120 mm Hg, or 200 mm Hg or above, 300 mm Hg or above, or 400 mm Hg or above, by injecting air through a connector with tubes 107 for a predetermined duration of time T. The elevated pressure temporarily stops blood flow and optionally empties the blood vessels in the tested body region. The device 100 may include data acquisition means comprising a light source 118, which may be activated after the predetermined duration of pressure application. The light source 118 may be used in conjunction with a photoresistor 122 to measure changes in blood volume in the tested body region. Photoresistor 122 is positioned within the housing 106 and is in electrical communication with contacts 121. Once the time T has elapsed, light source 118 is turned on, the pressure in the housing 106 is abruptly reduced to atmospheric level allowing blood to flow freely back into the tested body region. Signals from a photoresistor 122 pass to the processor (not shown) which tracks the changes in light transmission, which correspond to the dynamics of blood return. The resistance of the photoresistor 122 is tracked through electrical contacts 121. The signals from the photoresistor 122 may be amplified using a Wheatstone Bridge 108, which is configured to enhance the sensitivity and accuracy of the measurements as shown in Figure 5b. Device 100 is designed to provide accurate and consistent measurements of capillary hemodynamics by ensuring that the pressure applied is sufficient to stop blood flow without causing discomfort. The use of a pressurized chamber, in combination with advanced data acquisition and signal amplification techniques, enables precise monitoring of blood volume changes in the tested body region.

[0105] Another exemplary device 200 for measuring capillary hemodynamics in a finger of a subject is shown in Figures 6a-c. Device 200 includes a pressurizing mechanism 212, a capillary hemodynamics signal acquisition 214 and a processor 216. Device 200 includes housing 206 comprising a bottom base platform 236 and a lid 238.

[0106] The lid 238 features an opening 210 through which the tested body region, such as a finger, can be inserted. In device 200, the finger F (shown in figures 12b and 12c) is inserted through opening 210 within the lid 238. On top of base platform 236 there is a cushion 225 on which the finger F can be placed. Cushion 225 may be made from various elastic materials such as silicon, a rubber or the like. Cushion 225 may feature a closed cell foam with compressibility characteristics. Cushion 225 may be characterized with compressibility characteristics in the range of 15 to 25 Shore A.

[0107] Lid 238 may couple the mechanical pressurizing mechanism 212, which is positioned directly above the tested body region. Mechanical pressurizing mechanism 212 is coupled to the lid 238 just above cushion 225. Mechanical pressurizing mechanism 212 comprises a piston 230. Piston 230 is moveable within piston chamber 227 and is actuated by miniature electromagnetic linear actuator 242 in piston chamber 227. The actuator 242 incorporates a reversing motion spring 220, which enables the controlled movement of the piston 230. When electric current is supplied to the actuator 242, it pushes piston 230 downward to apply pressure to the tested body region, for example, towards the finger F. The force generated by the actuator 242 and piston 230 is sufficient to create a pressure higher than the estimated systolic blood pressure of the subject, ensuring occlusion of blood flow in the tested subject. The applied force is sufficient to generate pressure that is higher than the estimated systolic blood pressure of the tested subject such as 150 or 175, or 200 mm Hg. As such, if the contact area of the piston 230 of the linear actuator is 2 cm2, the actuator 242 must generate a force of at least 400 or at least 460 or at least 520 g, but not greater than 800 g to avoid discomfort.

[0108] The device 200 is equipped with data acquisition means 214, which include LEDs 218 and an imager 222. Data acquisition comprising a plethysmograph configured to measure and receive one or more signals associated with one or more hemodynamic parameters in the tested body region comprises LEDs 218 and an imager 222. The imager 222 and LEDs 218 are positioned in close proximity to the piston 230 to ensure accurate and real-time data collection. The data acquisition means 214 are used to monitor changes in blood volume in the tested body region during and after the application of pressure. The device 200 can be opened by lifting the upper lid 238 via hinge 244 to help position the finger F accurately on the imager or sensor 222 and the LEDs 218. Device 200 may comprise a heating member 240 designed to maintain a temperature of the tested body region within a range of between 38-43°C (shown in Figures 6b - 6c). This feature ensures standardized testing conditions and prevents cold-induced vasoconstriction, which could affect the accuracy of the measurements.

[0109] The device 200 may be equipped with a wire to receive power supply, allowing it to operate continuously while being directly connected to an external power source. In an alternative embodiment, device 200 can be battery-operated 224, providing flexibility for wireless and portable use. The device 200 may be equipped with a USB connector 232 for power supply, external control and data download. The data processing can be done by a processor comprising a microprocessor, optionally placed inside the lower part of the housing 206 (not shown). The signal analysis is described further below but numerical results are shown on a small display screen 208. Display screen 208 shows the measured hemodynamic parameters, such as the capillary filling rate. The device 200 may be equipped with a control panel 234, which allows the user to operate the device and select the duration of compression. Control panel 234 may be used to turn the device 200 on and select the duration of compression and display information on when the device is turned on and ready for use. A button 202 is provided to initiate the measurement process. Button 202 is pressed in order to make a measurement, or, in certain configurations, a succession of measurements, for example 5 measurements one after the other. The duration of compression in each measurement may be pre-set to be 2 or 5 or 10 seconds.

[0110] The design of the device 200 ensures that the pressure applied to the tested body region is sufficient to stop blood flow without causing discomfort. The abrupt release of pressure allows blood to flow freely back into the tested region, enabling the device 200 to measure the capillary filling rate accurately and consistently. The combination of advanced pressurizing mechanisms, data acquisition means, and processing functionalities makes the device 200 a reliable tool for evaluating hemodynamic parameters in a standardized and automated manner.

[0111] Another exemplary configuration 300 of the herein disclosed devices is shown in Figure 7a. The device 300 is configured for measuring capillary filling rate of a finger F. Device 300 utilizes gas jet means for applying pressure to a tested body region, such as a finger F. This configuration provides a non-contact method for compressing the vasculature of the tested body region. The device 300 includes a pressurizing mechanism 312 that generates and directs one or more gas jets 354 toward the surface of the tested body region. Pressurizing mechanism 312 features one or more jets of gas such as air 354 emitted from a nozzle or a plurality of nozzles 356 at a high velocity denoted as ‘u’ that generates sufficient pressure on the surface of the finger F to compress and pressurize the soft tissues and vasculature of the finger F. The velocity of the gas jets 354 u may range from 50 meters per second (m / s) to 100 or 200 m / s. The pressure is generated by a compressor, or a compressed gas cylinder or a pump without or with a reservoir (not shown). The flow of gas 360 is controlled by a valve or solenoid valve 352, which regulates the initiation and cessation of the gas flow. The gas jets 354 are directed at the tested body region, such as the finger F, to compress and pressurize the soft tissues. The pressure may be released by turning the valve or solenoid valve 352 to allow the gas flow 360 to start. The force generated by the gas jets 354 is sufficient to stop blood flow in the tested body region by applying a pressure greater than the systolic blood pressure of the subject. The gas flow 360 that is required in order to generate a pressure that is greater than the patient’s systolic pressure is equal to the force of the jet 354 divided by the area of impingement. Typically, a force of at least 2N is required. The force may be within the range of 2-4 N. Such a force can be achieved by air speeds of 100-200 m / s. This flow velocity corresponds to a flow rate of approximately 10-20 liters per second when the gas is emitted through a 1 cm2nozzle 356.

[0112] The device 300 also includes a data acquisition means comprising 322, which may comprise a photoelectric cell or an imaging sensor or any other means as disclosed herein. The data acquisition means 322 is positioned in close proximity to the tested body region to monitor changes in blood volume. A transparent window (not shown) may be positioned between the data acquisition means 322 and finger F within of device 300 to allow the data acquisition means 322 to detect changes in skin color or light transmission, which are indicative of blood volume dynamics. The data acquisition means 322 together with a processor (not shown) measure the rate of blood return to the tested body region after the gas flow is abruptly stopped by the valve 352. The transparent window is used for the imager or photoelectric cell 322 to be able to monitor the change of skin color. When the flow 360 is abruptly stopped by closing valve 352, the imager or photoelectric cell 322 measures the rate of blood return to the finger F. The main advantage of this embodiment is that no contact is needed with the skin surface during the FFP measurement. An example of the implementation of this embodiment is shown in Figure 7b where uncompressed finger F 370 is seen on the left panel and the effect of a nozzle 356 emitting a jet 354 of air is causing an indentation and blanching of the finger 372 shown in the right panel. Once the jet flow is stopped, the blood returns to the finger, and the dynamics of this return can be recorded by photoelectric sensor or by video imaging. The device 300 is particularly suitable for use in clinical environments where non-contact methods are preferred or required.

[0113] Various methods for the data analysis are contemplated. An exemplary data analysis method is shown in Figure 8. In this example, the return of the blood to the tested region is modelled by a single exponent. This indicates that the circulation to the tested region acts as a uniform elastic vascular bed supplied by a common blood vessel. This uniform compartment system is modelled with a single exponent expressed mathematically as follows: Y = A * exp(-t / T) where A and T are constants representing the amplitude, and the time constant of the exponent, respectively, and t is time. As shown in figure 8, the cardiac pulsations before the pressure around the finger is elevated 402 and after the pressure is released 408 with no pulsations during the time that the supra-systolic pressure is sustained 406. The curve 404 modelled by the exponential equation Y=4e'1 25tis showing a very good fit to the FFP signal. As such, the signal can be represented by the two parameters of this exponential equation.

[0114] However, in some embodiments, the signal is found to be as shown in Figure 16 and could not be modelled by a single exponent. However, when the sum of two exponents with two different time constants and amplitudes is used to model the signal, the fit is precise as shown in Figure 9a. In this example the following equations are used

[0115] Y = Al* exp(-t / T1) + A2 * exp(-t / T2) where Al = 2 * A2 and T 1 = 10 * T 2

[0116] Al and A2 are being the amplitudes of the exponents and T1 and T2 are being the time constants of the exponents. Figure 9 shows the fitted two-exponents curve 502 corresponding to the sum of the fast exponent in graph 504 and the slow exponent 506 to generate the total as curve 508. These curves are plotted in a semi-log presentation where line 510 corresponds to curve 504, line 512 corresponds to curve 506 and curve 514 corresponds to curve 508.

[0117] An embodiment of the signal analysis element of this invention may be therefore based on a two-exponents curve-fitting of the signal. The parameters of the best-fit curve are then used to characterize the FFP signal. The physiological basis of this method is depicted in Figure 9b as a two-compartment system, a fast one and a slower one filling sequentially with blood upon release of the pressure on the tested area. Another embodiment is shown in Figure 10 where the analysis is done by performing the first derivative of the raw signal. The raw signal 602 from a normal patient is shown at the bottom panel of Figure 10a. The corresponding raw signal 608 from a patient with slow capillary filling is shown at the bottom panel of Figure 10b. The first derivative of the normal raw signal 606 is shown in the top panel of Figure 10a and the derivative of the data from the patient with slow capillary filling 610 is shown in the top panel of Figure 10b. Note that the amplitude 610 of the derivative is much smaller in Figure 10b than the amplitude 606 in Figure 10a. This embodiment can be derived by analogue circuit or by digital signal analysis. Secondary parameters, such as the duration of the capillary filling can also be derived by this method in an accurate way.

[0118] The herein devices configured for measuring capillary hemodynamics comprise one or more method steps as follows.

[0119] Pressurizing a tested body region for a predetermined duration to squeeze blood out and block blood flow in the tested body region. Abruptly removing the pressure to allow blood to return to the tested body region. Measuring blood volume in the tested body region immediately after the pressure is removed. Processing and analyzing the measured data of the blood volume to obtain a numerical value of the measured data. The numerical value may be, for example, blood flow rate (e.g., blood volume per time - such as liters per minute).

[0120] The tested body region may be compressed and pressurized for a pre-set duration to stop blood flow and squeeze blood out of the tested body region using a pressurizing system. The pressurizing system may include mechanical members that apply a controlled force on the tested area. This pressure applied may be achieved through various means, and mechanisms, such as an elastic sealed compartment that inflates to pressurize the body region, a plate pressed against the body region using an electromagnetic linear actuator, solenoid, piezoelectric element, or linear motor, and / or a jet of gas blown onto the surface of the body region at sufficient force and speed. The tested body region may be heated to a temperature between 37°C and 45°C prior to and during the procedure to allow standardized conditions. The pressurizing system may be designed to ensure portability and suitability for clinical settings, facilitating its use in various environments. The application of pressure may be controlled to ensure that the blood is effectively squeezed out of the tested region.

[0121] The process may involve the abrupt and full removal of compression and pressure from the tested body region, allowing blood to return unimpeded. This ensures that the blood flow is not obstructed as it re-enters the tested area. Blood in the tested body region is now free to flow and fille the vasculature of the tested body region. The removal of pressure may be achieved through various mechanisms, such as the use of mechanical members or controlled force, which are integral to the device. The device may utilize components like inductive coils or a miniature electromagnetic linear actuator to apply and then release the pressure.

[0122] Data acquisition means configured to measure one or more signals associated with blood volume in the tested body region are then utilized to measure the refill of the vasculature. The data acquisition means may comprise a plethysmograph configured to monitor the volume of blood in the tested body region. The data acquisition means may incorporate various devices and technologies. For instance, a photoplethysmography device may be employed, which can measure light transmission or reflection from the tested body region using a broad-spectrum light source or light-emitting diodes (LEDs) at specific wavelengths in the visible or infrared spectrum. This device may further include phototransistors, photodiodes, or avalanche photodiodes (APDs) to detect light changes. Additionally, a CMOS imager may be utilized to video-record the tested body region at a throughput of approximately 30 frames per second, providing a visual representation of blood volume changes. Other potential components of the data acquisition means may include a mercury-in-silastic strain gauge device, which can measure the circumference of the tested body region, or a magnetic field plethysmograph or magnetometer, which may detect changes in circumference. Furthermore, a gamma camera may be used to monitor the quantity of blood in the tested body region as a function of time, with a radioactive substance linked to red blood cells. Alternatively, an imaging device may be employed to monitor blood quantity, with a radio-opaque contrast material injected into the bloodstream. These various technologies and devices may work in conjunction to provide comprehensive data on blood volume changes.

[0123] Analysis of the capillary filling rate involves tracking and measuring the blood volume in the tested body region. This analysis may involve the extraction of numerical values that provide a simple and accurate characterization of the capillary filling rate. The analysis may utilize various algorithms and computational methods to process the blood volume data. An output of the analysis is then provided and may be presented on the display screen of the herein device. Exemplary method steps using an exemplary of the herein devices may include for example the following steps: a subject first puts its tested body region (e.g., a finger or a toe) on a flat surface of, for example, device 10. It is to be noted that the herein method steps apply also to devices 100, 200 and 300. Pressure is then applied onto the tested body region of the subject using pressurizing means such as a piston that presses the tested body region, gas jets applied onto the tested body region or increased pressure surrounding the tested body region. The data acquisition means may be operated to record the measurements / signals before pressure is applied, by the pressurizing mechanism. The device is then turned on to activate the pressurizing means. For example, microswitches 4 and 11 of device 10 may be activated so that electrical current flows through coils 17 and 26 to start moving piston 30 and pushing it down towards the skin of the tested body region for a duration of T seconds. Optionally, a heating element is activated, and LED lights are lit. After T seconds the pressurizing means cease to apply pressure. For example, in device 10 the current in coils 17 and 26 is reversed, and the piston is abruptly pulled back up. Data acquisition starts and the signals associated with the hemodynamics of the tested capillaries are collected and transferred to the processor. Data collection may be done at a rate of 10 - 100 samples per second at 8-24 bits resolution for a duration of 5-25 seconds. A microprocessor analyses the data, determines signal quality, calculates the log 10 of the values and curve-fit the semi-log best-fit curve to the data. The parameters (slope, magnitude) of the best-fit semi-log curves are calculated as well as the regression coefficients. Raw data and best-fit parameters are stored in the processor’s memory. Information on the signal quality, parameters and a graphic display of the signal are shown on a display screen as alfa-numeric and / or graphic format. The herein device can calculate and show a trend of changes of the parameters of the best-fit curves or perform averaging of multiple signals obtained over time.

[0124] GENERAL DEFINITIONS

[0125] As used herein the terms ‘a’ and ‘an’ may mean ‘one’ or ‘more than one’.

[0126] As used herein the terms ‘comprising’, ‘including’, ‘containing’, ‘featuring’, ‘having’ and any forms of the terms thereof are inclusive and open ended and do not exclude additional elements or method steps, which are not recited.

[0127] The term 'consisting essentially of’ as used herein means that the scope is limited to the specified elements and those that do not materially affect the basic and novel characteristic(s) of the claimed device and materials.

[0128] Each of the phrases 'consisting of and 'consists of, as used herein, means 'including and limited to'. The term 'method', as used herein, refers to steps, procedures, manners, means, or / and techniques, for accomplishing a given task including, but not limited to, those steps, procedures, manners, means, or / and techniques, either known to, or readily developed from known steps, procedures, manners, means, or / and techniques, by practitioners in the relevant field(s) of the disclosed invention.

[0129] Throughout this disclosure, a numerical value of a parameter, feature, characteristic, object, or dimension, may be stated or described in terms of a numerical range format. Such a numerical range format, as used herein, illustrates implementation of some exemplary embodiments of the invention, and does not inflexibly limit the scope of the exemplary embodiments of the invention. Accordingly, a stated or described numerical range also refers to, and encompasses, all possible sub-ranges and individual numerical values (where a numerical value may be expressed as a whole, integral, or fractional number) within that stated or described numerical range. For example, a stated or described numerical range 'from 1 to 6' also refers to, and encompasses, all possible sub-ranges, such as 'from 1 to 3', 'from 1 to 4', 'from 1 to 5', 'from 2 to 4', 'from 2 to 6', 'from 3 to 6', etc., and individual numerical values, such as T, '1.3', '2', '2.8', '3', '3.5', '4', '4.6', '5', '5.2', and '6', within the stated or described numerical range of 'from 1 to 6'. This applies regardless of the numerical breadth, extent, or size, of the stated or described numerical range.

[0130] All ranges disclosed herein include the endpoints. The use of the term “or” shall be construed to mean “and / or” unless the specific context indicates otherwise.

[0131] The term 'about', in some embodiments, refers to ±30 % of the stated numerical value. In further embodiments, the term refers to ±20 % of the stated numerical value. In yet further embodiments, the term refers to ±10 % of the stated numerical value.

[0132] EXAMPLES

[0133] Example 1 - a typical test assay using an FFP.

[0134] When pressure is applied to a finger, it compresses blood vessels, reducing blood volume in the tissue. Since blood absorbs light, less blood means less absorption, allowing more light to pass through. As a result, light transmission increases when pressure is high. Figure 11 shows the load (pressure) applied to a tested body region. This pressure should be greater than the systolic blood pressure of the tested person; for example, above 200 mm Hg or above 250 mm Hg, or in terms of load above 200 kg / cm2,or above 250 kg / cm2. The pressure is applied for a pre-determined duration “T”, in most cases, 10 seconds. Figure 11b shows the light transmission through the tested region when photoplethysmography of device 100 is used to measure and monitor the blood volume.

[0135] Example 2 - physiological tests to validate that the measurement of a typical capillary filling method is indeed specific and sensitive to flow of blood to the test region.

[0136] Figure 12 illustrates that the measurement is indeed specific and sensitive to flow of blood to the finger. The finger was first pressurized to a supra-systolic pressure to remove the blood and block blood flow in the arteries. The blood flow to the subject’s hand was then occluded by inflating a standard blood-pressure cuff around the forearm to a supra-systolic pressure. The pressure on the finger was then released (point X) and a few seconds later the pressure on the forearm was released (point Y). Figure 12 shows that when the blood flow in the hand is blocked, there is no signal. However, once the forearm cuff is deflated, the typical signal is seen, indicating that blood flow is indeed the cause of the detected signal.

[0137] Example 3 - evaluation of the sensitivity of the FFP rate signal in vasoconstriction conditions caused by low temperature.

[0138] The sensitivity of the FFP rate signal was evaluated in well-known case of vasoconstriction, caused by cold temperature. The tested hand was cooled by holding it in water at 19°C. Serial measurements of FFP rate were then conducted while the tested finger was warming up. Figure 13 shows the FFP rates before and after cooling the tested finger. Figure 14 shows the FFP rates linearly increasing over time while the temperature was rising. This is an indication that the FFP rate measurement is sensitive to changes in resistance to blood flow due to cold-induced vasoconstriction. The lower panel shows signals at normal conditions, and the upper panel shows signals under cool temperature.

[0139] Example 4 - comparison between the rate of blood filling measured by FFP and by VOP.

[0140] The rate of blood filling measured by FFP (top) and by VOP (bottom) was compared and shown in Figure 15. The measurements were done in duplicate on the same person at the same time and under the same conditions. The rate of blood filling (reduced light transmission) is much slower with VOP as seen by the added dashed lines. Note also that the FFP measurement consists of two slopes, a fast and a slow, whereas the VOP tracing consists of only one slope.

[0141] Table 1 - the slope values during measurements of FFP and VOP in 3 normal subjects

[0142] The measurements were done multiple times under the same conditions. The slope values of the FFP measurements were 3-7 times steeper than in the VOP test, indicating faster filling of the tested area (finger) when cuff pressure is not restricting the flow into the tested area.

[0143] An exponential curve was fitted to the FFP signal as shown in Figure 16. The fast drop in light transmission follows this exponent accurately. However, the subsequent slow drop in light transmission deviates from the single exponent. This observation prompted the two- compartment analysis as shown below whereby the first exponent is very quick and the second exponent is slow, allowing a good visual separation between the rates (exponents).

Claims

CLAIMS1. A device for non-invasive monitoring of vasculature hemodynamics in a subject, the device comprising means configured to controllably apply to a tested body region a pressure that exceeds a systolic blood pressure of the subject and abruptly release said pressure after a predetermined duration to permit blood to freely flow into said tested body region; data acquisition means configured for measuring one or more signals associated with blood volume in the tested body region; and a processor operatively coupled to the data acquisition means configured to analyze the one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject.

2. The device of claim 1, wherein the hemodynamic status comprises one or more hemodynamic parameters selected from the group consisting of blood pressure, blood flow, blood volume change, blood filling rate, oxygen saturation parameter, and blood vessels capacitance (vasculature compliance).

3. The device of claim 1 or 2, wherein the means to apply pressure to the tested body region comprise at least one member selected from the group consisting of a mechanical pressurizing mechanism configured to mechanically compress the blood vessels in said body region of said subject, gas jets configured to be blown toward the tested body region, and means for increasing pressure within a closed chamber accommodating the tested body region.

4. The device of claim 3, wherein the mechanical pressurizing mechanism comprises a pressurizing plate, surface, or piston actuated via an electromagnetic linear actuator to squeeze the tested body region, or wherein the pressurizing mechanism comprises a circumferential inflatable member configured to apply supra-systolic pressure on the tested body region.

5. The device of claim 3, wherein the means configured to controllably apply pressure comprise one or more nozzles for emitting gas jets directed toward the tested body region and configured to be blown toward the tested body region.

6. The device of claim 3, wherein the means to apply pressure to the tested body region comprises a closed chamber with a pressure source for increasing pressure within the chamber accommodating the tested body region.

7. The device of any one of claims 1-6, wherein the data acquisition means comprise at least one member selected from the group consisting of an optical plethysmograph, a strain gauge plethysmograph, a mercury-in-silastic strain gauge, an electromagnetic inductive sensor, a gamma camera, an air displacement plethysmograph, a photoresistor, a complementary metal-oxide-semiconductor (CMOS) image sensor, and a photoelectric diode.

8. The device of any one of claims 1-7, which is configured for determining the capillary filling rate of the subject.

9. The device of any one of claims 1-8, wherein the processor is adapted to calculate a numerical best-fit single exponent of said measured signal to find the timeconstant of the rate of return of blood to the tested body region; calculate a numerical best-fit two exponents of said measured signal to find the timeconstants of the fast and slow rates of return of blood to the tested body region; and / or provide a derivative of the measured signal and measure the amplitude and duration of the derivative of said signal.

10. The device of any one of claims 1-9, wherein the pressure applied to the tested body region is sufficient to stop the arterial blood flow to the tested body region.

11. The device of any one of claims 1-10, wherein the applied pressure comprises applying a force of at least 400 g per square cm (g / cm2).

12. The device of claim 11, wherein the applied pressure comprises applying a force of at least 800 g per square cm (g / cm2).

13. The device of any one of claims 1-12, wherein the tested body region is a flat part of the body.

14. The device of any one of claims 1-13, wherein the flat part of the body is a finger or a toe.

15. The device of any one of claims 1-14, wherein the predetermined duration is in the range of 1 to 10 seconds.

16. The device of any one of claims 1-15, further comprising a heating member to maintain the temperature of the tested body region at 38°C to 43°C.

17. The device of any one of claims 1-16, wherein the data acquisition means comprises a light source emitting in the visible wavelength.

18. The device of any one of claims 1-17, wherein the light source comprises a near infrared wavelength light source, an infrared wavelength light source, and / or a light emitting diode.

19. The device of any one of claims 1-18, wherein the analysis is performed by curve fitting to a single exponent or multiple exponents.

20. The device of any one of claims 1-19, further comprising a display screen configured to show the output indicative of the measured hemodynamic status of the subject.

21. The device of claim 20, wherein the measured hemodynamic status is a blood filling rate, and the display screen is configured to show at least one of the amplitude of the signal derivative, and / or a measured time constant.

22. The device of any one of claims 1-21, configured to conduct multiple measurements over time.

23. The device of any one of claims 1-22, wherein the processor is configured to calculate averages, trends and / or standard deviations of the signals.

24. The device of any one of claims 1-23, further comprising a controller configured to initiate, control the duration of, and / or stop the pressure applied on the tested body region.

25. The device of any one of claims 1-24, comprising a housing configured to accommodate the means configured to controllably apply pressure to a tested body region, the data acquisition means, and optionally, the processor.

26. The device of any one of claims 1-25, further comprising a platform for positioning the tested body region.

27. The device of any one of claims 1-26, wherein the means configured to controllably apply pressure to a tested body region, and the data acquisition means are positioned in close proximity to each other.

28. A non-invasive method for monitoring hemodynamic status of a subject, the method comprising: applying to a tested body region a pressure that exceeds a systolic blood pressure of the subject for a predetermined duration; abruptly releasing the pressure to permit blood to freely flow into the tested body region; measuring one or more signals associated with blood volume in the tested body region using a data acquisition means; and analyzing the one or more measured signals to provide an output indicative of the hemodynamic status of the subject.

29. The method of claim 28, wherein removing the pressure applied onto the tested body region comprises abrupt removal of said pressure.

30. The method of claim 28 or 29, wherein the measuring step is conducted immediately after the step of releasing the pressure applied onto the tested body region.

31. The method of any one of claims 28-30, wherein applying pressure comprises pressing the tested body region, blowing one or more gas jets toward the tested body region or increasing the pressure surrounding the tested body region.

32. The method of any one of claims 28-31, further comprising initiating and controlling the testing process using a controller.

33. The method of any one of claims 28-32, further comprising accommodating the tested body region in a device comprising a housing.

34. The method of claim 33, further comprising positioning the tested body region onto a platform within the housing.

35. A device for monitoring capillary hemodynamics in a subject, the device comprising a mechanism configured for applying one or more gas jets imposing a compression force to a tested body region to stop blood flow in the tested body region and empty it from blood for a predetermined duration; data acquisition means configured to measure one or more signals associated with blood volume in the tested body region; and a processor configured to analyze said one or more measured signals and provide an output indicative of the vasculature hemodynamic status of the subject.

36. The device of claim 35, wherein the gas jets are a plurality of jets.

37. The device of claim 35, wherein the gas is air.

38. The device of claim 35, wherein the gas is selected from the group consisting of CO2,N2, O2, a noble gas, and a combination thereof.

39. The device of claim 35, wherein the noble gas is selected from He, Ar, and a combination thereof.

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