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    • 专利摘要:
    NON-INVASIVE GLUCOSE MEASUREMENT DEVICE In order to increase the accuracy of non-invasive glucose measurements, the device uses a combination of three non-invasive methods: ultrasonic, electromagnetic and thermal. The non-invasive glucose monitor comprises a main unit, which controls three different sensor channels (one per technology), located in an external unit configured as an ear socket attached to the subject's earlobe. For the realization of the ultrasonic channel, ultrasonic piezoelements are positioned in opposite portions of the ear socket and therefore on opposite sides of the ear lobe. For the implementation of the electromagnetic channel, capacitor plates are positioned in opposite portions of the ear socket and the ear lobe serves as a dielectric. The thermal channel includes a heater and a sensor positioned in the ear socket in juxtaposition close to the ear lobe.
    公开号:BR112012027711B1
    申请号:R112012027711-1
    申请日:2011-04-26
    公开日:2021-03-02
    发明作者:Avner Gal；Alexander M. Raykhman；Eugene Naidis；Yulia Mayzel；Alexander Klionsky；Anatoly Diber
    申请人:A. D. Integrity Applications Ltd.；
    IPC主号:
    专利说明:

    Field of invention
    [001] This invention relates to the medical field and the treatment of specific diseases and, in particular, to a device for the non-invasive measurement of a patient's blood glucose level. Fundamentals of the invention
    [002] Diabetes and its complications impose significant economic consequences on individuals, families, health systems and countries. Annual spending on diabetes in 2007 in the US alone was estimated to be over $ 170 billion, attributed to both direct and indirect costs (American Diabetes Association. Economic Costs of Diabetes in the US in 2007. Diabetes Care. March 2008, 31 ( 3): 1-20). In 2010, health spending on diabetes is expected to represent 11.6% of total global health spending. It is estimated that approximately 285 million people worldwide will have diabetes in 2010, representing 6.6% of the adult human population, with an estimated 438 million by 2030 (International Diabetes Federation. Diabetes Atlas, Fourth Edition. International Diabetes Federation, 2009).
    [003] In recent years, research has conclusively demonstrated that better glucose control reduces long-term complications of diabetes (DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin- dependent diabetes mellitus.North England Journal of Medicine.30 September 1993; 329 (14): 977-986; UKPDS Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk complications in subjects with type 2 diabetes (UKPDS33 The Lancet. 12 September 1998; 352 (9131): 837-853). According to the American Diabetes Association (ADA), self-monitoring of blood glucose (AMGS) has a positive impact on the outcome of treatment with insulin, oral agents and medical nutrition (American Diabetes Association. Clinical Practice Recommendations, Standards of medical care in diabetes. Diabetes Care. 29 January 2006: S4-S42). In its publication “Consensus Statement: a European Perspective”, the Diabetes Research Institute in Munich recommends the AMGS for all types of diabetes treatment approaches, in order to achieve an appropriate glucose control and values that are close to the normal value , without increasing the risk of hypoglycemia (Schnell O et al., Diabetes, Stoffwechsel und Herz, 2009; 4: 285-289). In addition, special guidelines with appropriate recommendations have recently been launched by the International Diabetes Federation (IDF), to support AMGS for DMT2 patients treated without insulin (Recommendations based on a workshop of the International Diabetes Federation Clinical Guidelines Taskforce in collaboration with the SMBG Internation Working group. Guidelines on Self-Monitoring of Bloog Glucose in Non-Insulin Treated Type 2 Diabetics. International Diabetes Federation, 2009).
    [004] AMGS has several benefits both in education and in the treatment of diabetes. It can help facilitate diabetes management by the individual by providing an instrument for an objective response to the impact of daily lifestyle, individual glucose profiles, including the impact of physical activity and diet on the profile, and thereby strengthens the individual to make the necessary changes. In addition, AMGS can support medical staff to provide individually tailored recommendations on lifestyle components and blood glucose-lowering (GS) medications, thereby helping to achieve specific glycemic goals.
    [005] The inconvenience, expenses, pain and complexity involved in conventional (invasive) AMGS, however, lead to its underutilization, mainly by people with type 2 diabetes (Mollema ED, Snoek FJ, Heine RJ, Van der Ploeg HM. Phobia of self-injecting and self-testing in insulin treated diabetes patients: Opportunites for screening.Diabet Med. 2001; 18: 671-674; Davidson MB, Castellanos M, Klain D, Duran P. The effect of self-monitoring of blood glucose concentrations on glycated hemoglobin levels in diabetic patients not taking insulin: a blinded, randomized trial.Am J Med. 2005; 118 (4): 422-425; Hall RF, Joseph DH, Schwartz-Barcott D: Overcoming obstacles to behavior change in diabetes self-management (Diabetes Educ. 2003; 29: 303-311). The availability of an accurate, painless, inexpensive and easy to operate device will encourage more frequent testing (Wagner J, Malchoff C, Abbott G. Invasiveness as a Barrier to Self-Monitoring of Blood Glucose in Diabetes. Diabetes Technology & Therapeutics. August 2005 ; 7 (4): 612-619; Soumerai SB, Mah C, Zhan F, Adams A, Baron M, Fajtova V, Ross-Degnan D. Effects of health maintenance organization coverage of self-monitoring devices on diabetes self-care and glycemic control Arch Arch Med 2004; 164: 645-652), leading to tighter glucose control and a delay / reduction in long-term complications and their associated health costs.
    [006] Non-invasive glucose monitoring (NI) can decrease the costs of AMGS and significantly increase the frequency of tests. The main concern in NI methods is the achievement of high precision results, despite the fact that no direct measurement of blood or interstitial fluid is performed.
    [007] Therefore, as is well known in the medical arts, one of the most important blood components for diagnostic purposes is glucose, especially for diabetic patients. The typical and well-known technique for determining blood glucose concentration is to obtain a blood sample and apply this blood to an enzymatically medicated colorimetric strip or electrochemical probe. This is usually achieved from a finger prick. For diabetic patients who may need to measure blood glucose a few times a day, it can be seen immediately that this procedure causes a great deal of discomfort, considerable irritation to the skin and, in particular, the finger prick and, of course, infection.
    [008] For many years, there have been a number of procedures for monitoring the level of glucose in humans and animals. These methods, however, generally involve invasive techniques and, therefore, carry some degree of risk, or at least some discomfort, for the patient. Recently, some non-invasive procedures have been developed, but they still do not always offer optimal blood glucose measurements. At present, there is no confirmed practical solution.
    [009] Most non-invasive monitoring techniques have emphasized the use of incident radiation, which is capable of penetrating tissue and probing blood. Currently known approaches to non-invasive glucose measurement are mainly based on optical technology. The relatively unusual and less successful electrical measurements focus on the dielectric properties of aqueous solutions in a given frequency range, typically between 1 - 50 MHz. In one way or another, such methods attempt to monitor the influence of glucose or another analyzed concentration about the glucose dielectric frequency response itself, or the side effect on water.
    [0010] Although investigations have been made on the use of acoustic monitoring, past studies have been predominantly directed towards differences in acoustic velocity between organs. These studies have attempted to correlate variations in acoustic velocity with chronic or continuous sick states. In addition, there is a large body of medical and scientific literature related to the use of acoustic absorption and spreading properties of organs for imaging, therapeutic and even diagnostic purposes.
    [0011] In the previous techniques, only one parameter is measured. Thus, the possibility of an error is increased.
    [0012] Freger (US patent 6,954,662) discloses a non-invasive technique and methods (but not devices) for measuring the speed of sound through the blood, the conductivity of the blood, and the thermal capacity of the blood. Subsequently, the glucose level for each of the three measurements is calculated, and the final glucose value is determined by a weighted average of the three calculated glucose values.
    [0013] Although Freger mentions that measurements of the speed of sound through the blood, the conductivity of the blood, and the thermal capacity of the blood can be taken, there is no disclosure as to how a device could be built to carry out such measurements. The invention described and claimed here, therefore, is an improvement over Freger, and specifies a device on which these measurements can be made.
    [0014] Therefore, there is a need for a more accurate non-invasive device for measuring the glucose level, by monitoring multiple parameters on a single device. Accordingly, an object of the present invention is to provide a non-invasive device for measuring a subject's blood glucose level. These objectives are achieved by the resources found in the claims and the description below, in particular by the following preferred aspects of the invention relating to additional and / or alternative modalities. Brief description of the invention
    [0015] These and other objectives of the invention are achieved by a device, preferably a unitary device, which is capable of non-invasively measuring the blood glucose level by three different protocols.
    [0016] In particular, the device according to the present invention preferably includes a main unit, containing hardware and also software applications, and preferably external unit (s) / external device (s) (preferably ear clip) for attachment to the patient. The external unit comprises a first and second portions that are connected to each other, the first and second portions being located on opposite sides of a part of the patient, to which said external unit is attached. For example, when the external unit is attached to a patient's earlobe, the two opposite sides are located on the two opposite sides of the earlobe, respectively.
    [0017] It is preferable to incorporate in the unitary external unit at least one of the following three elements, which perform three separate and distinct non-invasive glucose measurements. In addition, it is still preferable to provide at least two or three elements that perform two or three separate and distinct non-invasive glucose measurements, respectively. According to a preferred embodiment of the invention, at least three different elements for carrying out three separate and distinct non-invasive glucose measurements are provided within a unitary external device, such as, for example, within a single case.
    [0018] It must be observed and understood that each of the measurement channels is new and innovative in itself. Therefore, each measurement channel can be used alone (or with other measurement channels). By combining the three measurement channels in a single device, measurements are obtained from three separate and unique measurement channels, thereby improving the final measurement.
    [0019] For invasive measurement through the use of ultrasound, preferably a transmitter (such as an ultrasound transmitter) and a receiver (such as an ultrasound receiver) are mounted on opposite sides of the external unit. When the external unit is fitted to the patient, a portion of the patient's body (such as the earlobe) is located between the transmitter and the receiver. Upon receipt of the resulting signal, after it passes through the patient, the receiver sends the signal to the main unit for processing by appropriate algorithms. In some embodiments, membranes can be used to cover and protect the transmitter and receiver.
    [0020] To carry out an electromagnetic measurement, a capacitor is defined in the external unit. The capacitor plates are positioned on opposite sides of the external device, and the body part (such as the earlobe) disposed between the parts of the external unit serves as the dielectric. In some cases, the membrane used to protect or cover the transmitter and receiver can also serve as the capacitor plates.
    [0021] The third technology is based on thermal technology to measure the level of glucose. For this purpose, preferably a heater and a sensor are provided in the external device. It is preferable that the heater and the sensor (thermal sensor) are provided on opposite sides of the external device. According to another preferred embodiment, however, it is preferred to mount the heater and the sensor on the same side on the two opposite sides, for example, at the end of one side of the external unit a heater and a sensor are positioned.
    [0022] The objectives of the present invention are achieved, for example, by the following aspects of the invention.
    [0023] According to a first aspect, a unitary device for the non-invasive measurement of the glucose level in a subject comprises: ultrasonic piezoelements positioned in opposite portions of the device and involving a part of the subject's body to which the device is attached; capacitor plates positioned in opposite portions of said device and involving said part of the subject's body to which the external medium is fixable; self-oscillating means connected to said capacitor plates; and a heater and a sensor positioned in juxtaposition close to said part of the subject's body to which the device is fixable.
    [0024] In a preferred embodiment, the device further comprises an external means (such as a fitting for the ear) for attachment to the subject's body, with the ultrasonic piezo elements, the capacitor plates and the heater and sensor contained within said external means .
    [0025] There may also preferably be a main unit for the control of measurements and the calculation of the glucose level; and means of electrical connection of the main unit to the external environment, galvanic or wireless.
    [0026] Preferably, membranes cover the ultrasonic piezoelements.
    [0027] Ultrasonic piezoelements can preferably include a transducer and a receiver.
    [0028] Preferably, the capacitor plates comprise membranes. In such an embodiment, the membranes can also cover the ultrasonic piezoelements.
    [0029] A preferred embodiment may include means of determining a distance between opposite portions of said external environment. In some embodiments, this medium may include a magnet and a sensor.
    [0030] There may also preferably be an adjustment screw that determines the distance between opposite portions of said external means.
    [0031] In some embodiments, an ambient temperature sensor may be included.
    [0032] According to other aspects, the individual measurement channels can be used separately.
    [0033] According to a second aspect of the invention, a device for non-invasive measurement of the glucose level in a subject may comprise a wrapper, capacitor plates positioned on opposite portions of the wrapper and surrounding a part of the subject's body to which the subject device is fixable, and self-oscillating means connected to the capacitor plates.
    [0034] In a preferred embodiment, this device also includes processing means for calculating the glucose level based on a tissue impedance signal, and means of communicating the tissue impedance signal to the processing means.
    [0035] According to an alternative version of this modality, there may also be ultrasonic piezoelements positioned in opposite portions of the wrapper and involving said part of the subject's body to which the device is fixable. Capacitor plates comprised of membranes can be included, and the membranes can cover the ultrasonic piezoelements.
    [0036] A different alternative version of this modality may include ultrasonic piezoelements positioned in opposite portions of the envelope and involving the part of the subject's body to which the device is attached, means of detecting a phase change between a transmitted wave and a received wave , and processing means for the calculation of the glucose level based on the phase change in communication with the detection means.
    [0037] According to a third alternative version of this modality, there may also be a heater and a sensor positioned on the device in juxtaposition close to the part of the subject's body to which the device is fixable. Means of communicating the heat transfer characteristics to the processing means for calculating the glucose level can be included.
    [0038] According to a third aspect of the invention, a device for the non-invasive measurement of glucose level, attached to a part of a subject's body, comprises ultrasonic piezoelements positioned in opposite portions of the device and involving a part of the body of the subject subject to which the device is fixable, and means of detecting a phase change between a transmitted wave and a received wave.
    [0039] Processing means for calculating the glucose level based on said phase change in communication with the detection means may preferably be included.
    [0040] According to an alternative version of this modality, there may also be a heater and a sensor positioned on the device in juxtaposition close to the part of the subject's body to which the device is fixable. Means of communicating the heat transfer characteristics to the processing means for calculating the glucose level can be included.
    [0041] According to a fourth aspect of the invention, a device for non-invasive measurement of glucose level, attached to a part of a subject's body, comprises a heater and a sensor positioned on the device in juxtaposition close to the body part of the subject to which the device is fixable, and means of communicating the characteristics of thermal transfer to the means of processing for the calculation of the glucose level.
    [0042] Other objectives, resources and advantages of the present invention will be evident from reading the following detailed description in conjunction with the drawings and the claims. Brief description of the drawings
    [0043] The matter considered as an invention is particularly indicated and claimed in the concluding portion of the report. The invention, however, both in terms of organization and operation, together with its objectives, resources and advantages, can be better understood with reference to the following detailed description when dealing with the accompanying drawings, which illustrate examples of modalities of the invention , in which: - Figure 1 is a view of the present invention, showing the main unit (UP) and the personal ear socket (EOP); - Figure 2 is a side view, partially broken and cut, of the EOP; - Figure 3 is a view of the sensor-tissue structure for a thermal measurement channel modality; - Figure 4 is a graph showing the raw heating process of the sensor-tissue structure in a subject, reflecting different levels of glucose; - Figure 5 is a graph showing the integrated thermal signal and equivalent corrected temperature in a subject versus the glucose level; - Figure 6A is a schematic representation of the earlobe between the two ultrasonic piezoelements of the ultrasonic measurement channel; - Figure 6B is a graph showing the phase change between the received and transmitted waves, measured as ΔΦ; - Figure 7 is a graph showing the phase change versus the frequency of the input transducer in the low frequency region, which proved to be the ideal frequency during calibration for a subject; - Figure 8 is a graph for a subject, in the ultrasonic channel, showing the phase change (measured at the chosen frequency), corrected for temperature versus glucose level; Figure 9 is a schematic illustration showing the electromagnetic channel; - Figure 10 is a graph showing the electromagnetic signal (frequency) corrected for temperature versus glucose level, for a subject; Figure 11 is a perspective view of the ear socket; Figure 12 is a side view of the ear socket; Figure 13 is a side view, partially broken and cut, of the ear socket; Figure 14A is a perspective view of the elements of the thermal channel; Figure 14B is an end view, in partial section, of the elements of an alternative embodiment of the thermal channel; Figure 14C is a view similar to Figure 14B and shows an alternative embodiment; - Figure 15 is a cross-sectional side view of a membrane for the ultrasonic transducer, which preferably also serves as one of the capacitor plates for the electromagnetic channel; Figure 16 is a cross-sectional side view of a second membrane for the ultrasonic transducer, which preferably also serves as one of the capacitor plates for the electromagnetic channel; Figure 17A is an enlarged side cross-sectional view of the tip of the ear socket and shows the elements that constitute the measurement channels; and - Figure 17B is an enlarged upper cross-sectional view of a portion of the tip of the ear socket. Detailed description of the preferred modality
    [0044] In the following detailed description, several specific details are presented in order to offer a complete understanding of the invention. However, it should be understood by those skilled in the art that the present invention can be put into practice without these specific details. In other cases, well-known methods, procedures and components have not been described in detail so as not to obscure the present invention.
    [0045] The preferred mode of the system and its advantages are best understood with reference to the drawings and the following detailed description, in which similar numbers indicate similar and corresponding parts in the various drawings. References to preferred modalities are for the purpose of illustration and understanding, and should not be construed as limiting.
    [0046] Although the description refers to a human patient, it should be noted that the device can be used to measure glucose in any subject, including animals.
    [0047] In particular, the device includes a main unit 10 that contains the software applications and an external unit 12 for attachment to the patient. Typically, the external unit is placed on the patient's lobe (or subject or animal), so that the external unit is typically configured as an earloop.
    [0048] A cable 14 is preferably used to provide an operational connection between the main unit 10 and the external unit 12. It should be noted that wireless technology (for example, Bluetooth) can also be used, and the cable can be avoided .
    [0049] It should be noted that the external unit 12 can be placed in any other suitable location on the subject's body, such as a finger or toe, the skin that is between the thumb and the index finger. Generally, a part of the body that has skin and tissue characteristics similar to those of the earlobe should be used. When the external unit is placed on the body at a point other than the earlobe, some adjustments to the algorithms may be necessary, as the characteristics of the skin and tissues are not uniform throughout the body.
    [0050] With reference to Fig. 1, a unitary non-invasive device for measuring multiple glucose values and then obtaining a final glucose reading is shown. In order to increase the accuracy of non-invasive glucose measurements, the device uses a combination of three non-invasive methods: ultrasonic, electromagnetic and thermal. These methods take into account the physiological reaction of the tissue to changes in glucose, resulting in changes in physical properties, such as electrical and acoustic impedances, as well as the thermal transfer characteristics (TT) of cellular, interstitial and plasma compartments, by virtue of of changes in ion concentration, density, compressibility and hydration of these compartments.
    [0051] As shown in Fig. 1, this non-invasive glucose monitor comprises a main unit (UP) 10, which controls a plurality of different channels of different sensors (preferably one by technology), located in an external unit configured as a personal ear fitting (EOP) 12 (Fig. 1). To perform a local measurement, the EOP 12 is attached externally to the user's earlobe for the duration of the measurement (about 1 minute) and is then removed. A cable 14 (or any known wireless technology (for example, Bluetooth)) connects these two components of the device.
    [0052] The unique aspect of the invention is that the (single) external unit 12 comprises more than one measurement channel / protocol. More preferably, it comprises all the elements that perform a plurality of separate and distinct non-invasive glucose measurements. This single external device offers the advantage that only a single device needs to be connected to the subject's body, which is convenient for a doctor and / or patient. In the preferred embodiment, the external unit is configured as an earloop 12.
    [0053] It should also be noted and understood that each of the measurement channels is in itself new and innovative. Therefore, each measurement channel can be used alone (or with other measurement channels). By combining the three measurement channels in a single device, measurements are obtained from three separate and unique measurement channels, thus improving the final reading.
    [0054] Blood glucose variations affect thermal transfer characteristics (TT) through changes in thermal capacity (Zhao Z., Pulsed photoacoustic techniques and glucose determination in human blood and tissue. Acta Univ. Oul C 169. Oulu, Finland , 2002), density (Toubal M., Asmani M., Radziszewski E., Nongaillard B., Acoustic measurement of compressibility and thermal expansion coefficient of erythrocytes. Phys Med Biol. 1999; 44: 1277-1287), and conductivity (Muramatsu Y., Tagawa A., Kasai T., Thermal conductivity of several liquid foods. Food Sci. Technol. Res. 2005; 11 (3): 288-294) due to water / electrolyte changes (Hillier TA. Abbot RD, Barret EJ. Hyponatremia: evaluating a correction factor for hyperglycemia. Am J Med. Apr 1999; 106 (4): 399-403; Moran SM, RL Jamison. The variable hyponatremic response to hyperglycemia. West J Med. Jan 1985; 142 (1): 49-53). Thus, the change in heat transfer processes in the mechanical structure of a multilayer sensor-tissue is a direct result of changes in glucose concentration (Wissler EH. Pennes' 1948 paper revisited. J Appl Physiol. Jul 1998; 85 (1): 35-41). The higher the glucose concentration, the lower the thermal capacity and the lower the thermal conductivity, thus causing a greater temperature rise in the outer layers of tissue in reaction to heating. As the sensor (s) (for example, thermistor (s)), according to the present invention, is (are) preferably mounted (s) / fixed (s) on the epidermal layer, the rate and the magnitude of the temperature change measured after heating are greater than in the internal tissues.
    [0055] The thermal method according to the present invention applies a specific amount of energy to the tissue. Preferably, the rate and / or magnitude of the temperature variation, caused by the application of the known amount of energy to the fabric, are functions of the thermal capacity, density and thermal conductivity of the fabric. Thus, the device according to the present invention offers means for the glucose level to be preferably assessed indirectly by measuring variations in the characteristics of TT, obtained after heating the tissue for a predetermined duration of time.
    [0056] Fig. 3 shows a sensor-tissue structure, according to a preferred embodiment of the present invention. A bottom plate serves as a heater 18 and thermal conductors 20 are included (see Fig. 17). A thermal sensor 22 is located in the middle between the conductors 20. As shown in Fig. 2, the thermal sensor is located at the tip 24 of the ear socket (EOP) 12.
    [0057] With reference now to Figs. 12 and 13, the thermal module, which preferably comprises a thermistor 22, a heater 18 and conductors 20, located in an ear 26 that extends from the end of one side of the ear socket 12 (for example, in the first portion of the ear fitting). The opposite surface 28 (i.e., the second portion of the ear socket) is preferably empty, without thermistor elements. In other words, it is preferable that the heater 18 and the thermal sensor 22 are located on the same side with respect to the ear lobe, when the external unit 12 is fitted to the ear lobe.
    [0058] As shown in Figs. 14A, 14B and 14C, heater 18 is preferably made as a plate or block, and is preferably constituted by a resistor. Two plates 20 are attached to the top of the plate to conduct thermal energy and serve as conductors 20. This can be done by adhesion, gluing or bonding, or by any other suitable means. Preferably, the conductors 20 are aluminum, but any thermally conductive material can be used. At the base of the plate, welding terminals 30 are preferably provided, which can be used to connect the heater 18 to the integrated circuit boards 42 (see Fig. 13). Preferably, a wrapper contains all the modular elements of the sensor (for example, thermistor). Ideally, for a 4 V system, the resistor (for example, the heating plate) has a resistance between 23 and 43 Q and is preferably 33 Q. It generates heat in the range of approximately 15 - 45 ° C and preferably about 42 - 45 ° C. Any suitable thermal sensor can be used.
    [0059] The heater sends thermal energy into the ear. It starts the heating process at the standard room temperature of 15 - 35 ° C. Normally, the surface of the earlobe is slightly warmer at 28 - 32 ° C. The heater power preferably provides a maximum of 0.5 W and a minimum of 0.1 W. According to other preferred embodiments, however, heaters with lower thermal energies that heat for longer periods can be used. A heater with higher thermal energy that heats up for a shorter time can also be used.
    [0060] As can be seen, the thermistor module must be small enough to fit on the tip of the socket for the ear. Preferably, the resistive plate, which constitutes heater 18, is approximately 5 mm long, 0.6 mm thick and 2.4 mm wide. As for sensor 22, it is preferably 1.30 mm long, 0.8 mm thick and 2.0 mm wide. These are standardized elements available on the market; and therefore the standardized sensor available is not as wide as the resistive plate and conductors, and extends slightly above the conductors. A small difference in the global dimensions is not critical.
    [0061] There are several possible modalities for the thermal channel. A preferred embodiment is shown in Fig. 14A. This modality consists of the thermal sensor (thermistor) 22, heater 18 and thermal conductors 20. The surface of the thermal module, which comes into contact with the ear lobe, is covered with a biocompatible and thermally conductive cover 64. When heater 18 is When turned on, a heat flow passes through the thermal conductors 20 and the thermistor 22, through the cover to the ear lobe (or another part of the body). The thermal absorption of the ear lobe depends on the glucose level. Thermistor 22 measures temperature changes in the ear lobe, which is influenced by the intensity of heating and the absorption of the ear lobe. This temperature is used for data processing analysis and to determine the glucose level.
    [0062] Fig. 14B represents another preferred modality of the thermal channel. This consists of the thermal sensor (thermistor) 22, heater 18 and a metallic membrane 58, which has high thermal conductivity. These components - the membrane 58, the thermistor 22 and the heater 18 - are bonded together with a thermally conductive adhesive 54. Preferably, the membrane 58 is adhered to the EOP 12 with an adhesive 56. The outer surface of the membrane 58 has a good contact with the ear lobe. When the heater 18 is turned on, a flow of heat passes through the thermistor 22 and the membrane 58 to the ear lobe (or other part of the body). The temperature variation of the ear lobe depends on the glucose level, and the thermistor 22 measures the temperature changes in the ear lobe, which is used for data processing and determination of the glucose level.
    [0063] A third preferable modality of the thermal channel is shown in Fig. 14C. This consists of the thermal sensor (thermistor) 22, two heaters 18, the integrated circuit board (PCB - “Printed Circuit Board”) 60 and the metallic membrane 58, which has high thermal conductivity. These components - membrane 58, thermistor 22 and heaters 18 - are adhered with thermally conductive adhesive 54. Preferably, membrane 58 is glued to EOP 12 with an adhesive 56. Heaters 18 and thermistor 22 are welded onto the PCB 60. The outer surface of the membrane 58 has good thermal contact with the earlobe. When the heaters 18 are turned on, a flow of heat passes through the membrane 58 to the ear lobe (or another part of the body). The temperature variation of the ear lobe depends on the glucose level, and the thermistor 22 measures the temperature changes in the ear lobe, which is used for data processing and determination of the glucose level.
    [0064] Fig. 4 illustrates the raw process of heating the sensor-tissue structure in a subject. The different curve shapes of the heating process represent different concentrations of glucose. The temperature is represented in degrees Celsius in Fig. 4.
    [0065] The ambient temperature that defines the boundary condition of the surface temperature of the skin and the initial temperature of the sensor also influences the process. Consequently, the thermal process is integrated and normalized so that the surface temperature of the initial skin is considered, and then compensated for the difference between the ambient and skin temperatures (Equation 1). The integrated, corrected and compensated signal (thermal signal) is shown in Fig. 5, as a function of the glucose concentration.
    t0 and tf being the initial and final times of the heating process; Also the fabric and ambient temperatures are the temperature correction factor.
    [0066] Fig. 5 shows an integrated thermal signal corrected for temperature in a subject versus the level of glucose.
    [0067] Changes in glucose concentration can be assessed indirectly by measuring the speed of sound through tissue. As the concentration of glucose increases, the speed of propagation also increases (Zhao Z. Pulsed Photoacoustic Techniques and Glucose Determination in Human Blood and Tissue. Acta Univ. Oul C 169. Finland, 2002; Toubal M, Asmani M, Radziszewski E , Nongaillard B. Acoustic measurement of compressibility and thermal expansion coefficient of erythrocytes. Phys Med Biol. 1999; 44: 1277-1287; US Patent 5,119,819). As the speed of propagation depends linearly on the concentration of glucose, the higher the content of glucose in a tissue, the faster the ultrasonic wave propagates through it, thus decreasing the propagation time.
    [0068] The ultrasonic measurement channel consists, in a preferred modality, in piezoelements, specifically in an ultrasound transmitter 34 and an ultrasound receiver 36, fixed (or fixable) close to the subject's earlobe 16. Preferably, an electronic circuit is also provided for the ultrasonic measurement channel. The transmitter 34 (ultrasonic piezoelement) is located on the external device, so that (when the external device is attached to the ear lobe) a continuous ultrasonic wave produced by the transmitter travels through the ear lobe at a characteristic speed, causing a phase shift (ΔΦ) between the transmitted and the received wave (Fig. 6B).
    [0069] The piezoelements - transmitter 34 and receiver 36 (optionally followed by an amplifier) - are arranged one on each side of a subject's earlobe (see, for example, Fig. 6A). The main unit (UP) 10 sends a signal to transmitter 34 to transmit the signal. After propagation through the earlobe 16, the receiver 36 amplifies the received signal and sends it back to the UP 10 for processing with an algorithm in order to obtain the corresponding glucose value.
    [0070] On opposite sides of the ear socket 12, the piezoelements - the transmitter 36 and the receiver 34 - are arranged. Generally, these ultrasonic elements are sensitive to mechanical pressure. In order to protect the elements and preserve the effectiveness of the elements, membranes 38 and 40 are preferably placed over the ultrasonic elements (see Figs. 15 and 16). Preferably, an ultrasonic conductive adhesive or glue, such as epoxy, is placed between the membranes and the ultrasonic elements to hold the membranes firmly on the ultrasonic elements. Generally, the adhesive or lap or epoxy should be suitable for conducting ultrasonic waves, so that there is minimal signal loss. A 0.05 mm layer is generally suitable for the adhesive material.
    [0071] As the ultrasonic piezoelements are also arranged in the ear socket, here again they must be small. They can be of any suitable size, but preferably the ultrasonic elements are round and are approximately 9.0 mm in diameter and less than 3.0 mm thick in the preferred embodiment shown here. The membranes 38, 40 are preferably made round and have a diameter of approximately 9.5 mm. It should be noted that any size is acceptable as long as it fits in the earloop.
    [0072] An electrically conductive and biocompatible coating is preferably placed on the surface of the membrane 38, 40 to accentuate the propagation of the signal. Normally, a 0.01 mm coating is suitable.
    [0073] Membranes can preferably be made of nickel, which in general is biologically stable and conducts signals well. Any other suitable material, such as gold or titanium, can be used.
    [0074] Preferably, membranes 38, 40 are made of copper with a nickel coating. In an alternative embodiment, the membranes can be made of stainless steel and no coating is required.
    [0075] In the preferred embodiment, it has been found to be advantageous when one membrane 40 is flat and the other 38 is convex. This “hybrid” combination provides the best solution from a fitting point of view, and securely attaches the device to the subject's earlobe.
    [0076] The frequencies can vary in the range of 180 KHz to 1 MHz, and the amplitudes of the signals can vary from 0.5 V to 3 V. The amplitude of the received signal can vary between 5 mV and 50 mV. Preferably, the receiver amplifies the signal approximately 20 times.
    [0077] As shown in Figs. 15 and 16, the ultrasonic piezoelements preferably fit on the respective membranes with the adhesive (or epoxy) layer between them.
    [0078] The speed is related to the phase (Equation 2): V = (fxd) x 2π / Δy (Eq. 2)
    [0079] During calibration, two ideal frequencies are chosen, one from a low frequency range and the other from a high frequency range, with the frequency ranges not intersecting. After calibration, measurements are conducted at the two chosen frequencies.
    [0080] Fig. 7 presents a graph of the phase shift values measured as a family of functions with the excitation frequency as an argument and the glucose value as a parameter of the family. The thickness of the tissue determines the part of the measured phase change cycle (ascending or descending). In the arrangement shown in Fig. 7, the descending part of the cycle is seen, causing G1 x ΔΦ to increase with the increase in the glucose level.
    [0081] This graph in Fig. 7 shows the phase change vs. input frequency of the transducer in the low frequency region. The amplified phase shift values are seen at the selected frequency, which proved to be the ideal frequency during calibration for a subject. Different curves on the graph apply to different glucose levels.
    [0082] It is well known that the speed of ultrasound waves depends on the temperature of the propagation medium (US Patent 5,119,819; Zips A, Faust U. Determination of biomass by ultrasonic measurements. Appl. Environ. Microbiol. July 1989; 55 (7 ): 1801-1807; Sarvazyan A, Tatarinov A, Sarvazyan N. Ultrasonic assessment of tissue hydration status. Ultrasonics. 2005; 43: 661-671). The temperature of the environment affects the parameters of the sensor, while the tissue temperature impacts the propagation of the wave in the tissue itself. Therefore, temperature correction, using both ambient and tissue temperatures, is necessary. The temperature correction is performed in the measured amplified phase change (Fig. 8), using the following formula (Equation 3):
    where Mudança_ASE_corr is the temperature-amplified phase change corrected; G2 - correction factor; Tamb - room temperature; and Tor - ear lobe surface temperature. The correction signal depends on the direction of the phase change with the frequency.
    [0083] Fig. 8 is a graph showing the phase change (measured at the selected frequency) vs. glucose, corrected for temperature for a subject.
    [0084] The transport of water and ions induced by glucose across the cell membrane leads to changes in the electrical properties of cellular and consequently extracellular compartments (Genet S, Costalat R, Burger J. The influence of plasma membrane electrostatic properties on the stability of cell ionic composition. Biophys. J. Nov. 2001; 81 (5): 2442-2457; Hayashi Y, Livshits L, Caduff A, Feldman Y. Dielectric spectroscopy study of specific glucose influence on human erythrocyte membranes. J. Phys. D: Appl. Phys. 2003; 36: 369-374). Mainly, a change in dielectric properties is observed (Gudivaka R., Schoeller D., Kushner RF. Effect of skin temperature on multi-frequency bioelectrical impedance analysis. Appl. Physiol. August 1996; 81 (2): 838-845), which, consequently, is reflected in changes in the entire tissue impedance. To reflect changes in residual electrical impedance caused by glucose variation, the electromagnetic channel (EMF) includes a special self-oscillating circuit and the ear lobe, which functions as a dielectric material, positioned between two electrodes connected to the circuit (Fig. 9) .
    [0085] Fig. 9 shows the electromagnetic measurement channel (EMC), being: Rin - input resistance; Z (D, ε) - pickup element transfer operator - an EMC integrator that includes ear lobe tissue in the feedback; the time constants of the transfer operator depend on the electrical permittivity of the tissue denoted by ε; D = d / dt; Cp - parasitic capacitance; f-med - auto-oscillation frequency measurement circuit (f); T - hysteresis relay element that creates a positive feedback in the self-oscillating circuit; Es - electrical potential on the skin surface.
    [0086] The same membranes 38 and 40 used for the ultrasound channel can also preferably serve as capacitor plates, and the earlobe 16 serves as a dielectric. An oscillator is used to generate signals, and these signals depend on the parameters of the ear lobe. Frequencies can range from 5 KHz to 100 KHz, and amplitudes range from approximately 0.1 V to 1.5 V.
    [0087] The ear lobe temperature is also considered in the measurement, since tissue impedance depends on temperature (Gudivaka R., Schoeller D., Kushner RF. Effect of skin temperature on multi-frequency bioelectrical impedance analysis. Appl. Physiol. August 1996; 81 (2): 838-845). Among the variables that represent disturbances of the EM channel, the temperature of the environment plays two roles: a) influences tissue parameters; b) affects the electromagnetic parameters of the sensor, such as the parasitic capacitance of the electrodes. Thus, the electromagnetic signal is corrected for both temperature, environment and ear, using Equation 4, as shown in Fig. 10.
    with Sinal_eltetromagnético_corr an electromagnetic signal of corrected temperature (self-oscillating frequency); D - correction factor; Tamb - room temperature; and Tor - ear lobe surface temperature.
    [0088] In a preferred embodiment, there is also a distance sensor in the ear socket (EOP) 12 - a magnet 44 on one side and a sensor 46 on the other. Sensor 46, preferably a magnetic field measurement sensor, measures the intensity of the magnetic field to ensure that the distance between the membranes is the same as the calibration stage.
    [0089] Fig. 11 shows the preferred modality of the ear plug 12. Preferably, it is made of ABS plastic, but any suitable material will be effective. The size depends on the size of the subject's earlobe. In a preferred embodiment, it is preferably about 25 mm long and wide.
    [0090] As is well known in loops, preferably one side articulates around the other. One side has a pivot pin that fits into a suitable seat on the other part of the earloop. A spring is used for balance.
    [0091] Preferably, an ambient temperature sensor 52 is also provided which can be located on the external unit 12, on the main unit 10 and / or can be placed on the cable 14 (see Fig. 1).
    [0092] Preferably, as is common with modern electronic devices, integrated circuit boards 42 are mounted inside the ear socket 12 (see Fig. 13). The mentioned components of the three channels - ultrasonic, electromagnetic and thermal - are mounted on them. So, either via cable or wireless technology (such as Bluetooth), communication is established with the main unit. As needed, the main unit emits signals to activate each measurement channel and then collect data and thus calculate the glucose value.
    [0093] Preferably, there is a calibration carried out before glucose measurements, so that the influence of almost stable individual factors, such as tissue structure, can be minimized. The sensor is individually adjusted for the ideal fit, according to the thickness of the user's earlobe, before calibration. Preferably, an adjusting screw 50 (Figs. 2, 14 and 16) is used to adjust the distance between the sensors and consequently the pressure on the ear lobe for optimal fit. This action can be guided by the main unit 10. The optional distance sensor 44, 46 preferably ensures that this predetermined distance is maintained.
    [0094] After adjusting the ear plug (EOP) 12, the calibration process begins. A preferred procedure for calibration is presented here.
    [0095] The calibration procedure consists of the correlation of data of invasive basal and postprandial blood glucose, taken from capillaries of the fingertips, with six sequential measurements with the device and an invasive device used as a reference, generating a calibration curve. which is unique to each individual.
    [0096] The first three calibration points are performed at the same glucose level (fasting) and help to establish a relatively accurate starting point for the model used in the calibration. They are performed in a fasted state, consisting of an invasive measurement and three consecutive non-invasive measurements, followed by the consumption of food and drinks, in order to increase the blood glucose level by at least 30% of the fasting value, but no less 30 mg / dl. In some cases, this can be done outside the fasting state. 20 minutes after a meal, a set of five sequential measurement pairs, with time intervals of approximately 10 minutes between them, is taken. In total, the calibration process takes approximately 1.5 to 2 hours.
    [0097] At the first calibration point, the distance is automatically measured (using the optional distance sensor 44, 46, provided in the ear socket 12 or using an alternative method) and established as a reference distance (original location or predetermined reference point) of the sensors, which, at the following calibration points, as well as at the measurement points, will be checked before the measurements start. The earlobe is usually a parallel tissue with a homogeneous surface. Consequently, if the distance at any of the calibration points, or at a regular measurement point, is different (within a certain tolerance range) from the predetermined reference point, the user is guided by the device to move the EOP 12 as required. necessary to reach the reference distance. Once calibration has been completed, a vector of individual linear model parameters is determined for each technology response.
    [0098] For thermal technology, the heating intensity is checked during the measurement of the first point and a correction factor is calculated for the ideal heating intensity, to be used in the subsequent measurements. This factor is calculated individually for each user, in order to ensure an increase in the temperature of the tissue surface above a minimum incremental limit.
    [0099] For electromagnetic technology, oscillations are carried out in three similar, but different, frequency bands. The ideal frequency range is chosen according to the individual sensitivity to changes in glucose during calibration. In addition, the maximum and minimum deviations between the operating frequency range and the next next frequency range are determined as limit values for the filter of validity of the electromagnetic signal (Equation 5):
    where: EMmin and EMmax are the values of minimum and maximum limits of the electromagnetic signal; EMi - the electromagnetic signal in the operational frequency range; and EMj - the electromagnetic signal in the neighboring frequency range.
    [00100] In order to select the ideal operating frequencies for the acoustic measurement method, a scan of two frequency regions is performed in the low and high frequency regions, during calibration. In each region, the ideal frequency is selected, according to the amplitude of the signal (the intensity of the propagated signal) and the sensitivity of the phase change to changes in glucose at that specific frequency. After calibration, measurements are performed at these two selected frequencies (one from the low region and the other from the high region).
    [00101] At each calibration point, it is preferable that both room and tissue temperatures are taken. At the end of the calibration process, a correlation between the two temperatures is found. This correlation is later used to discover discrepancies in the measured ear and in the ambient temperatures for each measurement.
    [00102] After calibration, local glucose measurements can be performed by fitting earloop 12 to the earlobe over the duration of the measurement (approximately 1 minute) and removing it afterwards.
    [00103] After the verification of the positioning of the sensor (by the device), using the distance reference established during the adjustment, the measurement starts. Each measurement channel produces several responses, after which a three-stage signal processing is applied: signal validation and recognition of outliers; temperature compensation and temperature correction.
    [00104] In the first stage for the ultrasonic channel, the amplitude of the signal for each chosen frequency is checked in order to ensure an adequate wave propagation through the tissue.
    [00105] As the electromagnetic and ultrasonic sensors are physically mounted in the same tissue area, a low measured amplitude indicates a low quality of contact. In this case, the measurement is disregarded and a failure warning is given to the user. In thermal technology, the sensor is mounted in a region of tissue different from that of the electromagnetic and ultrasonic sensors. Therefore, a good quality contact for these two last technologies does not guarantee the same for the thermal channel. Therefore, the heating process is also checked for raising the minimum and maximum temperature limit, using a validity filter. An ascent out of range is considered to be a low quality contact and produces a failure warning for the user. The response of the electromagnetic channel is also checked for maximum and minimum deviations between the operating frequency range and the adjacent range, as discussed in the section on calibration.
    [00106] As both ambient and tissue temperatures are used for compensation in each measurement channel, they must be checked for validity first. Therefore, in the second stage, temperatures are tested for correlation with calibration. Thus, for each measurement, a low correlation indicates interference at one of the measured temperatures. The disturbed temperature is first compensated according to the other temperature, and then both are used to correct the temperature signal, orchestrated through all three technologies.
    [00107] The third stage includes temperature correction for all technology responses, as previously discussed. In addition, the glucose value is calculated for each measurement channel, using the model coefficients that were established in the calibration procedure.
    [00108] The glucose values received from each measurement channel are checked for correlation. Subsequently, weights are assigned to each of the three values, according to the degree of correlation. Finally, a thoughtful combination of the three responses from the technologies produces a more accurate glucose reading.
    [00109] Glucose and other blood solutes influence different tissue properties such as conductivity, permissiveness, thermal capacity, density and compressibility, in different tissue compartments (for example, interstitium, blood, cells). Thus, the measurement of such properties can lead to the assessment of the level of GS in a human body.
    [00110] Generally, non-invasive devices (in the development stages) that produce analyzes of trends or glucose values measure physiological phenomena that are reflected by variations in tissue parameters, correlated to blood glucose (). However, the glucose value derived from such a correlation is different from the actual glucose value, since factors other than glucose influence tissue parameters as well. These disturbing factors decrease the signal-to-noise ratio and cause inaccuracies in the readings.
    [00111] To minimize the impact of these disturbances, a methodology that combines multiple technologies and multiple sensors is suggested. Each technology measures different tissue parameters that are affected by the same variation in glucose concentration. Thus, each method alone is indicative of glucose, but is limited by the impact of intervening factors, because of the lack of specificity. Consequently, it is expected that a simultaneous assessment of the mentioned physiological variations by measuring different sets of tissue disorders, induced by variations in glucose concentration, will increase the validity of the final result.
    [00112] The presented methodology shows promising results in the sense of an approach of multiple sensors and multiple technologies, since this integration contributes to increase the signal-to-noise ratio. These multiple sensors allow the determination of the contact quality of the sensors, taking into account the validity of the measured parameters, as well as the compensation and correction of interferences (such as temperature).
    [00113] Although certain features of the invention have been illustrated and described here, many modifications, substitutions, alterations and equivalents will occur to those skilled in the art. The invention is described in detail with reference to a particular modality, however it should be understood that several other modifications can be made that are still within the spirit and scope of the invention. It should therefore be understood that the appended claims are intended to cover all such modifications and alterations that are in the true spirit of the invention.
    权利要求:
    Claims (14)
    [0001]
    1. Non-invasive glucose level measurement device in a subject, characterized by comprising: a unitary external unit (12) having a first portion and a second opposite portion configured to receive a part of the subject's body between them; (a) a first ultrasonic piezo element (34, 36) positioned in the first portion and a second ultrasonic piezo element positioned in the second opposite portion of said external unit, a first membrane (38) covering the first ultrasonic piezo element and a second membrane (40) covering the second ultrasonic piezoelement to measure glucose levels using ultrasound; (b) the first membrane and the second membrane constituting the respective first and second capacitor plates with a self-oscillating medium connected to them to measure glucose levels using electromagnetic; and (c) a heater (18) and a thermal sensor (22) both positioned in the first portion and spaced from the first ultrasonic piezo element to measure the glucose level by the thermal characteristics.
    [0002]
    Device according to claim 1, characterized in that said ultrasonic piezoelements (34, 36), said capacitor plates, said heater and said thermal sensor are contained within said external unit.
    [0003]
    Device according to claim 1 or 2, characterized in that it additionally comprises a main unit for the control of measurements, receiving glucose level values from said external unit and calculating a weighted combination of said glucose level values to produce a accurate glucose reading; and electrical connection means of said main unit and said external unit.
    [0004]
    Device according to any one of claims 1 to 3, characterized in that said ultrasonic piezo elements include a transducer and a receiver.
    [0005]
    Device according to any one of claims 1 to 4, characterized in that said external unit further comprises means for determining a distance between said first portion and said second opposite portion.
    [0006]
    Device according to claim 5, characterized in that said means of determination comprise a magnet and a sensor.
    [0007]
    Device according to any one of claims 1 to 6, characterized in that said external unit additionally comprises an adjustment screw that determines a distance between said first portion and said second opposite portion.
    [0008]
    Device according to any one of claims 1 to 7, characterized in that said external unit additionally includes an ambient temperature sensor.
    [0009]
    Device according to claims 1, 2 or 3 to 8, characterized in that the device additionally comprises means (14) for electrical connection of a main unit (10) and said external means (12).
    [0010]
    Device according to any one of claims 1 to 9, characterized in that said unitary external unit is a device comprising a wrap.
    [0011]
    Device according to any one of claims 1 to 10, characterized in that the unitary external unit additionally comprises a means for detecting a phase change between a wave transmitted by one of the ultrasonic piezo elements (34) and a corresponding wave received by one of the ultrasonic piezoelements (36), in which the aforementioned phase change forms a basis for a processing medium to calculate the glucose level.
    [0012]
    Device according to any one of claims 1 to 11, characterized in that the unitary external unit comprises means for communicating a tissue impedance signal to a processing means for calculating the glucose level.
    [0013]
    Device according to any one of claims 1 to 12, characterized in that the unitary external unit additionally comprises means of communicating thermal transfer characteristics to a processing means for calculating the glucose level.
    [0014]
    Device according to any one of claims 1 to 13, characterized in that the unitary outdoor unit, the main unit as defined in claim 3 and / or the electrical connection means as defined in claim 9 comprise a temperature sensor for measuring a room temperature.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2790438A|1956-01-13|1957-04-30|Taplin Ronald Harold|Earpieces for oximeters|
    US3085566A|1959-09-18|1963-04-16|Cutler Hammer Inc|Apparatus for measuring the electrical response of living tissue|
    US3412729A|1965-08-30|1968-11-26|Nasa Usa|Method and apparatus for continuously monitoring blood oxygenation, blood pressure, pulse rate and the pressure pulse curve utilizing an ear oximeter as transducer|
    US3638640A|1967-11-01|1972-02-01|Robert F Shaw|Oximeter and method for in vivo determination of oxygen saturation in blood using three or more different wavelengths|
    US4859078A|1986-02-07|1989-08-22|Massachusetts Institute Of Technology|Apparatus for the non-invasive measurement of thermal properties and perfusion rates of biomaterials|
    US5361758A|1988-06-09|1994-11-08|Cme Telemetrix Inc.|Method and device for measuring concentration levels of blood constituents non-invasively|
    US5086229A|1989-01-19|1992-02-04|Futrex, Inc.|Non-invasive measurement of blood glucose|
    JPH0310101A|1989-06-08|1991-01-17|Nok Corp|Magnetic proximity sensor and method for adjusting operating distance of the sensor|
    US5070874A|1990-01-30|1991-12-10|Biocontrol Technology, Inc.|Non-invasive determination of glucose concentration in body of patients|
    US5316008A|1990-04-06|1994-05-31|Casio Computer Co., Ltd.|Measurement of electrocardiographic wave and sphygmus|
    US5119819A|1990-05-02|1992-06-09|Miles Inc.|Method and apparatus for non-invasive monitoring of blood glucose|
    US5405069A|1992-02-25|1995-04-11|International Business Machines Corporation|Paper motion detection system|
    US5348003A|1992-09-03|1994-09-20|Sirraya, Inc.|Method and apparatus for chemical analysis|
    IL107396A|1992-11-09|1997-02-18|Boehringer Mannheim Gmbh|Method and apparatus for analytical determination of glucose in a biological matrix|
    DE4242232C2|1992-12-15|1998-12-10|Burkhard Kuhls|Device and method for the non-invasive determination of the concentration of polarizing substances in the human body|
    CA2124109A1|1993-05-24|1994-11-25|Mark T. Byrne|Endoscopic surgical instrument with electromagnetic sensor|
    US5792668A|1993-08-06|1998-08-11|Solid State Farms, Inc.|Radio frequency spectral analysis for in-vitro or in-vivo environments|
    DE4342105A1|1993-12-12|1995-06-14|Cho Ok Kyung|Method and device for the non-invasive determination of the concentration of glucose in parts of the human body, in particular in human blood, by performing highly accurate temperature measurements of the human body|
    DE4423663A1|1994-07-06|1996-01-11|Med Science Gmbh|Method and device for detecting thermal interactions between the human body and the device according to the invention and their correlation with the glucose concentration in human blood|
    US5673692A|1995-02-03|1997-10-07|Biosignals Ltd. Co.|Single site, multi-variable patient monitor|
    US5752512A|1995-05-10|1998-05-19|Massachusetts Institute Of Technology|Apparatus and method for non-invasive blood analyte measurement|
    US5657754A|1995-07-10|1997-08-19|Rosencwaig; Allan|Apparatus for non-invasive analyses of biological compounds|
    CA2229926C|1995-08-31|2002-02-26|Alcan International Limited|Ultrasonic probes for use in harsh environments|
    US6405069B1|1996-01-31|2002-06-11|Board Of Regents, The University Of Texas System|Time-resolved optoacoustic method and system for noninvasive monitoring of glucose|
    US5788632A|1996-03-19|1998-08-04|Abbott Laboratories|Apparatus and process for the non-invasive measurement of optically active compounds|
    US6517482B1|1996-04-23|2003-02-11|Dermal Therapy Inc.|Method and apparatus for non-invasive determination of glucose in body fluids|
    US5666956A|1996-05-20|1997-09-16|Buchert; Janusz Michal|Instrument and method for non-invasive monitoring of human tissue analyte by measuring the body's infrared radiation|
    US5910109A|1997-02-20|1999-06-08|Emerging Technology Systems, Llc|Non-invasive glucose measuring device and method for measuring blood glucose|
    US6259937B1|1997-09-12|2001-07-10|Alfred E. Mann Foundation|Implantable substrate sensor|
    AUPP030997A0|1997-11-10|1997-12-04|Clift, Vaughan|Intra aural integrated vital signs monitor|
    JP4369616B2|1997-11-12|2009-11-25|ライタッチメディカルインコーポレイテッド|Method and apparatus for non-invasively measuring a specimen|
    US5941821A|1997-11-25|1999-08-24|Trw Inc.|Method and apparatus for noninvasive measurement of blood glucose by photoacoustics|
    US6070093A|1997-12-02|2000-05-30|Abbott Laboratories|Multiplex sensor and method of use|
    US6587705B1|1998-03-13|2003-07-01|Lynn Kim|Biosensor, iontophoretic sampling system, and methods of use thereof|
    US5944179A|1998-05-26|1999-08-31|Walker; Diana G.|Protective sheath for medical probe|
    ES2185374T3|1998-07-07|2003-04-16|Lightouch Medical Inc|TISSULAR MODULATION PROCEDURE FOR IN VIVO QUANTITATIVE SPECTROSCOPIC ANALYSIS, NOT INVESTOR OF FABRICS.|
    DE19841154C2|1998-09-09|2002-11-07|Holger Loehmer|Method and device for measuring the transit time of sound waves|
    US6424851B1|1998-10-13|2002-07-23|Medoptix, Inc.|Infrared ATR glucose measurement system |
    US6895263B2|2000-02-23|2005-05-17|Medtronic Minimed, Inc.|Real time self-adjusting calibration algorithm|
    US6198949B1|1999-03-10|2001-03-06|Optiscan Biomedical Corporation|Solid-state non-invasive infrared absorption spectrometer for the generation and capture of thermal gradient spectra from living tissue|
    US6161028A|1999-03-10|2000-12-12|Optiscan Biomedical Corporation|Method for determining analyte concentration using periodic temperature modulation and phase detection|
    US6616819B1|1999-11-04|2003-09-09|Therasense, Inc.|Small volume in vitro analyte sensor and methods|
    US7003336B2|2000-02-10|2006-02-21|Medtronic Minimed, Inc.|Analyte sensor method of making the same|
    US6591125B1|2000-06-27|2003-07-08|Therasense, Inc.|Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator|
    US7220229B2|2000-07-18|2007-05-22|Global Monitors, Inc.|Density/solute monitor of multi-modalities and signal processing scheme|
    DE60133653T2|2000-08-18|2009-06-04|Animas Technologies Llc|APPARATUS FOR PREDICTING HYPOGLYECURE DROPS|
    JP2002202258A|2000-12-28|2002-07-19|Bios Ikagaku Kenkyusho:Kk|Spectroscopic blood sugar level measuring instrument|
    GB0106250D0|2001-03-13|2001-05-02|Hall Effect Technologies Ltd|Apparatus and method for analysing blood|
    US7011630B2|2001-06-22|2006-03-14|Animas Technologies, Llc|Methods for computing rolling analyte measurement values, microprocessors comprising programming to control performance of the methods, and analyte monitoring devices employing the methods|
    AT412060B|2001-07-06|2004-09-27|Schaupp Lukas Dipl Ing Dr Tech|METHOD FOR MEASURING CONCENTRATIONS IN LIVING ORGANISMS BY MEANS OF MICRODIALYSIS AND AND DEVICE FOR IMPLEMENTING THIS METHOD|
    US20030013947A1|2001-07-10|2003-01-16|Frattarola Joseph R.|Method and apparatus for non-invasive blood analyte detector|
    DE10143137C1|2001-09-03|2003-04-17|Fresenius Medical Care De Gmbh|Measuring device and method for determining parameters of medical liquids and method for calibrating such a device|
    US8154093B2|2002-01-16|2012-04-10|Nanomix, Inc.|Nano-electronic sensors for chemical and biological analytes, including capacitance and bio-membrane devices|
    US20050054908A1|2003-03-07|2005-03-10|Blank Thomas B.|Photostimulation method and apparatus in combination with glucose determination|
    US7050847B2|2002-03-26|2006-05-23|Stig Ollmar|Non-invasive in vivo determination of body fluid parameter|
    US6887239B2|2002-04-17|2005-05-03|Sontra Medical Inc.|Preparation for transmission and reception of electrical signals|
    US8328420B2|2003-04-22|2012-12-11|Marcio Marc Abreu|Apparatus and method for measuring biologic parameters|
    US6964871B2|2002-04-25|2005-11-15|Home Diagnostics, Inc.|Systems and methods for blood glucose sensing|
    WO2004023125A2|2002-09-05|2004-03-18|Pendragon Medical Ltd.|Impedance spectroscopy based systems and methods|
    US7087017B2|2002-10-31|2006-08-08|Medtronic, Inc.|Atraumatic sensor lead assemblies|
    US7666151B2|2002-11-20|2010-02-23|Hoana Medical, Inc.|Devices and methods for passive patient monitoring|
    US7120483B2|2003-01-13|2006-10-10|Isense Corporation|Methods for analyte sensing and measurement|
    JP3566276B1|2003-05-07|2004-09-15|株式会社日立製作所|Blood glucose meter|
    JP2007500336A|2003-07-25|2007-01-11|デックスコム・インコーポレーテッド|Electrode system for electrochemical sensors|
    KR20060082852A|2003-08-15|2006-07-19|애니머스 테크놀로지스 엘엘씨|Microprocessors, devices, and methods for use in monitoring of physiological analytes|
    US6954662B2|2003-08-19|2005-10-11|A.D. Integrity Applications, Ltd.|Method of monitoring glucose level|
    US6949070B2|2003-08-21|2005-09-27|Ishler Larry W|Non-invasive blood glucose monitoring system|
    US7559894B2|2003-09-18|2009-07-14|New Paradigm Concepts, LLC|Multiparameter whole blood monitor and method|
    CN101601583B|2003-10-09|2012-09-05|日本电信电话株式会社|Organism information detection device and sphygmomanometer|
    US7020506B2|2003-11-06|2006-03-28|Orsense Ltd.|Method and system for non-invasive determination of blood-related parameters|
    US20060009698A1|2004-04-07|2006-01-12|Triage Wireless, Inc.|Hand-held monitor for measuring vital signs|
    RU2279250C2|2004-09-24|2006-07-10|ЗАО "Интеграционная промышленная система"|Device for measuring blood glucose concentration in noninvasive way|
    EP1818910A4|2004-12-28|2009-11-25|Panasonic Corp|Scalable encoding apparatus and scalable encoding method|
    KR100698961B1|2005-02-04|2007-03-26|주식회사 아이센스|Electrochemical Biosensor|
    CN101188968B|2005-03-09|2010-09-29|拉米尔·法里托维奇·穆辛|Method and device for microcalorimetrically measuring a tissue local metabolism speed, intracellular tissue water content, blood biochemical component concentration and a cardio-vascular system tensio|
    GB2422197B|2005-05-17|2007-08-08|Bio Nano Sensium Technologies|Sensor calibration|
    JP2007105329A|2005-10-14|2007-04-26|Hitachi Ltd|Blood sugar level measuring apparauts, and metabolic rate measuring apparatus|
    JP4947440B2|2005-11-10|2012-06-06|バイオボーション・アーゲー|Device for determining glucose levels in body tissue|
    CN100342825C|2005-11-28|2007-10-17|何宗彦|Non-wound rapid blood sugar detecting method and its detecting instrument|
    JP2009536441A|2006-05-05|2009-10-08|スペンサージェイジー エップス|Embedded voltaic battery|
    US20080076972A1|2006-09-21|2008-03-27|Apple Inc.|Integrated sensors for tracking performance metrics|
    US8456150B2|2007-02-01|2013-06-04|Drexel University|Hand-held phase-shift detector for sensor applications|
    US20090275815A1|2008-03-21|2009-11-05|Nova Biomedical Corporation|Temperature-compensated in-vivo sensor|
    US8700114B2|2008-07-31|2014-04-15|Medtronic Minmed, Inc.|Analyte sensor apparatuses comprising multiple implantable sensor elements and methods for making and using them|
    US20100049007A1|2008-08-20|2010-02-25|Sterling Bernhard B|Integrated physiological sensor apparatus and system|
    US20110137141A1|2009-12-03|2011-06-09|At&T Intellectual Property I, L.P.|Wireless Monitoring of Multiple Vital Signs|WO2022020734A1|2020-07-24|2022-01-27|A.D. Integrity Applications Ltd.|Device for non-invasively measuring glucose concentration|
    NO336532B1|2011-01-12|2015-09-21|Mecsense As|Sensor for measuring the density of a body fluid and / or the resistance of a membrane|
    US8714017B2|2011-11-15|2014-05-06|Hema-Q, Inc.|Apparatus for non-invasive determination of sound velocity in a liquid and determining a parameter of the liquid from the sound velocity|
    CN103892843A|2012-12-27|2014-07-02|龙华科技大学|Non-intrusive blood glucose measurer|
    IL225182A|2013-03-12|2016-06-30|A D Integrity Ltd|Ear clip for medical monitoring device|
    US10219729B2|2013-06-06|2019-03-05|Profusa, Inc.|Apparatus and methods for detecting optical signals from implanted sensors|
    CN105326481B|2014-08-07|2018-05-18|何嘉健|A kind of hurtless measure dynamic glucose concentration early warning system|
    US9459201B2|2014-09-29|2016-10-04|Zyomed Corp.|Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing|
    CN109394185B|2014-11-11|2021-04-27|原相科技股份有限公司|Blood vessel sensing device with correction function|
    CN104921735A|2015-05-15|2015-09-23|深圳市一体太糖科技有限公司|Microwave noninvasive blood glucose measurement system|
    CN104983429A|2015-07-22|2015-10-21|李承昊|Human health measurer capable of measuring a plurality of indexes|
    DE102015218948A1|2015-09-30|2017-03-30|Brandenburgische Technische Universität Cottbus-Senftenberg|Apparatus and method for determining a medical health parameter of a subject by means of voice analysis|
    US10571390B2|2015-12-21|2020-02-25|The Boeing Company|Composite inspection|
    GB201602773D0|2016-02-17|2016-03-30|Orsus Medical Ltd|A method and apparatus for measuring the concentration of target substances in blood|
    US9554738B1|2016-03-30|2017-01-31|Zyomed Corp.|Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing|
    US10057395B1|2017-08-27|2018-08-21|Carydean Enterprises LLC|Case for a mobile electronic device|
    CN107595318A|2017-09-21|2018-01-19|中国科学院长春光学精密机械与物理研究所|A kind of Woundless blood sugar concentration detection method and equipment|
    US10035010B1|2017-09-28|2018-07-31|Carydean Enterprises LLC|Systems and methods for drug delivery|
    CN108309645A|2018-02-26|2018-07-24|张秋平|A kind of division of endocrinology diabetes patient nursing for treating box|
    US20200346043A1|2019-04-30|2020-11-05|General Electric Company|Neuromodulation techniques for perturbation of physiological systems|
    CN111110249B|2019-12-27|2021-08-27|中国科学院深圳先进技术研究院|Blood glucose fluctuation evaluation method and evaluation device|
    WO2021167235A1|2020-02-18|2021-08-26|박영권|Non-invasive blood glucose sensor|
    KR102164926B1|2020-03-03|2020-10-13|박영권|Non-Invasive Glucose Sensor|
    法律状态:
    2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-12-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-12-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-03-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/04/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US32834410P| true| 2010-04-27|2010-04-27|
    US61/328,344|2010-04-27|
    US13/090,535|2011-04-20|
    US13/090,535|US8235897B2|2010-04-27|2011-04-20|Device for non-invasively measuring glucose|
    PCT/IL2011/000328|WO2011135562A2|2010-04-27|2011-04-26|Device for non-invasively measuring glucose|
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