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    • 专利摘要:
    Portable device and method for non-invasive estimation of blood glucose level. The device (1) comprises a unit of measurement (2) with a glucose level measurement module (4), a first computing module (5), to process data from a first part of the glucose level measurement process, a first communication module (6), a first data storage module (7) and a push button (8). It also comprises a personal monitoring unit (3) with a second and third communications module (17, 20), a second computing module (18), to process data from a second part of the glucose level measurement process, a interface module (19), and a second data storage module (22). A non-invasive method of estimating the blood glucose level is also described. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2774983A1
    申请号:ES201930045
    申请日:2019-01-22
    公开日:2020-07-23
    发明作者:Tosina Luis Javier Reina；ROMERO LAURA Mª ROA；Hernández David Naranjo
    申请人:Universidad de Sevilla；
    IPC主号:
    专利说明:

    [0002] PORTABLE DEVICE AND METHOD FOR NON-INVASIVE ESTIMATION OF
    [0004] OBJECT OF THE INVENTION
    [0006] The object of the invention described here falls within the area of Information and Communication Technologies (ICTs).
    [0008] More specifically, the object of the invention has a place in biomedical engineering and medical technology, for the development of portable electronic devices for monitoring physiological variables of people and their state of health, in general, and the level of glucose in the blood. , in particular.
    [0010] BACKGROUND OF THE INVENTION
    [0012] In the world there are 425 million people who have diabetes mellitus and it is estimated that this number will increase to 629 million in 2045 as a result of population growth and aging, increasing urbanization, the prevalence of obesity, sedentary lifestyle and other lifestyle habits. unhealthy life. One in eleven adults has diabetes and one in seven pregnancies is affected by gestational diabetes. Efficient control of the disease requires monitoring of the blood glucose level. Glucometers, which measure glucose from blood samples, are the most commonly used glucose measurement device due to their accuracy. This method is painful and annoying, especially in cases where glucose level monitoring is necessary. To avoid this problem, numerous methods for non-invasive blood glucose measurement have been proposed in recent years.
    [0014] Reverse iontophoresis is based on the flow of a small electrical current through the skin, between an anode and a cathode placed on the surface of the skin. By applying an electric potential between the anode and the cathode, migration of the ions of sodium and chloride under the skin to the cathode and anode respectively. Uncharged molecules, such as glucose, are carried along with the ions along the convective flow. This flow causes the interstitial glucose to be transported through the skin, thus being collected at the cathode, where it is measured by a traditional sensor. The main drawback of this technique is that long exposure times to electrical potential are required, which often tend to cause skin irritation. Two examples of patents based on this technique are US6885882 and WO2008 / 120936.
    [0016] Impedance spectroscopy is based on the injection of current at multiple frequencies and on the measurement of the tension produced in the body region of measurement. The measurement of glucose is carried out indirectly from the analysis of its influence on the spectrum of impedances. Some examples of patents based on this technique are ES2445700, ES2582185, WO2007 / 053963, US2005 / 0192488, US2016 / 0007891 and US2015 / 0164387.
    [0018] Optical coherence tomography is a non-invasive imaging test based on low coherence light interferometry. The interference pattern obtained contains information on the optical characteristics of the sample and more specifically on the changes in the refractive index that can be used in estimating the glucose level. The main disadvantage of this method is its complexity and the need for expensive and large devices. In addition, it is sensitive to device movement, tissue heterogeneity, and interference with other analytes. Patents US2007 / 0027372 and US2016 / 0058347 make use of this method.
    [0020] Polarimetry is a technique that is based on the measurement of the optical rotation produced on a beam of polarized light when passing through an optically active substance. Because the high scattering coefficient of the skin causes beam depolarization, most researchers focus their attention on the aqueous humor of the eye. Some limitations of this method are errors due to eye movement, safety standards in light exposure so that no damage occurs, and discomfort when performing measurements on the eye. Polarimetry is used in patents ES2313140, US4014321, EP0534166, US6704588 and US6442410.
    [0021] Infrared thermal spectroscopy measures the thermal radiation emitted by the human body as a result of changes in glucose concentration. This method has many sources of error, such as movement of the measuring device, ambient temperature, and variation in body and tissue temperature. US2005 / 0043630 is an example patent based on this method.
    [0023] Raman spectroscopy is based on the use of laser light that induces the rotation and oscillation of molecules in a solution. The consequent emission of the scattered light is influenced by this vibration of the molecules, which depends on the concentration of the solutes in the solution. Its main disadvantage is that biological tissue can be damaged due to the powerful laser of the Raman system. This technique is used in ES2093243, ES2206610, ES2314906, US5448992, US8355767 and US2016 / 0100777.
    [0025] Photoacoustic spectroscopy is based on the use of laser light to excite a fluid and consequently generate an acoustic response. The photoacoustic signal depends on the specific heat of the tissue, which in turn depends on the glucose concentration. The main limitation of this technique is its sensitivity to chemical (other biological compounds) and physical (changes in temperature and pressure) interferences. EP1346684 makes use of this method.
    [0027] Infrared spectroscopy is based on the absorption of infrared radiation by vibrating molecules. A molecule will absorb energy from a beam of light if its frequency of vibration matches the wavelength of the light. In this way, the glucose concentration can be estimated according to the variation in the intensity of the light that passes through a tissue. As fundamental advantages, it can be highlighted that it is a completely non-invasive technology, the assembly of the systems is simple and the cost is relatively low. Near infrared (NIR) spectroscopy ranges from 700 nm to 2500 nm and mid-infrared (MIR) spectroscopy ranges from 2500 nm to 10 pm. Since the present invention is based on the infrared spectroscopy technique, a review of the state of the art on the application of this technique for the estimation of the concentration of glucose and other analytes is made below.
    [0028] Many documents that include the use of the infrared spectroscopy technique do not delve into the way in which this technique is implemented, as is the case of CN204318765, and are discarded from the review of the state of the art for this reason.
    [0030] Patent CN104970802 uses near infrared spectroscopy in the spectrum range from 1500 nm to 3000 nm, but does not indicate how to obtain glucose values. The device is integrated into a wristwatch that includes a microprocessor and a Bluetooth transmission module. In addition, it includes a gravity sensor to estimate walking steps and a skin temperature sensor.
    [0032] Patent CN105232055 uses a 1610 nm infrared light source on the earlobe. The device is based on an optical spectroscopy measurement of two trajectories: one for a beam of light that serves as a reference, and another trajectory affected by reflection in the body area of measurement.
    [0034] In US2009 / 004682 a method for the estimation of glucose in liquid blood samples is described. They use a method based on the absorption spectrum of infrared light in the wavelength range of 9615 to 9804 nm. For the estimation of glucose, it uses the integration of the absorption intensity, and the integration of the second derivative of the absorption intensity, although it does not mention how to obtain the absorption spectrum. Patent ES2101728 also uses the second derivative of the absorption intensity, although in the range between 1100 and 1900 nm. This document shows a procedure for the estimation of the absorption spectrum.
    [0036] In US2008 / 171925, multiple wavelengths obtained from different sources are used simultaneously, measuring the phase shift between the incident signal and the reflected signal to provide an estimate of the glucose level. Patent ES2133643 also uses two wavelengths in the estimation of glucose. The device of patent US2017 / 105663 performs two spectroscopy measurements in the near infrared region and fits the data using a convolution function and a simulation of Monte Carlo.
    [0038] The apparatus described in EP0869348 irradiates the measurement zone in three wavelengths: a first length related to the absorption peak of the OH group of the glucose molecule (typically from 1550 nm to 1650 nm), a second wavelength related to an absorption peak of the NH group (typically 1480 nm to 1550 nm) and a third wavelength related to the absorption peak of the CH group (typically 1650 nm to 1880 nm). Estimate glucose level from radiation received using multivariate analysis.
    [0040] According to the method shown in EP0807812, a low coherence light beam is irradiated to the eyeball. The beam that is reflected from different depths of the eyeball interferes with another beam of reference light reflected from a mirror capable of moving. The method used allows the light from the interface between the cornea and the anterior aqueous chamber (aqueous humor) to be separated from the light from the interface between the anterior aqueous chamber and the crystalline lens. The optical absorbance of the aqueous humor is calculated from the intensities captured from the two light beams. The process is repeated at different wavelengths to obtain the glucose concentration in the aqueous humor.
    [0042] Patents US2005 / 0107676 and WO2006 / 047273 use a broadband infrared light source and different optical filters to estimate the absorption spectrum of infrared light between 1100 and 1900 nm. To avoid the influence of temperature, they include an active temperature control system in the sensor area. Patents US2005 / 020892 and US7299080 have similar characteristics, but in the range between 1150 and 1850 nm. In addition, they use different optical fibers to access different detection zones. The use of multiple probes minimizes interference in the sample spectrum due to location errors.
    [0044] CN102198004 uses a halogen bulb as an infrared source and a digital signal processor (DSP) for glucose estimation. Said light source emits a range of wavelengths from 600 to 2500 nm, covering the band of wavelengths of absorption of glucose and water. Use the spectrum and a neural network to estimate the level glucose.
    [0046] In patents GB2531956 and WO2015 / 097190 a description is made of an apparatus for characterizing an analyte, which can be glucose, in a superficial layer of the skin. A reflector implanted under the surface layer of the skin receives incident radiation that has passed through the body measurement area and reflects it through it to a sensor located outside the body. It also uses the method of analysis by Raman spectroscopy. In addition, to promote hair growth in the measurement area, the possibility of applying growth factors is indicated.
    [0048] The invention CN103344597 describes a method for estimating the concentration of sugar and salt in lotus roots. It uses the mid-infrared spectroscopy technique and a model that is calibrated by the least squares method from measurements made on a set of samples with concentrations of 5%, 10%, 15%, 20% of salt and sugar. Patent WO2012 / 048897 shows a method for classifying sugar beet seeds by the absorption spectrum of the samples in the infrared region.
    [0050] Patent ES2102259 describes a procedure for the analytical determination of glucose concentration in a biological matrix, carried out based on the calculation of the propagation time of light within the biological matrix under study. The method described in US2011 / 0184260 makes two light sources with different polarization affect the sample, estimating glucose from the comparison of the light captured in each polarization. In contrast, ES2086969 characterizes the concentration of the glucose level in a biological matrix from the light received in two detectors located at different distances from the emitter.
    [0052] Patent GB2482378 describes an optical device and a method for the non-invasive determination of an analyte concentration in a tissue sample. The device has two optical interfaces on which the incident light is reflected, the second one being located on the sample. The interfaces are arranged to generate an interference pattern as a consequence of the phase difference between the light reflected from the first interface and the light reflected from the second interface. US6043492 makes use of two Fabry-Perot interferometers to obtain the absorption spectrum of glucose in the near infrared region.
    [0054] The method described in patent US8629399 allows analyzing the evolution of a biological process such as fermentation. According to this procedure, the initial absorption spectrum in the mid-infrared region is combined with a reference standard, which makes it possible to predict the expected spectrum when the biological process has concluded. The evolution of the process is analyzed by comparing the current spectrum with the expected one.
    [0056] WO2001 / 007894 protects a method to determine the concentration of an analyte (albumin, cholesterol, glucose, total protein, triglycerides and urea) in a biological fluid that comprises the following steps: drying a sample of the fluid on a glass plate to produce a film on the plate; directing an infrared beam through the plate and film at an infrared wavelength between 2500 to 5000 nm; and analyzing the spectrum thus acquired to determine the concentration of the analyte in the film.
    [0058] Within the analysis by infrared spectroscopy, absorption spectroscopy is an analytical technique used to determine the concentration of one or more substances in a sample. Absorption spectroscopy is performed using a device called a spectrophotometer, which in its most basic form consists of a light source, a sample holder and a detector. Documents WO2003076883 and US7133710 are based on spectrophotometers that measure different wavelengths in the range from 1180 to 2320 nm. The light produced from the source (incident light) passes through the sample to a detector that measures the amount of transmitted light. For a non-dispersive sample, the absorbance of the sample is proportional to the logarithm of the amount of incident light illuminating a sample divided by the amount of light transmitted through the sample. Incident light is obtained by measuring the amount of light that reaches the detector without the sample. However, it is common for light to be transmitted through the sample, the intensity of the incident light must be significantly greater than the amount of light required to saturate the detector.
    [0059] One method of compensating for detector saturation is to use a smaller integration time (time the detector remains exposed to light before measurement) for the reference measurement. However, the use of different integration times for reference and sample measurements can lead to error in analyte determinations.
    [0061] Another method to compensate the saturation of the detector is to attenuate the reference beam with a photometric filter, which allows to reduce the intensity of the incident light that reaches the detector. Patent WO2001 / 015596 describes an artificial filter made of polytetrafluoroethylene (PTFE) and glass fiber that mimics the absorbance spectrum of a part of the body and includes the spectral components of blood. Other similar patents are US6015610 and US5596450. However, any variation in the filter as a result of temperature fluctuations, can affect the accuracy of the estimates. Patent US2003 / 0174321 describes an artificial filter for wavelengths between 600 nm and 1650 nm, robust to temperature variations.
    [0063] Another commonly used method is attenuated total reflection (ATR) infrared spectroscopy. In this method, a beam of light is struck on a glass. The size and shape of the crystal favor a series of internal reflections before the beam can exit the crystal with the information. The top surface of the glass is on the surface of the sample, which may be the skin. When the infrared beam strikes the top surface of the glass at an angle that exceeds a critical angle, the beam is fully reflected within the glass. Each reflection against the upper surface provides a little more information about the composition of the sample.
    [0065] The reflected beam includes an evanescent wave that penetrates a short distance into the sample over a wide range of wavelengths. In those regions of the infrared spectrum where the sample absorbs radiation, some of the light does not return back to the glass. The amount of light absorbed provides the information necessary for the quantification of the glucose level.
    [0066] Patents WO2001 / 079818, WO2000 / 021437, EP1137364, US2005 / 0137469, US2004 / 225206, US2003 / 176775, US2005 / 0171413 and US6362144 are based on the ATR method. In these documents, the determination of the glucose level is carried out from the comparative analysis in two specific regions of the infrared spectrum, one of them used as a reference with a wavelength between 8250 and 8750 nm, and the other used as a measurement with a wavelength between 9500 and 10000 nm. JP2001174405 is a similar invention to the above, but employs a single wavelength generated by a laser and a total reflection prism as a crystal. Another example is JPH11188009, where an ATR prism or fiber optic is used.
    [0068] WO2006 / 079797 describes an apparatus for measuring an analyte such as glucose by means of an electrically heated tape as an infrared light source, an ATR waveguide, waveguide collimators and light detectors. The collimator and detector are positioned relative to the waveguide at an adjustable angle. The glucose value is obtained by applying a predictive algorithm to measurements taken at different time intervals. The effect of temperature is compensated by the measurement of a temperature sensor and the pressure is controlled by a pressure sensor. Patent WO2016 / 086448 also includes as an innovative element a pressure sensor to normalize glucose estimates.
    [0070] JP2010217097 describes a spectrometer that includes a light source in the mid-infrared region, an ATR unit, and a set of optical band-pass filters to detect the different wavelengths. Each of the filters is activated by rotating a prism driven by a motor.
    [0072] Patents CN103919560 and CN103919561 are also based on the ATR technique, but in this case the reflection element is the end of an optical fiber, which is implanted under the skin. The sensitivity of the measurement is reinforced by metal nanoparticles located at the end of the optical fiber. Other documents based on ATR are JPH0856565, which uses different wavelengths between 8333 and 11111 nm to estimate the degree of fermentation in a fluid; US2003 / 031597 and US7438855B2, which use an ATR prism and a custom calibration curve to estimate glucose concentration; or US2004 / 0097796.
    [0073] CN101947115 describes an implantable system for the measurement of glucose concentration in human blood based on ATR on optical fiber. In this case the light is divided into two different optical paths: in one path the light is coupled to the optical fiber by means of an ATR sensor, in the other path the received light is used directly as a reference signal.
    [0075] WO2002 / 082990 uses the infrared spectroscopy technique based on the Fourier transform. Rather than projecting a monochromatic beam of light onto the sample, this technique generates a beam of light that contains multiple wavelengths at once and measures how much the sample absorbs. The process is repeated numerous times, modifying the beam to contain different combinations of wavelengths. Finally, a computer infers the absorption at each wavelength from all the measurements. Other documents that use the technique of infrared spectroscopy by means of the Fourier transform are JP2008 / 256398, which incorporates a procedure for the elimination of noise generated by water; KR2015 / 0122381, applied to the estimation of galactose and anhydrous galactose in liquid media; US6865408, which integrates a diffuse reflectance accessory that creates an interferogram, from which a computer system estimates the glucose level; WO2013 / 135249, which uses a commercial infrared spectrometer based on the Fourier Transform (Shimadzu IRPrestige - 21 / 8400S, Japan) and an ATR glass prism mounted on a PIKE Technologies accessory (ATR-8200 HA), or CN1194133, where another commercial spectrometer (Nicolet Magna-IR 750 Series II) is used.
    [0077] DESCRIPTION OF THE INVENTION
    [0079] The present invention relates to a device and the method used by said device for the non-invasive estimation of the blood glucose level. The device is preferably made up of two devices: the measurement unit and the personal monitoring unit, communicating with each other wirelessly.
    [0081] The unit of measurement is a portable device that is placed on the skin of an area of the human body irrigated by a vascular bed, and that emits light in two lengths different waveforms, one of them corresponding to an absorbance maximum in the absorption spectrum in the glucose molecule within the near infrared range. The measurement unit also captures light passing through the measurement zone, and the personal monitoring unit estimates the blood glucose level based on this information, displaying the result of the estimation to the user.
    [0083] Regarding the common glucose level estimation devices, glucometers, the main advantage is a safe and painless use that avoids any kind of discomfort or discomfort to the user. In addition, the measurements can be repeated as many times as desired. Another advantage of the proposed device is its low cost, since it uses commonly used electronic components and does not require test strips that would increase the continued cost of the device. Regarding commercial clinical systems for automatic / semi-automatic monitoring of glucose in interstitial fluid, its main advantages are also its low cost (it does not need supplements that increase the ongoing cost), safety (it does not require insertion of elements under the skin that can cause irritations, in addition to the danger of infections that this supposes) and its precision, since it analyzes the glucose component in blood itself and not that of the interstitial fluid, which can be misleading.
    [0085] In addition, the device presents other innovative features and technical advantages:
    [0087] - The measurement principle is based on photoelectric effects, so that the measurements are innocuous and can be repeated as many times as desired without discomfort to the user. - It is a portable system capable of communicating with the outside by means of two-way wireless communications, for the integration of the measures in an e-Health system in the upstream direction, and the remote configuration and customization of the device in the downstream direction.
    [0089] The device object of the invention is based on the infrared spectroscopy technique. Compared to other proposals based on this technique, the device and method described in the present invention present a series of novelties and innovations: 1) An absolute normalization consisting of a comparative analysis with respect to a second wavelength not affected by the presence of glucose molecules. two) Access to the arterial component of the blood by identifying the pulsating components in the signals captured. 3) A relative normalization in the face of fluctuations in the level of light, movements, and other conditions, consisting of a comparative analysis with respect to the continuous levels in the signals captured. 4) Personalization of the glucose estimation model depending on the particular characteristics of the person and the context in which the measurement is made. The novelties of the object of the invention are represented in the set of claims that accompany this description.
    [0091] DESCRIPTION OF THE DRAWINGS
    [0093] To complement the description that is being made and in order to help a better understanding of the characteristics of the invention, according to a preferred example of a practical embodiment thereof, a set of drawings is attached as an integral part of said description. where, for illustrative and non-limiting purposes, the following has been represented:
    [0095] Figure 1.- Shows a diagram of the basic architecture of the device object of the patent and the devices that compose it.
    [0097] Figure 2.- Shows a diagram of the basic architecture of the measurement unit.
    [0099] Figure 3.- Shows a diagram of the basic architecture of the measurement module.
    [0101] Figure 4.- Shows a diagram of the basic architecture of the personal monitoring unit.
    [0103] Figure 5.- Shows a diagram of the monolithic device that combines the unit of measurement and the personal monitoring unit.
    [0105] Figure 6.- Illustrates the non-invasive estimation method of blood glucose level.
    [0107] PREFERRED EMBODIMENT OF THE INVENTION
    [0108] In a possible embodiment of a first aspect of the invention proposed here shown in figure 1 there is a device (1) for the non-invasive estimation of the blood glucose level, which in a preferred embodiment comprises a device formed by two units: a measurement unit (2) and a personal monitoring unit (3). The device (1) is capable of communicating wirelessly and bidirectionally with an external service provider (21).
    [0110] The unit of measurement (2) is a portable device that is placed on the skin of an area of the human body irrigated by a vascular bed, and that emits light at two different wavelengths, one of them corresponding to a maximum absorbance in the absorption spectrum in the glucose molecule within the near infrared range. The measurement unit (2) captures the light that passes through the measurement area, and in conjunction with the personal monitoring unit (3), performs an estimation of the blood glucose level using a computational model based on the following conditions: 1 ) isolating the influence of glucose from the relationship existing in the amount of light received at each of the wavelengths; 2) normalize the estimate with respect to the influence of ambient light and with respect to stationary properties of the measurement such as the level of emitted light, the properties of the tissues, the arrangement and characteristics of the light emitters and the photodetector, or the influence the measurement area, as well as motion artifacts and other sources of low-frequency noise; 3) isolate the influence of arterial blood considering the pulsating component of the received signals. In the preferred embodiment, the measurement unit (2) comprises the following modules, referred to in figure 2:
    [0112] a) a measurement module (4), which incorporates the components for the non-invasive measurement of the glucose level;
    [0113] b) a first computing module (5), responsible for activating some components of the measurement module (4) and a first part of the processing associated with estimating the glucose level from the data provided by the measuring module. measurement (4);
    [0114] c) a first communications module (6), which is responsible for receiving configuration commands and sending data associated with the first communication module. computing (5);
    [0115] d) a first data storage module (7), for the temporary storage of the information in the event of communication failure, or for the persistent registration of the information of the measurement unit (2);
    [0116] e) a push button (8), for activating the measurement unit (2);
    [0118] In turn, the measurement module (4) comprises the following components, referred to in figure 3:
    [0120] a) A first light emitter E1 (9), activatable from the first computation module (5), with a wavelength corresponding to a maximum absorbance in the absorption spectrum in the glucose molecule within the infrared range nearby, which affects the skin of an area of the human body (10) irrigated by a vascular bed. In one embodiment of the invention the wavelength corresponding to 950 nm is used, although other wavelengths are possible. b) A second light emitter E2 (11), also activatable from the first computing module (5) and with a wavelength corresponding to a minimum absorbance in the absorption spectrum in the glucose molecule, located in a close to the first emitter E1 (9), and which affects the same area of the skin (10). In one embodiment of the invention the wavelength corresponding to 660 nm is used, although other wavelengths are possible.
    [0121] c) A photodetector (12) sensitive to the wavelength of the first and second emitters (9, 11), which generates an electric current signal S1 whose amplitude depends on the intensity of light received in the sensitivity spectrum of the photodetector ( 12). In a preferred embodiment, the sensitivity spectrum of the photodetector integrates the wavelengths corresponding to 660 nm and 950 nm.
    [0122] d) When the signal S1 is very weak, a first amplification stage (13) generates the electrical voltage signal S2 amplified from the signal S1.
    [0123] e) A first filtering stage (14) that abstracts the components of the S2 signal that vary as a consequence of the arterial flow of blood in the vascular bed, generating the S3 signal. In a preferred embodiment, this step is performed by means of a high-pass filter with a cut-off frequency that lets through the pulsating components related to cardiac activity.
    [0124] f) When the S3 signal is very weak, a second amplification stage (15) that generates the amplified S4 signal from the S3 signal.
    [0125] g) A second filtering stage (16) that abstracts the components of the S2 signal related to stationary properties in the measurement (emitted light level, stationary properties of the tissues, arrangement and characteristics of the light emitters and the photodetector (12 ), or the influence of the measurement zone (10)), which may vary from one measurement to another, as well as possible motion artifacts and other sources of low-frequency error, generating the S5 signal. In a preferred embodiment, this step is carried out by means of a low-pass filter with a cutoff frequency that does not let the pulsating components related to cardiac activity pass.
    [0127] The information generated by the measurement unit (2) is transmitted wirelessly to the personal monitoring device (3), with which it maintains a bidirectional communication link. The measurement start time can be activated locally by means of a push button (8) on the measurement unit (2) or it can be activated remotely by sending a command from the personal monitoring unit (3) . Also by means of another command, the temporary instants in which the automatic glucose estimates would be carried out could be previously configured.
    [0129] In the personal monitoring unit (3), with greater capacities, both hardware and software, than the measurement unit (2), the processing part with the highest computational load associated with the glucose level estimation method is developed. The multilevel distribution of the processing favors energy savings and reduces the computational load. The personal monitoring unit (3) can also take care of the processing and management of the information coming from other portable sensors connected to it, which can be related to other physiological variables (respiratory rhythm, heart rate, ECG, frequency variability heart rate, body temperature, physical activity, falls, body composition, skin impedance and pulse oximetry, etc.). In the preferred embodiment, the personal monitoring unit (3) comprises the following modules, referred to figure 4:
    [0130] a) A second communications module (17) designed to establish bidirectional wireless communications with at least the unit of measurement (2). b) A second computing module (18) in charge of the second part of the processing associated with the estimation of the glucose level. Algorithms for the detection of alarm situations or that should be considered in attention are also executed in it.
    [0131] c) An interface module (19) to display the information of the measurement unit (2) and the results of the second computing module (18), and allow the user to interact in an adapted way: touch (19.a), visual (19.b), auditory (19.c), or controlled by voice (19.d), etc. If an alarm event is detected, the interface (19) includes adapted warning means (light, acoustic, vibrations, etc.). The user could then disable or silence the alarm while managing and reviewing the information provided. The interface (19) can be used by two types of user: the monitored user, as could happen in a home environment, or the professional user, as it could happen in a clinical environment.
    [0132] d) A third communications module (20) designed to establish bidirectional wireless communications with an external service provider (21).
    [0133] e) A second data storage module (22) that takes care of the temporary storage of the information of the personal monitoring unit (3) in case of failure in communications, or for the persistent recording of said information, which allows future access without the need for a remote connection to an external database.
    [0135] In a preferred embodiment of the invention, the personal monitoring unit (3) is portable, although in other possible embodiments it can also be of fixed installation. Such a device can be physically implemented using a smartphone or a tablet.
    [0137] The measurement unit (2) and the personal monitoring unit (3) maintain a real-time timing system to manage the measurement instants and the operation time periods. This timing system is also it is responsible for assigning each estimate of the time in which they are made. The personal monitoring unit (3) is in charge of coordinating the glucose estimations according to a pre-established plan, which can be configured by an expert user locally through the interface (19) of the device or remotely through telematic services of the e-Health system. Said estimates will be activated in the measurement unit (2) by sending a command. A hierarchical procedure is established from the personal monitoring unit (3) to the measurement unit (2) based on the sending of commands for the synchronization of the timing systems. Different users, both experts and monitored users, can also activate the instant realization of an estimate. This instantaneous activation can be done from the push button (8) of the measurement unit (2) or from the interface (19) of the personal monitoring unit (3).
    [0139] The personal monitoring unit (3) can manage the information in an autonomous way, including alarm management, establishing communications in a transparent way to the user with the measurement unit (2) and with an external service provider (21) to integrate information and alarms in an e-Health system.
    [0141] The structural and functional modularity of the device for the non-invasive estimation of blood glucose level allows two possible configurations: a distributed one (1), in which the measurement unit (2) is physically separated from the personal monitoring unit (3 ), and another monolithic one, shown in figure 5, in which the measurement unit (2) is integrated together with the personal monitoring unit (3) in a single device (23). In this second case, the communications between both units can be carried out directly or wired (not wireless). Furthermore, the measurement unit (2) and the personal monitoring unit (3) can share physical components in the monolithic configuration (device (23)), such as a single computing module.
    [0143] In a preferred embodiment of the invention, the first and second light emitters E1 and E2 (9, 11) are arranged in such a way that the light beams pass through a relatively translucent body area (10) (a finger of the hand, for example), and are captured by a photodetector (12) located on the opposite side of the body area. This first embodiment is focused on incorporating the measurement unit (2) in an opaque housing to the spectrum of light in which the photodetector (12) is sensitive, which is configured to maintain a constant pressure on the measurement area ( 10).
    [0145] In another embodiment, and as Figure 1 also shows, the measurement unit (2) incorporates a temperature module (24), which is responsible for measuring the temperature of the measurement area (10), so that the model The glucose estimation calculator incorporates this data to adjust the coefficients as a function of temperature.
    [0147] In addition to the components and elements that make up the device object of the patent (1), it is also characterized by the method used for the non-invasive estimation of the blood glucose level, which is carried out in a distributed way in two levels: a first level of processing in the measurement unit (2), and a second level of processing in the personal monitoring unit (3). Thus, a distributed processing methodology and architecture is established, which is advantageous at the computing and energy saving level. At the computing level, because said multilevel structure allows compensating the processing load between the two devices to avoid computational overload. At the energy level, because the highest energy consumption in portable devices is related to sending data wirelessly. As multilevel processing reduces and abstracts the wireless information to be transmitted, energy saving is thus favored.
    [0149] Said method comprises the following operations, referred to figure 6:
    [0151] a) During a preset period of time P1 (25) in which the first and second light emitters E1 and E2 (9, 11) are deactivated, the estimation (28) of the parameter D1 is performed as the mean value of the signal S5.
    [0152] b) During a second preset period of time P2 (26) in which the first transmitter E1 (9) is activated, and the second transmitter E2 (11) is deactivated, the estimation (29) of parameter D2 is performed as the mean value of signal S5.
    [0153] c) During the same period of time P2 (26), the estimate (30) of the parameter D3 as the mean value of the differences between successive maxima and minima identified in the pulsating signal S4 related to cardiac activity. d) During a third pre-configured time period P3 (27) in which the second emitter E2 (11) is activated, and the first emitter E1 (9) is deactivated, the estimation (31) of parameter D4 is performed as the mean value of signal S5.
    [0154] e) During the same period of time P3 (27), the estimation (32) of parameter D5 is made as the mean value of the differences between successive maximums and minimums identified in the pulsating signal S4 related to cardiac activity. f) Estimation (33) of the blood glucose level from a model that depends on the parameters D1, D2, D3, D4 and D5. The model isolates the influence of glucose by weighting the dependence on the parameters according to two conditions: with the glucose molecules subjected to a light associated with a maximum absorbance in the parameters D2 and D3, or subjected to a light associated with a minimum absorbance in parameters D4 and D5. The influence of ambient light on the measurement of the photodetector (12) is weighted in the dependence on the parameter D1. The influence of the signal components related to stationary properties on the measurement (emitted light level, stationary properties of the tissues, arrangement and characteristics of the light emitters and the photodetector (12), or the influence of the measurement area ( 10)), as well as possible motion artifacts and other sources of error that generate low frequency signals, is weighted in dependence on parameters D2 and D4. The model isolates the influence of arterial blood on the estimate, and eliminates the influence of other tissues, weighting the dependence on parameters D3 and D5.
    [0156] The dependence of the glucose level estimation model with respect to parameters D1, D2, D3, D4 and D5 is based on coefficients that can be remotely configured by sending commands. The value of the coefficients is set by a quantitative method (least squares methods, genetic algorithms, swarm intelligence or neural networks), which minimizes the mean square error of the estimates in a reference study, which is used as a method. calibration. There are three possible models for estimating the glucose level based on the coefficients: 1) a model generalized, in which the value of the coefficients is adapted for the use of the model in multiple users; 2) a custom model, in which the value of the coefficients is adjusted to optimize glucose estimates for a given user; 3) a generalized and customizable model, which includes the dependency on other parameters related to the particular characteristics of the user, such as age, sex, type of diabetes or the context of the measure.
    [0158] It is also possible to select the display method of the glucose level estimate in the user interface (19): text, graphic, auditory, etc. or a multiple selection of them. In addition, this proposal adds the possibility of selecting the user's classification method, based on the estimation results. The selected classification method will establish thresholds based on the blood glucose level, which will allow the user to be classified into different levels, for example: very high, high, normal, low or very low. The thresholds, levels and the result of the classification will be displayed in a manner related to the representation method selected for the estimation (text, graphic, auditory, etc. or a multiple selection of them). The classification method assumes prior clinical knowledge and classification standards to provide direct information on the user's status and thus facilitate their evaluation and diagnosis.
    [0160] The possibility of making a historical follow-up of the glucose estimates in the different measurements of a user is also considered. Said historical record will be displayed in a manner related to the selected representation method (text, graphic, auditory, etc. or a multiple selection of them). In each of the measurements, the date and time when the estimate was made can be identified.
    [0162] The object of the invention may comprise additional processing on the recording of the measurements whose purpose is to automatically establish trends, patterns and predictions in the history of the measurements, which may be notified to the user.
    [0164] The second computing module (18) also implements a system for detecting undesirable situations, which, if detected, would generate a series of Local and remote alarms that would allow preventive action on the user. Said system uses a library of configurable indicators, locally or remotely, and a table with critical values for the generation of alarms related to said indicators. These indicators can be associated with a specific glucose estimate, but also with an analysis of trends, patterns and predictions of the historical estimates. The logic and decision rules that govern the activation of the alarms can also be configured to relate one or more of the indicators.
    权利要求:
    Claims (12)
    [1]
    1.- A device (1) for non-invasive estimation of the blood glucose level, comprising:
    - a unit of measurement (2), comprising the following modules:
    - a glucose level measurement module (4), comprising a plurality of elements configured to carry out a non-invasive measurement process of the blood glucose level;
    - a first computing module (5), configured to control the measurement module (4), and to process data on a first part of the blood glucose level measurement process, from the data provided by the module measurement (4);
    - a first communications module (6), configured to receive configuration commands and send data associated with said commands to the first computing module (5);
    - a first data storage module (7), configured for storing the information of the measurement unit (2);
    - a push button (8), configured to activate the measurement unit (2);
    - a personal monitoring unit (3), comprising:
    - a second communications module (17), configured to establish bidirectional wireless communications with at least the measurement unit (2);
    - a second computing module (18), configured to process data on a second part of the blood glucose level measurement process;
    - an interface module (19), configured to display the information of the measurement unit (2) and the data provided by the second computing module (18), and to allow the user to interact;
    - a third communications module (20), configured to establish two-way wireless communications with an external service provider (21);
    - a second data storage module (22), configured for storing data from the personal monitoring unit (3);
    and characterized in that the measurement module (4) comprises:
    - a first light emitter E1 (9), activatable from the first computing module (5), and configured to emit with a wavelength corresponding to a maximum of absorbance in the absorption spectrum in the glucose molecule within the near infrared range, which affects the skin of a body area (10) irrigated by a vascular bed;
    - a second light emitter E2 (11), activatable from the first computing module (5), and configured to emit with a wavelength corresponding to a minimum absorbance in the absorption spectrum in the glucose molecule, and arranged close to the light emitter E1 (9);
    - a photodetector (12), sensitive to the wavelength of the first and second light E1 and E2 (9, 11), configured to generate an electric current signal (S1), the amplitude of which depends on the intensity of light received in the sensitivity spectrum of the photodetector (12);
    - a first amplification stage (13), which generates an electrical voltage signal (S2), amplified from the electrical current signal (S1), when said electrical current signal (S1) is weak;
    - a first filtering stage (14) that abstracts the components of the electrical voltage signal (S2) that vary due to arterial flow, generating a third signal (S3);
    - a second amplification stage (15), which generates an amplified signal (S4) from the third signal (S3);
    - a second filtering stage (16), which abstracts the components of the electrical voltage signal (S2) related to stationary properties in the measurement, as well as possible motion artifacts and other sources of low-frequency error, generating a fifth signal (S5).
    [2]
    2. - The device according to claim 1, characterized in that the first and second light emitters E1 and E2 (9, 11) are arranged so that the light beams pass through a relatively translucent body area (10), such as a finger. of the hand or an earlobe, and are captured by the photodetector (12) located on the opposite side of said body area (10).
    [3]
    3. - The device according to claim 1, characterized in that it is covered by a housing opaque to the light spectrum in which the photodetector (12) is sensitive.
    [4]
    4. The device according to claim 3, characterized in that the opaque casing is configured to exert constant pressure on the body area (10).
    [5]
    5. - The device according to claim 1, characterized in that the measurement unit (2) and the personal monitoring unit (3) comprise a real-time timing system configured to manage measurement instants and time periods of the operations.
    [6]
    6. - The device according to claim 1, characterized in that the measurement unit (2) comprises a temperature module (24) configured to measure the temperature in the body area (10) where the measurement is performed.
    [7]
    7. - The device according to claim 1, characterized in that the personal monitoring unit (3) is configured to additionally measure some physiological variables selected from: respiratory rate, heart rate, ECG, heart rate variability, body temperature, activity physics, falls, body composition, skin impedance and pulse oximetry.
    [8]
    8. - The device according to claim 1, characterized in that the measurement unit (2) and the personal monitoring unit (3) are physically separated or integrated into a monolithic device (23).
    [9]
    9. - Method for non-invasive estimation of blood glucose level using the device described in any one of claims 1 to 8, carried out in a distributed manner by the first computing module (5) and the second computing module (18 ), and which includes the following operations:
    - make a first estimation (28) of a first parameter (D1) as the mean value of the fifth signal (S5) during a pre-configured period of time P1 (25) in which the light emitters E1 (9) and E2 ( 11) are disabled;
    - make a second estimation (29) of a second parameter (D2) as the mean value of the fifth signal (S5) during a second preset period of time P2 (26) in which the emitter E1 (9) is activated, and the emitter E2 (11) is deactivated;
    - make a third estimate (30) of a third parameter (D3) during that second preset period of time P2 (26), where the third parameter corresponds to the mean value of the differences between successive maximums and minimums identified in the pulsing signal (S4);
    - make a fourth estimate (31) of a fourth parameter (D4) as the average value of the fifth signal (S5) during a third pre-configured time period P3 (27) in which the emitter E2 (11) is activated, and the emitter E1 (9) is deactivated;
    - make a fifth estimation (32) of a fifth parameter (D5) during the third pre-configured time period P3 (27), where said fifth parameter (D5) corresponds to the mean value of the differences between successive maximums and minimums identified in the pulsing signal (S4);
    - estimate the blood glucose level (33) from a model that depends on the parameters from the first to the fifth (D1, D2, D3, D4, D5) where the model isolates the influence of glucose by weighting the dependence on these parameters (D1, D2, D3, D4, D5) according to two conditions: with glucose molecules subjected to a light associated with a maximum absorbance in the second parameter (D2) and third parameter (D3) or subjected to an associated light at a minimum absorbance in the fourth parameter (D4) and the fifth parameter (D5) and where the influence of ambient light in the measurement of the photodetector (12) is weighted in the dependence with respect to the first parameter (D1), and where the influence of the signal components related to stationary properties in the measurement, with movement artifacts and sources of error that generate low frequency signals, is weighted in the dependence on the second and fourth parameters (D2, D4) and the model isolates the influence of blood arterial in the estimation, and eliminates the influence of other tissues, weighting the dependence with respect to the third and fifth parameters (D3, D5).
    [10]
    10. The method of claim 8 in which the dependence of the glucose level estimation model on the first to fifth parameters (D1, D2, D3, D4, D5) is performed based on coefficients that can be remotely configured by sending commands, and where the coefficient values generate a generalized model for use by different users, or a custom model for individual use, or a generalized and customizable model including dependency on other related parameters with the particular characteristics of the user.
    [11]
    11. The method of claim 8 that incorporates the measurement of the temperature modulus (24), as a parameter of the glucose level estimation model.
    [12]
    12. The method of claim 8 that incorporates an operation that activates an alarm locally and remotely when the glucose estimate registers a value considered inappropriate.
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    同族专利:
    公开号 | 公开日
    SG11202111220XA|2021-11-29|
    EP3916376A1|2021-12-01|
    KR20210118438A|2021-09-30|
    IL285043D0|2021-09-30|
    ES2774983B2|2021-06-10|
    US20220007975A1|2022-01-13|
    CA3127431A1|2020-07-30|
    AU2020211758A1|2021-08-12|
    CN113692530A|2021-11-23|
    WO2020152380A1|2020-07-30|
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    CA3127431A| CA3127431A1|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    PCT/ES2020/070027| WO2020152380A1|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    KR1020217026381A| KR20210118438A|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    CN202080021138.3A| CN113692530A|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    AU2020211758A| AU2020211758A1|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    SG11202111220XA| SG11202111220XA|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    EP20745840.7A| EP3916376A1|2019-01-22|2020-01-17|Portable device and method for non-invasive blood glucose level estimation|
    US17/424,734| US20220007975A1|2019-01-22|2020-01-17|Portable Device and Method for Non-Invasive Blood Glucose Level Estimation|
    IL285043A| IL285043D0|2019-01-22|2021-07-21|Portable device and method for non-invasive blood glucose level estimation|
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