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WO2021097545A2 - Système, procédé et dispositif de mesure de concentration d'un bioanalyte - Google Patents

Système, procédé et dispositif de mesure de concentration d'un bioanalyte Download PDF

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Publication number
WO2021097545A2
WO2021097545A2 PCT/BR2020/050495 BR2020050495W WO2021097545A2 WO 2021097545 A2 WO2021097545 A2 WO 2021097545A2 BR 2020050495 W BR2020050495 W BR 2020050495W WO 2021097545 A2 WO2021097545 A2 WO 2021097545A2
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WIPO (PCT)
Prior art keywords
electrode
bioanalyte
concentration
measurement
glucose
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PCT/BR2020/050495
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English (en)
Portuguese (pt)
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WO2021097545A3 (fr
Inventor
Nilton Braz GIRALDELLI
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Individual
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Individual
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Priority claimed from BR102019024450-0A external-priority patent/BR102019024450A2/pt
Priority claimed from BR102020003529-0A external-priority patent/BR102020003529A2/pt
Priority claimed from BR102020005234-9A external-priority patent/BR102020005234A2/pt
Application filed by Individual filed Critical Individual
Publication of WO2021097545A2 publication Critical patent/WO2021097545A2/fr
Publication of WO2021097545A3 publication Critical patent/WO2021097545A3/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis

Definitions

  • the present invention relates to a system for measuring the concentration of a bioanalyte present in the interstice of an organism.
  • the present invention also relates to a method and a device for measuring the concentration of a bioanalyte.
  • Diabetes mellitus is a disease caused by insufficient production or malabsorption of insulin, a hormone that regulates glucose in the blood and ensures energy for the organism, breaking down the molecules of glucose (sugar) transforming them into energy for the maintenance of the body's cells.
  • Diabetes brings together a group of diseases that result from the accumulation of sugar in the blood. Its most common types are: a) Type 2 diabetes: a chronic disease that affects the way the body processes blood glucose; b) Type 1 diabetes: chronic disease in which the pancreas produces little or no insulin; c) Pre-diabetes: condition in which blood glucose is in high concentration, but not enough to be classified as type 2 diabetes; d) Gestational diabetes: high blood glucose levels that affect pregnant women.
  • Glycemic control significantly reduces the complications of diabetes.
  • methods that assess the frequency and magnitude of hyperglycemia are essential in monitoring the disease, aiming at adjustments in treatment.
  • the assessment of glycemic control was done only with household measurement of glycosuria and occasional fasting blood glucose measurements.
  • HbA1 c glycated hemoglobin
  • AMGC capillary blood glucose self-monitoring
  • SMCG interstitial liquid glucose monitoring system
  • Blood glucose measurement is usually done in serum or plasma, but some laboratories measure it in whole blood, which is 10% to 159% lower.
  • the most used method currently in the state of the art for blood glucose measurement is enzymatic, with oxidase or hexokinase.
  • the ideal blood collection tube for blood glucose measurement must contain fluoride.
  • Blood glucose measurement is usually performed on an empty stomach (the absence of any food intake, except water, is recommended for at least 8 hours).
  • the measurement of postprandial glycemia can also be performed (1 h to 2 h after the beginning of food intake) and allows the assessment of postprandial hyperglycemic peaks associated with cardiovascular risk and oxidative stress. However, it also represents a one-off measure, which may not reflect what happens on other days and times not evaluated. However, such a dosage may be useful in patients with type 2 diabetes mellitus who do not perform AMGC.
  • the measurement of blood glucose simultaneously with the measurement of capillary blood glucose can be used to test the accuracy of the self-monitoring results. This test should preferably be done on an empty stomach, since the glucose concentration in venous and capillary blood is similar in an empty stomach, but postprandial samples can be 20% to 25% higher in capillary blood.
  • the use of venous blood in the glucometer, instead of capillary blood, can eliminate this problem.
  • the first state-of-the-art glucometers used a first glucose oxidase (GOx) enzyme electrode, based on a thin layer of enzyme on an oxygen electrode, where the reading relates the amount of oxygen consumed by GOx during the enzymatic reaction with glucose.
  • GOx glucose oxidase
  • GOx catalyzes the oxidation of glucose to gluconolactone. Therefore, GOx requires Flavin Adenine Dinucleotide (FAD) to act as an electron acceptor reducing to FADFI2, according to the following reaction: Glucose + GOx (FAD) ® Gluconolactone + GOx (FADFI2) Glucose + GOx (MANIA) ®
  • FADFI2 Flavin Adenine Dinucleotide
  • the FAD cofactor (active redox center) is deeply embedded in the molecular structure of GOx. This requires the use of mediators or other strategies to improve communication between the enzyme and the electrode surface by "guiding" the electrons to the electrode.
  • the natural mediator is the oxygen / hydrogen peroxide (O2 / FI2O2) pair, according to the reactions:
  • Flavin is reoxidated in the presence of oxygen, producing hydrogen peroxide. This is monitored by measuring the current generated after applying a potential (around +0.6 V vs. Ag / AgCI) between the working electrode and a reference electrode.
  • test strips that change color and can be read visually, without a meter, and have been widely used since the 1980s. They have the added advantage that they can be cut longitudinally to reduce costs, but are not as accurate or convenient as testing with meters.
  • lancets In the selected location, such as the finger, to allow the collection of 1 or 2 drops of blood from the small and abundant capillary vessels in the superficial vascular plexus under the epidermis, accessible all over the body.
  • Conventional lancets generally have a rigid body and a sterile needle that protrudes from one end.
  • the puncture / perforation can disrupt the tissue structure, causing an inflammatory reaction that can consume glucose followed by a repair process.
  • the interaction of a sensor with the traumatized microenvironment justifies the need for a waiting period for the sensor signal to stabilize, and this period varies according to the type of sensor.
  • the document BR 11 2019 012600-7 reveals a system of continuous glucose monitoring.
  • the system comprises a subcutaneous insertable glucose sensor, which has the aforementioned disadvantages.
  • the current commercial glucose sensors for indirect glucose measurement of the interstitial space use amperometric enzyme electrodes based on glucose oxidase (GOx), whose operating principle is the measurement of the current flowing from an oxidation reaction, in a working electrode, to a reduction reaction, in a counter electrode.
  • GOx glucose oxidase
  • a potential is applied between the working electrode and a reference electrode, although some sensors use a two-electrode configuration (working and counter-reference electrode), combining the counter and reference electrodes.
  • An example is the electrochemical sensor revealed by document BR 11 2017 000271 -0. However, such an electrochemical sensor is preferably introduced in the user's eye for measurements, which represents a great inconvenience and makes its use difficult.
  • bioanalytes such as, for example, glucose
  • a general objective of the present invention is to provide a system for measuring the concentration of a bioanalyte capable of eliminating or at least reducing the limitations of the techniques currently known.
  • the present invention has the particular objective of providing a device for measuring the concentration of a bioanalyte.
  • One or more objectives of the aforementioned invention is (are) achieved (s) by means of a concentration measurement system of a bioanalyte comprising an electrode; a reagent; a processor; an induction device; wherein the processor is communicatively coupled with the electrode and the induction device; in which an oxidation state of the electrode is modified by means of an oxidation reaction between the reagent and the bioanalyte caused by an interaction between the induction device and the electrode; where the processor is configured to: apply at least one electrical current to an electrode path; determining a transmission time for at least one electric current in the electrode path; determining at least one lag between an expected transmission time and the determined transmission time for at least one electrical current; determine the oxidation state of the electrode based on at least a certain lag; determine the concentration of the bioanalyte based on the oxidation state of the determined electrode.
  • One or more objectives of the aforementioned invention is (are) also achieved through a method of measuring the concentration of a bioanalyte comprising the steps of: modifying an oxidation state of an electrode through an oxidoreduction reaction between a reagent and the bioanalyte caused by an interaction between an induction device and the electrode; apply at least one electric current in an electrode path; determining a transmission time for at least one electric current in the electrode path; determining at least one lag between an expected transmission time and the determined transmission time for at least one electrical current; determine the oxidation state of the electrode based on at least a certain lag; determine the concentration of the bioanalyte based on the oxidation state of the determined electrode.
  • One or more objectives of the aforementioned invention is (are) also achieved (s) by means of a concentration measurement device of a bioanalyte, comprising: an electrode; a reagent; a processor; wherein the processor is communicatively coupled with the electrode; in which an oxidation state of the electrode is modified by means of an oxidation reaction between the reagent and the bioanalyte caused by an interaction between an induction device and the electrode; where the processor is configured to: apply at least one electrical current to an electrode path; determining a transmission time for at least one electric current in the electrode path; determining at least one lag between an expected transmission time and the determined transmission time for at least one electrical current; determine the oxidation state of the electrode based on at least a certain lag; determine the concentration of the bioanalyte based on the oxidation state of the determined electrode.
  • Figure 1 illustrates the behavior of interstitial glucose (Gl) in the body, notably its migration through the dermis (De) to the epidermis (Ep), reaching a measurement device (BS) according to an embodiment of the invention, where the interstitial fluid (LI), the cells (Ce) and the bloodstream (CS) are also perceived.
  • Gl interstitial glucose
  • Figure 2 illustrates a layered structure of the measuring device (BS) of the present invention, in an exploded view (2A) and a side view (2B), where the disposable substrate (SD), the edges of medical glue ( CM), the antenna (At), the processor (Cl), the connecting element (Li) and the breathable medical adhesive (AM).
  • FIG. 3 shows a detailed view of the antenna (At) in association with the processor (Cl) of the measuring device of the present invention, where the connection element (Li) is perceived.
  • Figure 4 illustrates the logic of converting the signal obtained into information by the processor (Cl) of the measuring device, highlighting the sampler (Am), the quantizer (at) and the converter (Cv).
  • Figure 5 shows the voltage detected by the processor (Cl), highlighting the peak of the resistance close to 800ms.
  • Figure 6 shows the relationship between oxidation resistance (RF) and glucose concentration, with the maximum oxidation peak.
  • Figure 7 illustrates an interaction between the induction device and the measuring device, according to an embodiment of the present application.
  • FIG 8 illustrates the arrangement of the system of the present invention, where the generation of the signal by an antenna is evidenced, the reception and treatment of the signal by the measuring device (BS) and the sending of the information to an external device (DE).
  • BS measuring device
  • DE external device
  • Figure 9 illustrates the steps of the operating logic of the system of the present invention, comprising:
  • FIG. 10 to 12 illustrate the interfaces for entering personal information (Fig. 10), information regarding the type of diabetes to be monitored (Fig. 11) and the features and configurations of the interpretation system (Fig. 12) of the interpretation system of the present invention.
  • FIG. 13 illustrates the generation of a base glucose value (GBV) during the calibration of the system of the present invention.
  • Figure 14 illustrates the visualization of the interstitial glucose measurement provided by the measurement system, according to an embodiment of the present invention.
  • Figure 15 illustrates the visualization of the interstitial glucose measurement on the external device (DE) screen.
  • Figure 16 represents the set of information acquired by the measurement system, according to an accomplishment of this request.
  • Figure 17 represents an embodiment of the measurement system of the present invention, where the result of the measurement of the concentration of the bioanalyte is visualized.
  • Figure 18 represents an embodiment of the measurement system of the present invention, where the trend of variation in the measurement of the concentration of the bioanalyte is visualized.
  • Figure 19 represents an embodiment of the measurement system of the present invention, where a history of measurements of bioanalyte concentrations is visualized.
  • the present invention discloses a system, method and device for tracking user glycemic indexes for monitoring a user's clinical status, more specifically non-invasive, for measuring a user's interstitial glucose.
  • the present invention discloses a non-invasive device for the continuous measurement of interstitial glucose concentration in an organism, comprising a semipermeable membrane, a printed circuit (processor) for processing information and an antenna for transmitting NFC, where the device measurement system (BS), which can also be referred to as “Biosensor”, it acts positioned on the user's skin in order to interact with bioanalytes and generate information that allows it to be related to the concentration of interstitial glucose.
  • BS device measurement system
  • biosensor refers to a device that uses biological recognition properties for the selective analysis of different analytes or biomolecules, generating a signal quantitatively related to the concentration of the substance to be measured.
  • the present invention reveals technical measurement and communication solutions, more specifically for the interpretation and management of the measurement of the concentration of bioanalytes and the consequent formation of useful information to the user.
  • the present invention comprises a bioanalyte concentration measurement system.
  • bioanalyte refers to the biological substance or component that is the target of analysis in an assay so that its properties can be measured, since they cannot be measured in themselves. For example, you cannot measure a table, but its height, width, etc. Likewise, glucose cannot be measured, but its concentration can be measured. In this example “glucose” is the component and “concentration” is the measurable property.
  • the measurement system comprises an electrode; a reagent; a processor and an induction device (also called an external device).
  • the bioanalyte may be interstitial glucose (that is, present in the interstice of the organism / user) and the reagent may be glucose oxidase.
  • glucose oxidase can be immobilized on or in the vicinity of the electrode, for example, when applied as a reagent layer.
  • the processor is connected communicatively with the electrode and the induction device.
  • An oxidation state of the electrode is modified by means of an oxidation reaction between the reagent and the bioanalyte caused by an interaction between the induction device and the electrode.
  • the processor is configured to: apply at least one electrical current to an electrode path; determining a transmission time for at least one electric current in the electrode path; determining at least one lag between an expected transmission time and the determined transmission time for at least one electrical current; determining the oxidation state of the electrode based, at least in part, on at least a certain lag; determine the concentration of the bioanalyte based, at least in part, on the oxidation state of the determined electrode.
  • the processor can be configured to: apply a plurality of electrical currents comprising different frequencies to the electrode; for each applied electric current, determine a transmission time for each electric current; for each applied electric current, determine a lag between an expected transmission time and the determined transmission time; determine the oxidation state of the electrode based, at least in part, on at least one lag among the determined lags.
  • the measurement system counts the estimate of the electrode's sensitivity.
  • the processor is configured to provide a disturbance control signal that affects the electrode response, for example, by changing the voltage level, current intensity and / or frequency that is applied to the biosensor (BS) between the working and reference.
  • the sensitivity estimate can be determined based, at least in part, on the difference in response measured at different voltage levels, current intensity and / or frequency according to a look-up table.
  • the processor can also be additionally configured to store information regarding the oxidation state of the electrode after a first measurement and, in a second measurement, after the first measurement, determine the concentration of the bioanalyte based, at least in part, on the information related to the oxidation state of the electrode after the first measurement and based, at least in part, on the oxidation state of the electrode after the second measurement.
  • the measurement system may comprise an antenna communicatively coupled to the processor.
  • the processor can be further configured to transmit information on the concentration of the bioanalyte to the induction device via the antenna.
  • the measuring system's antenna and electrode are the same physical component.
  • the electrode, antenna, processor and reagent are stacked in layers forming a single body.
  • the single body formed by the stacked layers can be termed as a measuring device or biosensor (BS).
  • This measuring device (BS) may comprise a means of attachment to a user, such as edges made of medical glue (CM), edges comprising medical glue or strips comprising medical glue.
  • CM medical glue
  • the antenna can be configured to capture energy from radiation emitted by the induction device and energize the processor.
  • NFC technology is used to collect / capture energy, but the antenna can be configured to capture any type of radiation incident in the environment, such as infrared radiation, visible light, ultraviolet, radio, among others.
  • FIG 7 illustrates an interaction between the antenna (At) of the biosensor (BS) and an antenna of the external device (DE), which can be applied both for the bidirectional transmission of information and for the capture of energy by the antenna ( At) for operation of the biosensor (BS).
  • the induction device (or external device), for example a smartphone or a tablet, can be configured to handle the bioanalyte concentration information received from the antenna and generate graphical information for a user, in which the information graphics comprise at least one of:
  • an induction device can be additionally configured to perform at least one function among:
  • the present invention also reveals a system for interpreting the information collected by a user's bioanalyte monitoring device and sending this interpreted information to an external device (DE), using a processor or integrated circuit, in the form of a chip (C ), which receives the signals generated by an antenna (At) and processes them in order to generate information that reflects the concentration of the bioanalyte that is being measured.
  • DE external device
  • C chip
  • the processor or integrated circuit (Cl) is activated by an interaction (for example, an approximation) between an external device (DE) equipped with approach-field communication (or near-field communication, also known by the abbreviation NFC ), allowing the transmission of information from the chip (Cl) to the external device (DE) for the interpretation and presentation of the treated information to the user.
  • an interaction for example, an approximation
  • DE external device
  • approach-field communication or near-field communication, also known by the abbreviation NFC
  • NFC near-field communication
  • an antenna (At) interacts with the bioanalyte to be measured and generates an electrical signal (Si) proportional to the concentration of the bioanalyte.
  • This signal (Si) is then received by the chip (Cl) and treated to generate information (If) that can be used by the external device (DE).
  • the antenna (At) operates with a previously defined transmission frequency.
  • the antenna (At) is a TAG NFC antenna with a transmission frequency of 13.56 MFIz and uses the communication protocols ISO 14443A / B or ISO 15693.
  • the antenna (At) is energized by the interaction (for example, an approximation) between the external device (DE) equipped with NFC, being traversed by an electric current that sweeps its course in different frequencies, up to 13.56 MFIz in 0.01 MHz intervals / increments, reaching the chip / processor (Cl) that perceives a possible delay / lag in the transmission of a current associated with some frequency.
  • the chip / processor (Cl) receives the electrical charge, while the biosensor (BS), already in contact with the user's skin, started its oxidation process. This change in the oxidation state interferes with the way the electrical charge travels through the biosensor (BS).
  • the magnetic field For each frequency traveled, the magnetic field generates a noise and, the greater the noise (or change of frequency), the more difficult it is for the biosensor (BS) to complete the transit of the electric current and arrive at the next frequency.
  • RF oxidation resistance
  • concentration of the bioanalyte such as glucose
  • a maximum RF occurred at the frequency 3.4 Mhz, which corresponds to a analyte measurement of 121 mg / dl according to a look-up table that can be stored on the chip / processor (Cl) or on the external device (DE).
  • the wave that travels through it will suffer some difficulty to continue on its path until the end of the frequency of 13.56 MFIz, due to the oxidation suffered by the antenna (At), which in this realization also works like an electrode.
  • This point corresponds to the peak of resistance detected by the integrated circuit (Cl) and, therefore, to a certain concentration of bioanalyte.
  • This delayed frequency corresponds to a concentration of the measured bioanalyte, since its measurement generated, in the antenna (At) a level of oxidation corresponding to its concentration and this oxidation interferes in the frequencies that travel through the body of the antenna (At).
  • the integrated circuit (Cl) of the measurement system described here is provided with programming (or a set of instructions or software) that, when executed by the integrated circuit (Cl), interprets the delayed frequencies identified in an information corresponding to the measured bioanalyte concentration, as described, sending this information to the external device (DE) through the antenna (At), using its transmission frequency.
  • the approximation of the external device allows a first reading of the frequency, which corresponds to a certain concentration of glucose in the user according to the consultation table.
  • Table 1 below presents hypothetical readings taken by the system of the present invention.
  • the measurement starts at the 0.01 Mhz frequency, performed in 0.001 Mhz increments.
  • the current travels through the biosensor (BS), at some point there will be a difficulty in reading, generating a delay / lag in the measurement.
  • This calculation for the delay results in the corresponding frequency and, by correspondence, in the definition of the concentration of the bioanalyte.
  • the time defined for electric current to complete the reading cycle is approximately 7.4 x 10 8 s, which is the time necessary for the current to cover all frequency lines, from 0.01 MHz to 13, 56MHz.
  • the RF (radio frequency) integrated circuit (Cl) operates by means of a sampler (Am), which performs the sampling of bioanalytes produced by the organism, associated with a quantizer (Qt), which validates the amount of information coming from the changes that occurred in frequency, which are sufficient to convert analog signals to digital (binary) signals, and specific programming on the external device (DE) is responsible for making the conversion (Cv) itself, transforming the collected information into equivalent bioanalyte concentration .
  • Am sampler
  • Qt quantizer
  • DE specific programming on the external device
  • the present invention features a non-invasive device for collecting information related to a user's interstitial glucose, constituting a small biosensor (BS), similar to a plastic tag, which, adhered to the skin / epidermis ( Ep) of the user, performs the collection of information from the activation by a device equipped with communication by approach field (or near-field communication - NFC), allowing the transmission of this information to an external device (DE) for interpretation and presentation information handled by the user.
  • BS small biosensor
  • Ep skin / epidermis
  • the concentration of glucose in the interstitial fluid (Gl) has a great correlation with the levels / concentrations of glucose observed in the blood, since the glucose diffuses directly from the blood stream (CS) to the interstitial fluid, in order to supply the cells of the tissues of the necessary nutrients to the skin, as illustrated in Figure 1.
  • interstitial glucose (Gl) can migrate through the dermis (De) to the epidermis (Ep) and interact with the biosensor (BS) allocated there, in order to enable its detection .
  • this diffusion process is not instantaneous and appears to be influenced by blood flow and capillary permeability.
  • the glucose biosensor is an amperometric electrochemical sensor, which typically employs the use of the glucose oxidase enzyme (GOx) to catalyze the reaction between glucose and oxygen and thus generate an electrical signal, as represented in the equations 1 and 2: glucose + O2 + H2O + GOx ® H2O2 + glycolic acid (equation 1) H2O2 ® O2 + 2H + + 2e (equation 2)
  • the formed H2O2 degrades, releasing electrons that interact as a biosensor (BS), providing the correlation with the concentration of interstitial glucose (Gl).
  • This degradation is motivated by the electrochemical tension generated by the interaction between the induction device and the electrode (for example, an approximation) promoting, then, the interaction between 0 H2O2 and 0 biosensor (BS), occurring the oxidation-reduction reaction in which
  • the amperometric electrochemical sensor is the reducing agent that allows the reduction of hydrogen peroxide, yielding electrons to hydrogen peroxide, resulting in the movement of charges between the electrodes.
  • an “electrochemical cell” is formed in that environment on the skin (Ep), where the electrons generated by the degradation of hydrogen peroxide migrate to the antenna (At), generating a signal proportional to the amount of interstitial glucose (Gl) that reacted with glucose oxidase.
  • the current measured by the biosensor is that generated by the oxidation of hydrogen peroxide (H2O2) in an electrode.
  • H2O2 hydrogen peroxide
  • the final current is also proportional to the amount of glucose that reacts with the enzyme.
  • the current will be proportional to the concentration of oxygen and not that of glucose.
  • glucose must be the limiting reagent, that is, the oxygen concentration must be in excess for all glucose concentrations, a requirement that is not easily achieved, since, in subcutaneous tissue, the oxygen concentration is much lower than that of glucose.
  • the measurement system in an embodiment of the present invention, comprises a semipermeable membrane (AM) to regulate the transport of oxygen and glucose to the sensitive elements of the biosensor (BS) and maximize the availability of oxygen.
  • a semipermeable membrane can be called “medical fabric", composed of a combination of a non-woven fabric (TNT) made of polyester with a medical grade acrylic adhesive.
  • TNT non-woven fabric
  • an elastic polyurethane TNT with acrylate adhesive can also be used.
  • the main function of the semipermeable membrane (AM) is to allow the exchange of fluids as a filter, releasing the passage of the interstitial liquid to the absorption area of the transducer (Cl), which is highly sensitive to pH variation, detecting small concentrations of glucose (Gl) in the middle when this molecule undergoes oxidation when it comes in contact with the part of the biosensor (BS).
  • the biosensor (BS) for measuring interstitial glucose (Gl) comprises a series of components, represented in Figure 2, which, combined, result in an apparatus capable of measuring interstitial glucose ( Gl) of a user.
  • the biosensor (BS) comprises a succession of overlapping layers, which can be described as follows: a) a disposable substrate (SD) is a protective element allocated to protect the adhesive capacity of the measuring device until its moment of use , when, then, the disposable substrate (SD) can be discarded; b) edges of medical glue (CM) consist of a thin layer of adhesive on the outer edges of the biosensor (BS) that promote the fixation of the device to the user's skin (Ep); c) the NFC antenna (At), which is characterized by being a metallic layer, preferably in a spiral shape, preferably in aluminum or brass, and serves to generate information proportional to the amount of interstitial glucose (Gl) from the interaction with the electrons supplied by hydrogen peroxide.
  • SD disposable substrate
  • CM edges of medical glue
  • the NFC antenna (At) which is characterized by being a metallic layer, preferably in a spiral shape, preferably in aluminum or brass, and serves to generate information proportional to the amount of interstitial glucose (Gl)
  • the antenna (At) acts as an electrode for an electrochemical cell
  • an Ntag (Cl) information processor or chip which performs the function of receiving the signal generated by the antenna (At), generating information proportional to the amount of interstitial glucose (Gl) reacted with GOx
  • a connecting element (Li) which is a solder between the antenna (At) and the chip (Cl), keeping them together and allowing their electrical connection
  • a breathable medical membrane or adhesive (AM) which is the adhesive that allows the biosensor (BS) to be in contact with the user's skin and allows the passage of oxygen for the chemical reactions in equations 1 and 2.
  • the electrons released by the degradation of FI2O2 from the approach of the NFC device interact with the antenna (At) and promote an oxidation of the material of the antenna (At), generating an electrical signal that is translated by the chip (Cl) to be sent to the NFC device and that is proportional to the concentration of glucose (Gl) captured by the measuring device.
  • the measurement system comprises a “smart sensor” architectural concept consisting of an analyte biosensor (BS) and three cascaded software modules.
  • BS analyte biosensor
  • the goal of intelligent biosensor algorithms is to make CGM (Continuous Glucose Monitoring) data more reliable and accurate, and this can be of great benefit for various applications, for example, generating hypoglycemia / hyperglycemia alerts.
  • CGM Continuous Glucose Monitoring
  • BS biosensor processor
  • a noise elimination module contains an algorithm designed to attenuate the measurement noise.
  • the original CGM data obtained by the bioanalyte concentration biosensor (BS) based, at least in part, on the oxidation state of the electrode, can present critical issues, such as measurement noise, estimates systematically above or below actual values and delays in generation of alerts.
  • the noise elimination module After processing the data by the noise elimination module, data with reduced measurement noise is obtained.
  • an enhancement module incorporates an algorithm that recalibrates CGM data to improve accuracy.
  • the enhancement module receives data with reduced measurement noise received from the noise elimination module and, optionally, data of glucose base values obtained by self-monitoring of glucose (SMBG) techniques ). After processing the data by the enhancement module, data are obtained with reduction of estimates systematically above or below real values;
  • SMBG self-monitoring of glucose
  • a prediction module presents an algorithm to predict in real time the concentration of glucose according to the latency of the frequency and resistance suffered by the frequency in the biosensor (BS) and thus generate more timely alerts.
  • the prediction module receives inputs with reduction of estimates systematically above or below the actual values received from the improvement module and, optionally, complementary information on food and liquids ingested, administered insulin doses, physical activity, among others. After processing the data by the prediction module, it obtains data CGM, which can be used to generate preventive alerts to compensate for any delays in the generation of alerts.
  • the present invention comprises a system for measuring and interpreting the information collected by a user's bioanalyte monitoring device and sending this interpreted information to an external device (DE) provided with a programming (or set of instructions) or software) dedicated to the management of this information in order to provide useful data to the user.
  • DE external device
  • the records collected from the measurements stored in a database of the interpretation system of the present invention, allow to generate a history of the measurements and, from the analysis of these data, to trace trends in the behavior of the user's glycemic index, facilitating the prediction of actions that must be taken in each situation.
  • the interpretation system described here starts from the insertion of the user's information, as illustrated in Figures 10 to 12.
  • Such information which ranges from (i) personal data ( Figure 10), such as name, email address, telephone, sex and password, passing through (ii) information related to the type of diabetes to be monitored ( Figure 11) and arriving at (ii) functionalities and configurations of the measurement and interpretation system ( Figure 12), are necessary so that the algorithm can help the user to manage their diabetes monitoring and control routine, crossing the settings fed by the user with the measurements collected by the system.
  • the application is installed on the external device (DE), such as smartphones or tablets, enabling it to operate on the device.
  • the external device (DE) is the induction device used to cause the reaction between the reagent (such as glucose oxidase) and the bioanalyte to be measured (such as glucose);
  • the biosensor (BS) is activated, releasing it to function, and its validity is verified with a security server in the cloud;
  • the measurement and interpretation system is calibrated, informing the initial GBV obtained by measuring the user's capillary blood;
  • the measurement and interpretation system preferably uses an application developed from an instant glucose measurement algorithm, or instant glucose measurement (IGM), to transform the information received from the measurement device (BS), illustrated in Figure 16, to generate a set of treated information, in order to help the user to monitor his glycemic indexes and adopt timely control measures, such as, for example, the administration of insulin.
  • IGM instant glucose measurement
  • Calibration may be necessary if the user realizes that the value of the measurement made on the biosensor (BS) is not consistent with his clinical condition at that time. Then, it enables the calibration function to be able to inform the measurement made at the fingertip (capillary blood glucose). This information is fed into the VBG field of the external device (DE) application.
  • the measurement and interpretation system requests information regarding the reason that led glucose to have changes, such as physical activity, food or liquids ingested by the user or application of insulin.
  • the real-time calibration algorithm uses data from previous time points that are available. A linear regression equation is modified and a linear regression technique is performed using four paired calibration data points, the most recent and points 6, 12 and 18 hours earlier.
  • the real-time calibration adjustment is performed to account for changes in sensor sensitivity over the life of the biosensor (BS). Feeding this information helps the user to make corrections and decide whether to take insulin or not. For the application, the information is used for trend arrow calculations to warn the user of glucose changes.
  • the collected measurements are stored by the measurement and interpretation system on a server and can be accessed by both the user and persons designated by him, so that they can be used by caregivers or doctors, as illustrated in Figure 14.
  • the information is presented to the user, as illustrated in Figure 15, presenting statistics, point measurements, trends, among other information applicable for the control of diabetes.
  • the interface of the measurement and interpretation system proposed here offers graphs to facilitate the understanding of the scenario to the user, as illustrated in Figures 17, 18 and 19, associated with a brief summary of the history of the measured glucose levels.
  • the system stores 180 days of glucose measurement data and provides a complete overview of the user's glucose levels over the past six months.
  • the graphs aim to present various information to the user, such as the time and value of the measurement performed, the glucose variation trends, using the “trend arrows”, and a history of the daily measurements taken, as shown in Figure 19.
  • the system allows the user to add notes referring to the foods consumed and the insulin doses administered, creating a particular history, referring to their habits and peculiarities.
  • Continuous monitoring of the user's glucose levels also provides the tendency for blood glucose levels to rise or fall and the speed of these variations, indicated by the “trend arrows” that the graphs show, indicating the direction (up or down) of the latest measurements, as can be seen in Figures 17 to 19.
  • the inclination of the arrows indicates the speed of variation and an inclined trend arrow shows that, at that moment, blood glucose levels are stable.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Electrochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)

Abstract

Le système de mesure de concentration d'un bioanalyte comprend un réactif et un processeur couplé en communication avec une électrode et un dispositif d'induction. Un état d'oxydation de l'électrode est modifié au moyen d'une réaction d'oxydoréduction entre le réactif et le bioanalyte provoquée par une interaction entre le dispositif d'induction et l'électrode. Le processeur est conçu pour : appliquer un courant électrique dans un trajet de l'électrode; déterminer un temps de transmission du courant électrique appliqué dans le trajet de l'électrode; déterminer un déphasage entre un temps de transmission souhaité et le temps de transmission déterminé pour le courant électrique appliqué; déterminer l'état d'oxydation de l'électrode sur la base du déphasage déterminé; déterminer la concentration du bioanalyte sur la base de l'état d'oxydation de l'électrode déterminé.
PCT/BR2020/050495 2019-11-20 2020-11-20 Système, procédé et dispositif de mesure de concentration d'un bioanalyte Ceased WO2021097545A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
BR102019024450-0A BR102019024450A2 (pt) 2019-11-20 2019-11-20 Dispositivo para medição da glicose intersticial por bioanalitos
BRBR1020190244500 2019-11-20
BRBR1020200035290 2020-02-20
BR102020003529-0A BR102020003529A2 (pt) 2020-02-20 2020-02-20 Sistema para interpretação da medição de bioanalitos
BR102020005234-9A BR102020005234A2 (pt) 2020-03-16 2020-03-16 Sistema para interpretação e gerenciamento da medição de bioanalitos
BRBR1020200052349 2020-03-16

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