WO2021097545A2

WO2021097545A2 - System, method and device for measuring the concentration of a bioanalyte

Info

Publication number: WO2021097545A2
Application number: PCT/BR2020/050495
Authority: WO
Inventors: Nilton Braz GIRALDELLI
Original assignee: Giraldelli Nilton Braz
Priority date: 2019-11-20
Filing date: 2020-11-20
Publication date: 2021-05-27
Also published as: WO2021097545A3

Abstract

The system for measuring the concentration of a bioanalyte comprises a reagent and a processor communicatively coupled with an electrode and an induction device. An oxidation status of the electrode is modified by means of an oxidation-reduction reaction between the reagent and the bioanalyte, caused by an interaction between the induction device and the electrode. The processor is configured to: apply an electric current to an electrode path; determine a transmission time of the electric current applied to the electrode path; determine a lag between an expected transmission time and the determined transmission time for the applied electric current; determine the oxidation status of the electrode based on the determined lag; determine the concentration of the bioanalyte based on the determined oxidation status of the electrode.

Description

SYSTEM, METHOD AND DEVICE FOR MEASURING THE CONCENTRATION OF A

BIOANALITE FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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. Thus, methods that assess the frequency and magnitude of hyperglycemia are essential in monitoring the disease, aiming at adjustments in treatment. Until the 1970s, the assessment of glycemic control was done only with household measurement of glycosuria and occasional fasting blood glucose measurements.

Since then, there have been significant advances in the state of the art in relation to the methods used, with the development of tests that evaluate long-term glycemic control, such as glycated hemoglobin (HbA1 c), as well as those that detect glycemic fluctuations throughout the period. day, such as capillary blood glucose self-monitoring (AMGC) and the interstitial liquid glucose monitoring system (SMCG). 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. Collection without fluoride can be performed, but it must be centrifuged immediately after venipuncture. Prolonged storage of the sample, without centrifugation and without fluoride, allows glucose metabolism by red blood cells, which do not require insulin for glucose uptake. Room temperature can speed up this process. In a refrigerator, the glucose remains stable for a few hours in the blood sample. The addition of fluoride to the tubes prevents these processes, since it inhibits glycolysis.

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). Today, it is known that fasting blood glucose is insufficient to monitor the glycemic control of patients with diabetes mellitus, as it reflects only a one-off measure at the time of blood collection.

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 adoption of portable devices to measure glucose levels greatly facilitated the practice of monitoring by patients with diabetes mellitus, enabling self-monitoring and dispensing with laboratory tests for glucose measurement.

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.

The GOx enzyme 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) ®

Gluconolactone + GOx (FADFl2)

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:

GOx (FADH2) +0 ₂ ® GOx (FAD) + H 0 ₂ ® 2H ⁺ + O2 + 2e G0X (FADH2) + 02®G0X (MANIA) + H ₂ 02®2H ⁺ + 0 ₂ + 2e-

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.

However, two main problems must be addressed: other electroactive molecules such as uric acid and ascorbic acid can interfere with the measurement, depending on the applied potential; and to reduce interference and increase glucose selectivity, membranes are included that limit the access of these molecules to the electrode surface, or the electrodes are constructed of materials that require less potential.

Another methodology uses 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.

For the collection of blood samples to be the target of the analysis of the level of glucose, obtained by puncture or perforation of the skin, the devices currently available in the state of the art use 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.

Even with the many improvements already made in the state of the art, pain associated with puncture remains a significant problem for many patients. The need for blood collection and the fear of associated pain is also a major obstacle for the millions of diagnosed diabetics, making proper monitoring difficult. In addition, puncture to obtain a blood sample for other diagnostic applications is increasingly common, and a less painful, minimally invasive device is needed to improve these applications and make these technologies more acceptable.

In addition, 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.

Currently, there are devices that can read information from a distance, using an implant or a needle, inserted in the patient's body, which interact with the organism and emit information translated by an external device, allowing greater comfort and speed.

However, all of these devices and methods incorporate the inconvenience of invading the patient's body to obtain a sample of blood or body fluids to be able to read glucose levels.

The document BR 11 2019 012600-7 reveals a system of continuous glucose monitoring. However, 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. For this purpose, 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.

Continuing, the adoption of portable devices to measure the levels of bioanalytes, such as, for example, glucose, greatly facilitated the practice of monitoring the health status of users, enabling self-monitoring and dispensing with laboratory tests to measure bioanalytes. .

From then on, sending the collected information to an external device became a challenge, in order to enable a fast and reliable communication, enabling the user to make decisions.

In addition, the introduction of new systems for continuous monitoring of bioanalyses, such as glucose, opened a new field of application that until then was not accessible, the interstitial space.

Most doctors and / or health professionals in general are familiar with the interpretation of changes in plasma glucose, measured in capillary blood, because the intravascular space is easily accessible.

Changes in plasma glucose generally precede changes in interstitial glucose and therefore provide an early warning signal regarding the evolution of hypo and hyperglycemia.

However, there are several circumstances in which there are discrepancies between plasma glucose levels and clinical symptoms. An example is the persistence of impaired cognition for prolonged periods after correction of hypoglycemia, which may be related to delays in the correction of glucose concentrations in the interstitium. In circumstances like these, it can be argued that accurate measurements of interstitial glucose levels may be more clinically important.

Advances in state-of-the-art sensor technology that eliminate the need to calibrate your signals against plasma glucose levels, eliminate an important source of sensor error and allow you to measure the glucose concentrations directly available to cells with more precision.

The technologies recently made available in the state of the art also require doctors and / or health professionals to develop a new set of metrics to assess the levels of normal interstitial glucose that has clinical relevance, establishing a new technological level, including a new terminology, which needs to adapt to the arrival of new devices.

In view of the above, it remains clear that the state of the art lacks improvements in non-invasive technologies for measuring and monitoring bioanalytes, such as glucose.

In addition, the state of the art would benefit from solutions that allow information collected by measurement systems or devices to be interpreted and transmitted to other devices, such as smartphones, enabling its use to inform the user about the health conditions related to the measured bioanalytes , for example, through dedicated and installed apps.

OBJECTIVES AND DESCRIPTION OF THE INVENTION

Therefore, 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.

In addition, it is a general objective of the present invention to provide a method of measuring the concentration of a bioanalyte.

Furthermore, 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 (s), among others, 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 (s), among others, 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 (s), among others, 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.

BRIEF DESCRIPTION OF THE DRAWINGS

The objectives, technical effects and advantages of the present invention will be apparent to those skilled in the art from the detailed description below which makes reference to the attached figures, which illustrate exemplary, but not limiting, achievements of the objects claimed:

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.

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).

Figure 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.

Figure 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).

Figure 9 illustrates the steps of the operating logic of the system of the present invention, comprising:

(a) installing an application on a smartphone;

(b) user registration;

(c) activation and validation of the measuring device (BS) with a security server in the cloud;

(d) calibration;

(e) carrying out the first measurement of the measuring device (BS);

(f) storage of information for the user;

(g) retransmission of the information collected to the cloud; and

(h) access to user information in real time.

Figures 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.

Figure 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.

DESCRIPTION OF ACCOMPLISHMENTS OF THE INVENTION

Initially, it should be noted that the system, method and device of the present invention will be described below according to particular realizations, but not limiting, since its realization can be carried out in different ways and variations and according to the application desired by the technician. on the subject.

In one embodiment, 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.

In another embodiment, 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.

In the context of the present invention, the term "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.

Furthermore, 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.

In one embodiment, the present invention comprises a bioanalyte concentration measurement system. In the context of the present invention, the term “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). For example, the bioanalyte may be interstitial glucose (that is, present in the interstice of the organism / user) and the reagent may be glucose oxidase. In addition, glucose oxidase can be immobilized on or in the vicinity of the electrode, for example, when applied as a reagent layer.

A person skilled in the art will immediately realize that other reagents or enzymes can be used to react with specific bioanalytes.

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.

In one embodiment, 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.

In another embodiment of the present invention, 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.

In another embodiment, 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. In addition, the measurement system may comprise an antenna communicatively coupled to the processor. Advantageously, the processor can be further configured to transmit information on the concentration of the bioanalyte to the induction device via the antenna.

In one embodiment, the measuring system's antenna and electrode are the same physical component.

In another embodiment, the electrode, antenna, processor and reagent are stacked in layers forming a single body. In this case, 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.

In addition, the antenna can be configured to capture energy from radiation emitted by the induction device and energize the processor. Preferably 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.

Figure 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).

In one embodiment, 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:

- time and value of the measurement performed;

- trends in the variation of the concentration of the bio-analyte by means of trend arrows, and

- a history of the daily measurements taken.

In another embodiment, an induction device (DE) can be additionally configured to perform at least one function among:

- registration of information related to the user and a clinical picture of the user; - activation and validation of the measurement system on a security server;

- calibration of the measurement system based, at least in part, on an initial glucose base value obtained by measuring the user's capillary blood,

- storage of user information in a measurement system database;

- transmission of the collected information to a cloud storage, made available for access to the user through a browser; and

- availability of user information in real time.

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.

In one embodiment, 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.

In an embodiment of the system proposed by the present invention, 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).

In the system proposed by the present invention, the antenna (At) operates with a previously defined transmission frequency. In one embodiment, 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.

In the operation of the measurement system described in the present invention, 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.

To establish the perception of the connection between frequency and measurement point, 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).

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.

This signal variation can be seen in Figure 5, where it is noticed that the voltage increase, caused by the resistance to the current flow, is detected by the integrated circuit (Cl). In the illustrated example, the voltage starts near 700ms and peaks at 800ms.

It is then possible to relate the oxidation resistance (RF) and the concentration of the bioanalyte, such as glucose, as shown in Figure 6. In the example shown in this figure, 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).

Therefore, at some point in the route through the antenna (At), 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.

In an embodiment of the present invention, shown in Table 1 below, the approximation of the external device (DE) 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.

In one performance, the measurement starts at the 0.01 Mhz frequency, performed in 0.001 Mhz increments. When 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.

To explain how the measurement delay is calculated to reflect the bioanalyte concentration, it must be understood that 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.

That is, in up to 7.4 x 10 ⁸ s, the electric current fluctuates due to the difficulty that oxidation in the antenna (At) imposes on the path, reducing the maximum frequency value to 13.56 Mhz, as shown below:

1 ¹

³ 13.56 MHz ~ t ^~ 7.4 x IO ⁸

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 .

In another embodiment, 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.

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. Thus, 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 . However, this diffusion process is not instantaneous and appears to be influenced by blood flow and capillary permeability.

The glucose biosensor (BS) 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.

In this scenario, 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.

Therefore, the current measured by the biosensor (BS) is that generated by the oxidation of hydrogen peroxide (H2O2) in an electrode. According to equation 1, if there is an excess of oxygen, then hydrogen peroxide is stoichiometrically related to the amount of glucose that reacts with the enzyme. In this case, the final current is also proportional to the amount of glucose that reacts with the enzyme.

However, if there is insufficient oxygen for all of the glucose to react with the enzyme, then the current will be proportional to the concentration of oxygen and not that of glucose.

Thus, for the glucose biosensor (BS) to be useful, 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.

To circumvent this limitation, 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. Such a 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. Alternatively, 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).

Briefly, the measuring device of the present invention, 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.

In one embodiment, 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. In this context, the antenna (At) acts as an electrode for an electrochemical cell; d) 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; e) a connecting element (Li), which is a solder between the antenna (At) and the chip (Cl), keeping them together and allowing their electrical connection; f) 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.

In this realization, 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.

In one embodiment, the measurement system comprises a “smart sensor” architectural concept consisting of an analyte biosensor (BS) and three cascaded software modules. 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.

A person skilled in the art will immediately understand that multiple software modules can be cascaded to a commercial CGM sensor. In one embodiment, three modules are considered and installed in the biosensor processor (BS), namely:

(1) 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. After processing the data by the noise elimination module, data with reduced measurement noise is obtained.

(2) 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;

(3) 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.

In another embodiment, 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.

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 operation of the interpretation system of this invention is represented schematically in Figure 9, where the successive steps are described as follows:

(a) the application is installed on the external device (DE), such as smartphones or tablets, enabling it to operate on the device. It is worth remembering that 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);

(b) the user is registered, inserting the information related to the user, diabetes and other settings of the measurement and interpretation system;

(c) the biosensor (BS) is activated, releasing it to function, and its validity is verified with a security server in the cloud; (d) the measurement and interpretation system is calibrated, informing the initial GBV obtained by measuring the user's capillary blood;

(e) a first measurement of the system is made, based on the collection of information;

(f) user information is stored in a system database;

(g) the information collected is transmitted to the cloud, made available for access via a browser;

(h) user information is accessed in real time.

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.

Capillary blood glucose measurements performed using a conventional glucometer are used to calibrate the IGM application, generating the base glucose value (GBV), as shown in Figure 13.

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, according to an embodiment of the present invention, 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.

Putting such information in the right way, clearly and for ready use, so that the user understands the speed of his own metabolism in different situations, is of paramount importance for the control to which the measurement and interpretation system revealed here is intended.

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.

On the screen of the external device (DE), receiver of the information, 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. In one embodiment, 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.

Still, aiming at a personalized use, 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.

Since changes in blood glucose (capillary glucose or finger tip) come first than changes in glucose in the interstitium (measured by the biosensor (BS)), there may be a delay in detecting a hyper or hypoglycemia in the glucose measured in the biosensor ( BS) when compared to the measurement obtained by capillary glycemia.

One can imagine the variations between these two measurements as train cars on a roller coaster, with the first car being capillary glucose and interstitial glucose a wagon that would follow. Thus, when going up and down these wagons would not be at the same level. That said, to assess the accuracy of the measurement of interstitial glucose (biosensor) compared to capillary glucose, one should look for moments when the trend arrow is straight on the reader.

Although the description of the particular embodiments above makes reference to certain embodiments, the present invention may present modifications in its form of implementation, so that the scope of protection of the invention is limited only by the content of the appended claims, including there the possible equivalent variations .

Claims

1. BIOANALITE CONCENTRATION MEASUREMENT SYSTEM, characterized by comprising: an electrode; a reagent; a processor (Cl); an induction device (DE); wherein the processor (Cl) is communicatively coupled with the electrode and the induction device (DE); 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 (DE) and the electrode; where the processor (Cl) 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.

2. SYSTEM, according to claim 1, characterized in that the processor (Cl) is additionally configured to: store information regarding the oxidation state of the electrode after a first measurement; and in a second measurement, determine the concentration of the bioanalyte based on the information regarding the oxidation state of the electrode after the first measurement and based on the oxidation state of the electrode after the second measurement.

SYSTEM, according to claim 1, characterized in that it comprises an antenna (At) coupled communicatively to the processor (Cl); wherein the processor (Cl) is additionally configured to transmit information on the concentration of the bioanalyte to the induction device (DE) by means of the antenna (At).

4. SYSTEM, according to claim 3, characterized in that the antenna (At) and the electrode are the same physical component.

5. SYSTEM, according to claim 3, characterized by the antenna (At) being a TAG NFC antenna with a transmission frequency of 13.56MHz and using a communication protocol selected from a group comprising ISO 14443A / B and ISO 15693.

6. SYSTEM, according to claim 3, characterized in that the electrode, the antenna (At), the processor (Cl) and the reagent are stacked in layers forming a single body.

7. SYSTEM, according to claim 6, characterized by the redox reaction occurring in the presence of oxygen, in which the single body comprises a semipermeable membrane (AM) to regulate oxygen transport.

8. SYSTEM, according to claim 7, characterized in that the semipermeable membrane (AM) comprises at least one of a combination of a non-woven polyester fabric with a medical grade acrylic adhesive and an elastic non-woven polyurethane fabric with adhesive. acrylate.

9. SYSTEM, according to claim 6, characterized in that the single body comprises a means of fixation (CM) to the epidermis of a user.

10. SYSTEM, according to claim 3, characterized in that the antenna (At) is configured to capture energy from radiation emitted by the induction device (DE) and energize the processor (Cl).

11. SYSTEM, according to claim 3, characterized by the induction device (DE) being configured to handle the bioanalyte concentration information received from the antenna and generate graphic information for a user, in which the graphic information comprises at least one among :

- time and value of the measurement performed;

- a history of the daily measurements taken.

12. SYSTEM, according to claim 11, characterized in that the induction device (DE) is additionally configured to perform at least one function among: - registration of information related to the user and a clinical picture of the user;

- activation and validation of the measurement system on a security server;

- calibration of the measurement system based on an initial glucose base value obtained by measuring the user's capillary blood,

- storage of user information in a measurement system database;

- availability of user information in real time.

13. SYSTEM, according to claim 1, characterized in that the processor (Cl) is configured to: apply to the electrode a plurality of electrical currents comprising different frequencies; 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 on at least one lag among the determined lags.

14. SYSTEM, according to claim 1, characterized in that the bioanalyte is glucose and the reagent is glucose oxidase.

15. SYSTEM, according to claim 14, characterized in that glucose oxidase is immobilized on or in the vicinity of the electrode.

16. METHOD OF MEASURING THE CONCENTRATION OF A BIOANALITE, characterized by understanding the steps of: modifying an oxidation state of an electrode by means of an oxidation reaction between a reagent and the bioanalyte caused by an interaction between an induction device (DE ) 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.

17. MEASUREMENT DEVICE (BS) FOR CONCENTRATION OF A BIOANALITE, characterized by comprising: an electrode; a reagent; a processor (Cl); wherein the processor (Cl) 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 (DE) and the electrode; where the processor (Cl) 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.

18. DEVICE (BS), according to claim 17, characterized by comprising a means of fixation (CM) to the epidermis of a user.