CN115956908A - Sensor and method for obtaining analyte concentration with temperature compensation taken into account - Google Patents

Abstract

The present disclosure provides a method of obtaining an analyte concentration with temperature compensation in mind, comprising: obtaining sensitivity information of the implanted portion at a predetermined analyte concentration prior to wearing the analyte sensor, the sensitivity information being a relationship between a sensitivity of the implanted portion and a temperature change; placing the implanted portion under the skin and the application portion on the body surface, obtaining a body surface temperature by a temperature sensor, and obtaining a subcutaneous temperature based on the body surface temperature; selecting a reference temperature; obtaining calibration information based on the sensitivity information, the reference temperature, and the subcutaneous temperature, and calibrating the response signal obtained by the implanted portion based on the calibration information; and obtaining an analyte concentration based on the reference temperature, and the calibrated response signal. Thereby, the accuracy of the obtained analyte concentration can be improved.

Description

Sensor and method for obtaining analyte concentration with temperature compensation taken into account

Technical Field

The present disclosure relates generally to the field of medical devices, and more particularly to sensors and methods for obtaining analyte concentrations with temperature compensation taken into account.

Background

Diabetes is a disease in which a series of metabolic disorders such as sugar, protein, fat, water, and electrolytes are disturbed, and if not well controlled, complications such as ketoacidosis, lactic acidosis, chronic renal failure, retinopathy, and the like may be caused. In the case of a diabetic patient, if the glucose concentration can be monitored continuously in real time, the occurrence of complications such as hyperglycemia and hyperglycemia can be predicted with priority.

Studies have shown that when the glucose concentration in blood begins to decrease, the glucose concentration in interstitial fluid decreases first compared to the glucose concentration in blood, which can be predictive of an impending low glucose. Glucose sensors for sensing glucose concentration typically include an implanted portion that can be placed subcutaneously to sense changes in glucose concentration in subcutaneous tissue fluid to enable prediction of glucose concentration in blood.

However, the temperature at the position where the implanted portion is located may vary by being affected by both ambient temperature changes and temperature changes in the body. The implanted portion typically includes an enzyme that catalyzes the reaction of glucose. Since the activity of the enzyme is affected by temperature, deviation of the response signal output from the implanted portion may occur, resulting in an inaccurate glucose concentration calculated based on the response signal. It is therefore necessary to calibrate the output response signal taking into account temperature compensation.

Disclosure of Invention

The present disclosure has been made in view of the above-mentioned state of the art, and an object thereof is to provide a sensor and a method for obtaining an analyte concentration in consideration of temperature compensation to improve the accuracy of the obtained analyte concentration.

To this end, the present disclosure provides a method of obtaining an analyte concentration by an analyte sensor including an implanted portion that can be placed subcutaneously and an application portion that can be placed topically and has a temperature sensor, in consideration of temperature compensation, the method comprising: obtaining sensitivity information of the implanted portion at a predetermined analyte concentration prior to wearing the analyte sensor, the sensitivity information being a sensitivity versus temperature relationship of the implanted portion; placing the implanted portion subcutaneously and the applied portion on the body surface, obtaining the body surface temperature by the temperature sensor, and obtaining the subcutaneous temperature based on the body surface temperature; selecting a reference temperature; obtaining calibration information based on the sensitivity information, the reference temperature, and the subcutaneous temperature, and calibrating a response signal obtained by the implanted portion based on the calibration information; and obtaining the analyte concentration based on the reference temperature and the calibrated response signal.

In the method according to the present disclosure, before wearing the analyte sensor, sensitivity information of the implanted portion, i.e. the sensitivity versus temperature of the implanted portion, is obtained at a predetermined analyte concentration. The implanted portion is placed subcutaneously and the application portion having the temperature sensor is placed on the body surface, the body surface temperature is obtained by the temperature sensor, and the subcutaneous temperature is obtained based on the body surface temperature. The reference temperature is selected, calibration information is obtained based on the sensitivity information, the reference temperature and the subcutaneous temperature, and the response signal obtained by the implanted portion is calibrated based on the calibration information, whereby a calibrated response signal can be obtained. The analyte concentration is calibrated based on the reference temperature and the calibrated response signal, thereby enabling the accuracy of the obtained analyte concentration to be improved.

Additionally, in methods contemplated by the present disclosure, optionally, the implanted portion is placed in a reagent comprising the analyte, the temperature of the reagent is varied and the sensitivity of the implanted portion is measured as a function of the temperature of the reagent to obtain sensitive information of the implanted portion. In this case, the variation of the sensitivity of the implanted portion with temperature is measured by using a reagent containing an analyte before wearing the analyte sensor, whereby sensitive information of the implanted portion can be easily obtained in advance.

Additionally, in methods contemplated by the present disclosure, optionally, the concentration of the analyte in the reagent is maintained constant while changing the temperature of the reagent. In this case, by controlling the concentration of the analyte in the reagent to be constant and changing the temperature of the reagent, the relationship between the sensitivity and the temperature of the implanted portion can be obtained more accurately.

Additionally, in methods to which the present disclosure relates, optionally, the calibration information is obtained based on the sensitivity information and a difference or ratio of the subcutaneous temperature and the reference temperature. In this case, by considering the relationship between the sensitivity of the implanted portion and the temperature, and the relationship between the subcutaneous temperature at which the implanted portion is located and the reference temperature, it is possible to facilitate temperature compensation.

Additionally, in the methods of the present disclosure, optionally, the subcutaneously inserted implanted portion simultaneously senses the subcutaneous analyte concentration and outputs a response signal when the temperature sensor senses a temperature at the body surface and outputs the body surface temperature. In this case, the subcutaneous temperature, that is, the temperature at the position where the implanted portion is located, and the response signal of the analyte concentration output sensed by the implanted portion can be obtained at the same time, whereby the response signal of the implanted portion can be temperature-compensated in real time, so that the accuracy of the analyte concentration calibration can be improved.

Further, in the method according to the present disclosure, optionally, there is no time delay between the output of the response signal by the implanted portion and the output of the body surface temperature by the temperature sensor. Thereby enabling an improved accuracy of the analyte concentration calibration.

Additionally, in methods contemplated by the present disclosure, optionally, the analyte is one or more of acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormone, hormones, ketone bodies, lactate, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. Thus, the concentration of analytes such as acetylcholine, amylase, bilirubin, etc. can be obtained.

Additionally, in methods contemplated by the present disclosure, optionally, a calibrated analyte concentration is obtained based on a relationship of a response signal of the implanted portion to a change in the analyte concentration at the reference temperature and the calibrated response signal.

The present disclosure also provides an analyte sensor for obtaining an analyte concentration in consideration of temperature compensation, the analyte sensor including an implanted portion that can be placed subcutaneously, a patch portion that can be placed on a body surface and has a temperature sensor, and a processing module that stores a first mapping relationship between a subcutaneous temperature and a body surface temperature obtained by the temperature sensor, sensitivity information of the implanted portion, and a second mapping relationship between a response signal output by the implanted portion at a predetermined temperature and a change in the analyte concentration, wherein the sensitivity information is a relationship between a sensitivity of the implanted portion at the predetermined analyte concentration and a change in the temperature; the temperature sensor senses a temperature of a body surface and outputs a body surface temperature when the implanted portion is placed under the skin and the applied portion is placed on the body surface; the processing module is configured to: obtaining a subcutaneous temperature based on the body surface temperature and the first mapping relationship, selecting a reference temperature, obtaining calibration information based on the sensitivity information, the subcutaneous temperature, and the reference temperature, calibrating a response signal obtained by the implanted portion based on the calibration information, and obtaining the analyte concentration based on the reference temperature, the calibrated response signal, and the second mapping relationship.

In the analyte sensor according to the present disclosure, the implanted portion is placed under the skin and the application portion having the temperature sensor is placed on the body surface, the body surface temperature is obtained by the temperature sensor, and the subcutaneous temperature is obtained based on the body surface temperature. The processing module is configured to: subcutaneous temperature is obtained based on the body surface temperature and the first mapping relation, a reference temperature is selected, calibration information is obtained based on the sensitivity information, the subcutaneous temperature and the reference temperature, a response signal obtained by the implanted part is calibrated based on the calibration information, and analyte concentration is obtained based on the reference temperature, the calibrated response signal and the second mapping relation, so that the analyte concentration under the condition of considering temperature compensation can be obtained, and the accuracy of the analyte sensor for sensing the analyte concentration is improved.

In addition, in the analyte sensor according to the present disclosure, the implanted portion includes a working electrode capable of reacting with an analyte, and a counter electrode forming a circuit with the working electrode. Whereby the implanted portion is capable of sensing the analyte concentration.

According to the present disclosure, it is possible to provide a sensor and a method for obtaining an analyte concentration in consideration of temperature compensation, whereby the accuracy of the obtained analyte concentration can be improved.

Drawings

Fig. 1 is a schematic view illustrating a wearing state of an analyte sensor for obtaining an analyte concentration in consideration of temperature compensation according to an embodiment of the present disclosure.

Fig. 2 is a schematic structural view illustrating an implanted portion of an analyte sensor according to an embodiment of the present disclosure.

Fig. 3 is a schematic structural view illustrating a working electrode of an implanted portion according to an embodiment of the present disclosure.

Fig. 4 is a first map showing subcutaneous temperatures and body surface temperatures obtained by the temperature sensors according to the embodiment of the present disclosure.

FIG. 5A is a graph illustrating the results of a linear regression simulation of the response current versus temperature of an implanted portion according to an embodiment of the present disclosure;

fig. 5B is a table showing a result chart corresponding to the linear regression simulation in fig. 5A.

Fig. 6 is a second map illustrating response current versus analyte concentration according to embodiments of the present disclosure.

Fig. 7 is a flow chart illustrating a method of obtaining an analyte concentration with temperature compensation in mind, in accordance with an embodiment of the present disclosure.

Detailed Description

The present disclosure will be described in further detail below with reference to the accompanying drawings and specific embodiments. In the drawings, the same components or components having the same functions are denoted by the same reference numerals, and redundant description thereof will be omitted.

The present disclosure relates to a method of obtaining an analyte concentration in consideration of temperature compensation, which can calibrate the obtained analyte concentration in consideration of temperature compensation. The method according to the present embodiment can contribute to improving the accuracy of the obtained analyte concentration.

In methods of obtaining an analyte concentration in view of temperature compensation to which the present disclosure relates, the analyte concentration may be obtained by an analyte sensor. For ease of understanding, the present disclosure first introduces an analyte sensor that obtains an analyte concentration with consideration of temperature compensation.

In some examples, the analyte sensor may also sometimes be referred to as an implantable analyte sensor, an analyte monitor, or an analyte monitor. Note that the respective names are for indicating the analyte sensor according to the present embodiment that can improve the accuracy of the obtained analyte concentration in consideration of the temperature compensation, and should not be construed as limiting.

Fig. 1 is a schematic view showing a wearing state of an analyte sensor 1 in which an analyte concentration is obtained in consideration of temperature compensation according to an embodiment of the present disclosure.

In some examples, the analyte sensor 1 may include an implanted portion 2 that may be placed subcutaneously, an application portion 3 that may be placed on a body surface, and a processing module (see fig. 1, processing module not shown). In some examples, when implanted portion 2 is placed subcutaneously, implanted portion 2 may sense the concentration of the analyte subcutaneously and output a response signal. In some examples, the application portion 3 may have a temperature sensor 4 (see fig. 1). In some examples, the temperature sensor 4 may detect the temperature of the body surface and output the body surface temperature when the application portion 3 is placed on the body surface. In some examples, the processing module may receive the response signal output by implanted portion 2 and the body surface temperature output by temperature sensor 4, and calculate and output a calibrated analyte concentration.

Fig. 2 is a schematic structural view showing an implanted portion 2 of the analyte sensor 1 according to the embodiment of the present disclosure.

In some examples, as described above, the analyte sensor 1 may include an implanted portion 2 (see fig. 1). In some examples, the implanted portion 2 of the analyte sensor 1 may be placed subcutaneously and in contact with subcutaneous interstitial fluid (see fig. 1). Implanted portion 2 may sense the concentration of the analyte in the interstitial fluid and output a response signal.

In some examples, the implanted portion 2 may be flexible. The implanted portion 2 may be provided in a puncture needle (not shown), the implanted portion 2 being separable from the puncture needle. When wearing the analyte sensor 1, the puncture needle with the implanted portion 2 wrapped around can be pierced into the tissue, and then the puncture needle is pulled out and separated from the implanted portion 2, whereby the implanted portion 2 is subcutaneously placed.

In some examples, the implanted portion 2 may be disposed in an arm (see fig. 1), an abdomen, a waist, or a leg, or the like.

In some examples, the implanted portion 2 may be placed 3mm to 20mm subcutaneously. In some examples, the depth to which the implanted portion 2 is placed subcutaneously is determined based on the location of penetration. When the fat layer is thick, it is placed deep, for example, in the abdomen of a human body, and the depth of placement may be about 10mm to 15mm. When the fat layer is thin, it is placed more shallowly, for example, at the arm, and the depth of placement may be about 5mm to 10mm.

In some examples, the implanted portion 2 may include a substrate S (see fig. 2).

In some examples, the substrate S may be flexible. The substrate S may be substantially made of at least one of Polyethylene (PE), polypropylene (PP), polyimide (PI), polystyrene (PS), polyethylene terephthalate (PET), polyethylene naphthalate (PEN). In addition, in other examples, the substrate S may also be made of a metal foil, an ultra-thin glass, a single-layer inorganic thin film, a multi-layer organic thin film, a multi-layer inorganic thin film, or the like. In some examples, the substrate S may also be inflexible.

In some examples, the implanted portion 2 may include a working electrode 10 and a counter electrode 30 (see fig. 2). In some examples, working electrode 10 may form a loop with working electrode 10. The implanted part 2 is thereby able to sense the analyte concentration.

In some examples, implanted portion 2 may also include a reference electrode 20. In some examples, the implanted portion 2 may further include a contact 40 (see fig. 2) connected to the working electrode 10 via a lead. Thereby, the implanted part 2 is able to transmit a response signal outwards via the contact 40.

In some examples, the working electrode 10, the reference electrode 20, and the counter electrode 30 may be disposed on the substrate S (see fig. 2).

Fig. 3 is a schematic structural view showing the working electrode 10 of the implantation portion 2 according to the embodiment of the present disclosure.

In some examples, as described above, the implanted portion 2 may include the working electrode 10 (see fig. 2). In some examples, the working electrode 10 may be provided with a substrate layer 110, a nanoparticle layer 120, an analyte enzyme sensing layer 130, a semi-permeable membrane 140, and a biocompatible membrane 150. The substrate layer 110, the nanoparticle layer 120, the analyte enzyme sensing layer 130, the semi-permeable membrane 140 and the biocompatible membrane 150 may be sequentially stacked (see fig. 3).

In some examples, the base layer 110 may be electrically conductive. In some examples, the base layer 110 may be made of at least one selected from gold, glassy carbon, graphite, silver chloride, palladium, titanium, iridium. In this case, the base layer 110 has good conductivity, and the electrochemical reaction of the base layer 110 can be suppressed, thereby improving the stability of the base layer 110.

In some examples, the base layer 110 may be disposed on the substrate S by a deposition or plating method. In some examples, the method of deposition may include physical vapor deposition, chemical vapor deposition, and the like. The plating method may include electroplating, electroless plating, vacuum plating, and the like. Additionally, in some examples, the base layer 110 may also be disposed on the substrate S by screen printing, extrusion, or electrolytic deposition, among others.

In some examples, the substrate layer 110 may have disposed thereon an analyte enzyme sensing layer 130.

In some examples, the concentration of multiple analytes may be obtained by altering the analyte enzyme sensing layer 130 on the implanted portion 2. For example, in some examples, the analyte may be one or more of acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormones, ketone bodies, lactate, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. In other examples, the concentration of a drug in a bodily fluid, such as an antibiotic (gentamicin, vancomycin, etc.), digitoxin, digoxin, theophylline, and warfarin (warfarin), etc., may also be monitored by altering the analyte enzyme sensing layer 130 on the implanted portion 2.

In some examples, the substrate layer 110 may have a nanoparticle layer 120 disposed thereon. That is, between the substrate layer 110 and the analyte enzyme sensing layer 130, the nanoparticle layer 120 may be disposed. In this case, the nanoparticles are able to further catalyze the analyte reaction, reducing the operating voltage required for the analyte reaction and increasing the reaction rate.

In particular, with GO _X (FAD) As an example of glucose oxidase, in the analyte sensing layer 130, when GO _X (FAD) when it encounters glucose in the tissue, the following reactions occur:

glucose + GOx (FAD) → gluconolactone + GOx (FADH) ₂ ) … … reaction formula (I)

GOx(FADH ₂ )+O ₂ →GOx(FAD)+H ₂ O ₂ … … reaction formula (II)

In the course of the above reaction, there will be H in the formula (II) ₂ O ₂ Generation of (a), H ₂ O ₂ May decrease the enzyme activity in the analyte enzyme sensing layer 130.

The nanoparticle layer 120 may act as a catalyst for H ₂ O ₂ Decomposition reaction occurs, and the specific reaction is as follows:

H ₂ O ₂ →2H ⁺ +O ₂ +2e ^- … … reaction formula (III)

By the above reaction formulae (I) to (III), the reaction of the implanted portion 2 with glucose can be continued. In addition, by catalyzing the decomposition of hydrogen peroxide by the nanoparticle layer 120, the voltage required to be applied during the reaction can be reduced, thereby contributing to the improvement of the sensitivity of the implanted portion 2, the extension of the lifetime of the analyte sensor 1, and the achievement of a low operating voltage. In other words, with the nanoparticle layer 120, a high-sensitivity sensing signal of tissue glucose can be continuously obtained, the service life of the analyte sensor 1 is prolonged, and meanwhile, the low working voltage is beneficial to improving the anti-interference performance.

In some examples, the nanoparticle layer 120 may be porous. In this case, the analyte enzyme in the analyte enzyme sensing layer 130 may infiltrate the nanoparticle layer 120. Thus, the nanoparticle layer 120 can sufficiently contact and catalyze the analyte reaction, thereby more effectively promoting the analyte reaction.

In some examples, the analyte enzyme may also be disposed in a three-dimensional network of conductive polymer nanofibers, i.e., the three-dimensional network of nanofibers is disposed between the nanoparticle layer 120 and the analyte enzyme sensing layer 130. Thereby, the adhesion of the analyte enzyme to the nanoparticle layer 120 is increased, increasing the immobilization amount of the analyte enzyme.

In some examples, the analyte enzyme may also be disposed on carbon nanotubes, where the carbon nanotubes are disposed on the nanoparticle layer 120. Thereby, the adhesion and immobilization of the analyte enzyme on the nanoparticle layer 120 is increased.

In some examples, the semi-permeable membrane 140 may be disposed over the analyte enzyme sensing layer 130. In some examples, the semi-permeable membrane 140 may further include a diffusion-controlling layer and a tamper-resistant layer laminated on the diffusion-controlling layer.

In some examples, the diffusion-control layer may be disposed outside the immunity layer. In the semi-permeable membrane 140, a diffusion-controlling layer may control diffusion of analyte molecules and a tamper-resistant layer may prevent diffusion of non-analyte species. Thus, tissue fluid or blood components passing through the semipermeable membrane 140 can be reduced, and then the interfering substance can be blocked outside the semipermeable membrane 140 by the interference-resistant layer. Common interferents may include uric acid, ascorbic acid, acetaminophen, etc., which are ubiquitous in the body. In other examples, the immunity layer may also be disposed outside of the diffusion control layer. Thereby, it is also possible to reduce the inaccuracy of the sensing result due to the interference of impurities to the working electrode 10 and to extend the life span of the implanted portion 2.

In some examples, the semi-permeable membrane 140 may control the passage rate of analyte molecules, i.e., the semi-permeable membrane 140 may limit the number of analyte molecules in the interstitial fluid or blood that reach the analyte enzyme sensing layer 130. In particular, the diffusion-controlling layer of the semi-permeable membrane 140 may effectively scale down the amount of analyte diffusing to the analyte enzyme sensing layer 130.

In some examples, the biocompatible membrane 150 may be disposed on the semi-permeable membrane 140. In some examples, the biocompatible membrane 150 may be made of a plant material. The plant material may be sodium alginate, tragacanth gum, pectin, acacia gum, xanthan gum, guar gum, agar or starch derivatives, cellulose derivatives, and other natural material derivatives. In other examples, the biocompatible membrane 150 may also be made of a synthetic material. The synthetic material may be a polyolefin. Thereby, the immune response of the human body to the implanted part 2 can be reduced, and the life span of the implanted part 2 can be extended.

Additionally, in some examples, the semi-permeable membrane 140 may also be biocompatible. Thus, the use of the biocompatible film 150 can be avoided, and the manufacturing cost can be reduced.

In some examples, the analyte enzyme sensing layer 130 is formed on the basis of the nanoparticle layer 120 for promoting the analyte enzyme to catalyze the analyte reaction disposed on the substrate layer 110 of the working electrode 10, followed by the formation of a semi-permeable membrane 140 coating on the analyte enzyme sensing layer 130, and finally the formation of a biocompatible membrane 150 layer on the semi-permeable membrane 140 coating (see fig. 3). Thereby, the service life of the implanted part 2 is prolonged, interference of other factors is reduced, and the response speed of the implanted part 2 to the analyte is improved.

In some examples, as described above, the implanted portion 2 may include a counter electrode 30 (see fig. 2). In some examples, the counter electrode 30 may be made of platinum, silver chloride, palladium, titanium, or iridium. Thereby, the electrochemical reaction at the working electrode 10 can be not affected with good conductivity. However, the present embodiment is not limited thereto, and in other examples, the counter electrode 30 may be made of at least one selected from gold, glassy carbon, graphite, silver chloride, palladium, titanium, or iridium. This can reduce the influence on the working electrode 10 while having good conductivity.

In some examples, the implanted portion 2 according to the present embodiment may enable continuous monitoring, and thus may enable continuous monitoring of human analyte concentration values for extended periods of time (e.g., 1 to 24 days).

In some examples, as described above, the analyte sensor 1 further includes an application portion 3 (see fig. 1 and 2).

In some examples, the application portion 3 may have a case 31 (see fig. 1). In some examples, the temperature sensor 4 provided with the application portion 3 may be located inside the case 31 (see fig. 1).

In some examples, the temperature sensor 4 may be disposed on an inner wall surface of the housing 31 near the body surface (see fig. 1). In other examples, the temperature sensor 4 may be provided on any wall surface of the housing 31.

In some examples, the number of the temperature sensors 4 of the application portion 3 may be one. In other examples, the temperature sensor 4 of the application portion 3 may be plural in number, whereby the accuracy of body surface temperature sensing can be improved, thereby improving the accuracy of the subcutaneous temperature obtained based on the body surface temperature.

In some examples, the applicator portion 3 may be connected with the implant portion 2. In some examples, the portion of the implanted portion 2 on the body surface may be electrically connected to the application portion 3 through contacts 40 (see FIG. 2). Thus, the current signal generated by the implanted portion 2 can be transmitted to the application portion 3 via the contact 40 through the base layer 110 and the transmission wire.

In some examples, the application portion 3 may be made of a flexible PCB and a flexible battery. Therefore, the skin can be attached to the skin, and the influence on the daily life of the user is reduced.

In some examples, as described above, the analyte sensor 1 further comprises a processing module (not shown).

In some examples, the process module may be mounted at the application portion 3. Thus, the current signal generated by the implanted portion 2 can be transmitted to the processing module for analysis through the contact 40, and the body surface temperature output by the temperature sensor 4 can be transmitted to the processing module for analysis.

In some examples, the processing module may store a first mapping between subcutaneous and body surface temperatures. In some examples, the body surface temperature may be obtained by the temperature sensor 4, as described above. In some examples, the processing module may store sensitive information of the implanted portion 2. In some examples, the processing module may store a second mapping of the response signal output by implanted portion 2 to changes in analyte concentration. Specifically, the second mapping may be a second mapping of the response signal output by the implanted portion 2 to a change in analyte concentration at a predetermined temperature.

In some examples, as described above, the processing module may store a first mapping between subcutaneous temperatures and body surface temperatures obtained by the temperature sensors 4.

Fig. 4 is a first map showing subcutaneous temperatures and body surface temperatures obtained by the temperature sensor 4 according to the embodiment of the present disclosure.

In some examples, three temperature sensors 4 with the same process parameters may be placed in the external environment, on the body surface of the simulated living body, and under the skin of the simulated living body by about 10mm, respectively. In some examples, the three temperature sensors 4 may be set to output respective sensed temperatures every 1 minute, changing the temperature of the external environment. The first mapping relationship between the body surface temperature and the subcutaneous temperature can be obtained by the temperature of the external environment, the body surface temperature, and the subcutaneous temperature respectively output by the three temperature sensors 4 (see fig. 4).

The temperature sensors 4 with the same process parameter may refer to temperature sensors 4 that are shipped from the same batch during production, and may be temperature sensors 4 that are prepared by the same batch of products in the same process. Thereby, systematic errors in measurements between different temperature sensors 4 can be reduced.

In some examples, the processing module may store sensitive information of the implanted portion 2, as described above.

In some examples, the sensitive information may be a temperature dependence of the sensitivity of the implanted portion 2. Specifically, in some examples, the sensitivity of the implanted portion 2 may be a change in the sensitivity of the implanted portion 2 at a reference temperature.

In some examples, the value of the change in the sensitivity of the implanted portion 2 may be obtained from the temperature dependence of the response current of the implanted portion 2 at a reference temperature.

Fig. 5A is a graph showing the results of a linear regression simulation of the response current versus temperature of the implanted portion 2 according to an embodiment of the present disclosure; fig. 5B is a table showing a result chart corresponding to the linear regression simulation in fig. 5A.

In some examples, analyte sensor 1 may sense the concentration of glucose. The implanted portion 2 of the analyte sensor 1 is placed in a glucose solution. In some examples, the concentration of the glucose solution can be 5mmol/L to 25mmol/L. In some examples, the temperature of the glucose solution is changed to obtain a response signal output by the implanted portion 2 when the temperature of the glucose solution is 30 ℃, 34 ℃, 37 ℃ and 40 ℃ (see fig. 5B). In some examples, the response signal may be a response current (see fig. 5B). In other examples, the response signal may be a response voltage.

In some examples, the response current versus temperature is analyzed, and the response current may be linearly related to temperature (see fig. 5A). In other examples, the response current may be non-linearly related to temperature by analyzing a relationship between the response current and temperature.

In some examples, the change in the sensitivity of the implanted portion 2 at the reference temperature may be a ratio of a slope (k value) of a linear regression equation of the linear simulation result to the response signal (see fig. 5A and 5B in combination). For example, when 30 ℃ is selected as the reference temperature, the variation value of the sensitivity of the implanted portion 2 at 30 ℃ can be 12.59% (0.428/3.40) in conjunction with fig. 5A and 5B; when 34 ℃ was selected as the reference temperature, the change in sensitivity of the implanted portion 2 at 34 ℃ was 8.82% (0.428/4.85); the change in sensitivity of implanted part 2 at 37 ℃ when 37 ℃ was chosen as the reference temperature was 6.95% (0.428/6.16); when 40 ℃ was selected as the reference temperature, the change in sensitivity of the implanted portion 2 at 40 ℃ was 5.56% (0.428/7.70).

In some examples, the variation value of the sensitivity of the implanted portion 2 at the reference temperature may be an average of results of a plurality of repeated measurements of the same implanted portion 2. In other examples, the variation value of the sensitivity of the implanted portion 2 at the reference temperature may be an average of a plurality of implanted portion 2 measurements. In both cases, the calculation of the average value can reduce the systematic error and improve the accuracy of the calculation result, which can be advantageous in improving the accuracy of the obtained analyte concentration.

In some examples, as described above, the processing module may store a second mapping of the response signal of the implanted portion 2 as a function of the analyte concentration at a predetermined temperature.

In some examples, the predetermined temperature includes a plurality of temperature values. For example, in some examples, the predetermined temperatures include 34 ℃, 35 ℃, 36 ℃, 36.5 ℃, 37 ℃, 37.5 ℃, 38 ℃, 39 ℃, 40 ℃ and 41 ℃. In some examples, the reference temperature may be selected from one of a plurality of temperature values. For example, in some examples, the reference temperature can be 34 ℃, 35 ℃, 36 ℃, 36.5 ℃, 37 ℃, 37.5 ℃, 38 ℃, 39 ℃, 40 ℃, or 41 ℃.

Fig. 6 is a second map illustrating response current versus analyte concentration according to an embodiment of the present disclosure.

In some examples, analyte sensor 1 may sense the concentration of glucose. 37 ℃ was chosen as reference temperature. The implanted parts 2 of the analyte sensor 1 are placed in glucose solutions of different concentrations, respectively. In some examples, the concentration of the glucose solution may be 0 to 25mmol (see fig. 6). Implanted portion 2 senses glucose solutions of different concentrations and outputs a corresponding response signal. In some examples, the response signal may be a response current (see fig. 6). In other examples, the response signal may be a response voltage.

In some examples, the response current and the analyte concentration are analyzed with respect to each other, and the response current and the glucose concentration may be linearly related (see fig. 6), i.e., the second mapping relationship is a linear relationship. In other examples, the response current and the analyte concentration are analyzed, and the response current and the analyte concentration may be non-linearly related, i.e., the second mapping relationship is a non-linear relationship.

In some examples, the processing module is configured to obtain the subcutaneous temperature. For example, the processing module is configured to obtain the subcutaneous temperature based on the body surface temperature and the first mapping. In some examples, the processing module is configured to select the reference temperature. In some examples, the processing module is configured to obtain calibration information. For example, the processing module is configured to obtain calibration information based on the sensitivity information, the subcutaneous temperature, and the reference temperature. In some examples, the processing module is configured to calibrate the response signal. For example, the processing module is configured to calibrate the response signal obtained by the implanted portion 2 based on the calibration information. In some examples, the processing module is configured to obtain the analyte concentration. For example, the processing module is configured to obtain the analyte concentration based on the reference temperature, the calibrated response signal, and the second mapping.

In some examples, as described above, the processing module is configured to obtain the subcutaneous temperature based on the body surface temperature and the first mapping. Specifically, the temperature sensor 4 may transmit the sensed body surface temperature to the processing module, and the processing module obtains the subcutaneous temperature based on the body surface temperature and the first mapping relation according to the first mapping relation preset in the processing module.

In some examples, the processing module is configured to select the reference temperature, as described above. In some examples, the reference temperature chosen for the process module configuration may be 37 ℃. In this case, the reference temperature is relatively close to the average body temperature of the human body, and thus the effect of calibrating the analyte concentration in consideration of temperature compensation can be improved. In other examples, the reference temperature may be other temperatures as well. For example, the reference temperature may be 35 ℃, 36 ℃, 36.5 ℃, 37.5 ℃ or 38 ℃ or the like.

In some examples, as described above, the processing module is configured to obtain calibration information based on the sensitivity information, the subcutaneous temperature, and the reference temperature. In particular, in some examples, the processing module is configured to calculate the difference between the reference temperature and the subcutaneous temperature, and then calculate the product of the difference and the value of the change in sensitivity of the implanted portion 2 at 37 ℃, thereby obtaining calibration information.

In some examples, the processing module is configured to calibrate the response signal obtained by the implanted portion 2 based on the calibration information, as described above. Specifically, in some examples, the response signal generated by implanted portion 2 can be transmitted through contacts 40 to a processing module configured to perform mathematical calculations on the calibration information and the response signal to calibrate the response signal obtained by implanted portion 2.

In some examples, the calibration formula for the response signal obtained by implanted portion 2 may be: b = a (1 + Δ T × Z). Where Δ T is expressed as a difference between the reference temperature and the subcutaneous temperature, Z is expressed as a change value of the sensitivity of the implanted portion 2 at the reference temperature, a is expressed as a response signal output by the implanted portion 2 to the processing module, and b is expressed as a calibrated response signal.

In some examples, the processing module is configured to obtain the analyte concentration based on the reference temperature, the calibrated response signal, and the second mapping, as described above. Specifically, in some examples, the processing module is configured to calculate the calibrated analyte concentration from the second mapping at the reference temperature preset by the processing module and the calibrated response signal.

In some examples, the temperature sensor 4 and the implanted portion 2 (particularly during fasting and during a period of time after meals) may transmit signals to the processing module at intervals, and the processing module may output calibrated analyte concentrations outwardly at intervals so that a user may be informed of the trend of the analyte concentration change in time to steer the change in the analyte concentration.

In some examples, the analyte concentration signal obtained by the processing module may be emitted via wireless communication, such as bluetooth, wifi, etc. An external reading device, such as a cell phone or a computer (not shown), may receive the analyte concentration signal from the processing module and display the analyte concentration.

In the analyte sensor 1 according to the present disclosure, the implanted portion 2 is placed subcutaneously and the application portion 3 having the temperature sensor 4 is placed on the body surface, the body surface temperature is obtained by the temperature sensor 4, and the subcutaneous temperature is obtained based on the body surface temperature. The processing module is configured to: subcutaneous temperature is obtained based on the body surface temperature and the first mapping relationship, reference temperature is selected, calibration information is obtained based on the sensitivity information, subcutaneous temperature, and reference temperature, the response signal obtained by the implanted portion 2 is calibrated based on the calibration information, and analyte concentration is obtained based on the reference temperature, the calibrated response signal, and the second mapping relationship. The analyte concentration can thereby be obtained with temperature compensation taken into account, improving the accuracy of analyte concentration sensing by the analyte sensor 1.

A method of obtaining an analyte concentration with consideration of temperature compensation, to which the present disclosure relates, is described below in conjunction with the analyte sensor 1 described above.

The method of obtaining the analyte concentration in consideration of the temperature compensation according to the present embodiment may be referred to as a method of calibrating the analyte concentration, a method of calibrating the analyte concentration by temperature compensation, and the like. It should be noted that the names are for illustrating a method of improving the accuracy of the obtained analyte concentration in consideration of the temperature compensation according to the present embodiment, and should not be construed as limiting.

Fig. 7 is a flow chart illustrating a method of obtaining an analyte concentration with temperature compensation in view according to an embodiment of the present disclosure.

Referring to fig. 7, a method of obtaining an analyte concentration in consideration of temperature compensation according to the present disclosure may include: obtaining sensitive information of the implanted portion 2 before wearing the analyte sensor 1 (step S100); obtaining a body surface temperature, obtaining a subcutaneous temperature based on the body surface temperature (step S200); selecting a reference temperature (step S300); obtaining calibration information, and calibrating the response signal based on the calibration information (step S400); an analyte concentration is obtained based on the reference temperature and the calibrated response signal (step S500).

In step S100, sensitive information of the implanted portion 2 may be obtained before wearing the analyte sensor 1, as described above. In some examples, sensitive information of the implanted portion 2 may be obtained at a predetermined analyte concentration prior to wearing the analyte sensor 1.

In some examples, in step S100, the predetermined analyte concentration may be a known and same analyte concentration. In some examples, implanted portion 2 may be placed in an analyte and a response signal output by the concentration of the analyte sensed by implanted portion 2 to obtain sensitive information about implanted portion 2.

In some examples, the sensitivity information may be a temperature dependence of the sensitivity of the implanted portion 2 in step S100.

In some examples, in step S100, the sensitivity of the implanted portion 2 may increase as the temperature increases. Specifically, in some examples, the sensitivity of the implanted portion 2 may increase with increasing temperature within a predetermined temperature range. Wherein, in some examples, the sensitivity of the implanted portion 2 may be linearly related to temperature. In other examples, the sensitivity of the implanted portion 2 may also be non-linearly related to temperature.

In other examples, the sensitivity of the implanted portion 2 may decrease with increasing temperature in step S100. Specifically, in some examples, in step S100, the sensitivity of the implanted portion 2 may decrease as the temperature increases within a predetermined temperature range. Wherein, in some examples, the sensitivity of the implanted portion 2 may be linearly related to temperature. In other examples, the sensitivity of the implanted portion 2 may also be non-linearly related to temperature.

In some examples, as previously described, the sensitivity information may be a change in sensitivity of the implanted portion 2 at a reference temperature. For example, in some examples, the sensitivity information may be a change in sensitivity of the implanted portion 2 at 37 ℃, i.e., 6.95%, as described above.

In some examples, in step S100, the implanted portion 2 may be placed in a reagent containing an analyte to obtain sensitive information of the implanted portion 2 by changing the temperature of the reagent and measuring the sensitivity of the implanted portion 2 as a function of the temperature of the reagent. That is, the relationship between the sensitivity of the implanted portion 2 and the temperature of the environment (location) in which the implanted portion 2 is located is obtained by changing the temperature of the reagent to change the temperature of the environment (location) in which the implanted portion 2 is located. In this case, the sensitivity of the implanted portion 2 with respect to temperature is measured by using a reagent containing an analyte before wearing the analyte sensor 1, whereby sensitive information of the implanted portion 2 can be easily obtained in advance.

In some examples, in step S100, the concentration of the analyte in the reagent is kept constant while changing the temperature of the reagent. In this case, when the temperature of the reagent is changed, the change in temperature does not affect the change in the analyte concentration, thereby enabling the accuracy of the sensitive sensing to the implanted portion 2 to be improved.

In step S200, as described above, the body surface temperature is obtained, and the subcutaneous temperature is obtained based on the body surface temperature. Specifically, in some examples, in step S200, the implanted portion 2 may be placed subcutaneously and the applied portion 3 may be placed on the body surface, the body surface temperature may be obtained by the temperature sensor 4, and the subcutaneous temperature may be obtained based on the body surface temperature.

In some examples, in step S200, when the application portion 3 is placed on the body surface, the temperature sensor 4 provided to the application portion 3 is placed on the body surface. Thereby, the temperature sensor 4 can sense the temperature of the body surface and output the body surface temperature.

In some examples, in step S200, there may be a first mapping between the body surface temperature and the subcutaneous temperature, as previously described. When the body surface temperature is obtained, the subcutaneous temperature may be obtained by the first mapping relation.

In some examples, in step S200, the body surface temperature and the subcutaneous temperature of the simulated living body may be sensed simultaneously at different environmental temperatures, so as to obtain a first mapping relationship between the body surface temperature and the subcutaneous temperature.

In some examples, in step S200, the body surface temperature and the subcutaneous temperature are affected by both the ambient temperature and the internal body temperature. The influence of the ambient temperature on the body surface temperature is greater than the influence of the subcutaneous temperature on the ambient temperature, and the influence of the internal temperature on the body surface temperature is less than the influence of the subcutaneous temperature on the internal temperature; thus, there may be a non-linear correlation between body surface temperature and subcutaneous temperature. That is, the first mapping relationship may be a non-linear mapping relationship.

In some examples, the implanted portion 2 may be placed subcutaneously 3mm to 20mm in step S200. It will be appreciated that the small distance between subcutaneous 3mm and subcutaneous 20mm, and the substantially equal temperature, will not result in a statistically significant difference in the response signal output by the implanted portion 2.

In step S300, a reference temperature may be selected, as described above.

In some examples, 37 ℃ may be selected as the reference temperature in step S300. In this case, the reference temperature is relatively close to the average body temperature of the human body, whereby the effect of calibrating the analyte concentration by temperature compensation can be improved. In other examples, the reference temperature may be other temperatures as well. For example, the reference temperature may be 35 ℃, 36 ℃, 36.5 ℃, 37.5 ℃ or 38 ℃ or the like.

In step S400, calibration information may be obtained based on the sensitivity information, the reference temperature, and the subcutaneous temperature, and the response signal obtained by the implanted portion 2 may be calibrated based on the calibration information, as described above.

In some examples, in step S400, the sensitivity information may be a sensitivity of the implanted portion 2 versus temperature change as described above. In some examples, the sensitivity information may be, in particular, a sensitivity of the implanted portion 2 at a reference temperature. Further, the sensitivity information may be a change value of the sensitivity of the implanted portion 2 at a reference temperature.

In some examples, in step S400, calibration information may be obtained based on a difference of the subcutaneous temperature and the reference temperature, and the sensitivity information. In this case, by considering the relationship between the sensitivity of the implanted portion 2 and the temperature, and the relationship between the subcutaneous temperature at which the implanted portion 2 is located and the reference temperature, it is possible to facilitate temperature compensation.

Specifically, in some examples, the calibration information may be the difference between the reference temperature and the subcutaneous temperature, multiplied by the sensitivity of the implanted portion 2 at the reference temperature. Further, the calibration information may be a product of a difference between the reference temperature and the subcutaneous temperature and a change in the sensitivity of the implanted portion 2 at the reference temperature.

In other examples, in step S400, calibration information may be obtained based on the sensitivity information and the ratio of the subcutaneous temperature to the reference temperature. Specifically, in some examples, the calibration information may be a ratio of a reference temperature to a subcutaneous temperature, multiplied by a sensitivity of the implanted portion 2 at the reference temperature. Further, the calibration information may be a ratio of the reference temperature to the subcutaneous temperature multiplied by a value of the change in the sensitivity of the implanted portion 2 at the reference temperature.

In some examples, in step S400, the response signal after calibration may be a product of the response signal before calibration and the calibration information, plus the response signal before calibration. That is, the response signal after calibration may be the product of the calibration information plus one and the response signal before calibration.

In other examples, in step S400, the calibrated response signal may be a quotient of the pre-calibration response signal and the calibration information. In still other examples, in step S400, the calibrated response signal may be the sum/difference between the pre-calibrated response signal and the calibration information.

In some examples, in step S400, when the temperature sensor 4 senses the temperature of the body surface to output the body surface temperature, the subcutaneously inserted implanted portion 2 may simultaneously sense the subcutaneous analyte concentration to output a response signal. In this case, the subcutaneous temperature, that is, the temperature at the position where the implanted portion 2 is located, and the response signal of the analyte concentration output sensed by the implanted portion 2 can be obtained at the same time, whereby the response signal of the implanted portion 2 can be temperature-compensated in real time, so that the accuracy of the analyte concentration calibration can be improved.

In some examples, in step S400, there is no time delay between the implant part 2 outputting the response signal and the temperature sensor 4 outputting the body surface temperature. In this case, the subcutaneous temperature (i.e., the temperature at the position where the implanted portion 2 is located) is obtained based on the body surface temperature, and the response signal output from the implanted portion 2 at the subcutaneous temperature at that time can be obtained without a time delay, whereby the accuracy of the analyte concentration calibration can be further improved.

In step S500, the analyte concentration may be obtained based on the reference temperature, and the calibrated response signal, as described above.

In some examples, the relationship of the response signal of the implanted portion 2 to the analyte concentration may be obtained at a reference temperature in step S500. In some examples, there may be a second mapping between the response signal of the implanted portion 2 and the concentration of the analyte at a reference temperature.

In some examples, the response signal of the implanted portion 2 may be linearly related to the analyte concentration in step S500. That is, the second mapping relationship may be a linear mapping relationship. In other examples, the response signal of implanted portion 2 may be non-linearly related to the analyte concentration. That is, the second mapping relationship may be a non-linear mapping relationship.

In some examples, in step S500, the implanted portions 2 are placed in analyte solutions of different concentrations, respectively, at a reference temperature, and the response signals output by the implanted portions 2 are measured to obtain a second mapping of the response signals of the implanted portions 2 to the analyte concentration.

In some examples, in step S500, the maximum concentration of the analyte for detecting that the second mapping is obtained is lower than the maximum sensed concentration of the implanted portion 2. In some examples, the concentration gradient used to detect the analyte that obtained the second mapping is increasing. In some examples, the concentration of the analyte used to obtain the second mapping is detected to be close to the concentration of the subcutaneous analyte. In this case, the proximity of the analyte concentration may allow a relatively small systematic error of detection, thereby enabling an improvement in the detection accuracy.

In some examples, in step S500, a calibrated analyte concentration may be obtained based on the relationship of the response signal of the implanted portion 2 at the reference temperature to the change in the analyte concentration, and the calibrated response signal. That is, the calibrated response signal of the implanted portion 2 may be obtained through the second mapping and the step S400 to obtain the calibrated analyte concentration.

In the method according to the present disclosure, before wearing the analyte sensor 1, sensitive information of the implanted portion 2 is obtained with a predetermined analyte concentration, i.e. the sensitivity of the implanted portion 2 is obtained as a function of temperature change. The implanted portion 2 is placed under the skin and the application portion 3 having the temperature sensor 4 is placed on the body surface, the body surface temperature is obtained by the temperature sensor 4, and the subcutaneous temperature is obtained based on the body surface temperature. The reference temperature is selected, calibration information is obtained based on the sensitivity information, the reference temperature, and the subcutaneous temperature, and the response signal obtained by the implanted portion 2 is calibrated based on the calibration information, whereby a calibrated response signal can be obtained. The analyte concentration is calibrated based on the reference temperature and the calibrated response signal, whereby the accuracy of the obtained analyte concentration can be improved.

While the present disclosure has been described in detail in connection with the drawings and the examples, it should be understood that the above description is not intended to limit the present disclosure in any way. Variations and changes may be made as necessary by those skilled in the art without departing from the true spirit and scope of the disclosure, which fall within the scope of the disclosure.

Claims (10)

1. A method of obtaining an analyte concentration with temperature compensation taken into account by an analyte sensor comprising an implanted portion positionable subcutaneously and an applicator portion positionable topically and having a temperature sensor, the method comprising: obtaining sensitivity information of the implanted portion at a predetermined analyte concentration prior to wearing the analyte sensor, the sensitivity information being a sensitivity versus temperature relationship of the implanted portion; placing the implanted portion under the skin and the applied portion on the body surface, obtaining a body surface temperature by the temperature sensor, and obtaining a subcutaneous temperature based on the body surface temperature; selecting a reference temperature; obtaining calibration information based on the sensitivity information, the reference temperature, and the subcutaneous temperature, and calibrating a response signal obtained by the implanted portion based on the calibration information; and obtaining the analyte concentration based on the reference temperature and the calibrated response signal.

2. The method of claim 1,

placing the implanted portion in a reagent comprising the analyte, changing the temperature of the reagent and measuring the sensitivity of the implanted portion as a function of the temperature of the reagent to obtain sensitive information of the implanted portion.

3. The method of claim 2,

the concentration of the analyte in the reagent is maintained constant while the temperature of the reagent is changed.

4. The method of claim 1,

the calibration information is obtained based on the sensitivity information and a difference or ratio of the subcutaneous temperature and the reference temperature.

5. The method of claim 1,

the implanted portion inserted under the skin simultaneously senses the subcutaneous analyte concentration and outputs a response signal when the temperature sensor senses a temperature at the body surface and outputs the body surface temperature.

6. The method of claim 5,

there is no time delay between the response signal output by the implanted part and the body surface temperature output by the temperature sensor.

7. The method of claim 1,

the analyte is one or more of acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormone, hormones, ketone bodies, lactate, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin.

8. The method of claim 1,

a calibrated analyte concentration is obtained based on the relationship of the response signal of the implanted portion to the change in analyte concentration at the reference temperature and the calibrated response signal.

9. An analyte sensor for obtaining an analyte concentration in consideration of temperature compensation, the analyte sensor comprising an implanted portion that is placed subcutaneously, a patch portion that is placed on a body surface and has a temperature sensor, and a processing module that stores a first mapping relationship between a subcutaneous temperature and a body surface temperature obtained by the temperature sensor, sensitivity information of the implanted portion, which is a relationship between a sensitivity of the implanted portion and a temperature change in the case of a predetermined analyte concentration, and a second mapping relationship between a response signal output from the implanted portion and an analyte concentration change at a predetermined temperature; the temperature sensor senses a temperature of a body surface and outputs a body surface temperature when the implanted portion is placed under the skin and the applied portion is placed on the body surface; the processing module is configured to: obtaining a subcutaneous temperature based on the body surface temperature and the first mapping relationship, selecting a reference temperature, obtaining calibration information based on the sensitivity information, the subcutaneous temperature, and the reference temperature, calibrating a response signal obtained by the implanted portion based on the calibration information, and obtaining the analyte concentration based on the reference temperature, the calibrated response signal, and the second mapping relationship.

10. The analyte sensor of claim 9,

the implanted portion includes a working electrode capable of reacting with an analyte, and a counter electrode in circuit with the working electrode.

Images