WO2023060953A1 - 在考虑温度补偿的情况下获得分析物浓度的传感器及方法 - Google Patents

在考虑温度补偿的情况下获得分析物浓度的传感器及方法 Download PDF

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WO2023060953A1
WO2023060953A1 PCT/CN2022/104810 CN2022104810W WO2023060953A1 WO 2023060953 A1 WO2023060953 A1 WO 2023060953A1 CN 2022104810 W CN2022104810 W CN 2022104810W WO 2023060953 A1 WO2023060953 A1 WO 2023060953A1
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temperature
analyte
body surface
examples
response signal
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PCT/CN2022/104810
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English (en)
French (fr)
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陈志�
刘石山
彭伟斌
方骏飞
龚明利
韩明松
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深圳硅基传感科技有限公司
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers

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  • the present disclosure relates generally to the field of medical devices, and more particularly to sensors and methods for obtaining analyte concentrations taking into account temperature compensation.
  • Diabetes is a disease of a series of metabolic disorders of sugar, protein, fat, water and electrolytes. If it is not well controlled, it may cause some complications, such as ketoacidosis, lactic acidosis, chronic renal failure and Retinopathy, etc. For diabetic patients, if the concentration of glucose can be monitored continuously in real time, the occurrence of complications such as glucose disease and hyperglucose disease can be preferentially predicted.
  • a glucose sensor for sensing glucose concentration generally includes an implanted part that can be placed subcutaneously to sense changes in glucose concentration in subcutaneous tissue fluid, thereby enabling prediction of glucose concentration in blood.
  • the implant typically includes an enzyme that catalyzes the glucose reaction. Since the activity of the enzyme is affected by the temperature, the response signal output by the implanted part will be deviated, thus resulting in inaccurate glucose concentration calculated based on the response signal. Therefore, it is necessary to calibrate the output response signal in consideration of temperature compensation.
  • the present disclosure is made in view of the above-mentioned state of the art, and its purpose is to provide a sensor and method for obtaining analyte concentration in consideration of temperature compensation, so as to improve the accuracy of the obtained analyte concentration.
  • the present disclosure provides a method of obtaining an analyte concentration obtained by an analyte sensor comprising an implantable portion placeable subcutaneously, and a An application part placed on a body surface and having a temperature sensor, the method includes: before wearing the analyte sensor, obtaining sensitive information of the implant part under a predetermined analyte concentration, the sensitive information is The relationship between the sensitivity of the implanted part and temperature; the implanted part is placed under the skin and the applied part is placed on the body surface, the body surface temperature is obtained by the temperature sensor, and based on the body surface temperature obtaining a subcutaneous temperature; selecting a reference temperature; obtaining calibration information based on the sensitive information, the reference temperature, and the subcutaneous temperature, and calibrating the response signal obtained by the implanted portion based on the calibration information; and The analyte concentration is obtained from the reference temperature, and the calibrated response signal.
  • the sensitivity information of the implanted part is obtained under the condition of predetermined analyte concentration, that is, the relationship between the sensitivity of the implanted part and the temperature is obtained.
  • the implanted part is placed under the skin and the applied part with the temperature sensor is placed on the body surface, the body surface temperature is obtained from the temperature sensor, and the subcutaneous temperature is obtained based on the body surface temperature.
  • a 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 from the implanted part is calibrated based on the calibration information, thereby obtaining a calibrated response signal.
  • the analyte concentration is calibrated based on the reference temperature and the calibrated response signal, thereby improving the accuracy of the obtained analyte concentration.
  • the implanted portion is placed in a reagent containing the analyte, the temperature of the reagent is varied and the sensitivity of the implanted portion is measured as a function of the Reagent temperature changes to obtain sensitive information on the implanted part.
  • the sensitivity information of the implanted part can be conveniently obtained in advance by measuring the sensitivity of the implanted part as a function of temperature using a reagent containing the analyte.
  • the concentration of the analyte in the reagent is kept constant when changing the temperature of the reagent.
  • the concentration of the analyte in the reagent is kept constant when changing the temperature of the reagent.
  • the calibration information is obtained based on the sensitive information and the difference or ratio between the subcutaneous temperature and the reference temperature.
  • temperature compensation can be facilitated by taking into account the relationship between the sensitivity of the implanted part and the temperature, and the relationship between the subcutaneous temperature at which the implanted part is located and the reference temperature.
  • the subcutaneous implant part when the temperature sensor senses temperature on the body surface and outputs the body surface temperature, the subcutaneous implant part simultaneously senses the subcutaneous analyte concentration and output a response signal.
  • the subcutaneous temperature that is, the temperature of the position where the implanted part is located, and the response signal output by the implanted part from sensing the analyte concentration can be obtained at the same time, so that the temperature of the response signal of the implanted part can be measured in real time. Compensation, which can improve the accuracy of the analyte concentration calibration.
  • the analyte is acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructose
  • concentrations of analytes such as acetylcholine, amylase, and bilirubin can be obtained.
  • the calibrated analyte is obtained based on the relationship between the response signal of the implanted part at the reference temperature and the change in the concentration of the analyte, and the calibrated response signal concentration.
  • the present disclosure also provides an analyte sensor for obtaining an analyte concentration in consideration of temperature compensation
  • the analyte sensor includes an implant part that can be placed under the skin, an application part that can be placed on the body surface and has a temperature sensor , and a processing module
  • the processing module stores the first mapping relationship between the subcutaneous temperature and the body surface temperature obtained by the temperature sensor, the sensitive information of the implant part, and the implant part at a predetermined temperature
  • the second mapping relationship between the response signal output by the input part and the change of the analyte concentration, wherein the sensitive information is the relationship between the sensitivity of the implant part and the temperature change under the condition of a predetermined analyte concentration
  • the temperature sensor senses the temperature of the body surface and outputs the body surface temperature
  • the processing module is configured to: based on the body surface temperature and the The first mapping relationship obtains the subcutaneous temperature, selects a reference temperature, obtains calibration information based on
  • the implanted part is placed under the skin and the applied part with the temperature sensor is placed on the body surface, the body surface temperature is obtained from the temperature sensor, and the subcutaneous temperature is obtained based on the body surface temperature.
  • the processing module is configured to: obtain the subcutaneous temperature based on the body surface temperature and the first mapping relationship, select a reference temperature, obtain calibration information based on the sensitive information, the subcutaneous temperature and the reference temperature, and calibrate the response signal obtained by the implant part based on the calibration information, And the analyte concentration is obtained based on the reference temperature, the calibrated response signal, and the second mapping relationship, thereby obtaining the analyte concentration in consideration of temperature compensation, and improving the accuracy of the analyte sensor for sensing the analyte concentration Spend.
  • the implanted part includes a working electrode capable of reacting with the analyte, and a counter electrode forming a loop with the working electrode.
  • the implanted portion is thereby capable of sensing analyte concentration.
  • FIG. 1 is a schematic diagram 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 showing an implanted portion of an analyte sensor according to an embodiment of the present disclosure.
  • FIG. 3 is a schematic structural view showing a working electrode of an implanted part according to an embodiment of the present disclosure.
  • FIG. 4 is a graph showing a first mapping relationship between subcutaneous temperature and body surface temperature obtained by a temperature sensor according to an embodiment of the present disclosure.
  • 5A is a graph showing 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 graph corresponding to the linear regression simulation result graph in FIG. 5A.
  • FIG. 6 is a graph showing a second mapping relationship between response current and analyte concentration according to an embodiment of the present disclosure.
  • FIG. 7 is a flowchart illustrating a method of obtaining an analyte concentration in consideration of temperature compensation according to an embodiment of the present disclosure.
  • the present disclosure relates to a method of obtaining an analyte concentration taking into account temperature compensation, which can calibrate the obtained analyte concentration taking temperature compensation into account.
  • the method according to this embodiment can help to improve the accuracy of the obtained analyte concentration.
  • the analyte concentration may be obtained by an analyte sensor.
  • the present disclosure first introduces an analyte sensor that obtains an analyte concentration in consideration of temperature compensation.
  • an analyte sensor may also sometimes be referred to as an implantable analyte sensor, analyte monitor, or analyte monitor. It should be noted that each name refers to the analyte sensor that can improve the accuracy of the obtained analyte concentration in consideration of temperature compensation according to this embodiment, and should not be construed as limiting.
  • FIG. 1 is a schematic diagram illustrating a wearing state of an analyte sensor 1 for obtaining an analyte concentration in consideration of temperature compensation according to an embodiment of the present disclosure.
  • the analyte sensor 1 may include an implant part 2 that can be placed under the skin, an application part 3 that can be placed on the body surface, and a processing module (see FIG. 1 , the processing module is not shown).
  • the implant portion 2 when the implant portion 2 is placed subcutaneously, the implant portion 2 can sense the subcutaneous analyte concentration and output a response signal.
  • the application portion 3 may have a temperature sensor 4 (see FIG. 1 ).
  • the temperature sensor 4 can detect the temperature of the body surface and output the body surface temperature.
  • the processing module may receive the response signal output by the implant portion 2 and the body surface temperature output by the temperature sensor 4, and calculate and output the calibrated analyte concentration.
  • FIG. 2 is a schematic structural view showing the implanted portion 2 of the analyte sensor 1 according to the embodiment of the present disclosure.
  • analyte sensor 1 may include implant portion 2 (see FIG. 1 ), as described above.
  • the implanted portion 2 of the analyte sensor 1 may be placed subcutaneously and be in contact with subcutaneous interstitial fluid (see FIG. 1 ).
  • the implant part 2 can sense the concentration of the analyte in the interstitial fluid, and output a response signal.
  • implant portion 2 may be flexible.
  • the implant part 2 can be set in a puncture needle (not shown), and the implant part 2 can be separated from the puncture needle.
  • the puncture needle wrapped with the implant part 2 can be inserted into the tissue, and then the puncture needle is pulled out and separated from the implant part 2, whereby the implant part 2 is placed under the skin.
  • the implant part 2 can be placed on an arm (see FIG. 1 ), abdomen, waist, or leg.
  • implant portion 2 may be placed 3mm to 20mm subcutaneously.
  • the subcutaneous insertion depth of the implant part 2 is determined according to the insertion position. When the fat layer is thicker, the insertion depth can be about 10mm to 15mm, such as the abdomen of a human body. When the fat layer is thin, the insertion is relatively shallow, such as in the arm, and the insertion depth can be about 5mm to 10mm.
  • implant portion 2 may include substrate S (see FIG. 2 ).
  • substrate S may be flexible.
  • the substrate S can be generally made of polyethylene (PE), polypropylene (PP), polyimide (PI), polystyrene (PS), polyethylene terephthalate (PET), polyethylene naphthalene Made of at least one of ethylene glycol formate (PEN).
  • the substrate S can also be generally made of metal foil, ultra-thin glass, single-layer inorganic thin film, multi-layer organic thin film, or multi-layer inorganic thin film.
  • substrate S may also be inflexible.
  • implant portion 2 can include working electrode 10 and counter electrode 30 (see FIG. 2 ).
  • working electrode 10 may form a loop with working electrode 10 . The implanted portion 2 is thereby capable of sensing the analyte concentration.
  • implant portion 2 may also include reference electrode 20 .
  • the implanted portion 2 may further include a contact 40 connected to the working electrode 10 via a wire (see FIG. 2 ).
  • the implanted part 2 can transmit a response signal to the outside via the contact 40 .
  • working electrode 10, reference electrode 20, and counter electrode 30 can be disposed on substrate S (see FIG. 2).
  • FIG. 3 is a schematic diagram showing the structure of the working electrode 10 of the implanted portion 2 according to the embodiment of the present disclosure.
  • implant portion 2 may include working electrode 10 (see FIG. 2 ), as described above.
  • working electrode 10 can have substrate layer 110 , nanoparticle layer 120 , analyte enzyme sensing layer 130 , semipermeable membrane 140 and biocompatible membrane 150 .
  • the base layer 110, the nanoparticle layer 120, the analyte enzyme sensing layer 130, the semipermeable membrane 140, and the biocompatible membrane 150 can be stacked in sequence (see FIG. 3).
  • base layer 110 can be electrically conductive.
  • the base layer 110 may be made of at least one selected from gold, glassy carbon, graphite, silver, silver chloride, palladium, titanium, and iridium. In this case, the base layer 110 has good electrical conductivity, and can inhibit the electrochemical reaction of the base layer 110 , thereby improving the stability of the base layer 110 .
  • the base layer 110 may be disposed on the substrate S by a deposition or plating method.
  • methods of deposition may include physical vapor deposition, chemical vapor deposition, and the like.
  • Plating methods may include electroplating, electroless plating, vacuum plating, and the like.
  • the base layer 110 may also be disposed on the substrate S by screen printing, extrusion or electrolytic deposition.
  • an analyte enzyme sensing layer 130 may be disposed on the base layer 110 .
  • the concentration of multiple analytes can be acquired.
  • the analyte may be acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth One or more of hormones, hormones, ketone bodies, lactate, peroxide, prostate-specific antigen, prothrombin, RNA, thyrotropin, and troponin.
  • the concentration of drugs in body fluids can also be monitored, such as antibiotics (gentamycin, vancomycin, etc.), digoxigenin, Digoxin, theophylline, and warfarin.
  • the nanoparticle layer 120 may be disposed on the base layer 110 . That is, between the base 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, reduce the operating voltage required for the analyte reaction and increase the reaction rate.
  • H 2 O 2 will be produced in the reaction formula (II), and the accumulation of H 2 O 2 will reduce the enzyme activity in the analyte enzyme sensing layer 130 .
  • the nanoparticle layer 120 can act as a catalyst to cause the decomposition reaction of H 2 O 2 , the specific reaction is as follows:
  • the reaction of the implanted portion 2 and glucose can be continued.
  • the hydrogen peroxide decomposition catalyzed by the nanoparticle layer 120 can reduce the applied voltage during the reaction, which is beneficial to improve the sensitivity of the implanted part 2, prolong the service time of the analyte sensor 1, and obtain low working voltage.
  • the high-sensitivity sensing signal of tissue glucose can be continuously obtained, prolonging the service life of the analyte sensor 1 , and the low working voltage is beneficial to improve the anti-interference performance.
  • nanoparticle layer 120 may be porous.
  • the analyte enzyme in the analyte enzyme sensing layer 130 can penetrate the nanoparticle layer 120 .
  • the nanoparticle layer 120 can fully contact and catalyze the reaction of the analyte, so as to more effectively promote the reaction of the analyte.
  • the analyte enzyme can also be disposed in a three-dimensional network of conductive polymer nanofibers, that is, the three-dimensional network of nanofibers is disposed between the nanoparticle layer 120 and the analyte enzyme sensing layer 130 .
  • the adhesion of the analyte enzyme on the nanoparticle layer 120 is increased, and the immobilization amount of the analyte enzyme is increased.
  • the analyte enzyme may also be disposed on carbon nanotubes, wherein the carbon nanotubes are disposed on nanoparticle layer 120.
  • the attachment and immobilization amount of the analyte enzyme on the nanoparticle layer 120 is increased.
  • a semipermeable membrane 140 can be distributed over the analyte enzyme sensing layer 130 .
  • the semipermeable membrane 140 may further include a diffusion control layer and an anti-interference layer laminated on the diffusion control layer.
  • a diffusion control layer may be disposed over the anti-interference layer.
  • the diffusion control layer can control the diffusion of analyte molecules, and the anti-interference layer can prevent the diffusion of non-analyte substances.
  • Common interfering substances may include uric acid, ascorbic acid, and acetaminophen, which are ubiquitous in the body.
  • the anti-interference layer can also be arranged outside the diffusion control layer. In this way, inaccurate sensing results caused by the interference of impurities on the working electrode 10 can also be reduced, and the service life of the implanted part 2 can be extended.
  • the semipermeable membrane 140 can control the passage rate of analyte molecules, that is, the semipermeable membrane 140 can limit the amount of analyte molecules in the interstitial fluid or blood that reach the analyte enzyme sensing layer 130 .
  • the diffusion control layer of the semipermeable membrane 140 can effectively reduce the amount of analyte that diffuses into the analyte enzyme sensing layer 130 by a certain ratio.
  • biocompatible membrane 150 may be disposed on semi-permeable membrane 140 .
  • biocompatible membrane 150 may be made from plant material.
  • the plant material may be sodium alginate, tragacanth, pectin, acacia, xanthan, guar, agar or derivatives of natural materials such as starch derivatives, cellulose derivatives, and the like.
  • the biocompatible film 150 can also be made of artificial synthetic materials. Synthetic materials can be polyolefins. Thus, the immune reaction of the human body to the implanted part 2 can be reduced, and the service life of the implanted part 2 can be prolonged.
  • the semipermeable membrane 140 may also be biocompatible.
  • the use of the biocompatible film 150 can be avoided, and the manufacturing cost can be reduced.
  • a nanoparticle layer 120 for promoting the reaction of the analyte enzyme to catalyze the analyte is provided, and then the analyte enzyme sensing layer 130 is formed on this basis, and then the analyte A semipermeable membrane 140 coating is formed on the enzyme sensing layer 130, and finally a biocompatible membrane 150 is formed on the semipermeable membrane 140 coating (see FIG. 3 ).
  • implant portion 2 may include counter electrode 30 (see FIG. 2 ), as described above.
  • counter electrode 30 may be made of platinum, silver, silver chloride, palladium, titanium, or iridium. As a result, the electrochemical reaction at the working electrode 10 may not be affected while having good electrical conductivity. But this embodiment is not limited thereto.
  • the counter electrode 30 may also be made of at least one selected from gold, glassy carbon, graphite, silver, silver chloride, palladium, titanium or iridium. Thus, the influence on the working electrode 10 can be reduced while having good conductivity.
  • the implanted part 2 involved in this embodiment can realize continuous monitoring, so it can realize the purpose of continuously monitoring the concentration value of the human body analyte for a long time (for example, 1 day to 24 days).
  • the analyte sensor 1 also includes an applicator portion 3 (see FIGS. 1 and 2 ), as described above.
  • the applicator portion 3 may have a housing 31 (see FIG. 1 ). In some examples, the temperature sensor 4 that the applicator portion 3 has may be located within the housing 31 (see FIG. 1 ).
  • the temperature sensor 4 may be disposed on the inner wall of the housing 31 close to the body surface (see FIG. 1 ). In other examples, the temperature sensor 4 may be disposed on any wall of the housing 31 .
  • the number of temperature sensors 4 of the application part 3 may be one. In some other examples, the number of temperature sensors 4 in the application part 3 may be multiple, thereby improving the accuracy of body surface temperature sensing, thereby improving the accuracy of subcutaneous temperature obtained based on body surface temperature.
  • the application portion 3 may be connected to the implant portion 2 .
  • the part of the implant part 2 located on the body surface can be electrically connected with the application part 3 through the contact 40 (see FIG. 2 ).
  • the current signal generated by the implant part 2 can be transmitted to the application part 3 via the base layer 110 and the transmission wire via the contact 40 .
  • the application part 3 can be made of a flexible PCB and a flexible battery. Thereby, it can stick to the skin and reduce the influence on the user's daily life.
  • analyte sensor 1 also includes a processing module (not shown), as described above.
  • a treatment module may be mounted on the applicator portion 3 .
  • the current signal generated by the implanted part 2 can be sent to the processing module through the contact 40 for analysis, and the body surface temperature output by the temperature sensor 4 can be sent to the processing module for analysis.
  • the processing module may store a first mapping relationship between subcutaneous temperature and body surface temperature.
  • body surface temperature may be obtained by temperature sensor 4, as described above.
  • the processing module may store sensitive information of the implanted portion 2 .
  • the processing module may store a second mapping relationship between the response signal output by the implant part 2 and the change in the concentration of the analyte.
  • the second mapping relationship may be a second mapping relationship between the response signal output by the implanted portion 2 and the change in the concentration of the analyte at a predetermined temperature.
  • the processing module may store a first mapping relationship between the subcutaneous temperature and the body surface temperature obtained by the temperature sensor 4 .
  • FIG. 4 is a graph showing a first mapping relationship between the subcutaneous temperature and the body surface temperature obtained by the temperature sensor 4 according to the embodiment of the present disclosure.
  • three temperature sensors 4 with the same process parameters can be respectively placed in the external environment, on the surface of the simulated living body, and about 10 mm below the skin of the simulated living body.
  • the three temperature sensors 4 can be set to output corresponding sensed temperatures every 1 minute.
  • the first mapping relationship between the body surface temperature and the subcutaneous temperature can be obtained through 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 parameters may refer to the temperature sensors 4 shipped from the same batch during production, and generally may be the temperature sensors 4 manufactured by the same batch of products under the same process. Systematic errors of measurements between different temperature sensors 4 can thus be reduced.
  • the processing module may store sensitive information of the implant portion 2, as described above.
  • the sensitivity information may be the sensitivity of the implant portion 2 as a function of temperature.
  • the sensitivity of the implanted portion 2 may be a variation of the sensitivity of the implanted portion 2 at a reference temperature.
  • the change in sensitivity of the implanted portion 2 can be obtained from the response current versus temperature of the implanted portion 2 at a reference temperature.
  • FIG. 5A is a graph showing the linear regression simulation results of the response current and temperature of the implanted portion 2 according to the embodiment of the present disclosure
  • FIG. 5B is a table showing the corresponding linear regression simulation results graph in FIG. 5A .
  • analyte sensor 1 can sense the concentration of glucose.
  • the implanted portion 2 of the analyte sensor 1 is placed in a glucose solution.
  • the glucose solution may have a concentration of 5 mmol/L to 25 mmol/L.
  • the temperature of the glucose solution is changed to obtain the response signal output by the implant part 2 when the temperature of the glucose solution is 30°C, 34°C, 37°C and 40°C (see FIG. 5B ).
  • the response signal can be a response current (see FIG. 5B ).
  • the response signal may be a response voltage.
  • the response current and temperature may be linearly related (see FIG. 5A ). In some other examples, the relationship between the response current and temperature is analyzed, and the response current and temperature may be nonlinearly related.
  • the change value of the sensitivity of the implanted part 2 at the reference temperature may be the ratio of the slope (k value) of the linear regression equation of the linear simulation result to the response signal (see FIG. 5A and FIG. 5B in conjunction).
  • the change value of the sensitivity of the implanted part 2 at the reference temperature may be the ratio of the slope (k value) of the linear regression equation of the linear simulation result to the response signal (see FIG. 5A and FIG. 5B in conjunction).
  • the change value of the sensitivity of the implant part 2 at 30°C can be 12.59% (0.428/3.40); when 34°C is selected as the reference temperature, the implanted part 2 The variation value of the sensitivity of the implanted part 2 at 34°C is 8.82% (0.428/4.85); when 37°C is selected as the reference temperature, the variation value of the sensitivity of the implanted portion 2 at 37°C is 6.95% (0.428/6.16); When 40°C is selected as the reference temperature, the change value of the sensitivity of the implanted portion 2 at 40°C is 5.56% (0.428/7.70).
  • the change value of the sensitivity of the implanted part 2 at the reference temperature may be the average value of the results of multiple repeated measurements of the same implanted part 2 .
  • the variation value of the sensitivity of the implanted part 2 at the reference temperature may be an average value of a plurality of implanted part 2 measurement results.
  • the processing module may store a second mapping of the response signal of the implanted portion 2 as a function of analyte concentration at a predetermined temperature, as described above.
  • the predetermined temperature includes multiple temperature values.
  • the predetermined temperatures include 34°C, 35°C, 36°C, 36.5°C, 37°C, 37.5°C, 38°C, 39°C, 40°C, and 41°C.
  • the reference temperature may be selected from one of a plurality of temperature values.
  • the reference temperature may be 34°C, 35°C, 36°C, 36.5°C, 37°C, 37.5°C, 38°C, 39°C, 40°C, or 41°C.
  • FIG. 6 is a graph showing a second mapping relationship between response current and analyte concentration according to an embodiment of the present disclosure.
  • analyte sensor 1 can sense the concentration of glucose. 37°C was chosen as the reference temperature.
  • the implanted part 2 of the analyte sensor 1 is respectively placed in different concentrations of glucose solutions.
  • the glucose solution may have a concentration of 0 to 25 mmol (see FIG. 6 ).
  • the implanted part 2 senses glucose solutions of different concentrations and outputs corresponding response signals.
  • the response signal may be a response current (see FIG. 6 ). In other examples, the response signal may be a response voltage.
  • analyzing the relationship between the response current and the concentration of the analyte, the response current and the glucose concentration may be linearly correlated (see FIG. 6 ), that is, the second mapping relationship is a linear relationship.
  • the relationship between the response current and the concentration of the analyte is analyzed, and the response current and the concentration of the analyte may be nonlinearly related, that is, the second mapping relationship is a nonlinear relationship.
  • the processing module is configured to obtain a subcutaneous temperature. For example, the processing module is configured to obtain the subcutaneous temperature based on the body surface temperature and the first mapping relationship. In some examples, the processing module is configured to select a 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 part 2 based on the calibration information. In some examples, the processing module is configured to obtain an 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.
  • the processing module is configured to obtain the subcutaneous temperature based on the body surface temperature and the first mapping relationship.
  • the temperature sensor 4 can send 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 relationship according to the first mapping relationship preset in the processing module.
  • the processing module is configured to select a reference temperature, as described above.
  • the reference temperature selected for the processing module configuration may be 37°C.
  • the reference temperature is relatively close to the average body temperature of the human body, thereby improving the effectiveness of the calibration of the analyte concentration taking temperature compensation into account.
  • the reference temperature may also be other temperatures.
  • the reference temperature may be 35°C, 36°C, 36.5°C, 37.5°C or 38°C.
  • the processing module is configured to obtain calibration information based on the sensitivity information, the subcutaneous temperature, and the reference temperature, as described above. Specifically, 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 change value of the sensitivity of the implant part 2 at 37° C., so as to obtain the calibration information.
  • the processing module is configured to calibrate the response signal obtained by the implant portion 2 based on the calibration information, as described above.
  • the response signal generated by the implanted part 2 can be delivered to the processing module through the contact 40, and the processing module is configured to perform mathematical calculations on the calibration information and the response signal, so as to analyze the output signal generated by the implanted part 2. The obtained response signal is calibrated.
  • ⁇ T represents the difference between the reference temperature and the subcutaneous temperature
  • Z represents the change value of the sensitivity of the implanted part 2 at the reference temperature
  • a represents the response signal output by the implanted part 2 to the processing module
  • b represents the calibration After the response signal.
  • 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 by using the second mapping relationship at the reference temperature preset by the processing module and the calibrated response signal.
  • the temperature sensor 4 and the implanted part 2 can transmit signals to the processing module at intervals, and the processing module can output the calibrated analyte concentration at intervals, so that The user can know the change trend of the analyte concentration in time, so as to control the change of the analyte concentration.
  • the analyte concentration signal obtained by the processing module can be transmitted through wireless communication means such as bluetooth, wifi and the like.
  • An external reading device such as a mobile phone or a computer (not shown), can receive the analyte concentration signal sent by the processing module and display the analyte concentration.
  • the implant part 2 is placed under the skin and the application part 3 with the temperature sensor 4 is placed on the body surface, the body surface temperature is obtained by the temperature sensor 4, and based on the body surface temperature Obtain a subcutaneous temperature.
  • the processing module is configured to: obtain the subcutaneous temperature based on the body surface temperature and the first mapping relationship, select a reference temperature, obtain calibration information based on the sensitive information, the subcutaneous temperature and the reference temperature, and calibrate the response signal obtained by the implant part 2 based on the calibration information , and the analyte concentration is obtained based on the reference temperature, the calibrated response signal, and the second mapping relationship. In this way, the analyte concentration can be obtained considering the temperature compensation, which improves the accuracy of the analyte sensor 1 in sensing the analyte concentration.
  • the method for obtaining analyte concentration in consideration of temperature compensation in this embodiment may also be referred to as an analyte concentration calibration method, a temperature compensation calibration method for analyte concentration, analyte concentration temperature compensation calibration method, and the like. It should be noted that each name is a method for improving the accuracy of the obtained analyte concentration in consideration of temperature compensation according to this embodiment, and should not be construed as limiting.
  • FIG. 7 is a flowchart illustrating a method of obtaining an analyte concentration in consideration of temperature compensation according to an embodiment of the present disclosure.
  • the method for obtaining the concentration of an analyte in consideration of temperature compensation may include: obtaining sensitive information of the implanted part 2 before wearing the analyte sensor 1 (step S100); obtaining body surface temperature , obtain subcutaneous temperature based on body surface temperature (step S200); select reference temperature (step S300); obtain calibration information, and calibrate response signal based on calibration information (step S400); obtain analysis based on reference temperature and calibrated response signal concentration (step S500).
  • the sensitive information of the implanted part 2 can be obtained before the analyte sensor 1 is worn.
  • sensitivity information of the implanted portion 2 may be obtained at predetermined analyte concentrations prior to wearing the analyte sensor 1 .
  • the predetermined analyte concentration may be a known and identical analyte concentration.
  • the implanted part 2 can be placed in the analyte, and the implanted part 2 can sense the output response signal of the concentration of the analyte to obtain the sensitive information of the implanted part 2 .
  • the sensitive information may be the relationship between the sensitivity of the implanted part 2 and the temperature.
  • the sensitivity of the implanted portion 2 may increase as the temperature increases. Specifically, in some examples, within a predetermined temperature range, the sensitivity of the implanted portion 2 may increase as the temperature increases. 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 dependent on temperature.
  • the sensitivity of the implanted part 2 may decrease as the temperature increases. Specifically, in some examples, in step S100, within a predetermined temperature range, the sensitivity of the implanted part 2 may decrease as the temperature increases. 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 dependent on temperature.
  • the sensitivity information may be the change value of the sensitivity of the implanted portion 2 at a reference temperature.
  • the sensitivity information may be the change value of the sensitivity of the implanted part 2 at 37° C., that is, 6.95%.
  • the implanted part 2 may be placed in a reagent containing an analyte, and by changing the temperature of the reagent and measuring the sensitivity of the implanted part 2 with the temperature of the reagent, the implanted part 2 can be obtained.
  • sensitive information That is, the relationship between the sensitivity of the implanted part 2 and the temperature of the environment (position) where the implanted part 2 is located is obtained by changing the temperature of the reagent to change the temperature of the environment (position) where the implanted part 2 is located.
  • the sensitivity information of the implanted part 2 can be obtained conveniently in advance by measuring the sensitivity of the implanted part 2 as a function of temperature using a reagent containing the analyte. .
  • 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 temperature change will not affect the change of the concentration of the analyte, thereby improving the accuracy of sensitivity sensing of the implanted part 2 .
  • step S200 as described above, the body surface temperature is obtained, and the subcutaneous temperature is obtained based on the body surface temperature.
  • the implant part 2 can be placed subcutaneously and the application part 3 can be placed on the body surface, the body surface temperature can be obtained through the temperature sensor 4, and the subcutaneous temperature can be obtained based on the body surface temperature. temperature.
  • step S200 when the application part 3 is placed on the body surface, the temperature sensor 4 of the application part 3 is placed on the body surface.
  • the temperature sensor 4 can sense the body surface temperature and output the body surface temperature.
  • step S200 there may be a first mapping relationship between the body surface temperature and the subcutaneous temperature.
  • the subcutaneous temperature can be obtained through the first mapping relationship.
  • the body surface temperature and the subcutaneous temperature of the simulated living body may be sensed simultaneously under different ambient temperatures, so as to obtain a first mapping relationship between the body surface temperature and the subcutaneous temperature.
  • the body surface temperature and the subcutaneous temperature are jointly affected by the ambient temperature and the body temperature.
  • Body surface temperature is more affected by ambient temperature than subcutaneous temperature, and body surface temperature is less affected by internal temperature than subcutaneous temperature; therefore, there can be a nonlinear correlation between body surface temperature and subcutaneous temperature. That is, the first mapping relationship may be a nonlinear mapping relationship.
  • the implant part 2 may be placed 3 mm to 20 mm below the skin. It can be understood that the distance between the subcutaneous 3mm and the subcutaneous 20mm is small, and the temperatures are approximately equal, which will not lead to a statistical difference in the response signal output by the implant part 2 .
  • a reference temperature may be selected.
  • 37°C may be selected as the reference temperature.
  • the reference temperature is closer to the average body temperature of the human body, thereby improving the effectiveness of calibrating the analyte concentration by temperature compensation.
  • the reference temperature may also be other temperatures.
  • the reference temperature may be 35°C, 36°C, 36.5°C, 37.5°C or 38°C.
  • step S400 as described above, calibration information can be obtained based on the sensitivity information, reference temperature and subcutaneous temperature, and the response signal obtained by the implant part 2 is calibrated based on the calibration information.
  • the sensitive information may be the relationship between the sensitivity of the implanted part 2 and the temperature change as described above.
  • the sensitive information may be the sensitivity of the implanted portion 2 at a reference temperature.
  • the sensitivity information may be the change value of the sensitivity of the implanted part 2 at the reference temperature.
  • step S400 calibration information may be obtained based on the difference between the subcutaneous temperature and the reference temperature, and sensitivity information.
  • temperature compensation can be facilitated by taking into account the relationship between the sensitivity of the implanted part 2 and the temperature, and the relationship between the subcutaneous temperature at which the implanted part 2 is located and the reference temperature.
  • the calibration information may be the product of the difference between the reference temperature and the subcutaneous temperature and the sensitivity of the implant part 2 at the reference temperature. Further, the calibration information may be the product of the difference between the reference temperature and the subcutaneous temperature and the change value of the sensitivity of the implant part 2 at the reference temperature.
  • the calibration information may be obtained based on the sensitivity information and the ratio of the subcutaneous temperature to the reference temperature.
  • the calibration information may be the product of the ratio of the reference temperature to the subcutaneous temperature and the sensitivity of the implant part 2 at the reference temperature.
  • the calibration information may be the product of the ratio of the reference temperature to the subcutaneous temperature and the change value of the sensitivity of the implant part 2 at the reference temperature.
  • the response signal after calibration may be the 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.
  • the response signal after calibration may be the quotient of the response signal before calibration and the calibration information. In still some examples, in step S400, the response signal after calibration may be the sum/difference of the response signal before calibration and the calibration information.
  • the subcutaneous implant part 2 may simultaneously sense the subcutaneous analyte concentration and output a response signal.
  • the subcutaneous temperature that is, the temperature of the position where the implanted part 2 is located, and the response signal output by the implanted part 2 to sense the concentration of the analyte can be obtained at the same time, so that the response of the implanted part 2 can be obtained in real time.
  • the signal is temperature compensated, which improves the accuracy of the analyte concentration calibration.
  • step S400 there is no time delay between the output of the response signal from the implant part 2 and the output of the body surface temperature from the temperature sensor 4 .
  • the subcutaneous temperature that is, the temperature at the position of the implanted part 2
  • the response signal output by the implanted part 2 at the subcutaneous temperature at this time can be obtained without time delay, by This can further improve the accuracy of the analyte concentration calibration.
  • step S500 as described above, the analyte concentration can be obtained based on the reference temperature and the calibrated response signal.
  • step S500 the relationship between the response signal of the implanted portion 2 and the concentration of the analyte can be obtained at a reference temperature. In some examples, there may be a second mapping relationship between the response signal of the implanted portion 2 and the concentration of the analyte at the reference temperature.
  • the response signal of the implanted portion 2 may be linearly related to the analyte concentration. That is, the second mapping relationship may be a linear mapping relationship. In other examples, the response signal of the implanted portion 2 may be non-linearly related to the analyte concentration. That is, the second mapping relationship may be a nonlinear mapping relationship.
  • step S500 at the reference temperature, the implanted part 2 is respectively placed in analyte solutions with different concentrations, and the response signal output by the implanted part 2 is measured to obtain the response of the implanted part 2 A second mapping of signal to analyte concentration.
  • the maximum concentration of the analyte used to detect the second mapping relationship is lower than the maximum sensing concentration of the implanted part 2 .
  • the concentration gradient of the analyte used to detect the second mapping relationship is increasing.
  • the concentration of the analyte used to detect the second mapping relationship approximates the concentration of the analyte subcutaneously. In this case, the closeness of the concentration of the analyte can make the systematic error of the detection relatively small, thereby improving the accuracy of the detection.
  • the calibrated analyte concentration may be obtained based on the relationship between the response signal of the implanted part 2 and the change in analyte concentration at the reference temperature, and the calibrated response signal. That is, the calibrated analyte concentration can be obtained through the second mapping relationship and the calibrated response signal of the implant part 2 in step S400.
  • the sensitivity information of the implanted part 2 is obtained under a predetermined analyte concentration, that is, the relationship between the sensitivity of the implanted part 2 and the temperature change is obtained.
  • the implant part 2 is placed under the skin and the application part 3 with the temperature sensor 4 is placed on the body surface, the body surface temperature is obtained from the temperature sensor 4, and the subcutaneous temperature is obtained based on the body surface temperature.
  • Select a reference temperature obtain calibration information based on the sensitivity information, reference temperature and subcutaneous temperature, and calibrate the response signal obtained from the implant part 2 based on the calibration information, thereby obtaining a calibrated response signal.
  • the analyte concentration is calibrated based on the reference temperature and the calibrated response signal, thereby improving the accuracy of the obtained analyte concentration.

Abstract

一种在考虑温度补偿的情况下获得分析物浓度的方法，包括：在佩戴分析物传感器（1）之前，在预定分析物浓度的情况下获得植入部分（2）的灵敏信息，灵敏信息为植入部分（2）的灵敏度与温度变化的关系（S100）；将植入部分（2）置于皮下并将敷贴部分（3）置于体表，通过温度传感器（4）获得体表温度，并基于体表温度获得皮下温度（S200）；选取参考温度（S300）；基于灵敏信息、参考温度和皮下温度获得校准信息，基于校准信息对由植入部分（2）获得的响应信号进行校准（S400）；并基于参考温度、以及校准后的响应信号获得分析物浓度（S500）。由此，能够提高获得的分析物浓度的精准度。

Description

在考虑温度补偿的情况下获得分析物浓度的传感器及方法 技术领域
本公开大体涉及医疗设备领域，具体涉及在考虑温度补偿的情况下获得分析物浓度的传感器及方法。
背景技术
糖尿病是糖、蛋白质、脂肪、水和电解质等一系列代谢紊乱的疾病，如果没有得到良好的控制，则有可能会引起一些并发症，例如酮症酸中毒、乳酸性酸中毒、慢性肾衰竭和视网膜病变等。对于糖尿病患者而言，如果能够实时地、连续地监测葡萄糖的浓度，可以优先预测葡萄糖症和高葡萄糖症等并发症的发生。
研究表明，当血液中的葡萄糖浓度开始降低时，组织液中的葡萄糖浓度比血液中的葡萄糖浓度先出现降低，组织液中的葡萄糖浓度的降低可以为即将出现的低葡萄糖做出预测。用于感测葡萄糖浓度的葡萄糖传感器一般包括植入部分，植入部分可以被置入皮下以感测皮下组织液中的葡萄糖浓度的变化，从而能够对血液中的葡萄糖浓度做出预测。
但是，植入部分所处位置的温度会受到环境温度改变和体内温度改变的共同影响而发生变化。植入部分一般包括可以催化葡萄糖发生反应的酶。由于酶的活性受温度影响，会导致植入部分输出的响应信号出现偏差，从而导致基于响应信号计算的葡萄糖浓度不够准确。因此需要在考虑温度补偿的情况下对输出的响应信号进行校准。
发明内容
本公开有鉴于上述现有技术的状况而完成，其目的在于提供在考虑温度补偿的情况下获得分析物浓度的传感器及方法，以提高所获得的分析物浓度的精准度。
为此，本公开提供一种在考虑温度补偿的情况下获得分析物浓度 的方法，所述分析物浓度通过分析物传感器获得，所述分析物传感器包括可置于皮下的植入部分、以及可置于体表且具有温度传感器的敷贴部分，所述方法包括：在佩戴所述分析物传感器之前，在预定分析物浓度的情况下获得所述植入部分的灵敏信息，所述灵敏信息为所述植入部分的灵敏度与温度的关系；将所述植入部分置于皮下并将所述敷贴部分置于体表，通过所述温度传感器获得体表温度，并基于所述体表温度获得皮下温度；选取参考温度；基于所述灵敏信息、所述参考温度和所述皮下温度获得校准信息，并基于所述校准信息对由所述植入部分获得的响应信号进行校准；并且基于所述参考温度、以及校准后的响应信号获得所述分析物浓度。
在本公开所涉及的方法中，在佩戴分析物传感器之前，在预定分析物浓度的情况下获得植入部分的灵敏信息，也即获得植入部分的灵敏度与温度的关系。将植入部分置于皮下并将具有温度传感器的敷贴部分置于体表，由温度传感器获得体表温度，并基于体表温度获得皮下温度。选取参考温度，基于灵敏信息、参考温度和皮下温度获得校准信息，并基于校准信息对由植入部分获得的响应信号进行校准，由此能够获得校准后的响应信号。基于参考温度、以及校准后的响应信号，对分析物浓度进行校准，由此能够提高获得的分析物浓度的精准度。
另外，在本公开所涉及的方法中，可选地，将所述植入部分置于包含所述分析物的试剂中，改变所述试剂的温度并测量所述植入部分的灵敏度随所述试剂的温度的变化，以获得所述植入部分的灵敏信息。在这种情况下，在佩戴分析物传感器之前，通过使用包含有分析物的试剂来测量植入部分的灵敏度随温度的变化关系，由此能够方便地预先获得植入部分的灵敏信息。
另外，在本公开所涉及的方法中，可选地，当改变所述试剂的温度时保持所述试剂中分析物的浓度不变。在这种情况下，通过控制试剂中分析物的浓度不变并改变试剂的温度，由此能够更准确地获得植入部分的灵敏度与温度之间的关系。
另外，在本公开所涉及的方法中，可选地，所述校准信息基于所 述灵敏信息、以及所述皮下温度与所述参考温度的差值或比值而获得。在这种情况下，通过考虑植入部分的灵敏度与温度之间的关系、以及植入部分所处的皮下温度与参考温度之间的关系，由此能够有利于进行温度补偿。
另外，在本公开所涉及的方法中，可选地，当所述温度传感器在体表感测温度并输出所述体表温度时，插入皮下的所述植入部分同时感测皮下的分析物浓度并输出响应信号。在这种情况下，能够同时获得皮下温度也即植入部分所处位置的温度、以及植入部分感测分析物浓度输出的响应信号，由此能够实时地对植入部分的响应信号进行温度补偿，从而能够提高分析物浓度校准的精确度。
另外，在本公开所涉及的方法中，可选地，所述植入部分输出所述响应信号与所述温度传感器输出所述体表温度之间无时间延迟。由此能够提高分析物浓度校准的精确度。
另外，在本公开所涉及的方法中，可选地，所述分析物为乙酰胆碱、淀粉酶、胆红素、胆固醇、绒毛膜促性腺激素、肌酸激酶、肌酸、肌酸酐、DNA、果糖胺、葡萄糖、谷氨酰胺、生长激素、激素、酮体、乳酸盐、过氧化物、前列腺特异性抗原、凝血酶原、RNA、促甲状腺激素和肌钙蛋白中的一种或多种。由此，能够获得乙酰胆碱、淀粉酶、胆红素等分析物的浓度。
另外，在本公开所涉及的方法中，可选地，基于在所述参考温度下所述植入部分的响应信号与分析物浓度变化的关系、以及校准后的响应信号获得校准后的分析物浓度。
本公开还提供一种在考虑温度补偿的情况下获得分析物浓度的分析物传感器，所述分析物传感器包括可置于皮下的植入部分、可置于体表且具有温度传感器的敷贴部分、以及处理模块，所述处理模块存储有皮下温度与由所述温度传感器所获得的体表温度之间的第一映射关系、所述植入部分的灵敏信息、以及在预定温度下所述植入部分输出的响应信号与分析物浓度变化的第二映射关系，其中，所述灵敏信息为在预定分析物浓度的情况下所述植入部分的灵敏度与温度变化的关系；当将所述植入部分置于皮下并将所述敷贴部分置于体表 时，所述温度传感器感测体表的温度并输出体表温度；所述处理模块配置为：基于所述体表温度和所述第一映射关系获得皮下温度，选取参考温度，基于所述灵敏信息、所述皮下温度和所述参考温度获得校准信息，基于所述校准信息对由所述植入部分获得的响应信号进行校准，并且基于所述参考温度、校准后的所述响应信号、以及所述第二映射关系获得所述分析物浓度。
在本公开所涉及的分析物传感器中，将植入部分置于皮下并将具有温度传感器的敷贴部分置于体表，由温度传感器获得体表温度，并基于体表温度获得皮下温度。处理模块配置为：基于体表温度和第一映射关系获得皮下温度，选取参考温度，基于灵敏信息、皮下温度和参考温度获得校准信息，基于校准信息对由植入部分获得的响应信号进行校准，并且基于参考温度、校准后的响应信号、以及第二映射关系获得分析物浓度，由此能够获得在考虑了温度补偿情况下的分析物浓度，提高了分析物传感器对分析物浓度感测的精准度。
另外，在本公开所涉及的分析物传感器中，所述植入部分包括能够与分析物发生反应的工作电极、以及与所述工作电极形成回路的对电极。由此植入部分能够感测分析物浓度。
根据本公开，能够提供考虑温度补偿的情况获得分析物浓度的传感器及方法，由此能够提高获得的分析物浓度的精准度。
附图说明
图1是示出了本公开的实施方式所涉及的在考虑温度补偿的情况下获得分析物浓度的分析物传感器的佩戴状态示意图。
图2是示出了本公开的实施方式所涉及的分析物传感器的植入部分的结构示意图。
图3是示出了本公开的实施方式所涉及的植入部分的工作电极的结构示意图。
图4是示出了本公开的实施方式所涉及的皮下温度与温度传感器所获得的体表温度之间的第一映射关系图。
图5A是示出了本公开的实施方式所涉及的植入部分的响应电流与温度的线性回归模拟结果图；
图5B是示出了与图5A中线性回归模拟结果图对应的表格。
图6是示出了本公开的实施方式所涉及的响应电流与分析物浓度的第二映射关系图。
图7是示出了本公开的实施方式所涉及的在考虑温度补偿的情况下获得分析物浓度的方法的流程图。
具体实施方式
下面，结合附图和具体实施方式，进一步详细地说明本公开。在附图中，相同的部件或具有相同功能的部件采用相同的符号标记，省略对其的重复说明。
本公开涉及一种在考虑温度补偿的情况下获得分析物浓度的方法，其可以在考虑温度补偿的情况下对获得的分析物浓度进行校准。通过本实施方式所涉及的方法，能够有助于提高获得的分析物浓度的精准度。
在本公开所涉及的在考虑温度补偿的情况下获得分析物浓度的方法中，分析物浓度可以通过分析物传感器获得。为了方便理解，本公开首先对在考虑温度补偿的情况下获得分析物浓度的分析物传感器进行介绍。
在一些示例中，分析物传感器有时也可以称为植入式分析物传感器、分析物监测器或分析物监测仪。需要说明的是，各名称是为表示本实施方式所涉及的在考虑温度补偿的情况下，能够提高获得的分析物浓度的精准度的分析物传感器，并且不应当理解为限定性的。
图1是示出了本公开的实施方式所涉及的在考虑温度补偿的情况下获得分析物浓度的分析物传感器1的佩戴状态示意图。
在一些示例中，分析物传感器1可以包括可置于皮下的植入部分2、可置于体表的敷贴部分3、以及处理模块(参见图1，处理模块未示出)。在一些示例中，当将植入部分2置于皮下时，植入部分2可以感测皮下的分析物的浓度并输出响应信号。在一些示例中，敷贴部分3可以具有温度传感器4(参见图1)。在一些示例中，将敷贴部分3置于体表时，温度传感器4可以检测体表的温度并输出体表温度。 在一些示例中，处理模块可以接收植入部分2输出的响应信号和温度传感器4输出的体表温度，并计算和输出校准后的分析物浓度。
图2是示出了本公开的实施方式所涉及的分析物传感器1的植入部分2的结构示意图。
在一些示例中，如上所述，分析物传感器1可以包括植入部分2(参见图1)。在一些示例中，分析物传感器1的植入部分2可以置入皮下，并与皮下的组织液接触(参见图1)。植入部分2可以感测组织液中的分析物的浓度，并输出响应信号。
在一些示例中，植入部分2可以为柔性。植入部分2可以设置在穿刺针(未图示)内，植入部分2与穿刺针可分离。在佩戴分析物传感器1时，可以将包裹有植入部分2的穿刺针刺入组织，接着将穿刺针拔出并与植入部分2分离，由此植入部分2被置入皮下。
在一些示例中，植入部分2可以配置在胳膊(参见图1)、腹部、腰部或者腿部等。
在一些示例中，植入部分2可以置入皮下3mm至20mm。在一些示例中，植入部分2置入皮下的深度根据刺入位置确定。当脂肪层较厚时置入较深，例如人体腹部，置入深度可以约为10mm至15mm。脂肪层较薄时置入较浅，例如手臂处，置入的深度可以约为5mm至10mm。
在一些示例中，植入部分2可以包括衬底S(参见图2)。
在一些示例中，衬底S可以是柔性的。衬底S可以大体由聚乙烯(PE)、聚丙烯(PP)、聚酰亚胺(PI)、聚苯乙烯(PS)、聚对苯二甲酸乙二醇酯(PET)、聚对萘二甲酸乙二醇酯(PEN)中的至少一种制成。另外，在另一些示例中，衬底S也可以大体由金属箔片、超薄玻璃、单层无机薄膜、多层有机薄膜或多层无机薄膜等制成。在一些示例中，衬底S也可以是非柔性的。
在一些示例中，植入部分2可以包括工作电极10和对电极30(参见图2)。在一些示例中，工作电极10可以与工作电极10形成回路。由此植入部分2能够感测分析物浓度。
在一些示例中，植入部分2还可以包括参比电极20。在一些示 例中，植入部分2还可以包括与工作电极10经由引线连接的触点40(参见图2)。由此，植入部分2能够经由触点40向外传输响应信号。
在一些示例中，工作电极10、参比电极20和对电极30可以设置在衬底S上(参见图2)。
图3是示出了本公开的实施方式所涉及的植入部分2的工作电极10的结构示意图。
在一些示例中，如上所述，植入部分2可以包括工作电极10(参见图2)。在一些示例中，工作电极10可以具备基底层110、纳米颗粒层120、分析物酶传感层130、半透膜140和生物相容膜150。基底层110、纳米颗粒层120、分析物酶传感层130、半透膜140和生物相容膜150可以依次层叠(参见图3)。
在一些示例中，基底层110可以导电。在一些示例中，基底层110可以由选自金、玻璃碳、石墨、银、氯化银、钯、钛、铱中的至少一种制成。在这种情况下，基底层110具有良好的导电性，而且能够抑制基底层110发生电化学反应，由此能够提高基底层110的稳定性。
在一些示例中，基底层110可以通过沉积或镀覆方法设置在衬底S上。在一些示例中，沉积的方法可以包括物理气相沉积、化学气相沉积等。镀覆的方法可以包括电镀、化学镀、真空镀等。另外，在一些示例中，基底层110还可以由丝网印刷、挤出或电解沉积等方式设置在衬底S上。
在一些示例中，基底层110上可以设置有分析物酶传感层130。
在一些示例中，通过改变植入部分2上的分析物酶传感层130，可以获取多种分析物的浓度。例如，在一些示例中，分析物可以为乙酰胆碱、淀粉酶、胆红素、胆固醇、绒毛膜促性腺激素、肌酸激酶、肌酸、肌酸酐、DNA、果糖胺、葡萄糖、谷氨酰胺、生长激素、激素、酮体、乳酸盐、过氧化物、前列腺特异性抗原、凝血酶原、RNA、促甲状腺激素和肌钙蛋白中的一种或多种。在另一些示例中，通过改变植入部分2上的分析物酶传感层130，还可以监测体液中药物的浓度，例如抗生素(庆大霉素、万古霉素等)、洋地黄毒苷、地高辛、 茶碱、和华法林(warfarin)等。
在一些示例中，基底层110上可以设置有纳米颗粒层120。也即，在基底层110与分析物酶传感层130之间，可以设置有纳米颗粒层120。在这种情况下，纳米颗粒能够进一步催化分析物反应，降低分析物反应所需的工作电压并提高反应速率。
具体而言，以GO X(FAD)作为葡萄糖氧化酶为例，在分析物传感层130中，当GO X(FAD)遇到组织里的葡萄糖时，会发生如下反应：
葡萄糖+GOx(FAD)→葡萄糖内酯+GOx(FADH 2)……反应式(I)
GOx(FADH 2)+O 2→GOx(FAD)+H 2O 2……反应式(II)
在上述反应过程中，反应式(II)中会有H 2O 2的产生，H 2O 2的集聚会使分析物酶传感层130中的酶活下降。
纳米颗粒层120可以作为催化剂使H 2O 2发生分解反应，具体反应如下：
H 2O 2→2H ++O 2+2e -……反应式(III)
通过上述反应式(I)至反应式(III)，能够使植入部分2与葡萄糖的反应持续进行。另外，通过纳米颗粒层120催化双氧水分解，能够降低反应过程中所需要施加的电压，从而有利于提高植入部分2的灵敏度、延长分析物传感器1的使用时间，并获得低工作电压。换言之，通过纳米颗粒层120，能够持续地获得组织葡萄糖的高灵敏度感测信号，延长分析物传感器1的使用时间，同时低工作电压有利于提升抗干扰性能。
在一些示例中，纳米颗粒层120可以呈多孔状。在这种情况下，分析物酶传感层130中的分析物酶可以渗入纳米颗粒层120。由此，纳米颗粒层120能够充分接触和催化分析物反应，从而能够更加有效地促进分析物发生反应。
在一些示例中，分析物酶还可以设置在导电聚合物纳米纤维三维网络中，也即，纳米纤维三维网络设置在纳米颗粒层120与分析物酶传感层130之间。由此，增加了分析物酶在纳米颗粒层120上的附着性，提高了分析物酶的固定量。
在一些示例中，分析物酶还可以设置在碳纳米管上，其中，碳纳 米管设置在纳米颗粒层120上。由此，增加了分析物酶在纳米颗粒层120上的附着性与固定量。
在一些示例中，半透膜140可以分布在分析物酶传感层130上。在一些示例中，半透膜140还可以包括扩散控制层和层叠在扩散控制层上的抗干扰层。
在一些示例中，扩散控制层可以设置在抗干扰层外。在半透膜140中，扩散控制层可以控制分析物分子的扩散，抗干扰层可以阻止非分析物物质的扩散。由此，可以先减少通过半透膜140的组织液或血液成分，再通过抗干扰层将干扰物阻挡在半透膜140外。常见的干扰物可以包括体内普遍存在的尿酸、抗坏血酸、醋氨酚等。在另一些示例中，还可以将抗干扰层设置在扩散控制层外。由此，同样可以降低因杂质对工作电极10的干扰导致的感测结果不准确，并延长植入部分2的使用寿命。
在一些示例中，半透膜140可以控制分析物分子的通过率，即半透膜140可以限制组织液或血液中到达分析物酶传感层130的分析物分子的数量。具体而言，半透膜140的扩散控制层可以有效地将扩散至分析物酶传感层130的分析物的数量按一定比例的缩小。
在一些示例中，生物相容膜150可以设置在半透膜140上。在一些示例中，生物相容膜150可以由植物材料制成。植物材料可以是海藻酸钠、西黄蓍胶、果胶、阿拉伯胶、黄原胶、瓜耳胶、琼脂或淀粉衍生物、纤维素衍生物等天然材料衍生物。在另一些示例中，生物相容膜150还可以由人工合成材料制成。人工合成材料可以是聚烯烃类。由此，能够降低人体对植入部分2的免疫反应，延长了植入部分2的使用寿命。
另外，在一些示例中，半透膜140还可以具有生物相容性。由此，能够避免使用生物相容膜150，降低了制作成本。
在一些示例中，在工作电极10的基底层110上设置一层用于促进分析物酶催化分析物反应的纳米颗粒层120后在此基础上形成分析物酶传感层130，再在分析物酶传感层130上形成半透膜140涂层，最后在半透膜140涂层上形成生物相容膜150层(参见图3)。由此， 在延长了植入部分2的使用寿命，降低了其他因素干扰的同时，还提高了植入部分2对于分析物的响应速度。
在一些示例中，如上所述，植入部分2可以包括对电极30(参见图2)。在一些示例中，对电极30可以由铂、银、氯化银、钯、钛或铱制成。由此，可以在具有良好导电性的情况下不影响工作电极10处的电化学反应。但本实施方式不限于此，在另一些示例中，对电极30还可以由选自金、玻璃碳、石墨、银、氯化银、钯、钛或铱中的至少一种制成。由此，可以在具有良好导电性的情况下降低对工作电极10的影响。
在一些示例中，本实施方式所涉及的植入部分2可以实现持续监测，因此能够实现长时间(例如1天至24天)持续监测人体分析物浓度值的目的。
在一些示例中，如上所述，分析物传感器1还包括敷贴部分3(参见图1和图2)。
在一些示例中，敷贴部分3可以具有外壳31(参见图1)。在一些示例中，敷贴部分3具有的温度传感器4可以位于外壳31内(参见图1)。
在一些示例中，温度传感器4可以设置在外壳31靠近体表的内壁面上(参见图1)。在另一些示例中，温度传感器4可以设置在外壳31的任意壁面上。
在一些示例中，敷贴部分3的温度传感器4的数量可以为一个。在另一些示例中，敷贴部分3的温度传感器4的数量可以为多个，由此能够提高体表温度感测的准确度，从而提高基于体表温度获得的皮下温度的准确度。
在一些示例中，敷贴部分3可以与植入部分2连接。在一些示例中，植入部分2位于体表的部分可以通过触点40与敷贴部分3电性连接(参见图2)。由此，植入部分2产生的电流信号能够通过基底层110和传输导线经由触点40传输至敷贴部分3。
在一些示例中，敷贴部分3可以由柔性PCB和柔性电池制成。由此，能够紧贴皮肤，降低对用户日常生活的影响。
在一些示例中，如上所述，分析物传感器1还包括处理模块(未图示)。
在一些示例中，处理模块可以安装在敷贴部分3。由此，植入部分2产生的电流信号能够经过触点40输送至处理模块中进行分析，温度传感器4输出的体表温度能够输送至处理模块中进行分析。
在一些示例中，处理模块可以存储有皮下温度与体表温度之间的第一映射关系。在一些示例中，如上所述，体表温度可以由温度传感器4所获得。在一些示例中，处理模块可以存储有植入部分2的灵敏信息。在一些示例中，处理模块可以存储有植入部分2输出的响应信号与分析物浓度变化的第二映射关系。具体而言，第二映射关系可以为在预定温度下植入部分2输出的响应信号与分析物浓度变化的第二映射关系。
在一些示例中，如上所述，处理模块可以存储有皮下温度与温度传感器4所获得的体表温度之间的第一映射关系。
图4是示出了本公开的实施方式所涉及的皮下温度与温度传感器4所获得的体表温度之间的第一映射关系图。
在一些示例中，可以分别将具有同一工艺参数的三个温度传感器4分别置于外界环境中、模拟活体的体表、模拟活体的皮下约10mm处。在一些示例中，改变外界环境的温度，三个温度传感器4可以设置为每隔1分钟输出相应的感测温度。通过三个温度传感器4分别输出的外界环境的温度、体表温度和皮下温度，能够得到体表温度和皮下温度的第一映射关系(参见图4)。
其中，同一工艺参数的温度传感器4可以是指在生产时同一批次出厂的温度传感器4，通常可以是同一批次产品在相同的工艺下制备的温度传感器4。由此能够降低不同温度传感器4之间测量的系统误差。
在一些示例中，如上所述，处理模块可以存储植入部分2的灵敏信息。
在一些示例中，灵敏信息可以为植入部分2的灵敏度与温度的关系。具体而言，在一些示例中，植入部分2的灵敏度可以为植入部分 2在参考温度下的灵敏度的变化值。
在一些示例中，植入部分2的灵敏度的变化值可以由在参考温度下植入部分2的响应电流与温度的关系获得。
图5A是示出了本公开的实施方式所涉及的植入部分2的响应电流与温度的线性回归模拟结果图；图5B是示出了与图5A中线性回归模拟结果图对应的表格。
在一些示例中，分析物传感器1可以感测葡萄糖的浓度。将分析物传感器1的植入部分2置于葡萄糖溶液中。在一些示例中，葡萄糖溶液的浓度可以为5mmol/L至25mmol/L。在一些示例中，改变葡萄糖溶液的温度，获得当葡萄糖溶液的温度为30℃、34℃、37℃以及40℃时，植入部分2输出的响应信号(参见图5B)。在一些示例中，响应信号可以为响应电流(参见图5B)。在另一些示例中，响应信号可以为响应电压。
在一些示例中，对响应电流和温度的关系进行分析，响应电流与温度可以为线性相关(参见图5A)。在另一些示例中，对响应电流和温度的关系进行分析，响应电流与温度可以为非线性相关。
在一些示例中，植入部分2在参考温度下的灵敏度的变化值可以为线性模拟结果的线性回归方程的斜率(k值)与响应信号的比值(结合参见图5A和图5B)。例如，结合图5A和图5B，当选取30℃作为参考温度时，植入部分2在30℃的灵敏度的变化值可以为12.59％(0.428/3.40)；当选取34℃作为参考温度时，植入部分2在34℃的灵敏度的变化值为8.82％(0.428/4.85)；当选取37℃作为参考温度时，植入部分2在37℃的灵敏度的变化值为6.95％(0.428/6.16)；当选取40℃作为参考温度时，植入部分2在40℃的灵敏度的变化值为5.56％(0.428/7.70)。
在一些示例中，植入部分2在参考温度下的灵敏度的变化值可以为同一植入部分2多次重复测量的结果的平均值。在另一些示例中，植入部分2在参考温度下的灵敏度的变化值可以为多个植入部分2测量结果的平均值。在上述两种情况下，通过平均值的计算能够降低系统误差，提高计算结果的准确度，由此能够有利于提高获得的分析物 浓度的准确度。
在一些示例中，如上所述，处理模块可以存储在预定温度下植入部分2的响应信号随分析物浓度变化的第二映射关系。
在一些示例中，预定温度包括多个温度值。例如，在一些示例中，预定温度包括34℃、35℃、36℃、36.5℃、37℃、37.5℃、38℃、39℃、40℃和41℃。在一些示例中，参考温度可以选自多个温度值中的一个。例如，在一些示例中，参考温度可以为34℃、35℃、36℃、36.5℃、37℃、37.5℃、38℃、39℃、40℃或41℃。
图6是示出了本公开的实施方式所涉及的响应电流与分析物浓度的第二映射关系图。
在一些示例中，分析物传感器1可以感测葡萄糖的浓度。选取37℃作为参考温度。将分析物传感器1的植入部分2分别置入不同浓度的葡萄糖溶液中。在一些示例中，葡萄糖溶液的浓度可以为0至25mmol(参见图6)。植入部分2感测不同浓度的葡萄糖溶液并输出相应的响应信号。在一些示例中，响应信号可以为响应电流(参见图6)。在另一些示例中，响应信号可以为响应电压。
在一些示例中，对响应电流和分析物浓度的关系进行分析，响应电流与葡萄糖浓度可以为线性相关(参见图6)，也即第二映射关系为线性关系。在另一些示例中，对响应电流和分析物浓度的关系进行分析，响应电流与分析物浓度可以为非线性相关，也即第二映射关系为非线性关系。
在一些示例中，处理模块配置为可以获得皮下温度。例如，处理模块配置为可以基于体表温度和第一映射关系获得皮下温度。在一些示例中，处理模块配置为可以选取参考温度。在一些示例中，处理模块配置为可以获得校准信息。例如，处理模块配置为可以基于灵敏信息、皮下温度和参考温度获得校准信息。在一些示例中，处理模块配置为可以对响应信号进行校准。例如，处理模块配置为可以基于校准信息对由植入部分2获得的响应信号进行校准。在一些示例中，处理模块配置为可以获得分析物浓度。例如，处理模块配置为可以基于参考温度、校准后的响应信号、以及第二映射关系获得分析物浓度。
在一些示例中，如上所述，处理模块配置为可以基于体表温度和第一映射关系获得皮下温度。具体而言，温度传感器4可以将感测的体表温度输送至处理模块中，处理模块根据预设在处理模块的第一映射关系，基于体表温度和第一映射关系获得皮下温度。
在一些示例中，如上所述，处理模块配置为可以选取参考温度。在一些示例中，处理模块配置选取的参考温度可以为37℃。在这种情况下，参考温度比较接近人体的平均体温，由此能够提高在考虑温度补偿的情况下对分析物浓度进行校准的效果。在另一些示例中，参考温度也可以为其他温度。例如参考温度可以为35℃、36℃、36.5℃、37.5℃或者38℃等。
在一些示例中，如上所述，处理模块配置为可以基于灵敏信息、皮下温度和参考温度获得校准信息。具体而言，在一些示例中，处理模块配置为可以计算参考温度与皮下温度的差值，再计算差值与植入部分2在37℃下灵敏度的变化值的乘积，从而获得校准信息。
在一些示例中，如上所述，处理模块配置为可以基于校准信息对由植入部分2获得的响应信号进行校准。具体而言，在一些示例中，植入部分2产生的响应信号能够经过触点40输送至处理模块中，处理模块配置为可以对校准信息和响应信号进行数学计算，以对由植入部分2获得的响应信号进行校准。
在一些示例中，对由植入部分2获得的响应信号的校准公式可以为：b＝a(1+ΔT×Z)。其中，ΔT表示为参考温度与皮下温度的差值，Z表示为植入部分2在参考温度下的灵敏度的变化值，a表示为植入部分2向处理模块输出的响应信号，b表示为校准后的响应信号。
在一些示例中，如上所述，处理模块配置为可以基于参考温度、校准后的响应信号、以及第二映射关系获得分析物浓度。具体而言，在一些示例中，处理模块配置为可以通过处理模块预设的参考温度下的第二映射关系、以及校准后的响应信号，计算出校准后的分析物浓度。
在一些示例中，温度传感器4和植入部分2(尤其在空腹和饭后的一段时间)可以间隔时间向处理模块传输信号，处理模块可以间隔 时间向外输出校准后的分析物浓度，以使用户可以及时得知分析物浓度的变化趋势，从而对分析物浓度的变化进行把控。
在一些示例中，处理模块获得的分析物浓度信号可以通过无线通信方式例如蓝牙、wifi等发射出去。外部的读取设备，例如手机、电脑(未图示)可以接收处理模块发出的分析物浓度信号，并且显示分析物的浓度。
在本公开所涉及的分析物传感器1中，将植入部分2置于皮下并将具有温度传感器4的敷贴部分3置于体表，由温度传感器4获得体表温度，并基于体表温度获得皮下温度。处理模块配置为：基于体表温度和第一映射关系获得皮下温度，选取参考温度，基于灵敏信息、皮下温度和参考温度获得校准信息，基于校准信息对由植入部分2获得的响应信号进行校准，并且基于参考温度、校准后的响应信号、以及第二映射关系获得分析物浓度。由此能够获得在考虑了温度补偿情况下的分析物浓度，提高了分析物传感器1对分析物浓度感测的精准度。
以下，结合上述描述的分析物传感器1，对本公开涉及的一种在考虑温度补偿的情况下获得分析物浓度的方法进行介绍。
本实施方式所涉及的在考虑温度补偿的情况下获得分析物浓度的方法，还可以称为分析物浓度的校准方法、温度补偿校准分析物浓度的方法、分析物浓度的温度补偿校准方法等。需要说明的是，各名称是为表示本实施方式所涉及的在考虑温度补偿的情况下，能够提高获得的分析物浓度的精准度的方法，并且不应当理解为限定性的。
图7是示出了本公开的实施方式所涉及的在考虑温度补偿的情况下获得分析物浓度的方法的流程图。
结合图7，本公开所涉及的在考虑温度补偿的情况下获得分析物浓度的方法可以包括：在佩戴分析物传感器1之前，获得植入部分2的灵敏信息(步骤S100)；获得体表温度，基于体表温度获得皮下温度(步骤S200)；选取参考温度(步骤S300)；获得校准信息，基于校准信息对响应信号进行校准(步骤S400)；基于参考温度、以及校准后的响应信号获得分析物浓度(步骤S500)。
在步骤S100中，如上所述，可以在佩戴分析物传感器1之前，获得植入部分2的灵敏信息。在一些示例中，可以在佩戴分析物传感器1之前，在预定分析物浓度的情况下获得植入部分2的灵敏信息。
在一些示例中，在步骤S100中，预定分析物浓度可以为已知且相同的分析物浓度。在一些示例中，可以将植入部分2置入分析物中，通过植入部分2感测分析物浓度输出的响应信号，以获得植入部分2的灵敏信息。
在一些示例中，在步骤S100中，灵敏信息可以为植入部分2的灵敏度与温度的关系。
在一些示例中，在步骤S100中，植入部分2的灵敏度可以随着温度的上升而上升。具体而言，在一些示例中，在预定的温度范围内，植入部分2的灵敏度可以随着温度的上升而上升。其中，在一些示例中，植入部分2的灵敏度与温度可以为线性相关。在另一些示例中，植入部分2的灵敏度与温度也可以为非线性相关。
在另一些示例中，在步骤S100中，植入部分2的灵敏度可以随着温度的上升而下降。具体而言，在一些示例中，在步骤S100中，在预定的温度范围内，植入部分2的灵敏度可以随着温度的上升而下降。其中，在一些示例中，植入部分2的灵敏度与温度可以为线性相关。在另一些示例中，植入部分2的灵敏度与温度也可以为非线性相关。
在一些示例中，如前文所述，灵敏信息可以为植入部分2在参考温度下的灵敏度的变化值。例如，在一些示例中，如前文所述，灵敏信息可以为植入部分2在37℃的灵敏度的变化值，即6.95％。
在一些示例中，在步骤S100中，植入部分2可以被置于包含分析物的试剂中，通过改变试剂的温度并测量植入部分2的灵敏度随试剂温度的变化，以获得植入部分2的灵敏信息。也即，通过改变试剂的温度来改变植入部分2所处环境(位置)的温度，来获得植入部分2的灵敏度与植入部分2所处环境(位置)的温度的关系。在这种情况下，在佩戴分析物传感器1之前，通过使用包含有分析物的试剂来测量植入部分2的灵敏度随温度的变化关系，由此能够方便地预先获 得植入部分2的灵敏信息。
在一些示例中，在步骤S100中，当改变试剂的温度时保持试剂中分析物的浓度不变。在这种情况下，当试剂的温度发生改变时，温度的变化不会影响分析物浓度的变化，由此能够提高对植入部分2灵敏度感测的精确性。
在步骤S200中，如上所述，获得体表温度，并基于体表温度获得皮下温度。具体而言，在一些示例中，在步骤S200中，可以将植入部分2置于皮下并将敷贴部分3置于体表，通过温度传感器4获得体表温度，并基于体表温度获得皮下温度。
在一些示例中，在步骤S200中，当将敷贴部分3置于体表时，敷贴部分3具有的温度传感器4即被置于体表。由此，温度传感器4能够感测体表的温度并输出体表温度。
在一些示例中，在步骤S200中，如前文所述，体表温度与皮下温度之间可以具有第一映射关系。当获得体表温度时，可以通过第一映射关系来获得皮下温度。
在一些示例中，在步骤S200中，可以在不同的环境温度下，同时感测模拟活体的体表温度与皮下温度，从而得到体表温度与皮下温度的第一映射关系。
在一些示例中，在步骤S200中，体表温度和皮下温度受到环境温度和体内温度的共同影响。体表温度受到环境温度的影响大于皮下温度受到环境温度的影响，体表温度受到体内温度的影响小于皮下温度受到体内温度的影响；因此，体表温度与皮下温度之间可以为非线性相关。也即第一映射关系可以为非线性映射关系。
在一些示例中，在步骤S200中，植入部分2可以置于皮下3mm至20mm处。可以理解地，皮下3mm与皮下20mm之间的距离微小，温度大致相等，不会导致植入部分2输出的响应信号具有统计学上的差异。
在步骤S300中，如上所述，可以选取参考温度。
在一些示例中，在步骤S300中，可以选取37℃作为参考温度。在这种情况下，参考温度比较接近人体的平均体温，由此能够提高通 过温度补偿校准分析物浓度的效果。在另一些示例中，参考温度也可以为其他温度。例如参考温度可以为35℃、36℃、36.5℃、37.5℃或者38℃等。
在步骤S400中，如上所述，可以基于灵敏信息、参考温度和皮下温度获得校准信息，并基于校准信息对由植入部分2获得的响应信号进行校准。
在一些示例中，在步骤S400中，灵敏信息可以为如上所述的植入部分2的灵敏度与温度变化的关系。在一些示例中，具体而言，灵敏信息可以为植入部分2在参考温度下的灵敏度。进一步地，灵敏信息可以为植入部分2在参考温度下的灵敏度的变化值。
在一些示例中，在步骤S400中，校准信息可以基于皮下温度与参考温度的差值、以及灵敏信息而获得。在这种情况下，通过考虑植入部分2的灵敏度与温度之间的关系、以及植入部分2所处的皮下温度与参考温度之间的关系，由此能够有利于进行温度补偿。
具体地，在一些示例中，校准信息可以为参考温度与皮下温度的差值，再与植入部分2在参考温度下的灵敏度的乘积。进一步地，校准信息可以为参考温度与皮下温度的差值，再与植入部分2在参考温度下的灵敏度的变化值的乘积。
在另一些示例中，在步骤S400中，校准信息可以基于灵敏信息、以及皮下温度与参考温度的比值而获得。具体地，在一些示例中，校准信息可以为参考温度与皮下温度的比值，再与植入部分2在参考温度下的灵敏度的乘积。进一步地，校准信息可以为参考温度与皮下温度的比值，再与植入部分2在参考温度下的灵敏度的变化值的乘积。
在一些示例中，在步骤S400中，校准后的响应信号可以为校准前的响应信号与校准信息的乘积，再加上校准前的响应信号。也即，校准后的响应信号可以为校准信息加一后，再与校准前的响应信号的乘积。
在另一些示例中，在步骤S400中，校准后的响应信号可以为校准前的响应信号与校准信息的商。在又一些示例中，在步骤S400中，校准后的响应信号可以为校准前的响应信号与校准信息的和/差。
在一些示例中，在步骤S400中，当温度传感器4感测体表的温度输出体表温度时，插入皮下的植入部分2可以同时感测皮下的分析物浓度输出响应信号。在这种情况下，能够同时获得皮下温度也即植入部分2所处位置的温度、以及植入部分2感测分析物浓度输出的响应信号，由此能够实时地对植入部分2的响应信号进行温度补偿，从而能够提高分析物浓度校准的精确度。
在一些示例中，在步骤S400中，植入部分2输出响应信号与温度传感器4输出体表温度之间无时间延迟。这种情况下，基于体表温度获得皮下温度(也即植入部分2所处位置的温度)，并能够无时间延迟地获得在此时皮下温度下的植入部分2输出的响应信号，由此能够进一步提高分析物浓度校准的精确性。
在步骤S500中，如上所述，可以基于参考温度、以及校准后的响应信号获得分析物浓度。
在一些示例中，在步骤S500中，可以在参考温度下获得植入部分2的响应信号与分析物浓度的关系。在一些示例中，在参考温度下，植入部分2的响应信号与分析物的浓度之间可以具有第二映射关系。
在一些示例中，在步骤S500中，植入部分2的响应信号与分析物浓度可以为线性相关。也即，第二映射关系可以为线性映射关系。在另一些示例中，植入部分2的响应信号与分析物浓度可以为非线性相关。也即，第二映射关系可以为非线性映射关系。
在一些示例中，在步骤S500中，在参考温度下，将植入部分2分别放置于不同浓度的分析物溶液中，并测量植入部分2输出的响应信号，以获得植入部分2的响应信号与分析物浓度的第二映射关系。
在一些示例中，在步骤S500中，用于检测获得第二映射关系的分析物的最大浓度低于植入部分2的最大感测浓度。在一些示例中，用于检测获得第二映射关系的分析物的浓度梯度递增。在一些示例中，用于检测获得第二映射关系的分析物的浓度接近皮下分析物的浓度。在这种情况下，分析物的浓度接近可以使得检测的系统误差比较小，由此能够提高检测的精准度。
在一些示例中，在步骤S500中，可以基于在参考温度下植入部 分2的响应信号与分析物浓度变化的关系、以及校准后的响应信号获得校准后的分析物浓度。也即，可以通过第二映射关系和步骤S400校准后的植入部分2的响应信号，以获得校准后的分析物浓度。
在本公开所涉及的方法中，在佩戴分析物传感器1之前，在预定分析物浓度的情况下获得植入部分2的灵敏信息，即获得植入部分2的灵敏度与温度变化的关系。将植入部分2置于皮下并将具有温度传感器4的敷贴部分3置于体表，由温度传感器4获得体表温度，并基于体表温度获得皮下温度。选取参考温度，基于灵敏信息、参考温度和皮下温度获得校准信息，并基于校准信息对由植入部分2获得的响应信号进行校准，由此能够获得校准后的响应信号。基于参考温度、以及校准后的响应信号，对分析物浓度进行校准，由此能够提高获得的分析物浓度的精准度。
虽然以上结合附图和实施例对本公开进行了具体说明，但是可以理解，上述说明不以任何形式限制本公开。本领域技术人员在不偏离本公开的实质精神和范围的情况下可以根据需要对本公开进行变形和变化，这些变形和变化均落入本公开的范围内。

Claims (10)

  1. 一种在考虑温度补偿的情况下获得分析物浓度的方法，所述分析物浓度通过分析物传感器获得，所述分析物传感器包括可置于皮下的植入部分、以及可置于体表且具有温度传感器的敷贴部分，其特征在于，所述方法包括：在佩戴所述分析物传感器之前，在预定分析物浓度的情况下获得所述植入部分的灵敏信息，所述灵敏信息为所述植入部分的灵敏度与温度的关系；将所述植入部分置于皮下并将所述敷贴部分置于体表，通过所述温度传感器获得体表温度，并基于所述体表温度获得皮下温度；选取参考温度；基于所述灵敏信息、所述参考温度和所述皮下温度获得校准信息，并基于所述校准信息对由所述植入部分获得的响应信号进行校准；并且基于所述参考温度、以及校准后的响应信号获得所述分析物浓度。
  2. 如权利要求1所述的方法，其特征在于，
    将所述植入部分置于包含所述分析物的试剂中，改变所述试剂的温度并测量所述植入部分的灵敏度随所述试剂的温度的变化，以获得所述植入部分的灵敏信息。
  3. 如权利要求2所述的方法，其特征在于，
    当改变所述试剂的温度时保持所述试剂中分析物的浓度不变。
  4. 如权利要求1所述的方法，其特征在于，
    所述校准信息基于所述灵敏信息、以及所述皮下温度与所述参考温度的差值或比值而获得。
  5. 如权利要求1所述的方法，其特征在于，
    当所述温度传感器在体表感测温度并输出所述体表温度时，插入皮下的所述植入部分同时感测皮下的分析物浓度并输出响应信号。
  6. 如权利要求5所述的方法，其特征在于，
    所述植入部分输出所述响应信号与所述温度传感器输出所述体表温度之间无时间延迟。
  7. 如权利要求1所述的方法，其特征在于，
    所述分析物为乙酰胆碱、淀粉酶、胆红素、胆固醇、绒毛膜促性腺激素、肌酸激酶、肌酸、肌酸酐、DNA、果糖胺、葡萄糖、谷氨酰胺、生长激素、激素、酮体、乳酸盐、过氧化物、前列腺特异性抗原、凝血酶原、RNA、促甲状腺激素和肌钙蛋白中的一种或多种。
  8. 如权利要求1所述的方法，其特征在于，
    基于在所述参考温度下所述植入部分的响应信号与分析物浓度变化的关系、以及校准后的响应信号获得校准后的分析物浓度。
  9. 一种在考虑温度补偿的情况下获得分析物浓度的分析物传感器，其特征在于，所述分析物传感器包括可置于皮下的植入部分、可置于体表且具有温度传感器的敷贴部分、以及处理模块，所述处理模块存储有皮下温度与由所述温度传感器所获得的体表温度之间的第一映射关系、所述植入部分的灵敏信息、以及在预定温度下所述植入部分输出的响应信号与分析物浓度变化的第二映射关系，其中，所述灵敏信息为在预定分析物浓度的情况下所述植入部分的灵敏度与温度变化的关系；当将所述植入部分置于皮下并将所述敷贴部分置于体表时，所述温度传感器感测体表的温度并输出体表温度；所述处理模块配置为：基于所述体表温度和所述第一映射关系获得皮下温度，选取参考温度，基于所述灵敏信息、所述皮下温度和所述参考温度获得校准信息，基于所述校准信息对由所述植入部分获得的响应信号进行校准，并且基于所述参考温度、校准后的所述响应信号、以及所述第二映射关系获得所述分析物浓度。
  10. 如权利要求9所述的分析物传感器，其特征在于，
    所述植入部分包括能够与分析物发生反应的工作电极、以及与所述工作电极形成回路的对电极。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004439A1 (en) * 2000-02-23 2005-01-06 Medtronic Minimed, Inc. Real time self-adjusting calibration algorithm
WO2006079797A2 (en) * 2005-01-28 2006-08-03 Melys Diagnostics Limited Apparatus for measurement of analyte concentration
CN101374455A (zh) * 2006-02-27 2009-02-25 拜尔健康护理有限责任公司 用于生物传感器系统的温度调节的分析物测定
CN108209936A (zh) * 2017-12-25 2018-06-29 重庆大学 一种皮下植入式血糖仪的自适应校准算法
CN111629660A (zh) * 2018-01-23 2020-09-04 德克斯康公司 补偿温度对传感器的影响的系统、设备和方法
CN112432988A (zh) * 2020-11-25 2021-03-02 重庆迈联医疗科技有限公司 电化学测试系统的温度校正方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004439A1 (en) * 2000-02-23 2005-01-06 Medtronic Minimed, Inc. Real time self-adjusting calibration algorithm
WO2006079797A2 (en) * 2005-01-28 2006-08-03 Melys Diagnostics Limited Apparatus for measurement of analyte concentration
CN101374455A (zh) * 2006-02-27 2009-02-25 拜尔健康护理有限责任公司 用于生物传感器系统的温度调节的分析物测定
CN108209936A (zh) * 2017-12-25 2018-06-29 重庆大学 一种皮下植入式血糖仪的自适应校准算法
CN111629660A (zh) * 2018-01-23 2020-09-04 德克斯康公司 补偿温度对传感器的影响的系统、设备和方法
CN112432988A (zh) * 2020-11-25 2021-03-02 重庆迈联医疗科技有限公司 电化学测试系统的温度校正方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Research on Real-time Self-adjusting Calibration Algorithm of Glucose Sensor", DEEP SPACE DATABASE, 1 January 2016 (2016-01-01), XP093057363, Retrieved from the Internet <URL:https://www.dgxue.com/skts/zlk/1710.html> [retrieved on 20230623] *

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