CN111982987A - Glucose sensor and measurement correction method - Google Patents

Abstract

The invention discloses a glucose sensor, comprising: a substrate layer, an electrode layer; the electrode layer is arranged on the substrate layer, and a first time detection electrode, a working electrode, a counter electrode and a sample introduction detection electrode are arranged on the electrode layer; the counter electrode is arranged between the working electrode and the sample introduction detection electrode. The invention also discloses a glucose measuring method. The invention also discloses a glucose measurement and correction method, which comprises the steps of converting the hematocrit of a blood sample according to the time difference delta t between two times of recording time according to the time when the blood fills the whole sample feeding channel and the measured current, correcting and compensating the glucose current value through the hematocrit and the environmental temperature measured by the temperature sensor, and finally converting and displaying the glucose value. The cost of the instrument and the test paper is greatly saved; and has better test accuracy in a wider range of hematocrit ratios.

Description

A kind of glucose sensor and measurement calibration method

technical field

The invention belongs to a blood glucose measuring device, and in particular relates to a glucose sensor and a measurement and calibration method.

Background technique

At present, there are two commonly used technical solutions to solve the influence of hematocrit ratio (hereinafter referred to as HCT) on the test results on the market: 1) Relying on the adjustment and optimization of the formula itself, adjust and optimize the hemolytic agent and electronic mediator in the formula. Type and dosage to minimize the impact of HCT on test results. The advantage of this scheme is that the cost is low, but the disadvantage is that it needs to try a lot of different hemolytic agents and electronic mediators. The research and development cost is high, and the effect is often poor. The application range of HCT is small, generally ranging from 30-55% or even smaller;

2) Add an alternating current test impedance module through the test paper to test the impedance of the blood sample, convert the tested impedance value into the corresponding HCT value, and then correct and compensate the final blood sugar test result through a mathematical algorithm. The advantage of this scheme is that the measured HCT has a high accuracy and a wide range. Generally, 10-70% or even 0-70% can be tested accurately, but the disadvantage is that the AC test impedance module must be added and The matching electrode structure greatly increases the research and development and production costs of test strips, and greatly increases the difficulty of the production process. This solution is often used in some high-end models. Due to cost issues, there are fewer corresponding models on the market.

SUMMARY OF THE INVENTION

In view of the above technical problems, the present invention provides a glucose sensor and a measurement and calibration method.

In order to achieve the above object, the technical solution adopted in the present invention is: a glucose sensor, comprising: a substrate layer and an electrode layer. The electrode layer is arranged on the substrate layer, and the electrode layer is provided with a first time detection electrode, a working electrode, a counter electrode, and a sample injection detection electrode; the counter electrode is arranged between the first time detection electrode and the working electrode.

Further, the electrode layer is printed on the substrate layer by screen printing; the electrode layer also includes a working electrode, a power button and a wire for connecting the electrode and the instrument.

Further, the glucose sensor also includes an insulating layer, a reagent layer, a hydrophilic separator combination layer and a masking tape layer, the insulating layer covers the electrode layer, and detects the electrode, the counter electrode, the working electrode and the sample injection detection electrode at the first time. There is a blank window on it. The reagent layer covers the blank window provided on the insulating layer, and is cured on the surface of the electrode layer by heating. The hydrophilic separator composite layer is covered on the insulating layer, and the reagent layer is contained in the hydrophilic membrane channel in the middle of the hydrophilic separator composite layer. The masking tape layer covers the insulating layer and the hydrophilic barrier composite layer to protect the glucose sensor.

In another preferred manner, a second time detection electrode is added, and the second time detection electrode is flush with the first time detection electrode. When the blood flows to the first time detection electrode and the second time detection electrode, the time point t ₁ is recorded, The time point t ₂ is recorded when the blood flows to the sampling detection electrode. The distance between the two time recording points is increased, and the gradient of the entire time difference Δt is greatly increased, so that the fitting of the hematocrit ratio is more accurate, and the accuracy of the final reading value is higher.

The distance from the first time detection electrode to the sample injection detection electrode is in the range of 0.5 to 5 mm. If it is too long, there will be many uncertain factors affecting the test results because the blood fills the entire channel for too long. If the time of the channel is too short, the error due to the time detection accuracy is too large, and 2mm is preferred. After the second time detection electrode is added, only the gradient of Δt is adjusted, and the test and correction logic for the entire sensor does not change.

The invention also discloses a glucose measurement and correction method. The hematocrit ratio of the blood sample is calculated according to the time when the blood fills the entire hydrophilic membrane channel, and the calculated hematocrit ratio is used to detect the working electrode and the counter electrode. The current is compensated and corrected by a specific mathematical calculation equation, and finally the corrected glucose value is obtained. This method uses a unique mathematical calculation method to greatly reduce the influence of the hematocrit ratio on the glucose value.

After inserting the glucose sensor into the test instrument, start the test instrument. The blood sample is drawn through the siphon effect. When the blood flows to the counter electrode, the detection electrode is connected to the counter electrode for the first time. The instrument recognizes the electrical signal and records the time t ₁ . When the blood flows to the injection detection electrode, the injection detection electrode Connected with the counter electrode, the instrument recognizes the electrical signal, records the time t ₂ , and the instrument determines that the blood fills the entire injection channel; due to the difference in the content of red blood cells in different HCTs, when flowing through the hydrophilic membrane channel, the blood of different HCTs , the t ₁ , t ₂ and Δt detected by the glucose sensor will have large differences (where Δt=t ₂ −t ₁ ). When the HCT is larger, the Δt detected by the glucose sensor is larger, and when the HCT is smaller, the Δt detected by the glucose sensor is smaller. Considering the effect of temperature on Δt, by systematically testing Δt at different temperatures and different HCTs, a set of mathematical equations for fitting HCT by Δt are fitted:

Calculate the temperature correction factor x of Δt, and obtain the temperature compensation factor calculation equation of Δt by fitting the ratio of Δt under different HCTs at different temperatures T to Δt under different HCTs at _room temperature T, namely: when T>T _room , x =j×(TT _room )+1; when T≤T _room , x=i×(TT _room )+1, where i and j are fixed values of parameters fitted by experiments;

The temperature correction factor is used to compensate Δt, and the compensated Δt ₂₃ can be obtained by the formula: Δt ₂₃ =Δt×x. By repeatedly testing the value of Δt ₂₃ under different HCT conditions, the relationship between HCT and Δt ₂₃ is obtained as: HCT=k×ln(Δt ₂₃ )^2+l×ln(Δt ₂₃ )+m, where k, l, m Fixed values for the parameters fitted to the experiment.

Further, a 200-500mV DC voltage is applied between the working electrode and the counter electrode to test the glucose current value i ₀ of the blood sample; due to the characteristics of the glucose sensor, the detected current is greatly affected by the glucose concentration and HCT. The influence of different HCTs on the detection current is quite different at different times, and the glucose concentration gradient and HCT are taken into account in the compensation of the detection current. HCT compensation equation: i ₁ =(i ₀ -o×(HCT-42%))/(1+n×(HCT-42%)), i ₁ is the current value after compensation and correction, n and o are the experimental results The fitted parameter has a fixed value.

Further, due to the difference in the current deviation trend between different HCT segments and 42% conditions, it is also necessary to fit different HCT segments separately to improve the accuracy of the HCT compensation equation. There are different n, o parameters for segmentation.

Further, the final glucose value G can be converted according to the linear relationship equation between the glucose concentration G and the current i ₁ fitted by multiple batches _of experiments. Improve the correlation coefficient of fitting, preferably G=a×i ₁ ^3+b×i ₁ ^2+c×i ₁ +d, where a, b, c, and d are fitted through multiple batches of experiments Parameter fixed value.

The present invention has the following beneficial effects: the present invention converts the hematocrit ratio of the blood by measuring the time that the blood passes through the entire sampling channel, and makes full use of the time when the blood enters the entire channel. The alternating current module only needs to detect the time of blood flowing through the entire channel while testing the glucose current with direct current, which greatly saves the cost of instruments and test strips; the refined HCT judgment and the targeted correction and compensation logic under different temperature and HCT conditions are used. Mathematically calculated, it will give better test accuracy over a wider range of hematocrit ratios than by formulation optimization. According to the different effects of different glucose concentrations and different hematocrit ratios on the detected current value, and comprehensively considering the test results under different conditions, the unique compensation logic judgment of hematocrit ratio on the detected current and the corresponding mathematical compensation equation are obtained. . Using the unique decision logic and mathematical compensation equation, the influence of the hematocrit ratio on the glucose value is greatly reduced.

Description of drawings

FIG. 1 is an exploded diagram of a glucose sensor according to an embodiment of the present invention.

FIG. 2 is a schematic diagram of an electrode layer of a glucose sensor according to an embodiment of the present invention.

FIG. 3 is a test result of a glucose sensor with different hematocrit ratios and different glucose values according to an embodiment of the present invention.

FIG. 4 is a schematic diagram of another electrode layer of a glucose sensor according to an embodiment of the present invention.

FIG. 5 is a test result of another glucose sensor with different hematocrit ratios and different glucose values according to an embodiment of the present invention.

Detailed ways

In order to facilitate the understanding of those skilled in the art, the present invention will be further described below with reference to the embodiments and the accompanying drawings.

The first specific embodiment: the structure of the glucose sensor includes: a substrate layer 1, an electrode layer 2, an insulating layer 3, a reagent layer 4, a hydrophilic separator composite layer 5 and a masking tape layer 6, as shown in FIG. 1 . The electrode layer 2 is printed on the substrate layer 1 by screen printing, and the electrode layer 2 is provided with a first time detection electrode 21, a counter electrode 22, a working electrode 23, a sample injection detection electrode 24, a power button 25, and a The wires connected to the instrument are shown in Figure 2. The insulating layer 3 covers the electrode layer 2 , and a blank window 31 is left on the detection electrode 21 , the counter electrode 22 , the working electrode 23 and the sample injection detection electrode 24 at the first time. The reagent layer 4 covers the blank window provided on the insulating layer 3 and is cured on the surface of the electrode layer 2 by heating. The hydrophilic barrier composite layer 5 covers the insulating layer 3 and contains the reagent layer 4 in the middle hydrophilic membrane channel 51 . The masking tape layer 6 covers the insulating layer 3 and the hydrophilic barrier composite layer 5 to protect the glucose sensor. The glucose sensor of this embodiment can be applied to all formula types of glucose test strips.

After inserting the glucose sensor into the test instrument, start the test instrument. The blood sample is drawn through the siphon effect. When the blood flows to the counter electrode 22, the detection electrode 21 is connected to the counter electrode 22 for the first time. The instrument recognizes the electrical signal and records the time t ₁ . When the blood flows to the sample injection detection electrode 24, The sample injection detection electrode 24 is connected to the counter electrode 22, the instrument recognizes the electrical signal, records the time t ₂ , and the instrument determines that the blood fills the entire injection channel and applies a 200-500mV DC voltage between the working electrode 23 and the counter electrode 22 to test The glucose current value i ₀ of the blood sample. According to the time difference Δt (Δt=t ₂ -t ₁ ) of the two recording times, the hematocrit ratio of the blood sample is converted, and the glucose current value is corrected and compensated by the hematocrit ratio and the ambient temperature measured by the temperature sensor, and finally The converted glucose value is displayed.

Due to the difference in the content of red blood cells in different HCTs, when the blood of different HCTs flows through the hydrophilic membrane channel, the t ₁ , t ₂ and Δt detected by the glucose sensor will have great differences (where Δt=t ₂ -t ₁ ). When the HCT is larger, the Δt detected by the glucose sensor is larger, and when the HCT is smaller, the Δt detected by the glucose sensor is smaller. Considering the effect of temperature on Δt, by systematically testing Δt at different temperatures and different HCTs, a set of mathematical equations for fitting HCT by Δt are fitted:

First calculate the temperature correction factor x of Δt, and obtain the temperature compensation factor calculation equation of Δt by fitting the ratio of Δt under different HCT at different temperatures (T) to Δt under different HCT at room temperature of 23°C, namely: when T>23°C , x=j×(T-23)+1; when T≤23℃, x=i×(T-23)+1, where i and j are fixed parameter values fitted by multiple batches of experiments . Then, the temperature correction factor is used to compensate Δt, and the compensated Δt ₂₃ can be obtained by the formula: Δt ₂₃ =Δt×x. By repeatedly testing the value of Δt ₂₃ under different HCT conditions, it can be obtained that there is a linear correlation between HCT and the natural logarithm of Δt ₂₃ , f(HCT, Δt ₂₃ ), that is, HCT=k×ln(Δt ₂₃ )^2+l ×ln(Δt ₂₃ )+m, where k, l, and m are fixed values of parameters fitted by multiple batches of experiments.

Due to the characteristics of the glucose sensor, the detected current is greatly affected by the glucose concentration and HCT, and the effects of different HCTs on the detection current at different concentrations are quite different. The glucose concentration gradient and HCT are taken into account in the compensation of the detection current at the same time. go. It can be known from multiple batches of experiments that with the increase of glucose concentration, the deviation between the current detected under different HCT and the current of 42% HCT will become larger and larger, so it is easy to know that the current under different HCT is different from that of 42% HCT. There is a linear relationship between the slope of the deviation of the current of HCT and the glucose concentration, and two formulas i ₀ =slope×(HCT-42%)+i ₁ are combined; slope=n×i ₁ +o, where n and o are passed through multiple batches The fixed value of the parameters fitted by this experiment, slope is the slope of the linear equation, i ₀ and i ₁ are the currents before and after the correction and compensation, respectively, and the final HCT compensation equation i ₁ =(i ₀ -o×(HCT-42 %))/(1+n×(HCT-42%)). In addition, due to the difference in the current deviation trend between different HCT segments and 42% HCT conditions, it is also necessary to fit different HCT segments separately to improve the accuracy of the HCT compensation equation. There are different n, o parameters for the segment.

The current i ₁ after the final compensation and correction is the most suitable current value under the current glucose concentration and HCT conditions, and then the linear relationship equation between the glucose concentration G and the current i ₁ fitted by multiple batches of experiments can be converted. The final glucose value G, according to the correlation between G and i ₁ , can establish a multivariate equation to improve the fitting correlation coefficient, preferably G=a×i ₁ ^3+b×i ₁ ^2+c×i ₁ +d, where a, b, c, and d are fixed values of parameters fitted by multiple batches of experiments.

The distance from the first time detection electrode to the sample injection detection electrode is in the range of 0.5 to 5 mm. If it is too long, there will be many uncertain factors affecting the test results because the blood fills the entire channel for too long. If the time of the channel is too short, the error due to the time detection accuracy is too large, and 2mm is preferred. After the second time detection electrode is added, only the gradient of Δt is adjusted, and the test and correction logic for the entire sensor does not change.

The above glucose sensor was tested on 6 blood samples with different hematocrit ratios at room temperature, and the injection time Δt was recorded respectively. The test was repeated 10 times for each blood sample, and the average value was obtained. The average value was then fitted with the true hematocrit ratios of 6 blood samples to obtain the fitting equation f(HCT, Δt).

Table 1

The above glucose sensor tested 50 blood samples with different hematocrit ratios and different glucose concentrations at room temperature, and recorded the glucose reading value and the YSI 2300 test value respectively for comparison, as shown in Figure 3. The deviation between the final glucose reading value and the YSI 2300 test result is within ±15%, which meets the requirements of the international standard ISO 15197-2013 for system accuracy.

Second specific embodiment: glucose sensor On the basis of the glucose sensor in the first specific embodiment, the electrode layer 2 is optimized and adjusted, and a second time detection electrode 26 is added, as shown in FIG. 4 , and the time between the two time recording points is increased. The distance greatly increases the gradient of the entire time difference Δt, which makes the fitting of the hematocrit ratio more accurate, and the accuracy of the final reading value is higher. The time point t 1 is recorded when the blood flows to the first time detection electrode 21 and the second time detection electrode 26 , and the time point t ₂ is recorded when the blood flows to the sample injection detection electrode ₂₄ .

The above glucose sensor was tested on 6 blood samples with different hematocrit ratios at room temperature, and the injection time Δt was recorded respectively. The test was repeated 10 times for each blood sample, and the average value was obtained. The average value was then fitted with the true hematocrit ratios of 6 blood samples to obtain the fitting equation f(HCT, Δt).

Table 2

hematocrit ratio 20% 30% 42% 50% 60% 70% Δt1(ms) 80 140 260 350 800 1400 Δt2(ms) 79 142 265 356 810 1430 Δt3(ms) 81 143 262 359 820 1450 Δt4(ms) 82 144 261 360 809 1420 Δt5(ms) 83 142 260 361 821 1430 Δt6(ms) 81 141 266 365 821 1460 Δt7(ms) 78 139 261 359 820 1410 Δt8(ms) 78 142 268 358 805 1400 Δt9(ms) 79 140 260 359 803 1420 Δt10(ms) 80 138 262 358 809 1460 average value 80.1 141.1 262.5 358.5 811.8 1428

The above-mentioned glucose sensor tested 50 blood samples with different hematocrit ratios and different glucose concentrations at room temperature, and recorded the glucose reading value and the YSI 2300 test value respectively for comparison, as shown in Figure 5. The deviation between the final glucose reading value and the YSI 2300 test result is within ±15%, which meets the requirements of the international standard ISO 15197-2013 for system accuracy.

1) The electrode structure of the glucose sensor of the present invention is uniquely designed and arranged. By setting up two groups of electrodes before and after the injection channel, when the blood passes through these two groups of electrodes, an electrical signal will be excited, and the sensor records the time difference between the two electrical signals. Measure the injection time. Due to the difference in viscosity and fluidity of different hematocrit ratios, the time for the flow through the same distance will be proportional to the hematocrit ratio. The larger the hematocrit ratio, the longer the time. The injection time is used to convert the corresponding hematocrit ratio;

2) The glucose sensor of the present invention has a separate test logic design for the electrode structure design of the test paper, which can identify the data obtained from the test and perform systematic correction and compensation on the final glucose test result, thereby improving the test accuracy of the glucose sensor.

The above embodiments are only to illustrate the technical idea of the present invention, and cannot limit the protection scope of the present invention. Any changes made on the basis of the technical solution according to the technical idea proposed by the present invention fall into the protection scope of the present invention. within.

Claims (10)

1. A glucose sensor, characterized by: the method comprises the following steps: a substrate layer, an electrode layer; the electrode layer is arranged on the substrate layer, and a first time detection electrode, a working electrode, a counter electrode and a sample introduction detection electrode are arranged on the electrode layer; the counter electrode is arranged between the working electrode and the sample introduction detection electrode.

2. The glucose sensor of claim 1, wherein: the electrode layer is printed on the substrate layer through screen printing; the electrode layer also comprises a working electrode, a starting key and a lead for connecting the electrode and an instrument.

3. The glucose sensor of claim 1, wherein: the glucose sensor also comprises an insulating layer, a reagent layer, a hydrophilic septal combination layer and a shielding adhesive tape layer, wherein the insulating layer covers the electrode layer, and blank windows are reserved on the first time detection electrode, the counter electrode, the working electrode and the sample injection detection electrode; the reagent layer covers the blank window arranged on the insulating layer and is solidified on the surface of the electrode layer by heating; the hydrophilic septal combination layer covers the insulating layer, and the reagent layer is contained in a hydrophilic membrane channel in the middle of the hydrophilic septal combination layer; the shielding adhesive tape layer covers the insulating layer and the hydrophilic water-separating combination layer to protect the glucose sensor.

4. The glucose sensor according to any one of claims 1 to 3, wherein: the distance between the first time detection electrode and the sample injection detection electrode is within the range of 0.5-5 mm.

5. The glucose sensor according to any one of claims 1 to 3, wherein: adding a second time detection electrode which is flush with the first time detection electrode, and recording the time point t when the blood flows to the first time detection electrode and the second time detection electrode₁Recording the time point t when the blood flows to the sample detection electrode₂。

6. The glucose sensor of claim 4, wherein: the distance between the first time detection electrode and the sample injection detection electrode is within the range of 0.5-5 mm.

7. A method for correcting a glucose measurement, comprising: when blood flows to the counter electrode, the first time detection electrode is communicated with the counter electrode, the instrument identifies an electric signal, and the time t is recorded₁When blood flows to the sample detection electrode, the sample detection electrode is communicated with the counter electrode, the instrument identifies an electric signal, and the time t is recorded₂And the instrument judges that the whole sample feeding channel is filled with the bleeding liquid; passing through t₁、t₂And Δ t, Δ t ═ t₂-t₁Testing the delta t at different temperatures and different HCTs, and fitting a mathematical calculation equation for fitting the HCT through the delta t:

calculating the temperature correction factor x of the delta T by fitting the delta T under different HCTs at different temperatures T to the room temperature T_ChamberObtaining the temperature compensation factor calculation equation of the delta t by the ratio of the delta t under different HCTs, namely: when T is>T_ChamberWhen x is j x (T-T)_Chamber) + 1; when T is less than or equal to T_ChamberWhen x is i × (T-T)_Chamber) +1, wherein i and j are fixed values of parameters fitted by experiments;

compensating for Δ t by using the temperature correction factor, the compensated Δ t₂₃Can be obtained by the formula: Δ t₂₃Δ t × x. By repeated testing of Δ t under different HCT conditions₂₃To obtain HCT and Δ t₂₃The relationship between the two is as follows: HCT ═ k × ln (Δ t)₂₃)^2+l×ln(Δt₂₃) + m, wherein k, l and m are fixed values of parameters fitted by experiments.

8. The method of correcting a glucose measurement according to claim 7, wherein: applying 200-500mV direct current voltage between the working electrode and the counter electrode to test the glucose current value i of the blood sample₀(ii) a Simultaneously taking the glucose concentration gradient and the HCT into account in the compensation of the detection current; HCT compensation equation: i.e. i₁＝(i₀-o×(HCT-42％))/(1+n×(HCT-42％))，i₁The corrected current value is compensated, and n and o are fixed parameter values fitted through experiments.

9. The method of correcting a glucose measurement according to claim 8, wherein: and respectively fitting different HCT segments, wherein different n and o parameters exist in different HCT segments.

10. The method of correcting a glucose measurement according to claim 8, wherein: fitting glucose concentration G and current i according to the experiment₁Linear relationship between G and a x i₁^3+b×i₁^2+c×i₁+ d, where a, b, c, d are fixed values of parameters fitted by multiple batches of experiments, to convert to the final glucose concentration value G.

Images