A method for improving the accuracy of glucose monitoring in counterion electroosmosis technology

Abstract

The present invention provides a method for improving the accuracy of glucose monitoring in counterion electroosmosis technology. A prediction model of subcutaneous glucose concentration is established through theoretical analysis; the electroosmotic mobility of glucose at different pH values is obtained through in vitro experiments, and then the functional relationship between the electroosmotic mobility of glucose and pH is obtained. This functional relationship can be used in the subsequent transdermal extraction and detection process of glucose; the calibration intercept is obtained by measuring the first blood sample; the measured pH and the extracted glucose concentration are substituted into the pH correction model to obtain a more accurate glucose test result, thereby improving the accuracy and reliability of transdermal glucose monitoring.

Description

Technical Field

[0001] The present invention relates to the technical field of continuous blood glucose monitoring, and in particular to a method for improving the accuracy of glucose monitoring in counterion electroosmosis technology. Background Art

[0002] Diabetes is one of the most common chronic diseases globally, usually leading to various tissue damages and dysfunctions, especially having a more significant impact on the eyes, heart, and blood vessels. With the improvement of living standards, the number of diabetes patients is increasing continuously. According to the "Global Diabetes Report" in 2021, this figure will reach 693 million by 2045. Therefore, the management and prevention of diabetes have become particularly important. Currently, the main blood glucose testing methods can be divided into two categories: one is the traditional fingertip blood glucose meter. Although this method can enable diabetes patients to self-manage their blood glucose levels, it has the drawback of ignoring hyperglycemic or hypoglycemic information. In addition, this monitoring method also has the problems of being unable to track blood glucose trends and continuous fluctuations in real time, and frequent finger tests will cause pain and inconvenience to patients. Another emerging continuous blood glucose monitoring method detects the glucose levels in biological microfluids such as sweat, saliva, tears, and interstitial fluid through non-invasive or minimally invasive means. The glucose levels in these biological microfluids are highly correlated with blood glucose levels. Therefore, this method can provide more real-time and accurate glucose level information, thereby improving the compliance of diabetes patients.

[0003] Current continuous blood glucose monitoring systems are mainly based on subcutaneous implanted electrode-based blood glucose biosensors, which mainly detect the glucose levels in subcutaneous interstitial fluid through electrochemical methods to achieve real-time continuous tracking of glucose levels. The feasibility, acceptance, and clinical accuracy of this commercially applied continuous blood glucose monitoring system are getting higher and higher, showing competitive performance in terms of wearability, accuracy, and specificity. However, the continuous blood glucose monitoring system with implanted electrodes is minimally invasive, and its microneedles are prone to breakage during long-term use, which may cause pain, bleeding, and inflammation, resulting in additional risks. Therefore, implanted continuous blood glucose monitoring devices need to be further developed to improve stability and reliability and reduce the discomfort and risks of patients.

[0004] Compared with subcutaneously implanted continuous glucose monitoring devices, transdermal extraction and detection integrated devices, represented by reverse ion osmosis technology, have great potential. This device can extract subcutaneous interstitial fluid through the epidermis and detect its glucose level. It has the advantages of painlessness, low infection and easy miniaturization, and is suitable for wearable flexible epidermal physiological information detection devices. In addition, biomarkers such as glucose in biomicrofluids extracted transdermally by reverse ion osmosis can be easily detected by electrochemical methods. This technology measures the extracted interstitial fluid glucose level by applying a mild current to the skin. In 2001, Cygnus launched the first commercial Gluco Watch glucose sensor based on reverse ion osmosis technology. However, due to interference such as skin perspiration and erythema caused by current stimulation, the product was withdrawn from the market in 2007. With the development of reverse ion osmosis technology, this problem has been initially solved by optimizing the applied current intensity and extraction time, but the accuracy of epidermal glucose detection levels based on reverse ion osmosis interstitial fluid extraction technology still needs to be further improved, which is crucial for continuous blood glucose monitoring systems. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for improving the accuracy of glucose monitoring in reverse iontophoresis technology.

[0006] In order to solve the above technical problems, the technical solution of the present invention is:

[0007] A method for improving the accuracy of glucose monitoring in reverse ion electroosmosis technology, which improves the accuracy of glucose monitoring in reverse ion electroosmosis technology based on pH correction, further obtains the relationship between pH and glucose electroosmotic mobility under fixed external current and duration through glucose electroosmotic mobility at different pH values, and establishes a pH correction model for monitoring subcutaneous glucose concentration.

[0008] Preferably, the above method for improving the accuracy of glucose monitoring in reverse iontophoresis technology obtains a calibration intercept by first sampling blood for measurement; and substitutes the measured pH and extracted glucose concentration into a pH correction model to obtain a more accurate glucose test result.

[0009] Preferably, the above method for improving the accuracy of glucose monitoring in reverse ion electroosmosis technology obtains glucose electroosmotic mobility at different pH values through in vitro experiments, and substitutes it into the epidermal glucose prediction model to obtain more accurate glucose concentration information after pH calibration.

[0010] Preferably, for the above method of improving the accuracy of glucose monitoring in the counterion electroosmosis technique, in vitro experiments include preparing Tris-HCl buffer solutions with pH values of 6.5, 6.9, 7.3, 7.7, 8.1, and 8.5, adding sodium chloride and glucose to simulate the sodium ion and glucose concentrations in interstitial fluid at normal human levels.

[0011] Preferably, for the above method of improving the accuracy of glucose monitoring in the counterion electroosmosis technique, before conducting in vitro experiments, cyclic voltammetry scanning is performed on the glucose sensor to stabilize the electrode, its chronoamperometry curve is tested in a phosphate buffered saline solution, and after the curve becomes stable, a glucose detection test is carried out and data is recorded.

[0012] Preferably, for the above method of improving the accuracy of glucose monitoring in the counterion electroosmosis technique, under the conditions of fixing the intensity of the applied current and the extraction time, glucose tests at different pH values are conducted. Among them, 7 consecutive extractions are performed at each pH value to obtain more accurate extraction results, and no less than 8 repeated measurements are carried out at each pH value to avoid accidental errors. By fitting the slope between the electroosmotic mobility of the extracted glucose and the number of extractions, the glucose extraction coefficient under this pH condition is obtained.

[0013] Preferably, for the above method of improving the accuracy of glucose monitoring in the counterion electroosmosis technique, with the pH value as the independent variable and the slope of the electroosmotic mobility of glucose at different pH values with respect to the number of extractions as the dependent variable for fitting, the functional relationship between the electroosmotic mobility of glucose and pH is obtained , where k is the extraction coefficient obtained through in vitro experiments; b is the calibration intercept.

[0014] Preferably, for the above method of improving the accuracy of glucose monitoring in the counterion electroosmosis technique, before each glucose extraction test, pH detection is first performed, and the electroosmotic mobility of glucose that varies dynamically with the pH value is obtained according to the pH detection result, and it is substituted into the subcutaneous glucose concentration pH correction model to obtain more accurate corrected glucose concentration data.

[0015] Preferably, for the above method of improving the accuracy of glucose monitoring in the counterion electroosmosis technique, a pH correction model for subcutaneous glucose concentration based on pH correction is established, and the pH correction model is , where, C iglu is the glucose concentration in subcutaneous interstitial fluid, C glu is the extracted glucose concentration, V gelV is the volume of the Nafion hydrogel, d is the distance between the extraction electrodes, T is the time of the counterion electroosmosis applied current, A is the surface area of the extraction electrodes, U is the magnitude of the applied voltage, k is the extraction coefficient obtained through in vitro experiments, pH is the pH value of the subcutaneous interstitial fluid, and b is the calibration intercept.

[0016] Preferably, the method for improving the accuracy of glucose monitoring in the counterion electroosmosis technology is as follows:

[0017] (1) Attach the glucose sensor to the skin surface on the front side of the human forearm. The glucose sensor includes a counterion electroosmosis extraction electrode and an extraction auxiliary electrode, and can apply a cross current to extract interstitial fluid. During the extraction process, apply a cross current of 200 μA / cm2 for 5 minutes to extract interstitial fluid.

[0018] (2) Detect glucose and pH in the extracted interstitial fluid. Each detection takes 1 minute. Detect glucose and pH values through the sensor element of the glucose sensor. Among them, the glucose sensor uses an enzyme-based electrochemical sensing technology, and the pH sensor uses a potential response-based sensing technology;

[0019] (3) Substitute the detection results into the pH correction model to obtain more accurate glucose concentration data after correction. The pH correction model can eliminate the errors caused by different physiological environments and is usually designed based on human tissue characteristics and biochemical reaction mechanisms. The entire extraction and detection process takes about 7 minutes, and then it can be measured cyclically to achieve continuous real-time dynamic monitoring of subcutaneous glucose concentration.

[0020] Beneficial effects:

[0021] The method for improving the accuracy of glucose monitoring in the counterion electroosmosis technology solves the core problem that the pH value fluctuation affects the detection result in the transdermal extraction method by dynamically and real-time correcting the pH value of the interstitial fluid, eliminates the influence of the pH of the interstitial fluid on the counterion electroosmosis transdermal extraction, and thus improves the accuracy and reliability of epidermal glucose monitoring. In addition, due to individual differences and the different pH values of interstitial fluid in different parts of the same individual, this method also has certain personalized characteristics, can correct the pH value specifically, improve the monitoring efficiency and portability, and provide a better solution for blood glucose monitoring. Brief description of the drawings

[0022] Figure 1 is the flow chart of the method for improving the accuracy of glucose monitoring in the counterion electroosmosis technology described in the present invention.

[0023] Figure 2 is the fitting relationship diagram between the glucose extraction concentration and the pH of subcutaneous interstitial fluid described in the present invention. Detailed implementation manners

[0024] In order to solve the problem of pH interference during the extraction of interstitial fluid by counter-ion electroosmosis, the present invention provides a method for improving the accuracy of glucose monitoring in counter-ion electroosmosis technology based on pH correction. First, a theoretical analysis is used to establish an epidermal glucose prediction model based on pH calibration. Then, through in vitro experiments, the relationship between glucose electroosmotic mobility and pH is initially obtained. According to this relationship, in each subsequent measurement, the pH of the extracted interstitial fluid is first detected and substituted into the glucose prediction model to obtain a more accurate detection result after pH correction, thereby obtaining more precise glucose concentration data.

[0025] The following will make a detailed description of a method for improving the accuracy of glucose monitoring in counter-ion electroosmosis technology based on pH correction of the present invention in combination with the embodiments.

[0026] Example 1

[0027] During the counter-ion electroosmosis extraction process, the pH value fluctuation of subcutaneous interstitial fluid is a key factor affecting the accuracy of epidermal glucose detection. The purpose of this example is to explore the influence mechanism of pH on the extraction of interstitial fluid by counter-ion electroosmosis, indicating that pH will significantly affect the accuracy of epidermal glucose measurement.

[0028] Iontophoretic extraction of interstitial fluid mainly involves charged ions and neutral molecules, such as sodium ions and glucose. For charged species like sodium ions, electromigration is the main transport mechanism, i.e., the movement of charged ions under the direct influence of an electric field force. The electron flux is converted into an ion flux through electrode reactions, and the duration of the current action and the intensity of the electric field determine the total amount of charge transport. The main transport mechanism of glucose is electroosmosis, and its extraction is based on the electromigration of sodium ions. The skin is negatively charged at physiological pH, which causes sodium ions in the interstitial fluid to migrate to the skin surface and form an electric double layer, which includes a surface charge layer and a diffusion layer. The diffusion layer can be further divided into two parts through the slip plane, which reflects the contribution of the ζ potential to the electroosmosis velocity. When the electrodes are placed near the skin, sodium ions migrate towards the cathode, resulting in the flow of sodium ions from the anode to the cathode. Therefore, under the osmotic pressure gradient caused by sodium ions, glucose dissolved in the subcutaneous interstitial fluid also moves towards the cathode. Glucose is catalyzed by glucose oxidase, which provides a measurable signal. Sodium ions attracted by the negative charge of the epidermis in the electric double layer play a decisive role in the electromigration flux. The pH value of the interstitial fluid in contact with the skin affects the glucose ion transport. Specifically, the isoelectric point range of human skin is 4 - 4.5. Above this pH value, the carboxylic acid groups of the epidermal surface proteins release protons and become negatively charged, while below this isoelectric point, they are positively charged. The pH value of the subcutaneous interstitial fluid is higher than this value; therefore, the epidermal skin is negatively charged at physiological pH. The skin charge amount can change with the change of pH value, which changes the ζ potential in the electric double layer, thereby affecting the rate of glucose extraction by RI.

[0029] It can be seen that under physiological conditions, the pH value of the interstitial fluid is maintained between 7.35 - 7.45. When the pH value changes after human ingestion or exercise, it may affect the skin charge and the permeability of the skin barrier, thereby affecting the transdermal extraction of glucose. Specifically, the selective permeability of the skin strongly depends on the pH value of the surrounding medium. The skin is negatively charged because the amphoteric electrolyte amino acids in the skin are negatively charged under normal physiological conditions, and the pH value of the interstitial fluid can change the degree of ionization of amino acids, thereby changing the amount of negative charge carried by the skin, and further affecting the flux of glucose electroosmosis. As an important physiological parameter, the pH value of the interstitial fluid can also affect the flux of transdermal glucose extraction due to the differences between individuals and different body parts of the same individual. Therefore, dynamic correction of the pH value fluctuation in transdermal glucose detection can more accurately monitor epidermal glucose.

[0030] Example 2

[0031] As Figure 1 shown, the method for improving the accuracy of glucose monitoring in iontophoretic technology based on pH correction is as follows:

[0032] Step S1: Theoretical analysis to establish a prediction model for subcutaneous glucose concentration based on pH correction

[0033] Theoretically, the transdermal extraction flux of glucose can be calculated by the following formula:

[0034]

[0035] Wherein, J glu is the glucose extraction flux, C glu is the extracted glucose concentration, V gel is the volume of the Nafion hydrogel, and T is the time of the counterion electroosmosis applied current. Further, J glu can also be expressed as:

[0036]

[0037] Wherein, A is the surface area of the extraction electrode, C iglu is the glucose concentration in the subcutaneous interstitial fluid, U is the applied voltage magnitude, d is the distance between the extraction electrodes, and u is the transdermal extraction rate of glucose by counterion electroosmosis, which is expressed as a function equation of the interstitial fluid pH . Wherein, k is the extraction coefficient that can be obtained through in vitro experiments; b is the intercept, which can be obtained by calibrating with a blood glucose meter during the first measurement. According to the above formula, the transdermally extracted glucose concentration C glu and the glucose concentration in the subcutaneous interstitial fluid C iglu have a relationship including the pH factor:

[0038]

[0039] Therefore, by detecting information such as the transdermally extracted glucose concentration and the interstitial fluid pH, the real-time measurement value of the glucose concentration can be obtained non-invasively.

[0040] Step S2: Obtain the relationship between the electroosmotic mobility of glucose and the pH function through in vitro experiments

[0041] First, prepare Tris-HCl buffer solutions with pH values of 6.5, 6.9, 7.3, 7.7, 8.1, and 8.5, and add sodium chloride and glucose to simulate the sodium ion and glucose concentrations in the interstitial fluid at normal human levels. Secondly, perform cyclic voltammetry scanning on the glucose sensor to stabilize the electrode, test its chronoamperometric curve in phosphate buffered saline solution. After the curve becomes stable, conduct a glucose extraction experiment and record the data. Before each extraction experiment, a preheating process is required to eliminate the problem of current source overload. Therefore, it is necessary to normalize the test results of each group to exclude the interference of background current generated by preheating. Then, conduct glucose extraction tests at different pH values. Among them, extract continuously 7 times at each pH value to obtain more accurate extraction results, and perform no less than 8 repeated measurements at each pH value to avoid accidental errors. By fitting the slope between the glucose extraction rate by counterion electroosmosis and the number of extractions, the electroosmotic mobility data of glucose under this pH condition can be obtained. Through a large number of experimental data, finally, with the pH value as the independent variable and the slope of the electroosmotic mobility of glucose at different pH values with respect to the number of extractions as the dependent variable, data fitting is performed to obtain the functional relationship between the glucose extraction rate and pH. That is to say, obtain the value of the extraction coefficient k.

[0042] Step S3: Obtain the calibration intercept through the first blood sampling measurement

[0043] Before conducting the first epidermal glucose extraction test, the influence of individual differences should be taken into account. To obtain more direct information on the relationship between the subcutaneous interstitial fluid glucose concentration and the transdermal extracted glucose concentration, before collecting samples, it is necessary to use a fingertip blood sampler to collect blood from the tested person to calibrate the intercept b. This step is crucial for the establishment of the epidermal glucose prediction model. The epidermal glucose prediction model contains key information on the extracted glucose concentration and the actual subcutaneous glucose concentration. This model also takes into account the measurement interference caused by pH fluctuations, thus providing more accurate glucose concentration information.

[0044] Step S4: Substitute the pH measurement result and the extracted glucose concentration into the calibration model to obtain the accurate value of the pH-calibrated glucose concentration

[0045] After obtaining the extraction coefficient k and calibration intercept b required for the epidermal glucose prediction model, by fitting the functional relationship between the electroosmotic mobility of glucose and pH, a more accurate relationship model between the subcutaneous interstitial fluid glucose concentration and the transdermally extracted glucose concentration is obtained. During each glucose extraction test, the measured pH value and the extracted glucose concentration are substituted into the calibration formula to achieve a more accurate epidermal glucose test result based on pH calibration. During the epidermal glucose test, changes in the pH value may interfere with the measurement results. To eliminate the measurement interference caused by pH fluctuations, the present invention provides a method for pH-calibrated epidermal glucose detection to achieve a more accurate epidermal glucose test result. The calibration formula is based on the functional relationship between the electroosmotic mobility of glucose and pH, uses pH to calibrate the data, and calculates the epidermal glucose concentration according to the extraction coefficient k and calibration intercept b. This will help to more accurately evaluate the effectiveness of the patient's diabetes management and treatment plan, and help prevent the occurrence of diabetes and its complications.

[0046] Example 3

[0047] The glucose monitoring method applying the technology described in Example 2 above is as follows:

[0048] First, attach the glucose sensor to the skin surface on the front side of the human forearm. The glucose sensor includes an anti-ion electroosmotic extraction electrode and an extraction auxiliary electrode, and can apply a cross current to extract interstitial fluid. During the extraction process, apply a cross current of 200 μA / cm 2 for 5 minutes to extract interstitial fluid.

[0049] Subsequently, perform glucose and pH detection on the extracted interstitial fluid, and each detection takes 1 minute. The sensor element included in the glucose sensor can detect glucose and pH values. Among them, the glucose sensor uses enzyme-based electrochemical sensing technology, and the pH sensor uses potential response-based sensing technology.

[0050] Finally, substitute the detection results into the pH correction model to obtain more accurate glucose concentration data after correction. The pH correction model can eliminate the errors caused by different physiological environments and is usually designed based on human tissue characteristics and biochemical reaction mechanisms. The entire extraction detection process takes about 7 minutes, and then cyclic measurement can be performed to achieve continuous real-time dynamic monitoring of the subcutaneous glucose concentration.

[0051] Such as Figure 2As shown, the preliminary results of step S2 indicate that the linear fitting of the glucose extraction results with respect to pH is good, with the slope and linear correlation coefficient being 0.88617 and 0.93014 respectively. Specifically, at different pH values, the amount of glucose extracted shows a linear relationship with the pH value. When the pH value is higher, the counter-ion electroosmotic mobility of glucose under the same conditions is greater, resulting in a larger glucose flux being extracted, which leads to errors in glucose detection. Since the extracted glucose concentration is linearly correlated with the glucose electroosmotic mobility, this result proves that the glucose electroosmotic mobility is linearly related to the subcutaneous interstitial fluid, further demonstrating the effectiveness of the calibration model. It shows that when performing continuous real-time dynamic monitoring of subcutaneous glucose concentration, it is necessary to calibrate the pH value to eliminate its interference with glucose detection. The pH correction model based on human tissue characteristics and biochemical reaction mechanisms can effectively eliminate errors and improve the detection accuracy of subcutaneous glucose concentration.

[0052] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art of this technology, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for improving the accuracy of glucose monitoring in counterion electroosmosis technology, characterized in that: Improving the accuracy of glucose monitoring in counterion electroosmosis technology based on pH correction. The electroosmotic mobility of glucose at different pH values was obtained through in vitro experiments. With the pH value as the independent variable and the slope of the electroosmotic mobility of glucose at different pH values with the number of extractions as the dependent variable for fitting, the functional relationship between the electroosmotic mobility of glucose and pH was obtained. , the extraction coefficient k was obtained, and a pH correction model for subcutaneous glucose concentration based on pH correction was established. The pH correction model is , where C iglu is the glucose concentration in subcutaneous interstitial fluid, C glu is the extracted glucose concentration, V gel is the volume of Nafion hydrogel, d is the distance between extraction electrodes, T is the time of applying current for counterion electroosmosis, A is the surface area of extraction electrodes, U is the magnitude of the applied voltage, k is the extraction coefficient obtained through in vitro experiments, pH is the pH value of subcutaneous interstitial fluid, and b is the calibration intercept, which is used for monitoring the glucose concentration in subcutaneous interstitial fluid; the calibration intercept was obtained by measuring the first blood sample; the measured pH and extracted glucose concentration were substituted into the pH correction model to obtain a more accurate glucose test result.

2. The method for improving the accuracy of glucose monitoring in the counterion electroosmosis technology according to claim 1, wherein: In vitro experiments included preparing Tris-HCl buffer solutions with pH values of 6.5, 6.9, 7.3, 7.7, 8.1, and 8.5, and adding sodium chloride and glucose to simulate the sodium ion and glucose concentrations in the interstitial fluid at normal human levels.

3. The method for improving the accuracy of glucose monitoring in counterion electroosmosis technology according to claim 1, characterized in that: Before conducting in vitro experiments, cyclic voltammetry scanning was performed on the glucose sensor to stabilize the electrode. Its chronoamperometric curve was tested in a phosphate buffered saline solution. After the curve became stable, a glucose detection test was carried out and data were recorded.

4. The method for improving the accuracy of glucose monitoring in counterion electroosmosis technology according to claim 1, characterized in that: The specific steps are as follows: (1) Attach the glucose sensor to the skin surface on the front side of the human forearm. The glucose sensor includes an anti-iontophoretic extraction electrode and an extraction auxiliary electrode, and is capable of applying a constant current to extract interstitial fluid. During the extraction process, apply a constant current of 200 μA / cm 2 for 5 minutes to extract interstitial fluid; (2) Glucose and pH in the extracted interstitial fluid were detected. Each detection took 1 minute. The glucose and pH values were detected through the sensor elements of the glucose sensor. Among them, the glucose sensor used enzyme-based electrochemical sensing technology, and the pH sensor used potential response-based sensing technology; (3) The detection results were input into the pH correction model to obtain more accurate glucose concentration data after correction.

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