Non-invasive high-precision blood glucose sensor and preparation method thereof

Abstract

The application provides a non-invasive high-precision blood glucose sensor and a preparation method thereof. The blood glucose sensor comprises two symmetrical sensing areas prepared on a flexible substrate layer; each sensing area comprises a glucose sensor working electrode, a glucose sensor auxiliary electrode / reference electrode, a sodium ion sensor working electrode, a pH sensor working electrode and a sodium ion / pH sensor common reference electrode; the electrodes are distributed in axial symmetry along the central axis in the sensor plane and are prepared by screen printing; and the symmetrical structure design of the blood glucose sensor can make the extraction electrodes exchange electrode polarity when extracted for two adjacent times to reduce electrode consumption and skin irritation, the integrated sodium ion and pH sensors can correct the change in the extraction amount of intercellular fluid, and high-precision blood glucose monitoring is achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of counter-ion electroosmosis and blood glucose monitoring, and particularly relates to a non-invasive high-precision blood glucose sensor and a preparation method thereof. BACKGROUND

[0002] Continuous blood glucose monitoring has important value for the diagnosis and treatment of diabetes and its complications, and non-invasive continuous blood glucose monitoring is an important development direction in the future, such as counter-ion electroosmosis technology. With the development of flexible electronic technology and nanotechnology, counter-ion electroosmosis has shown increasingly important application potential in the field of non-invasive biosensing and continuous monitoring. Counter-ion electroosmosis can effectively extract subcutaneous interstitial fluid to the skin surface by applying an alternating current or a direct current electric field on the skin surface and using the fluid driving force generated by the counter-ion under the action of the electric field. It can realize non-invasive and real-time monitoring of individual physiological status, and provide a continuous monitoring solution for patients with chronic diseases such as diabetes and metabolic syndrome, and help personalized precision medicine.

[0003] However, although counter-ion electroosmosis has significant advantages in theory, it still faces many challenges in practical application. One of the technical problems is the insufficient accuracy of individualized diagnosis based on counter-ion electroosmosis, which is mainly due to the instability of the interstitial fluid extraction process. During the extraction process, factors such as the pH value of the skin surface, ion concentration distribution, and electrode polarization can cause fluctuations in the extraction efficiency, thereby causing deviations in the prediction of biomarker concentrations. In addition, individual skin characteristics (such as thickness, conductivity, and hydration) differ significantly, making it difficult to maintain consistent extraction efficiency under the same current or electric field conditions, thereby limiting the promotion of the technology in large-scale clinical applications. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a non-invasive high-precision blood glucose sensor.

[0005] Another technical problem to be solved by the present application is to provide a preparation method of the non-invasive high-precision blood glucose sensor.

[0006] The technical solution adopted by the present application is:

[0007] A non-invasive high-precision blood glucose sensor, comprising a flexible substrate layer (1), an adhesive layer (A), and a sensing area (B), the adhesive layer (A) is fixedly attached to the flexible substrate layer (1), the adhesive layer (A) is provided with a corresponding contour, and the sensing area (B) is embedded in the corresponding contour of the adhesive layer (A) and fixedly attached to the flexible substrate layer (1).

[0008] Preferably, in the non-invasive high-precision blood glucose sensor, the material of the flexible substrate layer (1) is polyimide.

[0009] Preferably, the non-invasive high-precision blood glucose sensor, the material of the adhesive layer (A) is 3M medical tape, prepared by laser printing, which is helpful for the patterned modification of the functional layer and the protective layer and the adhesion of the sensor to the human body.

[0010] Preferably, the non-invasive high-precision blood glucose sensor, the sensing area (B) comprises two symmetrical areas, each of which comprises a glucose sensor auxiliary electrode / reference electrode (a), a glucose sensor working electrode (b), a sodium ion sensor working electrode (c), a pH sensor working electrode (d), a sodium ion / pH sensor common reference electrode (e) and an intercellular fluid extraction electrode (f).

[0011] Preferably, the non-invasive high-precision blood glucose sensor, the glucose sensor auxiliary electrode / reference electrode (a) comprises, from the flexible substrate layer (1) outward, a silver conductive layer (2), a silver / silver chloride layer (9) and a Nafion layer (11); the glucose sensor working electrode (b) comprises, from the flexible substrate layer (1) outward, a silver conductive layer (2), a carbon electrode layer (3), a platinum nanoparticle layer (4), a glucose oxidase layer (5) and a Nafion layer (11); the sodium ion sensor working electrode (c) comprises, from the flexible substrate layer (1) outward, a silver conductive layer (2), a carbon electrode layer (3), a conductive polymer layer (6), a sodium ion selective membrane layer (7) and a Nafion layer (11); the pH sensor working electrode (d) comprises, from the flexible substrate layer (1) outward, a silver conductive layer (2), a carbon electrode layer (3), a conductive polymer layer (6), a pH selective membrane layer (8) and a Nafion layer (11); the sodium ion / pH sensor common reference electrode (e) comprises, from the flexible substrate layer (1) outward, a silver conductive layer (2), a silver / silver chloride layer (9), a reference membrane layer (10) and a Nafion layer (11); the intercellular fluid extraction electrode (f) is the same as the glucose sensor working electrode (b).

[0012] Preferably, the non-invasive high-precision blood glucose sensor, the carbon electrode layer (3) is prepared from a carbon material containing Prussian blue (commercially available), which can improve the detection specificity of the sensor; the glucose oxidase layer (5) is prepared from a chitosan-based glucose oxidase solution; the conductive polymer layer (6) is prepared from poly(3,4-ethylenedioxythiophene) polyphenyl sulfonic acid (PEDOT / PSS); and the Nafion layer (11) is a perfluorosulfonic acid-based polymer, which serves as a micro-reaction pool and a protective layer of the sensor.

[0013] Preferably, the non-invasive high-precision blood glucose sensor, the glucose oxidase layer (5) is prepared by a chitosan-based glucose oxidase solution, the volume ratio of the glucose oxidase solution to the chitosan solution in the mixed configuration solution of the 10 mg / ml glucose oxidase solution and the chitosan solution is 2:1; the chitosan solution is prepared by adding 0.1 mg of chitosan to 10 ml of deionized water, then adding 200 μL of acetic acid and 1 mL of glycerol solution to the chitosan solution respectively, and stirring at 80°C for 2 hours.

[0014] Preferably, the non-invasive high-precision blood glucose sensor, the sodium ion selective membrane layer (7) is composed of sodium ion carrier X, sodium ion exchanger sodium tetra[3,5-bis(trifluoromethyl)phenyl]borate, high molecular weight polymer polyvinyl chloride and plasticizer di(2-ethylhexyl) sebacate and cyclohexanone, wherein a mixture of 1 w / w% sodium ion carrier X, 0.55 w / w% sodium ion exchanger sodium tetra[3,5-bis(trifluoromethyl)phenyl]borate, 33 w / w% high molecular weight polymer polyvinyl chloride and 65.45 w / w% plasticizer di(2-ethylhexyl) sebacate is dissolved in 354 uL of cyclohexanone.

[0015] Preferably, the non-invasive high-precision blood glucose sensor, the pH selective membrane layer (8) is composed of hydrogen ion carrier I tridodecylamine, hydrogen ion exchanger potassium tetra(4-chlorophenyl)borate, high molecular weight polymer polyvinyl chloride and plasticizer di(2-ethylhexyl) sebacate and cyclohexanone, wherein a mixture of 1 w / w% hydrogen ion carrier I, 0.55 w / w% hydrogen ion exchanger potassium tetra(4-chlorophenyl)borate, 33 w / w% high molecular weight polymer polyvinyl chloride and 65.45 w / w% plasticizer di(2-ethylhexyl) sebacate is dissolved in 354 uL of cyclohexanone.

[0016] Preferably, the non-invasive high-precision blood glucose sensor, the reference membrane layer (8) is prepared by dissolving 79.1 mg of polyvinyl butyral resin (PVB) and 50 mg of sodium chloride in 1 mL of methanol, then adding 2 mg of polyoxyethylene polyoxypropylene ether (F127) and 0.2 mg of multi-walled carbon nanotubes to the resulting mixture.

[0017] The proportions of the above mixtures can be increased or reduced in proportion.

[0018] The preparation method of the non-invasive high-precision blood glucose sensor, the specific steps are as follows:

[0019] 1) printing a layer of metal silver as a silver conductive layer (2) on the flexible substrate layer (1) by screen printing;

[0020] 2) printing a layer of silver / chloride silver material and a layer of carbon material on the silver conductive layer (2) respectively by means of silk screen printing to obtain a silver / chloride silver layer (9) and a carbon electrode layer (3);

[0021] 3) preparing a 3M medical adhesive tape containing corresponding contours by laser printing, and then adhering the tape and the flexible substrate layer (1) to realize the preparation of the adhesive layer (A); at the same time, the sensing area is embedded in the corresponding contour of the adhesive layer, and for any one of the two areas, the modification method involves the following steps to realize the modification of the sensor:

[0022] 4) dropping 1uL of a platinum nanoparticle aqueous solution on the carbon electrode layer (3) of the glucose sensor working electrode (b) to form a platinum nanoparticle layer (4) after natural drying; then dropping 1uL of a chitosan-based glucose oxidase solution on the platinum nanoparticle layer (4) to form a glucose oxidase layer (5) after natural drying;

[0023] 5) dropping 1uL of a PEDOT / PSS aqueous solution on the carbon electrode layer (3) of the sodium ion sensor working electrode (c) and the pH sensor working electrode (d) respectively to form a conductive polymer layer (6) of the sodium ion sensor and the pH sensor after natural drying;

[0024] 6) dropping 1uL of a sodium ion selective membrane solution on the conductive polymer layer (6) of the sodium ion sensor working electrode (c) to form a sodium ion selective membrane layer (7) after natural drying;

[0025] 7) dropping 1uL of a pH selective membrane solution on the conductive polymer layer (6) of the pH sensor working electrode (d) to form a pH selective membrane layer (8) after natural drying;

[0026] 8) dropping 1uL of a reference membrane solution on the silver / chloride silver layer (9) of the sodium ion / pH sensor common reference electrode (e) to form a reference membrane layer (10) after natural drying;

[0027] 9) after the above operation steps are completed, coating a layer of Nafion film as a Nafion layer (11) on the surface of the prepared blood glucose sensor, and drying it at room temperature to complete the preparation of the entire sensor.

[0028] The beneficial effects of the present application are:

[0029] The non-invasive high-precision blood glucose sensor adopts a symmetrical structure design, so that the extraction electrodes can exchange electrode polarity when extracting adjacent two times to reduce electrode consumption and skin irritation, the integrated sodium ion and pH sensor can correct the change of intercellular fluid extraction amount, and the extraction stability and measurement precision are significantly improved in the counter-ion electroosmosis process, thereby realizing high-precision blood glucose monitoring. Specifically:

[0030] (1) The symmetrical region design enables polarity alternation between adjacent extraction cycles, effectively reducing skin irritation and mitigating the decrease in extraction efficiency caused by electrode polarization or skin damage. In this way, not only is the consumption of extraction electrodes reduced and the lifespan of the sensor extended, but the accumulation of extracted substances on the skin surface is also avoided, reducing measurement errors caused by the accumulation effect and thus improving the reliability of monitoring data.

[0031] (2) The integration of sodium ion sensors plays a crucial calibration role in the extraction process. Since skin impedance fluctuates significantly due to factors such as hydration, skin thickness, and environmental conditions, the amount of interstitial fluid extracted may be uncertain. Sodium ion concentration, as a relatively stable parameter in the interstitial fluid, can effectively reflect impedance changes during extraction, thereby dynamically correcting the extraction throughput and reducing measurement deviations caused by impedance fluctuations.

[0032] (3) The integration of a pH sensor solves the problem of pH fluctuations on the skin surface during extraction. During reverse iontophoresis, the generation of hydrogen ion flow and the skin's self-healing mechanism may cause changes in the skin surface pH, thus affecting the extraction rate of interstitial fluid and the accuracy of glucose concentration measurement. The pH sensor can monitor the dynamic changes in skin surface pH in real time, thereby compensating for extraction instability caused by pH fluctuations and further improving the accuracy of blood glucose prediction.

[0033] (4) The strategy of multi-sensor collaboration not only enhances the application potential of counterion electroosmosis in non-invasive blood glucose monitoring, but also provides a reference technical path for the continuous monitoring of other biomarkers, which is expected to promote the widespread application of non-invasive sensors in personalized medicine and chronic disease management. Attached Figure Description

[0034] Figure 1 This is a schematic diagram of the non-invasive high-precision blood glucose sensor structure described in this invention;

[0035] Figure 2 This is a schematic diagram of the structure of the working electrode of the glucose sensor in this invention;

[0036] Figure 3 This is a schematic diagram of the structure of the working electrode of the sodium ion sensor in this invention;

[0037] Figure 4 This is a schematic diagram of the working electrode of the pH sensor in this invention;

[0038] Figure 5 This is a schematic diagram of the structure of the auxiliary electrode / reference electrode of the glucose sensor in this invention;

[0039] Figure 6This is a schematic diagram of the structure of the reference electrode shared by the sodium ion / pH sensor in this invention;

[0040] Figure 7 This is an experimental result diagram of the non-invasive high-precision blood glucose sensor described in this invention.

[0041] In the figure: 1-Flexible substrate layer, 2-Silver conductive layer, 3-Carbon electrode layer, 4-Platinum nanoparticle layer, 5-Glucose oxidase layer, 6-Conductive polymer layer, 7-Sodium ion selective membrane layer, 8-pH selective membrane layer, 9-Silver / silver chloride layer, 10-Reference membrane layer, 11-Nafion layer, A-Adhesive layer, B-Sensing region, a-Glucose sensor auxiliary electrode / reference electrode, b-Glucose sensor working electrode, c-Sodium ion sensor working electrode, d-pH sensor working electrode, e-Sodium ion / pH sensor shared reference electrode, f-Intercellular fluid extraction electrode pair. Detailed Implementation

[0042] To further illustrate the present invention, the technical solution will be clearly and completely described in conjunction with the following embodiments.

[0043] Example 1

[0044] like Figures 1-6 As shown, the non-invasive high-precision blood glucose sensor includes a flexible base layer 1, an adhesive layer A, and a sensing region B. The adhesive layer A is bonded and fixed to the flexible base layer 1, and the adhesive layer A has a corresponding contour. The sensing region B is embedded within the corresponding contour of the adhesive layer A and bonded and fixed to the flexible base layer 1. The flexible base layer 1 is made of polyimide; the adhesive layer A is made of 3M medical tape and is prepared by laser printing, which facilitates the patterning of the functional and protective layers and the adhesion of the sensor to the human body.

[0045] Sensing region B comprises two symmetrical regions, each including a glucose sensor auxiliary / reference electrode a, a glucose sensor working electrode b, a sodium ion sensor working electrode c, a pH sensor working electrode d, a sodium ion / pH sensor shared reference electrode e, and an intercellular fluid extraction electrode f. Specifically:

[0046] like Figure 2 As shown, the glucose sensor working electrode b, from the flexible substrate layer 1 outwards, comprises a silver conductive layer 2, a carbon electrode layer 3, a platinum nanoparticle layer 4, a glucose oxidase layer 5, and a Nafion layer 11; as shown... Figure 3 As shown, the working electrode c of the sodium ion sensor, from the flexible substrate layer 1 outwards, sequentially comprises a silver conductive layer 2, a carbon electrode layer 3, a conductive polymer layer 6, a sodium ion selective film layer 7, and a Nafion layer 11; Figure 4As shown, the working electrode d of the pH sensor, from the flexible substrate layer 1 outwards, comprises a silver conductive layer 2, a carbon electrode layer 3, a conductive polymer layer 6, a pH selective film layer 8, and a Nafion layer 11; Figure 5 As shown, the glucose sensor auxiliary electrode / reference electrode a comprises, from the flexible substrate layer 1 outwards, a silver conductive layer 2, a silver / silver chloride layer 9, and a Nafion layer 11; as Figure 6 As shown, the sodium ion / pH sensor common reference electrode e includes, from the flexible substrate layer 1 outwards, a silver conductive layer 2, a silver / silver chloride layer 9, a reference film layer 10, and a Nafion layer 11; the intercellular fluid extraction electrode f is the same as the glucose sensor working electrode b.

[0047] The non-invasive, high-precision blood glucose sensor significantly improves extraction stability and measurement accuracy during the reverse iontophoresis process. Its symmetrical region design allows for polarity alternation between adjacent extraction cycles, effectively reducing skin irritation and mitigating extraction efficiency decline caused by electrode polarization or skin damage. This approach not only reduces electrode consumption and extends sensor lifespan but also prevents the accumulation of extracted substances on the skin surface, minimizing measurement errors caused by cumulative effects and thus improving the reliability of monitoring data.

[0048] The non-invasive, high-precision blood glucose sensor integrates a sodium ion sensor, which plays a crucial calibration role during the extraction process. Because skin impedance fluctuates significantly due to hydration, skin thickness, and environmental factors, the amount of interstitial fluid extracted may be uncertain. Sodium ion concentration, as a relatively stable parameter in the interstitial fluid, can effectively reflect impedance changes during extraction, thereby dynamically correcting the extraction flux and reducing measurement deviations caused by impedance fluctuations. Simultaneously, the integrated pH sensor addresses the fluctuations caused by skin surface pH changes during extraction. During reverse iontophoresis, the generation of hydrogen ion current and the skin's self-healing mechanism can cause changes in skin surface pH, affecting the extraction rate of interstitial fluid and the accuracy of glucose concentration measurement. The pH sensor can monitor the dynamic changes in skin surface pH in real time, compensating for extraction instability caused by pH fluctuations and further improving the accuracy of blood glucose prediction.

[0049] This multi-sensor collaborative strategy not only enhances the application potential of counterion electroosmosis in non-invasive blood glucose monitoring, but also provides a referable technical path for the continuous monitoring of other biomarkers, and is expected to promote the widespread application of non-invasive sensors in personalized medicine and chronic disease management.

[0050] The specific steps of the above-mentioned non-invasive high-precision blood glucose sensor fabrication method are as follows:

[0051] 1) A layer of metallic silver is printed on the flexible substrate 1 as a silver conductive layer 2 using screen printing;

[0052] 2) A layer of silver / silver chloride material is printed on the silver conductive layer 2 by screen printing to obtain a silver / silver chloride layer 9 and a layer of carbon material to obtain a carbon electrode layer 3;

[0053] 3) Prepare 3M medical tape with corresponding contours by laser printing, and then bond this tape to the flexible substrate layer 1 to prepare adhesive layer A; at the same time, embed the sensing area within the corresponding contour of the adhesive layer. For either of these two areas, the modification method involves the following steps to modify the sensor:

[0054] 4) 1 μL of a platinum nanoparticle aqueous solution was drop-coated onto the carbon electrode layer 3 of the working electrode b of the glucose sensor, and after natural drying, a platinum nanoparticle layer 4 was formed; then, 1 μL of a chitosan-based glucose oxidase solution was drop-coated onto the platinum nanoparticle layer 4, and after natural drying, a glucose oxidase layer 5 was formed; the carbon electrode layer 3 was prepared from a commercially available Prussian blue-containing carbon material, which can improve the detection specificity of the sensor; the chitosan-based glucose oxidase solution was a mixed solution of chitosan solution and 10 mg / ml glucose oxidase solution, wherein the volume ratio of glucose oxidase solution to chitosan solution was 2:1; the chitosan solution was prepared by adding 0.1 mg chitosan to 10 ml of deionized water, followed by adding 200 μL of acetic acid and 1 mL of glycerol solution to the chitosan solution, and stirring at 80°C for 2 hours;

[0055] 5) 1 μL of PEDOT / PSS (poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid) aqueous solution was dropped onto the carbon electrode layer 3 of the sodium ion sensor working electrode c and the pH sensor working electrode d respectively, and after natural drying, the conductive polymer layer 6 of the sodium ion sensor and the pH sensor was formed.

[0056] 6) 1 μL of sodium ion selective membrane solution is drop-coated onto the conductive polymer layer 6 of the working electrode c of the sodium ion sensor, and sodium ion selective membrane layer 8 is formed after natural drying; the sodium ion selective membrane solution is composed of sodium ion carrier X, sodium ion exchanger tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, high molecular weight polymer polyvinyl chloride, plasticizer di(2-ethylhexyl) sebacate and cyclohexanone, wherein 100 mg of a mixture of 1 w / w% sodium ion carrier X, 0.55 w / w% sodium ion exchanger tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, 33 w / w% high molecular weight polymer polyvinyl chloride and 65.45 w / w% plasticizer di(2-ethylhexyl) sebacate is dissolved in 354 μL of cyclohexanone.

[0057] 7) 1 μL of pH selective membrane solution is drop-coated onto the conductive polymer layer 6 of the working electrode d of the pH sensor, and pH selective membrane layer 8 is formed after natural drying; the pH selective membrane solution is composed of hydrogen ion carrier I trilauramide, hydrogen ion exchanger potassium tetra(4-chlorophenyl)borate, high molecular weight polymer polyvinyl chloride, and plasticizer di(2-ethylhexyl) sebacate and cyclohexanone, wherein 100 mg of a mixture of 1 w / w% hydrogen ion carrier I, 0.55 w / w% hydrogen ion exchanger potassium tetra(4-chlorophenyl)borate, 33 w / w% high molecular weight polymer polyvinyl chloride and 65.45 w / w% plasticizer di(2-ethylhexyl) sebacate is dissolved in 354 μL of cyclohexanone.

[0058] 8) 1 μL of reference membrane solution was dropped onto the silver / silver chloride layer 9 of the sodium ion / pH sensor common reference electrode e, and after natural drying, a reference membrane layer 10 was formed; the reference membrane solution was prepared by dissolving 79.1 mg of polyvinyl butyral resin (PVB) and 50 mg of sodium chloride in 1 mL of methanol, and then adding 2 mg of polyoxyethylene polyoxypropylene ether (F127) and 0.2 mg of multi-walled carbon nanotubes to the resulting mixture.

[0059] 9) After the above operation steps are completed, a Nafion film is coated on the surface of the prepared blood glucose sensor as Nafion layer 11. After it dries at room temperature, the entire sensor is fabricated. The Nafion film is made of perfluorosulfonic acid polymer and serves as the microreactor and protective layer of the sensor.

[0060] Example 2

[0061] The stability and measurement accuracy of the non-invasive high-precision blood glucose sensor described in Example 1 were verified using an oral glucose tolerance test. The experimental setup included the non-invasive high-precision blood glucose sensor described in Example 1, a constant current source, an electrochemical workstation, a switch, and a computer. The non-invasive high-precision blood glucose sensor was attached to the anterior forearm for intercellular fluid extraction and testing. The constant current source provided the reverse ion electroosmotic extraction current. The electrochemical workstation was used for the electrochemical detection of glucose, sodium ions, and pH. The switch was used to automatically switch the constant current source and the electrochemical workstation on and off to achieve automatic data saving. The computer was used for data analysis and processing.

[0062] Six healthy volunteers were selected, and finger-prick blood glucose levels were obtained using a commercial blood glucose meter (ACCU-CHEK, Switzerland) to measure their actual blood glucose values. Before the first extraction test, the test site was disinfected with an alcohol swab. Then, the non-invasive high-precision blood glucose sensor was attached to the skin, and the extraction switch was turned on. After waiting for the extraction current to stabilize and ensure no overload occurred, the first extraction test was performed. This step was a warm-up operation to ensure a stable and tight fit between the sensor and the skin before actual use. After 30 minutes of testing, participants orally ingested 250 mL of an aqueous solution containing 75g of glucose, and then the test was conducted using the non-invasive high-precision blood glucose sensor of this invention. The total testing time was 2.5 hours. The single extraction current density was 150 μA / cm². 2 The extraction time for a single test was set to 3 minutes. The effectiveness of the non-invasive, high-precision blood glucose sensor described in this invention during actual blood glucose monitoring was evaluated by comparing the difference between the predicted blood glucose value and the actual reference value. Mean absolute relative difference (MARD) is an important indicator for evaluating the accuracy of blood glucose monitoring; the smaller the value, the higher the accuracy of blood glucose detection.

[0063] Experimental results are as follows Figure 7 As shown, the experimental results demonstrate that the non-invasive high-precision blood glucose sensor of the present invention, after integrating sodium ion and pH sensors, has a lower MARD value, which is more conducive to high-precision blood glucose monitoring.

[0064] In summary, the non-invasive high-precision blood glucose sensor described in this invention significantly improves extraction stability and measurement accuracy during the reverse iontophoresis process. This multi-sensor collaborative strategy not only enhances the application potential of reverse iontophoresis in non-invasive blood glucose monitoring but also provides a referable technical path for the continuous monitoring of other biomarkers, and is expected to promote the widespread application of non-invasive sensors in personalized medicine and chronic disease management.

[0065] The above-described embodiments are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A non-invasive, high-precision blood glucose sensor, characterized in that: The system includes a flexible substrate (1), an adhesive layer (A), and a sensing region (B). The adhesive layer (A) is bonded and fixed to the flexible substrate (1). The adhesive layer (A) has a corresponding contour. The sensing region (B) is embedded in the corresponding contour of the adhesive layer (A) and bonded and fixed to the flexible substrate (1). The sensing region (B) includes two symmetrical regions. Each region includes a glucose sensor auxiliary electrode / reference electrode (a), a glucose sensor working electrode (b), a sodium ion sensor working electrode (c), a pH sensor working electrode (d), a sodium ion / pH sensor shared reference electrode (e), and an intercellular fluid extraction electrode (f). The glucose sensor auxiliary electrode / reference electrode (a) includes a silver conductive layer (2), a silver / silver chloride layer (9), and a Nafion layer (11) from the flexible substrate (1) outwards. The glucose sensor working electrode (b) includes a silver conductive layer (2), a silver / silver chloride layer (9), and a Nafion layer (11) from the flexible substrate (1) outwards. The flexible substrate (1) comprises, in sequence, a silver conductive layer (2), a carbon electrode layer (3), a platinum nanoparticle layer (4), a glucose oxidase layer (5), and a Nafion layer (11); the sodium ion sensor working electrode (c) comprises, in sequence, a silver conductive layer (2), a carbon electrode layer (3), a conductive polymer layer (6), a sodium ion selective membrane layer (7), and a Nafion layer (11) from the flexible substrate (1); the pH sensor working electrode (d) comprises, in sequence, a silver conductive layer (2), a carbon electrode layer (3), a conductive polymer layer (6), a pH selective membrane layer (8), and a Nafion layer (11) from the flexible substrate (1); the sodium ion / pH sensor shared reference electrode (e) comprises, in sequence, a silver conductive layer (2), a silver / silver chloride layer (9), a reference membrane layer (10), and a Nafion layer (11) from the flexible substrate (1); the intercellular fluid extraction electrode (f) is the same as the glucose sensor working electrode (b).

2. The non-invasive high-precision blood glucose sensor according to claim 1, characterized in that: The flexible base layer (1) is made of polyimide; the adhesive layer (A) is made of 3M medical tape.

3. The non-invasive high-precision blood glucose sensor according to claim 1, characterized in that: The carbon electrode layer (3) is a carbon material containing Prussian blue; the glucose oxidase layer (5) is prepared from a chitosan-based glucose oxidase solution; the conductive polymer layer (6) is prepared from poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid; and the Nafion layer (11) is a perfluorosulfonic acid-based polymer.

4. The non-invasive high-precision blood glucose sensor according to claim 3, characterized in that: The glucose oxidase layer (5) is prepared by mixing a chitosan solution and a 10 mg / ml glucose oxidase solution, wherein the volume ratio of the glucose oxidase solution to the chitosan solution is 2:

1.

5. The non-invasive high-precision blood glucose sensor according to claim 1, characterized in that: The sodium ion selective membrane layer (7) is composed of sodium ion carrier X, sodium ion exchanger tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, high molecular weight polymer polyvinyl chloride, plasticizer di(2-ethylhexyl) sebacate, and cyclohexanone. Specifically, 100 mg of a mixture of 1 w / w% sodium ion carrier X, 0.55 w / w% sodium ion exchanger tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, 33 w / w% high molecular weight polymer polyvinyl chloride, and 65.45 w / w% plasticizer di(2-ethylhexyl) sebacate is dissolved in 354 μL of cyclohexanone.

6. The non-invasive high-precision blood glucose sensor according to claim 1, characterized in that: The pH-selective membrane (8) is composed of hydrogen ion carrier I trilauramide, hydrogen ion exchanger potassium tetra(4-chlorophenyl)borate, high molecular weight polymer polyvinyl chloride, and plasticizer di(2-ethylhexyl) sebacate and cyclohexanone. Among them, 100 mg of a mixture of 1 w / w% hydrogen ion carrier I, 0.55 w / w% hydrogen ion exchanger potassium tetra(4-chlorophenyl)borate, 33 w / w% high molecular weight polymer polyvinyl chloride and 65.45 w / w% plasticizer di(2-ethylhexyl) sebacate is dissolved in 354 μL of cyclohexanone.

7. The non-invasive high-precision blood glucose sensor according to claim 1, characterized in that: The reference film (10) was prepared by dissolving 79.1 mg of polyvinyl butyral resin and 50 mg of sodium chloride in 1 mL of methanol, and then adding 2 mg of polyoxyethylene polyoxypropylene ether and 0.2 mg of multi-walled carbon nanotubes to the resulting mixture.

8. A method for preparing the non-invasive high-precision blood glucose sensor according to any one of claims 1-7, characterized in that: The specific steps are as follows: 1) A layer of metallic silver is printed on a flexible substrate (1) as a silver conductive layer (2) by screen printing. 2) A layer of silver / silver chloride material is printed on the silver conductive layer (2) by screen printing to obtain a silver / silver chloride layer (9) and a layer of carbon material to obtain a carbon electrode layer (3). 3) Prepare 3M medical tape with corresponding contours by laser printing, and then bond this tape to a flexible substrate layer (1) to prepare an adhesive layer (A); at the same time, embed the sensing area within the corresponding contour of the adhesive layer. For either of these two areas, the modification method involves the following steps to modify the sensor: 4) A platinum nanoparticle aqueous solution was dropped onto the carbon electrode layer (3) of the working electrode (b) of the glucose sensor, and after natural drying, a platinum nanoparticle layer (4) was formed; then 1 μL of a chitosan-based glucose oxidase solution was dropped onto the platinum nanoparticle layer (4), and after natural drying, a glucose oxidase layer (5) was formed. 5) PEDOT / PSS aqueous solution was dropped onto the carbon electrode layer (3) of the sodium ion sensor working electrode (c) and the pH sensor working electrode (d), respectively, and after natural drying, conductive polymer layers (6) of sodium ion sensor and pH sensor were formed. 6) A sodium ion selective film solution is drop-coated onto the conductive polymer layer (6) of the working electrode (c) of the sodium ion sensor, and a sodium ion selective film layer (7) is formed after natural drying. 7) A pH selective membrane solution is drop-coated onto the conductive polymer layer (6) of the working electrode (d) of the pH sensor, and a pH selective membrane layer (8) is formed after natural drying. 8) A reference membrane solution is dropped onto the silver / silver chloride layer (9) of the sodium ion / pH sensor common reference electrode (e), and a reference membrane layer (10) is formed after natural drying. 9) After the above operation steps are completed, a Nafion film is coated on the surface of the prepared blood glucose sensor as the Nafion layer (11). After it dries at room temperature, the entire sensor is fabricated.

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