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

Abstract

The invention 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 an axial symmetry mode along the central axis of the sensor plane and are prepared through silk-screen printing. Due to the symmetrical structural design of the blood glucose sensor, the electrode polarity of the extraction electrode can be exchanged during two adjacent times of extraction so as to reduce electrode consumption and skin stimulation, the change of the extraction amount of intercellular fluid can be corrected by the integrated sodium ion and pH sensor, and therefore high-precision blood glucose monitoring is achieved.

Description

Technical Field

[0001] This invention relates to the fields of reverse ion electroosmosis and blood glucose monitoring technology, and in particular to a non-invasive high-precision blood glucose sensor and its preparation method. Background Technology

[0002] Continuous blood glucose monitoring is of great value in the diagnosis and treatment of diabetes and its complications. Non-invasive continuous blood glucose monitoring is an important future development direction, such as reverse iontophoresis technology. With the development of flexible electronics and nanotechnology, reverse iontophoresis is showing increasingly important application potential in the fields of non-invasive biosensing and continuous monitoring. Reverse iontophoresis effectively extracts subcutaneous interstitial fluid to the skin surface by applying alternating current or direct current electric field to the skin surface, utilizing the fluid driving force generated by the counterions under the action of the electric field. It can achieve non-invasive, real-time monitoring of individual physiological status, providing continuous monitoring solutions for patients with chronic diseases such as diabetes and metabolic syndrome, and contributing to personalized precision medicine.

[0003] However, despite the significant theoretical advantages of reverse iontophoresis, its practical application still faces numerous challenges. One technical difficulty lies in the insufficient accuracy of personalized diagnosis based on reverse iontophoresis, primarily due to the instability of the interstitial fluid extraction process. During extraction, factors such as skin surface pH, ion concentration distribution, and electrode polarization can all cause fluctuations in extraction efficiency, leading to deviations in biomarker concentration predictions. Furthermore, significant differences exist in individual skin characteristics (such as thickness, conductivity, and hydration), making it difficult to maintain consistent extraction efficiency under the same current or electric field conditions, thus limiting the widespread adoption of this technology in large-scale clinical applications. Summary of the Invention

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

[0005] Another technical problem to be solved by the present invention is to provide a method for preparing the above-mentioned non-invasive high-precision blood glucose sensor.

[0006] The technical solution adopted in this invention is:

[0007] A non-invasive high-precision blood glucose sensor includes a flexible substrate layer (1), an adhesive layer (A), and a sensing region (B). The adhesive layer (A) is bonded and fixed to the flexible substrate layer (1), and a corresponding contour is provided on the adhesive layer (A). The sensing region (B) is embedded in the corresponding contour of the adhesive layer (A) and bonded and fixed to the flexible substrate layer (1).

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

[0009] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, the adhesive layer (A) is made of 3M medical tape, which is prepared by laser printing, which helps to pattern the functional layer and the protective layer and to ensure the fit of the sensor to the human body.

[0010] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, the sensing area (B) includes two symmetrical areas, each of which 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).

[0011] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, 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); the glucose sensor working electrode (b) comprises, from the flexible substrate layer (1) outwards, 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) outwards, 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 working electrode (d) of the pH sensor comprises, from the flexible substrate (1) outwards, 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 working electrode (d) of the pH sensor comprises, from the flexible substrate (1) outwards, 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 working electrode (b) of the glucose sensor.

[0012] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, the carbon electrode layer (3) is prepared from a commercially available carbon material containing Prussian blue, 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)-polystyrene sulfonic acid (PEDOT / PSS); and the Nafion layer (11) is a perfluorosulfonic acid-based polymer, serving as the microreactor and protective layer of the sensor.

[0013] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, the glucose oxidase layer (5) is prepared from a chitosan-based glucose oxidase solution. In the mixed solution of the chitosan solution and the 10 mg / ml glucose oxidase solution, the volume ratio of the glucose oxidase solution to 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, and stirring at 80°C for 2 hours.

[0014] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, 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, and 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.

[0015] Preferably, in the above-mentioned non-invasive high-precision blood glucose sensor, the pH selective membrane layer (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, 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.

[0016] Preferably, in the above-mentioned 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, and 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 decreased proportionally.

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

[0019] 1) A layer of metallic silver is printed on a flexible substrate (1) as a silver conductive layer (2) by screen printing;

[0020] 2) A silver / silver chloride material layer (9) and a carbon material layer (3) are printed on the silver conductive layer (2) by screen printing.

[0021] 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:

[0022] 4) 1 μL of 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.

[0023] 5) 1 μL of 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 the sodium ion sensor and the pH sensor were formed.

[0024] 6) 1 μL of sodium ion selective film solution is dropped onto the conductive polymer layer (6) of the working electrode (c) of the sodium ion sensor, and sodium ion selective film layer (7) is formed after natural drying.

[0025] 7) 1 μL of pH selective membrane solution is dropped onto the conductive polymer layer (6) of the working electrode (d) of the pH sensor, and after natural drying, a pH selective membrane layer (8) is formed.

[0026] 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 the reference membrane layer (10) was formed after natural drying.

[0027] 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 fabrication of the entire sensor is completed.

[0028] The beneficial effects of this invention are:

[0029] The non-invasive, high-precision blood glucose sensor employs a symmetrical structural design, allowing the extraction electrodes to exchange polarity between adjacent extractions to reduce electrode consumption and skin irritation. Integrated sodium ion and pH sensors correct for changes in intercellular fluid extraction volume. During reverse ion electroosmosis, extraction stability and measurement accuracy are significantly improved, thus achieving 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 Figure 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 pH sensor working electrode d, 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 preparation 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 invention comprises a flexible base layer (1), an adhesive layer (A) and a sensing area (B), wherein the adhesive layer (A) is bonded and fixed to the flexible base layer (1), a corresponding contour is provided on the adhesive layer (A), and the sensing area (B) is embedded in the corresponding contour of the adhesive layer (A) and bonded and fixed to the flexible base layer (1).

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

3. The non-invasive high-precision blood glucose sensor according to claim 1, characterized in that: The sensing area (B) includes two symmetrical areas, each of which 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 common reference electrode (e) and an intercellular fluid extraction electrode (f).

4. The non-invasive high-precision blood glucose sensor according to claim 3, characterized in that: The auxiliary electrode / reference electrode (a) of the glucose sensor comprises, in order from the flexible substrate layer (1) to the outside, a silver conductive layer (2), a silver / silver chloride layer (9) and a Nafion layer (11); the working electrode (b) of the glucose sensor comprises, in order from the flexible substrate layer (1) to the outside, 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 working electrode (c) of the sodium ion sensor comprises, in order from the flexible substrate layer (1) to the outside, a silver conductive layer (2), a carbon electrode layer (3), a conductive polymer layer (6), a sodium ion The pH sensor working electrode (d) comprises, from the flexible substrate layer (1) to the outside, 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) to the outside, 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).

5. The non-invasive high-precision blood glucose sensor according to claim 4, 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.

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

1.

7. The non-invasive high-precision blood glucose sensor according to claim 4, characterized in that: The sodium ion selective membrane layer (7) is composed of a sodium ion carrier X, a sodium ion exchanger tetrakis[3,5-bis(trifluoromethyl)phenyl]sodium borate, a high molecular weight polymer polyvinyl chloride, a 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 tetrakis[3,5-bis(trifluoromethyl)phenyl]sodium borate, 33 w / w% high molecular weight polymer polyvinyl chloride and 65.45 w / w% plasticizer di(2-ethylhexyl)sebacate, totaling 100 mg, is dissolved in 354 uL of cyclohexanone.

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

9. The non-invasive high-precision blood glucose sensor according to claim 4, characterized in that: The reference film layer (8) 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.

10. The method for preparing the non-invasive high-precision blood glucose sensor according to any one of claims 1 to 9, characterized in that: The specific steps are as follows: 1) printing a layer of metallic silver as a silver conductive layer (2) on the flexible substrate layer (1) by screen printing; 2) printing a layer of silver / silver chloride material 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) preparing a 3M medical tape with a corresponding contour by laser printing, and then laminating the tape and the flexible base layer (1) to prepare the adhesive layer (A); and embedding the sensing area in the corresponding contour of the adhesive layer. For any of the two areas, the modification method involves the following steps to modify the sensor: 4) dripping a platinum nanoparticle aqueous solution on the carbon electrode layer (3) of the working electrode (b) of the glucose sensor, and forming a platinum nanoparticle layer (4) after natural drying; then dripping 1uL of chitosan-based glucose oxidase solution on the platinum nanoparticle layer (4), and forming a glucose oxidase layer (5) after natural drying; 5) respectively drop-coating an aqueous solution of PEDOT / PSS on the carbon electrode layer (3) of the working electrode (c) of the sodium ion sensor and the working electrode (d) of the pH sensor, and forming a conductive polymer layer (6) of the sodium ion sensor and the pH sensor after natural drying; 6) dripping a sodium ion selective membrane solution onto the conductive polymer layer (6) of the sodium ion sensor working electrode (c), and forming a sodium ion selective membrane layer (7) after natural drying; 7) dripping a pH selective membrane solution onto the conductive polymer layer (6) of the working electrode (d) of the pH sensor, and forming a pH selective membrane layer (8) after natural drying; 8) dripping a reference film solution onto the silver / silver chloride layer (9) of the sodium ion / pH sensor common reference electrode (e), and forming a reference film layer (10) after natural drying; 9) After the above steps are completed, a layer of Nafion membrane is coated on the surface of the prepared blood glucose sensor as a Nafion layer (11), and the Nafion layer is dried at room temperature to complete the production of the entire sensor.

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