Sensor for detecting saliva glucose concentration

Abstract

The invention discloses a sensor for detecting the concentration of trace glucose in saliva, the sensor is coated with a glucose conversion layer, and the glucose conversion layer is used for converting glucose in to-be-detected saliva into hydrogen ions, so that the hydrogen ions are captured by the sensor and converted into electric signals. The sensor disclosed by the invention is coated with the glucose conversion layer, and can correspond to the blood glucose level of a testee by detecting the glucose content of oral saliva. The sensor is simple in structure, convenient to manufacture, high in glucose detection sensitivity to oral saliva and capable of detecting the content of trace glucose in the oral saliva.

Description

Technical Field

[0001] The present invention relates to a sensor, in particular to an ISFET sensor for measuring glucose concentration. Background Art

[0002] Early detection and management of diabetes are crucial for patients. Traditional methods of testing blood sugar require blood sampling, which takes a long time to test, causes trauma and pain to the human body, and easily increases infection and transmission routes. Some existing electronic blood sugar testers still belong to the category of invasive testing, and are complicated to operate and inconvenient to use. To this end, various non-invasive blood sugar testing methods and equipment have been developed.

[0003] Chinese invention patent 201910230348.2 discloses a non-invasive blood glucose detection method, which uses a model to design a simulation experiment and uses human metabolic heat measurement to calculate blood glucose values. However, this simulation calculation method is complicated and the detection results are inaccurate.

[0004] Chinese invention patent 202410680902.8 discloses a blood glucose detector and detection method based on Raman spectroscopy, which measures blood glucose by detecting the spectrum of the skin surface. However, the measurement error of this method is very different from the actual result, so it is rarely used in practice.

[0005] In addition, there is a saliva glucose test strip on the market. This product is a non-invasive blood sugar test strip based on colorimetry, with low detection sensitivity. It can only provide a certain warning effect for patients with severe excessive blood sugar, and its application is too narrow. In addition, this product is expensive. For people with high blood sugar, blood sugar needs to be measured multiple times a day, and the average cost per person is too high.

[0006] Saliva, as an oral fluid, contains a variety of substances, including inorganic ions, small organic molecules, lipids, proteins and various hormones. Saliva is easy to collect and non-invasive, and can be used as a biological sample for research and clinical practice. In both type 1 diabetes and type 2 diabetes, salivary glucose levels can reflect blood sugar levels. Therefore, diabetes can be monitored by detecting low concentrations of glucose in saliva. The normal glucose concentration in human blood is 2-30mmol / L, and the glucose concentration in saliva is 0.025-0.1mmol / L. The glucose content in the saliva of diabetic patients is significantly increased, generally greater than 0.4mmol / L.

[0007] By testing the patient's saliva glucose concentration, the patient's corresponding blood sugar value can be indirectly detected, and the blood sugar value can be measured in a non-invasive way. Therefore, it is feasible to use saliva to detect blood sugar.

[0008] Nevertheless, compared with the glucose content in blood, the glucose content in saliva is still extremely low, and a more sensitive measurement method is needed to conveniently and effectively measure the glucose content in oral saliva, which is of practical application value. Existing sensors cannot detect the lower glucose concentration in saliva, so a sensor that can detect salivary blood sugar is needed. Summary of the invention

[0009] The core technical problem to be solved by the present invention is to provide a sensor for detecting trace glucose concentration in saliva.

[0010] To this end, the present invention proposes a sensor for detecting the glucose concentration in saliva, characterized in that the sensor is coated with a glucose conversion layer, and the glucose conversion layer is used to convert the glucose in the saliva to be detected into hydrogen ions, so that the hydrogen ions are captured by the sensor and converted into electrical signals.

[0011] Preferably, the sensor comprises a silicon-based substrate, an oxide layer formed on the silicon-based substrate, an ISFET transistor formed on the oxide layer, and a modification layer formed on the ISFET transistor, wherein the glucose conversion layer is coated on the modification layer.

[0012] Preferably, the ISFET transistor comprises a gate region, a drain region and a source region, wherein the gate region is formed on the oxide layer, the drain region and the source region are formed at intervals along both sides of the gate region, and a sensitive layer is formed on the drain region and the source region.

[0013] Preferably, the drain region and the source region are formed on a silicon-based substrate.

[0014] Preferably, the oxide layer is a SiO2 layer.

[0015] Preferably, a trench is formed in the oxide layer, the gate region is arranged in the trench, and the drain region and the source region are arranged outside the oxide layer.

[0016] Preferably, the glucose conversion layer comprises nano-organic materials capable of decomposing glucose to generate hydrogen ions, and the modified layer can allow hydrogen ions to pass through and be captured by the sensitive layer and converted into electrical signals.

[0017] Preferably, the modified layer comprises a chemically modified polymer material having a selective permeability to hydrogen ions.

[0018] Preferably, the polymer material is a polyethyleneimine (PEI) derivative, polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS) or polyparaphenylene vinylene (PPV) derivative.

[0019] Preferably, the sensitive layer comprises a metal oxide based semiconductor material.

[0020] Preferably, the metal oxide is zinc oxide (ZnO) nanoparticles.

[0021] Preferably, the sensitive layer may contain a doping element.

[0022] Preferably, the doping element is aluminum (Al).

[0023] Preferably, the nano-organic material of the modification layer comprises a metal organic framework (MOF) encapsulating glucose oxidase.

[0024] Preferably, the metal ion of the metal organic framework (MOF) is selected from one of alkali metals, alkaline earth metals, transition metals, Group IIIA metals, Group VIII metals, rare earth metals, and metal complexes; and the organic ligand of the metal organic framework (MOF) is selected from one of nitrogen-containing organic ligands, carboxylate ligands, amino group-modified ligands, photosensitizer-complex-modified ligands, and electron-rich conjugated ligands.

[0025] The advantages of the present invention are:

[0026] 1. The sensor of the present invention is coated with a glucose conversion layer, which can convert glucose in the saliva to be tested into hydrogen ions, and the hydrogen ions are captured by the sensor and converted into electrical signals, which can detect extremely small amounts of glucose content, thereby achieving the detection of small amounts of glucose content in oral saliva to correspond to the blood sugar level of the subject.

[0027] 2. The present invention uses a glucose conversion layer containing Gox-MOF material, which can improve detection sensitivity and can quickly and accurately detect glucose levels.

[0028] 3. The sensor of the present invention adopts ISFET biosensor, which has a simple structure, is easy to manufacture and has high sensitivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Schematic diagram of the silicon-based sensor of the present invention.

[0030] Figure 2 It is a comparison chart of the detection effect of glucose with and without the MOF sensitization system of the present invention.

[0031] To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures. It is contemplated that elements disclosed in one embodiment may be beneficially utilized on other embodiments without specific recitation. DETAILED DESCRIPTION

[0032] The invention relates to a sensor for detecting saliva glucose concentration.

[0033] like Figure 1 As shown, the sensor 10 of the present invention is a biosensor, in particular an ISFET (Ion Sensitive Field Effect Transistor) sensor, which is used to convert glucose in human saliva into electrical signal data to detect the glucose content.

[0034] According to one embodiment of the present invention, Figure 1 As shown, the silicon-based sensor 10 includes a silicon-based substrate 11 , an oxide layer 12 formed on the silicon-based substrate 11 , such as a SiO 2 layer, a semiconductor device 13 formed on the SiO 2 wafer, and a modification layer 14 formed on the semiconductor device 13 .

[0035] The glucose conversion layer 2 is coated on the modification layer 14 .

[0036] In one embodiment, the semiconductor device 13 is an ISFET transistor, wherein the gate region G of the ISFET is formed on the SiO2 layer 12, and the drain region D and the source region S are respectively formed on the silicon-based substrate 11. More specifically, the drain region D and the source region S are formed at intervals along both sides of the gate region G. A sensitive layer 16 is also formed on the drain region D and the source region S. The modification layer 14 covers the gate region G, the drain region D and the source region S, and also covers the sensitive layer 16 thereon.

[0037] like Figure 1 As described above, the oxide layer 12 is formed with a groove 12 a, the gate region G is accommodated in the groove 12 a, and the drain region D and the source region S are arranged outside the groove 12 a of the oxide layer 12 to ensure that the two are isolated from each other.

[0038] The glucose conversion layer includes nano-organic materials that can decompose glucose to generate hydrogen ions. The modified layer 14 can allow the hydrogen ions to pass through and be captured by the sensitive layer 16 and converted into electrical signals.

[0039] The modified layer 14 includes a specially designed polymer material, such as a polyethyleneimine (PEI) derivative, which is chemically modified and has specific functional groups, and has the ability to selectively permeate hydrogen ions, ensuring that the hydrogen ions generated by the glucose conversion layer can pass smoothly and reach the sensitive layer. In other embodiments, the polymer material can also be: polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS) or polyparaphenylene vinylene (PPV) derivatives. At the same time, the modified layer 14 may also contain small molecule additives, such as surfactants. These surfactants can improve the interface compatibility between the modified layer and other layers, reduce interlayer defects and gaps, and improve the overall performance of the sensor.

[0040] The sensitive layer 16 includes a semiconductor material based on a metal oxide, such as zinc oxide (ZnO) nanoparticles, which can stably fix the relevant components to prevent them from falling off or inactivating during use. ZnO has good chemical stability and electronic conductivity, can effectively capture hydrogen ions that penetrate through the modified layer, and convert them into electrical signals. ZnO nanoparticles have a large specific surface area, can provide more active sites, and improve the sensitivity of the sensor to hydrogen ions. In addition, the sensitive layer may contain doping elements, such as aluminum (Al). The electrical properties of ZnO can be adjusted by doping Al, and its response characteristics to hydrogen ions can be further optimized. For example, an appropriate amount of Al doping can increase the carrier concentration of ZnO, speed up the transmission speed of electrical signals, and thus improve the response speed of the sensor.

[0041] In one embodiment of the present invention, the glucose conversion layer 2 comprises nano-organic materials encapsulating glucose oxidase, wherein the enzyme is glucose oxidase.

[0042] The nano-organic material is a metal organic framework (MOF) combining metal ions and organic ligands. The metal ions of the metal organic framework (MOF) are selected from alkali metals, alkaline earth metals, transition metals, IIIA group metals, VIII group metals, rare earth metals, and metal complexes. The organic ligands of the metal organic framework (MOF) are selected from nitrogen-containing organic ligands, carboxylate ligands, amino group-modified ligands, photosensitizer-composite-modified ligands, and electron-rich conjugated ligands.

[0043] In some embodiments, the glucose conversion layer 2 comprises a zeolitic imidazolate framework (ZIF) as a metal organic framework, and glucose oxidase (GOx) is loaded on a GOx-MOF material in the ZIF.

[0044] Preparation method of the Gox-MOF comprises the following steps:

[0045] S1: Add water to the reaction bottle in advance, then add metal ions, enzymes, and organic ligands in a molar ratio of 100-1500:1-10:1-150, and 0.1%-0.5% (weight ratio) of ammonia water to the reaction bottle in sequence,

[0046] S2: Mixing reaction at room temperature for more than 6 hours,

[0047] S3: After centrifugation in a centrifuge, the supernatant is removed to obtain a solid precipitate of GOx-MOF material loaded with glucose oxidase.

[0048] S4: Use water to make up to volume, and store the obtained GOx-MOF material loaded with glucose oxidase at 2-8°C for later use.

[0049] In some preferred embodiments, the metal is a zinc derivative or an iron derivative; the organic ligand is an imidazole: 2-methylimidazole, 2-imidazolecarboxaldehyde, 3-methyl-1H-1,2,4-triazole, 2-imidazolecarboxylic acid, 2-aminoimidazole sulfate, 3-bromo-1,2,4-triazole, etc., or an aromatic carboxylic acid: 2-aminoterephthalic acid.

[0050] In addition, Bis-PEGn-Acid chains can be added as auxiliary agents, and Bis-PEG2-Acid, Bis-PEG4-Acid, and Bis-PEG8-Acid can be selected to effectively improve the water solubility of MOF materials.

[0051] In one embodiment, the glucose signal detected by the MOF-loaded GOx system is 5 times the detection signal of the single GOx system without MOF loading, such as Figure 2 shown.

[0052] Those skilled in the art will appreciate that the foregoing examples are illustrative and not restrictive. It will be apparent to those skilled in the art upon reading the specification and studying the drawings that all permutations, enhancements, equivalents, and improvements are included within the true spirit and scope of the present invention. Therefore, the appended claims are intended to include all such modifications, permutations, and equivalents that fall within the true spirit and scope of these teachings.

[0053] Description of Reference Numerals

[0054] 10 Sensors

[0055] 11 Silicon-based substrate

[0056] 12 Oxide layer

[0057] 12a Groove

[0058] 13 Semiconductor devices

[0059] 14. Modification layer

[0060] 16 Sensitive Layer

[0061] D Drain region

[0062] G Gate region

[0063] S Source region

[0064] 2 Glucose conversion layer

Claims

1. A sensor (10) for detecting saliva glucose concentration, characterized in that: The sensor is coated with a glucose conversion layer (2), and the glucose conversion layer (2) is used to convert glucose in the saliva to be detected into hydrogen ions, so that the hydrogen ions are captured by the sensor (10) and converted into electrical signals.

2. The sensor according to claim 1, characterized in that The sensor comprises a silicon-based substrate (11), an oxide layer (12) formed on the silicon-based substrate (11), an ISFET transistor (13) formed on the oxide layer, and a modification layer (14) formed on the ISFET transistor (13). The glucose conversion layer (2) is coated on the modification layer (14).

3. The sensor according to claim 2, characterized in that The ISFET transistor comprises a gate region (G), a drain region (D) and a source region (S), wherein the gate region (G) is formed on the oxide layer (12), the drain region (D) and the source region (S) are formed at intervals along both sides of the gate region (G), and a sensitive layer (16) is formed on the drain region (D) and the source region (S).

4. The sensor according to claim 3, characterized in that The drain region (D) and the source region (S) are formed on a silicon-based substrate (11).

5. The sensor according to claim 2, characterized in that The oxide layer (12) is a SiO2 layer.

6. The sensor according to claim 2, characterized in that The oxide layer (12) is formed with a groove (12a), the gate region (G) is arranged in the groove (12a), and the drain region (D) and the source region (S) are arranged outside the oxide layer (12).

7. The sensor according to claim 1, characterized in that The glucose conversion layer (2) includes nano-organic materials that can decompose glucose to generate hydrogen ions, and the modified layer can allow hydrogen ions to pass through and be captured by the sensitive layer (16) and converted into electrical signals.

8. The sensor according to claim 2, characterized in that The modified layer (14) comprises a chemically modified polymer material having a selective permeability to hydrogen ions.

9. The sensor according to claim 8, characterized in that The polymer material is a polyethyleneimine (PEI) derivative, polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS) or polyparaphenylene vinylene (PPV) derivative.

10. The sensor according to claim 1, characterized in that The sensitive layer (16) comprises a metal oxide based semiconductor material.

11. The sensor according to claim 10, characterized in that The metal oxide is zinc oxide (ZnO) nanoparticles.

12. The sensor according to claim 10, characterized in that The sensitive layer may contain doping elements.

13. The sensor according to claim 12, characterized in that The doping element is aluminum (Al).

14. The sensor according to claim 7, characterized in that The nano-organic material of the modification layer includes a metal organic framework (MOF) encapsulating glucose oxidase.

15. The sensor according to claim 14, characterized in that The metal ion of the metal organic framework (MOF) is selected from one of alkali metals, alkaline earth metals, transition metals, group IIIA metals, group VIII metals, rare earth metals, and metal complexes; and the organic ligand of the metal organic framework (MOF) is selected from one of nitrogen-containing organic ligands, carboxylate ligands, amino group-modified ligands, photosensitizer-composite-modified ligands, and electron-rich conjugated ligands.

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