MOF-based glucose detection system, sensor for detecting glucose concentration in saliva, and non-invasive oral glucose meter

Abstract

A method for preparing an MOF-based glucose detection system, wherein a Zeolitic Imidazolate Framework (ZIF) is used as a metal-organic framework, and glucose oxidase (GOx) is loaded in the zeolitic imidazolate framework. The preparation method comprises the following steps: S1: adding water to a reaction flask in advance, and then sequentially adding a metal ion, an enzyme and an organic ligand in a molar ratio of 100-1500:1-10:1-150, and 0.1-0.5% (by weight) of ammonia water to the reaction flask, S2: mixing and reacting same at room temperature for more than 6 hours, and S3: after centrifugation by means of a centrifuge, removing the supernatant to obtain a solid precipitate of the Gox-MOF material loaded with glucose oxidase. A sensor for detecting trace glucose concentration in saliva, and an oral glucose meter comprising the sensor.

Description

MOF glucose detection system, sensor for detecting saliva glucose concentration, non-invasive oral blood glucose meter Technical Field

[0001] This invention relates to a MOF-sensitized glucose detection system and its preparation method, a sensor using the MOF glucose detection system, and a non-invasive blood glucose detection device having the sensor. Background Technology

[0002] Early detection and management of diabetes are crucial for patients. Traditional methods of blood glucose testing all require blood samples, which are time-consuming, invasive, and painful, and can increase the risk of infection and transmission. Some existing electronic blood glucose meters are still invasive and complex to operate, making them inconvenient to use. Therefore, various non-invasive blood glucose testing methods and devices have been developed.

[0003] Chinese invention patent 201910230348.2 discloses a non-invasive blood glucose detection method, which calculates blood glucose values ​​by simulating experiments using human metabolic heat measurement through model design. However, this simulation calculation method is both complex and the detection results are inaccurate.

[0004] Chinese invention patent 202410680902.8 discloses a blood glucose meter and detection method based on Raman spectroscopy, which measures blood glucose by detecting the spectrum on the skin surface. However, the measurement error of this method is very large and differs greatly from the actual result. Therefore, 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 glucose test strip based on colorimetry, but it has low detection sensitivity and is only effective for patients with severely elevated blood glucose levels, making its application too narrow. Furthermore, this product is expensive; for people with high blood glucose, multiple blood glucose tests per day are required, resulting in excessively high costs per person.

[0006] Saliva, as an oral fluid, contains a variety of substances, including inorganic ions, small organic molecules, lipids, proteins, and various hormones. Saliva collection is convenient and non-invasive, making it suitable as a biological sample for research and clinical practice. In both type 1 and type 2 diabetes, saliva glucose levels reflect blood glucose levels. Therefore, diabetes can be monitored by detecting the low concentration of glucose in saliva. Normal human blood glucose concentration is 2-30 mmol / L, while saliva glucose concentration is 0.025-0.1 mmol / L. In diabetic patients, saliva glucose levels are significantly elevated, generally exceeding 0.4 mmol / L.

[0007] By detecting the glucose concentration in a patient's saliva, the corresponding blood glucose level can be indirectly detected, thus allowing for non-invasive blood glucose measurement. Therefore, using saliva to detect blood glucose is feasible.

[0008] However, compared to the glucose concentration in blood, the glucose concentration in saliva is extremely low. Current technologies struggle to directly detect the glucose content in saliva. A highly sensitive measurement method is needed to conveniently and effectively measure the glucose content of oral saliva for practical application. Existing technologies cannot detect the low glucose concentration in saliva; therefore, a new technology capable of detecting salivary blood glucose is required.

[0009] Metal-organic frameworks (MOFs) are linked together by the interaction of metal ions and organic ligands. Due to their large specific surface area, excellent thermal stability, variable functional groups, and uniformly tunable pore size, they play an important role in the biomedical field.

[0010] Zeolitic imidazolate frameworks (ZIFs) are an important type of molecular sieve (MOF), formed by the self-assembly of molecules and bridging organic links between metal nodes. They possess a tetrahedral three-dimensional network structure, structurally similar to zeolites, using zinc (Zn²⁺) or cobalt (Co²⁺) to replace silicon in zeolites and imidazolate ligands to replace oxygen bridges. ZIFs possess some of the functions of molecular sieves: ① uniform and tunable pore size, enabling molecular sieving; ② ion exchange and selective adsorption functions; ③ high-temperature stability and selective catalytic performance, allowing them to be used as membrane reactors to separate products while simultaneously catalyzing the reaction process, achieving integrated separation and catalysis; ④ diverse structural types, making them ideal separation and catalytic materials.

[0011] Enzymes are a crucial class of biological catalysts, enabling chemical reactions within organisms to proceed efficiently and specifically even under extremely mild conditions. Their efficiency, specificity, and selectivity far surpass those of artificial catalysts. However, the inherent fragility of enzymes, such as their susceptibility to temperature and pH fluctuations and their low tolerance to most organic solvents and small-molecule inhibitors, severely limits the effectiveness of enzyme systems in practical applications.

[0012] Methods for loading enzymes onto MOF nanomaterials include surface bioconjugation, pore permeation, or in-situ encapsulation. Details are as follows:

[0013] 1) Surface bio-coupling methods can be divided into physical adsorption, covalent bonding and coordination bonding according to different attachment processes and mechanisms.

[0014] ① Physical adsorption methods mainly rely on weak interactions to fix biomolecules onto MOFs, such as van der Waals forces, hydrogen bonds, π-π interactions, electrostatic interactions, or hydrophobic interactions.

[0015] ② The mechanism of covalent linkage involves biomolecules forming peptide bonds with amino or carboxyl groups on MOFs under the action of functional molecules or catalysts, thereby achieving linkage. Among these methods, glutaraldehyde coupling based on the Schiff base reaction is the most commonly used method for enzyme immobilization. One aldehyde group of the glutaraldehyde molecule reacts with the amino group of the enzyme molecule, while the other aldehyde group reacts with the amino group of the MOF. In addition, click reactions can also be used for enzyme immobilization, achieving linkage through CXC bonds formed between heteroatoms.

[0016] ③ Coordination linkage: There are unsaturated coordination metal sites on the outer surface of MOF crystals, which have the potential to form coordination bonds with amino acids, thus enabling coordination linkage.

[0017] 2) The pore permeation method binds biomolecules under mild conditions, largely avoiding impacts on their structure and activity. The abundant pores of MOFs also provide environmental protection for enzymes (e.g., organic solvents, extreme pH values, denaturants, high temperatures, etc.), thereby improving the enzyme's environmental tolerance. Furthermore, the tunable pore size of MOFs provides selectivity for substrate enzyme molecules. However, this method requires greater steric compatibility between the MOF and the coated enzyme; therefore, MOFs with larger pore sizes, such as MIL-100, Nu-100X, and IR MOF-74, are frequently used.

[0018] 3) A typical example of in-situ encapsulation is the one-pot method. In this method, MOF forms a protective shell around the enzyme, reducing enzyme leaching from the MOF matrix and maintaining enzyme activity even in extremely harsh environments. One-pot methods can be divided into co-precipitation and biomineralization, depending on the presence or absence of a co-precipitant. For co-precipitation, an auxiliary stabilizer is needed to maintain enzyme activity; a common co-precipitant is polyvinylpyrrolidone (PVP). For biomineralization, the enzyme can be directly mixed with MOF to form a biocomposite material, eliminating the need for a co-precipitant.

[0019] Studies have shown that biomacromolecules can induce and regulate the growth of MOFs in aqueous solutions, while MOFs can act as a protective coating, inhibiting the harmful effects of high temperatures and proteolytic agents on encapsulated biomacromolecules and ensuring their function under normal operating conditions. This in-situ encapsulation method, known as "one-pot precipitation" or "biomimetic mineralization," allows microporous MOFs to crystallize around biomolecules. This method has been used in biological systems, including enzymes, antibodies, and nucleic acids. The porous MOF exoskeleton can enhance the stability of encapsulated enzymes through structural confinement and selectively transport guest molecules through the microporous network accessible by the exoskeleton. The symbiotic reinforcement effect between MOF materials and enzymes makes MOF-immobilized enzymes have great potential in various fields.

[0020] To date, zeolite imidazole salt frameworks (ZIFs) composed of zinc and 2-methylimidazole (Hmim) are the most widely studied MOFs due to their simple synthetic conditions and compatibility with biological antibodies. For example, ZIF-8, due to its microporosity (pore size typically less than 2 nm), offers a tight structural constraint conducive to the stability of encapsulated biomolecules. However, enzymes encapsulated in ZIFs often exhibit low activity, which is far from satisfactory due to limited mass diffusion rates. The inherent micropores restrict the free access of large matrices to the micropores, hindering entry into the active sites of bioactive ZIF composites.

[0021] In view of the above problems, there is an urgent need to develop materials that can functionally load enzymes without affecting enzyme activity for use in biochemical sensing, thereby enhancing detection performance, expanding the detection limit, and improving signal quality. Meanwhile, applying the improved MOF-sensitized glucose detection system to glucose sensors, and subsequently fabricating glucose detection devices, has potential benefits. Summary of the Invention

[0022] The technical problem to be solved by the present invention is to provide a sensitized glucose detection system that can quickly and accurately detect low concentrations of glucose.

[0023] Another technical problem to be solved by the present invention is to provide a sensor for detecting trace amounts of glucose concentration in saliva.

[0024] Another technical problem to be solved by the present invention is to provide a non-invasive oral blood glucose meter.

[0025] According to one aspect of the present invention, a method for preparing a MOF glucose detection system is provided, which uses a zeolitic imidazolate framework (ZIF) as a metal-organic framework and loads glucose oxidase (GOx) into the ZIF. The preparation method includes the following steps:

[0026] S1: First, add water to the reaction flask, then add metal ions, enzymes, and organic ligands in a molar ratio of 100–1500:1–10:1–150, along with 0.1%–0.5% (by weight) ammonia water, sequentially into the reaction flask.

[0027] S2: Mixed reaction at room temperature for more than 6 hours.

[0028] S3: After centrifugation, the supernatant was removed to obtain a solid precipitate of GOx-MOF material loaded with glucose oxidase.

[0029] Preferably, in step S1, the amount of water added to the reaction flask is 80-95% (by weight).

[0030] Preferably, the preparation method further includes: S4: using water to make up the volume, and storing the obtained GOx-MOF material loaded with glucose oxidase at 2-8℃ for later use, wherein the ratio of the volume of water used for making up the volume to the total volume of the raw materials added to the reaction flask in step S1 is 0.1-100.

[0031] Preferably, the metal ion is selected from one of the following: alkali metals, alkaline earth metals, transition metals, group IIIA metals, group VIII metals, rare earth metals, metal complexes, and metal clusters.

[0032] Preferably, the organic ligand is selected from nitrogen-containing organic ligands, carboxylate ligands, ligands modified with amino groups, ligands modified with photosensitizers, and electron-rich conjugated ligands.

[0033] Preferably, the centrifuge speed is 1000-30000 rpm.

[0034] Preferably, an auxiliary agent may be added in step S1.

[0035] Preferably, the auxiliary agent is a Bis-PEGn-Acid chain.

[0036] Preferably, the Bis-PEGn-Acid chain is Bis-PEG2-Acid, Bis-PEG4-Acid, or Bis-PEG8-Acid.

[0037] Preferably, the metal ion is a zinc derivative or an iron derivative.

[0038] Preferably, the metal ion is zinc sulfide, zinc chloride, zinc bromide, zinc oxide, zinc iodide, zinc sulfate, zinc acetate, zinc carbonate, zinc nitrate, or their hydrates.

[0039] Preferably, the organic ligand is polydiaminoimidazole.

[0040] Preferably, the organic ligand is 2-methylimidazole, 2-imidazolium formaldehyde, imidazolium-2-carboxylic acid, benzimidazole, 2-methylbenzimidazole, 1,2,4-triazole, 3-methyl-1H-1,2,4-triazole, 1,2,4-triazole-3-carboxylic acid, polyazole or its derivatives.

[0041] Preferably, the water is ultrapure water.

[0042] Preferably, the mixing is performed by oscillation or stirring.

[0043] According to another aspect of the present invention, an application of an MOF glucose detection system in the detection of glucose content in saliva is provided, wherein the MOF glucose detection system is prepared by the above-described preparation method.

[0044] According to another aspect of the present invention, a sensor for detecting glucose concentration in saliva is provided, characterized in that the sensor is coated with a glucose conversion layer, the glucose conversion layer being used to convert glucose in the saliva to be detected into hydrogen ions, such that the hydrogen ions are captured by the sensor and converted into an electrical signal.

[0045] Preferably, the sensor includes a silicon substrate, an oxide layer formed on the silicon 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.

[0046] Preferably, the ISFET transistor includes a gate region, a drain region, and a source region, wherein the gate region is formed on the oxide layer, and 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.

[0047] Preferably, the drain region and the source region are formed on a silicon substrate.

[0048] Preferably, the oxide layer is a SiO2 layer.

[0049] Preferably, the oxide layer is formed with trenches, the gate region is disposed within the trenches, and the drain region and the source region are disposed outside the oxide layer.

[0050] Preferably, the glucose conversion layer comprises a nano-organic material capable of decomposing glucose to generate hydrogen ions, and the modified layer allows hydrogen ions to pass through, be captured by the sensitive layer, and be converted into an electrical signal.

[0051] Preferably, the modified layer comprises a chemically modified polymer material that selectively allows hydrogen ions to permeate.

[0052] Preferably, the polymer material is a polyethyleneimine (PEI) derivative, polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS), or poly(p-phenylenevinyl chloride) (PPV) derivative.

[0053] Preferably, the sensitive layer comprises a semiconductor material based on a metal oxide.

[0054] Preferably, the metal oxide is zinc oxide (ZnO) nanoparticles.

[0055] Preferably, the sensitive layer may contain doping elements.

[0056] Preferably, the doping element is aluminum (Al).

[0057] Preferably, the nano-organic material of the modified layer includes a metal-organic framework (MOF) encapsulating glucose oxidase.

[0058] 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, ligands modified with amino groups, ligands modified with photosensitizer complexes, and electron-rich conjugated ligands.

[0059] To address this, the present invention proposes an oral glucose meter, comprising: a mounting section; a detection section mounted in the mounting section, the detection section including a sensor coated with a glucose conversion layer, the sensor being used to receive saliva to be tested; a control section electrically connected to the detection section, the control section being used to measure the glucose content value of the saliva received by the silicon-based sensor; and a display section for displaying the glucose content value measured by the control section, wherein the glucose conversion layer is used to convert glucose in the saliva to be tested into hydrogen ions, such that the hydrogen ions are captured by the sensor and converted into an electrical signal, the electrical signal being input to the control section, and the control section calculating the glucose content value based on the electrical signal.

[0060] Preferably, the sensor is a silicon-based sensor.

[0061] Preferably, the silicon-based sensor includes a silicon substrate, an oxide layer formed on the silicon substrate, a semiconductor device formed on the oxide layer, and a modification layer formed on the semiconductor device, wherein the glucose conversion layer is coated on the modification layer.

[0062] Preferably, the semiconductor device is an ISFET field-effect transistor, which includes a gate region, a drain region, and a source region. The gate region is formed on the oxide layer, and the drain region and the source region are formed at intervals along both sides of the gate region. A sensitive layer is formed on the drain region and the source region.

[0063] Preferably, the drain region and the source region are formed on a silicon substrate.

[0064] Preferably, the oxide layer is a SiO2 layer.

[0065] Preferably, the oxide layer is formed with trenches, the gate region is disposed within the trenches, and the drain region and the source region are disposed outside the oxide layer.

[0066] Preferably, the modified layer comprises a chemically modified polymer material that selectively allows hydrogen ions to permeate.

[0067] Preferably, the polymer material is a polyethyleneimine (PEI) derivative, polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS), or poly(p-phenylenevinyl chloride) (PPV) derivative.

[0068] Preferably, the sensitive layer comprises a semiconductor material based on a metal oxide.

[0069] Preferably, the metal oxide is zinc oxide (ZnO) nanoparticles.

[0070] Preferably, the sensitive layer may contain doping elements.

[0071] Preferably, the doping element is aluminum (Al).

[0072] Preferably, the glucose conversion layer is a nano-organic material encapsulating the enzyme.

[0073] Preferably, the nano-organic material encapsulating the enzyme is a metal-organic framework (MOF) that combines metal ions and organic ligands.

[0074] Preferably, the metal ion of the metal-organic framework (MOF) is selected from one of the following: alkali metals, alkaline earth metals, transition metals, group IIIA metals, group VIII metals, rare earth metals, and metal complexes.

[0075] Preferably, the enzyme is glucose oxidase.

[0076] Preferably, the control unit includes an MCU and a power supply, wherein the MCU controls the signal transmission of the silicon-based sensor and the calculation of glucose content.

[0077] Preferably, the control unit further includes a wireless communication module for data communication with the outside world.

[0078] Preferably, the control unit further includes a power management module and a charging port.

[0079] Preferably, the silicon-based sensor is electrically connected to the control unit via a connector.

[0080] Preferably, the silicon-based sensor is provided with a protective cover.

[0081] According to another aspect of the present invention, an oral cleaning agent for use with a blood glucose meter is also provided, which is prepared from the following materials: 3-8g of nonionic surfactant, 2-6g of menthol oil, 8-16g of trimagnesium phosphate, 0.3-0.9g of vanillin, and 0.6-2.2g of pH adjuster.

[0082] Preferably, the oral cleanser further includes 10-20g of herbal enzymes and 0.05-0.1g of Magnolia officinalis extract.

[0083] Preferably, the herbal enzyme is composed of aloe vera enzyme, soapberry fruit enzyme, and papaya enzyme.

[0084] The present invention has the following advantages:

[0085] I. The MOF glucose detection system of this invention engineeres MOF materials into an outer framework using a water-based solvent "one-pot precipitation" method, encapsulating the enzyme within it for protection against the influence of complex environments. Results of this invention show that the porous MOF outer framework not only enhances the activity, stability, and sensitivity of the encapsulated enzyme through structural confinement, maintaining its biocatalytic function, but also endows the MOF material-encapsulated enzyme with great potential for complex applications due to the symbiotic reinforcement between the MOF material and the enzyme, including enzyme carriers in biochemical sensing, biocatalysis, and cancer therapy. In particular, the MOF glucose detection system of this invention can be applied to the detection of glucose in oral saliva; even at extremely low glucose concentrations, this invention can efficiently and accurately detect the glucose concentration in saliva.

[0086] Second, the sensor of the present invention is coated with a glucose conversion layer, which can convert glucose in the saliva to be detected into hydrogen ions, and the hydrogen ions are captured by the sensor and converted into an electrical signal, which can detect trace amounts of glucose, thereby achieving the detection of trace amounts of glucose in oral saliva to correspond to the blood sugar level of the test subject.

[0087] Third, the present invention uses a glucose conversion layer containing Gox-MOF material, which can improve detection sensitivity and enable rapid and accurate detection of glucose levels.

[0088] Fourth, the sensor of this invention uses an ISFET biosensor, which has a simple structure, is easy to manufacture, and has high sensitivity.

[0089] V. This invention uses a blood glucose meter with a silicon-based sensor to detect trace amounts of glucose in oral saliva to correspond to the blood glucose level of the test subject. It is convenient to use and non-invasive.

[0090] VI. Based on a highly sensitive glucose conversion layer combined with silicon-based sensor technology, it enables rapid and convenient saliva collection, suitable for daily monitoring, real-time monitoring, and rapid response, providing timely feedback on changes in blood glucose levels.

[0091] VII. Intelligent Functions: It can connect to smart devices to record and analyze data.

[0092] 8. The present invention also provides an oral cleaning agent for use with a blood glucose meter to avoid food residue, microorganisms and bacteria in the mouth from affecting the accuracy of the test. Attached Figure Description

[0093] Figures 1-4 are comparative graphs showing the glucose detection sensitization performance of GOx and GOx-MOF materials in various embodiments.

[0094] Figure 5 is a schematic diagram of the silicon-based sensor of the present invention.

[0095] Figure 6 is a comparison of the detection effects of glucose with and without the MOF sensitization system of the present invention.

[0096] Figure 7 is a schematic diagram of the oral blood glucose meter of the present invention.

[0097] For ease of understanding, the same reference numerals are used where possible to denote common elements in the figures. It is contemplated that elements disclosed in one embodiment may be advantageously used in other embodiments without specific description. Detailed Implementation

[0098] According to a MOF-sensitized glucose detection system of the present invention, a zeolitic imidazolate framework (ZIF) is used as a metal-organic framework, and glucose oxidase (GOx) is loaded in the ZIF.

[0099] The MOF-sensitized glucose detection system can be made from the following concentration ratio range: metal ions, enzymes and organic ligands in a molar ratio of 100-1500:1-10:10-150, plus 0.1%-0.5% (by weight) ammonia.

[0100] The specific preparation method includes the following steps:

[0101] S1: Add water to the reaction flask beforehand, and then add the materials with the appropriate molar ratios to the reaction flask in sequence.

[0102] S2: Mix at room temperature (e.g., shake, stir, or similar means) and react for more than 6 hours, observing the precipitation process.

[0103] S3: After centrifugation (1000-30000 rpm), remove the supernatant to obtain a solid precipitate.

[0104] S4: Use water to bring the volume to a final level, and then store the GOx-MOF material loaded with glucose oxidase at 2-8℃ for later use.

[0105] In the above preparation method, auxiliary agents, such as Bis-PEGn-Acid chains, can also be added to effectively improve the water solubility of MOF materials.

[0106] In the above preparation method, in step S1, the water added to the reaction flask is 80-95% (by weight), and in one embodiment, it is preferably 1-5 mL of ultrapure water.

[0107] In the above preparation method, in step S4, the ratio of the volume of water used for the final volume adjustment to the total volume of the raw materials added to the reaction flask in step S1 is 0.1-100. In one embodiment, 1-3 mL of ultrapure water is preferred.

[0108] The metal ions mentioned above are selected from at least one of the metals listed below:

[0109] 1) Alkali metals:

[0110] Lithium (Li + Lithium chloride, lithium fluoride, lithium carbonate, lithium sulfate, lithium nitrate, lithium phosphate, lithium bromide, lithium iodide, lithium acetate and their hydrates, etc.

[0111] Sodium (Na + Sodium chloride, sodium fluoride, sodium carbonate, sodium sulfate, sodium nitrate, sodium phosphate, sodium bromide, sodium iodide, sodium acetate and their hydrates, etc.

[0112] Potassium (K) + Potassium chloride, potassium fluoride, potassium carbonate, potassium sulfate, potassium nitrate, potassium phosphate, potassium bromide, potassium iodide, potassium acetate and their hydrates, etc.

[0113] Rubidium (Rb) + Rubidium chloride, rubidium fluoride, rubidium carbonate, rubidium sulfate, rubidium nitrate, rubidium bromide, rubidium iodide and their hydrates, etc.

[0114] Cesium (Cs) + Cesium chloride, cesium fluoride, cesium carbonate, cesium sulfate, cesium nitrate, cesium bromide, cesium iodide and their hydrates, etc.

[0115] 2) Alkaline earth metals:

[0116] Calcium (Ca 2+ ): Calcium chloride, calcium bromide, calcium oxide, calcium iodide, calcium sulfate, calcium acetate, calcium carbonate, calcium nitrate and their hydrates, etc.

[0117] Magnesium (Mg) 2+ Magnesium chloride, magnesium bromide, magnesium oxide, magnesium iodide, magnesium sulfate, magnesium acetate, magnesium carbonate, magnesium nitrate and their hydrates, etc.

[0118] Strontium (Sr 2+ ): Strontium chloride, strontium bromide, strontium oxide, strontium iodide, strontium carbonate, strontium nitrate and their hydrates, etc.

[0119] Barium (Ba 2+ Barium chloride, barium bromide, barium oxide, barium iodide, barium carbonate, barium nitrate and their hydrates, etc.

[0120] 3) Transition metals:

[0121] Manganese (Mn) 2+ Manganese sulfide, manganese chloride, manganese bromide, manganese fluoride, manganese iodide, manganese oxide, manganese acetate, manganese carbonate and their hydrates, etc.

[0122] Copper (Cu) + / Cu 2+ Copper sulfide, copper chloride, copper bromide, copper fluoride, copper iodide, copper oxide, copper acetate, copper carbonate and their hydrates, etc.

[0123] Zinc (Zn) 2+ ): Zinc sulfide, zinc chloride, zinc bromide, zinc oxide, zinc iodide, zinc sulfate, zinc acetate, zinc carbonate, zinc nitrate and their hydrates, etc.

[0124] Iron (Fe) 2+ / Fe 3+ Ferric chloride, ferric oxide, ferric sulfate, ferric sulfide, ferric citrate, ferric nitrate and their hydrates, etc.

[0125] Indium (In) 3+ Indium chloride, indium acetate, indium sulfate, indium nitrate, indium phosphide, indium bromide, indium oxide, indium iodide, indium fluoride and their hydrates, etc.

[0126] Thallium (Tl) + Thallium chloride, thallium acetate, thallium sulfate, thallium nitrate, thallium bromide, thallium oxide, thallium iodide and their hydrates, etc.

[0127] Palladium (Pd) + Palladium chloride, palladium acetate, palladium sulfate, palladium nitrate, palladium bromide, palladium oxide, palladium iodide and their hydrates, etc.

[0128] Silver (Ag) + Silver chloride, silver acetate, silver sulfate, silver nitrate, silver bromide, silver oxide, silver iodide, silver fluoride and their hydrates, etc.

[0129] Gold (Au) + Gold chloride, gold bromide, gold iodide and their hydrates, etc.

[0130] Zirconium (Zr) 2+ / Zr 4+ Zirconium oxide, zirconium chloride, zirconium fluoride, zirconium sulfate, zirconium acetate, zirconium hydrogen phosphate, zirconium dihydroxydioxane carbonate, zirconium oxychloride and its hydrates, etc.

[0131] 4) Group IIIA metals:

[0132] Aluminum (Al) 3+ Aluminum oxide, aluminum chloride, aluminum fluoride, aluminum carbonate, aluminum sulfate, aluminum nitrate, aluminum phosphate, aluminum bromide, aluminum iodide, aluminum acetate and their hydrates, etc.

[0133] Gallium (Ga 3+ Gallium oxide, gallium sulfate, gallium nitrate, gallium bromide, gallium iodide and their hydrates, etc.

[0134] 5) Group VIII metals: Cobalt (Co) 2+ Cobalt sulfide, cobalt oxide, cobalt carbide, cobalt bromide, zinc chloride, cobalt acetate, cobalt carbonate, cobalt nitrate and their hydrates, etc.

[0135] 6) Rare earth metals: compounds of rare earth metals such as lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), and lutetium (Lu).

[0136] 7) Metal complexes: lithium cobalt oxide, lithium cobalt phosphate, potassium cobalt cyanide, strontium titanate, potassium chloroaurate, etc.

[0137] 8) Metal clusters: Zr6O4(OH)4, Zr6O4(OH)4(H2O)4, Fe3O(OH)3, etc.

[0138] Preferably, the metal ion used is zinc (Zn). 2+ For example, zinc sulfide, zinc chloride, zinc bromide, zinc oxide, zinc iodide, zinc sulfate, zinc acetate, zinc carbonate, zinc nitrate, or their hydrates can be used.

[0139] The organic ligand is selected from at least one of the following organic ligands:

[0140] 1) Nitrogen-containing organic ligands:

[0141] ①Pyrimidines: pyrimidine, 4-amino-2-hydroxypyrimidine, 2,4-dihydroxy-5-methylpyrimidine, 2,4-dihydroxypyrimidine, etc.

[0142] ②Porphyrins: Porphyrins and their derivatives.

[0143] ③ Phthalocyanines: Phthalocyanines and their derivatives.

[0144] ④ Polyazoles: imidazoles (such as imidazole, 2-methylimidazolium, 2-imidazolium carboxaldehyde, imidazole-2-carboxylic acid, benzimidazole, 2-methylbenzimidazole, 1,2,4-triazole, 3-methyl-1H-1,2,4-triazole, 1,2,4-triazole-3-carboxylic acid, etc.), polyazoles and their derivatives.

[0145] 2) Carboxylate ligands:

[0146] ① Aliphatic carboxylic acids: acetic acid, propionic acid, etc.

[0147] ② Aromatic carboxylic acids: including monocyclic and polycyclic aromatic carboxylic acids, such as benzoic acid, cinnamic acid, terephthalic acid, phthalic acid, pyromellitic acid, biphenyl-4,4'-dicarboxylic acid, biphenyl-3,3'-dicarboxylic acid, 2,6-naphthalenedicarboxylic acid, [1,1':4',1”-terphenyl]-4,4”-dicarboxylic acid, 2',5'-dimethyl-[1,1':4',1”-terphenyl]-4,4”-dicarboxylic acid, [1,1':4',1”:4”,1”'-tetraphenyl]-4,4”' ... ['-Tetraphenyl]-3,3”',5,5”'-tetracarboxylic acid, 1,3,5-tris(4-carboxyphenyl)benzene, 1,2,4,5-tetra(4-carboxyphenyl)benzene, 5'-(3,5-dicarboxyphenyl)-[1,1':3',1”-terphenyl]-3,3”,5,5”-tetracarboxylic acid, 4,4-(anthracite-9,10-diyl)dibenzoic acid, 4,4',4”,4”'-(pyrene-1,3,6,8-tetramethyl)tetrabenzoic acid, 6,6',6”,6”'-(pyrene-1,3,6,8-tetramethyl)tetra(2-naphthoic acid), etc.

[0148] ③ Aromatic carboxylic acids containing additional functional groups: Carboxylic acids containing heteroatoms such as nitrogen, oxygen, sulfur, and bromine, such as 2-aminoterephthalic acid, 2,5-diaminophenyl-1,4-dicarboxylic acid, 2-bromoterephthalic acid, 4,4',4”-(phenyl-1,3,5-triyltri(oxy))tribenzoic acid, 4,4'-(benzo[c][1,2,5]thiadiazole-4,7-diyl)dibenzoic acid, etc.; Carboxylic acids containing unsaturated bonds, such as 4,4'-[1,4-phenylenebis(acetylene-2,1-diyl)]dibenzoic acid, 4,4',4”,4'-(ethylene-1,1,2,2-tetrayl)tetrabenzoic acid, 4,4',4”-(phenyl-1,3,5-triyltri(acetylene-2,1-diyl))tribenzoic acid, etc.

[0149] ④ Mixed carboxylic acid ligands: These combine multiple different types of carboxylic acid salt ligands.

[0150] 3) Other organic ligands: ligands modified with amino groups, ligands modified with photosensitizer complexes, electron-rich conjugated ligands, etc.

[0151] Preferably, the organic ligand is a polyazole class: imidazole (such as imidazole, 2-methylimidazole, 2-imidazole formaldehyde, imidazole-2-carboxylic acid, benzimidazole, 2-methylbenzimidazole, 1,2,4-triazole, 3-methyl-1H-1,2,4-triazole, 1,2,4-triazole-3-carboxylic acid, etc.), polyazole or its derivatives.

[0152] The enzyme can be selected from natural glucose oxidase (GOx) or directed-evolved glucose oxidase (GOx).

[0153] The following describes specific embodiments of GOx-MOF, using GOx-MOFN-M as the specific material name, where N refers to the number of the organic ligand and M refers to the number of the auxiliary agent Bis-PEGn-Acid.

[0154] Bis-PEGn-Acid can be selected from Bis-PEG2-Acid (numbered 1), Bis-PEG4-Acid (numbered 2), and Bis-PEG8-Acid (numbered 3). If Bis-PEG-Acid is not added, the number is 0.

[0155] Preferably, the organic ligands are imidazoles, including: 2-methylimidazolium (numbered 1), 2-imidazolium carboxaldehyde (numbered 2), 3-methyl-1H-1,2,4-triazole (numbered 3), 2-imidazolium carboxylic acid (numbered 4), 2-aminoimidazolium sulfate (numbered 5), and 3-bromo-1,2,4-triazole (numbered 6). The aromatic carboxylic acid is 2-aminoterephthalic acid (numbered 7).

[0156] Therefore, for example, GOx-MOF3-2 is a GOx-MOF material made using 3-methyl-1H-1,2,4-triazole as an organic ligand and Bis-PEG8-Acid as an auxiliary agent, and so on.

[0157] Example 1:

[0158] The metal is selected from the zinc derivative Zn(OAc)2·H2O, the organic ligand is selected from the imidazole derivative 3-methyl-1H-1,2,4-triazole, and the Bis-PEGn-Acid chain is selected from Bis-PEG2-Acid, Bis-PEG4-Acid, and Bis-PEG8-Acid (which can effectively improve the water solubility of MOF materials).

[0159] Add 1 mL of ultrapure water to a 5 mL EP tube, then add 25 μL of 0.5 M Zn(OAc)2·H2O, 50 μL of 0.05 M Bis-PEG2-Acid (or Bis-PEG4-Acid, or Bis-PEG8-Acid), 25 μL of 100 U / mL GOx, and 50 μL of 0.5 M 3-methyl-1H-1,2,4-triazole solution in sequence. Finally, add 25 μL of 10% ammonia water, seal the tube, and allow it to react with shaking at room temperature for 6 hours.

[0160] After the reaction was completed, the supernatant was removed by centrifugation at 8000 rpm, and then washed three times with 1 mL of ultrapure water to obtain a white solid precipitate. Finally, 1 mL of ultrapure water was added to make up the volume, and the precipitate was dispersed evenly using an ultrasonic machine to obtain a series of GOx-MOF materials with different water solubility, which were stored at 2-8℃ for later use.

[0161] Glucose detection experiment results: The TMB colorimetric method (detection principle: H2O2 produced by GOx oxidation of glucose causes TMB molecules to be oxidized, resulting in ultraviolet absorption at 450nm) was used to compare GOx enzyme activities. The results showed that the absorbance of GOx after responding to glucose was 0.356; the absorbance of GOx-MOF3-2 after responding to glucose was 0.650; and the absorbance of GOx-MOF3-3 after responding to glucose was 0.771.

[0162] Results analysis: The glucose detection signal of the MOF-loaded GOx system was 1.8 times and 2.2 times that of the MOF-free GOx-only system, respectively, as shown in Figure 1.

[0163] Example 2:

[0164] The metal is selected from the zinc derivative Zn(OAc)2·H2O, the organic ligand is selected from the imidazole derivative 3-bromo-1,2,4-triazole, and the Bis-PEGn-Acid chain is selected from Bis-PEG2-Acid, Bis-PEG4-Acid, and Bis-PEG8-Acid (which can effectively improve the water solubility of MOF materials).

[0165] Add 1 mL of ultrapure water to a 5 mL EP tube, then add 25 μL of 0.5 M Zn(OAc)2·H2O, 50 μL of 0.05 M Bis-PEG2-Acid (or Bis-PEG4-Acid, or Bis-PEG8-Acid), 25 μL of 100 U / mL GOx, and 50 μL of 0.5 M 3-bromo-1,2,4-triazole solution in sequence. Finally, add 25 μL of 10% ammonia solution, seal the tube, and allow it to react with shaking at room temperature for 6 hours.

[0166] After the reaction was completed, the supernatant was removed by centrifugation at 8000 rpm, and then washed three times with 1 mL of ultrapure water to obtain a white solid precipitate. Finally, 1 mL of ultrapure water was added to make up the volume, and the precipitate was dispersed evenly using an ultrasonic machine to obtain a series of GOx-MOF materials with different water solubility, which were stored at 2-8℃ for later use.

[0167] Glucose detection experiment results: The TMB colorimetric method (detection principle: H2O2 produced by GOx oxidation of glucose causes TMB molecules to be oxidized, resulting in ultraviolet absorption at 450nm) was used to compare GOx enzyme activity. The results showed that the absorbance of GOx after responding to glucose was 0.356; the absorbance of GOx-MOF6-0 after responding to glucose was 0.637; the absorbance of GOx-MOF6-1 after responding to glucose was 0.643; the absorbance of GOx-MOF6-2 after responding to glucose was 0.605; and the absorbance of GOx-MOF6-3 after responding to glucose was 0.705.

[0168] Results analysis: The glucose detection signal of the MOF-loaded GOx system was 1.8 times, 1.8 times, 1.7 times, and 2.0 times that of the MOF-free GOx-only system, as shown in Figure 2.

[0169] Example 3:

[0170] The metal is selected from the iron derivative FeCl3·6H2O, and the organic ligand is selected from the aromatic carboxylic acid derivative 2-aminoterephthalic acid.

[0171] Add 1 mL of ultrapure water to a 5 mL EP tube, then add 25 μL of 0.5 M FeCl3·6H2O, 25 μL of 100 U / mL GOx, and 50 μL of 0.5 M 2-aminoterephthalic acid in sequence. Cover the tube and shake at room temperature for 6 hours.

[0172] After the reaction was completed, the supernatant was removed by centrifugation at 8000 rpm, and then washed three times with 1 mL of ultrapure water to obtain a brown solid precipitate. Finally, 1 mL of ultrapure water was added to make up the volume, and the precipitate was dispersed evenly using an ultrasonic machine to obtain GOx-MOF material, which was stored at 2-8℃ for later use.

[0173] Glucose detection experiment results: The TMB colorimetric method (detection principle: H2O2 produced by GOx oxidation of glucose causes TMB molecules to be oxidized, and there is ultraviolet absorption at 450nm) was used to compare GOx enzyme activity. The results showed that the absorbance of GOx after responding to glucose was 0.356; the absorbance of GOx-MOF7 after responding to glucose was 0.675.

[0174] Results analysis: The glucose detection signal of the MOF-loaded GOx system was 1.9 times that of the MOF-free GOx-only system, as shown in Figure 3.

[0175] Example 4:

[0176] The metal is selected from the zinc derivative Zn(OAc)2·H2O, and the organic ligand is selected from the imidazole derivative 2-methylimidazole. The Bis-PEGn-Acid chain is selected from Bis-PEG2-Acid, Bis-PEG4-Acid, and Bis-PEG8-Acid (which can effectively improve the water solubility of MOF materials).

[0177] Add 1 mL of ultrapure water to a 5 mL EP tube, then add 25 μL of 0.5 M Zn(OAc)2·H2O, 50 μL of 0.05 M Bis-PEG2-Acid (or Bis-PEG4-Acid, or Bis-PEG8-Acid), 25 μL of 100 U / mL GOx, and 50 μL of 0.5 M 2-methylimidazole solution in sequence. Finally, add 25 μL of 10% ammonia water, cover the tube, and shake the tube at room temperature for 6 hours.

[0178] After the reaction was completed, the supernatant was removed by centrifugation at 8000 rpm, and then washed three times with 1 mL of ultrapure water to obtain a white solid precipitate. Finally, 1 mL of ultrapure water was added to make up the volume, and the precipitate was dispersed evenly using an ultrasonicator to obtain GOx-MOF material, which was stored at 2-8℃ for later use.

[0179] Glucose detection experiment results: The TMB colorimetric method (detection principle: H2O2 produced by GOx oxidation of glucose causes TMB molecules to be oxidized, and there is ultraviolet absorption at 450nm) was used to compare GOx enzyme activity. The results showed that the absorbance of GOx after responding to glucose was 0.086; the absorbance of GOx-MOF1-3 after responding to glucose was 0.536.

[0180] Results analysis: The glucose detection signal of the MOF-loaded GOx system was 5 times that of the MOF-unloaded GOx system alone, as shown in Figure 4.

[0181] The MOF glucose detection system of the present invention can be applied to glucose content detection, especially to glucose content detection in oral saliva. In particular, it can be used as a glucose conversion layer coated on a biosensor and made into an oral blood glucose meter.

[0182] An oral blood glucose meter according to the present invention. As shown in FIG7, the oral blood glucose meter according to one embodiment of the present invention includes a mounting part 1. The mounting part 1 is assembled from an upper housing 1a and a lower housing 1b, but is not limited thereto, and may also be integrally formed.

[0183] The detection unit 2 is installed in the mounting unit 1 and is electrically connected to the control unit 3. In this embodiment, the control unit 3 includes a substrate 30 on which various control elements (described in detail below) are disposed. A connector 36 is provided at one end of the substrate 30, and the detection unit 2 can be fixedly or detachably mounted to the substrate 30 via the connector 36.

[0184] The detection unit 2 is equipped with a sensor 20, which is a biosensor, specifically an ISFET (Ion Sensitive Field Effect Transistor) sensor, used to convert glucose in human saliva into electrical signal data to detect glucose content. The sensor 20 is coated with a glucose conversion layer 5, which is used to convert the glucose contained in saliva into electrical signal data, which is input to the control unit 3, allowing the control unit 3 to calculate the glucose content based on the electrical signal.

[0185] According to one embodiment of the present invention, the sensor 20 is a silicon-based sensor, as shown in FIG5. The silicon-based sensor 20 includes a silicon substrate 21, a SiO2 layer (oxide layer) 22 formed on the silicon substrate 21, a semiconductor device 23 formed on the SiO2 layer, and a modification layer 24 formed on the semiconductor device 23.

[0186] In this embodiment, the glucose conversion layer 5 contains glucose oxidase, specifically a nano-organic material encapsulating the enzyme. This nano-organic material is a metal-organic framework (MOF) combining metal ions and organic ligands (described in detail later).

[0187] In this embodiment, the semiconductor device 23 is an ISFET field-effect transistor, wherein the gate G of the field-effect transistor is formed on the SiO2 layer 22, and the drain D and source S are formed on the silicon substrate 21. 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 26 is also formed on the drain region D and the source region S. A modification layer 24 covers the gate region G, the drain region D, and the source region S, and also covers the sensitive layer 26 thereon.

[0188] As shown in Figure 5, a trench 22a is also formed on the oxide layer 22. The gate region G is accommodated in the trench 22a, and the drain region D and the source region S are disposed outside the trench 22a of the oxide layer 22 to ensure that the two are isolated from each other.

[0189] The glucose conversion layer includes nano-organic materials capable of breaking down glucose to generate hydrogen ions. The modification layer 24 allows hydrogen ions to pass through, be captured by the sensitive layer 26, and be converted into electrical signals.

[0190] The modification layer 24 comprises a specially designed polymer material, such as a polyethyleneimine (PEI) derivative, which is chemically modified to have specific functional groups and selectively allows hydrogen ions to pass through, ensuring that hydrogen ions generated by the glucose conversion layer 5 can pass smoothly to the sensitive layer 26. In other embodiments, the polymer material may also be a polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS), or a poly(p-phenylenevinyl)ethylene (PPV) derivative. The modification layer 24 may also contain small molecule additives, such as surfactants. These surfactants can improve the interfacial compatibility of the modification layer 24 with other layers, reduce interlayer defects and gaps, and improve the overall performance of the sensor.

[0191] The sensitive layer 26 comprises a metal oxide-based semiconductor material, such as zinc oxide (ZnO) nanoparticles, which stably immobilizes relevant components and prevents them from detaching or becoming deactivated during use. ZnO has good chemical stability and electronic conductivity, effectively capturing hydrogen ions that permeate from the modification layer and converting them into electrical signals. The large specific surface area of ​​ZnO nanoparticles provides more active sites, improving the sensor's sensitivity to hydrogen ions. Furthermore, the sensitive layer may contain doping elements, such as aluminum (Al). Al doping can adjust the electrical properties of ZnO, further optimizing its response characteristics to hydrogen ions. For example, appropriate Al doping can increase the carrier concentration of ZnO, accelerating the electrical signal transmission speed and thus improving the sensor's response speed.

[0192] A control unit 3 is also installed inside the housing 1. The control unit 3 is electrically connected to the silicon-based sensor 20, and is used to receive electrical signals and measure the glucose content based on the electrical signals using an algorithm. The control unit 3 includes a substrate 30 on which a microprocessor (MCU) 31 is mounted to control the signal data transmission of the silicon-based sensor and the calculation of the glucose content. The control unit 3 also includes a power supply 32 for providing power to the various components. The power supply 32 can be a battery or can be powered by connecting to mains power. When the power supply 32 is a battery, the control unit 3 also includes a power management module 34 and a charging port 35.

[0193] The control unit 3 also includes a communication module 33, particularly a wireless communication module, for receiving external commands and / or sending detection results to external devices, such as mobile phones, tablets and other smart devices, for data recording and analysis.

[0194] The control unit 3 also includes a connector 36 for connecting the silicon-based sensor 20. A power switch 37 is also provided on the substrate 30 for turning the device on and off. A display unit 4, connected to the control unit 3, is used to display the measured glucose value.

[0195] A protective cover 10 is provided on the outside of the silicon-based sensor 20 to protect the silicon-based sensor 20.

[0196] In one embodiment of the present invention, the glucose conversion layer 5 adopts a MOF-sensitized glucose detection system, which uses a zeolitic imidazolate framework (ZIF) as a metal-organic framework to load glucose oxidase (GOx) into the ZIF to form a Gox-MOF material.

[0197] The method for preparing this Gox-MOF is described above.

[0198] In this embodiment, the enzyme may be selected from natural glucose oxidase (GOx) or directed-evolved glucose oxidase (GOx).

[0199] In some preferred embodiments, the metal is selected from zinc or iron derivatives; the organic ligand is selected from imidazoles such as 2-methylimidazolium, 2-imidazolium carboxaldehyde, 3-methyl-1H-1,2,4-triazole, 2-imidazolium carboxylic acid, 2-aminoimidazolium sulfate, 3-bromo-1,2,4-triazole, etc., or from aromatic carboxylic acids such as 2-aminoterephthalic acid.

[0200] Furthermore, Bis-PEGn-Acid chains can be added as auxiliaries, such as Bis-PEG2-Acid, Bis-PEG4-Acid, and Bis-PEG8-Acid, to effectively improve the water solubility of MOF materials.

[0201] As shown in Figure 6, according to the experiment, the MOF-sensitized glucose detection system effectively improved the glucose detection sensitivity by approximately 5 times. Combined with this MOF-sensitized glucose detection system, the oral blood glucose meter of this invention can obtain detection results efficiently and reliably.

[0202] In practical use, when saliva comes into contact with the silicon-based sensor 20, glucose oxidase in the MOF-sensitized glucose detection system catalyzes the oxidation of glucose, generating hydrogen ions. These hydrogen ions can be captured by the modification layer 24 and converted into an electrical signal by the sensitive layer 26. This electrical signal is received by the semiconductor device 23 and transmitted to the control unit 3. The MCU 31 of the control unit 3 receives the electrical signal, calculates the corresponding glucose content value according to the algorithm, and displays it on the display unit 4. Alternatively, the calculation result can be sent to an external device via the communication module 33 for further recording or analysis.

[0203] Although the glucose conversion layer 5 in this embodiment uses a glucose detection system with an MOF structure, other glucose conversion methods that can achieve the same effect can also be used, such as photosensitized systems or similar methods.

[0204] To avoid interference, it is preferable to clean the mouth with an oral hygiene product before testing. This helps break down and remove food debris, microorganisms, and bacteria, while maintaining a neutral or suitable pH level in the oral cavity to avoid affecting the accuracy of the test. Oral hygiene products may contain antibacterial agents, enzymes, etc., to improve cleaning effectiveness.

[0205] A preferred oral cleanser is prepared from the following materials: 3-8g of nonionic surfactant, 2-6g of menthol oil, 8-16g of trimagnesium phosphate, 0.3-0.9g of vanillin, and 0.6-2.2g of pH adjuster. The cleanser may also include 10-20g of herbal enzymes and a small amount (e.g., 0.05-0.1g) of magnolia bark extract. The herbal enzymes consist of aloe vera enzymes, soapberry fruit enzymes, and papain. However, other oral cleansers may also be used.

[0206] Those skilled in the art will understand that the foregoing examples are exemplary and not restrictive. It will be apparent to those skilled in the art, upon reading the specification and studying the accompanying drawings, that all permutations, enhancements, equivalents, and modifications are included within the true spirit and scope of the invention. Therefore, the appended claims are intended to cover all such modifications, permutations, and equivalents that fall within the true spirit and scope of these teachings.

[0207] Explanation of reference numerals in the attached drawings: 1. Mounting part; 1a. Upper housing; 1b. Lower housing; 10. Protective cover; 2. Detection part; 20. Silicon-based sensor; 21. Silicon-based substrate; 22. SiO2 layer; 23. Semiconductor device; 24. Modification layer; 3. Control part; 30. Substrate; 31. MCU; 32. Power supply; 33. Communication module; 34. Power management module; 35. Charging port; 36. Connector; 37. Power button; 4. Display screen; 5. Glucose conversion layer; Drain; G gate; S source.

Claims

1. A method for preparing an MOF glucose detection system, characterized in that: Using a zeolitic imidazolate framework (ZIF) as a metal-organic framework, glucose oxidase (GOx) is loaded into the ZIF. The preparation method includes the following steps: S1: First, add water to the reaction flask, then add metal ions, enzymes, and organic ligands in a molar ratio of 100–1500:1–10:1–150, along with 0.1%–0.5% (by weight) ammonia water, sequentially into the reaction flask. S2: Mixed reaction at room temperature for more than 6 hours. S3: After centrifugation, the supernatant was removed to obtain a solid precipitate of GOx-MOF material loaded with glucose oxidase.

2. The method for preparing the MOF glucose detection system according to claim 1, characterized in that: In step S1, the amount of water added to the reaction flask is 80-95% (by weight).

3. The method for preparing the MOF glucose detection system according to claim 1 or 2, characterized in that: The preparation method further includes: S4: Use water to make up the volume again, and store the obtained GOx-MOF material loaded with glucose oxidase at 2-8℃ for later use. The ratio of the volume of water used for making up the volume to the total volume of the raw materials added to the reaction flask in step S1 is 0.1-100.

4. The method of claim 1-3, wherein the MOF glucose detection system is prepared by: The metal ion is selected from one of the following: alkali metals, alkaline earth metals, transition metals, group IIIA metals, group VIII metals, rare earth metals, metal complexes, and metal clusters.

5. The method of claim 1-3, wherein the MOF glucose detection system is prepared by: The organic ligand is selected from one of the following: nitrogen-containing organic ligands, carboxylate ligands, ligands modified with amino groups, ligands modified with photosensitizers, and electron-rich conjugated ligands.

6. The method of claim 1-3, wherein the MOF glucose detection system is prepared by, The centrifuge operates at a speed of 1000-30000 rpm.

7. The method of claim 1-3, wherein the MOF glucose detection system is prepared by: An adjuvant can also be added in step S1.

8. The method of claim 7, wherein the MOF glucose detection system is prepared by: The auxiliary agent is a Bis-PEGn-Acid chain.

9. The method of claim 8, wherein the MOF glucose detection system is prepared by: The Bis-PEGn-Acid chain is Bis-PEG2-Acid, Bis-PEG4-Acid, or Bis-PEG8-Acid.

10. The method of claim 4, wherein the MOF glucose detection system is prepared by: The metal ion is a zinc derivative or an iron derivative.

11. The method of claim 10, wherein the MOF glucose detection system is prepared by: The metal ions are zinc sulfide, zinc chloride, zinc bromide, zinc oxide, zinc iodide, zinc sulfate, zinc acetate, zinc carbonate, zinc nitrate, or their hydrates.

12. The method for preparing the MOF glucose detection system according to claim 5, characterized in that: The organic ligand is polydiaminoimidazole.

13. The method of claim 12, wherein the MOF glucose detection system is prepared by: The organic ligand is 2-methylimidazole, 2-imidazolium carboxaldehyde, imidazolium-2-carboxylic acid, benzimidazole, 2-methylbenzimidazole, 1,2,4-triazole, 3-methyl-1H-1,2,4-triazole, 1,2,4-triazole-3-carboxylic acid, polyazole or its derivatives.

14. The method of claim 1-3, wherein the MOF glucose detection system is prepared by, The water is ultrapure water.

15. The method of claim 1-3, wherein the MOF glucose detection system is prepared by, The mixing is performed by oscillation or stirring.

16. Use of a MOF glucose detection system in the detection of salivary glucose content, characterized in that, The MOF glucose detection system is prepared by the preparation method according to any one of claims 1-15.

17. A sensor for detecting salivary glucose concentration, characterized by, The sensor is coated with a glucose conversion layer, which is used to convert glucose in the saliva to be detected into hydrogen ions, so that the hydrogen ions are captured by the sensor and converted into an electrical signal.

18. The sensor of claim 17, wherein, The sensor includes a silicon substrate, an oxide layer formed on the silicon substrate, an ISFET transistor formed on the oxide layer, and a modification layer formed on the ISFET transistor. The glucose conversion layer is coated on the modified layer.

19. The sensor of claim 18, wherein, The ISFET transistor includes a gate region, a drain region, and a source region, wherein the gate region is formed on the oxide layer, and 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.

20. The sensor of claim 18, wherein, The drain region and the source region are formed on a silicon substrate.

21. The sensor of claim 18, wherein, The oxide layer is a SiO2 layer.

22. The sensor of claim 18, wherein, The oxide layer has trenches, the gate region is disposed in the trenches, and the drain region and the source region are disposed outside the oxide layer.

23. The sensor of claim 17, wherein, The glucose conversion layer includes nano-organic materials capable of breaking down glucose to generate hydrogen ions. The modified layer allows hydrogen ions to pass through, be captured by the sensitive layer, and be converted into electrical signals.

24. The sensor of claim 18, wherein, The modified layer comprises a chemically modified polymer material that selectively allows hydrogen ions to permeate.

25. The sensor of claim 24, wherein, The polymer material is a polyethyleneimine (PEI) derivative, polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS), or poly(p-phenylenevinyl chloride) (PPV) derivative.

26. The sensor of claim 17, wherein, The sensitive layer comprises a semiconductor material based on metal oxides.

27. The sensor of claim 26, wherein, The metal oxide is zinc oxide (ZnO) nanoparticles.

28. The sensor of claim 26, wherein, The sensitive layer may contain doping elements.

29. The sensor of claim 28, wherein, The doping element is aluminum (Al).

30. The sensor of claim 24, wherein, The nano-organic material of the modified layer includes a metal-organic framework (MOF) encapsulating glucose oxidase.

31. The sensor of claim 30, wherein, The metal ion of the metal-organic framework (MOF) is selected from one of the following: 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 the following: nitrogen-containing organic ligands, carboxylate ligands, ligands modified with amino groups, ligands modified with photosensitizer complexes, and electron-rich conjugated ligands.

32. An oral blood glucose meter, comprising: include: Installation Department; A detection unit installed in the mounting section, the detection unit including a sensor coated with a glucose conversion layer, the sensor being used to receive saliva to be detected; A control unit electrically connected to the detection unit, the control unit being used to measure the glucose content value of saliva received by the silicon-based sensor; The display unit is used to display the glucose content value measured by the control unit. The glucose conversion layer is used to convert glucose in the saliva to be detected into hydrogen ions, so that the hydrogen ions are captured by the sensor and converted into an electrical signal. The electrical signal is input to the control unit, and the control unit calculates the glucose content value based on the electrical signal.

33. The oral blood glucose meter of claim 32, wherein, The sensor (20) is a silicon-based sensor.

34. The oral blood glucose meter of claim 33, wherein, The silicon-based sensor includes a silicon substrate, an oxide layer formed on the silicon substrate, a semiconductor device formed on the oxide layer, and a modification layer formed on the semiconductor device, wherein the glucose conversion layer is coated on the modification layer.

35. The oral blood glucose meter of claim 34, wherein, The semiconductor device is an ISFET field-effect transistor, which includes a gate region, a drain region, and a source region. The gate region is formed on the oxide layer, and the drain region and the source region are formed at intervals along both sides of the gate region. A sensitive layer is formed on the drain region and the source region.

36. The oral blood glucose meter of claim 35, wherein, The drain region and the source region are formed on a silicon substrate.

37. The oral blood glucose meter of any one of claims 34-36, wherein, The oxide layer is a SiO2 layer.

38. The oral blood glucose meter of any one of claims 34-36, wherein, The oxide layer has trenches, the gate region is disposed in the trenches, and the drain region and the source region are disposed outside the oxide layer.

39. The oral blood glucose meter of claim 32, wherein, The modified layer comprises a chemically modified polymer material that selectively allows hydrogen ions to permeate.

40. The oral blood glucose meter of claim 39, wherein, The polymer material is a polyethyleneimine (PEI) derivative, polyacrylic acid (PAA), polymethacrylic acid (PMAA), polystyrene sulfonic acid (PSS), or poly(p-phenylenevinyl chloride) (PPV) derivative.

41. The oral blood glucose meter of claim 32, wherein, The sensitive layer comprises a semiconductor material based on metal oxides.

42. The oral blood glucose meter of claim 41, wherein, The metal oxide is zinc oxide (ZnO) nanoparticles.

43. The oral blood glucose meter of claim 41 or 42, wherein, The sensitive layer may contain doped elements.

44. The oral blood glucose meter of claim 43, wherein, The doping element is aluminum (Al).

45. The oral blood glucose meter of claim 32, wherein, The glucose conversion layer is a nano-organic material encapsulating the enzyme.

46. The oral blood glucose meter of claim 45, wherein, The nanomaterials encapsulating the enzyme are metal-organic frameworks (MOFs) that combine metal ions and organic ligands.

47. The oral blood glucose meter of claim 46, wherein, The metal ion of the metal-organic framework (MOF) is selected from one of the following: alkali metals, alkaline earth metals, transition metals, group IIIA metals, group VIII metals, rare earth metals, and metal complexes.

48. The oral blood glucose meter of claim 46, wherein, The organic ligands of the metal-organic framework (MOF) are selected from nitrogen-containing organic ligands, carboxylate ligands, ligands modified with amino groups, ligands modified with photosensitizer complexes, and electron-rich conjugated ligands.

49. The oral blood glucose meter of claim 35, wherein, The enzyme is glucose oxidase.

50. The oral blood glucose meter of claim 32, wherein, The control unit includes an MCU and a power supply, wherein the MCU controls the signal transmission of the silicon-based sensor and the calculation of glucose content.

51. The oral blood glucose meter of claim 50, wherein, The control unit also includes a wireless communication module for data communication with the outside world.

52. The oral blood glucose meter of claim 50, wherein, The control unit also includes a power management module and a charging port.

53. The oral blood glucose meter of claim 32, wherein, The silicon-based sensor is electrically connected to the control unit via a connector.

54. The oral blood glucose meter of claim 32, wherein, The silicon-based sensor is equipped with a protective cover.

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