Tear Glucose Detection Device and Its Production Process

Abstract

The present invention discloses a tear glucose detection device, which comprises a tear glucose detection strip and a support assembly. The tear glucose detection strip includes two identical detection strip units connected in parallel along a first direction. Each detection strip unit includes a tear sampling area, a hydrophobic isolation zone and a holding portion. The hydrophobic isolation zone is located between the tear sampling area and the holding portion. The two detection strip units are connected at the holding portion and separated between the tear sampling area and the hydrophobic isolation zone. The tear sampling area is used for collecting tears and reacting with a glucose detection reagent to measure tear glucose. The hydrophobic isolation zone is used to prevent the further diffusion of tears. The holding portion is used for bonding with the support assembly to enhance the rigidity of the tear glucose detection strip. The first direction is the width direction of the strip-shaped tear glucose detection strip. This device can quickly detect tear glucose, is suitable for non-professionals to regularly measure tear glucose, and can be used for qualitative measurement of tear glucose for the prevention of diabetic retinopathy, or for quantitative measurement of tear glucose by using the parallel relationship between tear glucose and blood glucose.

Description

Technical Field

[0001] The present invention relates to the technical field of glucose detection, and particularly relates to a tear glucose detection device and its production process. Background Art

[0002] Diabetic retinopathy (also known as diabetic retinopathy) is the most common diabetic complication, with high incidence and blindness rates. However, there are no obvious symptoms in the early stage of diabetic retinopathy. When symptoms are found and an eye examination is performed, it often reaches the advanced stage, thus missing the best time for drug and surgical treatment. Therefore, early detection and early treatment are the best ways to prevent diabetic retinopathy.

[0003] Through comparing the group of diabetic patients with diabetic retinopathy and the group without diabetic retinopathy, relevant research found that the tear glucose content in the group with diabetic retinopathy was higher than that in the group without diabetic retinopathy, and the difference was statistically significant. The above clinical data indicate that the tear glucose content has a high correlation with the risk of diabetic retinopathy in diabetic patients. Therefore, diabetic retinopathy can be prevented by regularly measuring the tear glucose content.

[0004] However, when testing tear glucose during the research, a self-made polyvinyl gelatin sponge tear collector was used, which needed to be placed in the lower fornix of the conjunctival sac for a long time to absorb a large volume of tears, or a capillary glass tube was used to collect tears from the outer canthus tear film of the examined eye. Obviously, these sampling methods are only suitable for scientific research and not suitable for non-professionals to regularly and repeatedly measure tear glucose. Moreover, although the existing tear glucose detection technology has solved the problem of non-invasive micro-quantitative collection of tears, the steps for detecting glucose in the sampled tears are relatively cumbersome. If a reagent package for single-person testing is used, a special colorimetric cup is required to place an integrated device composed of a tear sampling strip and a micro reagent bottle, which has problems such as many detection steps, high consumable costs, is not conducive to storage and transportation, and is not suitable for non-professionals to use.

[0005] Therefore, clinically, there is a need to provide a tear glucose detection device that is suitable for non-professionals and integrates sampling and detection for diabetic patients. Summary of the Invention

[0006] The purpose of the present invention is to provide a tear glucose detection device and its production process. The device can quickly detect tear glucose, is suitable for non-professionals to regularly measure tear glucose, and can be used for the prevention of diabetic retinopathy.

[0007] To achieve the above and other related purposes, the present invention provides a tear glucose detection device, including a tear glucose detection strip and a support component. The tear glucose detection strip includes two identical detection strip units connected in parallel along a first direction.

[0008] The detection strip unit includes a tear sampling area, a hydrophobic isolation zone, and a holding portion. The hydrophobic isolation zone is located between the tear sampling area and the holding portion. The two detection strip units are connected at the holding portion and separated between the tear sampling area and the hydrophobic isolation zone.

[0009] The tear sampling area is used to collect tears and react with a glucose detection reagent to measure tear glucose. The hydrophobic isolation zone is used to prevent the further spread of tears. The holding portion is used to adhere to the support assembly to fix the tear glucose detection strip.

[0010] The first direction is the width direction of the strip-shaped tear glucose detection strip.

[0011] Preferably, the tear sampling area includes a tear film contact area at the outer canthus of the eye to be examined, a pH buffer zone, and a detection reagent zone. The tear film contact area at the outer canthus of the eye to be examined is close to one end of the detection strip unit. The pH buffer zone is located between the tear film contact area at the outer canthus of the eye to be examined and the detection reagent zone. There is a gap between the pH buffer zone and the detection reagent zone.

[0012] No chemical reagent is applied to the tear film contact area at the outer canthus of the eye to be examined. The pH buffer zone is coated with a pH buffer reagent. The detection reagent zone is coated with a glucose detection reagent. The hydrophobic isolation zone is coated with a waterproof agent.

[0013] Preferably, the glucose detection reagent includes a chromogen reagent and an enzyme reagent. The detection reagent zone includes a first detection zone and a second detection zone. The first detection zone is made by coating with the chromogen reagent. The second detection zone is made by coating with the enzyme reagent. The number of the hydrophobic isolation zones is multiple.

[0014] Preferably, the edge of the tear sampling area is arc-shaped. On both sides of each unit of the tear glucose detection strip along the first direction, there is a cut between the tear sampling area and the hydrophobic isolation zone. The four cuts on the two detection strip units are symmetric about the symmetry line of the two detection strip units.

[0015] Preferably, the glucose detection reagent, the waterproof agent, and the pH buffer agent are dried after being coated by scribing in the tear sampling area to form the detection reagent zone, the hydrophobic isolation zone, and the pH buffer zone.

[0016] Preferably, the chromogen reagent is selected from one or more of 2,4,6-tribromo-3-hydroxybenzoic acid, sodium N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniline, sodium N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methoxyaniline, sodium N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline, sodium N-ethyl-N-(3-sulfopropyl)-3-methoxyaniline, sodium 3,5-dichloro-2-hydroxybenzenesulfonate, N-2-ethyl(3-methylphenyl)aminoethylacetamide, N-ethyl-N-ethylsulfonate m-toluidine, 2,4-dichlorophenol, and 3,3',5,5'-tetramethylbenzidine;

[0017] The enzyme reagent includes glucose oxidase, peroxidase, and 4-aminoantipyrine;

[0018] The waterproof agent is made of a mixture composed of one or more of polyethylene wax, palm wax emulsion, paraffin wax emulsion, Tianshi wax emulsion, water-soluble wax, wax emulsion, hydrogen-containing silicone oil, nano-silicon, soluble hot melt adhesive, and acrylic resin and water in a ratio of 1:1 - 1:100;

[0019] The pH buffer reagent is prepared by mixing one or more of strong base weak acid salt compounds such as sodium carbonate, sodium citrate, and sodium acetate and dissolving them in water, with a concentration of 1 - 30 g / L.

[0020] Preferably, the support assembly includes two support bars with parallel corresponding surfaces, and one end of the support bars is connected while the other end is separated to form a groove for accommodating the holding part.

[0021] Preferably, the tear sugar detection device is used to qualitatively measure tear sugar according to the fact that qualitative tear sugar is a significant pathogenic influencing factor for diabetic retinopathy in both eyes, and is used to quantitatively measure tear sugar according to the parallel relationship between tear sugar and blood sugar, for blood sugar monitoring.

[0022] Preferably, the tear sugar detection device is used to qualitatively measure tear sugar, and the color development result can be used for risk stratification of diabetic retinopathy in diabetic patients. By comparing the tear sugar detection result with the color of the glucose standard product, the corresponding numerical range and the result of positive or negative tear sugar can be obtained, and the critical value for risk stratification of diabetic retinopathy in diabetic patients can be obtained based on the clinical assessment results for risk stratification of diabetic retinopathy in diabetic patients. If a diabetic patient has 2+ in one eye, > 0.30 mmol / L or above, or 1+ in both eyes, > 0.15 mmol / L or above, it is judged as positive for the risk of diabetic retinopathy in this detection, and the pathogenic risk of related diabetic retinopathy increases significantly, and they must go to the ophthalmology department of the hospital for examination. If the tear sugar of a diabetic patient is colorless, light yellow, or 1+ in one eye, ≤ 0.15 mmol / L, it is judged as negative for the risk of diabetic retinopathy in this detection. Currently, the pathogenic risk of diabetic retinopathy is relatively low, but qualitative tear sugar still needs to be monitored regularly.

[0023] The present invention also provides a production process for a tear glucose detection device for manufacturing the tear glucose detection device as described above, including the following steps:

[0024] S1: Manufacture a first module and a second module. The length of the first module along a first direction is greater than or equal to the width of N tear glucose detection strips, and the length of the second module along the first direction is greater than or equal to the width of N support components. The first module includes a groove for accommodating the second module, where N≥2;

[0025] S2: Apply the pH buffer, the glucose detection reagent, and the waterproof agent along the first direction on the first module and penetrate the first module to form a first total strip, a second total strip, and a third total strip. The arrangement of the first total strip, the second total strip, and the third total strip along the first direction is the same as the arrangement of the PH buffer strip, the detection reagent strip, and the hydrophobic isolation strip of the tear glucose detection strip along the length direction of its long strip shape;

[0026] S3: Place one end of the first module away from the first total strip, the second total strip, and the third total strip into the groove of the second module and paste it to the groove wall to form a total module;

[0027] S4: Cut the total module to form N tear glucose detection devices.

[0028] In summary, the present invention provides a tear glucose detection device. This device integrates sampling and detection. When performing tear glucose detection, the detection strip only needs to be placed at the outer canthus tear film of the eye to be examined. After several minutes, when the sampling area is full of tears, the detection result can be obtained by colorimetry. This enables patients to obtain tear glucose detection results through non-invasive sampling methods for the chronic disease management of diabetes, without the need for strong professional knowledge, and patients can independently complete it in the community and at home; further, this device uses a method of separately coating the chromogen and enzyme reagents in the pH buffer strip and the glucose detection reaction strip, rather than overlapping or coating them together, which can ensure that the activities of the chromogen and enzyme reagents are not greatly lost during the entire coating and drying process, and does not require consumables such as colorimetric cups, having a very high cost performance; furthermore, this detection device combines two tear fluid glucose test strips into one combination, which is only connected by a saddle stitch at the holding part. At the same time, by adding support at the holding part, the hardness of the rear end of the holding part is strengthened, reducing the damage rate of the test strip during packaging and test opening. When the patient uses it, as long as the saddle stitch of the holding part is torn open, the tear glucose test of both eyes can be started; finally, this device can not only qualitatively measure tear glucose for the prevention of diabetic retinopathy, but also quantitatively measure tear glucose using the parallel relationship between tear glucose and blood glucose.

[0029] In addition, the present invention also provides a production process for the above-mentioned device. The production process adopts a manufacturing process of first coating and scribing and then die-cutting. By modularizing rather than performing coating and scribing in a single strip, the requirements of mass production can be met. Brief Description of the Drawings

[0030] Figure 1 Schematic diagram of a single tear sugar detection strip unit of the tear sugar detection strip of the tear sugar detection device provided by an embodiment of the present invention;

[0031] Figure 2 Schematic diagram of the tear sugar detection strip of the tear sugar detection device provided by an embodiment of the present invention

[0032] Figure 3 Schematic diagram of the support assembly of the tear sugar detection device provided by an embodiment of the present invention;

[0033] Figure 4 Schematic diagram of the tear sugar detection device provided by an embodiment of the present invention;

[0034] Figure 5 Schematic diagram of the production process of the tear sugar detection device provided by an embodiment of the present invention;

[0035] Figure 6 Schematic diagram of the production process flow of the tear sugar detection device provided by an embodiment of the present invention;

[0036] Figure 7 Schematic diagram of the comparison of the detection results of the tear sugar detection device provided by an embodiment of the present invention;

[0037] Figure 8 Schematic diagram of the standard curve of the gray value of the detection result of the tear sugar detection device provided by an embodiment of the present invention.

[0038] Among them, the description of the reference numerals is as follows:

[0039] a - First detection strip unit, b - Second detection strip unit, 1 - Tear sampling area, 2 - Hydrophobic isolation zone, 3 - Holding part, 4 - Support assembly, 10 - Contact area of the outer canthus tear film of the eye to be examined, 11 - pH buffer zone, 12 - First detection zone, 13 - Second detection zone, 21 - First hydrophobic isolation zone, 100 - First module, 200 - Second module. Detailed Embodiments

[0040] The following will describe the specific embodiments of the present invention in more detail with reference to the schematic diagrams. According to the following description, the advantages and features of the present invention will be clearer. It should be noted that the drawings are all in a very simplified form and use non-precise scales, and are only used to facilitate and clearly assist in explaining the purpose of the embodiments of the present invention.

[0041] In the description of the present invention, it should be understood that the orientation or positional relationship indicated by the terms "center", "upper", "lower", "left", "right", etc. is based on the orientation or positional relationship shown in the drawings. It is only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation. Therefore, it should not be construed as a limitation to the present invention.

[0042] In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, the meaning of "a plurality of" is at least two, such as two, three, etc., unless otherwise specifically defined.

[0043] Figures 1 - 4 The figure is a schematic diagram of a tear glucose detection device provided by an embodiment of the present invention. The tear glucose detection device provided by this embodiment includes a tear glucose test strip and a support assembly 4. Refer to Figures 1 to 2 , the tear glucose test strip includes two exactly the same tear glucose test strip units connected in parallel: a first test strip unit a and a second test strip unit b. The test strip unit is divided into a tear sampling area 1, a hydrophobic isolation zone 2, and a holding part 3. The hydrophobic isolation zone 2 is located between the tear sampling area 1 and the holding part 3. The first test strip unit a and the second test strip unit b are connected at the holding part 3 and separated between the tear sampling area 1 and the hydrophobic isolation zone 2. The tear sampling area 1 is used to collect tears and react with a glucose detection reagent to measure the tear glucose concentration. The hydrophobic isolation zone 2 is used to prevent the further diffusion of tears. The holding part 3 is used to adhere to the support assembly 4 to fix the tear glucose test strip.

[0044] The inventors have found through research that it is more accurate to detect the tear glucose in both the left and right eyes. When implementing this device, the tester can tear the tear glucose test strip along the central axis and use the first test strip unit a and the second test strip unit b to detect the left and right eyes respectively. During the detection, only need to place the test strip at the outer canthus tear film of the eye to be tested. After several minutes, when the tear sampling area 1 is full of tears, the detection result can be obtained by colorimetry. And because the support assembly 4 has a certain rigidity, it is very suitable for non-professionals to use.

[0045] In addition, since the hydrophobic isolation zone 2 needs to have a certain width to have a better effect of blocking the continuous diffusion of tears, the optimal length of the hydrophobic isolation zone 2 is generally 3-12 mm, and it can be composed of several straight lines with a width of 1-3 mm arranged closely and parallel to each other. Among them, the first hydrophobic isolation zone 21 is the boundary line between the hydrophobic isolation zone 2 and the tear sampling area 1, and is composed of a straight line closely adjacent to the tear sampling area 1. Several hydrophobic straight lines arranged closely and parallel to each other can be coated closely adjacent to the first hydrophobic isolation zone 21 in the direction away from the tear sampling area 1. Moreover, on both sides of the detection strip unit connected in parallel along the first direction of the first hydrophobic isolation zone 21, there is a cut respectively, and the four cuts located on the two detection strip units are symmetric about the symmetry line of the two detection strip units. The edge of the tear sampling area is generally made into an arc shape, so that the contact area with the outer canthus tear film of the eye to be examined is minimized to avoid irritating the eyes and collect basal tears. The existence of the small cuts is to avoid pricking the eyelids of the detector with sharp corners. The settings of the arc shape and the small cuts are both to improve the comfort of the detector when collecting tears.

[0046] To improve the detection accuracy, the detection reagent strip generally adopts a two-reagent (enzyme reagent and chromogen reagent) formulation of glucose oxidase coupled with the Trinder reaction. The detection reagent strip is divided into a first detection strip 12 and a second detection strip 13. The first detection strip 12 is made by coating the chromogen reagent, and the second detection strip 13 is made by coating the enzyme reagent. The order is not absolute. It can also be that the first detection strip 12 is made by coating the enzyme reagent, and the second detection strip 13 is made by coating the chromogen reagent. And a pH buffer zone 11 is provided between the outer canthus tear film contact area 10 of the eye to be examined and the detection reagent strip, and a pH buffer is coated.

[0047] Regarding the coating of the enzyme reagent, chromogen reagent for detecting tear glucose and the pH buffer for maintaining and providing a relatively ideal biochemical reaction environment, the inventor has found that the pH buffer zone 11 and the detection reagent strip (the first detection strip 12 and the second detection strip 13) can be not overlapped or coated together, and there is a certain gap between them, which can ensure that the activities of the chromogen and the enzyme reagent are not greatly lost during the entire coating and drying process.

[0048] During specific manufacturing, the glucose detection reagent, the waterproofing agent, and the pH buffer are coated by scribing in the tear sampling area 1 and then dried to form the detection reagent strip (the first detection strip 12 and the second detection strip 13), the hydrophobic isolation strip 2, and the pH buffer strip 11. The coating concentrations of the glucose detection reagent, the waterproofing agent, and the pH buffer are generally 1 - 30 g / L. The chromogen reagent generally includes one or more of 2,4,6-tribromo-3-hydroxybenzoic acid, sodium N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniline, sodium N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methoxyaniline, sodium N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline, sodium N-ethyl-N-(3-sulfopropyl)-3-methoxyaniline, sodium 3,5-dichloro-2-hydroxybenzenesulfonate, N-2-ethyl(3-methylphenyl)aminoethylacetamide, N-ethyl-N-ethylsulfonate metatoluidine, 2,4-dichlorophenol, and 3,3',5,5'-tetramethylbenzidine; the enzyme reagent generally includes glucose oxidase, peroxidase, and 4-aminoantipyrine; the waterproofing agent is made of a mixture of one or more of polyethylene wax, palm wax emulsion, paraffin wax emulsion, Tianshi wax emulsion, water-soluble wax, wax emulsion, hydrogen-containing silicone oil, nano-silicon, soluble hot melt adhesive, and acrylic resin and water in a ratio of 1:1 - 1:100; the PH buffer reagent is generally prepared by mixing one or more of strong base weak acid salt compounds such as sodium carbonate, sodium citrate, and sodium acetate and dissolving them in water.

[0049] The support assembly 4 for facilitating use by non-professionals generally includes two support bars arranged in parallel and corresponding to each other on the surface. One end of the support bars is connected, and the other end is separated to form a groove for accommodating the holding part 3. The support bars are generally made of hard paper and have a certain stiffness. The tear glucose detection strip is made of qualitative filter paper. There is a tear glucose detection strip pasting area at the rear end of the holding part 3, with an optimal length of 5 - 30 millimeters. The holding part 3 can be inserted into the groove of the support assembly 4 and adhered to the groove wall; the external canthus tear film contact area 10 of the eye to be examined, the pH buffer strip 1, the first detection strip 12, the second detection strip 13, and the hydrophobic isolation strip 2 are all symmetric along the central axis.

[0050] The present invention is a tear glucose detection device integrating sampling and detection. There are two modes for result interpretation of this device. One is a qualitative or semi-quantitative interpretation mode, where the detection result is compared with the glucose standard concentration color patches to qualitatively obtain the concentration range of tear glucose. The other is a quantitative interpretation mode, where the color depth of the glucose detection reagent strip in the sampling area after color development is detected by instrument equipment, and the obtained gray value is compared with the standard glucose curve stored in the instrument to obtain the tear glucose concentration.

[0051] I. The usage method of the qualitative semi - quantitative interpretation mode is as follows:

[0052] Separate the tear glucose detection device, and place the tear sampling area 1 at the outer canthus tear film of the left and right eyes to be examined to collect tears. After the tear sampling area 1 is fully saturated with tears, take it out and wait for about three minutes, then it can be compared with Figure 7 to obtain the corresponding glucose concentration value range and the result of positive or negative tear glucose, and based on the clinical assessment results, obtain the critical value for risk stratification of diabetic retinopathy in diabetic patients for risk stratification of diabetic retinopathy in diabetic patients. If a diabetic patient has 2+ in one eye, > 0.30 mmol / L or above, or 1+ in both eyes, > 0.15 mmol / L or above, it is judged as positive for the risk of diabetic retinopathy in this test. If the tear glucose of a diabetic patient is colorless, light yellow, or 1+ in one eye, ≤ 0.15 mmol / L, it is judged as negative for the risk of diabetic retinopathy in this test.

[0053] In this trial, the number of diabetic patients included was 155 (the course of diabetes, fasting blood glucose, and glycated hemoglobin values of diabetic patients were also statistically counted). Among them, 51 patients had been diagnosed with diabetic retinopathy, and 104 patients were diabetic patients without diabetic retinopathy. The test results are statistically as follows:

[0054] 1. The relationship between the level of tear glucose (qualitative) value and the stage of diabetic retinopathy (for the convenience of statistics, diabetic retinopathy is divided into two stages: early stage of diabetic retinopathy (stages I / II / III) and late stage of diabetic retinopathy (stages IV / V / VI), and the tear glucose value of the eye with the higher tear glucose is included in the statistics)

[0055]

[0056] The statistical results show that:

[0057] The proportion of 4+ positive with high tear glucose is the highest in both early and late stage diabetic retinopathy patients. The proportion in the early stage of diabetic retinopathy is 33.3%, and in the late stage is 30.0%. It is also the highest in the total proportion without staging;

[0058] There is no obvious positive proportional relationship between the level of tear glucose (qualitative) value and the stage of diabetic retinopathy, and the proportion of each positive segment is relatively scattered.

[0059] 2. The relationship between single - eye or binocular detection positive of tear glucose (qualitative) and the stage of diabetic retinopathy

[0060]

[0061] The statistical results show that:

[0062] The proportion of binocular tear glucose (qualitative) positive is the highest in both early (90.5%) and late (73.3%) stage diabetic retinopathy patients, and it is also the highest in the total proportion without staging;

[0063] There is no positive correlation between the stage of diabetic retinopathy and the positive result of tear glucose (qualitative) in one or both eyes, and the proportion of positive results in one or both eyes is relatively scattered.

[0064] From the above analysis, it can be seen that whether in the early or late stage of diabetic retinopathy, the proportion of high tear glucose values (4+, accounting for 31.4%) combined with positive results in both eyes (accounting for 80.4%) is the highest, indicating that high tear glucose values (qualitative) in both eyes can reflect the severity of diabetic retinopathy to a certain extent.

[0065] 3. Analyze the correlation between qualitative tear glucose results and other factors as the pathogenic factors of diabetic retinopathy

[0066] ①. Chi-square test

[0067] To analyze the pathogenic factors of diabetic retinopathy, chi-square tests were performed on factors such as diabetes duration ≥ 10 years, glycated hemoglobin ≥ 8.0%, and fasting blood glucose ≥ 8.0 mmol / L. The results are as follows:

[0068] Pathogenic influencing factors of diabetic retinopathy <![CDATA[X 2 value]]> P value Correlation Diabetes duration (≥10 years) 9.742 0.0018 Significantly correlated ** Glycated hemoglobin ≥ 8.0% 7.340 0.0067 Correlated * Fasting blood glucose ≥ 8.0 mmol / L 5.903 0.015 Correlated * Tear glucose (qualitative) 11.139 0.0008 Significantly correlated **

[0069] Statistics show that:

[0070] There is a significant correlation between diabetic retinopathy and diabetes duration ≥ 10 years and tear glucose (qualitative);

[0071] There is a correlation between diabetic retinopathy and glycated hemoglobin ≥ 8.0% and fasting blood glucose ≥ 8.0 mmol / L, but it is not significant.

[0072] ②. Logistic regression analysis

[0073] Analyze several factors related to diabetic retinopathy: diabetes duration ≥ 10 years, glycated hemoglobin ≥ 8.0%, fasting blood glucose ≥ 8.0 mmol / L, and tear glucose (qualitative). Taking diabetic retinopathy as the dependent variable, logistic regression analysis was performed on these four factors. The results are as follows:

[0074]

[0075]

[0076] Statistics show that:

[0077] The P-value for diabetes duration ≥ 10 years is 0.003, and the P-value for tear glucose (qualitative) is 0.003, both less than 0.005. Therefore, diabetes duration ≥ 10 years and tear glucose (qualitative) are important pathogenic factors for diabetic retinopathy;

[0078] The P values of glycated hemoglobin ≥ 8.0% and fasting blood glucose ≥ 8.0 mmol / L are both greater than 0.05, and they are not important pathogenic influencing factors for diabetic retinopathy.

[0079] 4. Analyze the correlation between tear glucose (qualitative) and other pathogenic influencing factors related to diabetic retinopathy

[0080] ①. Chi-square test

[0081] Tear glucose (qualitative) was subjected to chi-square test with three pathogenic influencing factors: diabetes duration ≥ 10 years significantly related to diabetic retinopathy, glycated hemoglobin ≥ 8.0% related to diabetic retinopathy, and fasting blood glucose ≥ 8.0 mmol / L related to diabetic retinopathy. The results are as follows:

[0082] Pathogenic influencing factors of diabetic retinopathy <![CDATA[X 2 value]]> P value Correlation Diabetes duration (≥10 years) 0.003 0.955 Uncorrelated Glycated hemoglobin ≥ 8.0% 3.210 0.073 Uncorrelated Fasting blood glucose ≥ 8.0 mmol / L 7.517 0.006 Correlated *

[0083] Statistics show that:

[0084] Tear glucose (qualitative) is related to fasting blood glucose ≥ 8.0 mmol / L;

[0085] Tear glucose (qualitative) is not related to diabetes duration ≥ 10 years and glycated hemoglobin ≥ 8.0%.

[0086] ②. Perform logistic regression analysis on the pathogenic influencing factors of diabetic retinopathy related to tear glucose (qualitative)

[0087] Taking tear glucose (qualitative) as the dependent variable, logistic regression analysis was performed on the pathogenic influencing factor of diabetic retinopathy, fasting blood glucose ≥ 8.0 mmol / L, which is related to tear glucose (qualitative). The results are as follows:

[0088] Factor B SE Wald P Exp(B) Fasting blood glucose ≥ 8.0 mmol / L 1.099 0.411 7.150 0.007 3.002

[0089] Statistics show that: the P value of fasting blood glucose ≥ 8.0 mmol / L is 0.007, which is less than 0.05, indicating statistical significance. Fasting blood glucose ≥ 8.0 mmol / L is a risk factor related to tear glucose (qualitative).

[0090] Using tear glucose (qualitative) as an important pathogenic factor for diabetic retinopathy in the risk stratification detection of diabetic patients has the advantage of a large range of positive and negative differences (regardless of early and late diabetic retinopathy patients, the proportion of high tear glucose positive (4+, accounting for 33.9%) combined with both eyes being positive (accounting for 82.8%) is the highest). The test results are relatively easy to judge, with a high sensitivity (38 / 51 = 74.5%), and other indicators also meet the technical test requirements.

[0091] After performing a correlation analysis between tear glucose (qualitative) as a pathogenic influencing factor for diabetic retinopathy and diabetic retinopathy, the results of chi-square test and logistic regression analysis showed that only tear glucose (qualitative), diabetes duration were significantly correlated with diabetic retinopathy. Therefore, these two are the most important pathogenic influencing factors for diabetic retinopathy.

[0092] To analyze whether tear glucose (qualitative) is an independent pathogenic influencing factor for diabetic retinopathy, the results of chi-square test and logistic regression analysis showed that tear glucose (qualitative) was correlated but not significantly with fasting blood glucose ≥ 8.0 mmol / L, and not correlated with diabetes duration. Therefore, tear glucose (qualitative) is an independent pathogenic influencing factor for diabetic retinopathy that has a certain degree of association with hyperglycemia.

[0093] The qualitative or semi-quantitative interpretation mode is the most common and convenient method for non-professionals. This method first performs value transfer. Using four glucose concentration standards (S1 0.153 mmol / L, S2 0.306 mmol / L, S3 0.613 mmol / L, and S4 1.226 mmol / L), 3 μl of each is spotted on the sampling area of the tear glucose detection device. The colors after the color reaction are made into standard color blocks and printed in the instruction manual to complete the value transfer. The higher the concentration, the darker the color block.

[0094] The collected trace amount of tear fluid is reacted with a highly sensitive glucose oxidase reagent and then colored. The test result is obtained by comparing the color with the standard color block in the instruction manual to obtain the qualitative result and concentration value range of tear glucose.

[0095] II. The usage method of the quantitative interpretation mode is as follows:

[0096] After the collected trace amount of tear fluid for the quantitative detection of tear glucose is reacted with the reagent and colored, the test result is obtained by reading the gray value through a micro reflection light, and according to the glucose value standard curve stored in the instrument, as Figure 8 shown, the content of tear glucose can be obtained through conversion. At the same time point within a day (the tear glucose value may be delayed by 30 minutes), tear glucose and capillary blood glucose of diabetic patients are detected simultaneously. The concentration change of tear glucose has a parallel relationship with capillary blood glucose and can be used for blood glucose detection.

[0097] Another major advantage of the present invention is to provide a production process for the above-mentioned tear glucose detection device. This production process adopts the form of module combination and then cutting, which is suitable for mass production of the above-mentioned tear glucose detection device. Refer to Figure 5 and Figure 6 The steps of this production process are as follows:

[0098] S1: Manufacture the first module 100 and the second module 200, wherein the length of the second module 200 along the second direction is greater than or equal to the width of N (N≥2) tear sugar detection strips, and the length of the first module 100 along the first direction is greater than or equal to the width of N support components 4. The first module 100 includes a groove for accommodating the second module 200.

[0099] S2: Apply the pH buffer, the glucose detection reagent, and the waterproof agent along the first direction on the second module 200 and penetrate through the second module 200 to form a first total strip, a second total strip, and a third total strip. The arrangement of the first total strip, the second total strip, and the third total strip along the first direction is the same as the arrangement of the pH buffer strip, the detection reagent strip, and the hydrophobic isolation strip of the tear sugar detection strip along the length direction of its long strip shape.

[0100] S3: Place one end of the second module 200 away from the first total strip, the second total strip, and the third total strip into the groove of the first module 100 and paste it to the groove wall to form a total module.

[0101] S4: Cut the total module to form N tear sugar detection devices.

[0102] Those skilled in the technical field of the present invention should understand that the order of steps S2 and S3 of this method is not unique. It can be coating first and then combining, or combining first and then coating.

[0103] Specifically, the production process is to first make the tear glucose detection device into two modules: the first module 100 and the second module 200. For example, the width of the tear glucose detection device can be set to 10 mm. If it is determined that the length of the module needs to be greater than the sum of the widths of 30 tear glucose detection devices, the lengths of the first module 100 and the second module 200 should be greater than 300 mm. The first module 100 can be made of a single-sided non-drying adhesive paper of cotton fiber with a height of 40 mm and a weight of 100 g. After folding in half, the single-sided height is 20 mm, and the inner side is a non-drying adhesive surface, which can be pasted together with the holding part of the second module 200. A qualitative filter paper with the same length as the first module 100 and a height of 50 mm is selected as the second module 200. After the long side of the second module 200 coincides with the folding line of the inner surface of the first module 100, the first module 100 and the second module 200 are bonded together through the non-drying adhesive. The first hydrophobic isolation band 21 is coated at the best height not less than 8 mm along the other long side of the second module 200. The selection of the waterproof agent and the optimal working concentration of the present invention depend on three factors. One is the actual waterproof effect, that is, after coating, it can completely block the tear from crossing the hydrophobic isolation band 2 on the filter paper; the second is that the effective period of the waterproof effect should be longer than the effective periods of the pH buffer and the glucose detection reagent; the third is that it does not inhibit the work of the pH buffer and the glucose detection reagent.For example, a polyethylene wax waterproofing agent can be mixed with water at a ratio of 1:30 and then line-coated with a width of 1 mm. After that, it is dried at 60°C for 2 hours. After the coating of the first hydrophobic isolation zone 21 is completed, above it, that is, in the area away from the tear sampling zone 1, three hydrophobic lines with different numbers can be coated next to the first hydrophobic isolation zone 21, and then dried at 60°C for 2 hours. After the coating of the hydrophobic isolation zone 2 is completed, the coating of the pH buffer zone 11 is carried out. At a position 3 mm away from the outer canthus tear film contact zone 10 of the eye to be examined (5 mm away from the first hydrophobic line), a solution prepared by dissolving sodium acetate in water with a final working concentration of 10 g / L is used to coat a 1-mm-wide straight line of the pH buffer zone 11. After line coating, it is dried at 60°C. Finally, the coating of the test reagent strip is carried out. 2,4,6-tribromo-3-hydroxybenzoic acid can be selected as the chromogen, and the final working concentration of the chromogen is 15 g / L. The first detection strip 12 with a width of 2 mm and parallel to the first hydrophobic isolation zone 21 is coated 1 mm behind the pH buffer zone 11. After the scribing is completed, it is vacuum dried at a temperature below 20°C for 3 hours. Then, a 2-mm-wide second detection strip 13 is coated in the gap between the first detection strip 12 and the first hydrophobic isolation zone 21. After the scribing is completed, it is vacuum dried at a temperature below 20°C for 3 hours. Finally, die cutting is carried out. The small incision of the die cutter is aligned with the first hydrophobic isolation zone 21, and the length of the sampling area of the die cutter can be 7 mm. In the outer canthus tear film contact zone 10 in front of the pH buffer zone 11, the template of the tear glucose detection device with the chemical reagent coated is cut into individual tear glucose detection device finished products using a die cutter in the shape of the tear glucose detection device.

[0104] The advantages of the present invention are to provide a tear glucose detection device, which integrates sampling and detection. When performing tear glucose detection, the detection strip only needs to be clamped between the upper and lower eyelids. After a few minutes, when the sampling area is filled with tears, the detection result can be obtained by colorimetry. This enables patients to obtain tear glucose detection results through non-invasive sampling methods for the chronic disease management of diabetes, without the need for strong professional knowledge, and patients can independently complete it in the community and at home. Further, the device uses a method of separately coating the chromogen and enzyme reagents in the pH buffer zone and the glucose detection reaction zone, rather than overlapping or combining them for coating, which can ensure that the activities of the chromogen and enzyme reagents are not greatly lost during the entire coating and drying process, and no consumables such as colorimetric cups are used, having a very high cost performance. Furthermore, the detection device combines two tear glucose test strips into one combination, which is only connected by a saddle stitch at the holding part. At the same time, by adding support to the holding part, the hardness of the rear end of the holding part is enhanced, reducing the damage rate of the test strip during packaging and test opening. When the patient uses it, as long as the saddle stitch of the holding part is torn open, the tear glucose test of the left and right eyes can be started. In addition, the present invention also provides a production process for this device. This production process uses a production process of first coating and scribing and then die-cutting. By modularizing rather than coating and scribing a single strip, the requirements for mass production can be met.

[0105] The above are only the preferred embodiments of the present invention and do not impose any limitations on the present invention. Any person skilled in the art, without departing from the technical solution of the present invention, making any form of equivalent substitution or modification and other changes to the technical solution and technical content disclosed by the present invention shall fall within the content of the technical solution of the present invention and still be within the protection scope of the present invention.

Claims

1. A tear sugar detection device, characterized in that, It includes a tear glucose test strip and a support component. The tear glucose test strip includes two identical test strip units connected in parallel along a first direction. Each test strip unit includes a tear sampling area, a hydrophobic isolation zone, and a holding part. The hydrophobic isolation zone is located between the tear sampling area and the holding part. The two test strip units are connected at the holding part and separated between the tear sampling area and the hydrophobic isolation zone. The tear sampling area is used for collecting tears and reacting with a glucose detection reagent to measure tear glucose. The hydrophobic isolation zone is used to prevent further diffusion of tears. The holding part is used for bonding with the support component to fix the tear glucose test strip. The first direction is the width direction of the strip-shaped tear glucose test strip. The tear sampling area includes an outer canthus tear film contact area of the eye to be examined, a pH buffer zone, and a detection reagent zone. The outer canthus tear film contact area of the eye to be examined is close to one end of the test strip unit. The pH buffer zone is located between the outer canthus tear film contact area of the eye to be examined and the detection reagent zone, and there is a gap between the pH buffer zone and the detection reagent zone. No chemical reagent is applied to the outer canthus tear film contact area of the eye to be examined. The pH buffer zone is coated with a pH buffer reagent. The detection reagent zone is coated with a glucose detection reagent. The hydrophobic isolation zone is coated with a waterproof agent. The glucose detection reagent, the waterproof agent, and the pH buffer reagent are coated and dried in lines in the tear sampling area to form the detection reagent zone, the hydrophobic isolation zone, and the pH buffer zone.

2. The tear glucose detection device according to claim 1, wherein, The glucose detection reagent includes a chromogen reagent and an enzyme reagent. The detection reagent zone includes a first detection zone and a second detection zone. The first detection zone is made by coating with the chromogen reagent. The second detection zone is made by coating with the enzyme reagent. The number of the hydrophobic isolation zones is multiple.

3. The tear sugar detection device according to claim 2, wherein The edge of the tear sampling area is arc-shaped. There is a cut on each of the two sides along the first direction of each unit of the tear glucose test strip between the tear sampling area and the hydrophobic isolation zone. The four cuts on the two test strip units are symmetric about the symmetry line of the two test strip units.

4. The tear sugar detection device according to claim 2, characterized in that, The chromogen reagent is selected from one or more of 2,4,6-tribromo-3-hydroxybenzoic acid, N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniline sodium salt, N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methoxyaniline sodium salt, N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline sodium salt, N-ethyl-N-(3-sulfopropyl)-3-methoxyaniline sodium salt, 3,5-dichloro-2-hydroxybenzenesulfonic acid sodium salt, N-2-ethyl(3-methylphenyl)aminoethylacetamide, N-ethyl-N-ethylsulfonate m-toluidine, 2,4-dichlorophenol, and 3,3',5,5'-tetramethylbenzidine. The enzyme reagent includes glucose oxidase, peroxidase, and 4-aminoantipyrine. The waterproofing agent is made of a mixture composed of one or more of polyethylene wax, palm wax emulsion, paraffin wax emulsion, Tianshi wax emulsion, water-soluble wax, wax emulsion, hydrogen-containing silicone oil, nano-silicon, soluble hot melt adhesive and acrylic resin and water in a ratio of 1:1 - 1:100; The pH buffer reagent is prepared by mixing one or more of strong base-weak acid salt compounds such as sodium carbonate, sodium citrate and sodium acetate and dissolving them in water, and the concentration is 1 - 30 g / L.

5. The tear glucose detection device according to any one of claims 1-4, characterized in that, The support assembly includes two support bars arranged parallel to each other on the surfaces, one end of the support bars is connected and the other end is separated to form a groove for accommodating the holding part.

6. The tear sugar detection device according to claim 1, characterized in that, The tear sugar detection device is used for binocular qualitative measurement of tear sugar according to the fact that qualitative tear sugar is a significant pathogenic influencing factor of diabetic retinopathy, and is used for quantitative measurement of tear sugar according to the parallel relationship between tear sugar and blood sugar, and is used for blood sugar monitoring.

7. The tear glucose detection device according to claim 1, wherein The tear sugar detection device is used for qualitative measurement of tear sugar. The color development result can be used for risk stratification of diabetic retinopathy in diabetic patients. By comparing the tear sugar detection result with the color patches of the glucose standard product, the corresponding tear sugar concentration value range and the result of positive or negative tear sugar can be obtained, and the critical value applied to the risk stratification of diabetic retinopathy in diabetic patients can be obtained based on the clinical assessment result. This critical value is a set of data conditions composed of the qualitative results of tear sugar in one or both eyes and the glucose concentration range. As long as any one of the positive data conditions is met or exceeded, it can be determined that there is a risk of diabetic retinopathy.

8. A production process of a tear sugar detection device for manufacturing the tear sugar detection device as described in claim 1, characterized in that, It includes the following steps: S1: Manufacture the first module and the second module. The length of the first module along the first direction is greater than or equal to the width of N tear sugar detection strips, and the length of the second module along the first direction is greater than or equal to the width of N support assemblies. The first module includes a groove for accommodating the second module, where N≥2; S2: Apply the PH buffer reagent, the glucose detection reagent and the waterproofing agent along the first direction on the first module and penetrate the first module to form a first total strip, a second total strip and a third total strip. The arrangement of the first total strip, the second total strip and the third total strip along the first direction is the same as the arrangement of the pH buffer strip, the detection reagent strip and the hydrophobic isolation strip of the tear sugar detection strip along the length direction of its long strip shape; S3: Place one end of the first module away from the first total strip, the second total strip and the third total strip in the groove of the second module and paste it to the groove wall to form a total module; S4: Cut the total module to form N tear sugar detection devices.

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