WO2023061471A1 - Tear glucose test device and production process therefor - Google Patents

Abstract

A tear glucose test device comprises a tear glucose test strip and a support assembly (4), wherein the tear glucose test strip comprises two identical test strip units (a, b) connected in parallel in a first direction; the test strip units (a, b) each comprise a tear sampling area (1), a hydrophobic isolation zone (2), and a holding portion (3); the hydrophobic isolation zone (2) is located between the tear sampling area (1) and the holding portion (3); the two test strip units (a, b) are connected at the holding portion (3), and are separated between the tear sampling area (1) and the hydrophobic isolation zone (2); the tear sampling area (1) is configured to sample tears and react same with a glucose test reagent to test tear glucose, the hydrophobic isolation zone (2) is configured to prevent further diffusion of the tears, and the holding portion (3) is configured to be bonded to the support assembly (4) so as to enhance the rigidity of the tear glucose test strip; and the first direction is a width direction of the elongated tear sugar test strip. The tear glucose test device can rapidly test tear glucose, is suitable for non-professionals to regularly test the tear glucose, can qualitatively measure the tear glucose for prevention of diabetic retinopathy, and can also quantitatively measure the tear glucose by means of the parallel relationship between the tear glucose and blood glucose.

Description

Tear sugar detection device and its production process technical field

The invention relates to the technical field of glucose detection, in particular to a tear sugar detection device and a production process thereof.

Background technique

Diabetic retinopathy (also known as diabetic retinopathy) is the most important complication of diabetes. It has the characteristics of high incidence and blindness. However, diabetic retinopathy has no obvious symptoms in the early stage. It has reached the advanced stage, thus missing the best time for drug and surgical treatment, so early detection and early treatment are the best ways to prevent diabetes.

A related study compared the diabetic retinopathy group with the non-diabetic retinopathy group, and found that the tear sugar content of the diabetic retinopathy group was higher than that of the non-diabetic retinopathy group. content, and the difference was statistically significant. The above clinical data show that the tear sugar content has a high correlation with the risk of diabetes mellitus disease in diabetic patients, so it is possible to prevent diabetes mellitus disease by regularly testing the tear sugar content.

However, the tear sugar was tested using a self-made polyethylene gelatin sponge lacrimal device, which needs to be placed in the subfornix of the conjunctiva for a long time to absorb a large volume of tears, or a capillary glass tube is used to collect tears from the outer canthus tear film of the tested eye. Obviously, these sampling methods are only suitable for scientific research, and are not suitable for non-professionals to measure tear sugar regularly and repeatedly; and although the existing tear sugar detection technology solves the problem of non-invasive micro-quantitative tear collection, it is difficult to complete the detection of tear glucose. The steps are cumbersome. If the reagent packaging for a single-person test requires a special cuvette to place an integrated device consisting of tear fluid sampling strips and miniature reagent bottles, it has the problems of many detection steps and high cost of consumables. It is convenient for storage and transportation, and it is not suitable for non-professionals.

Therefore, it is clinically necessary to provide a tear sugar detection device that integrates sampling and detection for diabetics and is suitable for use by non-professionals.

Contents of the invention

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

In order to achieve the above object and other related objects, the present invention provides a tear sugar detection device, which includes a tear sugar detection strip and a support assembly, and the tear sugar detection strip includes two identical detection strip units connected side by side along the first direction ,

The test strip unit includes a tear sampling area arranged along the second direction, a hydrophobic isolation zone and a handle, the hydrophobic isolation zone is located between the tear sampling area and the handle, and the two test strip units The holding part is connected and separated between the tear fluid sampling area and the hydrophobic isolation zone;

The tear fluid sampling area is used to collect tear fluid, and the collected tear fluid reacts with the glucose detection reagent to measure tear sugar, the hydrophobic isolation belt is used to prevent tear fluid from further spreading, and the gripping part is used to adhere to the support component to fix the tear sugar. The tear sugar test strip;

The first direction is perpendicular to the second direction.

Preferably, the tear sampling area includes an outer canthus tear film contact area of the tested eye, a pH buffer zone and a detection reagent belt arranged along the second direction, and the outer canthus tear film contact area of the tested eye is close to the detection zone. One end of the strip unit, the pH buffer zone is located between the outer canthus tear film contact area of the subject eye 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 tear film contact area of the outer canthus of the subject eye, the pH buffer strip is coated with a pH buffer reagent, and the detection reagent strip is coated with a glucose detection reagent.

Preferably, the glucose detection reagent includes a chromogen reagent and an enzyme reagent, and the detection reagent strip includes a first detection strip and a second detection strip adjacently arranged along the second direction, and the first detection strip smears With the chromogen reagent, the second detection zone is coated with the enzyme reagent.

Preferably, the edge of the tear sampling area is arc-shaped; between the tear sampling area and the hydrophobic isolation zone, each unit is provided on both sides of the tear sugar detection strip along the first direction. There is one cutout, and four cutouts on two of said test strip units are symmetrical about a line of symmetry between said two said test strip units.

Preferably, the hydrophobic isolation zone is coated with a waterproofing agent, and the hydrophobic isolation zone includes a plurality of hydrophobic isolation strips arranged side by side along the second direction;

The waterproofing agent is 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-sol and acrylic resin The mixture of water and water is made in a ratio of 1:1-1:100.

Preferably, the chromogen reagent is selected from 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-hydroxybenzenesulfonate sodium, N-2-ethyl (3-methylphenyl)aminoethylacetamide, N-ethyl-N-ethanesulfonate sodium m-toluidine, 2,4-dichlorophenol and 3,3',5,5'-tetramethyl One or more of benzidines;

The enzyme reagents include glucose oxidase, peroxidase and 4-aminoantipyridine;

The pH buffer reagent is prepared by mixing and dissolving one or more of strong base and weak salt compounds including sodium carbonate, sodium citrate and sodium acetate in water, and the concentration is 1-30g/L.

Preferably, the support assembly includes two support bars whose surfaces are parallel and correspondingly arranged, one end of the two support bars is connected, and the other end is separated to form a groove for accommodating the handle.

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

Preferably, the tear sugar detection device is used for qualitative measurement of tear sugar, and the color development result can be used for the risk stratification of diabetic patients with diabetes. By comparing the tear sugar detection result with the color of the glucose standard, it can be obtained Corresponding numerical range and lacrimal sugar positive or negative results, and based on the clinical assessment results, the critical value applied to the risk stratification of diabetes mellitus disease in diabetic patients is obtained, so as to stratify the risk of diabetes mellitus disease in diabetic patients, if Diabetic patients with 2+ in one eye, >0.30mmol/L and above, or 1+ in both eyes, >0.15mmol/L and above are all judged to be positive for the risk of diabetic reticulopathy in this test, and the risk of related diabetic reticulopathy is significantly increased. Go to the ophthalmology department of the hospital for investigation. If the tear sugar of diabetic patients is colorless, light yellow, and 1+ in one eye, ≤0.15mmol/L, it is judged that the risk of diabetic reticulopathy in this test is negative. At present, the risk of diabetic reticulopathy is low, but Qualitative tear sugar monitoring is also required on a regular basis.

The present invention also provides a production process for a tear sugar detection device, which is used to manufacture the tear sugar detection device as described above, comprising the following steps:

S1: Manufacture a first module and a 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 The length is greater than or equal to the width of N support components, and the first module includes a groove for accommodating the second module, where N≥2;

S2: apply the pH buffer agent, the glucose detection reagent and the water repellent on the first module along the first direction, and run through the first module to form a first overall zone, a second overall band and the third total band, the first total band, the second total band and the third total band correspond to the pH buffer band, the detection reagent band and the The hydrophobic isolation zone;

S3: Place the end of the first module away from the first total belt, the second total belt and the third total belt in the groove of the second module, and stick it to the groove wall , forming the total module;

S4: cutting the total module to form N tear sugar detection devices.

To sum up, the present invention provides a tear sugar detection device, which integrates sampling and detection. When the device detects tear sugar, it only needs to place the detection strip at the tear film of the outer canthus of the eye to be tested. Minutes later, after the sampling area is full of tears, the test results can be obtained by colorimetry, so that patients can obtain tear sugar test results through non-invasive collection methods, which can be used for the management of chronic diseases of diabetes without strong professional knowledge. Patients in the community and at home It can be completed independently; further, the device adopts the method of separately coating the chromogen and enzyme reagent in the pH buffer zone and the glucose detection reaction zone, instead of overlapping or coating together, which can ensure that the chromogen and enzyme reagent The activity is not greatly lost during the entire coating and drying process, and there is no need to use consumables such as cuvettes, which has a high cost performance; further, the detection device combines two tear glucose test strips into one combination, Only the grip part is connected by riding sutures. At the same time, by adding support to the grip part, the hardness of the rear end of the grip part is strengthened, which reduces the damage rate of the test strip during the packaging and test unsealing process. When the suture is torn, the test of left and right tear sugar can be started; finally, the device can not only qualitatively measure tear sugar for the prevention of diabetic retinopathy, but also quantitatively measure tear sugar by using the parallel relationship between tear sugar and blood sugar.

In addition, the present invention also provides the production process of the above-mentioned device. The production process adopts the production process of coating and marking first and then die-cutting, and the coating and marking of a single line can meet the requirements of mass production.

Description of drawings

1 is a schematic diagram of a single tear sugar detection strip unit of a tear sugar detection strip of a tear sugar detection device provided by an embodiment of the present invention;

Fig. 2 is a schematic diagram of the tear sugar detection strip of the tear sugar detection device provided by an embodiment of the present invention

Fig. 3 is a schematic diagram of a support assembly of a tear sugar detection device provided by an embodiment of the present invention;

Fig. 4 is a schematic diagram of a tear sugar detection device provided by an embodiment of the present invention;

Fig. 5 is a schematic diagram of the production process of the tear sugar detection device provided by an embodiment of the present invention;

Fig. 6 is a schematic diagram of the production process of the tear sugar detection device provided by an embodiment of the present invention;

Fig. 7 is a schematic diagram of the comparison of the detection results of the tear sugar detection device provided by an embodiment of the present invention;

Fig. 8 is a schematic diagram of a standard curve of the gray value of the detection results of the tear sugar detection device provided by an embodiment of the present invention.

Wherein, the reference signs are explained as follows:

a-the first test strip unit, b-the second test strip unit, 1-tear fluid sampling area, 2-hydrophobic isolation zone, 3-holding part, 4-support component, 10-the outer canthus tear film contact area of the tested eye, 11-pH buffer zone, 12-first detection zone, 13-second detection zone, 21-first hydrophobic isolation zone, 100-first module, 200-second module.

Detailed ways

The specific implementation manner of the present invention will be described in more detail below with reference to schematic diagrams. The advantages and features of the present invention will be more apparent from the following description. It should be noted that all the drawings are in a very simplified form and use imprecise scales, and are only used to facilitate and clearly assist the purpose of illustrating the embodiments of the present invention.

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 , is only for the convenience of describing the present invention and simplifying the description, but does not indicate or imply that the referred device or element must have a specific orientation, be constructed and operated in a specific orientation, and thus should not be construed as limiting the present invention.

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

Figures 1 to 4 are schematic diagrams of a tear sugar detection device provided by an embodiment of the present invention. The tear sugar detection device provided in this embodiment includes a tear sugar detection strip and a support assembly 4. Referring to Figures 1 to 2, the tear sugar detection The strip includes two identical tear sugar detection strip units connected side by side: the first detection strip unit a and the second detection strip unit b, and the detection strip unit is divided into a tear sampling area 1, a hydrophobic isolation strip 2 and a grip part 3 , the hydrophobic isolation strip 2 is located between the tear sampling area 1 and the holding part 3, the first detection strip unit a and the second detection strip unit b are connected at the holding part 3, in the The tear sampling area 1 is separated from the hydrophobic isolation zone 2; the tear sampling area 1 is used to collect tears and react with glucose detection reagents to measure tear sugar concentration, and the hydrophobic isolation zone 2 is used to prevent further diffusion of tears, so The holding part 3 is used for bonding with the supporting component 4 to fix the tear sugar test strip.

The tear sampling area 1 includes a test eye outer canthus tear film contact area 10, a pH buffer zone 11 and a detection reagent strip. The test eye outer canthus tear film contact area 10 is close to one end of the test strip unit, and the pH The buffer strip is located between the outer canthus tear film contact area 10 of the subject eye and the detection reagent strip.

The inventors have found through research that when testing tear sugar, it is necessary to detect both the left and right eyes to be more accurate. When the device is implemented, the tester can tear the tear sugar detection strip along the central axis, and use the first The detection strip unit a and the second detection strip unit b detect the left and right eyes respectively. During the detection, you only need to place the detection strip at the tear film of the outer canthus of the eye to be tested. After a few minutes, 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 use by non-professionals.

In addition, because the hydrophobic isolation zone 2 needs a certain width (the size in the left and right direction in Fig. 1 ) to have a better effect of blocking tear fluid from continuing to spread, the optimal width of the hydrophobic isolation zone 2 is generally 3-12mm. mm, can be composed of several 1-3 mm wide linear strips arranged in parallel next to each other, wherein one side (right side in Fig. 1) of the first hydrophobic isolation zone 21 constitutes the hydrophobic isolation zone 2 and The boundary line of the tear sampling area 1, the first hydrophobic isolation zone 21 is composed of a straight line strip next to the tear sampling area 1, and is next to the first water sampling area 1 in the direction away from the tear sampling area 1 The hydrophobic isolation zone 21 can be coated with several hydrophobic linear strips arranged next to each other in parallel. In addition, a cutout is respectively provided on both sides of the first hydrophobic isolation zone 21 in the length direction (the up-and-down direction in FIG. An incision is also provided on both sides in the length direction, and the incision outline of the first hydrophobic isolation zone 21 and the incision outline of the detection reagent strip are spliced into a smooth arc. Both the first hydrophobic isolation zone 21 and the detection reagent zone of the two detection strip units connected in parallel have cutouts. The four cutouts respectively located on the two test strip units are symmetrical about the symmetry line of the two test strip units, and the edge of the tear sampling area is generally made into a circular arc, so that it is in line with the outer canthus tear of the tested eye. The contact area of the membrane is the smallest to avoid eye irritation, and the basic tears are collected. The existence of small incisions is to avoid corners from poking around the eyelids of the tester. The arc shape and small incisions are set to improve the comfort of the tester when taking tears. Spend.

In order to improve detection accuracy, the detection reagent strip generally adopts the glucose oxidase coupling Trinder reaction of the formula of two reagents (enzyme reagent and chromogen reagent), and the detection reagent strip is divided into the first detection strip 12 and the second detection strip. Detection zone 13, the first detection zone 12 is made by smearing a chromogen reagent, and the second detection zone 13 is made by smearing an enzyme reagent. As a result, the second detection zone 13 is made by applying a chromogen reagent. In addition, a pH buffer zone 11 is provided between the outer canthus tear film contact zone 10 of the subject's eye and the detection reagent zone, and the pH buffer agent is applied.

For the smearing of enzyme reagents, chromogen reagents and pH buffers used to maintain and provide an ideal biochemical reaction environment for detecting tear sugar, the inventors found that the pH buffer zone 11 and the detection The reagent strips (the first detection strip 12 and the second detection strip 13) are not overlapped or coated together, and there is a certain gap between them, which can ensure that the activity of the chromogen and the enzyme reagent can be fully applied during the entire coating and drying process. No major losses in the process.

During specific manufacture, the glucose detection reagent, the water repellent and the pH buffering agent are streaked and coated on the tear fluid sampling area 1 and then dried to form the detection reagent strip (the first detection strip 12 and the second strip) Two detection zone 13), the hydrophobic isolation zone 2 and the pH buffer zone 11. The application concentration of the glucose detection reagent, the waterproofing agent and the pH buffering agent is generally 1-30 g/L. The chromogen reagent generally includes 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-methyl Aniline sodium salt, N-ethyl-N-(3-sulfopropyl)-3-methoxyaniline sodium salt, 3,5-dichloro-2-hydroxybenzenesulfonate sodium, N-2-ethyl (3 -methylphenyl)aminoethylacetamide, N-ethyl-N-ethanesulfonic acid sodium m-toluidine, 2,4-dichlorophenol and 3,3',5,5'-tetramethylbenzidine One or more of them; the enzyme reagent generally includes glucose oxidase, peroxidase and 4-aminoantipyridine; One or more mixtures of emulsion, water-soluble wax, wax emulsion, hydrogen-containing silicone oil, nano-silicon, soluble hot-sol and acrylic resin are prepared with water at a ratio of 1:1-1:100; the pH buffer reagent Generally, it is prepared by mixing and dissolving one or more of strong base and weak salt compounds including sodium carbonate, sodium citrate and sodium acetate in water.

In order to facilitate the use of non-professionals, the support assembly 4 generally includes two support bars with parallel surfaces, one end of the support bar is connected, and the other end is separated to form a groove for accommodating the handle 3. The support strip is generally made of hard paper with a certain rigidity, and the tear detection strip is made of qualitative filter paper. The rear end of the holding part 3 has a sticking area for the tear sugar detection strip, the optimum length is 5-30 mm, and the holding part 3 can be inserted into the groove of the support assembly 4, and is connected with the wall of the groove Adhere to each other; the outer canthus tear film contact zone 10 of the subject eye, the pH buffer zone 1, the first detection zone 12 and the second detection zone 13, and the hydrophobic isolation zone 2 are all symmetrical along the central axis.

The present invention is a tear fluid glucose detection device integrating sampling and detection. There are two modes for interpretation of the results of the device, one is qualitative or semi-quantitative interpretation mode, and the detection result is compared with the glucose standard concentration color block. , so as to qualitatively draw the concentration range of tear sugar. The other is the quantitative interpretation mode, which uses instruments and equipment to detect the color depth of the glucose detection reagent strip in the sampling area after color development, and compares the obtained gray value with the standard glucose curve stored in the instrument to obtain the tear sugar concentration.

1. The method of using the qualitative and semi-quantitative interpretation mode is as follows:

Separate the tear sugar detection device and place the tear sampling area 1 at the front end on the tear film of the outer canthus of the left and right eyes to collect tear fluid. After the tear fluid has filled the entire tear fluid sampling area 1, take it out and wait for about three minutes before it can be used with the tear sugar detection device. Figure 7 is compared to obtain the corresponding glucose concentration value range and tear sugar positive or negative results, and according to the clinical assessment results, the critical value applied to the risk stratification of diabetic patients with diabetes mellitus is obtained for the sugar Risk stratification of diabetes mellitus disease. If a diabetic has 2+ in one eye, >0.30mmol/L and above, or 1+ in both eyes, >0.15mmol/L and above, it is judged to be positive for the risk of diabetes mellitus disease in this test. Tear sugar is colorless, light yellow, and 1+ in one eye, ≤0.15mmol/L, all of which are judged to be negative for the risk of diabetes in this test.

The number of diabetic patients enrolled in this test is 155 cases (the course of disease, fasting blood sugar and glycosylated hemoglobin value of diabetic patients are counted at the same time), of which 51 cases are diagnosed as diabetic patients, and 104 cases are non-diabetic diabetic patients. The result statistics are as follows:

1. The relationship between the level of tear glucose (qualitative) value and the stages of diabetic reticulopathy (for the convenience of statistics, diabetic reticulopathy is divided into early stage (I\II\III stage) and late stage (IV\V\VI Phase) Phase II, and the single tear sugar value with high tear sugar value is listed)

Statistics show:

The proportion of tear sugar high value 4+ positive in the early and late stages of diabetic reticulosis is the highest, the early stage of diabetic reticulum disease accounts for 33.3%, and the late stage accounts for 30.0%, which is also the highest in the total proportion regardless of stage;

There is no obvious proportional relationship between tear glucose (qualitative) value and the stage of diabetic reticulopathy, and the proportion of each positive segment is scattered.

2. The relationship between the positive detection of tear glucose (qualitative) in one or both eyes and the stage of diabetic retinopathy

Statistics show:

Double tear glucose (qualitative) positive rate is the highest in the early (90.5%) and late (73.3%) patients of diabetic reticulosis, and it is also the highest in the total proportion regardless of stage;

Tear fluid glucose (qualitative) monocular or binocular positive is not proportional to the stage of diabetic retinopathy, and the proportion of monocular and binocular positive is relatively scattered.

From the above analysis, it can be seen that in both early and late diabetic reticulum patients, the proportion of tear glucose high positive (4+, accounting for 31.4%) combined with both eyes being positive (80.4%) is the highest, indicating that tear glucose (qualitative ) high value in both eyes reflects the severity of diabetic retinopathy to some extent.

3. Analyze the correlation between qualitative tear sugar results, etc. as the pathogenic factors of DR and DR

① Chi-square test

In order to analyze the pathogenic influencing factors of diabetic retinopathy, the Chi-square test results for factors such as diabetes duration ≥ 10 years, glycosylated hemoglobin ≥ 8.0%, and fasting blood glucose ≥ 8.0mmol/L are as follows:

Factors affecting the pathogenesis of diabetic reticulosis	X2 value	P value	Correlation
Duration of diabetes (≥10 years)	9.742	0.0018	Significant correlation**
Glycosylated hemoglobin ≥ 8.0%	7.340	0.0067	relevant*
Fasting blood sugar ≥ 8.0mmol/L	5.903	0.015	relevant*
Tear glucose (qualitative)	11.139	0.0008	Significant correlation**

Statistics show:

Diabetes reticulosis was significantly correlated with diabetes duration ≥ 10 years and tear glucose (qualitative);

Diabetic retinopathy was correlated with glycosylated hemoglobin ≥ 8.0% and fasting blood glucose ≥ 8.0mmol/L but not significant.

②, logistic regression analysis

Several factors related to diabetic retinopathy were analyzed: duration of diabetes ≥ 10 years, glycosylated hemoglobin ≥ 8.0%, fasting blood glucose ≥ 8.0mmol/L and tear glucose (qualitative). Taking diabetic retinopathy as the dependent variable, logistic regression analysis was performed on these four factors, and the results are as follows:

Factors affecting the pathogenesis of diabetic reticulosis	B	SE	Wald	P	Exp(B)
Disease duration ≥ 10 years	1.172	0.400	8.593	0.003	3.227
Tear glucose (qualitative)	1.211	0.403	9.012	0.003	3.356
Glycosylated hemoglobin ≥ 8.0%	0.666	0.458	2.109	0.146	1.946
Fasting blood sugar ≥ 8.0mmol/L	0.220	0.485	0.206	0.650	1.246

Statistics show:

The P value of the course of disease ≥ 10 years is 0.003, and the P value of tear glucose (qualitative) is 0.003, both of which are less than 0.005. Therefore, the duration of diabetes ≥ 10 years and tear glucose (qualitative) are important pathogenic factors of DR;

The P values of glycosylated hemoglobin ≥ 8.0% and fasting blood glucose ≥ 8.0mmol/L are both greater than 0.05, which are not important pathogenic factors of diabetic retinopathy.

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

① Chi-square test

Tear glucose (qualitative) and the duration of diabetes ≥ 10 years significantly related to diabetic reticulopathy, as well as glycosylated hemoglobin ≥ 8.0% and fasting blood glucose ≥ 8.0mmol/L related to diabetic reticulopathy were tested by Chi-square test. The result is as follows:

Factors affecting the pathogenesis of diabetic reticulosis	X2 value	P value	Correlation
Duration of diabetes (≥10 years)	0.003	0.955	irrelevant
Glycosylated hemoglobin ≥ 8.0%	3.210	0.073	irrelevant
Fasting blood sugar ≥ 8.0mmol/L	7.517	0.006	relevant*

Statistics show:

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

Tear glucose (qualitative) was not associated with diabetes duration ≥ 10 years and HbA1c ≥ 8.0%.

②. Logistic regression analysis on the pathogenic factors of diabetic retinopathy related to tear glucose (qualitative)

The fasting blood glucose ≥ 8.0mmol/L related to tear glucose (qualitative) was used as the dependent variable of tear glucose (qualitative), which is the pathogenic factor of diabetic reticulosis. Logistic regression analysis was carried out, and the results are as follows:

factor	B	SE	Wald	P	Exp(B)
Fasting blood sugar ≥ 8.0mmol/L	1.099	0.411	7.150	0.007	3.002

Statistics show that the P value of fasting blood glucose ≥ 8.0mmol/L is 0.007 and less than 0.05, which is statistically significant. Fasting blood glucose ≥ 8.0mmol/L is a risk factor related to tear glucose (qualitative).

Tear glucose (qualitative) as an important pathogenic factor of diabetic reticulosis is used in the detection of diabetic reticulum risk stratification, and it has the advantage of a large range of positive and negative differences (whether in early or late diabetic reticulum patients, the high value of tear glucose Positive (4+, accounting for 33.9%) combined with simultaneous positive in both eyes (accounting for 82.8%) has the highest proportion), the test result is easier to judge, has a high sensitivity (38/51=74.5%), and other indicators are also in line with Technical testing requirements.

After correlation analysis of tear glucose (qualitative) as the pathogenic factor of diabetic reticulopathy and diabetic reticulopathy, chi-square test and logistic regression analysis results showed that only tear glucose (qualitative) and the duration of diabetes were significantly correlated with diabetic reticulopathy, so These two are the most important factors affecting the pathogenesis of DR.

To analyze whether tear glucose (qualitative) is an independent risk factor for DRD, chi-square test and logistic regression analysis showed that tear glucose (qualitative) was correlated with fasting blood glucose ≥ 8.0mmol/L but not significant, and not related to the course of diabetes Therefore, tear glucose (qualitative) is an independent factor affecting the pathogenesis of diabetic retinopathy that has a certain degree of correlation with hyperglycemia.

Qualitative or semi-quantitative interpretation mode is the most common method convenient for non-professionals to use. This method first performs quantitative value transfer and uses four glucose concentration standards (S1 0.153mmol/L, S2 0.306mmol/L, S3 0.613mmol /L and S4 1.226mmol/L) in the sampling area of each 3μl pointing tear glucose detection device, the color after the color reaction is made into a standard color block and printed on the instruction manual to complete the value transfer. The higher the concentration, the more color color block. deep.

The collected micro-tear fluid is reacted with a high-sensitivity glucose oxidase reagent to develop color, and the test result is compared with the color of the standard color block on the instruction manual to obtain the qualitative result and concentration range of tear glucose.

2. The method of using the quantitative interpretation mode is as follows:

After reacting the micro-amount of tear reagent collected for the quantitative detection of tear glucose and developing the color, the test result is read through the micro-reflected light to read the gray value, and according to the standard curve of glucose value stored in the instrument, as shown in Figure 8, the conversion is carried out The content of tear glucose can be obtained. At the same time point in a day (the tear sugar value may be delayed by 30 minutes), the tear sugar and capillary blood sugar are detected at the same time for diabetics. The change of tear glucose concentration and capillary blood sugar are parallel. Relationship, can be used for blood sugar detection.

Another advantage of the present invention is that it provides a production process for the above-mentioned tear sugar detection device. The production process adopts the form of module combination and cutting, and is suitable for mass production of the above-mentioned tear sugar detection device. Referring to Fig. 5 and Fig. 6, the steps of this production process are as follows:

S1: Manufacture the first module 100 and the second module 200, 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, the first module The length of 100 along the first direction is greater than or equal to the width of N support assemblies 4, and the first module 100 includes a groove for accommodating the second module 200;

S2: apply the pH buffer agent, the glucose detection reagent and the water repellent on the second module 200 along the first direction, and run through the second module 200 to form a first overall zone, a second The second total zone and the third total zone, the arrangement of the first total zone, the second total zone and the third total zone along the first direction is consistent with the pH buffer zone and the pH buffer zone of the tear detection strip. The arrangement of the detection reagent strip and the hydrophobic isolation strip along the length direction of its elongated shape is the same;

S3: Place the end of the second module 200 away from the first total belt, the second total belt and the third total belt in the groove of the first module 100, and make it contact with the wall of the groove Paste to form the total module;

S4: cutting the total module to form N tear sugar detection devices.

Persons in the technical field of the present invention should understand that the order of step S2 and step S3 of the method is not unique, it can be coating first and then combining, or combining first and then coating.

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. The length of the module needs to be greater than the sum of the widths of 30 tear glucose detection devices, so the length of the first module 100 and the second module 200 should be greater than 300 mm, and the first module 100 can be 40 mm in height and 100 grams in height Heavy cotton fiber single-sided self-adhesive paper, the height of one side after folding in half is 20 mm, and the inner surface is one side of self-adhesive, which can be pasted together with the holding part of the second module 200, and the length of qualitative filter paper and the above-mentioned The length of the first module 100 is the same as the height of 50 mm as the second module 200, and the first module 100 is overlapped with the long side of the second module 200 and the fold line of the inner surface of the first module 100. and the second module 200 are bonded together by self-adhesive, and the first hydrophobic isolation tape 21 is coated on the optimal height of the second module 200 along the other long side of not less than 8 mm, and the present invention is waterproof The selection of the agent and the optimum working concentration depend on three factors. The first is the actual waterproof effect, which means that the tears can be completely blocked on the filter paper and cross the hydrophobic isolation zone 2 after being applied; the second is that the effective period of the waterproof effect is longer than The validity period of the pH buffer and the glucose detection reagent is long; 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 coated with a width of 1 mm, and then dried at 60° C. for 2 hours. After the coating of the first hydrophobic isolation belt 21 is completed, it can , that is, the area away from the tear sampling area 1, three different numbers of hydrophobic lines can be coated next to the first hydrophobic isolation zone 21, and then dried at 60°C for 2 hours; the coating of the hydrophobic isolation zone 2 is completed. After cloth, carry out the coating of described pH buffer zone 11 again, adopt sodium acetate to be dissolved in water and prepare final pH buffer zone 11 at the place 103 mm away from the tear film contact area of the outer canthus of the subject's eye (5 mm away from the first hydrophobic line). A solution with a working concentration of 10g/L is used to coat the pH buffer zone 11 with a straight line of 1mm width, and then dry at 60°C after scribing and coating; finally, the detection reagent strip can be coated with 2.4.6-tribromo- 3-Hydroxybenzoic acid is used as the chromogen, and the final working concentration of the chromogen is 15g/L, and the 2mm-width parallel to the first hydrophobic isolation zone 21 is coated at 1mm behind the pH buffer zone 11. The first detection zone 12 is vacuum-dried at a temperature below 20°C for 3 hours after the scribing is completed, and then the first detection zone 12 and the first hydrophobic isolation zone 21 are coated with a 2mm-wide gap between the first detection zone 12 and the first hydrophobic isolation zone 21. Two detection belts 13, vacuum dry below 20 ℃ for 3 hours after the scribing is completed; finally carry out die-cutting, the small incision of the knife mold is aligned with the first hydrophobic isolation zone 21, and the length of the knife mold sampling area can be 7mm. The outer canthus tear film contact area 10 in front of the pH buffer zone 11 cuts the tear glucose detection device template coated with the chemical reagent into a single tear glucose detection device finished product with a knife mold in the shape of the tear glucose detection device.

The advantage of the present invention is that it provides a tear sugar detection device, which integrates sampling and detection. When the device detects tear sugar, it only needs to clamp the detection strip between the upper and lower eyelids, and after a few minutes, the sampling area After the tears are filled, the test results can be obtained by colorimetry, so that patients can obtain tear sugar test results through non-invasive collection methods, which can be used for chronic disease management of diabetes, without strong professional knowledge, and patients can complete it independently in the community and at home; further Specifically, the device adopts the method of separately coating the chromogen and the enzyme reagent in the pH buffer zone and the glucose detection reaction zone, instead of overlapping or coating together, which can ensure the activity of the chromogen and enzyme reagent throughout the coating. There is no large loss during the drying process, and there is no need to use consumables such as cuvettes. Suture connection, at the same time, by adding support to the grip part, the hardness of the back end of the grip part is strengthened, which reduces the damage rate of the test strip during the packaging and test unsealing process. Can start the test of left and right tear sugar; in addition, the present invention also provides a kind of production process of this device, this production process adopts the production process of first coating scribing and then die-cutting, and coating scribing is carried out by modularization instead of single strip line, which can meet the requirements of mass production.

The foregoing are only preferred embodiments of the present invention, and do not limit the present invention in any way. Any person skilled in the technical field, within the scope of the technical solution of the present invention, makes any form of equivalent replacement or modification to the technical solution and technical content disclosed in the present invention, which does not depart from the technical solution of the present invention. The content still belongs to the protection scope of the present invention.

Claims (10)

1. A tear sugar detection device, characterized in that it includes a tear sugar detection strip and a support assembly, the tear sugar detection strip includes two identical detection strip units connected side by side along the first direction,

   The test strip unit includes a tear sampling area arranged along the second direction, a hydrophobic isolation zone and a handle, the hydrophobic isolation zone is located between the tear sampling area and the handle, and the two test strip units The holding part is connected and separated between the tear fluid sampling area and the hydrophobic isolation zone;

   The tear fluid sampling area is used to collect tear fluid, and the collected tear fluid reacts with the glucose detection reagent to measure tear sugar, the hydrophobic isolation belt is used to prevent tear fluid from further spreading, and the gripping part is used to adhere to the support component to fix the tear sugar. The tear sugar test strip;

   The first direction is perpendicular to the second direction.
2. The tear sugar detection device according to claim 1, wherein the tear fluid sampling area comprises an outer canthus tear film contact area, a pH buffer zone and a detection reagent strip arranged along the second direction, and the The tear film contact area of the outer canthus of the tested eye is close to one end of the test strip unit, and the pH buffer zone is located between the tear film contact zone of the outer canthus of the tested eye and the detection reagent belt, and the pH buffer zone is in contact with the test strip unit. There is a gap between the detection reagent strips;

   No chemical reagent is applied to the tear film contact area of the outer canthus of the subject eye, the pH buffer strip is coated with a pH buffer reagent, and the detection reagent strip is coated with a glucose detection reagent.
3. The tear sugar detection device according to claim 2, wherein the glucose detection reagents include chromogen reagents and enzyme reagents, and the detection reagent strips include first detection strips arranged adjacently along the second direction and a second detection zone, the first detection zone is coated with the chromogen reagent, and the second detection zone is coated with the enzyme reagent.
4. The tear sugar detection device according to claim 3, wherein the edge of the tear sugar sampling area is arc-shaped; between the tear sampling area and the hydrophobic isolation zone, between the tear sugar detection strips One notch is provided on both sides of the unit along the first direction, and the four notches on the two test strip units are symmetrical about the line of symmetry of the two test strip units.
5. The tear sugar detection device according to claim 1, wherein the hydrophobic isolation zone is coated with a waterproof agent, and the hydrophobic isolation zone comprises a plurality of hydrophobic isolation strips arranged side by side along the second direction;

   The waterproofing agent is 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-sol and acrylic resin The mixture of water and water is made in a ratio of 1:1-1:100.
6. The tear sugar detection device protected as claimed in claim 3, wherein the chromogen reagent is selected from 2,4,6-tribromo-3-hydroxybenzoic acid, N-(2-hydroxyl-3-sulfopropyl base)-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 -Sodium 2-hydroxybenzenesulfonate, N-2-ethyl(3-methylphenyl)aminoethylacetamide, N-ethyl-N-sodium ethanesulfonate m-toluidine, 2,4-dichlorophenol One or more of 3,3',5,5'-tetramethylbenzidine;

   The enzyme reagents include glucose oxidase, peroxidase and 4-aminoantipyridine;

   The pH buffer reagent is prepared by mixing and dissolving one or more of strong base and weak salt compounds including sodium carbonate, sodium citrate and sodium acetate in water, and the concentration is 1-30g/L.
7. The tear sugar detection device according to any one of claims 1-6, characterized in that, the support assembly includes two support bars whose surfaces are parallel and correspondingly arranged, one end of the two support bars is connected, and the other end is separated, so as to A groove for accommodating the holding portion is formed.
8. The tear sugar detection device according to claim 1, wherein the tear sugar detection device is used to qualitatively measure the tear sugar according to the qualitative tear sugar is a significant pathogenic factor of diabetes retinopathy, and is used to measure the tear sugar according to the tear sugar and Parallel Relationship of Blood Glucose Quantitative measurement of tear sugar for blood glucose monitoring.
9. The tear sugar detection device according to claim 1, characterized in that the tear sugar detection device is used for qualitative measurement of tear sugar, and the color development results can be used for the risk stratification of diabetic patients with diabetic retinopathy. The result is compared with the color block of the glucose standard, and the corresponding tear sugar concentration value range and positive or negative results are obtained, and the threshold applied to the risk stratification of diabetic diabetic retinoid disease is obtained based on the clinical assessment results Value, this critical value is a set of data conditions consisting of the qualitative results of tear sugar in one or both eyes and the range of glucose concentration. As long as any positive data condition is met or exceeded, it can be determined that there is a risk of diabetes.
10. A production process for a tear sugar detection device, used to manufacture the tear sugar detection device according to claim 2, characterized in that it comprises the steps of:

    S1: Manufacture a first module and a 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 The length is greater than or equal to the width of N support components, and the second module includes a groove for accommodating the first module, where N≥2;

    S2: Apply the pH buffer, the glucose detection reagent, and the water repellent on the first module along the first direction, and run through the first module to form a first total belt, a second total band and the third total band, the first total band, the second total band and the third total band correspond to the pH buffer band, the detection reagent band and the The hydrophobic isolation zone;

    S3: Place the end of the first module away from the first total belt, the second total belt and the third total belt in the groove of the second module, and stick it to the groove wall , forming the total module;

    S4: cutting the total module to form N tear sugar detection devices.

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