A MEASUREMENT SYSTEM FOR TEAR CHEMICALS IN TEARS FOR THE DIAGNOSIS OF DISEASES.

Abstract

The measurement system (1) in question includes a set of biosensors (6) that change color according to the amount of tear chemicals, including dopamine, glucose, ascorbate, lactate and proteins, found in tears. When the measurement process is complete, the biosensor set (6) is visually analyzed, and thus the level of various chemicals such as dopamine in tears can be determined.

Description

29280.14 TARIFF A MEASUREMENT SYSTEM FOR TEAR CHEMICALS IN TEARS FOR THE DIAGNOSIS OF DISEASES. Technical Area This invention relates to a measurement system that enables the detection of chemical levels in tears, which can be used to identify diseases detectable through tear samples. Previous Technique An increase in dopamine levels in the striatum region of our brain can trigger the onset of schizophrenia¹, while a decrease in dopamine levels can lead to neurological degeneration in the brain and Parkinson's disease due to increased iron levels². Furthermore, disturbances in dopamine level balance are detected in drug addicts and in cases of HIV infection resulting from drug addiction³. Unfortunately, the level of dopamine release in the brain, one of the most important indicators for monitoring the condition of individuals suspected of or diagnosed with neurological diseases, particularly Parkinson's disease, is very difficult to detect. Scientific research has proven that the level of dopamine in tears is directly related to changes in the brain. Systemic diseases (diseases affecting the entire body) are diagnosed through chemical analysis of blood and / or urine samples obtained from patient-reported symptoms, signs observed during examination, or a medical history file. Patient samples are typically sent to a diagnostic laboratory to determine levels of a wide range of markers, including ions, antibodies, hormone levels, and various disease-specific biomarkers. 1Biol Psychiatry. 2017 Jan 1 ;81 (1 ):52-66. doi: 10.1016 / j.biopsych.2016.05.021. Epub 2016 Jun 1. 2Prog Ncurobiol. Aug 2017; 155:96-119. doi: 10.1016 / j.pneurobio.2015.09.012. Epub 2015 Oct 9. 3Moles Ncurobiol. 2011 Aug;44(l): 102-10. doi: 10.1007 / s 12035-011 -8195-z. Epub 2011 Jul 1. 4Acta Naturae. 2018 Jul-Sep; 10(3): 62-67. 29280.14 TARIFF A MEASUREMENT SYSTEM FOR TEAR CHEMICALS IN TEARS FOR THE DIAGNOSIS OF DISEASES. Technical Area This invention relates to a measurement system that enables the detection of chemical levels in tears, which can be used to identify diseases detectable through tear samples. Previous Technique An increase in dopamine levels in the striatum region of our brain can trigger the onset of schizophrenia¹, while a decrease in dopamine levels can lead to neurological degeneration in the brain and Parkinson's disease due to increased iron levels². Furthermore, disturbances in dopamine level balance are detected in drug addicts and in cases of HIV infection resulting from drug addiction³. Unfortunately, the level of dopamine release in the brain, one of the most important indicators for monitoring the condition of individuals suspected of or diagnosed with neurological diseases, particularly Parkinson's disease, is very difficult to detect. Scientific research has proven that the level of dopamine in tears is directly related to changes in the brain. Systemic diseases (diseases affecting the entire body) are diagnosed through chemical analysis of blood and / or urine samples obtained from patient-reported symptoms, signs observed during examination, or a medical history file. Patient samples are typically sent to a diagnostic laboratory to determine levels of a wide range of markers, including ions, antibodies, hormone levels, and various disease-specific biomarkers. 1Biol Psychiatry. 2017 Jan 1 ;81 (1 ):52-66. doi: 10.1016 / j.biopsych.2016.05.021. Epub 2016 Jun 1. 2Prog Ncurobiol. Aug 2017; 155:96-119. doi: 10.1016 / j.pneurobio.2015.09.012. Epub 2015 Oct 9. 3Moles Ncurobiol. 2011 Aug;44(l): 102-10. doi: 10.1007 / s 12035-011 -8195-z. Epub 2011 Jul 1. 4Acta Naturae. 2018 Jul-Sep; 10(3): 62-67. 29280.14 After a period ranging from minutes to days, depending on the test, the laboratory report is sent back to the doctor, and the results are communicated to the patient. To facilitate these analysis methods, home test kits were developed in the 1950s.5 These test kits react to biomarkers of diseases through color changes. The rate of color change is directly proportional to the rate of chemical change. Color-changing strips, used by patients, non-specialist caregivers, or specialists, are graded using a color guide. The color comparison determines the concentration range of the analyzed biomarker. Blood and blood plasma or serum, which are crucial bodily chemicals, are not always sufficient for the examination of diseases. This is because changes in the concentration of chemicals in the blood are sometimes too small to be detected, leading to difficulties in measurements and / or misdiagnosis. For example, the dopamine concentration in the blood of a healthy individual is around 475<10⁹ mM. In contrast, the concentration of dopamine in tears can be around 370<10⁹ mM. In other words, the molarity of dopamine in tears is approximately 780,000 times higher than its concentration in blood. The concentrations of some other chemicals in tears are also sufficient for measurement. Therefore, tears offer a more suitable basis for the diagnosis of many diseases.6 Similarly, the molarity of lactate is between 2 and 5 mM in tears, while it is between 0.36 and 0.75 mM in blood plasma (approximately 10 times more concentrated in tears).The molarity of ascorbate is between 0.22 and 1.31 mM in tears, while it is between 0.04 and 0.06 mM in blood plasma (it is approximately 15 times more concentrated in tears). 5patent: GB7 845486Contact Lens Sensors in Ocular Diagnostics Nicholas M. et.al. DOL 10.1002 / adhm.201400504 (Table #2) 29280.14 After a period ranging from minutes to days, depending on the test, the laboratory report is sent back to the doctor, and the results are communicated to the patient. To facilitate these analysis methods, home test kits were developed in the 1950s.5 These test kits react to biomarkers of diseases through color changes. The rate of color change is directly proportional to the rate of chemical change. Color-changing strips, used by patients, non-specialist caregivers, or specialists, are graded using a color guide. The color comparison determines the concentration range of the analyzed biomarker. Blood and blood plasma or serum, which are crucial bodily chemicals, are not always sufficient for the examination of diseases. This is because changes in the concentration of chemicals in the blood are sometimes too small to be detected, leading to difficulties in measurements and / or misdiagnosis. For example, the dopamine concentration in the blood of a healthy individual is around 475<10⁹ mM. In contrast, the concentration of dopamine in tears can be around 370<10⁹ mM. In other words, the molarity of dopamine in tears is approximately 780,000 times higher than its concentration in blood. The concentrations of some other chemicals in tears are also sufficient for measurement. Therefore, tears offer a more suitable basis for the diagnosis of many diseases.6 Similarly, the molarity of lactate is between 2 and 5 mM in tears, while it is between 0.36 and 0.75 mM in blood plasma (approximately 10 times more concentrated in tears).The molarity of ascorbate is between 0.22 and 1.31 mM in tears, while it is between 0.04 and 0.06 mM in blood plasma (it is approximately 15 times more concentrated in tears). 5patent: GB7 845486Contact Lens Sensors in Ocular Diagnostics Nicholas M. et.al. DOL 10.1002 / adhm.201400504 (Table #2) 29280.14 Analyte Molarity in Tears [mM] Molarity in Blood [mM] Related Disease Glucose 0.013-0.051 3.3-6.5 Diabetes Ascorbate 0.22-1.31 0.04-0.06 Diabetes Lactate 2-5 0.36-0.75 Liver diseases and cancer Dopamine 0.37 475x1 0.9 Parkinson's, Glaucoma Table 1. Comparison of molarity of analytes found in tears and blood. In another scientific study7, using an ELISA kit, higher dopamine levels were found in tear fluid compared to plasma5: Sample Dopamine Concentration pg / ml (mean ± Standard error) Plasma (blood plasma) 97.2 ± 11.80 Tears (Schirmer Strip) 279 ± 14.8 Tears (capillary tube) 470.4 ± 37.64 Table 2. Comparison of dopamine concentrations in tears and blood. The subject of this invention is the colorimetry and fluorescence determination of dopamine using a Cu-MnxOy / C-dots / TMB composite system. This sensor responds to tear fluid containing dopamine molecules. The color of the sensor material, which is coated on carbon nanoparticles and copper-manganese oxide based TMB, is determined by the free state of dopamine.7Dopamine levels in human tear fluid. Indian J Ophthalmol. 2019 Jan; 67(1):38-41. Sharma NS et.al. 29280.14 Analyte Molarity in Tears [mM] Molarity in Blood [mM] Related Disease Glucose 0.013-0.051 3.3-6.5 Diabetes Ascorbate 0.22-1.31 0.04-0.06 Diabetes Lactate 2-5 0.36-0.75 Liver diseases and cancer Dopamine 0.37 475x1 0.9 Parkinson's, Glaucoma Table 1. Comparison of molarity of analytes found in tears and blood. In another scientific study7, using an ELISA kit, higher dopamine levels were found in tear fluid compared to plasma5: Sample Dopamine Concentration pg / ml (mean ± Standard error) Plasma (blood plasma) 97.2 ± 11.80 Tears (Schirmer Strip) 279 ± 14.8 Tears (capillary tube) 470.4 ± 37.64 Table 2. Comparison of dopamine concentrations in tears and blood. The subject of this invention is the colorimetry and fluorescence determination of dopamine using a Cu-MnxOy / C-dots / TMB composite system. This sensor responds to tear fluid containing dopamine molecules. The color of the sensor material, which is coated on carbon nanoparticles and copper-manganese oxide based TMB, is determined by the free state of dopamine.7Dopamine levels in human tear fluid. Indian J Ophthalmol. 2019 Jan; 67(1):38-41. Sharma NS et.al. Tears are dark blue, but become transparent due to the dopamine they contain.8 This color change is related to dopamine concentration. In the current state of technology, some methods used to diagnose diseases in individuals—particularly Parkinson's disease—and their drawbacks can be summarized as follows: 1. When 60% to 80% of the dopamine-producing cells in the brain are lost, sufficient dopamine cannot be produced, and the motor symptoms of Parkinson's disease appear. Accordingly, Parkinson's disease is clinically determined by looking at motor symptoms, lifestyle factors, and medical history data.⁹ Since this method relies on clinical data for diagnosis, supporting laboratory measurements are needed because there is a high probability of confusion with Parkinson's-like diseases or diseases that mimic Parkinson's disease. 2. Since there is no reliable way to directly measure dopamine levels in the brain, some indirect methods are used to determine this level imbalance. Doctors can measure the density of dopamine transporters, which are directly associated with nerve cells that use dopamine. This test involves injecting a radioactive material that binds to dopamine transporters, which doctors can measure using a camera.10 Because this method measures dopamine indirectly, the dopamine level cannot be directly shown. On the other hand, the use of radioactive materials in this method is generally not preferred due to their harmful effects. 3. As another method, diffusion-weighted magnetic resonance imaging (DMR) findings of the Substantia Nigra in Parkinson's disease8Sensors and Actuators B: Chemical, Volume 290, 1 July 2019, Pages 125-1329Clinical Features of Parkinson's Disease, Neurology Symposium Series for Non-Neurologists No: 42, January 2005; pp. 249-25410Scmiquantitative Analysis of Dopamine Transporter Scans in Patients With Parkinson's Disease, Clinical Nuclear Medicine. 43(1 ):el-e7, JAN 2018 Tears are dark blue, but become transparent due to the dopamine they contain.8 This color change is related to dopamine concentration. In the current state of technology, some methods used to diagnose diseases in individuals—particularly Parkinson's disease—and their drawbacks can be summarized as follows: 1. When 60% to 80% of the dopamine-producing cells in the brain are lost, sufficient dopamine cannot be produced, and the motor symptoms of Parkinson's disease appear. Accordingly, Parkinson's disease is clinically determined by looking at motor symptoms, lifestyle factors, and medical history data.⁹ Since this method relies on clinical data for diagnosis, supporting laboratory measurements are needed because there is a high probability of confusion with Parkinson's-like diseases or diseases that mimic Parkinson's disease. 2. Since there is no reliable way to directly measure dopamine levels in the brain, some indirect methods are used to determine this level imbalance. Doctors can measure the density of dopamine transporters, which are directly associated with nerve cells that use dopamine. This test involves injecting a radioactive material that binds to dopamine transporters, which doctors can measure using a camera.10 Because this method measures dopamine indirectly, the dopamine level cannot be directly shown. On the other hand, the use of radioactive materials in this method is generally not preferred due to their harmful effects. 3. As another method, the findings of diffusion-weighted magnetic resonance imaging (DWMRI) of the Substantia Nigra in Parkinson's disease8Sensors and Actuators B: Chemical, Volume 290, 1 July 2019, Pages 125-1329Clinical Features of Parkinson's Disease, Neurology Symposium Series for Non-Neurologists No: 42, January 2005; pp. 249-25410Scmiquantitative Analysis of Dopamine Transporter Scans in Patients With Parkinson's Disease, Clinical Nuclear Medicine. 43(1 ):el-e7, JAN 2018 It can also be viewed via 29280.14. Images resulting from the molecular movement of water in the tissue are obtained using the diffusion MR technique11,12'13. Since this method is an expensive and limited imaging method, it cannot be applied to all patients or those in suspected cases. In addition, obtaining the laboratory result of dopamine analysis with MRI and similar methods can take hours. However, monitoring the treatment process does not always require measurements with very high sensitivity. Especially in bedside tests, being able to obtain quick measurements and results is more important than sensitivity. 4. An ELISA kit that quantitatively determines dopamine in urine and blood plasma via color change is available on the market. These kits are for research purposes only and should not be used in clinical, therapeutic, or diagnostic procedures. Dopamine is extracted using a cis-diol-specific afmite gel and acylated to N-acyl-dopamine, which is then enzymatically converted to N-acyl-3-methoxytyramine. Dopamine binds to the solid phase of a microtiter plate. Acylated dopamine obtained from the sample and solid-phase bound dopamine competes for a fixed number of antiserum binding sites. When the system is in equilibrium, free antigen and free antigen-antiserum complexes are washed away. Antibody bound to solid-phase dopamine is detected by anti-rabbit IgG / peroxidase. The substrate TMB / peroxidase reaction is monitored at 450 nm. The amount of antibody bound to solid-phase dopamine is inversely proportional to the dopamine concentration of the sample. ELISA kits are considered an expensive measurement method (currently costing $280) and require technical knowledge to use. Available ELISA kits are calibrated for urine and plasma and are not suitable for tears. Furthermore, it takes hours to obtain test results. 11Diffusion Weighted MRI Findings of Substantia Nigra in Parkinson's Disease, F.Ü.Sağ.Bil.Tıp Derg. 2015; 29 (2):79-8612The role of diffusion magnetic resonance imaging in Parkinson's disease and in the differential diagnosis with atypical parkinsonism, Radiol Bras. 2017 Jul-Aug; 50(4): 250-25713Magnetic resonance spectroscopy in Parkinson's disease and parkinsonian syndromes, Funct Neurol. 2007; 22(2):75-9 It can also be viewed via 29280.14. Images resulting from the molecular movement of water in the tissue are obtained using the diffusion MR technique11,12'13. Since this method is an expensive and limited imaging method, it cannot be applied to all patients or those in suspected cases. In addition, obtaining the laboratory result of dopamine analysis with MRI and similar methods can take hours. However, monitoring the treatment process does not always require measurements with very high sensitivity. Especially in bedside tests, being able to obtain quick measurements and results is more important than sensitivity. 4. An ELISA kit that quantitatively determines dopamine in urine and blood plasma via color change is available on the market. These kits are for research purposes only and should not be used in clinical, therapeutic, or diagnostic procedures. Dopamine is extracted using a cis-diol-specific afmite gel and acylated to N-acyl-dopamine, which is then enzymatically converted to N-acyl-3-methoxytyramine. Dopamine binds to the solid phase of a microtiter plate. Acylated dopamine obtained from the sample and solid-phase bound dopamine competes for a fixed number of antiserum binding sites. When the system is in equilibrium, free antigen and free antigen-antiserum complexes are washed away. Antibody bound to solid-phase dopamine is detected by anti-rabbit IgG / peroxidase. The substrate TMB / peroxidase reaction is monitored at 450 nm. The amount of antibody bound to solid-phase dopamine is inversely proportional to the dopamine concentration of the sample. ELISA kits are considered an expensive measurement method (currently costing $280) and require technical knowledge to use. Available ELISA kits are calibrated for urine and plasma and are not suitable for tears. Furthermore, it takes hours to obtain test results. 11Diffusion Weighted MRI Findings of Substantia Nigra in Parkinson's Disease, F.Ü.Sağ.Bil.Tıp Derg. 2015; 29 (2):79-8612The role of diffusion magnetic resonance imaging in Parkinson's disease and in the differential diagnosis with atypical parkinsonism, Radiol Bras. 2017 Jul-Aug; 50(4): 250-25713Magnetic resonance spectroscopy in Parkinson's disease and parkinsonian syndromes, Funct Neurol. 2007; 22(2):75-9 29280.14 Patent applications under the prior art are as follows: United States patent application US20140194706Al describes apparatus, systems, and methods using contact lenses that have one or more sensors detecting an analyte in tear fluid and one or more wells for collecting tear fluid. These lenses contain at least one sensor configured to detect the presence of an analyte in the collected tear fluid. The claims of this patent involve collecting a tear sample into a micro-scale reservoir and then analyzing it by a sensor with a microprocessor. The signals detected by the sensor are transmitted via electronic circuitry and antennas to a device connected to the internet. The Chinese patent application document numbered CNI07860805 describes an electrochemical dopamine aptamer sensor based on aptamer-gold nanoparticle / reduced graphene oxide-Nile blue nanocomposite. The South Korean patent application document, numbered KR20180103653, describes a dopamine-detecting biosensor. It contains a field-effect transistor (FET) that senses an electrical current, with an electrode providing the source. The functional layer contains a reactant that selectively reacts with dopamine. Patent number WO2016029139 describes a contact lens with a hydrogel coating on its surface for detecting biomarkers in tears. This application develops a method for colorimetric analysis using aptamer molecules. However, it does not present any method for observing the resulting color change or transmitting analytical information, nor does it offer any methodology that generates numerical output. The European patent application document numbered EP3131454 describes a functional contact lens and related systems and methods. The invention involves a contact lens that detects changes resulting from the detection of at least one target analyte using electronic and electrochemical methods, and transmits the detected signal to an external device via an antenna integrated into the lens structure. 29280.14 Patent applications under the prior art are as follows: United States patent application US20140194706Al describes apparatus, systems, and methods using contact lenses that have one or more sensors detecting an analyte in tear fluid and one or more wells for collecting tear fluid. These lenses contain at least one sensor configured to detect the presence of an analyte in the collected tear fluid. The claims of this patent involve collecting a tear sample into a micro-scale reservoir and then analyzing it by a sensor with a microprocessor. The signals detected by the sensor are transmitted via electronic circuitry and antennas to a device connected to the internet. The Chinese patent application document numbered CNI07860805 describes an electrochemical dopamine aptamer sensor based on aptamer-gold nanoparticle / reduced graphene oxide-Nile blue nanocomposite. The South Korean patent application document, numbered KR20180103653, describes a dopamine-detecting biosensor. It contains a field-effect transistor (FET) that senses an electrical current, with an electrode providing the source. The functional layer contains a reactant that selectively reacts with dopamine. Patent number WO2016029139 describes a contact lens with a hydrogel coating on its surface for detecting biomarkers in tears. This application develops a method for colorimetric analysis using aptamer molecules. However, it does not present any method for observing the resulting color change or transmitting analytical information, nor does it offer any methodology that generates numerical output. The European patent application document numbered EP3131454 describes a functional contact lens and related systems and methods. The invention involves a contact lens that detects changes resulting from the detection of at least one target analyte using electronic and electrochemical methods, and transmits the detected signal to an external device via an antenna integrated into the lens structure. It is used for transmitting 29280.14. It does not perform colorimetric sensing or data transmission. United States patent application US2012245444 describes a wirelessly powered contact lens with a glucose sensor. The contact lens incorporates an electrochemical sensor that measures the glucose level in a person's tear fluid. This contact lens is powered via an RF antenna or photovoltaic device and can also transmit data via the electrochemical sensor. It does not perform colorimetric sensing or data transmission. Document WO2018187693 describes the implemented ocular devices and their operating methods. The device in question is implanted in the eyelid (lacrimal punctum or conjunctival sac) and detects the chemical composition of tears using one or more sensor materials sensitive to one or more components. Each sensor material transmits the person's medical status via electromagnetic signals. It does not propose any coding method for disease diagnosis. The international patent application document numbered WO2018187693 mentions ocular devices. The analysis method used in these devices is colorimetric, but in the detection method, color change is determined from wavelength change. The Turkish patent application document numbered TR 2015 / 17446 describes a contact lens design that detects glucose levels in tears. The invention is intended for use by diabetic patients and relates to the development of a material that detects glucose levels in tears using a biosensor. No method or methodology is presented for observing the resulting color change and transmitting analytical information, or for generating numerical output. The European patent application document numbered EP3148435 describes a system for displaying information related to individuals' health. It is used for transmitting 29280.14. It does not perform colorimetric sensing or data transmission. United States patent application US2012245444 describes a wirelessly powered contact lens with a glucose sensor. The contact lens incorporates an electrochemical sensor that measures the glucose level in a person's tear fluid. This contact lens is powered via an RF antenna or photovoltaic device and can also transmit data via the electrochemical sensor. It does not perform colorimetric sensing or data transmission. Document WO2018187693 describes the implemented ocular devices and their operating methods. The device in question is implanted in the eyelid (lacrimal punctum or conjunctival sac) and detects the chemical composition of tears using one or more sensor materials sensitive to one or more components. Each sensor material transmits the person's medical status via electromagnetic signals. It does not propose any coding method for disease diagnosis. The international patent application document numbered WO2018187693 mentions ocular devices. The analysis method used in these devices is colorimetric, but in the detection method, color change is determined from wavelength change. The Turkish patent application document numbered TR 2015 / 17446 describes a contact lens design that detects glucose levels in tears. The invention is intended for use by diabetic patients and relates to the development of a material that detects glucose levels in tears using a biosensor. No method or methodology is presented for observing the resulting color change or transmitting analytical information. The European patent application document numbered EP3148435 describes a system for displaying information related to individuals' health. 29280.14 The European patent application document, numbered EP2846182, describes an ophthalmic lens capable of providing an interconnection with an external device. United States patent application document number US20170371128 describes a disposable lens applied to an electronic operating device for diagnostic purposes. Patent document EP2569667 describes a method for preparing an ophthalmic lens containing a QR code. The invention described herein provides a printing method for printing and transferring QR codes and similar codes onto the lens, and does not mention any use as a detection or sensor device. The European patent application document numbered EP3159693 describes a sensing device method and program, which is an electronic device consisting of pressure, temperature, and motion sensors. Patent number WO2017178621 describes a system that performs analysis through image processing. A sample of saliva, a bodily fluid, comes into contact with a test cell, causing a color change. This color change is analyzed using a digital photograph, and the results are communicated to the user via a QR code. Commercially available urine test strips are used to determine several parameters such as urine pH, protein, glucose, and pregnancy hormone (hCG) through color change. A few drops of urine sample are placed on the colored cells on the test strip, and the color change is awaited for a certain period. Results are obtained by directly comparing the color blocks written on the box. The color blocks represent pseudo-values; the actual values ​​will vary close to the pseudo-values. There are some issues and risks that limit the use of these strips: Visual color reading carries a high probability of error. 14http: / / peramed.com / peramed / docs / 52001 -52002-52003-52005-52010-5201 l_TR.pdf 29280.14 The European patent application document, numbered EP2846182, describes an ophthalmic lens capable of providing an interconnection with an external device. United States patent application document number US20170371128 describes a disposable lens applied to an electronic operating device for diagnostic purposes. Patent document EP2569667 describes a method for preparing an ophthalmic lens containing a QR code. The invention described herein provides a printing method for printing and transferring QR codes and similar codes onto the lens, and does not mention any use as a detection or sensor device. The European patent application document numbered EP3159693 describes a sensing device method and program, which is an electronic device consisting of pressure, temperature, and motion sensors. Patent number WO2017178621 describes a system that performs analysis through image processing. A sample of saliva, a bodily fluid, comes into contact with a test cell, causing a color change. This color change is analyzed using a digital photograph, and the results are communicated to the user via a QR code. Commercially available urine test strips are used to determine several parameters such as urine pH, protein, glucose, and pregnancy hormone (hCG) through color change. A few drops of urine sample are placed on the colored cells on the test strip, and the color change is awaited for a certain period. Results are obtained by directly comparing the color blocks written on the box. The color blocks represent pseudo-values; the actual values ​​will vary close to the pseudo-values. There are some issues and risks that limit the use of these strips: Visual color reading carries a high probability of error. 14http: / / peramed.com / peramed / docs / 52001 -52002-52003-52005-52010-5201 l_TR.pdf 29280.14 Because the references are printed on a piece of paper on the box, unrealistic reference colors may be presented. Given the wide range of values ​​provided, it is difficult to determine an exact figure. Since it's not possible to view multiple cell colors simultaneously, the reading time may expire and the color scale may change. Tracking results is difficult and the potential for confusion is high. Recording and reporting results presents challenges and potential errors (such as the difficulties of taking notes manually). Cutting strips and cells into large sizes results in high material consumption. Larger-sized test cells require larger urine samples. The instructions for using the strips state that they should be left in a small cupful (200 ml) of urine sample, which is far too much for other body fluids besides urine. Some studies use mobile phone applications to determine urine analysis results using image processing to overcome some of these problems. For example, Vivoo15 analyzes a few drops of urine sample after it comes into contact with a strip kit and provides the user with numerical values. Image processing helps in obtaining more accurate color analysis, but in this study, the problem of sample collection and the risk of confusing results have not been eliminated. Brief Description of the Invention The aim of the invention is to create an easy-to-use, highly reliable, low-cost, recordable, and technically training-free measurement system for determining the levels of various tear chemicals, such as dopamine. 13www.vivoo.io 29280.14 Because the references are printed on a piece of paper on the box, unrealistic reference colors may be presented. Given the wide range of values ​​provided, it is difficult to determine an exact figure. Since it's not possible to view multiple cell colors simultaneously, the reading time may expire and the color scale may change. Tracking results is difficult and the potential for confusion is high. Recording and reporting results presents challenges and potential errors (such as the difficulties of taking notes manually). Cutting strips and cells into large sizes results in high material consumption. Larger-sized test cells require larger urine samples. The instructions for using the strips state that they should be left in a small cupful (200 ml) of urine sample, which is far too much for other body fluids besides urine. Some studies use mobile phone applications to determine urine analysis results using image processing to overcome some of these problems. For example, Vivoo15 analyzes a few drops of urine sample after it comes into contact with a strip kit and provides the user with numerical values. Image processing helps in obtaining more accurate color analysis, but in this study, the problem of sample collection and the risk of confusing results have not been eliminated. Brief Description of the Invention The aim of the invention is to create an easy-to-use, highly reliable, low-cost, recordable, and technically training-free measurement system for determining the levels of various tear chemicals, such as dopamine. 13www.vivoo.io 29280.14 Detailed Description of the Invention The contact sensor structure implemented to achieve the purpose of this invention is shown in the attached figures; these figures are as follows: Figure 1. Appearance of the measurement system subject to the invention when it has a substrate in the form of a strip. Figure 2 illustrates the operating principle of the measurement system described in the invention when the substrate is in the form of a strip. Figure 3. Appearance of the measurement system described in the invention when it has a substrate in the form of a strip placed under the eyelid. Figure 4 illustrates the operating principle of the measurement system described in the invention when the substrate is in the form of a strip placed under the eyelid. Figure 5. Appearance of the measurement system, which is the subject of the invention, when it has a substrate in the form of a contact lens. Figure 6 illustrates the operating principle of the measurement system described in the invention when the substrate is in the form of a contact lens. The parts in the figures are numbered, and their corresponding parts are given below. 1. Measurement system 2. Substrate 21. Absorbent part 22. Non-absorbent part 23. Holding area 3. Code area Code 31 32. Reference colors 4. Sensor area 5. The part to be placed under the eyelid. 6. Sensor biosensor set 29280.14 Detailed Description of the Invention The contact sensor structure implemented to achieve the purpose of this invention is shown in the attached figures; these figures are as follows: Figure 1. Appearance of the measurement system subject to the invention when it has a substrate in the form of a strip. Figure 2 illustrates the operating principle of the measurement system described in the invention when the substrate is in the form of a strip. Figure 3. Appearance of the measurement system described in the invention when it has a substrate in the form of a strip placed under the eyelid. Figure 4 illustrates the operating principle of the measurement system described in the invention when the substrate is in the form of a strip placed under the eyelid. Figure 5. Appearance of the measurement system, which is the subject of the invention, when it has a substrate in the form of a contact lens. Figure 6 illustrates the operating principle of the measurement system described in the invention when the substrate is in the form of a contact lens. The parts in the figures are numbered, and their corresponding parts are given below. 1. Measurement system 2. Substrate 21. Absorbent part 22. Non-absorbent part 23. Holding area 3. Code area Code 31 32. Reference colors 4. Sensor area 5. The part to be placed under the eyelid. 6. Sensor biosensor set 29280.14 The subject of the invention, the Measurement system (1), is used to determine the levels of tear chemicals, including dopamine, glucose, ascorbate, lactate and proteins. - at least one substrate (2) containing at least one absorbent part (21) and at least one non-absorbent part (22) suitable for taking tears, - at least one code field (31) containing information about one, several or all of the following: sensor number, sensor type, sensor purpose and method of use, production date and LOT number, located in the non-absorbent region (22) of the substrate (2), - It contains at least one sensor area (4) containing at least one set of biosensors (6) that are suitable for interacting with the analyte in question and whose color changes as a result of this interaction, for each analyte located on the substrate (2) and to be detected. In one application of the invention, the substrate (2) may be in the form of a strip onto which a sample of tears taken from the patient’s eye can be dropped. If a strip of this structure is used, in order to obtain basal tears from the patient’s eye, a local anesthetic eye drop solution USP (Proparacaine Hydrochloride Ophthalmic Solution 0.5%)16 is instilled into the patient’s eye, which will not prevent eye irritation, and the resulting tear sample is taken by means of a micropipette and dropped onto the absorbent part (21) on the surface of the strip-shaped substrate (2). In another application of the invention, the substrate (2) may be in the form of a strip that is placed under the eyelid and takes tears directly from the eye. In another application of the invention, the substrate (2) may be in the form of a contact lens that is positioned like an ordinary contact lens placed directly over the pupil and takes tears directly from the eye. This lens16https: / / www.drugs.cotn / pro / proparacaine.httnl 29280.14 The subject of the invention, the Measurement system (1), is used to determine the levels of tear chemicals, including dopamine, glucose, ascorbate, lactate and proteins. - at least one substrate (2) containing at least one absorbent part (21) and at least one non-absorbent part (22) suitable for taking tears, - at least one code field (31) containing information about one, several or all of the following: sensor number, sensor type, sensor purpose and method of use, production date and LOT number, located in the non-absorbent region (22) of the substrate (2), - It contains at least one sensor area (4) containing at least one set of biosensors (6) that are suitable for interacting with the analyte in question and whose color changes as a result of this interaction, for each analyte located on the substrate (2) and to be detected. In one application of the invention, the substrate (2) can be in the form of a strip onto which a sample of tears taken from the patient’s eye can be dropped. If a strip of this structure is used, in order to obtain basal tears from the patient’s eye, a local anesthetic eye drop solution USP (Proparacaine Hydrochloride Ophthalmic Solution 0.5%)16 is instilled into the patient’s eye, which will not prevent eye irritation, and the resulting tear sample is taken through a micropipette and dropped onto the absorbent part (21) on the surface of the strip-shaped substrate (2). In another application of the invention, the substrate (2) may be in the form of a strip that is placed under the eyelid and takes tears directly from the eye. In another application of the invention, the substrate (2) may be in the form of a contact lens that is positioned like an ordinary contact lens placed directly over the pupil and allows tears to be taken directly from the eye. This lens16https: / / www.dmgs.com / pro / proparacaine.httnl The central region (21 and 23) of the 29280.14 lens has high light transmittance (90% and above) and ensures the patient's vision during the waiting time for tear sample collection. In addition, the central region (23) will be used as a support point for placing the contact lens on the eye surface. In one application of the invention, the surface of the strip-shaped substrate (2) has at least one gripping zone (23) which allows the user to easily grip the substrate (2) except for the absorbent part (21) and the non-absorbent part (22). In one application of the invention, the substrate (2) is in the form of a strip placed on the eyelid, and there is a sub-eyelid insert (5) suitable for placing under the eyelid in order to make direct contact with the tear. In one application of the invention, the measurement system (1) contains at least one reference color (32) for comparison with the color of the sensor biosensor set (6). This reference color (32) corresponds to the color of the said sensor biosensor set (6) at a specific concentration for a particular tear chemical such as dopamine. In one application of the invention, the substrate (2) can be made from any material such as paper, cellulose, acrylic, plastic or PMMA (polymethyl methacrylate). In one application of the invention, the information contained within the code area (31) can be encoded using any method currently available or that may be developed in the future, such as iQR, QR code, datamatrix, etc. In one application of the invention, the sensor biosensor set (6) interacts with tear chemicals including dopamine, glucose, ascorbate, lactate and proteins, and as a result of this interaction the color of the sensor biosensor set (6). The central region (21 and 23) of the 29280.14 lens has high light transmittance (90% and above) and ensures the patient's vision during the waiting time for tear sample collection. In addition, the central region (23) will be used as a support point for placing the contact lens on the eye surface. In one application of the invention, the surface of the strip-shaped substrate (2) has at least one gripping zone (23) which allows the user to easily grip the substrate (2) except for the absorbent part (21) and the non-absorbent part (22). In one application of the invention, the substrate (2) is in the form of a strip placed on the eyelid, and there is a sub-eyelid insert (5) suitable for placing under the eyelid in order to make direct contact with the tear. In one application of the invention, the measurement system (1) contains at least one reference color (32) for comparison with the color of the sensor biosensor set (6). This reference color (32) corresponds to the color of the said sensor biosensor set (6) at a specific concentration for a particular tear chemical such as dopamine. In one application of the invention, the substrate (2) can be made from any material such as paper, cellulose, acrylic, plastic or PMMA (polymethyl methacrylate). In one application of the invention, the information contained within the code area (31) can be encoded using any method currently available or that may be developed in the future, such as iQR, QR code, datamatrix, etc. In one application of the invention, the sensor biosensor set (6) interacts with tear chemicals including dopamine, glucose, ascorbate, lactate and proteins, and as a result of this interaction the color of the sensor biosensor set (6). 29280.14 is changing. Thus, the presence and / or concentration of the chemicals in question can be detected. Examples of the aforementioned set of sensing biosensors (6) include Cu-Mn-0 microcrystals and carbon nanoparticles for measuring dopamine levels and boric acid for measuring glucose levels, but are not limited to these. Different sensing biosensors (6) can also contain different concentrations of the same analyte. In one application of the invention, the sensor biosensor set (6) can be produced by, but not limited to, the methods of dip-coating, spin-coating, spray-coating, electrospinning, inkjet printing, microjet printing, and nanojet printing. In one application of the invention, the sensor area (4) contains multiple sets of biosensors (6) arranged to form a pattern. This pattern can be formed in any regular or irregular shape such as a matrix of size m*n, circle, ellipse, triangle, etc. Similarly, reference colors (32) can also be formed in any regular or irregular shape such as a matrix of size mxn, circle, ellipse, triangle, etc. The measurement system (1) subject to the invention includes at least one strip substrate (2) with at least one retention area (23) containing at least one absorbent part (21) and at least one non-absorbent part (22) suitable for taking tears. The strip substrate (2) preferably has at least one code area (3) containing at least one code (31) containing information about one, several or all of the following: sensor number, sensor type, intended use and method of use, manufacturing date and LOT number of the strip substrate (2). The strip substrate (2) has at least one sensor area (4) containing at least one set of biosensors (6) suitable for interacting with each analyte to be detected, and whose color changes as a result of this interaction, for each analyte to be detected. 29280.14 is changing. Thus, the presence and / or concentration of the chemicals in question can be detected. Examples of the aforementioned sensor biosensor set (6) include Cu-Mn-0 microcrystals and carbon nanoparticles to measure dopamine levels and boric acid to measure glucose levels, but are not limited to these. Different sensor biosensors (6) can also contain different concentrations of the same analyte. In one application of the invention, the sensor biosensor set (6) can be produced by, but not limited to, the methods of dip-coating, spin-coating, spray-coating, electrospinning, inkjet printing, microjet printing, and nanojet printing. In one application of the invention, the sensor area (4) contains multiple sets of biosensors (6) arranged to form a pattern. This pattern can be formed in any regular or irregular shape such as a matrix of size m*n, circle, ellipse, triangle, etc. Similarly, reference colors (32) can also be formed in any regular or irregular shape such as a matrix of size mxn, circle, ellipse, triangle, etc. The measurement system (1) subject to the invention includes at least one strip substrate (2) with at least one retention area (23) containing at least one absorbent part (21) and at least one non-absorbent part (22) suitable for taking tears. The strip substrate (2) preferably has at least one code area (3) containing at least one code (31) containing information about one, several or all of the following: sensor number, sensor type, intended use and method of use, manufacturing date and LOT number of the strip substrate (2). The strip substrate (2) has at least one sensor area (4) containing at least one set of biosensors (6) suitable for interacting with each analyte to be detected, and whose color changes as a result of this interaction, for each analyte to be detected. The part (5) to be placed under the eyelid so that it can be absorbed by the substrate (2) is placed directly under the eyelid. The measurement system (1) in question is measured by contacting the tear for a predetermined period of time. At the end of the measurement process, the image of the code area (3) and the sensor area (4) is captured by an image sensor such as a camera. This sensor may be a mobile phone or portable computer with a camera. This image is then processed and analyzed by the device that captured the image or by a central server.The processing of the mentioned image may include one, several or all of the following operations: calibrating the image, obtaining the color information of the sensor biosensor set (6), normalizing the said color information in accordance with the calibration data, comparing the said normalized and / or unnormalized color information with the data in the said device and / or central server, and interpreting the information obtained as a result of this comparison according to the table or tables in the said device and / or central server. Image processing can be carried out by means of any image processing algorithm that is currently available or may be developed in the future. In one application of the invention that can be used in conjunction with other applications, the information and / or interpretations obtained from image processing are added to the user's profile, which is stored on the device and / or a central server. This allows the user to easily view the results of past measurements and the interpretations made based on those results. In one application of the invention that can be used in conjunction with other applications, an optical element such as a filter or lens can be attached in front of the image sensor. This optical element can be used to modify various properties of the light being transmitted, such as the color, focus, and / or polarization, but not limited to these. The part (5) to be placed under the eyelid so that it can be absorbed by the substrate (2) is placed directly under the eyelid. The measurement system (1) in question is measured by contacting the tear for a predetermined period of time. At the end of the measurement process, the image of the code area (3) and the sensor area (4) is captured by an image sensor such as a camera. This sensor may be a mobile phone or portable computer with a camera. This image is then processed and analyzed by the device that captured the image or by a central server.The processing of the mentioned image may include one, several or all of the following operations: calibrating the image, obtaining the color information of the sensor biosensor set (6), normalizing the said color information in accordance with the calibration data, comparing the said normalized and / or unnormalized color information with the data in the said device and / or central server, and interpreting the information obtained as a result of this comparison according to the table or tables in the said device and / or central server. Image processing can be carried out by means of any image processing algorithm that is currently available or may be developed in the future. In one application of the invention that can be used in conjunction with other applications, the information and / or interpretations obtained from image processing are added to the user's profile, which is stored on the device and / or a central server. This allows the user to easily view the results of past measurements and the interpretations made based on those results. In one application of the invention that can be used in conjunction with other applications, an optical element such as a filter or lens can be attached in front of the image sensor. This optical element can be used to modify various properties of the light being transmitted, such as the color, focus, and / or polarization, but not limited to these. 29280.14 If the substrate considered within the scope of the invention (2) is in the form of a strip on which a sample of tear taken from the patient’s eye can be dropped, it can be applied as follows, for example (Figure 2): 1- To obtain basal tears, use eye drops that will not irritate the eye and leave them on for approximately 60 seconds. 2- Next, a sample of basal tear fluid is taken from a position close to the patient's eyelids using a micropipette (Micro Capillary Tubes (MCT)) or a cellulose sponge and polyester swab. 3- A few drops of tear sample are dropped onto the sensor area (4) located on the absorbent part (21) of the measurement system (1) which is the subject of the invention. 4- Images are taken from the code area (3). 5- The German image is sent over the internet to an advanced software located on a remote server (cloud), where image analysis is performed. Thus, color and contrast or wavelength differences detected in the image are compared with analytical tables, and the amount of tear chemicals is determined. This amount is sent to the application to inform the user, and reports are added to the patient's file. If the substrate considered within the scope of the invention (2) is in the form of a strip placed under the eyelid, it can be applied as follows, for example (Figure 4): 2.1. To obtain basal tears, use eye drops that will not irritate the eye and wait for approximately 60 seconds. 2.2. Next, the part of the measurement system (1) that is to be placed under the eyelid (5) is placed under the eyelid and left there for about 60 seconds. 2.3. At the end of this period, the measurement system (1) that is the subject of the invention is removed from under the eyelid. 2.4. Images are taken from the code area (3). 29280.14 If the substrate considered within the scope of the invention (2) is in the form of a strip on which a sample of tear taken from the patient’s eye can be dropped, it can be applied as follows, for example (Figure 2): 1- To obtain basal tears, use eye drops that will not irritate the eyes and wait for approximately 60 seconds. 2- Next, a sample of basal tear fluid is taken from a position close to the patient's eyelids using a micropipette (Micro Capillary Tubes (MCT)) or a cellulose sponge and polyester swab. 3- A few drops of tear sample are dropped onto the sensor area (4) located on the absorbent part (21) of the measurement system (1) which is the subject of the invention. 4- Images are taken from the code area (3). 5- The German image is sent over the internet to an advanced software located on a remote server (cloud), where image analysis is performed. Thus, color and contrast or wavelength differences detected in the image are compared with analytical tables, and the amount of tear chemicals is determined. This amount is sent to the application to inform the user, and reports are added to the patient's file. If the substrate considered within the scope of the invention (2) is in the form of a strip placed under the eyelid, it can be applied as follows, for example (Figure 4): 2.1. To obtain basal tears, use eye drops that will not irritate the eye and wait for approximately 60 seconds. 2.2. Next, the part of the measurement system (1) that is to be placed under the eyelid (5) is placed under the eyelid and left there for about 60 seconds. 2.3. At the end of this period, the measurement system (1) that is the subject of the invention is removed from under the eyelid. 2.4. Images are taken from the code area (3). 29280.14 2.5. The German image is sent over the internet to the enhanced software located on a remote server (cloud), and image analysis is performed. Thus, color and contrast or wavelength differences detected in the image are compared with analytical tables, and the amount of tear chemicals is determined. This amount is sent to the application to inform the user, and the reports are added to the patient's file. The substrate considered within the scope of the invention (2) can be applied in the form of a contact lens that is positioned like an ordinary contact lens placed directly over the pupil and allows tears to be taken directly from the eye, for example as follows (Figure 6): 3.1. To obtain basal tears, use eye drops that will not irritate the eye and wait for approximately 60 seconds. 3.2. Then, the subject measurement system (1), which has a substrate (2) in the form of a contact lens, is placed over the patient's pupil like a lens and left there for approximately 60-300 seconds. 3.3. An image is taken from the code area (3) while it is in the user's eyes or after it is removed. 3.4. The acquired image is sent over the internet to the advanced software located on a remote server (cloud), where image analysis is performed. Thus, color and contrast or wavelength differences detected in the image are compared with analytical tables, and the amount of tear chemicals is determined. This amount is sent to the application to inform the user, and reports are added to the patient's file. 29280.14 2.5. The German image is sent over the internet to an enhanced software located on a remote server (cloud), where image analysis is performed. Thus, color and contrast or wavelength differences detected in the image are compared with analytical tables, and the amount of tear chemicals is determined. This amount is sent to the application to inform the user, and reports are added to the patient's file. The substrate discussed in the invention (2) can be applied in the form of a contact lens that is positioned like an ordinary contact lens placed directly over the pupil and allows tears to be taken directly from the eye, for example as follows (Figure 6): 3.1. To obtain basal tears, use eye drops that will not irritate the eye and wait for approximately 60 seconds. 3.2. Then, the subject measurement system (1), which has a substrate (2) in the form of a contact lens, is placed over the patient's pupil like a lens and left there for approximately 60-300 seconds. 3.3. An image is taken from the code area (3) while it is in the user's eyes or after it is removed. 3.4. The acquired image is sent over the internet to the advanced software located on a remote server (cloud), where image analysis is performed. Thus, color and contrast or wavelength differences detected in the image are compared with analytical tables, and the amount of tear chemicals is determined. This amount is sent to the application to inform the user, and reports are added to the patient's file.

Claims

29280.14 REQUIREMENTS 1. To determine the level of tear chemicals, a measurement system (1) characterized by: - ​​at least one substrate (2) containing at least one absorbent part (21) and at least one non-absorbent part (22) suitable for taking tears; - at least one code area (3) containing information about one, several or all of the following: sensor number, sensor type, purpose and method of use of the sensor, production date and LOT number, located in the non-absorbent region (22) of the substrate (2); - at least one sensor area (4) containing at least one set of biosensors (6) located on the substrate (2) that are suitable for interacting with the analyte in question and whose color changes as a result of this interaction, for each analyte to be detected.

2. A measurement system (1) as in Claim 1, characterized by a substrate (2) in the form of a strip on which a sample of tear taken from the patient’s eye can be dropped.

3. A measurement system (1) as in Claim 1, characterized by a substrate (2) in the form of a strip placed under the eyelid to take tears directly from the eye.

4. A measurement system (1) as in Claim 1, characterized by a substrate (2) that is positioned like an ordinary contact lens placed directly over the pupil and that allows tears to be drawn directly from the eye.

5. A measurement system (1) as in Claim 2 or 3, which includes at least one holding zone (23) enabling the user to easily hold the substrate (2). 29280.14 6. If it is in the form of a strip placed on the eyelid, a measurement system (1) as in Claim 3, including a sub-eyelid insert (5) suitable for placing under the eyelid in order to make direct contact with the tear.

7. A measurement system (1) as in Claim 1, containing at least one reference color (32) to compare with the color of the sensing biosensor set (6).

8. A measurement system (1) as in Claim 1, containing a strip substrate (2) made of any material such as paper, cellulose, acrylic, plastic, PMMA (polymethyl methacrylate).

9. A measurement system (1) as in Claim 1, containing a set of sensing biosensors (6) suitable for interacting with tear chemicals including dopamine, glucose, ascorbate, lactate and proteins.

10. A measurement system (1) as in Claim 1, characterized by a sensor area (4) containing multiple sets of biosensors (6) arranged to form a pattern.

11. A matrix of dimensions m x n, characterized by a pattern of any shape such as circle, ellipse, triangle, etc., regular or irregular, as in Claim 10, is a measurement system (1).

12. A measurement system as in Claim 10 (1) containing reference colours (32) of any shape, such as a matrix of dimensions m*n, circle, ellipse, triangle etc., regular or irregular.

13. A measurement method characterized by the following steps: contact of a measurement system (1) with tears for a predetermined period of time, capture of the image of the code area 29280.14 (3) and the sensor area (4) by means of an image sensor such as a camera, and processing and analysis of the captured image by the device capturing the image or a central server.

14. A measurement method as described in Claim 13, characterized by one, several, or all of the following steps in the image processing: calibrating the image, obtaining the color information of the sensor biosensor set (6), normalizing the said color information in accordance with the calibration data, comparing the said normalized and / or unnormalized color information with the data in the said device and / or central server, and interpreting the information obtained as a result of this comparison according to the table or tables in the said device and / or central server.

15. A measurement method, such as in Claim 13, which includes the step of adding the obtained information and / or comments to the user's profile held on the aforementioned device and / or central server.

16. The manufacturing method of a measurement system (1) as in any of Claims 1 to 12, characterized by the fabrication of the sensor biosensor set (6) by any of the methods of dip-coating, spin-coating, spray-coating, electrospinning, inkjet printing, microjet printing, nanojet printing.

Images