Nasogastric tube online precision ph sensor ph sensitive electrode and application

Abstract

The application provides a pH sensitive electrode of a nasogastric tube online precision pH sensor and application. The pH sensitive electrode of the nasogastric tube online precision pH sensor is provided, an electrochemical calibration-free pH sensing method is realized, the nasogastric tube is enabled, the nasogastric tube has the function of automatically judging whether placement is in place, in-situ diagnosis of gastroesophageal reflux disease and clinical big data accumulation of precise values of the gastric environment pH can be realized, the use value of the patient is improved, and valuable research data are provided for medical workers.

Description

Technical Field

[0001] This invention belongs to the fields of electrochemical detection and analysis, chemical sensor technology and medical devices, and relates to a pH-sensitive electrode of an online precision pH sensor for nasogastric tubes and its application. Background Technology

[0002] A nasogastric tube is a medical device typically inserted into a patient's nasal cavity or mouth, through the pharynx, and down to the stomach. Its purpose is to deliver nutrients or medications to the patient, or to facilitate gastric drainage and emptying. For patients requiring timed medication administration, a multi-functional nasogastric tube can ensure effective delivery of medications to the stomach or intestines. For patients with dysphagia, a multi-functional nasogastric tube can assist with eating and drinking, maintaining the energy and hydration necessary for life. However, existing nasogastric tubes have the following limitations:

[0003] 1. After the nasogastric tube is placed in the stomach, auscultation or X-ray is still needed to help determine whether the tube is in place. Under current technology, abdominal auscultation of air sloshing or X-ray is the preferred method to help determine the tube, but there are the following drawbacks: (1) Abdominal auscultation of air sloshing is the most commonly used method to determine the tube is in place, but this method is limited by the medical habits and skills of clinicians. Misjudgment or failure to perform auscultation may result in the tube not being in place. (2) For critically ill patients, X-ray examination to determine the tube is in place requires waiting for the examination to be carried out, which delays the patient's treatment. (3) X-rays can cause radiation damage to patients. (4) Some units do not have bedside X-ray equipment. 2. Some drugs, such as sodium bicarbonate tablets and calcium tablets, are easy to form hard crystals with other nutrition solutions, which can block the nasogastric tube, causing feeding failure or forced re-insertion of the tube, causing secondary damage to the patient. 3. Existing nasogastric tubes have a closed end face at the front, while multiple side holes are provided on the front side for injecting medications and food. Medications (especially large ones like sustained-release tablets and capsules) need to be crushed before injection when fed through a nasogastric tube, affecting normal drug use and forcing a change in drug absorption. 4. Current nasogastric tubes with integrated sensors are mainly endoscopic, meaning an endoscope camera is coupled to the front of the tube. This approach is costly, requires complex equipment, and still relies on the visual judgment of a professional physician. Furthermore, this strategy can only be used to determine if the nasogastric tube is properly placed, with no further functional expansion potential. 5. Another mainstream technique for determining the placement status of a nasogastric tube is to immediately aspirate gastric fluid after placement and test the sample with pH test strips. This method has ideal accuracy, high cost-effectiveness, and clear standards, requiring no professional skills or experience. However, it still requires manual operation by medical staff; and due to its low resolution, it is also difficult to utilize it for other purposes. Summary of the Invention

[0004] The purpose of this invention is to provide a pH-sensitive electrode for an online precision pH sensor for nasogastric tubes.

[0005] Another objective of this invention is to provide the application of a pH-sensitive electrode in determining the position of a nasogastric tube.

[0006] A pH-sensitive electrode for an online precision pH sensor for nasogastric tubes is prepared by the following method:

[0007] (1) Dissolve 2,4-diamino-N,N-dimethylaniline in DMF-methanol solution;

[0008] (2) Dissolve 1-chloro-2-hydroxynaphthalene in DMF-methanol solution, add Zn and trifluoromethanesulfonic acid, and then add the mixed solution obtained in step (1) under stirring. React under an inert atmosphere to obtain product (I).

[0009] (3) Prepare a DMF mixed solution of product (I), add a weak base salt aqueous solution to it while stirring, add a DMF solution of benzoyl peroxide after stirring under an inert atmosphere, complete the cyclization reaction, and obtain product (II).

[0010] (4) Product (II) was dissolved in an acidic acetonitrile solution, and 4-allyl ether pyridine was added. The reaction yielded a purple-red solution. After removing the solvent, product (III) was obtained.

[0011] (5) Dissolve product (III) in DMSO containing imidazole and hexafluorophosphate, add a DMSO solution containing lauroyl peroxide and mix well. Immerse the substrate electrode in the reaction solution, react under an inert atmosphere, remove the substrate electrode, immerse it in DMSO solution, and continue the reaction under light-protected conditions to obtain a pH-sensitive electrode; or

[0012] (6) Dissolve product (III) in a DMSO mixed solution containing 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxy radical, imidazole and hexafluorophosphate to obtain a reaction solution. Then, use the base electrode as the working electrode and form a three-electrode system with the counter electrode and reference electrode. Immerse the system in the reaction solution under an inert atmosphere and apply a constant voltage to the three-electrode system to obtain a pH-sensitive electrode.

[0013] Furthermore, in steps (1) and (2), the volume ratio of DMF to methanol in the DMF-methanol solution is 7:1 to 6, preferably 7:3.

[0014] The concentration of 2,4-diamino-N,N-dimethylaniline in DMF-methanol solution in step (1) is 60-150 mM, preferably 80-120 mM, and more preferably 100 mM.

[0015] The concentration of 1-chloro-2-hydroxynaphthalene in DMF-methanol solution in step (2) is 30-80 mM, preferably 40-60 mM.

[0016] The mass-volume ratio of DMF-methanol solution, Zn and trifluoromethanesulfonic acid in step (2) is 60-120 mL: 2.5 g: 0.5-12 mL, preferably 97 mL: 2.5 g: 3 mL.

[0017] The concentration of product (I) in DMF in step (3) is 10-40 mM, preferably 15-30 mM, and more preferably 20 mM;

[0018] Furthermore, the weak base salt mentioned in step (3) includes at least one of K2CO3, KHCO3, Na2CO3, KHCO3, etc.

[0019] The concentration of the weak base salt aqueous solution in step (3) is 10-40 mM, preferably 15-30 mM, more preferably 20 mM; the concentration of the benzoyl peroxide DMF solution is 25-75 mM, preferably 40-60 mM, more preferably 50 mM; the volume ratio of DMF, weak base salt aqueous solution and benzoyl peroxide DMF solution is 100-150 mL: 200-400 μL: 180 μL; preferably 120 mL: 300 μL: 180 μL.

[0020] The mass-to-volume ratio of product (II), acetonitrile acidic solution, 4-allyl ether pyridine, and lauroyl peroxide in step (4) is 1.5 g: 150-250 mL: 1-5 g: 5-20 mg, preferably 1.5 g: 200 mL: 2.5 g: 10 mg;

[0021] In step (5), the concentrations of imidazole and hexafluorophosphate in DMSO are 0.5–3 mM and 0.005 g–0.03 g / mL, respectively, preferably 1 mM and 0.01 g / mL; the mass-to-volume ratio of lauroyl peroxide to DMSO is 0.5–5 mg:1 mL, preferably 2 mg:1 mL;

[0022] In step (5), the mass-to-volume ratio of product (III) to DMSO is 1g:10-40mL, preferably 1g:15-30mL, and more preferably 1g:20mL;

[0023] The mass-to-volume ratio of product (III) to DMSO in step (6) is 1g:10-40mL, preferably 1g:15-30mL, and more preferably 1g:20mL;

[0024] The concentrations of 3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxy radical, imidazole, and hexafluorophosphate in DMSO in step (6) are 0.05–0.5 mM, 0.05–4 mM, and 0.005–0.03 g / mL, respectively, preferably 0.2 mM, 1 mM, and 0.01 g / mL.

[0025] The base electrode described in steps (5) and (6) is at least one of pure metal, alloy, carbon material, special diamond, conductive glass, special ceramic, semiconductor material, special polymer, and nanomaterial.

[0026] The counter electrode in step (6) is at least one of Pt, carbon, etc., and the reference electrode is at least one of Al, Ag, Ag / AgCl, Cu, Au, Sn and C.

[0027] Furthermore, the reaction temperature in step (2) is 45–70°C and the reaction time is 4–14 h; the reaction temperature in step (3) is 60–100°C and the reaction time is 6–18 h; the reaction temperature in step (4) is 20–35°C and the reaction time is 12–36 h; the temperature of the two reactions in step (5) is 70–110°C, the reaction time of the first reaction is 5–20 min, and the reaction time of the second reaction is 12–36 h.

[0028] An application of the above-mentioned pH-sensitive electrode in online detection of gastric fluid.

[0029] A method for online detection of gastric juice using the above-mentioned pH-sensitive electrode includes the following steps:

[0030] The pH of a pH standard buffer solution was detected using an electrode system that included both pH-sensitive and pH-insensitive electrodes.

[0031] The pH indicator parameter au was defined by voltammetric analysis. Where E f ΔI1 and ΔI2 are the peak potentials, HWHM is the half-peak half-width potential, ΔI1 and ΔI2 are the peak current intensities corresponding to the pH-sensitive electrode and the pH-insensitive electrode, respectively, and a is the electrode constant.

[0032] A regression curve was generated based on the relationship between au value and pH value of standard buffer solution;

[0033] The same electrode system was used to detect the gastric fluid at the sampling end of the nasogastric tube, and the pH value was determined based on the regression curve.

[0034] The current and potential signals generated by the pH-sensitive electrode will respond to changes in the pH being measured.

[0035] The current and potential signals generated by the pH-insensitive electrode do not respond to changes in pH.

[0036] Furthermore, the current and potential signals generated by the pH-sensitive electrode will respond to changes in the pH being measured and environmental interference factors; the current and potential signals generated by the pH-insensitive electrode will not change with pH but will only respond to changes in environmental interference factors.

[0037] Furthermore, the interfering factors mainly include ion types, ion concentrations, solution viscosity, strong acids and bases, extreme temperatures, fluorides, sulfides, adhering substances, biological pollutants, etc. These are all environmental factors that seriously interfere with the accuracy of traditional methods. This solution has good anti-interference performance against these known interfering factors.

[0038] Furthermore, the pH-sensitive electrode and the pH-insensitive electrode can be integrated onto the same base electrode or used separately; when on the same base electrode, the order of modification of the two electrodes depends on the properties of the specific electrode material used, and can be adjusted or optimized flexibly according to the specific situation.

[0039] The pH-insensitive electrode is prepared by modifying the substrate electrode with functionalized materials or introducing functionalized materials in situ.

[0040] Furthermore, the substrate electrode is one or more of the following: pure metal, alloy, carbon material, special diamond, conductive glass, special ceramic, semiconductor material, special polymer, nanomaterial, etc.

[0041] Furthermore, the functional materials for the pH-insensitive electrode include, but are not limited to, at least one of the following: pure metals, alloys, carbon materials, metal chelates and their derivatives, benzene compounds and their derivatives, heterocyclic aromatic hydrocarbons and their derivatives, and electrochemically active biomolecules and their derivatives. Even further, the functional materials for the pH-insensitive electrode include, but are not limited to, at least one of the following: silver, gold, gold amalgam, tin-lead alloy, boron-doped diamond, carbon black, glassy carbon, ruthenium bipyridine, phenanthroline iron, (poly)phenylthiol, and poly(4-vinylpyridine).

[0042] Furthermore, the modification method of the functionalized material on the substrate electrode is at least one of chemical vapor deposition, vacuum sputtering, evaporation, electroplating, electrochemical deposition, chemical in-situ synthesis, electrochemical in-situ synthesis, and film formation.

[0043] Furthermore, the electrode system is one of a two-electrode, a three-electrode, or a four-electrode system.

[0044] Furthermore, the electrode form of each electrode in the three-electrode system is, but is not limited to, one of the following: columnar electrode, planar printed electrode, planar sputtered thin film electrode, planar MEMS microelectrode, coaxial filament microelectrode, etc.

[0045] Furthermore, the current-voltage analysis method includes, but is not limited to, at least one of linear current-voltage analysis, cyclic current-voltage analysis, pulse current-voltage analysis, differential pulse current-voltage analysis, and square wave pulse current-voltage analysis.

[0046] Furthermore, for linear voltammetry and cyclic voltammetry, the scanning potential window is -2.5 to +2.5 V; the scanning rate is 0.01 mV / s to 10 V / s; for pulse voltammetry, the potential increment is 0.01 to 1000 mV / s, the potential amplitude is 1 to 500 mV, and the frequency is 1 to 100000 Hz.

[0047] Furthermore, after the data is measured by the volt-ampere analysis method, the data undergoes primary processing, including but not limited to linear filtering and linear parameter extraction; further still, the linear filtering includes at least one of differential filtering, high-pass filtering, and low-pass filtering; the linear parameter extraction includes at least one of derivative function analysis, nonlinear fitting, machine learning fitting, and interpolation.

[0048] The voltammetric pH sensing technology described in this invention is a novel electrochemical sensor and electrochemical sensing method composite based on an all-solid-state pH electrode and a dynamic current-based electrochemical pH analysis method. The all-solid-state pH electrode is a three-electrode system composed of a pH-sensitive electrode and a pH-insensitive reference electrode as core materials.

[0049] Compared with the prior art, the present invention has the following technical effects:

[0050] This invention empowers nasogastric tubes with an electrochemical calibration-free pH sensing method by providing a pH-sensitive electrode for an online precision pH sensor. This enables the tubes to automatically determine whether they are properly positioned. Simultaneously, it allows for the in-situ diagnosis of gastroesophageal reflux disease and the accumulation of clinical big data on the precise pH values ​​of the gastric environment. This enhances the value for patients while providing valuable research data for healthcare professionals. Attached Figure Description

[0051] Figure 1 This is the synthetic route for product (III) of pH in Example 1.

[0052] Figure 2 The synthesis route for the pH-sensitive electrode in Example 1 is shown.

[0053] Figure 3 The pH response characteristics of the polymer all-solid-state calibration-free electrode in Example 2 are shown below. Figure 3 (a) is a differential pulse voltammogram. Figure 3 (b) is the regression curve.

[0054] Figure 4 Example 3 shows the anti-interference characteristics of the polymer all-solid-state calibration-free electrode under complex environments, where 4(a) shows the CBFc electrode under different pH and salinity environments; Figure 4 (b) shows the CBFc electrode under different pH and viscosity gradients.

[0055] Figure 5 This is the result of a comparative measurement of pH in clinical samples of gastric fluid from patients using an all-solid-state, calibration-free electrode as described in Example 5.

[0056] Figure 6 This is a comparison of the simulated clinical diagnostic test results for gastroesophageal reflux disease using an all-solid-state calibration-free electrode and a glass bulb pH meter, as described in Example 6. Detailed Implementation

[0057] Example 1: Polymer Synthesis and pH Electrode Preparation

[0058] 2,4-Diamino-N,N-dimethylaniline was dissolved in DMF-methanol (v:v = 7:3) to form a 100 mM solution, denoted as A. 1-Chloro-2-hydroxynaphthalene was dissolved in DMF-methanol (v:v = 7:3) to form a 50 mM solution, denoted as B. 97 mL of B was added to a three-necked flask, mixed with 2.5 g of Zn powder, and 3 mL of trifluoromethanesulfonic acid was added dropwise under magnetic stirring. The reaction was maintained at 60 °C under a nitrogen atmosphere. After 8 hours of reaction, the mixture was repeatedly precipitated in pure water and then dissolved in DMF for purification to obtain product (I). The yield of this reaction was identified as 74.6%. Prepare 120 mL of a 20 mM DMF solution of product (I). Add 300 μL of a 0.2 M KCO3 aqueous solution to the solution while stirring. Stir the reaction system at room temperature for 30 min under nitrogen purging. Then add 180 μL of a 50 mM benzoyl peroxide DMF solution. Maintain uniform stirring and adjust the reaction temperature to 80 °C. React for 12 h to complete the cyclization reaction. Mix the reaction solution with 0.5 times its volume of chloroform, add a large amount of pure water to precipitate, wash the precipitate with ethanol, and dry to obtain product (II). The yield of this reaction was identified as 90.1%. Dissolve 1.5 g of product (II) in 200 mL of a mixed solution of acetonitrile containing 0.1 M HCl. After standing for 30 min, add 2.5 g of 4-allyl ether pyridine to the system and react at room temperature for 24 h. The reaction yielded a purplish-red solution, which was vacuum filtered through a sintered glass filter with a 0.45 μm microporous membrane. The reaction solution was collected, and the solvent was evaporated to obtain product (III). Alternatively, glacial acetic acid can be added to the above mixture to precipitate a solid, which can then be separated by filtering off the solvent. The solid was washed with anhydrous ethanol to obtain pure product (III).

[0059] A 1.5 mm diameter graphite rod was cut into 6.0 mm long cylinders, and one end was polished sequentially with 800 and 2000 grit sandpaper. 1 g of product (III) was weighed and dissolved in 20 mL of DMSO containing 1 mM imidazole and 0.2 g hexafluorophosphate. After complete dissolution, the mixture was allowed to stand in the dark for 30 min. Then, 5 mL of DMSO solution containing 10 mg lauroyl peroxide was added and mixed thoroughly. The polished end was immersed in the reaction solution, and the reaction system was heated to 90 °C under nitrogen protection. After 10 min, the graphite rod was removed and immersed in a 2 g / L DMSO solution, maintaining the temperature at 90 °C in the dark for 24 h. The graphite rod was then rinsed with pure water and air-dried to obtain a pH-sensitive electrode.

[0060] Example 2: pH response characteristics of a polymer all-solid-state calibration-free electrode

[0061] Prepare 1 mL of DMF solution containing 1 mM ferrocene aminodicarboxylate. Add this solution dropwise to 250 mL of a 50 v:v ethanol aqueous solution containing 1 v:v glacial acetic acid, under stirring. Then add 1 mL of an aqueous solution containing 0.2 mM sodium nitrite. Place the solution in an ice bath and react for 8 hours before using it as the electrolyte. Immerse the working surface of the graphite electrode (i.e., the pH-sensitive electrode) treated according to the method described in Example 1 into this electrolyte. Construct a three-electrode system using Pt and Ag-AgCl (3MKCl) as the electrode body (WE) and electrode resonator (RE), respectively. Apply a cyclic voltammetric excitation potential of -1 to 0 V at a scan rate of 100 mV / s to the electrode system for 10 consecutive cycles. Remove the electrode, rinse with pure water, and air dry. Introduce a pH-insensitive material onto the indicator electrode (WE). The graphite rod processed as described above is used as the working surface of the working electrode (WE) (WE is both a pH-sensitive electrode and a pH-insensitive electrode). Together with a Pt counter electrode (CE) with a diameter of 0.5 mm and an Ag pseudo-reference electrode (PRE) with a diameter of 1.0 mm, a three-electrode system is formed. The ends of the three electrodes and the wires are connected with conductive paint and solder respectively. The three electrodes are encapsulated at equal intervals in medical-grade POM to form a columnar three-electrode system with a diameter of 6.0 mm and a height of 10.0 mm, denoted as CBFc.

[0062] According to the Chinese Pharmacopoeia (ChP) formula, different amounts of HCl solution were added to 800 mL of an aqueous solution containing 130 mM NaCl and 0.1 M sodium taurocholate. 10 g of pepsin was added, and the solution was shaken well and then diluted with water to 1000 mL to prepare a standard pH solution of artificial gastric fluid. Differential pulse voltammetry (scanning potential from 800 to -500 mV, pulse potential increment of 5 mV, pulse amplitude of 50 mV, pulse frequency of 20 Hz) was used to perform SWV tests on artificial gastric fluids at different pH values ​​using CBFc. The changes in current and potential with pH were recorded to obtain pH response curves. The differential pulse voltammetry plots in buffer solutions with pH 0.5-10 are shown below. Figure 3As shown in (a). The microcontroller software automatically calculates E based on the curve results data. f The values ​​of HWHM, ΔI1, ΔI2, a, and au were recorded, and the relationship between the au value and the pH value of the standard buffer was used to generate a regression curve, such as... Figure 3 As shown in (b). The au-pH relationship of this curve was used to establish a quantitative method for pH detection. This involved contacting the three-electrode system with the test solution to obtain the au value, and then measuring the pH based on the regression curve. The results show that the CBFc electrode and the standard glass bulb pH meter exhibit high consistency in measurement results, enabling high-precision quantitative pH analysis in a gastric fluid environment.

[0063] Table 1. pH response performance of polymer all-solid-state calibration-free electrodes using the SWV method.

[0064]

[0065]

[0066] Example 3: Response of Polymer All-Solid-State Calibration-Free Electrode in Complex Environments

[0067] The CBFc prepared in Example 2 was measured in standard artificial gastric fluid samples with pH values ​​of 0.5, 3.0, and 7.0. Gradient samples with NaCl concentrations of 0, 50, 100, 200, 500, and 1000 mM were set up at each pH level as ion concentration interference test samples. Similarly, mucin (M1778, Sigma-Aldrich) was used... TM As a thickener, viscosity gradient samples at various pH levels were prepared and used as viscosity interference test samples (viscosities of 0.01, 0.5, 1.0, 2.0, and 3.0 Pa·s, respectively). The test results are as follows: Figure 4 As shown in Tables 2 and 3, CBFc can accurately quantify the pH of artificial gastric juice within a wide range of salinity and viscosity, far exceeding the actual range of gastric juice indicators, with an effective resolution of no more than 0.05 pH. This indicates that the sensor can effectively shield against major interference factors in the quantitative analysis of gastric juice pH. Compared with the current mainstream method of pH test strip colorimetry, which has an effective resolution of over 1.0 pH unit, this method belongs to a high-precision gastric juice pH sensor.

[0068] Table 2. Test results of salinity interference of polymer all-solid-state calibration-free electrodes on artificial gastric fluid.

[0069]

[0070] Table 3. Test results of viscosity interference of polymer all-solid-state calibration-free electrodes on artificial gastric fluid.

[0071]

[0072] Example 4: Electrochemical in-situ synthesis of polymer all-solid-state calibration-free pH electrode

[0073] Following the same strategy as in Example 1, product (III) was synthesized. 1 g of product (III) was dissolved in 20 mL of DMSO containing 0.2 mM 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxy radical, 1 mM imidazole, and 0.2 g hexafluorophosphate. A graphite rod with a diameter of 1.5 mm was successively polished with 800 and 2000 grit sandpaper, and one end of a 6.0 mm long cylinder was cut as the electrode reaction (WE). A three-electrode system was constructed using Pt and Ag-AgCl (3MKCl) as WE and RE, respectively. The three-electrode system was immersed in the above reaction solution under nitrogen protection. A constant voltage of 1.2 V was applied to the three-electrode system and maintained for 500 s. The electrodes were then removed, rinsed with pure water, and air-dried to obtain an electrochemically synthesized, in-situ polymer-based, all-solid-state, calibration-free pH electrode.

[0074] In this process, the WE to be functionalized serves as the specific site for the polymerization reaction, and free radicals required to initiate the polymerization are controllably generated through electrochemical excitation. Unlike homogeneous reaction systems, this method synthesizes polymers in situ only at the desired modification sites. Furthermore, it utilizes relatively expensive reactants intensively, representing an economical and refined synthesis model. Simultaneously, the degree of polymerization and molecular physicochemical properties of the polymer can be precisely controlled by adjusting the voltage. Sensors designed and fabricated using this approach are more suitable for applications requiring long-term pipe storage scenarios necessitating in-situ pH analysis exceeding seven consecutive days.

[0075] Example 5: All-solid-state calibration-free electrode for precise quantification of gastric contents pH.

[0076] A CBFc electrode was prepared as the sensor to be evaluated using the method described in Example 2. Gastric fluid samples were collected from six ICU patients during their normal treatment by medical staff. The six samples were independently measured using a commercially available standard glass bulb pH meter, pH test strips, and the CBFc electrode as sensors. The glass bulb pH meter readings were directly read using a compatible host computer; the pH test strip readings were obtained by medical staff through naked-eye testing. The pH regression curve of the CBFc electrode was obtained using the method described in Example 2, and the measurement results were analyzed based on the regression curve.

[0077] Measurement results are shown Figure 5See Table 4. It can be seen that both the glass bulb pH meter and the CBFc electrode can perform high-precision quantitative pH analysis of gastric fluid samples, while the accuracy of pH test strips is lower, potentially leading to misjudgments by professionals exceeding 1.0 unit. Meanwhile, the CBFc electrode exhibits a smaller measurement error than the glass bulb pH meter, mainly due to its superior anti-interference performance in the complex measurement environment of gastric fluid, thus possessing higher accuracy and reliability in resolving gastric fluid pH.

[0078] Table 4. Comparative measurement results of pH of clinical gastric fluid samples from patients using CBFc electrodes.

[0079]

[0080] Example 6: Polymer all-solid-state calibration-free electrode for nasogastric tube placement assessment and real-time diagnosis of gastroesophageal reflux disease.

[0081] Assessing the placement of a nasogastric tube by sampling the pH of gastric fluid is a crucial requirement for its clinical application. Real-time, precise sensing of gastric fluid pH is a vital physiological indicator for gastroesophageal reflux disease (GERD) and requires automated data accumulation. To address this, a 55cm long, 1.5cm diameter tubular container with two independently separated 300mL sealed pouches at the ends was prepared using ballistic gel casting to simulate the human upper digestive tract and lungs. One side of the simulated stomach pouch has an opening for connecting a peristaltic pump tube. 100mL of pH 3.0 standard artificial gastric fluid (prepared as described in Example 2) was pre-injected into the simulated stomach pouch. Simultaneously, 1L of pH 0.5 and pH 7.0 standard artificial gastric fluids were prepared and pumped into the simulated upper digestive tract pouch using a peristaltic pump. 200mL of 0.1M PBS buffer solution with a pH of 7.4 was injected into the simulated lung side at once. A commercially available standard nasogastric tube (16Fr type) was used, and a custom reactor and Y-type interface were 3D printed to allow the glass bulb pH meter and CBFc electrode to be directly connected to the sampling end of the nasogastric tube, forming an online testing system. The CBFc electrode was prepared using the method described in Example 4 as the sensor to be tested, while a general-purpose glass bulb pH meter was used as a control method to simulate clinical testing.

[0082] First, the nasogastric tube was inserted through an entrance simulating the upper digestive tract of the human body until the tip of the tube reached the bottom of the bag-shaped closed end. The sensor response was tested multiple times when the tip of the tube was correctly inserted into the simulated stomach and when it was mistakenly inserted into the simulated lung. During each test, approximately 2 mL of test fluid was manually drawn from the nasogastric tube using a syringe for online in-situ testing, simulating the current mainstream clinical procedure.

[0083] Subsequently, nasogastric tubes equipped with different sensors were left in the simulated stomach, and syringe sampling and online analysis were performed every 8 hours. Multiple sets of measurements were conducted during this period, and the solution in the simulated stomach was randomly changed to standard artificial gastric fluid with pH values ​​of 0.5, 3.0, and 7.0 to simulate common gastroesophageal reflux disease diagnostic scenarios, such as patients with acid reflux, normal individuals, and those with abnormal gastric fluid conditions.

[0084] The first round of testing showed that both the glass bulb pH meter and the CBFc electrode could correctly determine the pH state of the sampled liquid and whether the nasogastric tube was correctly placed. However, in the second round of testing, significant differences emerged between the two: for example... Figure 6 As shown, the pH measurement of the glass bulb electrode began to show a significant error compared to the true value after several hours, and the error gradually increased until its pH resolution accuracy decreased to a level similar to that of pH test strips. In contrast, the CBFc electrode was able to continuously and accurately measure the pH level of the sampled solution, with measurement accuracy remaining unchanged over time. Observation revealed that due to the high viscosity of artificial gastric fluid, it is prone to evaporation at the sensor probe after sample collection and backtracking, leading to a significant change in the sensor probe interface state. The glass bulb electrode is more sensitive to this type of problem, resulting in response instability; while the CBFc electrode, due to its calibration-free analysis method, is unaffected by general changes in the electrode surface state, thus exhibiting more ideal online continuous working performance.

Claims

1. A pH-sensitive electrode for an online precision pH sensor for nasogastric tubes, characterized in that... It is prepared by the following method: (1) Dissolve 2,4-diamino-N,N-dimethylaniline in DMF-methanol solution; (2) Dissolve 1-chloro-2-hydroxynaphthalene in DMF-methanol solution, add Zn and trifluoromethanesulfonic acid, and then add the mixed solution obtained in step (1) under stirring. React under an inert atmosphere to obtain product (I). (3) Prepare a DMF mixed solution of product (I), add a weak base salt aqueous solution to it while stirring, add a DMF solution of benzoyl peroxide after stirring under an inert atmosphere, and complete the cyclization reaction to obtain product (II). (4) Product (II) was dissolved in an acidic acetonitrile solution, and 4-allyl ether pyridine was added. The reaction yielded a purple-red solution. After removing the solvent, product (III) was obtained. (5) Dissolve product (III) in DMSO containing imidazole and hexafluorophosphate, add DMSO solution containing lauroyl peroxide and mix well to obtain reaction solution, immerse the substrate electrode in the reaction solution, react under an inert atmosphere, remove the substrate electrode and immerse it in DMSO solution, continue the reaction under the protection of light to obtain pH sensitive electrode, the structure of the compound on the pH sensitive electrode is shown in formula (VI). or (6) Dissolve product (III) in a DMSO mixed solution containing 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxy radical, imidazole and hexafluorophosphate to obtain a reaction solution. Then, use the base electrode as the working electrode and form a three-electrode system with the counter electrode and reference electrode. Immerse the system in the reaction solution under an inert atmosphere and apply a constant voltage to the three-electrode system to obtain a pH-sensitive electrode. The structure of the compound on the pH-sensitive electrode is shown in formula (VI). 。 2. The pH-sensitive electrode according to claim 1, characterized in that: In steps (1) and (2), the volume ratio of DMF to methanol in the DMF-methanol solution is 7:(1~6). The concentration of 2,4-diamino-N,N-dimethylaniline in DMF-methanol solution in step (1) is 60~150 mM.

3. The pH-sensitive electrode according to claim 1, characterized in that: In step (2), the concentration of 1-chloro-2-hydroxynaphthalene in the DMF-methanol solution is 30~80 mM; The mass-volume ratio of DMF-methanol solution, Zn and trifluoromethanesulfonic acid in step (2) is 60~120 mL: 2.5 g: 0.5~12 mL.

4. The pH-sensitive electrode according to claim 1, characterized in that: The concentration of product (I) in DMF in step (3) is 10-40 mM; the concentration of the weak base salt aqueous solution in step (3) is 10-40 mM; the concentration of the DMF solution of benzoyl peroxide is 25-75 mM. The volume ratio of the DMF, weak alkaline salt aqueous solution to benzoyl peroxide DMF solution is 100~150 mL: 200~400 μL: 180 μL.

5. The pH-sensitive electrode according to claim 1, characterized in that: The mass-to-volume ratio of product (II), acetonitrile acidic solution, 4-allyl ether pyridine, and lauroyl peroxide in step (4) is 1.5 g: 150-250 mL: 1-5 g: 5-20 mg; In step (5), the concentrations of imidazole and hexafluorophosphate in DMSO are 0.5~3 mM and 0.005 g~0.03 g / mL, respectively; In step (5), the mass-to-volume ratio of product (III) to DMSO is 1 g: 10~40 mL.

6. The pH-sensitive electrode according to claim 1, characterized in that: The mass-to-volume ratio of product (III) to DMSO in step (6) is 1 g: 10~40 mL; In step (6), the concentrations of 3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxy radical, imidazole, and hexafluorophosphate in DMSO are 0.05~0.5 mM, 0.05~4 mM, and 0.005 g~0.03 g / mL, respectively.

7. The pH-sensitive electrode according to claim 1, characterized in that: The reaction temperature in step (2) is 45~70 ℃ and the reaction time is 4~14 h; the reaction temperature in step (3) is 60~100 ℃ and the reaction time is 6~18 h; the reaction temperature in step (4) is 20~35 ℃ and the reaction time is 12~36 h; the temperature of the two reactions in step (5) is 70~110 ℃, the reaction time of the first reaction is 5~20 min and the reaction time of the second reaction is 12~36 h; The base electrode described in steps (5) and (6) is at least one of pure metal, alloy, carbon material, special diamond, conductive glass, special ceramic, semiconductor material, special polymer, and nanomaterial.

8. The application of a pH-sensitive electrode according to any one of claims 1 to 7 in online detection of gastric juice.

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