PH sensitive electrode of nasogastric tube online precise PH sensor and application

Abstract

The invention provides a pH sensitive electrode of a nasogastric tube online precise pH sensor and application. According to the present invention, by providing the pH sensitive electrode of the nasogastric tube online precision pH sensor, the nasogastric tube is energized by the electrochemical calibration-free pH sensing method, such that the nasogastric tube has the function of automatically determining whether the placement is in place or not, and the gastroesophageal reflux pathogen diagnosis and the clinical big data accumulation of the intra-gastric environment pH accurate value can be achieved so as to provide the accurate pH value of the nasogastric tube. And valuable research data is provided for medical workers while the use value of the patient is improved.

Description

Technical Field

[0001] The present invention belongs to the fields of electrochemical detection and analysis, chemical sensor technology and medical equipment, and relates to a pH-sensitive electrode for an online precision pH sensor for a nasogastric tube and its application. Background Art

[0002] A nasogastric tube is a medical device that is usually inserted into the patient's nasal cavity or oral cavity, passing through the pharynx and into the stomach. Its purpose is to deliver nutrients or medicines to the patient, or to perform drainage and emptying of the stomach. For patients who need to administer medications on a regular basis, a multifunctional nasogastric tube can be used to ensure that the medication effectively reaches the stomach or intestines. For patients with dysphagia, a multifunctional nasogastric tube can be used to help them eat and drink water, maintaining the energy and water intake required for life. The nasogastric tubes in the prior art have the following shortcomings:

[0003] 1. After the nasogastric tube is placed in the stomach, auscultation or X-rays are still needed to help determine whether the tube is in place. Under the existing technology, abdominal auscultation to detect the sound of air passing through water or X-rays are preferred to help determine the tube. However, there are the following defects: (1) Abdominal auscultation to detect the sound of air passing through water is the most commonly used method to determine whether the tube is in place, but this method is limited by the medical habits and skills of clinical physicians. Auscultation misjudgment or omission may fail to detect that the tube is not in place. (2) Severe patients need to wait for the examination to be performed before an X-ray examination is performed to determine whether the tube is in place, which delays the patient's treatment. (3) X-rays can cause radioactive damage to patients. (4) Some units do not have bedside X-ray equipment. 2. Some drugs, such as sodium bicarbonate tablets and calcium tablets, can easily form hard crystals with other nutrient solutions to block the nasogastric tube, causing feeding failure or forcing re-insertion of the tube, causing secondary damage to the patient. 3. The front end of existing nasogastric tubes is closed, but multiple side holes are provided on the side for the injection of medication and food. Medication (especially large drugs such as sustained-release tablets and capsules) must be crushed before injection through a nasogastric tube, which affects the proper use of the medication and forces changes in its absorption pattern. 4. Existing nasogastric tubes with self-contained sensors are primarily endoscopic, with an endoscopic camera coupled to the front end. This approach is costly, requires complex equipment, and still relies on the naked eye of a professional physician. Furthermore, this strategy can only be used to determine whether the nasogastric tube is properly placed, leaving no room for further expansion. 5. Another mainstream technique for determining the placement status of a nasogastric tube is to immediately withdraw gastric fluid and test the sample with pH test paper after placement. This method offers excellent accuracy, is cost-effective, has clear standards, and does not require specialized skills or experience. However, it still requires manual operation by medical staff and, due to its low resolution, is also limited in other applications. Summary of the Invention

[0004] The present invention aims to provide a pH sensitive electrode for an online precision pH sensor for a nasogastric tube.

[0005] Another object of the present invention is to provide an 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 a nasogastric tube is prepared by the following method:

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

[0008] (2) dissolving 1-chloro-2-hydroxynaphthalene in a DMF-methanol solution, adding Zn and trifluoromethanesulfonic acid, and then adding the mixed solution obtained in step (1) under stirring, and reacting under an inert atmosphere to obtain product (I);

[0009] (3) preparing a DMF mixed solution of product (I), adding a weak base salt solution thereto under stirring, and adding a DMF solution of benzoyl peroxide after stirring under an inert atmosphere to complete the cyclization reaction to obtain product (II);

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

[0011] (5) dissolving the product (III) in DMSO containing imidazole and hexafluorophosphate, adding a DMSO solution containing lauroyl peroxide and mixing evenly, immersing the base electrode in the reaction solution, reacting under an inert atmosphere, taking out the base electrode, immersing it in a DMSO solution, and continuing the reaction in the dark to obtain a pH sensitive electrode; or

[0012] (6) The product (III) is dissolved in a DMSO mixed solution containing 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl free radical, imidazole and hexafluorophosphoric acid to obtain a reaction solution, and then the base electrode is used as a working electrode to form a three-electrode system with a counter electrode and a reference electrode. The system is immersed in an inert atmosphere in the reaction solution, and a constant voltage is applied to the three-electrode system to obtain a pH-sensitive electrode.

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

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

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

[0016] The mass volume ratio of the 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 the product (I) in step (3) in DMF is 10-40 mM, preferably 15-30 mM, more preferably 20 mM;

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

[0019] The concentration of the weak alkaline salt 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 the DMF, weak alkaline salt 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 volume ratio of the product (II) in step (4), the acetonitrile acidic solution, 4-butyl ether pyridine and lauroyl peroxide 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 hexafluorophosphoric acid 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 volume ratio of lauroyl peroxide to DMSO is 0.5-5 mg:1 mL, preferably 2 mg:1 mL;

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

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

[0024] The concentrations of the 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl free radical, imidazole and hexafluorophosphoric acid in DMSO in step (6) are 0.05-0.5 mM, 0.05-4 mM and 0.005 g-0.03 g / mL, respectively, preferably 0.2 mM, 1 mM and 0.01 g / mL.

[0025] The base electrode in step (5) and step (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 4-14h; the reaction temperature in step (3) is 60-100°C, and the reaction time is 6-18h; the reaction temperature in step (4) is 20-35°C, and the reaction time is 12-36h; the temperature of the two reactions in step (5) is 70-110°C, the reaction time for the first reaction is 5-20min, and the reaction time for the second reaction is 12-36h.

[0028] An application of the pH sensitive electrode in online detection of gastric juice.

[0029] A method for online detection of gastric juice using the pH sensitive electrode comprises the following steps:

[0030] The pH of the pH standard buffer solution is detected using an electrode system including a pH sensitive electrode and a pH insensitive electrode;

[0031] The pH indicator parameter au obtained by voltammetry is defined as Among them E f is the peak potential, HWHM is the half-width at half maximum potential, ΔI1 and ΔI2 are the peak current intensities corresponding to the pH sensitive electrode and pH non-sensitive electrode respectively, and a is the electrode constant;

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

[0033] The same electrode system is used to detect the gastric fluid at the sampling end of the nasogastric tube, and the pH value is measured according to the regression curve;

[0034] The current and potential signals generated by the pH sensitive electrode will respond to changes in the pH to be 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 measured pH and environmental interference factors; the current and potential signals generated by the pH insensitive electrode do not respond to changes in pH but only to changes in environmental interference factors.

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

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

[0039] The pH non-sensitive electrode is prepared by modifying a functional material on a base electrode or introducing a functional material in situ.

[0040] Furthermore, the base electrode is one of pure metal, alloy, carbon material, special diamond, conductive glass, special ceramic, semiconductor material, special polymer, nanomaterial, etc., or a composite material composed of more than one of them.

[0041] Furthermore, the functional material of the pH-insensitive electrode includes, but is not limited to, at least one of pure metals, alloys, carbon materials, metal chelates and their derivatives, benzene-based substances and their derivatives, heterocyclic aromatic hydrocarbons and their derivatives, and electrochemically active biomolecules and their derivatives. Furthermore, the functional material of the pH-insensitive electrode includes, but is not limited to, at least one of silver, gold, gold amalgam, tin-lead alloy, boron-doped diamond, carbon black, glassy carbon, ruthenium bipyridine, phenanthroline iron, (poly)benzene mercaptan, 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 double electrode, a triple electrode, and a quadruple electrode.

[0044] Furthermore, the electrode form of each electrode in the three-electrode system includes but is not limited to one of a columnar electrode, a planar printed electrode, a planar sputtered thin film electrode, a planar MEMS microelectrode, a coaxial wire microelectrode, and the like.

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

[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-10 V / s; for pulse voltammetry, the potential increment is 0.01-1000 mV / s, the potential amplitude is 1-500 mV, and the frequency is 1-100000 Hz.

[0047] Furthermore, after the data is measured by the voltammetric analysis method, the data is subjected to primary processing, and the processing methods include but are not limited to linear filtering and linear parameter extraction; further, 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 judgment, nonlinear fitting judgment, machine learning fitting judgment and interpolation judgment.

[0048] The voltammetric pH sensing technology described in this invention is a novel electrochemical sensor and electrochemical sensing method complex based on an all-solid-state pH electrode and a dynamic amperometric 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 its core materials.

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

[0050] The present invention provides a pH-sensitive electrode for an online precision pH sensor for a nasogastric tube, thereby realizing an electrochemical calibration-free pH sensing method to enable the nasogastric tube, so that the tube has the function of automatically determining whether it is properly placed. At the same time, it can realize the in situ diagnosis of gastroesophageal reflux disease and the accumulation of clinical big data on the precise pH value of the intragastric environment, thereby improving the use value for patients and providing valuable research data for medical workers. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0052] Figure 2 This is the synthesis route of the pH sensitive electrode in Example 1.

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

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

[0055] Figure 5 The comparative measurement results of pH of clinical gastric fluid samples from patients using the all-solid-state calibration-free electrode in Example 5 are shown.

[0056] Figure 6 The comparison results of the simulated clinical diagnostic test of gastroesophageal reflux disease using the all-solid-state calibration-free electrode and the glass bulb pH meter in Example 6 are shown. DETAILED DESCRIPTION

[0057] Example 1 Synthesis of polymer and preparation of pH electrode

[0058] 2,4-Diamino-N,N-dimethylaniline was dissolved in DMF-methanol (v:v = 7:3) to form a 100 mM solution, designated A. 1-Chloro-2-hydroxynaphthalene was weighed and dissolved in DMF-methanol (v:v = 7:3) to form a 50 mM solution, designated 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. 3 mL of A was then 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 purified by dissolving in DMF to obtain product (I). The yield was determined to be 74.6%. A 20 mM solution of product (I) in DMF (120 mL) was prepared. 300 μL of a 0.2 M aqueous KCO solution was added with stirring. The reaction system was stirred at room temperature under nitrogen for 30 minutes, followed by the addition of 180 μL of a 50 mM solution of benzoyl peroxide in DMF. Maintaining uniform stirring, the reaction temperature was adjusted to 80°C for 12 hours to complete the cyclization reaction. The reaction solution was mixed with 0.5 volumes of chloroform, allowed to settle in a large amount of pure water, rinsed with ethanol, and dried to yield product (II). The yield was determined to be 90.1%. 1.5 g of product (II) was dissolved in 200 mL of a 0.1 M HCl / acetonitrile mixture. The mixture was allowed to stand for 30 minutes, followed by the addition of 2.5 g of 4-butyl ether pyridine and the reaction was continued at room temperature for 24 hours. The reaction produces a purple-red solution, which is placed on a sand core filter with a 0.45 μm pore size microporous membrane and vacuum filtered to collect the reaction solution. After evaporation of the solvent, product (III) is obtained. Alternatively, glacial acetic acid can be added to the above mixture to precipitate a solid, and the purple-red solid can be isolated by filtering out the solvent. The solid is washed with anhydrous ethanol to obtain pure product (III).

[0059] A graphite rod with a diameter of 1.5 mm was cut into 6.0 mm long cylinders, and one end was polished with 800 and 2000 grit sandpaper in turn. 1 g of product (III) was weighed and dissolved in 20 mL of DMSO containing 1 mM imidazole and 0.2 g of hexafluorophosphate. After fully dissolved and allowed to stand in the dark for 30 minutes, 5 mL of DMSO solution containing 10 mg of lauroyl peroxide was added and mixed evenly. The polished end was immersed in the above reaction solution, and the reaction system was heated to 90 ° C under nitrogen protection. After 10 minutes, the graphite rod was taken out and immersed in a 2 g / L DMSO solution, maintained at 90 ° C in the dark for 24 hours. The graphite rod was taken out, rinsed with pure water, and dried to obtain a pH sensitive electrode.

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

[0061] Prepare 1 mL of a DMF solution containing 1 mM aminoferrocene and dropwise add it 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 in an ice bath and react for 8 hours before using as an electrolyte. Immerse the working surface of a graphite electrode (i.e., a pH-sensitive electrode) treated as described in Example 1 in the electrolyte, and construct a three-electrode system using Pt and Ag-AgCl (3MKCl) as WE and RE, respectively. Apply a cyclic voltammetry excitation potential of -1 to 0 V and 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. A pH-insensitive material is introduced onto the indicator electrode (WE). The graphite rod treated as described above was used as the working surface of the working electrode (WE) (WE is both a pH-sensitive electrode and a pH-insensitive electrode), and a three-electrode system was formed 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. The ends and wires of the three electrodes were connected with conductive paint and solder respectively, and the three electrodes were equidistantly encapsulated in medical-grade POM to form a cylindrical three-electrode system with a diameter of 6.0 mm and a height of 10.0 mm, which was recorded 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, shaken, and then diluted with water to 1000 mL to prepare an artificial gastric fluid standard pH solution. Differential pulse voltammetry (scanning potential of 800 to -500 mV, pulse potential increment of 5 mV, pulse amplitude of 50 mV, and pulse frequency of 20 Hz) was used. SWV tests were performed using CBFc in artificial gastric fluids of different pH values. The changes in current and potential with pH were recorded to obtain pH response curves. The differential pulse voltammetry in buffers with pH values ​​of 0.5-10 is shown in the figure. Figure 3(a) is shown. The microcontroller software automatically calculates E according to the curve result data. f , HWHM, ΔI1, ΔI2, a and au values, record the relationship between au value and pH value of standard buffer solution to generate regression curve, such as Figure 3 (b) This curve's au-pH relationship is used to establish a quantitative relationship for pH measurement. Specifically, the three-electrode system is placed in contact with the test solution to obtain the au value, and the pH is then measured using the regression curve. The results demonstrate high consistency between the CBFc electrode and a standard glass-bulb pH meter, enabling high-precision pH quantitative analysis in gastric fluid environments.

[0063] Table 1 SWV pH response performance of polymer all-solid-state calibration-free electrode

[0064]

[0065]

[0066] Example 3 Response of polymer all-solid-state calibration-free electrode in complex environment

[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. At each pH level, a gradient sample with NaCl concentrations of 0, 50, 100, 200, 500, and 1000 mM was set as the ion concentration interference test sample. Similarly, mucin (M1778, Sigma-Aldrich) was used to measure the ion concentration of the CBFc. TM ) was used as a thickener to prepare viscosity gradient samples at different pH levels as viscosity interference test samples (viscosities were 0.01, 0.5, 1.0, 2.0 and 3.0 Pa·s respectively). The test results are shown in Figure 4 As shown in Tables 2 and 3, the CBFc accurately quantified the pH of artificial gastric fluid over a wide range of salinity and viscosity, far exceeding the actual range of gastric fluid. This demonstrates that the sensor effectively blocks the major interfering factors in gastric fluid pH analysis. Compared to the current mainstream pH test paper colorimetry method, which has an effective resolution exceeding 1.0 pH units, this method is a high-precision gastric fluid pH sensor.

[0068] Table 2 Test results of the polymer all-solid-state calibration-free electrode for the salinity interference of artificial gastric juice

[0069]

[0070] Table 3 Viscosity interference test results of polymer all-solid-state calibration-free electrode on artificial gastric juice

[0071]

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

[0073] Product (III) was synthesized according to the same strategy as in Example 1, and 1 g of product (III) was dissolved in 20 mL of DMSO containing 0.2 mM 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl radical, 1 mM imidazole and 0.2 g hexafluorophosphate. A graphite rod with a diameter of 1.5 mm was polished with 800 and 2000 grit sandpaper in sequence, and one end of the cylinder was cut into 6.0 mm long as WE, and Pt and Ag-AgCl (3MKCl) were used as WE and RE to form a three-electrode system. The three-electrode system was immersed in the above-mentioned reaction solution and protected by nitrogen. A constant voltage of 1.2 V was applied to the three-electrode system and the treatment was continued for 500 s. The electrodes were then taken out, rinsed with pure water and dried to obtain an electrochemical in situ synthesized polymer all-solid-state calibration-free pH electrode.

[0074] In this process, the functionalized WE serves as a specific site for polymerization, and electrochemical stimulation allows for the controlled generation of free radicals necessary to initiate the polymerization reaction. Unlike homogeneous reaction systems, this method allows for in situ polymerization only at the site where polymer modification is desired. Furthermore, it utilizes relatively expensive reactants in an extremely intensive manner, resulting in an economical, precision synthesis model. Furthermore, the polymer's degree of polymerization and molecular physicochemical properties can be precisely controlled through voltage regulation. Sensors designed and fabricated using this approach are particularly well-suited for applications requiring long-term pipe retention requiring in situ pH analysis for more than seven consecutive days.

[0075] Example 5: Accurate quantification of gastric pH using a solid-state calibration-free electrode

[0076] A CBFc electrode was prepared using the method described in Example 2 as the sensor to be evaluated. Gastric fluid samples were collected on-site by medical staff from six ICU patients during normal treatment. Each sample was independently measured using a commercially available standard glass pH meter, pH test paper, and a CBFc electrode as a sensor. The glass pH meter reading was directly read using a manufacturer-adapted host instrument; the pH test paper reading was obtained by medical staff using the naked eye during on-site testing. A pH regression curve for the CBFc electrode was obtained using the method described in Example 2, and the measurement results were obtained using the regression curve.

[0077] The measurement results are shown in Figure 5and Table 4. It can be seen that both the glass-bubble pH meter and the CBFc electrode are capable of highly accurate quantitative pH analysis of gastric fluid samples, whereas the pH test strips have lower accuracy, even leading to misjudgments exceeding 1.0 pH units by professionals. Furthermore, the CBFc electrode exhibits smaller measurement errors than the glass-bubble pH meter. This is primarily due to its excellent anti-interference performance in the complex gastric fluid measurement environment, resulting in higher gastric fluid pH resolution accuracy and greater reliability.

[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 and Real-Time Diagnosis of Gastroesophageal Reflux Disease

[0081] Determining the placement of a nasogastric tube by sampling the pH of withdrawn gastric fluid is a key requirement for clinical nasogastric tube applications. Real-time, precise sensing of gastric fluid pH is a key physiological indicator of gastroesophageal reflux disease (GERD) of interest to digestive medicine practitioners, and requires automated big data accumulation. To address this issue, a flexible container with a 55 cm long, 1.5 cm diameter tubular structure and two independently separated, 300 mL bag-shaped sealed ends was fabricated using a ballistic gel casting method to simulate the human upper gastrointestinal tract and lungs. One of the bag-shaped sealed ends of the simulated stomach had an opening at the end for connection to a peristaltic pump tube. 100 mL of standard artificial gastric fluid (pH 3.0) (prepared as described in Example 2) was pre-injected into one of the bag-shaped sealed ends of the simulated stomach. Simultaneously, 1 L of standard artificial gastric fluid (pH 0.5 and pH 7.0) was prepared and delivered to the bag-shaped sealed end of the simulated upper gastrointestinal tract via a peristaltic pump. 200 mL of 0.1 M PBS buffer solution (pH 7.4) was injected into one side of the simulated lungs. A commercially available standard 16Fr nasogastric tube was used. A custom 3D-printed reactor and Y-shaped connector were used to directly connect a glass-bubble pH meter and CBFc electrode to the tube's sampling port, 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 conventional glass-bubble pH meter was used as a control for simulated clinical testing.

[0082] First, a nasogastric tube was inserted through the entrance of a simulated upper digestive tract until the tip of the tube reached the bottom of the bagged, sealed end. Sensor responses were tested multiple times, both when the tip of the tube was correctly inserted into the simulated stomach and when it mistakenly reached the simulated lungs. During each test, approximately 2 mL of test fluid was manually drawn from the nasogastric tube via syringe for in-situ testing, simulating the current mainstream clinical procedure.

[0083] Subsequently, a nasogastric tube equipped with various sensors was placed in the simulated stomach, and syringe sampling and online analysis were performed every 8 hours. Multiple sets of measurements were performed during this period, and the simulated stomach solution was randomly replaced with standard artificial gastric fluid at pH values ​​of 0.5, 3.0, and 7.0 to simulate common GERD diagnostic scenarios, including those in patients with acid reflux, healthy individuals, and those with abnormal gastric fluid.

[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 properly placed. However, in the second round of testing, the two differed significantly: Figure 6 As shown, after several hours, the glass bulb pH begins to show a large measurement error from the true value, and the error tends to gradually increase until its pH resolution accuracy decreases to a level similar to that of pH test paper. In contrast, the CBFc electrode is able to continuously and accurately measure the pH level of the sampled liquid, and the measurement accuracy does not change over time. It has been observed that due to the high viscosity of artificial gastric fluid, it is easy to evaporate from the sensor probe after the liquid sample is collected and pushed back, resulting in a significant change in the sensor probe interface state. Glass bubble electrodes are more sensitive to such problems and can cause problems such as response instability. However, due to the use of a calibration-free analysis method, the sensing results of the CBFc electrode are not affected by general changes in the electrode surface state, and therefore have more ideal online continuous working performance.

Claims

1. A pH sensitive electrode for a nasogastric tube online precision pH sensor, characterized in that Prepared by the following method: (1) Dissolve 2,4-diamino-N,N-dimethylaniline in DMF-methanol solution; (2) dissolving 1-chloro-2-hydroxynaphthalene in a DMF-methanol solution, adding Zn and trifluoromethanesulfonic acid, and then adding the mixed solution obtained in step (1) under stirring, and reacting under an inert atmosphere to obtain product (I); (3) preparing a DMF mixed solution of product (I), adding a weak base salt solution thereto under stirring, and adding a DMF solution of benzoyl peroxide after stirring under an inert atmosphere to complete the cyclization reaction to obtain product (II); (4) Product (II) is dissolved in an acidic acetonitrile solution, 4-butyl ether pyridine is added, and a purple-red solution is obtained by reaction. After removing the solvent, product (III) is obtained; (5) dissolving the product (III) in DMSO containing imidazole and hexafluorophosphate, adding a DMSO solution containing lauroyl peroxide and mixing evenly, immersing the base electrode in the reaction solution, reacting under an inert atmosphere, taking out the base electrode, immersing it in a DMSO solution, and continuing the reaction in the dark to obtain a pH sensitive electrode; or (6) The product (III) is dissolved in a DMSO mixed solution containing 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl free radical, imidazole and hexafluorophosphoric acid to obtain a reaction solution, and then the base electrode is used as a working electrode to form a three-electrode system with a counter electrode and a reference electrode. The system is immersed in an inert atmosphere in the reaction solution, and a constant voltage is applied to the three-electrode system to obtain a pH-sensitive electrode.

2. The pH sensitive electrode according to claim 1, wherein: The volume ratio of DMF to methanol in the DMF-methanol solution in step (1) and step (2) is 7:1-6; The concentration of the 2,4-diamino-N,N-dimethylaniline in the DMF-methanol solution in step (1) is 60-150 mM.

3. The pH sensitive electrode according to claim 1, wherein: The concentration of the 1-chloro-2-hydroxynaphthalene in the DMF-methanol solution in step (2) is 30-80 mM; The mass volume ratio of the 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, wherein: The concentration of the product (I) in DMF in step (3) is 10-40 mM; the concentration of the weak alkaline salt solution in step (3) is 10-40 mM; the concentration of the benzoyl peroxide DMF solution is 25-75 mM; The volume ratio of the DMF, weak alkaline salt solution and benzoyl peroxide DMF solution is 100-150 mL: 200-400 μL: 180 μL.

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

6. The pH sensitive electrode according to claim 1, characterized in that: The mass volume ratio of the product (III) in step (6) to DMSO is 1 g: 10-40 mL; The concentrations of the 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl free radical, imidazole and hexafluorophosphate in DMSO in step (6) 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° 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 in step (5) for the two reactions is 70-110° C., the reaction time for the first reaction is 5-20 min, and the reaction time for the second reaction is 12-36 h; The base electrode in step (5) and step (6) is at least one of pure metal, alloy, carbon material, special diamond, conductive glass, special ceramic, semiconductor material, special polymer, and nanomaterial.

8. Use of the pH sensitive electrode according to any one of claims 1 to 7 in online detection of gastric juice.

9. A method for online detection of gastric juice using a pH sensitive electrode according to any one of claims 1 to 7, characterized in that include: The pH of the pH standard buffer solution is detected using an electrode system including a pH sensitive electrode and a pH insensitive electrode; The pH indicator parameter au obtained by voltammetry is defined as Among them E f is the peak potential, HWHM is the half-width at half maximum potential, ΔI1 and ΔI2 are the peak current intensities corresponding to the pH sensitive electrode and pH non-sensitive electrode respectively, and a is the electrode constant; A regression curve was generated based on the relationship between the au value and the pH value of the standard buffer solution; The electrode system composed of the same pH sensitive electrode and pH insensitive electrode is used to detect the gastric fluid to be tested at the sampling end of the nasogastric tube, and the pH value is measured according to the regression curve; The current and potential signals generated by the pH sensitive electrode will respond to changes in the pH to be measured; The current and potential signals generated by the pH insensitive electrode do not respond to changes in pH.

10. The method according to claim 9, characterized in that: The base electrode of the pH-insensitive electrode is one of pure metal, alloy, carbon material, special diamond, conductive glass, special ceramic, semiconductor material, special polymer, nanomaterial, or a composite material composed of more than one of them; the functional material of the pH-insensitive electrode includes but is not limited to at least one of pure metal, alloy, carbon material, metal chelate and its derivatives, benzene-based substances and its derivatives, heterocyclic aromatic hydrocarbons and their derivatives, and electrochemically active biological molecules and their derivatives.

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