Implantable flexible pH sensor capable of continuously monitoring and preparation method thereof

Abstract

The invention provides an implantable flexible pH sensor capable of continuous monitoring and a preparation method thereof, the implantable flexible pH sensor comprises a flexible substrate support, and a pH sensitive electrode and a pH reference electrode are arranged on the flexible substrate support. The pH sensitive electrode adopts polyaniline as a sensitive material and is synthesized through an electrochemical deposition method, so that the sensitivity to pH change is improved. The PEDOT: PSS polymer conductive material is used for modifying the electrode, so that the conductivity and the stability are enhanced. Furthermore, the silver / silver chloride modified reference electrode provides stable reference potential, and the measurement precision is ensured. The sensor can be manufactured by adopting a photoetching technology, high precision and high reliability are realized, the sensor is particularly suitable for continuous monitoring of the pH value in tumor cells, the problem of signal drift in long-term monitoring of a traditional sensor in the cells is solved, and the efficiency of tumor metabolism research and drug screening is improved.

Description

Technical Field

[0001] The invention relates to a sensor, in particular to an implantable flexible pH sensor capable of continuous monitoring and a preparation method thereof. Background Art

[0002] Flexible pH sensor is a sensor that can detect the acidity or alkalinity of a solution or medium. Due to its good flexibility, it can adapt to application scenarios of different shapes and surfaces. This sensor is commonly used in biomedicine, food industry, environmental monitoring and other fields, especially for the detection of pH values ​​on curved or irregular surfaces. The serpentine structure has high flexibility and tensile properties, good deformation and recovery capabilities, low bending stiffness and high durability. It can effectively absorb energy and buffer, evenly distribute stress, and maintain stable mechanical properties at different temperatures. In implantable medical devices and wearable health monitoring devices, the serpentine structure can provide the necessary flexibility and comfort while ensuring reliability.

[0003] Among the existing tumor metabolism detection methods, the detection kit method is not suitable for the measurement of a large number of samples due to the complex operation process. At the same time, the samples tested are taken from the external environment of the tumor and there are certain differences between the internal microenvironment of the tumor; the energy metabolism analyzer can achieve a certain degree of continuous measurement, but its measurement cost is relatively high and it also detects the external environment of the tumor; for electrochemical detection based on enzymatic reactions, it can well realize the measurement during cell culture, but the generation of its signal is heavily dependent on the activity of the enzyme and is easily interfered by hydrogen peroxide from other sources. At the same time, the measurement point is also located in the external environment of the tumor. Therefore, the above detection methods are not suitable.

[0004] It should be noted that the information disclosed in the above background technology section is only used for understanding the background of the present application, and therefore may include information that does not constitute prior art known to ordinary technicians in the field. Summary of the invention

[0005] The main purpose of the present invention is to solve the problems existing in the above-mentioned background technology and to provide an implantable flexible pH sensor capable of continuous monitoring and a preparation method thereof.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] An implantable flexible pH sensor capable of continuous monitoring, comprising:

[0008] A flexible substrate for providing structural support for the sensor;

[0009] A pH sensitive electrode, comprising a conductive layer and polyaniline deposited on the conductive layer, wherein the polyaniline is used to improve sensitivity to changes in pH value;

[0010] A pH reference electrode, used in conjunction with the pH sensitive electrode, to provide a stable reference potential;

[0011] PEDOT:PSS polymer conductive material modification is used to enhance the conductivity and stability of the pH sensitive electrode and / or the pH reference electrode;

[0012] Wherein, the pH sensitive electrode and the pH reference electrode are both arranged on the flexible substrate to realize continuous monitoring of the pH value.

[0013] Furthermore, the conductive layer includes a material that does not react with the electrolyte and an insoluble and easily electrolytic material, the material that does not react with the electrolyte serves as a growth substrate for polyaniline, and the insoluble and easily electrolytic material is oxidized after voltage is applied to provide cations for polyaniline.

[0014] Furthermore, the material that does not react with the electrolyte includes carbon, FTO, platinum and gold, and the insoluble and easily electrolytic material includes one or more of silver, aluminum, iron, tungsten, zinc and calcium.

[0015] Furthermore, the mass ratio of the material that does not react with the electrolyte to the insoluble and easily electrolyzed material is 3 to 20:1.

[0016] Furthermore, the pH reference electrode is a silver / silver chloride, mercurous sulfate, calomel electrode, mercury / mercuric oxide, or copper / copper sulfate electrode.

[0017] Furthermore, the pH sensitive electrode and the pH reference electrode have a serpentine structure.

[0018] A method for preparing the implantable flexible pH sensor capable of continuous monitoring comprises the following steps:

[0019] preparing a flexible substrate;

[0020] forming a conductive layer of a pH sensitive electrode on the flexible substrate;

[0021] Depositing polyaniline on the conductive layer by electrochemical deposition to form a pH sensitive electrode;

[0022] forming a pH reference electrode at an appropriate location on the flexible substrate;

[0023] Modifying the pH sensitive electrode and / or the pH reference electrode with a PEDOT:PSS polymer conductive material;

[0024] Preferably, the electrochemical deposition method comprises applying a voltage in an electrolyte containing aniline monomer and an acid to promote polymerization of polyaniline on the conductive layer;

[0025] Preferably, the PEDOT:PSS modification step comprises immersing the electrode in a solution containing EDOT and PSS, and depositing PEDOT:PSS on the electrode surface by cyclic voltammetry.

[0026] Furthermore, the acid is any one of sulfuric acid, hydrochloric acid, phosphoric acid, oxalic acid, dodecylbenzenesulfonic acid, and salicylic acid; preferably, the content of the hydrochloric acid is 1-1.5 mol / L, and the content of the aniline is 0.1-0.7 mol / L.

[0027] Furthermore, the method also includes using an auxiliary electrode to form an electrochemical cell together with a pH sensitive electrode and a pH reference electrode during the electrochemical deposition of polyaniline and / or in the PEDOT:PSS polymer conductive material modification step to control the voltage applied between the auxiliary electrode and the pH sensitive electrode, wherein the material of the auxiliary electrode is selected from any one of platinum, nickel, tungsten, lead or glassy carbon.

[0028] Furthermore, the electrode preparation process includes:

[0029] A sacrificial layer is deposited on the surface of a polished and crystallized silicon wafer substrate; a photoresist is then spin-coated on the surface of the silicon wafer substrate to obtain a protective layer base; a lift-off process is used to obtain a sandwich structure of a photoresist protective layer-a metal wire layer-a photoresist protective layer, and then the photolithographic structure is separated from the silicon wafer substrate to obtain an electrode, so as to further form the pH sensitive electrode and the pH reference electrode.

[0030] In one embodiment, an electrolyte solution containing acid and aniline is prepared, and a polyaniline composite material is prepared by cyclic voltammetry using a working electrode in combination with a reference electrode and an auxiliary electrode, and then dried to obtain a pH sensitive electrode.

[0031] In one embodiment, the sacrificial layer material is a nickel layer, a copper layer, a silicon oxide layer, or a silicon nitride layer.

[0032] In one embodiment, the lift-off process is one of a double-layer glue process and a single-layer glue process.

[0033] In one embodiment, the conditions for preparing the polyaniline composite material using cyclic voltammetry are: a voltage range of -0.2-1 V, a scan rate of 0.1 V / s, and 40 scans.

[0034] In one embodiment, the drying is performed in an oven at 70-90°C.

[0035] In one embodiment, the pH reference electrode is combined with a conductive material to prepare a working electrode, with silver / silver chloride as the reference electrode and platinum wire as the auxiliary electrode, and the silver / silver chloride reference electrode is prepared by cyclic voltammetry in an acid-containing solution.

[0036] In one embodiment, when preparing the silver reference electrode, the acid-containing solution is a silver nitrate and potassium nitrate solution, the mass ratio of the silver nitrate to potassium nitrate is 0.005:1, and the conditions of the cyclic voltammetry are a voltage range of -0.9-0.9V, a scan rate of 0.1V / s, and 28 scans.

[0037] In one embodiment, when preparing the silver chloride reference electrode, the acid-containing solution is a potassium chloride and hydrochloric acid solution, the mass ratio of potassium chloride to hydrochloric acid is 0.1:0.01, and the conditions of the cyclic voltammetry are a voltage range of -0.3-0.9V, a scan rate of 0.05V / s, and 8 scans.

[0038] The present invention also provides an application of the above-mentioned implantable flexible pH sensor capable of continuous monitoring in a tumor tissue microenvironment.

[0039] The present invention also provides a flexible pH detection system, which comprises the flexible pH sensor and an external circuit.

[0040] The present invention also provides a pH sensing test paper, which is prepared based on the flexible pH sensor.

[0041] The present invention also provides an application of the flexible pH sensor in saliva pH detection to reflect oral health status and freshness detection of fresh food.

[0042] The present invention has the following beneficial effects:

[0043] The present invention proposes an implantable flexible pH sensor capable of continuous monitoring. A micro-flexible biosensor manufacturing process based on photolithography can be used to synthesize polyaniline on a pH-sensitive electrode by electrochemical deposition, thereby realizing a high-precision sensor and improving the performance and reliability of the sensor. The PEDOT:PSS polymer conductive material modified on the electrode improves the conductivity of the anode substrate, enhances the conductivity and stability of the sensor, makes it more suitable for long-term continuous monitoring, and is conducive to the deposition of polyaniline on the pH-sensitive electrode. The modified silver / silver chloride electrode is used as a reference electrode, has good stability and can be used for continuous monitoring. This sensor solution can realize continuous monitoring of pH in tumor cells, and has continuous monitoring stability and reliability.

[0044] The improved electrode material and stable reference electrode design of the present invention ensure long-term continuous and accurate measurement, and effectively solve the problem of signal drift in long-term intracellular monitoring of traditional sensors.

[0045] The flexible pH sensor of the present invention can be "implanted" in tumor cells and support the adhesion and growth of cells, realizing continuous real-time monitoring of pH changes inside tumor tissues, improving the efficiency of studying tumor metabolism and drug effects, and shortening the experimental cycle. When constructing in vivo / in vitro tumor models based on organ chip technology and mouse transplantation model methods and screening natural drugs for the Warburg effect of tumor metabolism, the implantable flexible pH sensor of the present invention is used to monitor the metabolic state of the tumor model under the action of drugs in real time, providing a new and powerful tool for tumor metabolism research and drug screening.

[0046] Other beneficial effects of the embodiments of the present invention will be further described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is a process flow chart of a flexible pH sensor according to an embodiment of the present invention;

[0048] Figure 2 This is a lift-off process flow chart of an embodiment of the present invention;

[0049] Figure 3 A serpentine unit structure diagram is selected for the sensor of the embodiment of the present invention;

[0050] Figure 4 A three-dimensional model diagram of a sensor according to an embodiment of the present invention.

[0051] Figure 5 4 is a diagram of a three-layer mask structure according to an embodiment of the present invention.

[0052] Figure 6 This is a diagram showing the repeatability test results of the pH sensitive electrode according to an embodiment of the present invention.

[0053] Figure 7 This is a graph showing the stability test results of the modified silver / silver chloride electrode according to an embodiment of the present invention. DETAILED DESCRIPTION

[0054] The following is a detailed description of the embodiments of the present invention. It should be emphasized that the following description is only exemplary and is not intended to limit the scope and application of the present invention.

[0055] It should be noted that when an element is referred to as being "fixed to" or "disposed on" another element, it can be directly on the other element or indirectly on the other element. When an element is referred to as being "connected to" another element, it can be directly connected to the other element or indirectly connected to the other element. In addition, connection can be used for fixing as well as for coupling or communication.

[0056] It should be understood that the orientation or position relationship indicated by terms such as "length", "width", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" are based on the orientation or position relationship shown in the accompanying drawings, and are only for the convenience of describing the embodiments of the present invention and simplifying the description, and do not indicate or imply that the referred device or element must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present invention.

[0057] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the embodiments of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0058] An embodiment of the present invention provides an implantable flexible pH sensor that can be continuously monitored, comprising: a flexible substrate for providing structural support for the sensor; a pH sensitive electrode, comprising a conductive layer and polyaniline deposited on the conductive layer, wherein the polyaniline is used to improve the sensitivity to changes in pH value; a pH reference electrode, used in conjunction with the pH sensitive electrode to provide a stable reference potential; PEDOT:PSS polymer conductive material modification, used to enhance the conductivity and stability of the pH sensitive electrode and / or the pH reference electrode; wherein the pH sensitive electrode and the pH reference electrode are both arranged on the flexible substrate to achieve continuous monitoring of the pH value.

[0059] In a preferred embodiment, the conductive layer includes a material that does not react with the electrolyte and an insoluble and easily electrolytic material. The material that does not react with the electrolyte serves as a growth substrate for polyaniline. The insoluble and easily electrolytic material is oxidized after voltage is applied to provide cations for polyaniline. Preferably, the material that does not react with the electrolyte includes carbon, FTO, platinum and gold, and the insoluble and easily electrolytic material includes one or more of silver, aluminum, iron, tungsten, zinc and calcium. Preferably, the mass ratio of the material that does not react with the electrolyte to the insoluble and easily electrolytic material is 3 to 20:1.

[0060] In some embodiments, the pH reference electrode can be a silver / silver chloride, mercurous sulfate, calomel electrode, mercury / mercuric oxide, or copper / copper sulfate electrode.

[0061] See also Figure 3 In a preferred embodiment, the electrode of the present invention has a serpentine structure. Selecting the serpentine structure as the basic unit of the sensor can prevent the sensor from being damaged by cell proliferation after being implanted into the cell.

[0062] An embodiment of the present invention also provides a method for preparing the implantable flexible pH sensor that can be continuously monitored, comprising the following steps: preparing a flexible substrate; forming a conductive layer of a pH sensitive electrode on the flexible substrate; depositing polyaniline on the conductive layer by electrochemical deposition to form a pH sensitive electrode; forming a pH reference electrode at an appropriate position on the flexible substrate; and modifying the pH sensitive electrode and / or the pH reference electrode with a PEDOT:PSS polymer conductive material.

[0063] In a preferred embodiment, the electrochemical deposition method comprises applying a voltage in an electrolyte containing aniline monomer and an acid to promote polymerization of polyaniline on the conductive layer.

[0064] In a preferred embodiment, the PEDOT:PSS modification step comprises immersing the electrode in a solution containing EDOT and PSS, and depositing PEDOT:PSS on the electrode surface by cyclic voltammetry.

[0065] In some embodiments, the acid is any one of sulfuric acid, hydrochloric acid, phosphoric acid, oxalic acid, dodecylbenzenesulfonic acid, and salicylic acid; preferably, the content of the hydrochloric acid is 1-1.5 mol / L, and the content of the aniline is 0.1-0.7 mol / L.

[0066] In some embodiments, the method further includes using an auxiliary electrode to form an electrochemical cell together with a pH sensitive electrode and a pH reference electrode during the electrochemical deposition of polyaniline and / or in the PEDOT:PSS polymer conductive material modification step to control the voltage applied between the auxiliary electrode and the pH sensitive electrode, wherein the material of the auxiliary electrode is selected from any one of platinum, nickel, tungsten, lead or glassy carbon.

[0067] In some embodiments, the preparation process of the electrode includes: depositing a sacrificial layer on the surface of a polished and crystallized silicon wafer substrate; then spin coating photoresist on the surface of the silicon wafer substrate to obtain a protective layer base; through a lift-off process, a sandwich structure of a photoresist protective layer-metal wire layer-photoresist protective layer is obtained, and then the photolithography structure is separated from the silicon wafer substrate to obtain an electrode, so as to further form the pH sensitive electrode and the pH reference electrode.

[0068] The specific embodiments of the present invention are further described below.

[0069] A method for preparing an implantable flexible pH sensor capable of continuous monitoring may specifically include the following steps:

[0070] 1. Preparation of sacrificial layer

[0071] A layer of silicon nitride material with a thickness of 500nm is deposited on the surface of the polished and crystallized silicon wafer substrate as a sacrificial layer, while ensuring good adhesion between the silicon wafer substrate and the photoresist.

[0072] 2. Network substrate preparation

[0073] Example 1

[0074] Use SU-82002 photoresist, apply 8mL (1mL / inch) of glue on the silicon wafer, set the parameters of the glue machine to rotate from 100rpm / s to 500rpm / s for 5-10s, and from 300rpm / s to 3000rpm for 30s; pre-bake at 65℃ and 95℃ for 2min / pre-bake at 95℃ for 1min; use 365nm wavelength ultraviolet light for exposure, and the energy density is 200mJ / cm^2 (60-80mJ / cm^2); then post-bake at 65℃ and 95℃ for 2min / post-bake at 95℃ for 2min; use developer for 1min after post-bake; after development, hard bake at 180℃ for 40min / bake at 150℃-250℃ for 5-30min.

[0075] Example 2

[0076] Use SU-82025 photoresist, apply 2mL (1mL / inch) of glue on the silicon wafer, set the parameters of the glue machine to rotate from 100rpm / s to 500rpm / s for 5-10s, and from 300rpm / s to 4000rpm for 30s; pre-bake at 65℃ for 0-3min and at 95℃ for 5-6min (after cooling to room temperature); use 365nm wavelength ultraviolet light with an energy density of 200mJ / cm^2 (150-160mJ / cm^2) for exposure, and expose for 5-15s; then post-bake at 65℃ and 95℃ for 2min / post-bake at 95℃ for 2min; use developer for 1min after post-bake; after development, hard bake at 180℃ for 40min / bake at 150℃-250℃ for 5-30min.

[0077] 3. Metal wire deposition

[0078] Example 1

[0079] First, select LOR3A photoresist, set the parameters of the photoresist spreader to 3000rpm spinning, and bake at 180℃ for 5min; then select S1805 photoresist, set the parameters of the photoresist spreader to 3000rpm spinning, and bake at 115℃ for 5min; use 405nm ultraviolet light for exposure, with an energy density of 40mJ / cm^2; use developer CD-26 for development for 70s; deposit a chromium layer with a thickness of 20nm; deposit a gold layer with a thickness of 80nm, and one or more materials selected from silver, aluminum, iron, tungsten, zinc and calcium can be added; finally, treat overnight in the debonding agent PG.

[0080] Example 2

[0081] The substrate is cleaned with deionized water and blown dry; an appropriate amount of AZ5214E ​​photoresist is selected and added to the silicon wafer, the parameters of the photoresist spreader are set to 3000rpm spinning, and the pre-bake parameters are set to 90℃-100℃ for 60s; 405nm ultraviolet light is selected for exposure, and the energy density is 90mJ / cm^2 (exposure dose is 84mJ / cm^2 when the thickness is 1.25μm); AZ300MIF is used for room temperature development for 30-60s; the post-bake parameters are set to 120℃ for 120s; a deposited chromium layer with a thickness of 20nm is obtained; a gold layer with a thickness of 80nm is deposited, and one or more materials selected from silver, aluminum, iron, tungsten, zinc and calcium can be added; finally, the photoresist is stripped in AZ stripping solution.

[0082] 4. Network base packaging

[0083] Select SU-82002 photoresist, apply 8mL (1mL / inch) of glue on the silicon wafer, set the parameters of the glue spreader to rotate from 100rpm / s to 500rpm / s for 5-10s, and from 300rpm / s to 3000rpm for 30s; then perform pre-baking, with the parameters set to pre-bake at 65℃ and 95℃ for 2min / pre-bake at 95℃ for 1min; select 365nm wavelength ultraviolet light for exposure, with an energy density of 200mJ / cm^2 (60-80mJ / cm^2); post-bake parameters set to post-bake at 65℃ and 95℃ for 2min / post-bake at 95℃ for 2min; then use developer for treatment for 1min; finally, hard bake at 180℃ for 40min / bake at 50℃-250℃ for 5-30min.

[0084] 5. Electrode modification

[0085] (1) Preparation of sensitive electrode—polyaniline deposition

[0086] The electrode to be modified was immersed in a mixed solution of 0.1M aniline (ANI) and 1M HCl, with a platinum electrode as the auxiliary electrode and an Ag / AgCl electrode as the reference electrode. The polyaniline composite material was deposited by cyclic voltammetry in a salt bridge (saturated potassium chloride solution), with the voltage range set to -0.2V to 1.0V, the scan rate to 0.1V / s, 40 scans, and dried overnight.

[0087] (2) Reference electrode preparation—Ag / AgCl deposition

[0088] The gold electrode to be modified was placed in a mixed aqueous solution of 5mM AgNO3 and 1M KNO3. Relative to the Ag electrode, the cyclic voltammetry parameters were set to a scan rate of 0.1V / s from -0.9V to 0.9V for 28 segments; then the electrode to be modified was immersed in a mixed aqueous solution of 0.1M KCl and 0.01M HCl. The cyclic voltammetry parameters were set to a voltage range of -0.15V to 1.05V, and a scan rate of 0.05V / s for 8 segments.

[0089] (3) Improved conductivity—PEDOT:PSS deposition

[0090] Example 1

[0091] Add 5 mg / mL PSS to 50 mL of deionized water, then add 0.01 MEDOT, stir evenly for 2 hours, and use cyclic voltammetry to perform 50 cycles in the voltage range of -1.0 V to 1.0 V at a scan rate of 1 V / s in phosphate buffered saline (PBS) to clean the electrode. Then use a platinum electrode as the auxiliary electrode and an Ag / AgCl electrode as the reference electrode at a current density of 0.4 mA / cm2 for 10 minutes.

[0092] Example 2

[0093] 0.02MPSS and 0.01MEDOT were added to deionized water and stirred evenly for 2 hours. Cyclic voltammetry was used to perform 50 cycles in the voltage range of -1.0V to 1.0V at a scan rate of 1V / s in phosphate buffered saline (PBS) to clean the electrode. Then, a platinum electrode was used as the auxiliary electrode and an Ag / AgCl electrode was used as the reference electrode. The current density was 0.5mA / cm2 for 10 minutes.

[0094] Experimental testing

[0095] The pH sensor prepared in the above example was tested for repeatability and stability.

[0096] In order to further test the repeatability of the pH sensitive electrode, the potential difference between the modified electrode and the reference electrode was measured once a day at pH 5.5 and 7.4 for two days, and two sets of potential differences between the modified electrode and the reference electrode at pH 5.5 and pH 7.4 were measured. The repeatability test results are shown in Figure 2. Figure 6 shown.

[0097] The measured potential difference of the modified electrode was 88.3 mV at pH = 5.5 and -14.3 mV at pH = 7.4. The relative standard deviations (RSDs) of the two sets of data were 0.54% and 7.48%, respectively. The results showed that the modified electrode had good repeatability.

[0098] In order to verify the stability of the modified silver / silver chloride electrode potential, the standard silver / silver chloride electrode was used as the reference electrode and the modified silver / silver chloride electrode was used as the working electrode. The potential difference between the modified electrode and the standard silver / silver chloride electrode under different conditions was measured. First, the potential difference under pH = 7.4 was measured on the first day, and then the potential difference under pH = 5.5 and pH = 7.4 was measured on the second day. The stability test results are shown in Figure 2. Figure 7 shown.

[0099] The test results show that the change of the modified silver / silver chloride electrode potential with time is basically less than 1mV, and the change with pH is also basically less than 1mV. When the modified silver / silver chloride electrode is used as a reference electrode, the floating potential will cause a deviation in the measured potential. The potential deviation ΔE=1mV is roughly selected from the experimental results, and the pH measurement error caused is calculated to be about 0.017, which has a small impact. Therefore, it can be considered that the modified silver / silver chloride electrode potential has a certain stability and can be used as a reference electrode.

[0100] The above content is a further detailed description of the present invention in combination with specific / preferred embodiments, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, without departing from the concept of the present invention, it can also make several substitutions or modifications to these described embodiments, and these substitutions or modifications should be regarded as belonging to the protection scope of the present invention. In the description of this specification, the description of the reference terms "an embodiment", "some embodiments", "preferred embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in combination with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily target the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In the absence of mutual contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples. Although the embodiments of the present invention and their advantages have been described in detail, it should be understood that various changes, substitutions and modifications can be made herein without departing from the scope of protection of the patent application.

Claims

1. An implantable flexible pH sensor for continuous monitoring, It is characterized in that include: A flexible substrate for providing structural support for the sensor; A pH sensitive electrode, comprising a conductive layer and polyaniline deposited on the conductive layer, wherein the polyaniline is used to improve sensitivity to changes in pH value; A pH reference electrode, used in conjunction with the pH sensitive electrode, to provide a stable reference potential; PEDOT:PSS polymer conductive material modification is used to enhance the conductivity and stability of the pH sensitive electrode and / or the pH reference electrode; Wherein, the pH sensitive electrode and the pH reference electrode are both arranged on the flexible substrate to realize continuous monitoring of the pH value.

2. The continuously monitorable implantable flexible pH sensor according to claim 1, It is characterized in that The conductive layer includes a material that does not react with the electrolyte and an insoluble and easily electrolytic material. The material that does not react with the electrolyte serves as a growth substrate for polyaniline. The insoluble and easily electrolytic material is oxidized after voltage is applied to provide cations for polyaniline.

3. The continuously monitorable implantable flexible pH sensor according to claim 2, It is characterized in that The material that does not react with the electrolyte includes carbon, FTO, platinum and gold, and the insoluble and easily electrolytic material includes one or more of silver, aluminum, iron, tungsten, zinc and calcium.

4. The continuously monitorable implantable flexible pH sensor according to any one of claims 2 to 3, It is characterized in that The mass ratio of the material that does not react with the electrolyte to the insoluble and easily electrolyzed material is 3 to 20:

1.

5. The continuously monitorable implantable flexible pH sensor according to any one of claims 1 to 4, It is characterized in that The pH reference electrode is a silver / silver chloride, mercurous sulfate, calomel electrode, mercury / mercuric oxide, or copper / copper sulfate electrode.

6. The continuously monitorable implantable flexible pH sensor according to any one of claims 1 to 5, It is characterized in that The pH sensitive electrode and the pH reference electrode have a serpentine structure.

7. A method for preparing a continuously monitored implantable flexible pH sensor according to any one of claims 1 to 6, It is characterized in that The following steps are involved: preparing a flexible substrate; forming a conductive layer of a pH sensitive electrode on the flexible substrate; Depositing polyaniline on the conductive layer by electrochemical deposition to form a pH sensitive electrode; forming a pH reference electrode at an appropriate location on the flexible substrate; Modifying the pH sensitive electrode and / or the pH reference electrode with a PEDOT:PSS polymer conductive material; Preferably, the electrochemical deposition method comprises applying a voltage in an electrolyte containing aniline monomer and an acid to promote polymerization of polyaniline on the conductive layer; Preferably, the PEDOT:PSS modification step comprises immersing the electrode in a solution containing EDOT and PSS, and depositing PEDOT:PSS on the electrode surface by cyclic voltammetry.

8. The method for preparing the implantable flexible pH sensor capable of continuous monitoring according to claim 7, It is characterized in that The acid is any one of sulfuric acid, hydrochloric acid, phosphoric acid, oxalic acid, dodecylbenzenesulfonic acid and salicylic acid; preferably, the content of the hydrochloric acid is 1-1.5 mol / L, and the content of the aniline is 0.1-0.7 mol / L.

9. A method for preparing a continuously monitored implantable flexible pH sensor according to claim 7 or 8, It is characterized in that The method also includes using an auxiliary electrode to form an electrochemical cell together with a pH sensitive electrode and a pH reference electrode during the electrochemical deposition of polyaniline and / or in the PEDOT:PSS polymer conductive material modification step to control the voltage applied between the auxiliary electrode and the pH sensitive electrode, wherein the material of the auxiliary electrode is selected from any one of platinum, nickel, tungsten, lead or glassy carbon.

10. A method for preparing a continuously monitored implantable flexible pH sensor according to any one of claims 7 to 9, It is characterized in that The electrode preparation process includes: A sacrificial layer is deposited on the surface of a polished and crystallized silicon wafer substrate; a photoresist is then spin-coated on the surface of the silicon wafer substrate to obtain a protective layer base; a lift-off process is used to obtain a sandwich structure of a photoresist protective layer-a metal wire layer-a photoresist protective layer, and then the photolithographic structure is separated from the silicon wafer substrate to obtain an electrode, so as to further form the pH sensitive electrode and the pH reference electrode.

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