CN113616200B

CN113616200B - Wireless capsule sensing device and method for gastrointestinal tract pH value detection

Info

Publication number: CN113616200B
Application number: CN202111067896.1A
Authority: CN
Inventors: 刘清君; 程晨; 吴越; 卢妍利; 张芬妮; 安子建
Original assignee: Zhejiang University ZJU
Current assignee: Zhejiang University ZJU
Priority date: 2021-09-13
Filing date: 2021-09-13
Publication date: 2022-09-20
Anticipated expiration: 2041-09-13
Also published as: CN113616200A

Abstract

The invention discloses a wireless capsule sensing device and a wireless capsule sensing method for gastrointestinal tract pH value detection. The apparatus includes an ingestible capsule including a capsule structure, a capsule detection circuit, and a pH sensor; the pH sensor is used for generating chemical reaction with hydrogen ions for detecting the gastrointestinal tract environment and outputting a response voltage capable of reflecting the pH value; the capsule detection circuit is electrically connected with the pH sensor and used for reading the response voltage and converting the response voltage into a digital signal; the capsule structure comprises a sensor chamber for mounting a pH sensor and a circuit chamber for mounting a capsule detection circuit, the sensor chamber is provided with a grid for liquid to pass through; and the in-vitro receiving end is wirelessly connected with the capsule detection circuit and is used for receiving the digital signal. The problem that the pH value of the gastrointestinal tract is difficult to detect in a clinical non-anesthesia state is solved, and the method has the advantages of convenience, real time, ingestion and noninvasive sensing detection.

Description

Wireless capsule sensing device and method for gastrointestinal tract pH value detection

Technical Field

The application relates to an electrochemical detection technology, in particular to a wireless capsule sensing device and a wireless capsule sensing method for gastrointestinal tract pH value detection.

Background

The pH of the gastrointestinal tract is a very important physiological indicator, and many gastrointestinal diseases may involve changes in pH, such as gastric ulcer, duodenal ulcer, dyspepsia, gastroesophageal reflux disease (GERD), crohn's colitis, ulcerative colitis (IBD), and the like. Therefore, in clinical practice, repeated measurements of the pH of the gastrointestinal tract of a patient are often required. Currently, intubation of the gastrointestinal tract with a pH probe is a common means of clinical measurement of pH. Endoscopic biopsy of the digestive tract is also performed to detect pH in vitro, if necessary. Such procedures often require anesthesia to the patient, can be painful to the patient, and risk complications with cardiopulmonary disease.

Disclosure of Invention

In view of this, the embodiments of the present application provide a wireless capsule sensing device and method for gastrointestinal tract pH detection, so as to solve the problem that it is difficult to detect the gastrointestinal tract pH in a clinical non-anesthetic state.

According to a first aspect of embodiments of the present application, there is provided a wireless capsule sensing device (hereinafter referred to as a capsule device) for gastrointestinal tract pH detection, comprising:

an ingestible capsule comprising a capsule structure, a capsule detection circuit, and a pH sensor;

the pH sensor is used for generating chemical reaction with hydrogen ions for detecting the gastrointestinal tract environment and outputting a response voltage capable of reflecting the pH value;

the capsule detection circuit is electrically connected with the pH sensor and used for reading the response voltage and converting the response voltage into a digital signal;

the capsule structure comprises a sensor chamber for mounting the pH sensor and a circuit chamber for mounting the capsule detection circuit, the sensor chamber having a grid thereon for passage of liquid;

and the external receiving end is wirelessly connected with the capsule detection circuit and is used for receiving the digital signal.

Further, the receiving end is one or more of a smart phone, a personal computer and a capsule auxiliary circuit.

Furthermore, the external receiving end is provided with upper computer application software which is used for receiving and processing the digital signals from the wireless capsule and displaying the digital signals in real time.

Further, before the gastrointestinal tract pH value detection, the whole capsule structure surface needs to be subjected to biocompatibility treatment.

Further, the biocompatibility treatment method of the capsule structure comprises the following steps:

coating a layer of ethyl cellulose film on the grid gaps;

and coating a layer of Polydimethylsiloxane (PDMS) glue on the outer surface of the capsule structure except the grid, and naturally drying the glue to complete biocompatibility treatment.

Furthermore, the capsule detection circuit is manufactured by adopting a rigid-flexible composite printed circuit board process and comprises a first rigid substrate, a second rigid substrate, a third rigid substrate, a fourth rigid substrate, a fifth rigid substrate, a first flexible substrate, a second flexible substrate, a third flexible substrate and a fourth flexible substrate; wherein

A first wireless communication module and a battery are arranged on the first rigid substrate;

a first power management module is arranged on the second rigid substrate and used for improving the power output of the battery;

a singlechip minimum system and a digital/analog conversion module are arranged on the third rigid substrate;

a constant potential meter circuit and an analog/digital conversion module are arranged on the fourth rigid substrate;

a second connector is arranged on the fifth rigid substrate and connected with the pH sensor;

the second connector is electrically connected with the potentiostat circuit through a fourth flexible substrate, the potentiostat circuit is electrically connected with the analog/digital conversion module on a fourth rigid substrate through a copper foil lead, the potentiostat is electrically connected with the digital/analog conversion module through a third flexible substrate, the minimum single-chip microcomputer system is electrically connected with the digital/analog conversion module on a third rigid substrate through a copper foil lead, the minimum single-chip microcomputer system is electrically connected with the analog/digital conversion module through a third flexible substrate, the minimum single-chip microcomputer system and the first wireless communication module are electrically connected with the first flexible substrate through copper foil leads on the second flexible substrate and the second rigid substrate, the battery is electrically connected with the first power management module through the first flexible substrate, and then the battery and the first power management module are electrically connected with the first wireless communication module, The minimum system of the single chip microcomputer, the digital/analog conversion module, the constant potential meter circuit and the analog/digital conversion module are electrically connected.

Further, the pH sensor includes:

a first substrate; and a counter electrode, a working electrode and a reference electrode disposed on the first substrate surface.

Further, the working electrode is divided into two layers, namely a carbon ink layer and an iridium oxide deposition layer.

Further, the capsule auxiliary circuit comprises a sixth rigid substrate, a second wireless communication module, a second power management module, an upper computer communication module and a third connector, wherein the sixth rigid substrate bears the second wireless communication module, the second power management module and the upper computer communication module;

the second wireless communication module and the upper computer communication module are electrically connected on the sixth rigid substrate through copper foil leads; the second power management module is electrically connected with the second wireless communication module and the upper computer communication module respectively;

the second wireless communication module is in half-duplex communication with the first wireless communication module of the capsule detection circuit to transmit control instructions and detection data.

According to a second aspect of the embodiments of the present application, there is provided a method for gastrointestinal tract pH detection, wherein the method is implemented in the apparatus of the first aspect, and comprises the following steps:

s1, preparing standard solutions with different pH values, sequentially carrying out open-circuit voltage-time detection in the standard solutions by using a plurality of pH sensors according to the rising/falling gradient of the pH values, and drawing a linear fitting curve of the pH sensors according to the open-circuit voltage-time detection;

s2, putting the ingestion type capsule into artificial saliva, artificial gastric juice, artificial small intestine juice and artificial colon juice respectively to carry out open circuit voltage-time detection, wherein the detection time accords with the digestion cycle of a human body;

s3, selecting artificial gastric juice and adjusting the pH to the gastric pH environment of the gastric ulcer patient, adding a hydrotalcite tablet to simulate the treatment process, detecting the pH change by using the ingestion capsule, and assisting a professional pH instrument to perform contrast;

s4, selecting artificial colon liquid, adjusting pH to colon pH environment of diarrhea patient, dripping acetic acid to simulate illness state recovery process, detecting pH change with ingestion capsule, and assisting professional pH instrument for comparison;

s5, feeding the ingestion capsule through the mouth of the animal to the gastrointestinal tract to detect pH when the animal is awake, and transmitting the detected pH parameter to a receiving end outside the body through wireless transmission.

The technical scheme provided by the embodiment of the application can have the following beneficial effects:

according to the embodiments, the pH sensor and the capsule detection circuit are miniaturized by adopting the screen printing electrode process and the rigid-flexible printed circuit board process, have the characteristics of flexibility and bending, and can be assembled in the capsule structure. The ingestion type capsule can be soaked in a liquid environment to stably measure the pH value for a long time, thereby being beneficial to solving the problem of detecting the pH value of the gastrointestinal tract in a clinical non-anesthesia state. Experiments on large animals prove that the ingestion capsule does not generate wound and needs no anesthesia during the measurement of the gastrointestinal tract. After the test is completed, the ingestible capsule may be recovered. The capsule detection circuit and the pH sensor can be reused after necessary treatment. Therefore, the device and the method for detecting the pH value of the gastrointestinal tract by using the capsule device can realize long-time stable detection of the pH value in the gastrointestinal tract.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and together with the description, serve to explain the principles of the application.

FIG. 1 is a system diagram of a wireless capsule device for gastrointestinal pH detection in an embodiment of the present invention;

FIG. 2 is an assembly view of an ingestible capsule in an embodiment of the present invention;

FIG. 3 is a block diagram of a capsule detection circuit in an embodiment of the invention;

FIG. 4 is a block diagram of a capsule auxiliary circuit in an embodiment of the present invention;

FIG. 5 is a diagram of a personal computer application software interface in an embodiment of the present invention;

FIG. 6 is a diagram of a smartphone application software interface in an embodiment of the invention;

FIG. 7 is a diagram of a pH sensor structure in an embodiment of the invention;

FIG. 8 is a flow chart of the operation of a wireless capsule device for gastrointestinal pH detection in an embodiment of the present invention;

fig. 9 is a graph showing the results of the sensitivity detection of the pH sensor from pH 0.95 to pH 9.00 in the example of the present invention;

fig. 10 is a graph showing the results of the sensitivity detection of the pH sensor from pH 9.00 to pH 0.95 in the example of the present invention;

FIG. 11 is a linear fit curve of a pH sensor in an embodiment of the invention;

FIG. 12 is an open circuit potential versus time test of a wireless capsule device for gastrointestinal pH detection in artificial saliva for 30 seconds in an embodiment of the invention;

FIG. 13 is an open circuit potential versus time detection of a wireless capsule device for gastrointestinal pH detection in an embodiment of the present invention in simulated gastric fluid for 6 hours;

FIG. 14 is an open circuit potential versus time detection graph of a wireless capsule device for gastrointestinal pH detection in artificial intestinal fluid for 8 hours according to an embodiment of the present invention;

FIG. 15 is a diagram of an open circuit potential versus time test for a wireless capsule device for gastrointestinal pH testing in artificial colon fluid for 16 hours according to an embodiment of the present invention;

FIG. 16 is a graph showing the results of a test of simulating gastric ulcer using a wireless capsule device for gastrointestinal pH measurement in accordance with an embodiment of the present invention;

FIG. 17 is a graph of the results of a test of simulated diarrhea using a wireless capsule device for gastrointestinal pH measurement in accordance with an embodiment of the present invention;

FIG. 18 is a graph of the results of a test in which a wireless capsule device for gastrointestinal pH detection is fed to a large animal while awake in an embodiment of the invention;

FIG. 19 is a line-fit curve of a sensitivity test of a pH sensor used in a wireless capsule device for gastrointestinal pH detection before and after being administered to a large animal while awake, in accordance with an embodiment of the present invention;

FIG. 20 is a graph of the results of a test conducted on a large animal's stomach under anesthesia with a wireless capsule device for gastrointestinal pH detection in accordance with an embodiment of the present invention;

FIG. 21 is a graph of the results of a test conducted on a large animal intestine under anesthesia with a wireless capsule device for gastrointestinal pH detection in accordance with an embodiment of the present invention.

In the figure: an ingestible capsule 0, a capsule structure 1, a capsule detection circuit 2, a pH sensor 3, upper computer application software 4, a capsule auxiliary circuit 5, a sensor chamber 11, a detection circuit chamber 12, a first rigid substrate 21, a first flexible substrate 22, a second rigid substrate 23, a second flexible substrate 24, a third rigid substrate 25, a third flexible substrate 26, a fourth rigid substrate 27, a fourth flexible substrate 28, a fifth rigid substrate 29, a first wireless communication module 211, a battery 212, a first connector 231, a first power management module 232, a one-chip microcomputer minimal system 251, a digital/analog conversion module 252, a potentiostat circuit 271, a digital/analog conversion module 272, a second connector 291, a first substrate 31, a counter electrode 32, a counter electrode lead 33, a working electrode 34, a working electrode lead 35, a reference electrode 36, a reference electrode lead 37, a sensor circuit 271, a digital/analog conversion module 272, a second connector 291, a first substrate 31, a counter electrode 32, a counter electrode lead 33, a working electrode 34, a working electrode lead 35, a reference electrode 36, a reference electrode lead 37, The carbon ink layer 341, the iridium oxide crystal deposition layer 342, the personal computer application software 41, the smart phone application software 42, the sixth rigid substrate 51, the second wireless communication module 52, the second power management module 53, the upper computer communication module 54, the capsule detection circuit debugging module 55, and the third connector 56.

Detailed Description

Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present application. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the present application, as detailed in the appended claims.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.

It is to be understood that although the terms first, second, third, etc. may be used herein to describe various information, such information should not be limited to these terms. These terms are only used to distinguish one type of information from another. For example, first information may also be referred to as second information, and similarly, second information may also be referred to as first information, without departing from the scope of the present application. The word "if," as used herein, may be interpreted as "at … …" or "when … …" or "in response to a determination," depending on the context.

As shown in fig. 1, an embodiment of the present invention provides a wireless capsule sensing device for gastrointestinal tract pH detection, including: the device comprises an ingestion type capsule 0 and an in-vitro receiving end, wherein the ingestion type capsule 0 comprises a capsule structure 1, a capsule detection circuit 2 and a pH sensor 3; the pH sensor 3 is used for generating chemical reaction with hydrogen ions for detecting the gastrointestinal tract environment and outputting a response voltage capable of reflecting the pH value; the capsule detection circuit 2 is electrically connected with the pH sensor 3 and used for reading the response voltage and converting the response voltage into a digital signal; the capsule structure 1 comprises a sensor chamber for mounting the pH sensor 3 and a circuit chamber for mounting the capsule detection circuit 2, the sensor chamber having a grid thereon for the passage of liquid; the in vitro receiving end is wirelessly connected with the capsule detection circuit and used for receiving the digital signal.

According to the embodiments, the present application adopts the design of the ingestion type capsule to realize the miniaturization of the sensor and the circuit, and the capsule is flexible and easy to bend, can be assembled in the capsule structure with a small volume, and can be soaked in a liquid environment to stably measure the pH value for a long time. Therefore, the problem that the pH value of the gastrointestinal tract is difficult to detect in a clinical non-anesthesia state is solved. The use of the ingestible capsule does not cause a wound during measurement in the gastrointestinal tract of large animals, and does not require anesthesia. After the test is completed, the ingestible capsule may be recovered. The capsule detection circuit and the pH sensor can be reused after necessary treatment. Therefore, the device and the method for detecting the pH value of the gastrointestinal tract by using the capsule device can realize long-time stable detection of the pH value in the gastrointestinal tract.

In this example, the capsule structure 1 is made by a 3D printing process using a photosensitive resin (DSM IMAGE 8000, imperial group, the netherlands) as material. As shown in fig. 2, the capsule structure 1 includes a sensor chamber 11 in which the pH sensor 3 can be loaded and a detection circuit chamber 12 in which the capsule detection circuit 2 can be loaded.

A layer of ethyl cellulose membrane is attached to the grid at the top of the sensor chamber 11 to prevent solid particles and biological macromolecules from entering the sensor chamber 11 and polluting the pH sensor 3.

The pH sensor 3 and the capsule detection circuit 2 may be assembled in the capsule structure 1 by bending and folding. After the assembly is completed, the sensor cavity 11 and the detection circuit cavity 12 may be connected by interference fit, and the connection gap is closed by a quick-drying glue (Ergo5011, Kisling, llc, switzerland). The other outer surface of the capsule structure 1 is coated with Polydimethylsiloxane (PDMS) glue except for the grid at the top of the sensor chamber 11 to achieve a biocompatible treatment.

As can be seen from the above embodiments, the present application, through the design of the capsule-shaped housing, enables the size and shape of the ingestible capsule 0 to conform to the gi tract without causing damage when passing through the strictures of the gi tract. Moreover, the ingestible capsule 0 is subjected to biocompatibility treatment, and the normal physiological activities of the gastrointestinal tract are not affected in the detection process.

As shown in fig. 3, in one possible implementation method, the capsule detection circuit 2 is manufactured by a rigid-flexible composite printed circuit board process, and includes a first rigid substrate 21, a first flexible substrate 22, a second rigid substrate 23, a second flexible substrate 24, a third rigid substrate 25, a third flexible substrate 26, a fourth rigid substrate 27, a fourth flexible substrate 28, and a fifth rigid substrate 29. Wherein the first rigid substrate 21 is connected to the second rigid substrate 23 through the first flexible substrate 22, the second rigid substrate 23 is connected to the third rigid substrate 24 through the second flexible substrate 24, the third rigid substrate 24 is connected to the fourth rigid substrate 26 through the third flexible substrate 25, and the fourth rigid substrate 26 is connected to the fifth rigid substrate 28 and the fourth flexible substrate 27.

Further, the first rigid substrate 21 is welded with a first wireless communication module 211 on the front side and a battery 212 on the back side; the second rigid substrate 23 is welded with a first connector 231 (optional, mainly used for debugging) on the front side, and welded with a first power management module 232 on the back side; the third rigid substrate 25 is welded with a singlechip minimum system 251 on the front side and a digital/analog conversion module 252 on the back side; the front surface of the fourth rigid substrate 27 is welded with a constant potential meter circuit 271, and the back surface is welded with an analog/digital conversion module 272; the fifth rigid substrate 29 is back-soldered with a second connector 291. The above-mentioned components can be electrically connected in order by copper foil wires embedded in a rigid substrate and a flexible substrate.

In a possible implementation method, the wireless communication module 211 welded to the front surface of the first rigid substrate 21 may be WH-BLE103 (south china, science and technology limited), the battery welded to the back surface may be a lithium ion battery (10mm × 10mm × 4mm, 30mAh), the first connector 231 welded to the front surface of the second rigid substrate 23 may be an FPC connector (10pin, 0.5mm pitch), and the resistor and capacitor associated with the first power management module 232 on the back surface may be a 0201 package type patch element; the minimum system 251 of the single chip microcomputer on the front surface of the third rigid substrate 25 can be selected from MSP430FR5959 (texas instruments, usa) as a microcontroller, the peripheral resistor capacitor can be selected from 0201 packaging type patch elements, the digital/analog conversion module 252 on the back surface can be selected from DAC8562 (texas instruments, usa) as a main control chip, and the peripheral resistor capacitor can be selected from 0201 packaging type patch elements; the potentiostat circuit 271 on the front surface of the fourth rigid substrate 27 may select four single-channel integrated operational amplifiers AD8605 (idenoro semiconductor corporation, usa) as main components, the peripheral resistive and capacitive elements may select 0201 package type patch elements, the analog/digital conversion module 272 on the back surface may select ADs1115 (texas instruments corporation, usa) as a main chip, and the peripheral resistive and capacitive elements may select 0201 package type patch elements; the second connector 291 on the back of the fifth rigid substrate 29 may be an FPC connector (8pin,1mm pitch).

According to the embodiment, the capsule detection circuit 2 is manufactured by adopting a rigid-flexible composite printed circuit board process, and circuit elements with small volume and low power consumption are selected, so that the whole capsule detection circuit 2 can be packaged in the capsule structure 1 in a small volume through bending and folding, and detection can be completed by depending on an internal power supply under the condition that the capsule detection circuit is taken into a gastrointestinal tract and energy cannot be obtained from the outside.

As shown in fig. 4, the capsule auxiliary circuit 5 is a substrate constituted by a sixth rigid substrate 51. A second wireless communication module 52, a second power management module 53, an upper computer communication module 54, a capsule detection circuit debugging module 55 (which is an optional module), and a third connector 56 are welded on the surface of the sixth rigid substrate 51, respectively. The above-mentioned individual modules can be electrically connected in order to each other by means of copper foil conductors embedded in the sixth rigid substrate 51.

In a possible implementation method, the second wireless communication module 52 employs a WH-BLE103 (china, science and technology ltd), and may be externally connected with a 2.4GHz planar directional antenna of 24DB, so as to improve the receiving sensitivity of the wireless signal; the second power management module 53 selects AMS1117 (austria microelectronics, austria), and the peripheral resistor and capacitor adopt 0805 packaged type chip elements; the upper computer communication module 54 provides a communication interface with an upper computer terminal (such as a personal computer) for the capsule auxiliary circuit 5 to realize real-time UART half-duplex communication; the capsule detection circuit debugging module 55 provides an embedded software debugging interface of the JTAG 14 packaging type, and after the third connector 56 is connected with the first connector 231 of the capsule detection circuit 2 through the FPC flexible flat cable, downloading and debugging services of an embedded program can be provided for the capsule detection circuit 2.

Known from the above-mentioned embodiment, capsule auxiliary circuit 5 of this application design both can provide power and embedded program download interface for capsule detection circuit 2 when capsule detection circuit 2 debugs, also can detect in intestines and stomach through bluetooth module when taking into formula capsule 0, communicates with it through bluetooth module, transmits out the reading of taking into formula capsule 0 in real time.

As shown in fig. 5 and 6, the upper computer application software 4 includes a personal computer application software 41 running on a Windows platform of a personal computer and a smartphone application software 42 running on an Android platform of a smartphone. In this embodiment, the upper computer software 4 mainly refers to a smart phone application software 42 running on an Android platform of a smart phone.

In one possible implementation method, the personal computer application software 41 running on the Windows platform of the personal computer is developed by using a Microsoft Visual Studio 2019 development tool, and the smartphone application software 42 running on the Android platform of the smartphone is developed by using an Android Studio v3.2 development tool.

According to the embodiment, the upper computer application software 4 designed by the application can analyze and process the received data when receiving the data transmitted by the ingestion type capsule 0, and displays the data in real time, so that the device and the method can be conveniently adjusted in the detection process.

In one possible implementation, as shown in fig. 7, the pH sensor 3 may be formed by a screen printing electrode process, using Polyethylene terephthalate (PET) as a substrate material, and printing carbon ink (C2030519P4, sun) on the surface of the substrate materialChemical limited, uk) to construct the counter electrode 32, the working electrode 34, a conductive silver paste (C2130809D5, solar chemical limited, uk) to construct the reference electrode 36, the counter electrode lead 33, the working electrode lead 35, the reference electrode lead 37. The counter electrode lead 33, the working electrode lead 35 and the reference electrode lead 37 can be electrically connected to the capsule detection circuit 2 through the second connector 291. Further, the pH sensor 3 was immersed in an iridium oxide precursor solution at an applied current density of 0.2mA/cm ² After constant current, an iridium oxide deposition layer 342 may be formed on the working electrode 34, over the carbon ink layer 341.

As can be seen from the above embodiments, the present application uses PET with better bending property as a substrate, so that the pH sensor 3 can be bent and folded to be placed in the capsule structure 1.

In one possible implementation, the working flow of the wireless capsule sensing device for gastrointestinal tract pH detection is shown in fig. 8. After the battery 212 is connected to the capsule detection circuit 2, the first power management module 232 adjusts the output of the battery to supply power to the whole capsule detection circuit 2. Meanwhile, the minimum system 251 of the single chip starts to work, a control instruction is sent, the digital/analog conversion module 252 provides reference electrode voltage for the constant potential meter circuit 271 to serve as a reference, hydrogen ions in a liquid environment generate electrochemical reaction on the pH sensor 3, response voltage generated by the reaction is transmitted to the constant potential meter circuit 271, the constant potential meter circuit is conditioned by signals and then transmitted to the analog/digital conversion module 272 for analog-to-digital conversion, and converted data are transmitted to the first wireless communication module 211 through the minimum system 251 of the single chip. The first wireless communication module 211 can communicate with an external device with a bluetooth module, such as a smart phone with a bluetooth module, a personal computer or a capsule auxiliary circuit 5.

Another object of the present invention is to provide a method for gastrointestinal tract pH detection using the capsule device, comprising the following steps:

s1, drawing a linear fit curve of the pH sensor 3:

dilution with concentrated hydrochloric acid (36.5 wt%) gave 30mL of a standard solution with pH 1. Buffer A (0.2M boric acid and 0.05M citric acid) and buffer B (0.1M Na3PO4) were mixed at different ratios to prepare 30mL of 8 standard solutions with pH values of 2, 3, 4, 5, 6, 7, 8, and 9, respectively. All the standard solutions used above were made to have a concentration of 0.1M by adding NaCl.

Taking five modified pH sensors 3, sequentially soaking the five modified pH sensors in a standard solution with the pH value from 9 to 1 to perform open-circuit potential-time detection method detection, and continuously testing each sensor for 60 seconds under the standard solution with each pH value; and soaking the same five pieces of pH sensors in a standard solution with the pH value from 1 to 9 to perform open-circuit potential-time detection, and continuously testing each piece of electrode for 60 seconds under the standard solution with each pH value. And a linear fit curve of the pH sensor 3 is drawn therefrom.

S2, detecting pH values in different artificial digestive fluids using a capsule device:

and (3) respectively soaking the assembled ingestion type capsule 0 in artificial saliva, artificial gastric juice, artificial small intestine juice and artificial colon juice to carry out open-circuit potential-time detection, wherein the detection time is determined according to the digestion cycle of a human body. The detection is carried out continuously in artificial saliva for 30 seconds, in artificial gastric juice for 6 hours, in artificial small intestine juice for 8 hours and in artificial colon juice for 16 hours.

S3, simulating the gastric ulcer treatment process, and detecting the change of the pH environment in the treatment process by using a capsule device:

taking 60mL of artificial gastric juice, determining the actual pH value of the artificial gastric juice by using a pH meter, adding dilute hydrochloric acid into the artificial gastric juice, and adjusting the pH value of the artificial gastric juice to 1.55 so as to simulate the gastric pH environment of a patient suffering from gastric ulcer. Meanwhile, the artificial gastric juice was measured by a pH meter and an ingestible capsule 0, and after 30 minutes, a dalxi magnesium carbonate tablet (0.5g, Bayer healthcare Co., Ltd., Germany) was put in and the measurement was continued for 30 minutes. And then stirring by using a magnetic stirrer, setting the rotating speed to be 200 revolutions per minute, and continuously detecting until the pH value of the artificial gastric juice is stable.

S4, simulating the diarrhea treatment process, and detecting the change of the pH environment in the treatment process by using a capsule device:

60mL of artificial colon solution was taken, the actual pH was determined using a pH meter, and Na3PO4 was added to the artificial colon solution to adjust the pH of the artificial colon solution to 9, in this way simulating the colonic pH environment of a patient with diarrhea. Meanwhile, the pH meter and the intake type capsule 0 are used for detecting the artificial colon liquid. After 30 minutes, 0.1M CH3COOH was slowly dropped into the artificial colon solution at a constant speed using a syringe, and the pH of the artificial colon solution was continuously measured. And stopping dripping CH3COOH after the pH value of the artificial colon liquid is reduced to 7.5, and continuing to detect for 20 minutes.

S5, detecting the pH value in the animal body by the capsule device in the waking state:

male beagle dogs weighing 15 kg and 12 months of age were used for in vivo evaluation. The beagle dogs were quarantined and observed for two weeks from the date of purchase, and given good care. All animal experimental procedures related to this experiment have been approved by the institutional animal care and ethics committee of traditional Chinese medicine university in Zhejiang (animal ethics approval No.: IACUC-20201103-04).

Beagle dogs were fasted for 48 hours before the start of the experiment and were fixed on a restraint frame after the end of the fasting period. The ingestible capsule 0 is administered orally to beagle dogs after being biocompatible. The 24DB 2.4GHz plate directional antenna is placed on the abdomen of the beagle dog and connected to the second wireless communication module 52 in the capsule auxiliary circuit 5, the capsule auxiliary circuit 5 is connected to the personal computer, and the reading of the ingested capsule 0 in the body is displayed on the personal computer application 41 in real time. After 10 minutes of continuous testing, the beagle dogs were lowered from the holding rack, allowed to move freely for 5 minutes, and again held on the holding rack and given 20mL of drinking water from the mouth. The test was continued for 15 minutes after the end of the water feeding. Finally, the beagle dog is returned to the rearing cage, and after the beagle dog naturally excretes the ingestion capsule 0, the shape of the feces excreted by the beagle dog is observed, and the ingestion capsule 0 is recovered. Wherein the capsule detection circuit 2 and the pH sensor 3 are reused after necessary processing. The pH sensor 3 performs an evaluation of electrochemical properties and compares with the relevant results before the in vivo evaluation.

S6, detecting the pH value of the gastrointestinal tract of the animal by the capsule device under the anesthesia state:

after ingestion of capsule 0 to be naturally excreted from the gastrointestinal tract of beagle dogs, beagle dogs were fasted for 12 hours. After the fasting period, beagle dogs were anesthetized with intravenous propofol (2 mg/kg). After the beagle had started anesthesia, a breathing tube was inserted into the trachea of the beagle and oxygen containing 1% isoflurane was inhaled. After the beagle dog is fully anesthetized and the vital signs are stabilized, the beagle dog is kept in a supine position, the hair on the upper part of the stomach and the colon is shaved off, and the naked part is disinfected by using 75% alcohol. The epidermis was incised with a scalpel, and the muscle tissue was incised with a high frequency electric knife. The stomach was then exposed, an incision approximately 2 cm long was made along the stomach wall, while the probe of the pH meter and the ingestible capsule 0 were immersed through the incision in the biological fluid of the stomach, continuously monitored for 15 minutes, and the stomach tissue was observed through the incision for the presence of lesions, such as bleeding, ulcers, cuts, etc. After the detection, the probe of the ingestion capsule 0 and the probe of the pH meter were removed and washed, and the gastric incision was closed. The pH of the transverse colon of beagle dogs was then measured in a similar manner.

The present invention is described in further detail below by way of examples.

The embodiment is as follows:

s1, drawing a linear fit curve of pH sensor 3:

fig. 9 and 10 show open circuit voltage-time response curves of the pH sensor 3 in the standard solution in which the pH is sequentially increased and decreased, respectively. It can be seen from the figure that the sensor exhibited a good gradient in both cases, the potential response difference in the standard solutions of adjacent pH was substantially the same, and the potential response of pH sensor 3 remained stable with a maximum potential drift of 0.93mV in the continuous 60 second open circuit voltage-time measurements. Fig. 11 shows a linear fit curve of a plurality of pH sensors 3(N ═ 5), and it was calculated that the response sensitivity of the pH sensor 3 was about-74.37 mV/pH, and the goodness of fit (R ═ 5) ² ) 0.9992, suggesting that it has higher sensitivity than conventional pH sensors, and good linearity and reproducibility. From the figure, we can know the linear relation between the response potential and the pH value of the pH sensor 3, so that the pH value detected by the pH sensor 3 can be calculated through the reading of the response voltage in the following experiment.

as shown in fig. 12 to 15, the ingested capsule 0 exhibited long-term stability under four different artificial digestive fluids, wherein the ingested capsule 0 exhibited the greatest deviation in reading and standard deviation when tested in artificial intestinal fluid, the greatest deviation being-0.13 and the standard deviation being-0.038. The deviation of the readings of the ingested capsule 0 in the other three artificial digestive juices is far less than the value, the maximum deviation is below 0.03, the standard deviation in the artificial gastric juice reaches-0.024, and the other two artificial digestive juices are below 0.01. It was demonstrated that ingesting capsule 0 can maintain stable operation in the digestive tract environment for a long period of time without interference from other substances in the solution.

as shown in fig. 16, the readings of the capsule 0 and the pH meter were not changed much and very close to each other at the beginning of the test, with a maximum error of-0.03, and the readings of the capsule 0 and the pH meter both fluctuated after the administration of the dalbergia magnesium tablet, wherein the fluctuation of the reading of the capsule 0 was more severe, and the difference in the readings between the two devices was gradually increased to-0.26 at the maximum. With the gradual dissolution of the dalxi hydrotalcite tablet, the readings of the ingested capsule 0 and the pH meter gradually tend to be consistent, and the maximum error is-0.1. After the stirring by the magnetic stirrer, the pH value of the artificial gastric juice is increased from 1.94 to 4.55 within 5 minutes and tends to be stable, and in the process, the detection results of the ingestion type capsule 0 and the pH meter have good consistency, and the maximum error is-0.2.

the results are shown in FIG. 17, from which it can be seen that the readings of the ingestible capsule 0 and the pH meter are stable and very close, with a maximum error of 0.07, at the very beginning of the test. Beginning to add CH dropwise ₃ After COOH, the readings of the ingested capsule 0 and the pH meter decrease simultaneously, at a rate that is fast first and slow later, during which both devicesThe difference of the readings is larger and larger, and the maximum error is 0.07. Stopping adding CH ₃ After COOH, the readings of the ingested capsule 0 and pH meter gradually stabilized. The test results of the ingested capsule 0 and the pH meter are basically consistent in the whole process, and the test result is converted into 0.1 when the difference of the pH values is maximum.

S5, detecting the pH value of the gastrointestinal tract of the animal by the capsule device in the waking state:

as shown in fig. 18, the scattergram capsule device was obtained at a sampling rate of 1/30Hz, and it can be seen that there was a large fluctuation in the pH value displayed by the scattergram, and for this reason, 5-point mean filtering was performed on the basis of the scattergram, so as to obtain a fitted curve in the graph. When 0 is swallowed by beagle dog ingesting capsule 0, the pH detected by ingesting capsule 0 is-2 and remains relatively stable for several minutes. After about 5 minutes of continuous detection, the received pH value fluctuates and shows a downward trend. After continuous pH measurements for about 8 minutes, the beagle dogs were released to move freely, when the received pH dropped, ranging between 0.9 and 2.1. After that, beagle dogs were fed 20ml of water, the pH value detected by the ingestable capsule 0 started to rise and gradually stabilized to-3.0 over the next ten minutes.

After swallowing the ingestible capsule 048 hours, the beagle excreted the ingestible capsule 0 by natural excretion, with normal feces excreted with the ingestible capsule 0, without drying, loose stool and blood stain. The ingested capsule 0 excreted by beagle dogs is recovered and the pH sensor 3 is taken out, the linear sensitivity test is carried out on the pH sensor 3 by using the standard solution, the result is shown in figure 19, the potential response and the slope of the pH sensor are respectively reduced by 20mV and 3mV/pH before and after the in vivo evaluation experiment, and the fact that the pH sensor 3 keeps normal working characteristics in the in vivo evaluation experiment process is verified, and obvious faults do not occur.

as shown in FIGS. 20 and 21, FIG. 20 shows the results of the test of the ingestible capsule 0 and the pH meter in the stomach, and both the pH value of the stomach measured by the ingestible capsule 0 and the pH meter were 2.5 in the initial test, and then the pH value was slowly increased. The results of the ingestible capsule 0 and the pH meter were in good agreement throughout the test, with a maximum pH test error of-0.3 between the two devices.

FIG. 21 shows the results of measurements in the colon of ingested capsule 0 and pH meter, with the pH value measured by the pH meter at the beginning of the measurement being about 6.9 and the pH value measured by ingested capsule 0 being about 6.6, with the pH values measured by both devices rising continuously throughout the measurement and having good consistency, with the pH value difference being at most-0.2.

Other embodiments of the present application will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the application being indicated by the following claims.

It will be understood that the present application is not limited to the precise arrangements described above and shown in the drawings and that various modifications and changes may be made without departing from the scope thereof. The scope of the application is limited only by the appended claims.

Claims

1. A wireless capsule sensing device for gastrointestinal tract pH detection, comprising:

the pH sensor is used for generating chemical reaction with hydrogen ions for detecting the gastrointestinal tract environment and outputting response voltage capable of reflecting the pH value;

the capsule detection circuit is electrically connected with the pH sensor and used for reading the response voltage and converting the response voltage into a digital signal; the capsule detection circuit is manufactured by adopting a rigid-flexible composite printed circuit board process and comprises a first rigid substrate, a second rigid substrate, a third rigid substrate, a fourth rigid substrate, a fifth rigid substrate, a first flexible substrate, a second flexible substrate, a third flexible substrate and a fourth flexible substrate; wherein

a constant potential instrument circuit and an analog/digital conversion module are arranged on the fourth rigid substrate;

the second connector is electrically connected with the potentiostat circuit through a fourth flexible substrate, the potentiostat circuit is electrically connected with the analog/digital conversion module on a fourth rigid substrate through a copper foil lead, the potentiostat is electrically connected with the digital/analog conversion module through a third flexible substrate, the minimum single-chip microcomputer system is electrically connected with the digital/analog conversion module on a third rigid substrate through a copper foil lead, the minimum single-chip microcomputer system is electrically connected with the analog/digital conversion module through a third flexible substrate, the minimum single-chip microcomputer system and the first wireless communication module are electrically connected with the first flexible substrate through copper foil leads on the second flexible substrate and the second rigid substrate, the battery is electrically connected with the first power management module through the first flexible substrate, and then the battery and the first power management module are electrically connected with the first wireless communication module, The minimum system of the single chip microcomputer, the digital/analog conversion module, the constant potential instrument circuit and the analog/digital conversion module are electrically connected;

the in-vitro receiving end is wirelessly connected with the capsule detection circuit and used for receiving the digital signal, and the in-vitro receiving end is a capsule auxiliary circuit;

before gastrointestinal tract pH value detection, the whole capsule structure surface needs to be subjected to biocompatibility treatment, and the biocompatibility treatment method of the capsule structure comprises the step of coating a layer of ethyl cellulose film on the grid gaps.

2. The wireless capsule sensing device of claim 1, wherein the external receiving end has a host computer application software for receiving and processing the digital signals from the wireless capsule and displaying them in real time.

3. The wireless capsule sensing device of claim 1, wherein the biocompatible treatment of the capsule structure further comprises:

and coating a layer of polydimethylsiloxane PDMS glue on the outer surface of the capsule structure except the grid, and naturally drying the glue to finish the biocompatibility treatment.

4. The wireless capsule sensing device of claim 1, wherein the receiving end further comprises one or more of a smartphone, a personal computer.

5. The wireless capsule sensing device of claim 1, wherein the pH sensor comprises:

a first substrate; and a counter electrode, a working electrode and a reference electrode disposed on a surface of the first substrate.

6. The wireless capsule sensing device of claim 5, wherein the working electrode is divided into two layers, a carbon ink layer and an iridium oxide deposition layer.

7. The wireless capsule sensing device of claim 1, wherein the capsule accessory circuit comprises a sixth rigid substrate, a second wireless communication module, a second power management module, an upper computer communication module, and a third connector, the sixth rigid substrate carrying the second wireless communication module, the second power management module, and the upper computer communication module;

the second wireless communication module and the upper computer communication module are electrically connected on a sixth rigid substrate through copper foil leads; the second power management module is electrically connected with the second wireless communication module and the upper computer communication module respectively;