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

Abstract

The invention discloses a wireless capsule sensing device and method for detecting the pH value of the gastrointestinal tract. The device includes an ingestible capsule, the ingestible capsule includes a capsule structure, a capsule detection circuit and a pH sensor; the pH sensor is used for chemically reacting with hydrogen ions detected in the gastrointestinal tract environment, and outputting a pH capable of reacting the response voltage of the value; the capsule detection circuit is electrically connected with the pH sensor for reading the response voltage and converting the response voltage into a digital signal; the capsule structure includes a sensor chamber for installing the pH sensor and a circuit chamber for installing the capsule detection circuit, the sensor chamber has a grid for liquid to pass through; the in vitro receiving end, the in vitro receiving end is wirelessly connected with the capsule detection circuit for receiving the digital signal. It solves the problem that it is difficult to detect the pH of the gastrointestinal tract in the clinical non-anesthesia state, and has the advantages of convenient, real-time, ingested, and non-invasive sensing detection.

Description

A wireless capsule sensing device and method for gastrointestinal pH detection

technical field

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

Background technique

The pH value of the gastrointestinal tract is a very important physiological indicator, and many gastrointestinal diseases may involve changes in pH value, such as gastric ulcer, duodenal ulcer, indigestion, gastroesophageal reflux disease (gastroesophageal reflux, GERD), Crohn's colitis, ulcerative colitis (inflammatory bowel disease, IBD), etc. Therefore, in clinical practice, it is often necessary to repeatedly detect the pH value of the patient's gastrointestinal tract. At present, intubation to insert a pH probe into the gastrointestinal tract is a common method for clinical detection of pH. If necessary, an endoscopic biopsy of the gastrointestinal tract is also performed to measure pH in vitro. These types of tests often require anesthesia, which can be painful and carry the risk of developing heart and lung disease.

SUMMARY OF THE INVENTION

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

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

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

The pH sensor is used to generate a chemical reaction with hydrogen ions that detect the gastrointestinal tract environment, and output a response voltage that can reflect the pH value;

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

The capsule structure includes a sensor chamber for installing the pH sensor and a circuit chamber for installing the capsule detection circuit, the sensor chamber having a grid for the passage of liquid;

An in vitro receiving end, which is wirelessly connected to the capsule detection circuit 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.

Further, the in vitro receiving end has host computer application software, and the host computer application software is used to receive and process the digital signal from the wireless capsule, and display it in real time.

Further, before the pH value of the gastrointestinal tract is detected, the entire surface of the capsule structure needs to be treated for biocompatibility.

Further, the biocompatibility treatment method of the capsule structure is as follows:

Coating a layer of ethyl cellulose film to the grid gap;

A layer of polydimethylsiloxane (PDMS) glue is coated on the outer surface of the capsule structure except the grid, and the biocompatibility treatment is completed after it is naturally dried.

Further, the capsule detection circuit is fabricated by a rigid-flexible composite printed circuit board process, including a first rigid substrate, a second rigid substrate, a third rigid substrate, a fourth rigid substrate, a fifth rigid substrate, and 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 base;

A first power management module is arranged on the second rigid base for improving the power output of the battery;

The third rigid base is arranged with a single-chip minimum system and a digital/analog conversion module;

A potentiostat circuit and an analog/digital conversion module are arranged on the fourth rigid substrate;

A second connector is arranged on the fifth rigid base and is connected with the pH sensor;

The second connector is electrically connected with the potentiostat circuit through the fourth flexible substrate, the potentiostat circuit and the analog/digital conversion module are electrically connected on the fourth rigid substrate through copper foil wires, and the potentiostat is electrically connected with the digital/analog conversion The modules are electrically connected through the third flexible substrate, the minimum system of the single-chip microcomputer and the digital/analog conversion module are electrically connected on the third rigid substrate through copper foil wires, the minimum system of the single-chip microcomputer is electrically connected with the analog/digital conversion module through the third flexible substrate, and the minimum single-chip microcomputer system is electrically connected with the analog/digital conversion module. The system and the first wireless communication module are electrically connected through the second flexible substrate, the copper foil wires on the second rigid substrate, and the first flexible substrate, and the battery is electrically connected to the first power management module through the first flexible substrate. The first power management module is electrically connected with the above-mentioned first wireless communication module, the minimum system of single-chip microcomputer, the digital/analog conversion module, the potentiostat circuit and the analog/digital conversion module.

Further, the pH sensor includes:

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

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

Further, the capsule auxiliary circuit includes a sixth rigid base, a second wireless communication module, a second power management module, a host computer communication module and a third connector, and the sixth rigid base carries the second wireless communication module, the first Two power management module and host computer communication module;

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

The second wireless communication module performs half-duplex communication with the first wireless communication module of the capsule detection circuit to transmit control commands and detection data.

According to a second aspect of the embodiments of the present application, a method for detecting pH value of the gastrointestinal tract is provided, characterized in that, the method is implemented in the device described in the first aspect, and includes the following steps:

S1, prepare standard solutions of different pH, use multiple pH sensors to perform open-circuit voltage-time detection in the standard solution according to the rising/falling gradient of pH, and draw the linear fitting curve of the pH sensor based on this;

S2, the ingestible capsules are respectively put into artificial saliva, artificial gastric juice, artificial small intestinal juice and artificial colonic juice to perform open circuit voltage-time detection, and the detection time conforms to the human digestive cycle;

S3, select artificial gastric juice and adjust pH to the stomach pH environment of gastric ulcer patient, put into aluminum magnesium carbonate tablet to simulate the treatment process, use described ingested capsule to detect its pH change, and assist professional pH instrument to carry out comparison;

S4, select the artificial colonic fluid and adjust the pH to the colonic pH environment of the diarrhea patient, drop acetic acid into it to simulate the recovery process of the disease, use the ingested capsule to detect the pH change, and assist the professional pH instrument for comparison;

S5 , when the animal is awake, the ingested capsule is fed into the gastrointestinal tract through its oral cavity to detect pH, and the detected pH parameter is sent to the in vitro receiving end through wireless transmission.

The technical solutions provided by the embodiments of the present application may include the following beneficial effects:

It can be seen from the above embodiments that the present application adopts the screen printing electrode process and the rigid-flexible printed circuit board process to realize the miniaturization of the pH sensor and the capsule detection circuit respectively, and has the characteristics of flexibility and bendability, and can be assembled in the capsule structure. Inside. The ingestible capsule can be immersed in a liquid environment for stable pH measurement over a long period of time, thereby helping to solve the problem of gastrointestinal pH detection in the clinical non-anesthesia state. Through experiments on large animals, it has been confirmed that the ingested capsules do not cause wounds and do not require anesthesia during the measurement of the gastrointestinal tract. After testing is complete, the ingestible capsule can be recycled. Its capsule detection circuit and pH sensor two components can be reused after necessary processing. Therefore, the device and method for detecting the pH value of the gastrointestinal tract by using the capsule device can realize the stable detection of the pH value in the gastrointestinal tract for a long time.

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

Description of drawings

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

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

Fig. 2 is the assembly drawing of the ingestible capsule in the embodiment of the present invention;

3 is a block diagram of a capsule detection circuit structure in an embodiment of the present invention;

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

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

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

7 is a structural diagram of a pH sensor in an embodiment of the present invention;

Fig. 8 is the working flow chart of the wireless capsule device for gastrointestinal pH value detection in an embodiment of the present invention;

FIG. 9 is a graph of the sensitivity detection result of the pH sensor from pH=0.95 to pH=9.00 in the embodiment of the present invention;

FIG. 10 is a graph of the sensitivity detection result of the pH sensor from pH=9.00 to pH=0.95 in the embodiment of the present invention;

Fig. 11 is the linear fitting curve of the pH sensor in the embodiment of the present invention;

12 is an open-circuit potential-time detection diagram of the wireless capsule device for gastrointestinal pH detection in artificial saliva for 30 seconds in an embodiment of the present invention;

13 is an open circuit potential-time detection diagram of the wireless capsule device used for gastrointestinal pH detection in the artificial gastric juice for 6 hours according to the embodiment of the present invention;

14 is an open circuit potential-time detection diagram of the wireless capsule device used for gastrointestinal pH detection in the artificial small intestinal fluid for 8 hours according to the embodiment of the present invention;

15 is an open circuit potential-time detection diagram of the wireless capsule device for gastrointestinal pH detection in artificial colonic fluid for 16 hours according to an embodiment of the present invention;

Fig. 16 is a test result diagram of a simulated gastric ulcer by the wireless capsule device used for gastrointestinal pH detection in an embodiment of the present invention;

17 is a graph of the test results of the wireless capsule device for gastrointestinal pH detection simulating diarrhea in an embodiment of the present invention;

FIG. 18 is a test result diagram of feeding a large animal in a awake state by the wireless capsule device for gastrointestinal pH detection in an embodiment of the present invention;

19 is a linear fitting curve obtained by performing a sensitivity test on the pH sensor used before and after feeding a large animal in a awake state to a wireless capsule device for gastrointestinal pH value detection in an embodiment of the present invention;

20 is a graph of the results obtained by testing the stomach of a large animal under anesthesia with the wireless capsule device used for gastrointestinal pH detection in an embodiment of the present invention;

FIG. 21 is a graph of the results obtained by testing the large animal intestine under anesthesia with the wireless capsule device for pH detection in the gastrointestinal tract according to the embodiment of the present invention.

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

Detailed ways

Exemplary embodiments will be described in detail herein, examples of which are illustrated in the accompanying drawings. Where the following description refers to the drawings, the same numerals in different drawings refer to the same or similar elements unless otherwise indicated. The implementations described in the illustrative examples below are not intended to represent all implementations consistent with this application. Rather, they are merely examples of apparatus and methods consistent with some aspects of the present application as recited in the appended claims.

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

It should be understood that although the terms first, second, third, etc. may be used in this application to describe various information, such information should not be limited by these terms. These terms are only used to distinguish the same type of information from each other. For example, the first information may also be referred to as the second information, and similarly, the second information may also be referred to as the first information without departing from the scope of the present application. Depending on the context, the word "if" as used herein can be interpreted as "at the time of" or "when" or "in response to determining."

As shown in FIG. 1 , an embodiment of the present invention provides a wireless capsule sensing device for gastrointestinal pH detection, including: an ingested capsule 0 and an in vitro receiving end, the ingested capsule 0 includes a capsule structure 1. Capsule detection circuit 2 and pH sensor 3; the pH sensor 3 is used to produce a chemical reaction with hydrogen ions that detect the gastrointestinal environment, and output a response voltage that can reflect the pH value; the capsule detection circuit 2 and pH The sensor 3 is electrically connected for reading the response voltage and converting the response voltage into a digital signal; the capsule structure 1 includes a sensor chamber for installing the pH sensor 3 and a sensor chamber for installing the capsule In the circuit chamber of the detection circuit 2, the sensor chamber is provided with a grid for the passage of liquid; the in vitro receiving end is wirelessly connected with the capsule detection circuit for receiving the digital signal.

It can be seen from the above embodiments that the present application adopts the design of an ingestible capsule to realize the miniaturization of sensors and circuits, which is flexible and easy to bend, can be assembled in a capsule structure with a small volume, and can be immersed in a liquid environment. Long-term stable measurement of pH. In this way, the problem that it is difficult to detect the pH of the gastrointestinal tract in the clinical non-anesthesia state is solved. Measurements in the gastrointestinal tract of large animals using ingestible capsules are wound-free and do not require anesthesia. After testing is complete, the ingestible capsule can be recycled. Its capsule detection circuit and pH sensor two components can be reused after necessary processing. Therefore, the device and method for detecting the pH value of the gastrointestinal tract by using the capsule device can realize the stable detection of the pH value in the gastrointestinal tract for a long time.

In this example, the capsule structure 1 is made of a photosensitive resin (DSM IMAGE 8000, Royal DSM, The Netherlands) as a material, and is manufactured by a 3D printing process. As shown in FIG. 2 , the capsule structure 1 includes a sensor chamber 11 that can be loaded with a pH sensor 3 and a detection circuit chamber 12 that can be loaded with a capsule detection circuit 2 .

A layer of ethyl cellulose film is attached to the grid on the top of the sensor chamber 11 to prevent solid particles and biological macromolecules from immersing in the sensor chamber 11 and contaminating the pH sensor 3 .

The pH sensor 3 and the capsule detection circuit 2 can be assembled in the capsule structure 1 by bending and folding. After the assembly is completed, the sensor chamber 11 and the detection circuit chamber 12 can be connected by interference fit, and the connection gap is closed by quick-drying glue (Ergo5011, Kisling Co., Ltd., Switzerland). Except for the grid at the top of the sensor chamber 11 , other outer surfaces of the capsule structure 1 are coated with polydimethylsiloxane (PDMS) glue for biocompatibility processing.

It can be seen from the above-mentioned embodiments that the size and shape of the ingestible capsule 0 can conform to the gastrointestinal tract through the capsule-shaped shell design of the present application, and will not cause damage when passing through the stenosis of the gastrointestinal tract. In addition, the ingestible capsule 0 has undergone biocompatibility treatment, and will not affect the normal physiological activities of the gastrointestinal tract during the detection process.

As shown in FIG. 3 , in a possible implementation method, the capsule detection circuit 2 is fabricated by a rigid-flexible composite printed circuit board process, including a first rigid substrate 21 , a first flexible substrate 22 , and a second rigid substrate 23. Second flexible substrate 24, third rigid substrate 25, third flexible substrate 26, fourth rigid substrate 27, fourth flexible substrate 28, fifth rigid substrate 29. The first rigid base 21 and the second rigid base 23 are connected through the first flexible base 22, the second rigid base 23 and the third rigid base 24 are connected through the second flexible base 24, and the third rigid base 24 is connected with the fourth rigid base 26 is connected through the third flexible base 25 , and the fourth rigid base 26 is connected with the fifth rigid base 28 and the fourth flexible base 27 .

Further, a first wireless communication module 211 is welded on the front of the first rigid base 21, and a battery 212 is welded on the back; a first connector 231 (optional, mainly used for debugging) is welded on the front of the second rigid base 23, The first power management module 232 is welded on the back side; the single-chip minimum system 251 is welded on the front side of the third rigid base 25 , and the digital/analog conversion module 252 is welded on the back side; the potentiostat circuit 271 is welded on the front side of the fourth rigid base 27 , and the analog circuit 271 is welded on the back side. /Digital conversion module 272 ; the second connector 291 is welded on the back of the fifth rigid base 29 . The individual components described above can be electrically connected in an orderly manner through copper foil conductors embedded in rigid and flexible substrates.

In a possible implementation method, the wireless communication module 211 welded on the front of the first rigid base 21 can be WH-BLE103 (Jinan Renren Technology Co., Ltd., China), and the battery welded on the back can be a lithium-ion battery (10mm× 10mm×4mm, 30mAh), the first connector 231 on the front of the second rigid base 23 can be an FPC connector (10pin, 0.5mm pitch), and the resistance and capacitance of the first power management module 232 on the back can be 0201 package type stickers. Chip components; the minimum system 251 of the single-chip microcomputer on the front of the third rigid substrate 25 can choose MSP430FR5959 (Texas Instruments, USA) as the microcontroller, the peripheral resistors and capacitors can choose the chip components of 0201 package type, and the digital/analog conversion module 252 on the back DAC8562 (Texas Instruments, USA) can be selected as the main control chip, and the peripheral resistors and capacitors can be selected from 0201 package type SMD components; the potentiostat circuit 271 on the front of the fourth rigid substrate 27 can be selected from four single-channel integrated operational amplifiers AD8605 (Analog Semiconductor, USA) as the main component, the peripheral resistors and capacitors can use 0201 package type SMD components, the analog/digital conversion module 272 on the back can use ADS1115 (Texas Instruments, USA) as the main chip, the peripheral The resistor and capacitor can be selected from 0201 package type SMD components; the second connector 291 on the back of the fifth rigid substrate 29 can be selected from an FPC connector (8pin, 1mm pitch).

It can be seen from the above embodiments that the present application adopts the rigid-flexible composite printed circuit board process, and selects circuit components with small size and low power consumption, so that the entire capsule detection circuit 2 can be bent and folded and packaged in a small volume. In the capsule structure 1, the detection can be completed by relying on the internal power supply under the condition that it is ingested into the gastrointestinal tract and cannot obtain energy from the outside.

As shown in FIG. 4 , the capsule auxiliary circuit 5 is constituted by a sixth rigid base 51 . A second wireless communication module 52 , a second power management module 53 , a host computer communication module 54 , a capsule detection circuit debugging module 55 (an optional module), and a third connector 56 are respectively welded on the surface of the sixth rigid base 51 . Through the copper foil wires embedded in the sixth rigid base 51 , the above-mentioned modules can be electrically connected to each other in an orderly manner.

In a possible implementation method, the second wireless communication module 52 adopts WH-BLE103 (Jinan Renren Technology Co., Ltd., China), which can be connected to a 24DB 2.4GHz flat panel directional antenna to improve the receiving sensitivity of wireless signals; The second power management module 53 selects AMS1117 (Austria Microelectronics, Austria), and the peripheral resistor and capacitor adopts 0805 package type SMD components; the host computer communication module 54 provides the capsule auxiliary circuit 5 with the host computer terminal (such as personal computer) communication interface to realize real-time UART half-duplex communication; the capsule detection circuit debugging module 55 provides an embedded software debugging interface of JTAG 14 package type, and the third connector 56 communicates with the first connector 231 of the capsule detection circuit 2 through FPC software. After the cables are connected, the download and debugging services of embedded programs can be provided for the capsule detection circuit 2 .

It can be seen from the above embodiments that the capsule auxiliary circuit 5 designed in the present application can not only provide power supply and an embedded program download interface for the capsule detection circuit 2 when the capsule detection circuit 2 is being debugged, but also can provide power and an embedded program download interface for the capsule detection circuit 2 when the capsule detection circuit 2 is debugged. When testing in the intestine, it communicates with it through the Bluetooth module, and transmits the readings of the ingestible capsule 0 in real time.

As shown in FIG. 5 and FIG. 6 , the host computer application software 4 includes personal computer application software 41 running on the Windows platform of the personal computer and smart phone application software 42 running on the Android platform of the smart phone. In this specific embodiment, the host computer software 4 mainly refers to the smart phone application software 42 running under the Android platform of the smart phone.

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

It can be seen from the above embodiment that the host computer application software 4 designed in this application can analyze and process the received data when receiving the data transmitted by the ingested capsule 0, and display it in real time, which is convenient for us to check the device during the detection process. and methods to adjust.

As shown in FIG. 7 , in a possible implementation method, the pH sensor 3 can use polyethylene terephthalate (PET) as the base material through a screen printing electrode process. Carbon ink (C2030519P4, Sun Chemicals Ltd, UK) was printed on its surface to construct counter electrode 32, working electrode 34, and conductive silver paste (C2130809D5, Sun Chemicals Ltd, UK) was printed to construct reference electrode 36, counter electrode lead 33 , working electrode lead 35, 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 is immersed in the iridium oxide precursor solution, and after being applied with a constant current with a current density of 0.2 mA/cm ² , an iridium oxide deposition layer 342 can be formed on the working electrode 34, which is located in the carbon ink. above layer 341 .

It can be seen from the above-mentioned embodiments that the present application uses PET with good bendability as the substrate, so that the pH sensor 3 can be bent and folded into the capsule structure 1 .

In a possible implementation method, the workflow of the wireless capsule sensing device for pH detection in the gastrointestinal tract is shown in Figure 8. After the battery 212 is connected to the capsule detection circuit 2 , the first power management module 232 supplies power to the entire capsule detection circuit 2 after adjusting the output of the battery. At the same time, the minimum system 251 of the single-chip microcomputer starts to work, and sends a control command, so that the digital/analog conversion module 252 provides the reference electrode voltage for the potentiostat circuit 271 as a reference, and the hydrogen ions in the liquid environment undergo an electrochemical reaction on the pH sensor 3, The response voltage generated by the reaction is transmitted to the potentiostat circuit 271, and then sent to the analog/digital conversion module 272 for analog-to-digital conversion after signal conditioning. The converted data is transmitted to the first wireless communication module 211 through the single-chip minimum system 251. The first wireless communication module 211 can communicate with an external device with a bluetooth module, and the external device can be a smart phone with a bluetooth module, or a personal computer or the capsule auxiliary circuit 5 .

Another object of the present invention is to provide a method for detecting the pH value of the gastrointestinal tract using the above-mentioned capsule device, comprising the steps of:

S1, draw the linear fitting curve of pH sensor 3:

Diluted with concentrated hydrochloric acid (36.5 wt%) to obtain 30 mL of pH=1 standard solution. Use buffer A (0.2M boric acid and 0.05M citric acid) and buffer B (0.1M Na3PO4) in different proportions to prepare 30 mL of pH 2, 3, 4, 5, 6, 7, 8, and 9, respectively. 8 standard solutions. All standard solutions used above should be added with NaCl to a concentration of 0.1M.

Take five pieces of modified pH sensor 3 and immerse it in the standard solution with pH from 9 to 1 in turn for open-circuit potential-time detection. Each piece of sensor is tested continuously for 60 seconds under each pH standard solution; The same five pH sensors were immersed in standard solutions with pH from 1 to 9 for open circuit potential-time detection, and each electrode was tested continuously for 60 seconds at each pH standard solution. And draw the linear fitting curve of pH sensor 3 based on this.

S2, use a capsule device to detect pH values in different artificial digestive juices:

The assembled ingestible capsule 0 is immersed in artificial saliva, artificial gastric juice, artificial small intestinal juice, and artificial colonic juice respectively for open circuit potential-time detection, and the detection time is determined according to the human digestive cycle. Continuous detection was performed in artificial saliva for 30 seconds, in artificial gastric juice for 6 hours, in artificial small intestinal fluid for 8 hours, and in artificial colonic fluid for 16 hours.

S3, simulate the treatment process of gastric ulcer, and use the capsule device to detect the change of pH environment during the treatment:

Take 60 mL of artificial gastric juice, use a pH meter to determine its actual pH, add dilute hydrochloric acid to the artificial gastric juice, adjust the pH value of the artificial gastric juice to 1.55, and simulate the gastric pH environment of gastric ulcer patients in this way. At the same time, the artificial gastric juice was detected with a pH meter and an ingested capsule 0. After 30 minutes, Daxi aluminum magnesium carbonate tablets (0.5 g, Bayer Healthcare Co., Ltd., Germany) were put in, and the detection was continued for 30 minutes. After that, a magnetic stirrer was used for stirring, and the rotational speed was set to 200 rpm, and the pH value of the artificial gastric juice was continuously detected until the pH value was stable.

S4, simulate the treatment process of diarrhea, and use the capsule device to detect the change of pH environment during the treatment:

Take 60 mL of artificial colonic fluid, use a pH meter to determine its actual pH, add Na3PO4 to the artificial colonic fluid, adjust the pH of the artificial colonic fluid to 9, and simulate the colonic pH environment of diarrhea patients in this way. At the same time, the artificial colonic fluid was detected by pH meter and ingested capsule 0. After 30 minutes, use a syringe to drop 0.1M CH3COOH into the artificial colonic fluid slowly and uniformly, and continue to detect the pH value of the artificial colonic fluid. After the pH value of the artificial colonic fluid dropped to 7.5, the dropwise addition of CH3COOH was stopped, and the detection was continued for 20 minutes.

S5, the capsule device detects the pH value in the animal in the awake state:

In vivo evaluations were performed using male, 15 kg, 12-month-old beagle dogs. Beagles are placed under quarantine observation 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 Laboratory Animal Management and Ethics Committee of Zhejiang University of Traditional Chinese Medicine (animal ethics approval number: IACUC-20201103-04).

Before the start of the experiment, the beagle dogs were fasted for 48 hours, and after the fasting period, the beagle dogs were fixed on a restraining frame. The ingestible capsule 0 is administered orally to beagle dogs after biocompatibility treatment. The 24DB 2.4GHz flat panel directional antenna is placed on the belly of the beagle 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 to read the ingested capsule 0 in the body. It is displayed on the personal computer application software 41 in real time. After 10 minutes of continuous detection, the beagle was put down from the restraint frame, and the beagle was allowed to move freely for 5 minutes. The beagle was fixed on the restraint frame again, and 20 mL of drinking water was fed from the mouth. Continue to test for 15 minutes after the end of feeding. Finally, the beagle was returned to the breeding cage, and after the ingestible capsule 0 was naturally excreted, the shape of the feces excreted by the beagle was observed, and the ingestible capsule 0 was recovered. The capsule detection circuit 2 and the pH sensor 3 are reused after necessary processing. The electrochemical performance of pH Sensor 3 was evaluated and compared with the relevant results prior to the in vivo evaluation.

S6, the capsule device detects the pH value of the animal's gastrointestinal tract under anesthesia:

Beagle dogs were fasted for 12 hours after ingestion capsule 0 was naturally excreted from the beagle's gastrointestinal tract. After the fasting period, the dogs were anesthetized with intravenous propofol (2 mg/kg). After the beagle began anesthesia, a breathing tube was inserted into the beagle's trachea and oxygen containing 1% isoflurane was inhaled. After the beagle was fully anesthetized and vital signs stabilized, the beagle was kept in a supine position, the stomach and upper colon were shaved, and the exposed areas were sterilized with 75% alcohol. The epidermis was incised with a scalpel, and the muscle tissue was incised using a high-frequency electrocautery. After that, the stomach was exposed, and an incision of about 2 cm long was made along the stomach wall. At the same time, the probe of the pH meter and the ingestible capsule 0 were immersed in the biological fluid of the stomach through the incision, and the detection was continued for 15 minutes, and the stomach was observed through the incision. Whether there is damage to the tissue, such as bleeding, ulcers, cuts, etc. After the detection, the probe of the ingestible capsule 0 and pH meter was taken out and cleaned, and the gastric incision was sutured. A similar procedure was then used to measure pH in the transverse colon of beagle dogs.

The present invention will be described in further detail below by means of examples.

Example:

S1, draw the linear fitting curve of pH sensor 3:

FIG. 9 and FIG. 10 respectively show the open-circuit voltage-time response curves of pH sensor 3 in a standard solution whose pH is successively increased and successively decreased. It can be seen from the figure that the sensor shows a good gradient in both cases, the potential response difference in the standard solution of adjacent pH is basically the same, and in the continuous 60-second open-circuit voltage-time detection, The potential response of pH sensor 3 remained stable with a maximum potential drift of 0.93 mV. Figure 11 shows the linear fitting curve of the multi-chip pH sensor 3 (N=5). Through calculation, the response sensitivity of the pH sensor 3 is about -74.37mV/pH, and the goodness of fit (R ² ) is ~0.9992. It is suggested that it has higher sensitivity than traditional pH sensors, and has good linearity and repeatability. From the changed figure, we can know the linear relationship between the response potential of the pH sensor 3 and the pH value, so that the pH value detected by the pH sensor 3 can be calculated by the reading of the response voltage in the following experiments.

S2, use a capsule device to detect pH values in different artificial digestive juices:

The test results are shown in Figures 12 to 15. The ingestible capsule 0 showed long-term stability under four different artificial digestive juices. Among them, the reading deviation and The standard deviation is the largest with a maximum deviation of ~0.13 and a standard deviation of ~0.038. However, when the ingested capsule 0 was tested in the other three artificial digestive juices, the reading deviation was far less than this value, and the maximum deviation was below 0.03. The standard deviation of the test in artificial gastric juice reached ~ 0.024. The digestive juices were all below 0.01. It is proved that the ingestible capsule 0 can maintain long-term stable operation in the digestive tract environment without being disturbed by other substances in the solution.

S3, simulate the treatment process of gastric ulcer, and use the capsule device to detect the change of pH environment during the treatment:

The test results are shown in Figure 16. At the beginning of the test, the readings of the ingested capsule 0 and the pH meter did not change much and were very close, and the maximum error was ~0.03. The readings of pH meter and pH meter fluctuated, among which the reading of ingested capsule 0 fluctuated more violently, and the reading difference between the two devices gradually increased, and the maximum was ~0.26. As the Daxi aluminum magnesium carbonate tablets gradually dissolve, the readings of the ingestible capsule 0 and the pH meter gradually tend to be consistent, with a maximum error of ~0.1. After stirring with a magnetic stirrer, the pH value of the artificial gastric juice rose from 1.94 to 4.55 within 5 minutes and became stable. The error is ~0.2.

S4, simulate the treatment process of diarrhea, and use the capsule device to detect the change of pH environment during the treatment:

The test results are shown in Figure 17. It can be seen from the figure that at the beginning of the test, the readings of the ingested capsule 0 and the pH meter are stable and close, with a maximum error of ~0.07. After the CH ₃ COOH was added dropwise, the readings of the ingested capsule 0 and the pH meter decreased at the same time, and the rate of decrease was fast at first and then slow. During this period, the difference between the readings of the two devices became larger and the maximum error was 0.07. After the dropwise addition of CH ₃ COOH was stopped, the readings of the ingestible capsule 0 and the pH meter gradually became stable. The detection results of the ingested capsule 0 and the pH meter are basically the same throughout the process, and the maximum difference between the detection results and the pH value is 0.1.

S5, in the awake state, the capsule device detects the pH value of the gastrointestinal tract of the animal:

The test results are shown in Figure 18. The scatter diagram capsule device in the figure is obtained with a sampling rate of 1/30Hz. It can be seen that the pH value displayed by the scatter diagram has a large fluctuation. On the basis of the dot graph, a 5-point mean filter is performed to obtain the fitting curve in the graph. When the beagle swallowed the ingested capsule 0, the pH detected by the ingested capsule 0 was ~2 and remained relatively stable for several minutes. After about 5 minutes of continuous testing, the pH value received fluctuated and showed a downward trend. After approximately 8 minutes of continuous pH monitoring, the beagle was released to move freely, at which point the received pH dropped to a range between 0.9 and 2.1. Afterwards, the beagle was fed 20 mL of water and the pH detected by the ingestible capsule 0 began to rise and gradually stabilized to ~3.0 over the next ten minutes.

After swallowing the ingested capsule 0 for 48 hours, the beagle dog excreted the ingested capsule 0 through natural excretion, and the feces excreted with the ingested capsule 0 were normal, without dryness, looseness and blood. The ingested capsule 0 excreted by the beagle was recovered and the pH sensor 3 was taken out. The linear sensitivity test of the pH sensor 3 was carried out using a standard solution. The results are shown in Figure 19. The potential response and slope of the pH sensor before and after the in vivo evaluation experiment were respectively The decrease of ~20mV and ~3mV/pH confirms that pH sensor 3 maintains normal working characteristics during the in vivo evaluation experiments without obvious failure.

S6, the capsule device detects the pH value of the animal's gastrointestinal tract under anesthesia:

The test results are shown in Figure 20 and Figure 21. Figure 20 shows the test results of the ingestible capsule 0 and pH meter in the stomach. In the initial test, the stomach pH value detected by the ingestible capsule 0 and the pH meter Both were ~2.5, after which the pH rose slowly. The results of the ingested capsule 0 and the pH meter were in good agreement throughout the detection process, with a maximum pH detection error of ~0.3 between the two devices.

Figure 21 shows the test results of the ingested capsule 0 and the pH meter in the colon. At the beginning of the test, the pH of the colon measured by the pH meter was about 6.9, and the pH of the colon measured by the ingested capsule 0 was about 6.6. During the whole measurement process, the pH values measured by the two devices continued to increase with good consistency, with a maximum pH value difference of ~0.2.

Other embodiments of the present application will readily occur to those skilled in the art upon consideration of the specification and practice of what is disclosed herein. This application is intended to cover any variations, uses or adaptations of this application that follow the general principles of this application and include common knowledge or conventional techniques in the technical field not disclosed in this application . The specification and examples are to be regarded as exemplary only, with the true scope and spirit of the application being indicated by the following claims.

It is to be understood that the present application is not limited to the precise structures described above and illustrated in the accompanying 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 (7)

1. A wireless capsule sensing 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 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 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 instrument 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 instrument circuit and the analog/digital conversion module are electrically connected;

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;

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;

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.

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