A time-division multiplexing dual-mode monitoring sensor for blood glucose and implanted wound infection and its monitoring method

Abstract

This invention discloses a time-division multiplexed dual-mode monitoring sensor for blood glucose and implanted wound infection, and its monitoring method. The sensor includes an electrically connected sensing unit and a detection unit. The sensing unit includes a three-electrode system of sensing electrodes, and the detection unit includes a chronoamperometry circuit for blood glucose measurement, an open-circuit voltage method circuit for wound pH measurement, a switching circuit, and a control module. The control module regulates the switching circuit, enabling the sensor to alternately perform blood glucose and implanted wound pH measurements in a time-division multiplexed manner. Based on the pH measurement data, the blood glucose measurement results can be dynamically calibrated, and an alarm is triggered when the wound infection level measured by the pH measurement data exceeds a preset threshold. This invention optimizes the combination relationship of the three-electrode system and the timing control of the detection modes, achieving simultaneous detection of two indicators without adding additional electrodes. This not only improves detection accuracy and wearing comfort but also simplifies the device structure and reduces costs, showing great application potential.

Description

Technical Field

[0001] This invention belongs to the field of electrochemical biosensor technology, specifically relating to a time-division multiplexing dual-mode monitoring sensor for blood glucose and implanted wound infection, and its monitoring method. Background Technology

[0002] With the increasing incidence of diabetes, blood glucose monitoring technology has become a key means of diabetes management. In recent years, implantable blood glucose sensors have received widespread attention due to their ability to achieve continuous blood glucose monitoring, and their usage rate among patients has gradually increased. However, existing implantable blood glucose sensors still face many challenges in practical applications, especially since a certain percentage of implantation results in local inflammatory reactions. Inflammation not only leads to a decrease in sensor performance (such as reduced sensitivity and signal drift) but also affects the wearer's comfort and medical compliance.

[0003] Inflammation is the body's natural immune response to implants, typically accompanied by reactive oxygen species, inflammatory factors, and pH changes in local tissues. The accumulation of these inflammation-related markers can interfere with the glucose detection signal of the sensor, and even lead to sensor failure. Therefore, developing an implantable sensor capable of simultaneously monitoring blood glucose fluctuations and local inflammation is crucial for improving sensor accuracy, extending its lifespan, and enhancing patient health management. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a time-division multiplexed dual-mode monitoring sensor for blood glucose and implantation wound infection, and a monitoring method thereof. This sensor utilizes electrochemical sensing technology, combined with a multifunctional electrode design. By expanding the combination relationship of the original implantable sensor's three-electrode system and optimizing the outer membrane material, it achieves time-division multiplexed detection of blood glucose and inflammation-related pH values ​​at the implantation wound site without adding additional electrodes.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention proposes a time-division multiplexing dual-mode monitoring sensor for blood glucose and implantation wound infection, comprising at least an electrically connected sensing unit and a detection unit, wherein...

[0007] The sensing unit includes a three-electrode system of sensing electrodes, which includes a working electrode, a counter electrode, and a reference electrode.

[0008] The detection unit includes:

[0009] The detection circuit includes a chronoamperometry circuit for blood glucose measurement and an open-circuit voltage method circuit for wound pH measurement.

[0010] Switching circuits are used for:

[0011] The working electrode, counter electrode, and reference electrode are connected to the chronoamperometry circuit to form a three-electrode blood glucose measurement circuit.

[0012] Alternatively, the counter electrode and reference electrode can be connected to an open-circuit voltage method circuit to form a two-electrode wound pH measurement circuit.

[0013] The control module is used to control the switching state of the switching circuit, so that the sensor alternately performs blood glucose measurement and wound pH measurement through time-division multiplexing.

[0014] Preferably, the sensor further includes a data processing unit, which is integrated inside the sensor or in an external receiver, and is used for:

[0015] Receive and process the measurement signal output by the detection circuit;

[0016] Dynamic calibration of blood glucose measurement results based on wound pH measurement data;

[0017] The degree of wound infection is determined based on pH measurement data. When the degree of wound infection exceeds a preset threshold, an infection warning signal is triggered.

[0018] Preferably, the control module controls the switching state of the switching circuit, enabling the sensor to alternately perform blood glucose measurement and wound pH measurement via time-division multiplexing, including:

[0019] Set the sensor's operating cycle to alternate between the blood glucose measurement cycle T1 and the wound pH measurement cycle T2;

[0020] During the blood glucose measurement cycle T1, the switching circuit is controlled to switch to the blood glucose measurement loop;

[0021] During wound pH measurement cycle T2, the switching circuit is controlled to switch to wound pH measurement loop;

[0022] The durations of T1 and T2 are determined based on measurement requirements.

[0023] Preferably, the working electrode comprises a base support layer, a conductive layer, a catalytic layer, an enzyme layer, and an outer membrane layer stacked sequentially, wherein,

[0024] The basic support layer includes any one of polyester, polyimide, and polydimethylsiloxane;

[0025] The conductive layer includes any one of gold, carbon, and conductive polymer materials;

[0026] The catalyst layer comprises any one of platinum, palladium, and osmium;

[0027] The enzyme layer is loaded with glucose oxidase or glucose dehydrogenase.

[0028] The outer membrane layer includes any one of polyvinyl alcohol, polyvinyl butyral, and polyurethane.

[0029] Preferably, the counter electrode comprises a base support layer, a conductive layer, a signal enhancement layer, and an outer film layer stacked sequentially, wherein,

[0030] The basic support layer includes any one of polyester, polyimide, and polydimethylsiloxane;

[0031] The conductive layer includes any one of gold, carbon, and conductive polymer materials;

[0032] The signal enhancement layer comprises carbon-based nanomaterials, including any one of carbon nanotubes, graphene, and carbon nanospheres.

[0033] The outer membrane layer is a hydrogen ion-selective outer membrane layer, which includes any one of perfluorosulfonic acid membrane, sulfonated polyether ether ketone, and sulfonated polysulfone; the outer membrane layer is modified with a hydrogen ion carrier.

[0034] Preferably, the reference electrode comprises a base support layer, a silver-silver chloride layer, and an outer film layer stacked sequentially, wherein,

[0035] The basic support layer includes any one of polyester, polyimide, and polydimethylsiloxane;

[0036] The outer membrane layer includes any one of polyvinyl alcohol, polyvinyl butyral, and polyurethane.

[0037] In another aspect, this invention proposes a time-division multiplexing dual-mode monitoring method for blood glucose and implantation wound infection, which utilizes the aforementioned sensor and includes the following steps:

[0038] The sensor's sensing electrodes are implanted into the human body. Based on the time-division multiplexing mechanism, the sensor's working cycle is set to alternately execute the blood glucose measurement cycle T1 and the wound pH measurement cycle T2.

[0039] During the blood glucose measurement cycle T1, the control module controls the switching circuit to connect the working electrode, counter electrode, and reference electrode in the three-electrode system to the timing current method circuit, forming a blood glucose measurement loop and measuring to obtain the initial blood glucose measurement result.

[0040] During wound pH measurement cycle T2, the control module controls the switching circuit to switch the counter electrode and reference electrode in the three-electrode system to the open-circuit voltage method circuit, forming a wound pH measurement loop and measuring the wound pH measurement data.

[0041] The initial blood glucose measurement results in adjacent T1 cycles are dynamically calibrated based on wound pH measurement data from the T2 cycle to obtain calibrated blood glucose measurement results; and the degree of wound infection measured by pH measurement data is compared with a preset threshold.

[0042] When the degree of wound infection exceeds the preset threshold, an infection warning signal is triggered; otherwise, the above detection steps are repeated.

[0043] Preferably, the measurement to obtain the initial blood glucose measurement result includes:

[0044] A voltage is applied between the working electrode and the reference electrode, wherein the reference electrode is used to provide a stable potential reference;

[0045] The current value generated by the enzyme-catalyzed reaction between the working electrode and the counter electrode is collected;

[0046] The current value is converted into a measurement value that is linearly related to blood glucose concentration.

[0047] Preferably, the measurement of wound pH data includes:

[0048] The potential difference between the counter electrode and the reference electrode is acquired, wherein the reference electrode is used to provide a stable potential reference.

[0049] The potential difference is converted into a measurement value that is linearly related to the logarithm of the hydrogen ion concentration;

[0050] The wound pH value is obtained based on the measured hydrogen ion concentration.

[0051] Preferably, the dynamic calibration of initial blood glucose measurement results in adjacent T1 cycles based on wound pH measurement data from the T2 cycle includes:

[0052] The current values ​​generated in adjacent T1 cycles are calibrated using wound pH measurement data from cycle T2. The calibration formula is as follows:

[0053] ,

[0054] Where I c For the calibrated current value, I m The measured current value is given by k1, the second-order influence coefficient of pH is given by k2, the absolute influence coefficient of pH is given by pH, and pH is the measured pH value. opt To calibrate the pH value of the test, 'a' is the intercept coefficient;

[0055] The calibrated current value is converted into a measurement value that is linearly related to blood glucose concentration, thus obtaining the calibrated blood glucose measurement result.

[0056] The beneficial effects of this invention are as follows:

[0057] (1) The sensor of the present invention has a dual-modal function based on a time-division multiplexing mechanism. Without adding additional electrodes, it expands the combination relationship of the original implantable sensor three-electrode system and optimizes the outer membrane material, such as using a hydrogen ion selective membrane on the counter electrode. While maintaining the electron transfer efficiency required for glucose detection, it enhances the selective response to hydrogen ions, allowing the sensor to switch alternately between blood glucose measurement mode and implantation wound pH measurement mode. There is no need to set up two independent monitoring systems. It realizes the synchronous monitoring of blood glucose and inflammation-related pH value (hydrogen ion concentration) at the implantation wound within a single sensor, which greatly simplifies the device structure, reduces the cost of use, and improves the convenience of monitoring. In addition, considering that an excessively large subcutaneous implantation device would cause serious discomfort to the human body and increase the risk of infection, the sensor of the present invention controls the size of the implantation device through electrode multiplexing, improving the comfort and safety of wearing.

[0058] (2) Since infection of the implantation wound of the sensor electrode may cause changes in the local physiological environment and thus affect the accuracy of blood glucose measurement, the sensor of the present invention can dynamically calibrate the blood glucose measurement results based on the pH measurement data related to the inflammation of the implantation wound, making the blood glucose measurement results more reliable and providing more accurate data support for blood glucose management of diabetic patients.

[0059] (3) The sensor of the present invention can provide real-time feedback on the progress of inflammation at the implantation site. When the degree of wound infection exceeds a preset threshold, an infection warning signal can be triggered, prompting the wearer to stop using the device and remove the implanted electrode in time. Through real-time monitoring and active warning, the sensor performance degradation caused by inflammation is avoided, thus extending its service life. On the other hand, the wearer's comfort and medical compliance are also improved. Attached Figure Description

[0060] Figure 1 This is a schematic diagram illustrating the composition of a time-division multiplexed dual-mode monitoring sensor for blood glucose and implanted wound infection according to an embodiment of the present invention;

[0061] Figure 2 This is a schematic diagram illustrating the working principle of the time-division multiplexing dual-mode monitoring sensor for blood glucose and implanted wound infection according to an embodiment of the present invention;

[0062] Figure 3 This is a current response diagram of glucose measurement after sensor implantation in Embodiment 1 of the present invention;

[0063] Figure 4 This is a monitoring diagram of pH changes around the wound after sensor implantation in Embodiment 1 of the present invention;

[0064] Figure 5 This is a comparison chart of the accuracy of blood glucose measurement data before and after calibration in Embodiment 1 of the present invention;

[0065] Figure 6 This is a current response diagram of glucose measurement after sensor implantation in Embodiment 2 of the present invention;

[0066] Figure 7 This is a monitoring diagram of pH changes around the wound after sensor implantation in Embodiment 2 of the present invention;

[0067] Figure 8 This is a comparison chart of the accuracy of blood glucose measurement data before and after calibration in Embodiment 2 of the present invention.

[0068] In the diagram: 1. Reference electrode; 2. Working electrode; 3. Counter electrode; 4. Switching circuit; 401. Switch 1; 402. Switch 2; 403. Switch 3; 404. Switch 4; 405. Switch 5; 5. Timing current method circuit; 6. Open circuit voltage method circuit; 7. Control module. Detailed Implementation

[0069] To make the objectives and technical solutions of this invention clearer and more complete, the invention will be further described in detail below with reference to embodiments. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. Modifications or equivalent substitutions made by those skilled in the art based on their understanding of the technical solutions of this invention, without departing from the spirit and scope of the technical solutions of this invention, are all within the scope of protection of this invention.

[0070] Unless otherwise specified, all reagents and materials involved in the embodiments of this invention are commercially available products and can be purchased through commercial channels.

[0071] See Figure 1 This invention provides a time-division multiplexing dual-mode monitoring sensor for blood glucose and implantation wound infection, comprising at least an electrically connected sensing unit and a detection unit. The sensing unit includes a three-electrode sensing electrode system, and the detection unit includes a detection circuit, a switching circuit 4, and a control module 7. It should be noted that in some embodiments, the detection unit is encapsulated in a sealed housing and implanted into the human body along with the sensing unit; in other embodiments, the detection unit is disposed on the human body surface near the implantation site of the sensing unit.

[0072] Specifically, the sensing electrode system of the three-electrode system includes a working electrode 2, a counter electrode 3, and a reference electrode 1. The working electrode 2 further comprises, from bottom to top, a base support layer, a conductive layer, a catalytic layer, an enzyme layer, and an outer membrane layer. The base support layer serves as the substrate of the working electrode 2 and is preferably made of a flexible material with excellent biocompatibility, such as polyester, polyimide, or polydimethylsiloxane. The conductive layer, located on the surface of the base support layer, is responsible for conducting the electrochemical current generated by the enzyme-catalyzed reaction to the detection circuit and can be made of materials such as gold, carbon, or conductive polymers. The catalytic layer, modified on the surface of the conductive layer, is used to accelerate the electron transfer process of the glucose oxidation reaction and is preferably made of materials such as platinum, palladium, or osmium. The enzyme layer, as the core functional layer of the working electrode 2, is loaded with glucose oxidase (GOD) or glucose dehydrogenase (GDH) to catalyze glucose in the tissue fluid surrounding the implantation site of the sensing electrode, thereby generating an electrochemical current signal for measurement. The outer membrane layer covers the surface of the enzyme layer, acting as a selective permeation and biological barrier, and is made of materials such as polyvinyl alcohol, polyvinyl butyral, or polyurethane. The outer membrane layer allows glucose to diffuse freely into the enzyme layer, while blocking large molecular interferences such as proteins in the tissue fluid. It can also reduce direct contact between the enzyme layer and the tissue, thus reducing the risk of immune rejection.

[0073] Furthermore, the counter electrode 3 comprises, from bottom to top, a base support layer, a conductive layer, a signal enhancement layer, and an outer film layer, stacked sequentially. The base support layer shares the same flexible substrate as the working electrode 2, and the conductive layer uses the same conductive material as the working electrode 2, namely gold, carbon, or a conductive polymer. The signal enhancement layer is modified on the surface of the conductive layer, significantly enhancing the response signal to hydrogen ions by increasing the specific surface area and active site density, thereby improving the electrode's sensitivity to changes in hydrogen ion concentration. This allows the detection circuit to more sensitively identify minute changes in hydrogen ion concentration during wound infection. Carbon-based nanomaterials such as carbon nanotubes, graphene, and carbon nanospheres are preferred materials. The outer film layer covers the surface of the signal enhancement layer and possesses selective hydrogen ion permeability and anti-interference functions. Polymer materials with ion selectivity, such as perfluorosulfonic acid membranes, sulfonated polyether ether ketones, and sulfonated polysulfones, are preferred materials. These materials contain a large number of hydrophilic groups such as sulfonic acid groups in their molecular structure, which can selectively allow hydrogen ions to pass through while effectively blocking other ions (such as sodium ions, potassium ions, etc.) and macromolecules (such as proteins, glucose, etc.) in tissue fluid. Furthermore, hydrogen ion carriers are modified in the outer membrane layer to selectively bind target hydrogen ions and trigger subsequent charge transfer and potential difference generation processes, thereby enabling the electrode to respond to hydrogen ions.

[0074] Furthermore, the reference electrode 1 comprises, from bottom to top, a base support layer, a silver-silver chloride layer, and an outer film layer. The base support layer shares the same flexible substrate with the working electrode 2 and the counter electrode 3. The silver-silver chloride layer, located on the surface of the base support layer, is the core functional layer of the reference electrode 1, providing a stable reference potential; its material consists of a silver substrate and a surface layer of silver chloride. The outer film layer covers the surface of the silver-silver chloride layer, serving functions of ion conduction, corrosion protection, and biocompatibility isolation. It uses the same materials as the working electrode 2, such as polyvinyl alcohol, polyvinyl butyral, or polyurethane.

[0075] Furthermore, the detection circuit includes a chronoamperometry circuit 5 for blood glucose measurement and an open-circuit voltage method circuit 6 for wound infection monitoring. The chronoamperometry circuit 5 uses an enzyme-catalyzed reaction to detect blood glucose concentration, while the open-circuit voltage method circuit 6 monitors the degree of wound infection via pH value (hydrogen ion concentration). During sensor operation, the switching circuit 4 switches the corresponding electrodes in the three-electrode system to the corresponding detection circuits to form detection loops for the corresponding measurement modes. The control module 7 controls the switching state of the switching circuit 4 to allow the sensor to alternate between blood glucose measurement mode and wound pH measurement mode via time-division multiplexing.

[0076] It should be noted that the time-division multiplexing method in this embodiment of the invention refers to the sensor performing different measurement tasks, namely blood glucose measurement and wound pH measurement, within different time periods by dividing the time into segments, thereby achieving electrode sharing. For example... Figure 1 As shown, in this embodiment of the invention, the sensor's operating cycle is set to alternately execute a blood glucose measurement cycle T1 and a wound pH measurement cycle T2. During the blood glucose measurement cycle T1, the control module 7 closes switches 402, 404, and 405 in the switching circuit 4, keeping switches 401 and 403 open, thereby connecting the working electrode 2, the counter electrode 3, and the reference electrode 1 to the timing current method circuit 5, forming a three-electrode measurement circuit. During the wound pH measurement cycle T2, the control module 7 closes switches 401 and 403 in the switching circuit 4, keeping switches 402, 404, and 405 open, thereby connecting the counter electrode 3 and the reference electrode 1 to the open-circuit voltage method circuit 6, forming a two-electrode measurement circuit. For ease of understanding, Figure 1 The switches in the switch circuit 4 shown are all schematic switches, which can be electronic switches, analog switches, etc.

[0077] Furthermore, such as Figure 2As shown, during blood glucose measurement, the chronoamperometry circuit 5 applies a voltage of 0.55V between the working electrode 2 and the reference electrode 1. The reference electrode 1 provides a stable potential reference during this process, ensuring that the voltage applied to the working electrode 2 remains within a preset range, thus guaranteeing the stability of the enzyme catalytic reaction and electron transfer process. Under the aforementioned voltage conditions, glucose in the tissue fluid diffuses through the outer membrane layer of the working electrode 2 to the enzyme layer, where it undergoes an oxidation reaction catalyzed by GOD or GDH to generate hydrogen peroxide (GOD system) or NADH (GDH system). Taking the GOD system as an example, the catalytic layer transfers electrons generated by the oxidation of hydrogen peroxide to the conductive layer, forming an electrochemical current proportional to the glucose concentration. This current is conducted through the conductive layer into the chronoamperometry circuit 5 and returns through the counter electrode 3 to form a closed loop. Therefore, by measuring the enzyme catalytic current value between the working electrode 2 and the counter electrode 3, the current glucose concentration in the tissue fluid can be inferred. Furthermore, since there is a linear proportional relationship between the glucose concentration in the tissue fluid and the blood glucose concentration, this method can be used to measure and obtain blood glucose fluctuations.

[0078] Furthermore, during wound pH measurement, the chronoamperometry circuit 5 is short-circuited, and no voltage is applied to the working electrode 2; the open-circuit voltage method circuit 6 directly collects the potential difference between the counter electrode 3 and the reference electrode 1. According to the Nernst equation, this potential difference is linearly related to the logarithm of the hydrogen ion activity (concentration) in the solution. By measuring the potential difference, the hydrogen ion concentration and pH value changes can be inferred, thereby determining the degree of wound infection. In this process, the reference electrode 1 provides a stable reference potential, ensuring the accuracy of the potential difference measurement. Specifically, in the above process, the counter electrode 3, as a hydrogen ion-selective response electrode, has a hydrogen ion-selective outer membrane layer on its surface. When hydrogen ions in the solution combine with L ion carriers (hydrogen ion carriers) in the membrane, hydrophobic ion pairs are formed, triggering charge transfer. The signal enhancement layer can quickly capture and amplify the weak charge changes generated by the combination of hydrogen ions and ion carriers. The conductive layer can quickly conduct these charges away, thereby generating a potential difference between the counter electrode 3 and the reference electrode 1. When the hydrogen ion concentration decreases, the binding equilibrium between the ion carrier and hydrogen ions shifts in the opposite direction, the complex dissociates, the charge transfer inside the electrode weakens, and the potential difference changes accordingly through the amplification effect of the signal enhancement layer.

[0079] Furthermore, the sensor also includes a data processing unit. It should be noted that in some embodiments, the data processing unit is integrated within the sensor. This unit receives and processes the blood glucose measurement signal output from the chronoamperometry circuit 5 and the wound pH measurement signal output from the open-circuit voltage method circuit 6. It dynamically calibrates the blood glucose measurement results based on the wound pH measurement data. Simultaneously, when the wound infection level measured by the pH measurement data exceeds a preset threshold, an infection warning signal is triggered. The data processing unit transmits the detection results to an external receiver (e.g., an instrument, mobile phone, fitness tracker, etc.) via communication methods including Bluetooth and wireless networks to provide a visual presentation of the detection results and provide warning prompts.

[0080] In other embodiments, the data processing unit is located in the external receiver of the sensor. The detection circuit directly transmits the collected electrochemical measurement signal to the data processing unit of the external receiver. The data processing unit receives and processes the blood glucose measurement signal output by the chronoamperometry circuit 5 and the wound pH measurement signal output by the open-circuit voltage method circuit 6. It also dynamically calibrates the blood glucose measurement result based on the wound pH measurement data. At the same time, when the wound infection degree measured by the pH measurement data exceeds a preset threshold, an infection warning signal is triggered.

[0081] Specifically, in the time-division multiplexed blood glucose measurement cycle T1, the data processing unit of the sensor's internal or external receiver calculates the glucose concentration in the tissue fluid from the current value output by the timing current method circuit 5, and obtains the blood glucose concentration value based on the linear proportional relationship between glucose concentration and blood glucose concentration. In the wound pH measurement cycle T2, the data processing unit of the sensor's internal or external receiver calculates the hydrogen ion concentration in the tissue fluid from the potential difference signal output by the open-circuit voltage method circuit 6, obtains the pH value, and determines the degree of wound infection in conjunction with clinical infection diagnostic criteria. The normal wound tissue fluid pH is approximately 7.2~7.4. When infection occurs (such as bacterial infection), the hydrogen ion concentration changes, and the pH value deviates from the normal value. The greater the deviation, the more severe the wound infection. When the infection degree reaches a preset threshold (e.g., pH ≤ 6.4 for more than 6 hours, or pH ≥ 7.4 for more than 12 hours), an alarm signal is triggered to remind the user to stop the test.

[0082] Furthermore, since the current value during blood glucose measurement is affected by the ambient pH value, the pH value obtained from the T2 cycle can be used to calibrate the current value of the adjacent T1 cycle, thereby obtaining the calibrated blood glucose measurement result. In some embodiments, the blood glucose measurement cycle T1 is set to 1 hour, with a sampling interval of 1 minute, so 60 current values ​​can be generated in one T1 cycle; the wound pH measurement cycle T2 is set to 1 minute, and measurements are continuously taken for 1 minute within this cycle, so a pH value is finally obtained in one T2 cycle. The above times can be adjusted according to actual needs. It should be understood that in some embodiments, the pH value obtained from the T2 cycle is used to calibrate the current value of the previous adjacent T1 cycle, and in other embodiments, the pH value obtained from the T2 cycle can also be used to calibrate the current value of the subsequent adjacent T1 cycle. The calibrated blood glucose value can be calculated from the calibrated current value, and the calibration formula for the current value is as follows:

[0083] ,

[0084] Where I c For the calibrated current value, I m The measured current value is given by k1, the second-order influence coefficient of pH is given by k2, the absolute influence coefficient of pH is given by pH, and pH is the measured pH value. opt The pH value is used for calibration testing, where 'a' is the intercept coefficient. It should be noted that pH... opt The calibrated pH value is obtained during in vitro calibration testing after the sensors from the same batch were manufactured.

[0085] The following further describes the method for simultaneously monitoring blood glucose and implantation wound infection using the time-division multiplexing dual-mode sensor of this invention, specifically including the following steps:

[0086] S1, the sensor's sensing electrodes are implanted into the human body; based on the time-division multiplexing mechanism, the sensor's working cycle is set to alternately execute the blood glucose measurement cycle T1 and the wound pH measurement cycle T2;

[0087] S2, During the blood glucose measurement cycle T1, the control module 7 controls the switching circuit 4 to connect the working electrode 2, the counter electrode 3 and the reference electrode 1 in the three-electrode system to the timing current method circuit 5 to form a blood glucose measurement loop and measure;

[0088] S3, the data processing unit of the sensor's internal or external receiver receives and processes the blood glucose measurement signal output by the timing current method circuit 5 to obtain the initial blood glucose measurement result. In this embodiment of the invention, the blood glucose measurement signal is the current value between the working electrode 2 and the counter electrode 3.

[0089] S4, during wound pH measurement cycle T2, control module 7 controls switch circuit 4 to switch counter electrode 3 and reference electrode 1 in the three-electrode system to open circuit voltage method circuit 6 to form wound pH measurement loop and measure;

[0090] S5, the data processing unit of the sensor's internal or external receiver receives and processes the wound pH measurement signal output by the open-circuit voltage method circuit 6 to obtain wound pH measurement data. In this embodiment of the invention, the wound pH measurement signal is the potential difference signal value between the counter electrode 3 and the reference electrode 1.

[0091] S6. Based on the wound pH measurement data of the T2 cycle, dynamically calibrate the initial blood glucose measurement results in the T1 cycle that are adjacent to the T2 cycle and share the same local physiological environment to obtain the calibrated blood glucose measurement results; and compare the wound infection degree measured by the pH measurement data with the preset threshold.

[0092] S7. When the degree of wound infection exceeds the preset threshold, an infection warning signal is triggered, prompting the user to remove the sensing electrode and stop the test; otherwise, repeat steps S2-S6.

[0093] Example 1

[0094] The implantable sensing electrode in this embodiment adopts a three-electrode configuration, including a working electrode 2, a counter electrode 3, and a reference electrode 1. All three electrodes are based on a polyimide base support layer. The working electrode 2 has a gold conductive layer, a platinum nanoparticle catalytic layer, an enzyme layer immobilized with glucose oxidase, and an outer membrane material of polyurethane. The counter electrode 3 has a gold conductive layer, a carbon nanotube signal enhancement layer, and an outer membrane layer of perfluorosulfonic acid. The reference electrode 1 has a silver-silver chloride mixed layer on its base support layer, and an outer membrane material of polyurethane.

[0095] The sensing and detection process begins immediately after the electrode is inserted subcutaneously via a guide needle. A three-electrode system is used to measure the glucose concentration in the subcutaneous tissue fluid. Switching circuit 4 connects the electrode to the timing current method circuit 5 for measurement. A voltage of 0.55 V is applied between the working electrode 2 and the reference electrode 1. By measuring the current value between the working electrode 2 and the counter electrode 3, the current glucose concentration in the tissue fluid can be inferred. The sampling interval is 1 minute. Since the glucose concentration in the tissue fluid is directly proportional to the blood glucose concentration, this method can be used to measure and obtain blood glucose fluctuations. Figure 3 ).

[0096] The switching circuit 4 switches to the open-circuit voltage method circuit 6 every hour, using the counter electrode 3 and the reference electrode 1 to measure the open-circuit voltage for 1 minute. During the open-circuit voltage measurement, the timing current method circuit 5 is in a short-circuit state and no voltage is applied to the working electrode 2. The membrane potential on the counter electrode 3 can be described by the Nernst equation; as the pH increases, the hydrogen ion concentration decreases, and the potential decreases.

[0097] During normal testing, the electrode implantation process causes skin trauma, causing the pH value to slowly rise from the initial slightly acidic environment to a neutral environment. Later, as the wound heals, the pH value will decrease again. The measured pH value change curve is shown below. Figure 4 As shown. The current value measured by the three-electrode chronoamperometry at 0.55V is also affected by the ambient pH value, therefore it can be combined with... Figure 4 The pH data was used to further calibrate the current measurement. During the measurement process, blood samples were collected for biochemical analysis to calibrate blood glucose levels. Simultaneously, an implanted sensor was used to measure blood glucose levels at the same time points, and calibration was performed using a formula.

[0098] ,

[0099] Where I c For the calibrated current value, I m The measured current value is given by k1, the second-order influence coefficient of pH is given by k2, the absolute influence coefficient of pH is given by pH, and pH is the measured pH value. opt The pH value is used for calibration testing, and 'a' is the intercept coefficient.

[0100] like Figure 5 As shown, the calibrated sensor data is closer to the biochemical analysis calibration value, indicating that the data calibrated according to the pH value is more accurate.

[0101] Example 2

[0102] The implantable sensing electrode in this embodiment adopts a three-electrode configuration, including a working electrode 2, a counter electrode 3, and a reference electrode 1. All three electrodes are based on a polyethylene terephthalate (PET) base support layer. The working electrode 2 has a gold conductive layer, a platinum nanoparticle catalytic layer, an enzyme layer immobilized with glucose oxidase, and an outer membrane material of polyurethane-polyethylene glycol. The counter electrode 3 has a gold conductive layer, a graphene sheet-like signal enhancement layer, and an outer membrane layer of sulfonated polyetheretherketone (PEEK). The reference electrode 1 has a silver-silver chloride hybrid layer on its base support layer and an outer membrane material of polyvinyl alcohol.

[0103] The sensing and detection process begins immediately after the electrode is inserted subcutaneously via a guide needle. A three-electrode system is used to measure the glucose concentration in the subcutaneous tissue fluid. Switching circuit 4 connects the electrode to the timing current method circuit 5 for measurement. A 0.5 V voltage is applied between the working electrode 2 and the reference electrode 1. By measuring the current value between the working electrode 2 and the counter electrode 3, the current glucose concentration in the tissue fluid can be inferred. The sampling interval is 1 minute. Since the glucose concentration in the tissue fluid is directly proportional to the blood glucose concentration, this method can be used to measure and obtain blood glucose fluctuations. Figure 6 ).

[0104] The switching circuit 4 switches to the open-circuit voltage method circuit 6 every hour, using the counter electrode 3 and the reference electrode 1 to measure the open-circuit voltage for 1 minute. During the open-circuit voltage measurement, the timing current method circuit 5 is in a short-circuit state and no voltage is applied to the working electrode 2. The membrane potential on the counter electrode 3 can be described by the Nernst equation; as the pH increases, the hydrogen ion concentration decreases, and the potential decreases.

[0105] Because the electrode implantation process causes skin trauma, the pH value will slowly rise from the original slightly acidic environment to a neutral environment. Bacterial infection of the wound causes abnormal metabolites in the microenvironment, leading to an increase in local pH. The measured pH change curve is shown in the figure. Figure 7 As shown. During the measurement process, blood samples are collected for biochemical analysis to calibrate blood glucose levels. Simultaneously, an implantable sensor is used to measure blood glucose levels at the same time points, such as... Figure 8 As shown, the calibrated sensor data is closer to the biochemical analysis calibration value, indicating that the data calibrated according to the pH value is more accurate. Before calibration, 50% of the data points fell outside the 15% error line, while after calibration, all data points were within the 15% error range.

[0106] like Figure 7 As shown, the local pH value of the wound remained at around 8 for a long time, indicating that the wound infection was relatively serious. Therefore, the electrode was removed early on the 6th day after implantation to stop the test.

Claims

1. A time-division multiplexing dual-mode monitoring sensor for blood glucose and implantation wound infection, characterized in that, It includes at least a sensing unit and a detection unit that are electrically connected, wherein, The sensing unit includes a three-electrode system of sensing electrodes, which includes a working electrode (2), a counter electrode (3), and a reference electrode (1). The detection unit includes: The detection circuit includes a timing current method circuit (5) for blood glucose measurement and an open-circuit voltage method circuit (6) for wound pH measurement. Switching circuit (4), used for: The working electrode (2), the counter electrode (3) and the reference electrode (1) are connected to the chronoamperometry circuit (5) to form a three-electrode blood glucose measurement circuit. Alternatively, the counter electrode (3) and the reference electrode (1) can be connected to the open-circuit voltage method circuit (6) to form a wound pH measurement circuit with two electrodes; the counter electrode (3) includes a base support layer, a conductive layer, a signal enhancement layer and an outer membrane layer stacked in sequence, wherein the outer membrane layer is a hydrogen ion selective outer membrane layer, and the hydrogen ion selective outer membrane layer includes any one of perfluorosulfonic acid membrane, sulfonated polyether ether ketone, and sulfonated polysulfone, and the outer membrane layer is modified with a hydrogen ion carrier; The control module (7) is used to control the switching state of the switching circuit (4) so ​​that the sensor can alternately perform blood glucose measurement and wound pH measurement through time-division multiplexing. The sensor also includes a data processing unit, which is integrated inside the sensor or in an external receiver, and is used for: Receive and process the measurement signal output by the detection circuit; The blood glucose measurement results are dynamically calibrated based on the wound pH measurement data.

2. The sensor according to claim 1, characterized in that, The data processing unit is also used for: The degree of wound infection is determined based on pH measurement data. When the degree of wound infection exceeds a preset threshold, an infection warning signal is triggered.

3. The sensor according to claim 1 or 2, characterized in that, The control module (7) controls the switching state of the switching circuit (4), enabling the sensor to alternately perform blood glucose measurement and wound pH measurement via time-division multiplexing, including: Set the sensor's operating cycle to alternate between the blood glucose measurement cycle T1 and the wound pH measurement cycle T2; During the blood glucose measurement cycle T1, the switching circuit (4) is controlled to switch to the blood glucose measurement circuit; During the wound pH measurement cycle T2, the switching circuit (4) is controlled to switch to the wound pH measurement circuit; The durations of T1 and T2 are determined based on measurement requirements.

4. The sensor according to claim 1 or 2, characterized in that, The working electrode (2) comprises a base support layer, a conductive layer, a catalytic layer, an enzyme layer, and an outer membrane layer stacked sequentially, wherein, The basic support layer includes any one of polyester, polyimide, and polydimethylsiloxane; The conductive layer includes any one of gold, carbon, and conductive polymer materials; The catalyst layer comprises any one of platinum, palladium, and osmium; The enzyme layer is loaded with glucose oxidase or glucose dehydrogenase. The outer membrane layer includes any one of polyvinyl alcohol, polyvinyl butyral, and polyurethane.

5. The sensor according to claim 1 or 2, characterized in that, In the counter electrode (3), The basic support layer includes any one of polyester, polyimide, and polydimethylsiloxane; The conductive layer includes any one of gold, carbon, and conductive polymer materials; The signal enhancement layer comprises carbon-based nanomaterials, including any one of carbon nanotubes, graphene, and carbon nanospheres.

6. The sensor according to claim 1 or 2, characterized in that, The reference electrode (1) comprises a base support layer, a silver-silver chloride layer, and an outer film layer stacked sequentially, wherein, The basic support layer includes any one of polyester, polyimide, and polydimethylsiloxane; The outer membrane layer includes any one of polyvinyl alcohol, polyvinyl butyral, and polyurethane.

7. A time-division multiplexing dual-mode monitoring method for blood glucose and implantation wound infection, characterized in that, The application of the sensor as described in any one of claims 1-6 includes the following steps: The sensor's sensing electrodes are implanted into the human body. Based on the time-division multiplexing mechanism, the sensor's working cycle is set to alternately execute the blood glucose measurement cycle T1 and the wound pH measurement cycle T2. During the blood glucose measurement cycle T1, the control module (7) controls the switching circuit (4) to connect the working electrode (2), the counter electrode (3) and the reference electrode (1) in the three-electrode system to the timing current method circuit (5) to form a blood glucose measurement loop and measure to obtain the initial blood glucose measurement result; During the wound pH measurement cycle T2, the control module (7) controls the switching circuit (4) to switch the counter electrode (3) and reference electrode (1) in the three-electrode system to the open-circuit voltage method circuit (6) to form a wound pH measurement loop and measure and obtain wound pH measurement data. The initial blood glucose measurement results in adjacent T1 cycles are dynamically calibrated based on wound pH measurement data from the T2 cycle to obtain calibrated blood glucose measurement results; and the degree of wound infection measured by pH measurement data is compared with a preset threshold. When the degree of wound infection exceeds the preset threshold, an infection warning signal is triggered; otherwise, the above detection steps are repeated.

8. The monitoring method according to claim 7, characterized in that, The measurement to obtain the initial blood glucose measurement results includes: A voltage is applied between the working electrode (2) and the reference electrode (1), wherein the reference electrode (1) is used to provide a stable potential reference; The current value generated by the enzyme catalytic reaction between the working electrode (2) and the counter electrode (3) is collected; The current value is converted into a measurement value that is linearly related to blood glucose concentration.

9. The monitoring method according to claim 7, characterized in that, The measured wound pH data includes: The potential difference between the counter electrode (3) and the reference electrode (1) is collected, wherein the reference electrode (1) is used to provide a stable potential reference; Based on the linear relationship between the potential difference and the logarithm of the hydrogen ion concentration, the potential difference is converted into a measured value of hydrogen ion concentration. The wound pH value is obtained based on the measured hydrogen ion concentration.

10. The monitoring method according to claim 7, characterized in that, The dynamic calibration of initial blood glucose measurements in adjacent T1 cycles based on wound pH measurement data from the T2 cycle includes: The current values ​​generated in adjacent T1 cycles are calibrated using wound pH measurement data from cycle T2. The calibration formula is as follows: ， Where I c For the calibrated current value, I m The measured current value is given by k1, the second-order influence coefficient of pH is given by k2, the absolute influence coefficient of pH is given by pH, and pH is the measured pH value. opt To calibrate the pH value of the test, 'a' is the intercept coefficient; The calibrated current value is converted into a measurement value that is linearly related to blood glucose concentration, thus obtaining the calibrated blood glucose measurement result.

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