An implantable blood glucose sensor outer membrane swelling calibration method and system based on ion concentration monitoring

Abstract

The application discloses an implantable blood glucose sensor outer membrane swelling calibration method based on ion concentration monitoring, which comprises the following steps: establishing a target ion concentration-functional outer membrane swelling kinetics relationship model, determining each parameter in the model through in-vitro simulation test; acquiring an initial electrochemical signal in subcutaneous tissue fluid by using a blood glucose sensing unit; acquiring the concentration of a target ion by using an ion concentration sensing unit; correcting the outer membrane swelling rate based on the target ion concentration-functional outer membrane swelling kinetics relationship model; and compensating and calibrating the initial electrochemical signal to obtain an electrochemical signal and a blood glucose concentration value after swelling correction. The application also discloses a system for executing the above method. The method effectively overcomes the problem of insufficient measurement accuracy caused by outer membrane swelling in the initial implantation stage, significantly improves the accuracy and reliability of the sensor in the key start-up stage, provides more timely and reliable blood glucose dynamic information for users, and has important application value.

Description

Technical Field

[0001] This invention belongs to the field of electrochemical biosensor technology, specifically relating to a method and system for calibrating the outer membrane swelling of an implantable blood glucose sensor based on ion concentration monitoring. Background Technology

[0002] Implantable glucose sensors are a key technology for continuous glucose monitoring, and their core typically comprises three closely cooperating parts: an enzyme-sensing electrode, an electronic signal processing unit, and a functional outer membrane covering the surface of the enzyme-sensing electrode. The enzyme-sensing electrode utilizes an immobilized enzyme to catalyze a specific electrochemical reaction in glucose, generating a measurable electrochemical signal. The electronic signal processing unit is responsible for amplifying, filtering, and digitizing the weak raw signal generated by the electrode, providing a basis for subsequent analysis. The functional outer membrane surrounding the enzyme-sensing electrode plays a crucial multiple role:

[0003] (1) It plays a role in mass transfer balance. By regulating the amount of essential small molecule substrates such as glucose and oxygen diffused to the electrode surface, it balances the substrate ratio of the enzyme-catalyzed reaction and expands the linear detection range of the electrode.

[0004] (2) As a selective permeability barrier, it can effectively block larger molecules and cells in the blood and remove the permeation of some common electrochemical interferences, ensuring high selectivity of the measurement signal.

[0005] (3) It is also a biocompatible interface that comes into direct contact with human tissues, which can minimize the host’s immune rejection response and fibrin encapsulation, and maintain the long-term stability and physiological response performance of the sensing interface.

[0006] However, a significant challenge in practical applications of sensors employing such functional outer membranes is insufficient measurement accuracy in the initial post-implantation period, particularly within the first 24 hours, making it difficult to meet the demand for immediate and reliable monitoring. The core reason for this bottleneck lies in the interaction between the sensor's functional outer membrane and the subcutaneous tissue fluid environment. Specifically, after implantation, the outer membrane material begins to absorb tissue fluid and swell, a continuous physicochemical process that continues until equilibrium is reached. This dynamic swelling process profoundly affects sensor performance in two ways:

[0007] (1) It changed the thickness of the diffusion layer and the mass transfer resistance of the covering electrode, which interfered with the stable transport rate of glucose and oxygen to the reaction site.

[0008] (2) The selective permeability of the membrane material to glucose and potential interfering substances is in a state of constant change before swelling reaches equilibrium.

[0009] The combined effect of the above factors causes the sensor's output measurement signal to change continuously and unstablely in the initial stage after implantation, which severely restricts its measurement accuracy and reliability in the early stages of user application. Summary of the Invention

[0010] To address the aforementioned problems, the present invention aims to provide a method and system for calibrating the swelling of the outer membrane of an implantable blood glucose sensor based on ion concentration monitoring. Research has revealed a quantifiable and strong correlation between the concentrations of specific key ions such as sodium, chloride, and potassium ions in subcutaneous tissue fluid and the swelling kinetics rate of the sensor's outer membrane material. Based on this important finding, the present invention proposes establishing a precise model relating ion concentration to the outer membrane swelling rate. After sensor implantation, the concentrations of key ions in the surrounding tissue fluid are monitored in real time, and the aforementioned model is used to dynamically predict the current swelling state of the outer membrane and its specific impact on the glucose sensing signal. Based on this prediction result, the original glucose measurement data is then compensated and calibrated in real time.

[0011] To achieve the above objectives, the present invention adopts the following technical solution:

[0012] This invention proposes a method for calibrating the outer membrane swelling of an implantable blood glucose sensor based on ion concentration monitoring, comprising the following steps:

[0013] A target ion concentration-functional outer membrane swelling kinetics model was established, and the parameters in the model were determined through in vitro simulation tests.

[0014] A sensor containing a blood glucose sensing unit and an ion concentration sensing unit is implanted in the body, and the blood glucose sensing unit is used to measure and acquire the initial electrochemical signal of glucose concentration conversion in subcutaneous tissue fluid.

[0015] The concentration of at least one target ion in the subcutaneous tissue fluid is measured and obtained using the ion concentration sensing unit.

[0016] Based on the target ion concentration-functional outer membrane swelling kinetics model, the difference in swelling rate of the functional outer membrane of the blood glucose sensing unit during the measurement process is corrected to obtain the swelling correction factor at different times.

[0017] The initial electrochemical signal at the corresponding time point is compensated and calibrated using the swelling correction factor to obtain the swelling-corrected electrochemical signal and blood glucose concentration value.

[0018] Preferably, the target ion includes one or more of sodium ions, chloride ions, potassium ions, and calcium ions.

[0019] Preferably, the formula for the target ion concentration-functional outer membrane swelling kinetics model is as follows:

[0020]

[0021] Where S(t) is the functional outer membrane swelling degree at time t, S ∞ c represents the maximum swelling degree of the functional outer membrane at equilibrium. i Let a be the concentration of the i-th target ion. i is the weighting coefficient for the i-th target ion, K is the intrinsic swelling rate constant of the functional outer membrane material, and n is the diffusion kinetics exponent;

[0022] The swelling correction factor is determined by and The ratio or a functional relationship based on this ratio is used to quantify the degree of interference of functional outer membrane swelling on electrochemical signals.

[0023] Preferably, the blood glucose sensing unit includes an enzyme working electrode, a counter electrode, a reference electrode, and a blood glucose measurement circuit electrically connected to each electrode via an electrode connector, wherein the functional outer membrane covers the surface of the enzyme working electrode.

[0024] Preferably, the blood glucose measurement circuit adopts a chronoamperometry circuit, in which the electrochemical reaction current between the enzyme working electrode and the counter electrode is collected as the initial electrochemical signal of glucose concentration conversion during measurement.

[0025] Preferably, the ion concentration sensing unit includes a reference electrode and at least one ion indicator electrode, and at least one ion concentration measuring circuit electrically connected to the corresponding electrode via an electrode connector. The surface of the ion indicator electrode is coated with a corresponding ion-selective outer membrane, which is selected from any one of sodium ion-selective outer membrane, chloride ion-selective outer membrane, potassium ion-selective outer membrane, and calcium ion-selective outer membrane.

[0026] Preferably, the ion concentration measuring circuit adopts the open-circuit voltage method circuit. During measurement, the open-circuit voltage difference between each ion indicator electrode and the reference electrode is collected, and the concentration of the corresponding target ion in the tissue fluid is inferred from the difference.

[0027] Preferably, the measurement and acquisition of the concentration of at least one target ion in the subcutaneous tissue fluid includes:

[0028] Within the first 24 hours after sensor implantation, the concentration of target ions was measured every T1 time.

[0029] The concentration of the target ion was measured every T2 time interval after 24 hours.

[0030] T1 and T2 are determined based on actual measurement requirements, and T1 <T2。

[0031] Preferably, T1 is set to 5 minutes and T2 is set to 2 hours.

[0032] Preferably, the initial electrochemical signal at the corresponding time point is compensated and calibrated using the swelling correction factor based on the following calibration algorithm to obtain the swelling-corrected electrochemical signal and blood glucose concentration value, wherein the algorithm formula is:

[0033]

[0034]

[0035] Among them, I C For the calibrated electrochemical signal, I raw The raw electrochemical signal detected by the blood glucose sensing unit, K c S is the calibration coefficient, and S(t) is the functional outer membrane swelling degree at time t. ∞ G represents the maximum swelling degree of the functional outer membrane at equilibrium. Cal S0 represents the calibrated blood glucose concentration, and S0 represents the baseline sensitivity of the sensor's functional outer membrane in equilibrium.

[0036] The swelling correction factor is defined in the formula. This item is used to compensate for and correct the interference of outer membrane swelling in the original electrochemical signal.

[0037] In another aspect, this invention also proposes an implantable blood glucose sensor outer membrane swelling calibration system based on ion concentration monitoring, used to perform the above-mentioned implantable blood glucose sensor outer membrane swelling calibration method, comprising:

[0038] The sensing module includes a blood glucose sensing unit and an ion concentration sensing unit, wherein...

[0039] The blood glucose sensing unit is used to measure and acquire the initial electrochemical signal of glucose concentration conversion in subcutaneous tissue fluid;

[0040] The ion concentration sensing unit is used to measure and acquire the concentration of at least one target ion in the subcutaneous tissue fluid;

[0041] The calibration module includes a swelling correction unit and a compensation calibration unit, wherein...

[0042] The swelling correction unit is used to correct the difference in swelling rate of the functional outer membrane of the blood glucose sensing unit during the measurement process based on the target ion concentration-functional outer membrane swelling kinetics model, and to obtain the swelling correction factor at different times.

[0043] The compensation calibration unit is used to compensate and calibrate the initial electrochemical signal at the corresponding time using the swelling correction factor to obtain the swelling-corrected electrochemical signal and blood glucose concentration value.

[0044] The beneficial effects of this invention are as follows:

[0045] (1) This invention establishes a data relationship model between ion concentration and outer membrane swelling. By adding an ion concentration sensing unit to the sensor to obtain local ion concentration data of the implantation site, it is possible not only to monitor the concentration of specific key ions in the subcutaneous tissue fluid in real time, but also to correct the difference in swelling rate of the functional outer membrane of the blood glucose sensing unit by the concentration of specific key ions, thereby compensating and calibrating the original glucose measurement data in real time.

[0046] (2) This invention directly corrects the root cause of glucose signal drift during the functional outer membrane swelling period, effectively overcoming the problem of insufficient measurement accuracy caused by outer membrane swelling in the early stage of implantation, especially in the first 24 hours. It significantly improves the accuracy and reliability of the sensor in the critical start-up stage, greatly shortens the user's waiting time, and enables the sensor to be "used immediately after implantation". This provides users with more timely and reliable dynamic blood glucose information and has important application value. Attached Figure Description

[0047] Figure 1 This is a schematic flowchart of the outer membrane swelling calibration method for an implantable blood glucose sensor based on ion concentration monitoring, according to an embodiment of the present invention.

[0048] Figure 2 This is a schematic diagram of the composition of the outer membrane swelling calibration system for an implantable blood glucose sensor based on ion concentration monitoring, according to an embodiment of the present invention.

[0049] Figure 3 This is a graph of the original glucose current collected by the blood glucose sensing unit in Example 1;

[0050] Figure 4 This is a graph showing the trend of potassium ion concentration in the tissue fluid in Example 1.

[0051] Figure 5 This is the glucose current curve after swelling correction in Example 1;

[0052] Figure 6 This is a comparison chart of the accuracy of blood glucose measurement data before and after calibration in Example 1;

[0053] Figure 7 The above are glucose current curves before and after calibration in Example 2;

[0054] Figure 8This is a graph showing the trend of potassium ion concentration in the tissue fluid in Example 2;

[0055] Figure 9 This is a graph showing the trend of calcium ion concentration in the tissue fluid in Example 2.

[0056] Figure 10 This is a comparison chart of the accuracy of blood glucose measurement data before and after calibration in Example 2.

[0057] In the diagram: 1. Enzyme working electrode; 2. Counter electrode; 3. Reference electrode; 4. Ion indicator electrode; 5. Electrode connector; 6. Blood glucose measurement circuit; 7. Ion concentration measurement circuit. Detailed Implementation

[0058] 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. Unless otherwise specified, the reagents and materials involved in the embodiments of this invention are all commercially available products and can be purchased through commercial channels.

[0059] See Figure 1 This invention provides a method for calibrating the outer membrane of an implantable blood glucose sensor based on ion concentration monitoring, comprising the following steps:

[0060] S1. Establish a kinetic model of target ion concentration-functional outer membrane swelling relationship, and determine the parameters in the model through in vitro simulation tests.

[0061] Research has revealed a quantifiable and strong correlation between the concentrations of specific key ions such as sodium, chloride, potassium, and calcium ions in subcutaneous tissue fluid and the swelling kinetics of the sensor's functional outer membrane material. Therefore, this invention first establishes a model for the relationship between target ion concentration and functional outer membrane swelling kinetics. The model formula is as follows:

[0062]

[0063] Where S(t) is the functional outer membrane swelling degree at time t, S ∞ c represents the maximum swelling degree of the functional outer membrane at equilibrium. i Let a be the concentration of the i-th target ion. i denoted as the weighting coefficient for the i-th target ion, K is the intrinsic swelling rate constant of the functional outer membrane material, and n is the diffusion kinetics exponent.

[0064] Furthermore, the parameters in the model were determined through in vitro simulated environmental testing. Using material A as the material for the functional outer membrane, and taking the i-th target ion as an example, specifically, the concentration gradient of the i-th ion was adjusted and set at 37℃. Using instruments such as a laser confocal microscope and a quartz crystal microbalance, the swelling kinetic curves of the outer membrane material A under different ion concentrations were simultaneously measured. A quantitative mapping relationship between ion concentration and swelling parameters was constructed, and the weighting coefficient c of the i-th target ion was determined. i The diffusion kinetic index n was determined. Similarly, the weighting coefficients and diffusion kinetic indices of other target ions were determined using the same method. Simultaneously, the maximum swelling degree S of the outer membrane material A at equilibrium was obtained by prolonged immersion in pure water. ∞ And its intrinsic swelling rate constant K.

[0065] S2, a sensor containing a blood glucose sensing unit and an ion concentration sensing unit is implanted in the body, and the blood glucose sensing unit is used to measure and acquire the initial electrochemical signal of glucose concentration conversion in subcutaneous tissue fluid.

[0066] Specifically, such as Figure 2 As shown, the blood glucose sensing unit in this embodiment of the invention includes an enzyme working electrode 1, a counter electrode 2, a reference electrode 3, and a blood glucose measurement circuit 6 electrically connected to each electrode via an electrode connector 5. It should be understood that the surface of each electrode is covered with a corresponding functional outer membrane, which is a conventional technique in the art. However, the functional outer membranes involved in this invention specifically refer to the functional outer membrane covering the surface of the enzyme working electrode 1. The materials include, but are not limited to, polyurethane-polyvinyl alcohol copolymer, polyvinyl alcohol, polyvinyl butyral, and polyurethane, which play a role in conduction balance, selective barrier, and biocompatibility during sensor operation. Simultaneously, it is precisely due to the swelling phenomenon of this functional outer membrane that the sensor experiences insufficient measurement accuracy in the initial stage after implantation. Further, preferably, the blood glucose measurement circuit 6 employs a chronoamperometry circuit. During measurement, a voltage of 0.55V is applied between the enzyme working electrode 1 and the reference electrode 3, and the electrochemical reaction current between the enzyme working electrode 1 and the counter electrode 2 is collected as the initial electrochemical signal. The preferred time interval for collection is 1 minute.

[0067] S3, using an ion concentration sensing unit to measure and acquire the concentration of at least one target ion in the subcutaneous tissue fluid.

[0068] Specifically, the ion concentration sensing unit includes a reference electrode 3 and at least one ion indicator electrode 4, as well as at least one ion concentration measuring circuit 7 electrically connected to the corresponding electrodes via electrode connectors 5. The surface of the ion indicator electrode 4 is coated with a corresponding ion-selective outer membrane. Since the target ions detected by the ion concentration sensing unit include one or more of sodium ions, chloride ions, potassium ions, and calcium ions, the ion-selective outer membrane coated on the surface of each of the at least one ion indicator electrode 4 is selected from any one of sodium ion selective outer membranes, chloride ion selective outer membranes, potassium ion selective outer membranes, and calcium ion selective outer membranes. Figure 2 The diagram illustrates the connection structure of the ion concentration sensing unit when the ion indicator electrode 4 is a single electrode. Specifically, the ion indicator electrode 4 and the reference electrode 3 are electrically connected to the ion concentration measurement circuit 7 via electrode connectors 5. It should be understood that when there are multiple ion indicator electrodes 4, the ion concentration sensing unit requires an equal number of ion concentration measurement circuits 7. In this case, multiple ion indicator electrodes 4 share a single reference electrode 3, and each ion indicator electrode 4 and the reference electrode 3 independently form a two-electrode system, and are electrically connected to a corresponding ion concentration measurement circuit 7. It should be noted that, in order to reduce the size of the sensor structure and avoid creating a large incision during implantation, increasing implantation discomfort, and the risk of infection at the implantation site, in this embodiment of the invention, each ion indicator electrode 4 and the enzyme working electrode 1 are located on the same flexible substrate of the sensor and share the same reference electrode 3. It should be understood that in other embodiments, the ion indicator electrode 4 and the enzyme working electrode 1 may also be disposed on different substrates, each using a separate reference electrode 3.

[0069] Preferably, the ion concentration measurement circuit 7 adopts an open-circuit voltage method circuit. During measurement, the open-circuit voltage difference between the ion indicator electrode 4 and the reference electrode 3 is collected, and the target ion concentration in the tissue fluid is inversely deduced through the difference. It should be noted that when there is one ion indicator electrode 4, the open-circuit voltage difference between this ion indicator electrode 4 and the reference electrode 3 can be directly collected; when there are multiple ion indicator electrodes 4, there are also multiple open-circuit voltage measurement circuits accordingly. The multiple ion indicator electrodes 4 share one reference electrode 3 but are connected to different open-circuit voltage measurement circuits. That is, each ion indicator electrode 4 and the shared reference electrode 3 form a two-electrode system group, and each two-electrode system group is independently connected to an open-circuit voltage measurement circuit. By collecting the open-circuit voltage differences between each two-electrode system group, the concentrations of multiple target ions can be obtained. It should be understood that in the initial stage of sensor implantation, especially within the initial 24 hours after implantation, after the functional outer membrane contacts the subcutaneous tissue fluid environment, it continuously absorbs the tissue fluid and swells, resulting in the drift of the glucose measurement signal; after about 24 hours, the swelling basically reaches equilibrium. Therefore, in the embodiment of the present invention, within the initial 24 hours after sensor implantation, the target ion concentration is measured every T1 time, and after 24 hours, the target ion concentration is measured every T2 time, and T1 < T2. Preferably, the time of T1 is set to 5 minutes to increase the measurement frequency of the target ion concentration and effectively calibrate the glucose electrochemical signal in the corresponding time period in the initial stage of implantation; the time of T2 is set to 2 hours. At this time, the measurement frequency can be reduced, and the main purpose of continuous monitoring is to prevent large fluctuations in the subsequent ion concentration.

[0070] It should be noted that the electrodes and circuits involved in the blood glucose sensing unit and the ion concentration sensing unit are all conventional technical means in the art, so the structures and material compositions of each electrode and the structures and working principles of each circuit will not be elaborated here.

[0071] S4. Based on the target ion concentration-functional outer membrane swelling kinetics relationship model established in step S1, correct the swelling rate differences of the functional outer membrane of the blood glucose sensing unit during the measurement process to obtain the swelling correction factors at different times.

[0072] In this step, after obtaining the concentration of at least one target ion at time t through step S3, substitute it into the target ion concentration-functional outer membrane swelling kinetics relationship model with the determined parameters in step S1 to obtain the swelling degree S(t) of the functional outer membrane at time t. The swelling correction factor is determined by and the ratio of or a functional relationship based on this ratio, which is used to quantify the interference degree of outer membrane swelling on the electrochemical signal. The method for obtaining the swelling correction factors at other times is the same as above.

[0073] S5. The swelling correction factor obtained in step S4 is used to compensate and calibrate the initial electrochemical signal at the corresponding time in step S2 to obtain the swelling-corrected electrochemical signal and blood glucose concentration value.

[0074] Specifically, the raw glucose measurement electrochemical signal output by the blood glucose sensing unit is compensated and calibrated in real time using the following calibration algorithm to obtain the glucose electrochemical signal and blood glucose concentration value after swelling correction. The algorithm formula is:

[0075]

[0076]

[0077] Among them, I C This is the calibrated electrochemical signal;

[0078] I raw The raw electrochemical signal detected by the blood glucose sensing unit of the sensor;

[0079] K c The calibration coefficients are determined by the same batch of sensors after factory calibration.

[0080] S(t) represents the functional outer membrane swelling degree at time t, which is calculated using the target ion concentration-functional outer membrane swelling kinetics model.

[0081] S ∞ The maximum swelling degree of the functional outer membrane at equilibrium;

[0082] The swelling correction factor is in the formula This item is used to compensate for and correct the interference of outer membrane swelling in the original electrochemical signal;

[0083] G Cal This refers to the calibrated blood glucose concentration.

[0084] S0 is the reference sensitivity of the sensor's functional outer membrane in equilibrium. It is calibrated after factory calibration and reflects the relationship between the electrochemical signal and blood glucose concentration when there is no swelling interference.

[0085] See Figure 2 This invention also provides an implantable blood glucose sensor outer membrane swelling calibration system based on ion concentration monitoring, comprising:

[0086] The sensing module includes a blood glucose sensing unit and an ion concentration sensing unit. The blood glucose sensing unit is used to measure and acquire the initial electrochemical signal of glucose concentration conversion in subcutaneous tissue fluid; the ion concentration sensing unit is used to measure and acquire the concentration of at least one target ion in subcutaneous tissue fluid.

[0087] The calibration module includes a swelling correction unit and a compensation calibration unit. The swelling correction unit is used to correct the difference in the swelling rate of the functional outer membrane of the blood glucose sensing unit during the measurement process based on the target ion concentration-functional outer membrane swelling kinetics model, and obtain the swelling correction factor at different times. The compensation calibration unit is used to compensate and calibrate the initial electrochemical signal at the corresponding time using the swelling correction factor, and obtain the swelling-corrected electrochemical signal and blood glucose concentration value.

[0088] It should be noted that, in some embodiments, the blood glucose measurement circuit 6 of the blood glucose sensing unit and the ion concentration measurement circuit 7 of the ion concentration sensing unit are both encapsulated in a sealed housing and implanted into the subcutaneous tissue of the human body together with the sensor electrodes. In some embodiments, the blood glucose measurement circuit 6 and the ion concentration measurement circuit 7 are disposed on the surface of the human skin near the electrode implantation site and are electrically connected to the corresponding electrodes through the electrode connector 5.

[0089] Furthermore, in some embodiments, the calibration module is electrically connected to the blood glucose measurement circuit 6 of the blood glucose sensing unit and the ion concentration measurement circuit 7 of the ion concentration sensing unit, respectively. After receiving and processing electrical signals or detection data, it sends the calibration measurement results to an external smart device, such as an instrument, mobile phone, or fitness tracker, for display via wireless communication methods such as Bluetooth or Wi-Fi. In some embodiments, the calibration module is pre-installed in the aforementioned smart device, and the blood glucose sensing unit and the ion concentration sensing unit directly send electrical signals or detection data to the calibration module of the external smart device via wireless communication for compensation calibration processing and display.

[0090] The technical solution provided by the present invention will be further described below through specific embodiments.

[0091] Example 1

[0092] In this embodiment, the blood glucose sensing unit employs a three-electrode configuration, including an enzyme working electrode 1, a counter electrode 2, and a reference electrode 3. The functional outer membrane is made of a 50 μm thick polyurethane-polyvinyl alcohol copolymer. The ion concentration sensing unit employs a two-electrode configuration, including a reference electrode 3 and an ion indicator electrode 4. The ion indicator electrode 4 is a potassium ion indicator electrode, with a potassium ion-selective outer membrane coated on its surface. The ion indicator electrode 4 and the enzyme working electrode 1 are located on the same flexible substrate and share the same reference electrode 3.

[0093] The parameters in the target ion concentration-functional outer membrane swelling kinetics model were determined through the following in vitro simulation experiments: At 37℃, potassium ion concentration gradients (2 mM, 3 mM, 4 mM, 5 mM, 6 mM) were adjusted, and the thickness change of the polyurethane-polyvinyl alcohol copolymer outer membrane was monitored in real time using a laser confocal microscope at different concentrations. The weighting coefficient for potassium ions was determined to be 0.8, and the diffusion kinetics index to be 2.1. The maximum swelling degree S at the equilibrium state of the outer membrane was obtained through long-term immersion in pure water for 32 hours. ∞ The rate is 85%, and the intrinsic swelling rate constant K of the outer membrane material is 0.74.

[0094] During actual sensor implantation and monitoring, the blood glucose sensing unit employs a chronoamperometry circuit. A 0.55V voltage is applied between the enzyme working electrode 1 and the reference electrode 3 to collect the electrochemical reaction current between the enzyme working electrode 1 and the counter electrode 2, representing the initial electrochemical signal of glucose concentration conversion. The potassium ion concentration sensing unit uses an open-circuit voltage method circuit to measure the potassium ion concentration at the implantation site. The difference in open-circuit voltage between the potassium ion indicator electrode and the reference electrode 3 is collected, and the potassium ion concentration in the tissue fluid can be inferred from this difference. Since the continuous swelling of the functional outer membrane mainly occurs within the first 24 hours after sensor implantation, the potassium ion concentration is measured every 5 minutes during this initial 24 hours, and then periodically monitored every 2 hours after 24 hours.

[0095] The raw glucose current signal curve acquired by the blood glucose sensing unit is shown in the figure below. Figure 3 As shown in the figure, the current baseline is in a continuous upward tilting process for the first 20 hours or so. This phenomenon is mainly caused by the swelling of the functional outer membrane on enzyme working electrode 1 when it comes into contact with tissue fluid. Directly using this data to convert blood glucose concentration will lead to an excessive deviation between the measured blood glucose value and the actual value.

[0096] The potassium ion concentration in the tissue fluid measured by the potassium ion concentration sensing unit is as follows: Figure 4 As shown, through Figure 4 The potassium ion concentration curve in the target ion concentration-functional outer membrane swelling kinetics model was used to correct for the differences in outer membrane swelling rates at different times. Based on the correction results, the aforementioned calibration algorithm was then applied to... Figure 3 The current signal curve at the corresponding moment is compensated and calibrated. The calibrated curve is as follows: Figure 5 As shown, the blood glucose concentration can be deduced from the magnitude of the current amplitude, thus obtaining the calibrated blood glucose concentration value.

[0097] During the actual sensor implantation and monitoring process, blood samples were collected simultaneously at the same time point for biochemical analysis to calibrate blood glucose concentration values, such as... Figure 6As shown, the calibrated blood glucose concentration value is closer to the biochemical analysis calibration value. The average deviation ratio between the original measured value and the calibration value is 11.5%, while the average deviation ratio between the calibrated blood glucose concentration and the calibration value is 4.1%. This indicates that the data after swelling correction is more accurate and can more accurately reflect the blood glucose fluctuation in the early stage of implantation.

[0098] Example 2

[0099] In this embodiment, the blood glucose sensing unit employs a three-electrode configuration, including an enzyme working electrode 1, a counter electrode 2, and a reference electrode 3. The functional outer membrane is made of polyurethane material with a thickness of 100 μm. The ion concentration sensing unit employs one reference electrode 3 and two ion indicator electrodes 4, namely a potassium ion indicator electrode and a calcium ion indicator electrode, with potassium-selective and calcium-selective outer membranes coated on their surfaces, respectively. The ion indicator electrodes 4 and the enzyme working electrode 1 are located on the same flexible substrate and share the same reference electrode 3. The potassium ion indicator electrode and the reference electrode 3 form a two-electrode system, which, after being connected to an ion concentration measurement circuit 7, is used to measure potassium ion concentration. The calcium ion indicator electrode and the reference electrode 3 form a second two-electrode system, which, after being connected to another ion concentration measurement circuit 7, is used to measure calcium ion concentration.

[0100] The parameters in the target ion concentration-functional outer membrane swelling kinetics model were determined through the following in vitro simulation experiments: At 37℃, potassium ion concentration gradients (2 mM, 3 mM, 4 mM, 5 mM, 6 mM) and calcium ion concentration gradients (0.5 mM, 1 mM, 1.5 mM, 2 mM, 2.5 mM, 3 mM) were adjusted and set. The thickness change of the polyurethane outer membrane was monitored in real time using a laser confocal microscope at different concentrations. The weighting coefficient for potassium ions was determined to be 0.72, with a diffusion kinetics index of 2.2; the weighting coefficient for calcium ions was also determined to be 0.72, with a diffusion kinetics index of 1.9. The maximum swelling degree S at equilibrium was obtained by long-term immersion in pure water for 24 hours. ∞ The rate is 80%, and the intrinsic swelling rate constant K of the outer membrane material is 0.69.

[0101] During actual sensor implantation and monitoring, the blood glucose sensing unit employs a chronoamperometry circuit. By applying a 0.55V voltage between the enzyme working electrode 1 and the reference electrode 3, it acquires the electrochemical reaction current between the enzyme working electrode 1 and the counter electrode 2, representing the initial electrochemical signal of glucose concentration conversion. The ion concentration sensing unit uses an open-circuit voltage method circuit to measure the potassium and calcium ion concentrations at the implantation site. It acquires the open-circuit voltage difference between the two ion indicator electrodes 4 and the reference electrode 3, and the potassium and calcium ion concentrations in the tissue fluid can be inferred from this difference. Since the continuous swelling of the functional outer membrane mainly occurs within the first 24 hours after sensor implantation, the concentrations of both ions are measured every 5 minutes during this initial 24 hours, and then periodically monitored every 2 hours after 24 hours.

[0102] The raw glucose current signal curve acquired by the blood glucose sensing unit is shown in the figure below. Figure 7 As shown by the dashed curves, the potassium and calcium ion concentrations in the tissue fluid measured by the ion concentration sensing unit are as follows: Figure 8 and Figure 9 As shown, through Figure 8 Potassium ion concentration curve and Figure 9 The calcium ion concentration curve in the image was used, combined with a target ion concentration-functional outer membrane swelling kinetics model, to correct for differences in the outer membrane swelling rate at different times; then, based on the correction results, a calibration algorithm was applied to... Figure 7 The current signal curve at the corresponding moment is compensated and calibrated. The calibrated curve is as follows: Figure 7 As shown by the solid line, the calibration curve deviates somewhat from the original data curve in the first 16 hours due to differences in outer membrane swelling. After 16 hours, the two curves are basically aligned. The blood glucose concentration can be inferred from the current amplitude, thus obtaining the calibrated blood glucose concentration value.

[0103] During the actual sensor implantation and monitoring process, blood samples were collected simultaneously at the same time point for biochemical analysis to calibrate blood glucose concentration values, such as... Figure 10 As shown, the calibrated blood glucose concentration value is closer to the biochemical analysis calibration value. The average deviation ratio between the original measurement value and the calibration value is 12.7%, while the average deviation ratio between the calibrated blood glucose concentration and the calibration value is 4.8%. This indicates that the data after swelling correction is more accurate and can more accurately reflect the blood glucose fluctuation in the early stage of implantation.

Claims

1. A method for calibrating the outer membrane swelling of an implantable blood glucose sensor based on ion concentration monitoring, characterized in that, Includes the following steps: A target ion concentration-functional outer membrane swelling kinetics model was established, and the parameters in the model were determined through in vitro simulation tests. Measurements are performed using a sensor comprising a blood glucose sensing unit and an ion concentration sensing unit, wherein the blood glucose sensing unit is used to measure and acquire the initial electrochemical signal of glucose concentration conversion in subcutaneous tissue fluid; and the ion concentration sensing unit is used to measure and acquire the concentration of at least one target ion in subcutaneous tissue fluid. Based on the target ion concentration-functional outer membrane swelling kinetics model, the difference in swelling rate of the functional outer membrane of the blood glucose sensing unit during the measurement process is corrected to obtain the swelling correction factor at different times. The swelling correction factor is used to compensate and calibrate the initial electrochemical signal at the corresponding time to obtain the swelling-corrected electrochemical signal and blood glucose concentration value. The formula for the target ion concentration-functional outer membrane swelling kinetics model is as follows: ， Where S(t) is the functional outer membrane swelling degree at time t, S ∞ c represents the maximum swelling degree of the functional outer membrane at equilibrium. i Let a be the concentration of the i-th target ion. i is the weighting coefficient for the i-th target ion, K is the intrinsic swelling rate constant of the functional outer membrane material, and n is the diffusion kinetics exponent; The swelling correction factor is determined by and The ratio or a functional relationship based on this ratio is used to quantify the degree of interference of functional outer membrane swelling on electrochemical signals.

2. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 1, characterized in that, The target ions include one or more of sodium ions, chloride ions, potassium ions, and calcium ions.

3. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 1, characterized in that, The blood glucose sensing unit includes an enzyme working electrode, a counter electrode, a reference electrode, and a blood glucose measurement circuit electrically connected to each electrode via an electrode connector. The functional outer membrane covers the surface of the enzyme working electrode.

4. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 3, characterized in that, The blood glucose measurement circuit uses a chronoamperometry method. During measurement, the electrochemical reaction current between the enzyme working electrode and the counter electrode is collected as the initial electrochemical signal for glucose concentration conversion.

5. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 1, characterized in that, The ion concentration sensing unit includes a reference electrode and at least one ion indicator electrode, as well as at least one ion concentration measuring circuit electrically connected to the corresponding electrode via an electrode connector. The surface of the ion indicator electrode is coated with a corresponding ion-selective outer membrane, which is selected from any one of sodium ion-selective outer membrane, chloride ion-selective outer membrane, potassium ion-selective outer membrane, and calcium ion-selective outer membrane.

6. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 5, characterized in that, The ion concentration measurement circuit adopts the open-circuit voltage method. During measurement, the open-circuit voltage difference between each ion indicator electrode and the reference electrode is collected, and the concentration of the corresponding target ion in the tissue fluid is inferred from the difference.

7. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 1, characterized in that, The measurement and acquisition of the concentration of at least one target ion in the subcutaneous tissue fluid includes: Within the first 24 hours after sensor implantation, the concentration of target ions was measured every T1 time. The concentration of the target ion was measured every T2 time interval after 24 hours. T1 and T2 are determined based on actual measurement requirements, and T1 <T2。 8. The method for calibrating the outer membrane of an implantable blood glucose sensor according to claim 1, characterized in that, The initial electrochemical signal at the corresponding time point is compensated and calibrated using the swelling correction factor based on the following calibration algorithm to obtain the swelling-corrected electrochemical signal and blood glucose concentration value. The algorithm formula is as follows: ， ， Among them, I C For the calibrated electrochemical signal, I raw The raw electrochemical signal detected by the blood glucose sensing unit, K c S is the calibration coefficient, and S(t) is the functional outer membrane swelling degree at time t. ∞ G represents the maximum swelling degree of the functional outer membrane at equilibrium. Cal S0 represents the calibrated blood glucose concentration, and S0 represents the baseline sensitivity of the sensor's functional outer membrane in equilibrium. The swelling correction factor is defined in the formula. This item is used to compensate for and correct the interference of outer membrane swelling in the original electrochemical signal.

9. A swelling calibration system for the outer membrane of an implantable blood glucose sensor based on ion concentration monitoring, comprising performing the swelling calibration method for the outer membrane of an implantable blood glucose sensor as described in any one of claims 1-8, characterized in that, include: The sensing module includes a blood glucose sensing unit and an ion concentration sensing unit, wherein... The blood glucose sensing unit is used to measure and acquire the initial electrochemical signal of glucose concentration conversion in subcutaneous tissue fluid; The ion concentration sensing unit is used to measure and acquire the concentration of at least one target ion in the subcutaneous tissue fluid; The calibration module includes a swelling correction unit and a compensation calibration unit, wherein... The swelling correction unit is used to correct the difference in swelling rate of the functional outer membrane of the blood glucose sensing unit during the measurement process based on the target ion concentration-functional outer membrane swelling kinetics model, and to obtain the swelling correction factor at different times. The compensation calibration unit is used to compensate and calibrate the initial electrochemical signal at the corresponding time using the swelling correction factor to obtain the swelling-corrected electrochemical signal and blood glucose concentration value.

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