Micro biosensor and measuring method thereof

Abstract

The invention relates to a microbiosensor and a measuring method thereof. The invention provides a measuring method for prolonging the service life of a microbiosensor, and the microbiosensor is used for being implanted subcutaneously to measure a physiological signal of a physiological parameter related to an analyte and comprises a working electrode, a counter electrode and a chemical reagent which at least partially covers the working electrode, the electrode material of the counter electrode includes silver and silver halide having an initial amount, the method comprising: applying a measurement voltage to drive the working electrode to measure a physiological signal and obtain a physiological parameter, and the silver halide being consumed by a specific amount; stopping applying the measuring voltage; and applying a recharging voltage to drive the counter electrode every time the physiological parameter is obtained, thereby recharging the amount of silver halide by a recharging amount, in which a value obtained by subtracting each consumed amount from the sum of each recharging amount and the initial amount is controlled within a range of the initial amount plus or minus a specific value.

Description

[0001] This application is a divisional application of the invention patent application with the application date of August 3, 2020, application number 202010767014.1, and invention title "Micro biosensor and its measurement method". Technical Field

[0002] The present invention relates to a micro biosensor and its measurement method, and particularly to a micro biosensor and its measurement method that can extend the service life of the micro biosensor. Background Art

[0003] The population of diabetes patients is growing rapidly, and there is an increasing emphasis on monitoring the changes of glucose in the body. Therefore, many studies have started to develop implantable continuous glucose monitoring (CGM) systems to solve the inconvenience of repeated blood sampling and testing for patients throughout the day.

[0004] In the field of CGM systems based on enzyme-based biosensors, biochemical reaction signals depending on the analyte concentration are converted into measurable physical signals, such as optical or electrochemical signals. For glucose measurement, an electrochemical reaction, for example, uses glucose oxidase (GOx) to catalyze the reaction of glucose to generate gluconolactone and reduced enzyme. Subsequently, the reduced enzyme will transfer electrons with oxygen in the body's biological fluid to generate the product hydrogen peroxide (H2O2). Finally, the glucose concentration is quantified by catalyzing the oxidation reaction of the product H2O2. The reaction formula is as follows.

[0005] Glucose + GOx(FAD) → GOx(FADH2) + Gluconolactone

[0006] GOx(FADH2) + O2 → GOx(FAD) + H2O2

[0007] In the above reaction, FAD (flavin adenine dinucleotide) is the active center of GOx.

[0008] Users usually wear CGMs for a long time, such as more than 14 days. Therefore, miniaturization of CGMs has become an inevitable trend. The basic structure of a CGM includes: (a) a biosensor for measuring physiological signals corresponding to the glucose concentration in the human body; and (b) a transmitter for transmitting these physiological signals. The biosensor can be a two-electrode system or a three-electrode system. In the biosensor of the three-electrode system, it includes a working electrode (WE), a counter electrode (CE), and a reference electrode (RE). The biosensor of the two-electrode system includes a working electrode (WE) and a counter electrode (CE), where the counter electrode also has the function of a reference electrode. Therefore, it is sometimes also called the reference / counter electrode (R / C). The reference electrode in the biosensor of the three-electrode system and the counter electrode serving as the reference electrode in the biosensor of the two-electrode system are suitable materials for stable measurement of glucose concentration are silver / silver chloride (Ag / AgCl). However, after the sensor is implanted into the living body, when the working electrode undergoes a redox reaction to measure the glucose concentration, the corresponding reference electrode (RE) or reference / counter electrode (R / C) undergoes a reduction reaction, reducing silver chloride to silver and consuming the silver chloride. In addition, if the sensor implanted into the living body is a sensor of a two- or three-electrode system, due to the dissociation of silver chloride in body fluid, the silver chloride on the reference electrode will be lost, which will cause a problem of drift of the reference voltage. However, in the reference / counter electrode (R / C) of the two-electrode system, because it participates in the reaction, the degree of silver chloride loss is even higher than that of the three-electrode system. Therefore, the service life of the sensor is limited by the content of silver chloride on the counter electrode and / or the reference electrode.

[0009] Currently, there are also many inventions proposed for the problem of the service life of biosensors. Taking the two-electrode system as an example, at an average sensing current of 20 nanoamperes (nA), the consumption of the counter electrode is about 1.73 millicoulombs (mC) per day. Assuming that the length, width, and height of the counter electrode are 3.3 millimeters, 0.25 millimeters, and 0.01 millimeters respectively, and the originally designed electrode capacity is only 6 mC, the stable measurement state can last for at most about one day. However, if the service life is to be extended, if the biosensor is to be implanted subcutaneously for continuous 16-day glucose monitoring, the capacity of the counter electrode needs to reach at least 27.68 mC. Without changing the width and thickness, the length of the counter electrode in the prior art would need to be as long as 15.2 mm. Therefore, the prior art attempts to lengthen the counter electrode to be greater than 10 mm. In order to avoid implanting deep into the subcutaneous tissue, such biosensors need to be implanted at an oblique angle. Therefore, it causes problems such as larger implantation wounds and higher infection risks to patients, and due to the long implantation length, the pain during implantation is also more significant.

[0010] US 8,620,398 describes a biosensor, mainly a three - electrode system. Although the reference electrode basically does not participate in chemical reactions, silver chloride is still gradually consumed naturally in the body environment. However, the consumption rate is slower than that of the two - electrode system. It is disclosed in the text that regeneration is carried out only when AgCl is about to be exhausted, that is, when the measurement signal is unstable, that is, when the measured signal is already noise, the program to recharge AgCl will be started to restore AgCl to an amount sufficient for multiple measurements. Then, until the next occurrence of noise, AgCl needs to be recharged again. It can be understood that although US 8,620,398 considers the consumption of AgCl during measurement and recharges AgCl when the biosensor fails. However, the measured value at the time of failure is no longer reliable. One needs to wait for the biosensor to complete the AgCl recharge program to obtain the correct measured value, temporarily adopt the method of blood sampling for measurement, or directly skip this measurement. This problem is always very troublesome for patients or those who need to know the blood glucose concentration at that time. In addition, since such a biosensor has to cope with multiple measurements for at least several consecutive times or even several days, it must prepare a larger AgCl capacity, but inevitably, it will cause the problem of a longer implantation length of the biosensor. It also does not propose a way to use real - time AgCl recharge to provide uninterrupted measurement, a biosensor with a shorter implantation length, and a longer service life.

[0011] US 9,351,677 is mainly a two - electrode system. The reference / counter electrode (R / C) participates in chemical reactions, so silver chloride is consumed along with the electrochemical reaction. The text proposes an analyte sensor with an increased AgCl capacity, which uses H2O2 to regenerate AgCl on the reference electrode. However, since H2O2 is easily reduced to H2O or oxidized to O2, it is not easily stably present in the human body. Therefore, during the regeneration / recharge period, the concentration of H2O2 in the body may not be sufficient to stably recharge enough AgCl, and relatively, its biosensor needs to be configured with a larger AgCl electrode size, and its implantation end is as long as 12 mm.

[0012] Therefore, the present invention provides a biosensor that can achieve on - the - fly charging to provide uninterrupted measurement, can stably recharge AgCl, extend its service life, and miniaturize the small size of the implantation end, and can further reduce the manufacturing cost of the product. These effects can solve the problems that are difficult to overcome by the aforementioned prior art.

[0013] In view of the deficiencies in the prior art, the applicant of the present invention, through careful experiments and research, and with an unwavering spirit, finally conceived the present invention, which can overcome the deficiencies of the prior art. The following is a brief description of the present invention. Summary of the Invention

[0014] Through the recharge technology of the present invention, the micro-biosensor of the present invention has an extended service life, and the size of the counter electrode signal sensing section can be reduced, thereby reducing biotoxicity. In addition, the reduction of the electrode size especially refers to shortening the implantation end length of the sensor, so the implantation pain of the user can be reduced.

[0015] One object of the present invention is to provide a method for measuring an analyte that can extend the service life of a micro-biosensor. The biosensor is used for subcutaneous implantation to measure a physiological signal related to a physiological parameter associated with the analyte in a biological fluid. The biosensor includes a working electrode and a pair of electrodes. The working electrode is at least partially covered by a chemical reagent and is used to generate an electrochemical reaction with the analyte. An electrode material of the pair of electrodes includes silver and silver chloride. The method includes the following cyclic steps: a) performing a first measurement step, including: i. applying a first measurement potential difference between the working electrode and the pair of electrodes during a first measurement period, making the voltage of the working electrode higher than the voltage of the pair of electrodes, so that a first oxidation reaction occurs on the working electrode, and an electrochemical reaction is carried out with the chemical reagent and the analyte to output a first physiological signal. At the same time, the silver chloride of the pair of electrodes has a first consumption amount corresponding to the first physiological signal; and ii. removing the first measurement potential difference, stopping the first measurement step, and the first physiological signal is output as a first physiological parameter after calculation; b) performing a first recharge step, including: i. applying a first recharge potential difference between the pair of electrodes and the working electrode during a first recharge period, making the voltage of the pair of electrodes higher than the voltage of the working electrode, so that a second oxidation reaction occurs on the silver of the pair of electrodes, and the silver chloride has a first recharge amount, where the first recharge amount corresponds to the first consumption amount, controlling the amount of the silver chloride on the pair of electrodes within a safety inventory range, so that the next physiological signal and the next physiological parameter obtained in the next measurement step maintain a stable proportional relationship; and ii. removing the first recharge potential difference, stopping the first recharge step; c) performing a second measurement step the same as step a) to obtain the second physiological signal and output a second physiological parameter; d) performing a second recharge step the same as step b); and e) sequentially and repeatedly performing an Nth measurement step and an Nth recharge step.

[0016] Another object of the present invention is to provide a method for measuring an analyte that can extend the service life of a biosensor. The biosensor is used for subcutaneous implantation to measure a physiological signal of a physiological parameter associated with the analyte, and includes a working electrode and a pair of electrodes. The working electrode is at least partially covered by a chemical reagent. An electrode material of the pair of electrodes includes silver and silver halide, and the silver halide has an initial amount. The method includes the following steps: applying a measurement voltage to drive the working electrode to measure the physiological signal and obtain the physiological parameter, and the silver halide is consumed by a specific amount; stopping applying the measurement voltage; and whenever the physiological parameter is obtained once, applying a recharge voltage to drive the pair of electrodes, so that an amount of the silver halide is recharged by a recharge amount, wherein a value obtained by adding each recharge amount to the initial amount and subtracting each consumption amount is controlled within a range of the initial amount plus or minus a specific value.

[0017] Yet another object of the present invention is to provide an implantable micro-biosensor for subcutaneous implantation to measure a physiological signal of a physiological parameter associated with an analyte in a living body. The biosensor includes: a substrate; a chemical reagent; a working electrode disposed on the substrate, at least partially covered by the chemical reagent, and driven during a measurement period to undergo a first oxidation reaction to measure the physiological signal and generate the physiological parameter; a pair of electrodes disposed on the substrate, an electrode material of the pair of electrodes includes silver and silver halide, wherein the silver halide has an initial amount and is consumed by a specific amount during the measurement period; and whenever the physiological parameter is obtained once, during a recharge period, the pair of electrodes is driven, so that the silver halide of the driven pair of electrodes is recharged by a recharge amount, wherein a value obtained by adding each recharge amount to the initial amount and subtracting each consumption amount is controlled within a range of the initial amount plus or minus a specific value. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The above objects and advantages of the present invention will become more immediately apparent to those of ordinary skill in the art after referring to the following detailed description and the accompanying drawings.

[0019] Figure 1 It is a schematic diagram of the physiological signal measuring device of the present invention.

[0020] Figure 2A It is a front schematic diagram of the micro-biosensor of the present invention.

[0021] Figure 2B It is a back schematic diagram of the micro-biosensor of the present invention.

[0022] Figure 2C For the present invention Figure 2A It is a schematic cross-sectional view along line A-A' in the present invention.

[0023] Figure 3 Schematic cross-sectional view of the second embodiment of the micro biosensor of the present invention.

[0024] Figure 4A Constant voltage circuit in the measurement mode of the present invention.

[0025] Figure 4B Constant voltage circuit in the recharge mode of the present invention.

[0026] Figure 5A Current schematic diagram of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in the first manner.

[0027] Figure 5B Current schematic diagram of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in the second manner.

[0028] Figure 5C Current schematic diagram of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in the third manner.

[0029] Figure 5D Current schematic diagram of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in the fourth manner.

[0030] Figure 5E Current schematic diagram of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in the fifth manner.

[0031] Figure 5F Current schematic diagram of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in the sixth manner.

[0032] Figure 6A Stepped-switching constant current circuit in the measurement mode of the present invention.

[0033] Figure 6B Stepped-switching constant current circuit in the recharge mode of the present invention.

[0034] Figure 7A Continuously-switching constant current circuit in the measurement mode of the present invention.

[0035] Figure 7B Continuously-switching constant current circuit in the recharge mode of the present invention.

[0036] Figure 8A Voltage schematic diagram of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in the first manner.

[0037] Figure 8B Voltage schematic diagram of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in the second manner.

[0038] Figure 8C The voltage schematic diagram of the constant current circuit of the present invention alternately performs a measurement mode and a recharge mode in a third manner.

[0039] Figure 8D The schematic diagram of the constant current circuit of the present invention alternately performs a measurement mode and a recharge mode in a third manner.

[0040] Figure 9 A method for measuring an analyte according to an embodiment of the present invention.

[0041] Figure 10 A method for measuring an analyte according to another embodiment of the present invention. Detailed implementation manners

[0042] The invention proposed by the present invention can be fully understood through the following illustrative embodiments, so that those with ordinary knowledge in the technical field can implement it accordingly. However, the implementation of the present invention is not limited to the following embodiments. Those with ordinary knowledge in the technical field can still deduce other embodiments based on the spirit of the disclosed embodiments, and all such embodiments should fall within the scope of the present invention.

[0043] Unless otherwise restricted in specific examples, the following definitions apply to the terms used throughout the specification.

[0044] The term "quantity" refers to the capacity of silver halide (AgX) or silver chloride (AgCl) in the electrode, and is preferably expressed in units of microcoulomb (μC), millicoulomb (mC), or coulomb (C), but is not limited to being expressed in terms of weight percentage concentration wt%, number of moles, molar concentration, etc.

[0045] Please refer to Figure 1 , which is a schematic diagram of the physiological signal measurement device of the present invention. The physiological signal measurement device 10 of the present invention can be used to implant subcutaneously to measure the physiological signals of physiological parameters associated with analytes in biological fluids. The physiological signal measurement device 10 of the present invention includes a micro-biosensor 100 and a sensing unit 200, wherein the sensing unit 200 is electrically connected to the micro-biosensor 100 and has a processor 210, a power supply 220, a circuit switching unit 230, a temperature sensing unit 240, and a communication unit 250. The power supply 220 provides voltage to the micro-biosensor 100 through the processor 210 to control the circuit switching unit 230 for physiological signal measurement, and the temperature sensing unit 240 measures the body temperature. Therefore, the temperature measurement signal and the physiological signal measured by the micro-biosensor 100 are transmitted to the processor 210, and then the processor 210 calculates the physiological signal into physiological parameters. The communication unit 250 can perform wired or wireless transmission with the user device 20.

[0046] Please refer to Figure 2A and 2B , which are the front and back schematic diagrams of the micro-biosensor of the present invention. The micro-biosensor 100 of the present invention includes a substrate 110, a working electrode 120 and a counter electrode 130 disposed on the substrate 110, and a chemical reagent 140 (such as Figure 2C shown) surrounding the working electrode 120 and the counter electrode 130. The material of the substrate 110 can be selected from any known material suitable for use as an electrode substrate and preferably has flexibility and insulating properties. For example, but not limited to: high molecular materials such as polyester and polyimide. The foregoing high molecular materials can be used alone or in combination of multiple types. The substrate 110 has a surface 111 (i.e., the first surface), an opposite surface 112 (i.e., the second surface) to the surface 111, a first end 113 and a second end 114, and the substrate 110 is divided into three regions, namely a signal output region 115 near the first end 113, a sensing region 116 near the second end 114, and a connection region 117 located between the signal output region 115 and the sensing region 116. The working electrode 120 is disposed on the surface 111 of the substrate 110 and extends from the first end 113 to the second end 114 of the substrate 110. The working electrode 120 includes a signal output segment 121 located in the signal output area 115 of the substrate 110 and a signal sensing segment 122 located in the sensing area 116 of the substrate 110. The material of the working electrode 120 includes but is not limited to: carbon, platinum, aluminum, gallium, gold, indium, iridium, iron, lead, magnesium, nickel, manganese, molybdenum, osmium, palladium, rhodium, silver, tin, titanium, zinc, silicon, zirconium, mixtures of the foregoing elements, or derivatives of the foregoing elements (such as alloys, oxides or metal compounds, etc.). Preferably, the material of the working electrode 120 is a noble metal, a derivative of a noble metal or a combination of the foregoing. More preferably, the working electrode 120 is a platinum-containing material.

[0047] The counter electrode 130 is disposed on the opposite surface 112 of the substrate 110 and extends from the first end 113 to the second end 114 of the substrate 110. The counter electrode 130 includes a signal output segment 131 located in the signal output region 115 of the substrate 110 and a signal sensing segment 132 located in the sensing region 116 of the substrate 110. The material on the surface of the counter electrode 130 contains silver and silver halide, wherein the silver halide is preferably silver chloride or silver iodide, enabling the counter electrode 130 to also function as a reference electrode. That is, the counter electrode 130 of the present invention can (1) form an electronic circuit with the working electrode 120 to allow current to flow smoothly on the working electrode 120, ensuring that an electrochemical reaction occurs on the working electrode 120; and (2) provide a stable relative potential as a reference potential. Therefore, the working electrode 120 and the counter electrode 130 of the present invention form a two-electrode system. To further reduce costs and improve the biocompatibility of the biosensor of the present invention, the silver / silver halide can be used in combination with carbon. For example, the silver / silver halide is mixed into a carbon paste, and the content of the silver halide only needs to enable the counter electrode 130 to stably perform the set measurement operation. A conductive material can also be coated on a part of the surface of the counter electrode 130 to prevent the dissociation of silver halide, thereby protecting the counter electrode 130. The conductive material is mainly selected from conductive materials that do not affect the measurement performance of the working electrode. For example, the conductive material is carbon.

[0048] In another embodiment, the biosensor is not limited to a wire-type or laminated electrode structure.

[0049] In another embodiment of the present invention, before the biosensor is ready to be shipped out of the factory for sale, the initial amount of silver halide can be zero. In this case, there is no silver halide on the counter electrode 130 of the biosensor. During the initial charging period after the biosensor is subcutaneously implanted into a patient and before the first measurement, the silver coated on the counter electrode 130 can be oxidized to recharge the initial amount of silver halide on the counter electrode 130.

[0050] The chemical reagent 140 covers at least the signal sensing section 122 of the working electrode 120 and the surface of the counter electrode 130 located in the sensing area 116. In another embodiment, the chemical reagent 140 covers at least the signal sensing section 122 of the working electrode 120 (not shown in the figure). That is, the counter electrode 130 may not be covered by the chemical reagent 140. The sensing area 116 of the micro-biosensor 100 can be implanted subcutaneously to measure the physiological signals associated with the analyte in the biological fluid by the signal sensing section 122 of the working electrode 120. The physiological signals will be transmitted to the signal output section 121 of the working electrode 120 and then transmitted by the signal output section 121 to the processor 210 to obtain physiological parameters. In addition to obtaining from the sensing unit 200, the physiological parameters can also be transmitted to the user device 20 via wireless / wired communication. Common user devices 20 include, for example, smart phones, physiological signal receivers, or blood glucose meters.

[0051] Please refer to Figure 2C , which is Figure 2A the schematic cross-sectional view along the line A-A' in Figure 2C , where the line A-A' is the cross-sectional line of the sensing area 116 of the micro-biosensor 100. In Figure 9 , the working electrode 120 is disposed on the surface 111 of the substrate 110, the counter electrode 130 is disposed on the opposite surface 112 of the substrate 110, and the chemical reagent 140 covers the surfaces of the working electrode 120 and the counter electrode 130. Basically, the chemical reagent 140 covers at least a part of the surface of the working electrode 120. The micro-biosensor 100 of the present invention performs a measurement step during measurement and a recharge (i.e., regeneration) step during recharge. When performing the measurement step, the voltage of the working electrode 120 is higher than that of the counter electrode 130, causing the current to flow from the working electrode 120 to the counter electrode 130, thereby causing an oxidation reaction to occur on the working electrode 120 (i.e., the electrochemical reaction between the working electrode 120, the chemical reagent 140, and the analyte) to measure the physiological signal, and a reduction reaction occurs on the counter electrode 130, causing the silver halide in the counter electrode 130 to be consumed and dissociated into silver (Ag) and halide ions (X-). Since the silver halide in the counter electrode 130 is consumed, it is necessary to recharge the silver halide in the counter electrode 130 for the next measurement step. When performing the recharge step, the voltage of the counter electrode 130 is higher than that of the working electrode 120, causing the current to flow from the counter electrode 130 to the working electrode 120, thereby causing an oxidation reaction to occur on the counter electrode 130 so that the silver combines with the halide ions in the organism or the Cl- after oxidation (or dissociation) of AgCl to recharge the silver halide. For the detailed measurement step and recharge step, see Figure 9 the description.

[0052] In another embodiment, the working electrode 120 and the counter electrode 130 of the present invention can be disposed on the same surface of the substrate 110, that is, both the working electrode 120 and the counter electrode 130 are disposed on the surface 111 or the opposite surface 112 of the substrate 110, as Figure 3 shown. Similarly, when performing the measurement step, current flows from the working electrode 120 towards the counter electrode 130, thereby causing an oxidation reaction to occur on the working electrode 120 to measure the physiological signal, and the silver halide in the counter electrode 130 is consumed and dissociated into silver (Ag) and halide ions (X-). When performing the recharging step, current flows from the counter electrode 130 towards the working electrode 120, thereby causing an oxidation reaction to occur on the counter electrode 130 to combine silver and halide ions to recharge the silver halide.

[0053] Above Figure 2C-3 The detailed electrode stack is omitted, and only the electrode positions are schematically shown.

[0054] In any of the above embodiments, in order to prevent disconnection due to excessive chlorination of the silver electrode material, a layer of conductive material (such as carbon) can also be added between the opposite surface 112 of the substrate 110 and the silver of the counter electrode 130. However, if the bottom layer of the counter electrode 130 is carbon, it will cause too high a resistance at the switch, so a conductive layer can be further added between the carbon conductive material and the opposite surface 112 of the substrate 110, for example, silver, to reduce the impedance of the signal output end, so that the counter electrode 130 of the present invention starts from the opposite surface 112 of the substrate 110 and is sequentially a conductive layer, a carbon layer, and a silver / silver halide layer.

[0055] Constant voltage circuit switching application

[0056] Please refer to Figure 4A-4B and FIGS. 5A - 5D, wherein Figure 4A and Figure 4B respectively show the constant voltage circuits in the measurement mode and the recharging mode in the present invention, Figure 5A-5D respectively show the current schematic diagrams of the constant voltage circuit alternately performing the measurement mode and the recharging mode in different ways. The measurement mode can be started and stopped by applying and removing the measurement potential difference Vl respectively, and the corresponding current is represented by Ia. In the measurement mode, the measurement potential difference Vl is applied between the working electrode W and the counter electrode R / C during the measurement period Tl, so that the voltage of the working electrode W is higher than the voltage of the counter electrode R / C. As Figure 4A shown, at this time, the switches S1 and S4 are in the closed state, while the switches S2 and S3 are in the open state, the working electrode W is at +Vl, and the counter electrode R / C is grounded, so that the working electrode W undergoes an oxidation reaction and electrochemically reacts with the chemical reagent and the analyte to output the physiological signal Ia, and at the same time, the AgCl of the counter electrode R / C has a consumption amount corresponding to the physiological signal Ia. As Figure 5A-5DAs shown, there is an unmeasured period T2 between multiple measurement periods T1. In some preferred embodiments, T2 is a fixed value.

[0057] The charge - back mode can be started and stopped by applying and removing a charge - back potential difference V2 respectively, and the corresponding current is represented by Ib. V2 is a fixed value between 0.1V and 0.8V, preferably a fixed value between 0.2V and 0.5V. In the charge - back mode, a charge - back potential difference V2 is applied between the working electrode W and the counter electrode R / C for a charge - back period t2 (where t2 ranges from 0 to T2), making the voltage of the counter electrode R / C higher than that of the working electrode W. As Figure 4B shown, at this time, switches S1 and S4 are in an open state, while switches S2 and S3 are in a closed state. The working electrode W is grounded, and the counter electrode R / C is at + V2, so that the Ag on the counter electrode R / C undergoes an oxidation reaction, and the AgCl on the counter electrode R / C is charged back to a certain charge - back amount. The charge - back potential difference V2 in the constant - voltage circuit is a fixed voltage, and the measured output current is Ib. In the present invention, the capacity of AgCl (Capacity, unit coulomb, represented by the symbol "C") is defined by calculating the area under the current curve. Therefore, the consumption amount of AgCl in the measurement mode is Ia*T1, and the charge - back amount of AgCl in the charge - back mode is Ib*t2. Thus, the charge - back amount of AgCl can be controlled by adjusting the application time t2 of the charge - back potential difference V2. In other words, on the premise that the AgCl on the counter electrode R / C is kept within the safety inventory, the charge - back amount can be equal to or not equal to (including approximately similar, greater than or less than) the consumption amount.

[0058] Figure 5A-5D In the horizontal axis is time. The line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the charge - back potential difference V2. Please refer to Figure 5A , in a preferred embodiment, both V2 and T2 are fixed values, and the application time t2 of V2 (i.e., the charge - back period) is a variable value. The charge - back period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As Figure 5A shown, t2 can be t2’, t2’’, or t2’’’…. In other words, the charge - back period t2 can be changed according to the consumption amount of AgCl. If the consumption amount of AgCl is large, a longer charge - back time can be used to keep the AgCl on the counter electrode R / C within the safety inventory. For example, the amount of AgCl charged back during the t2’’ period will be greater than the amount of AgCl charged back during the t2’ period.

[0059] Please refer to Figure 5B, in another preferred embodiment, V2, T2, and t2 are all fixed values, where t2 = T2. That is to say, the measurement mode and the recharge mode are seamlessly alternated, and the period during which no measurement is performed is the recharge period. Please refer to Figure 5C and 5D , in some preferred embodiments, V2, T2, and t2 are all fixed values, where t2 is a fixed value greater than 0 and less than T2, such as t2 = 1 / 2 of T2, 2 / 5 of T2, 3 / 5 of T2, etc. Figure 5C and 5D The difference from Figure 5C is that in Figure 5D , after each measurement mode ends, a buffer time (buffer time = T2 - t2) elapses before the recharge mode starts;

[0060] Please refer to Figure 5E and 5F , which show the current schematic diagrams of the constant voltage circuit of the present invention alternately performing the measurement mode and the recharge mode in different ways. Figure 5E and 5F , the horizontal axis is time, the vertical axis is current, and the curve represents the curve of the physiological parameter value converted from the measured physiological signal Ia. In these two embodiments, similar to Figure 5A , V2 and T2 are fixed values, and the recharge period t2 is a variable value. Figure 5E and 5F , the white area under the curve represents the consumption amount of AgCl (Ia * Tl) in the measurement mode, and the shaded area represents the recharge amount of AgCl (Ib * t2) in the recharge mode. It can be seen from the figure that in order to make Ib * t2 close to Ia * Tl or within a certain range of Ia * Tl, the recharge period t2 is dynamically adjusted between 0 and T2 according to the measured physiological signal Ia and the measurement period T1. As needed, it can be selected to perform the recharge mode in the first half (as shown in Figure 5E ) or the second half (as shown in Figure 5F ) of the period (T2) during which the measurement mode is not executed.

[0061] Segment-switching constant current circuit switching application

[0062] Please refer to Figure 6A-6B and Figure 8A -C, where Figure 6A and Figure 6B respectively show the segment-switching constant current circuit of the present invention in the measurement mode and the recharge mode, Figure 8A-C shows three voltage schematic diagrams of the constant current circuit of the present invention alternately performing measurement mode and recharge mode in different ways. The measurement mode can be started and stopped by applying and removing a measurement potential difference Vl respectively, and the corresponding current is represented by Ia. During the measurement mode, the measurement potential difference Vl is applied between the working electrode W and the counter electrode R / C for a continuous measurement period T1. As Figure 6A shown, at this time, switches S1 and S4 are in a closed state, while other switches are in an open state. The working electrode W is at +V1, and the counter electrode R / C is grounded, so that the working electrode W undergoes an oxidation reaction, and an electrochemical reaction occurs with the chemical reagent and the analyte to output a physiological signal Ia. At the same time, the AgCl of the counter electrode R / C has a consumption corresponding to the physiological signal Ia. As Figure 8A -C shows, the period between multiple measurement periods Tl is a period T2 during which no measurement is performed. In some preferred embodiments, T2 is a fixed value.

[0063] The recharge mode can be started and stopped by applying and removing a recharge potential difference V2 (V2 is a variable value) respectively, and the corresponding current is represented by Ib. During the recharge mode, the recharge potential difference V2 is applied between the working electrode W and the counter electrode R / C for a continuous recharge period t2 (t2 ranges from 0 to T2). As Figure 6B shown, at this time, switches S1 and S4 are in an open state, and at least one of the switches corresponding to S2 and I_F1 to I_Fn is in a closed state (exemplarily shown in the figure that the switches corresponding to I_F1 and I_F3 are in a closed state). The working electrode W is grounded, and the counter electrode R / C is at +V2, so that the Ag on the counter electrode R / C undergoes an oxidation reaction, and then AgCl is recharged. During the recharge mode, at least one of the switches corresponding to I_F1 to I_Fn can be selected to output a fixed current Ib according to the magnitude of the physiological signal Ia and the measurement period T1, and the recharge amount of AgCl can be controlled by adjusting the application time t2 of the potential difference V2. In other words, on the premise that the AgCl on the counter electrode R / C is kept within the safety inventory, the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption amount.

[0064] Stepless switching application of constant current circuit

[0065] Please refer to Figure 7A-7B and Figure 8A-8C where Figure 7A and Figure 7B respectively show the stepless switching constant current circuits of the present invention in the measurement mode and the recharge mode. The measurement mode and the recharge mode of this embodiment are the same as Figure 6A-6BSimilarly, it will not be elaborated here as it is similar. The difference from the embodiment of FIG. 6 is only that in the recharge mode of this embodiment, according to the physiological signal Ia, a fixed current Ib can be output under the control of a digital-to-analog converter (DAC), and the recharge amount of AgCl can be controlled by regulating the application time t2 of the potential difference V2. In other words, on the premise that the AgCl on the counter electrode R / C is maintained within the safety inventory, the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption amount.

[0066] Figure 8A - In FIG. -C, the horizontal axis is time and the vertical axis is current. The line of V1 represents the application and removal of the measured potential difference V1, and the line of V2 represents the application and removal of the recharge potential difference V2. Please refer to Figure 8A , in a preferred embodiment, T2 is a fixed value, and V2 and the application time t2 of V2 (i.e., the recharge period) are variable values. The recharge period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As Figure 8A shown in, t2 can be t2’, t2”, or t2”’…. In other words, the recharge period t2 can be changed according to the consumption amount of AgCl. If the consumption amount of AgCl is large, a longer recharge time can be used to keep the AgCl on the counter electrode R / C within the safety inventory.

[0067] Please refer to Figure 8B , in another preferred embodiment, V2 is a variable value, and T2 and t2 are both fixed values, where t2 is a fixed value greater than 0 and less than T2, such as t2 = 1 / 2 of T2, 2 / 5 of T2, 3 / 7 of T2, etc. In this embodiment, V2 is dynamically adjusted according to the consumption amount of AgCl in the physiological signal measurement step (i.e., in the measurement mode). One embodiment of the dynamic adjustment method is as follows. Use a segmented-switching constant-current circuit as described above. The circuit has n fixed current sources and n switches, and each fixed current source corresponds to a switch. In the recharge mode, according to the consumption amount of AgCl, at least one of the n switches is selected to be turned on (i.e., the switch is in a closed state) to output a fixed current value. When the recharge period t2 is a fixed value, the recharge amount of AgCl can be controlled by selecting different fixed current outputs.

[0068] Please refer to Figure 8C , in another preferred embodiment, V2 is a variable value, and T2 and t2 are both fixed values, where t2 = T2. That is to say, the measurement mode and the recharge mode are seamlessly alternated, and the period when no measurement is being performed is the recharge period.

[0069] Compared with the constant-current circuit without segment switching, the constant-current circuit with segment switching can control multiple current paths through multiple switches, and can perform recharge in a segmented constant current according to the required amount of current. In this way, it is more power-saving and can reduce costs. In addition, whether it is a constant-voltage circuit or a constant-current circuit, the potential difference can come from a DC power supply or an AC power supply.

[0070] Figures 5A to 8C The embodiments of to Figures 5A to 8C all describe an operation mode in which the measurement step and the recharge step alternate in a cycle, that is, there is an AgCl recharge step between each measurement step. This way can preferably ensure that AgCl remains within the safety inventory. However, in some preferred embodiments, it is also possible to selectively match Y times of AgCl recharge during N times of measurement, where Y ≤ N, so that the cumulative recharge amount of AgCl can still be kept within the safety inventory range. The measurement step and the recharge step do not necessarily need to be carried out in an alternating cycle manner. It is also possible to carry out a recharge step after several measurement steps, or to carry out a recharge step only after a predetermined measurement time. For example, a recharge step can be carried out after measuring 10 times, or a recharge step can be carried out only after the cumulative measurement time reaches 1 hour.

[0071] Please refer to Figure 8D which shows a schematic diagram of the constant-current circuit of the present invention alternately performing a measurement mode and a recharge mode in a manner similar to Figure 8C . Figure 8D In Figure 8D , the curve represents the curve of the physiological parameter value converted from the measured physiological signal Ia, and is similar to Figure 8C , where T2 and t2 are both fixed values and V2 is a variable value. Figure 8D In Figure 8D , the white area under the curve represents the consumption amount of AgCl (Ia * Tl) in the measurement mode, and the hatched area represents the recharge amount of AgCl (Ib * t2) in the recharge mode. It can be seen from the figure that in order to make Ib * t2 close to Ia * Tl or within a certain range of Ia * Tl, the recharge potential difference V2 is dynamically adjusted according to the consumption amount of AgCl.

[0072] In addition Figure 5E , 5F and Figure 8D , although the output timing points of each physiological parameter value after each execution of the physiological signal measurement step are not shown, the physiological parameter values are not limited to being output when the measurement is completed or during the recharge period, and the AgCl recharge step is not limited to being executed after each physiological parameter output or after obtaining the physiological signal.

[0073] Please refer to Figure 9 which shows a method for measuring an analyte according to an embodiment of the present invention. Through this method, the service life of the micro-biosensor can be extended. The micro-biosensor can be, for example Figures 2A to 3The micro biosensor shown is for subcutaneous implantation to measure a physiological signal related to a physiological parameter associated with the analyte in a biological fluid (such as interstitial fluid). Figure 9 In an embodiment of Figure 9 , the analyte can be glucose in interstitial fluid, the physiological parameter is the glucose value in the human body, and the physiological signal is the current value measured by the micro biosensor. In this embodiment, the method for measuring the analyte includes repeatedly and cyclically performing a measurement step (S901) and a recharging step (S902). The measurement step (S901) includes using the aforementioned constant voltage or constant current circuit to perform the aforementioned measurement mode during a measurement period T1 to output a physiological signal (i.e., the current value), and at the same time, the AgCl on the electrode has a consumption amount corresponding to the current value. The measurement step (S901) further includes stopping the measurement step by stopping the aforementioned measurement mode, and the current value is calculated and output as a physiological parameter (i.e., the glucose value).

[0074] In the measurement step (S901), the chemical reaction formula is as follows:

[0075] The following oxidation reaction occurs at the working electrode 120:

[0076]

[0077]

[0078]

[0079] The following reduction reaction occurs at the counter electrode 130:

[0080]

[0081] The recharging step (S902) includes using the aforementioned constant voltage or constant current circuit to perform the aforementioned recharging mode during the recharging period, so that the AgCl on the counter electrode has a recharging amount corresponding to the consumption amount, thereby controlling the amount of AgCl on the counter electrode within the safety inventory range. Thus, the potential difference between the working electrode and the counter electrode can be kept stable, and the obtained current value can still maintain a stable proportional relationship with the glucose value (if the detected substance is other analytes, it may also be a direct or inverse proportional relationship). In other words, the next current value obtained in the next measurement step can maintain a stable proportional relationship with the next glucose value. The recharging step (S902) further includes stopping the recharging step by stopping the aforementioned recharging mode. After the recharging step (S902) ends, it loops back to execute the measurement step (S901) until the measurement step (S901) and the recharging step (S902) are executed N times each.

[0082] In the recharging step (S902), the chemical reaction formula is as follows:

[0083] The following reduction reaction is carried out on the working electrode 120:

[0084]

[0085] The positive potential of the counter electrode 130 promotes the following oxidation reaction on the counter electrode 130:

[0086]

[0087] Among them, Ag on the counter electrode is oxidized to Ag⁺, which combines with Cl⁻ from the biological body or Cl⁻ after the oxidation (or dissociation) of AgCl to form AgCl, so that part or all of the AgCl consumed during the measurement period T1 is recharged onto the counter electrode.

[0088] The human body can obtain chloride ions and iodide ions through iodized salt, so the available halide ions at least include chloride ions and iodide ions for recharging silver halide.

[0089] The following embodiments are directed to the cycle of N measurement steps (S901) and N recharging steps (S902), where the physiological parameter mentioned is preferably the glucose value, and the physiological signal mentioned is preferably the current value. According to some preferred embodiments, each measurement potential difference V1 is applied during the measurement period T1, each recharging potential difference V2 is applied during the recharging period t2, and the measurement period T1 is a fixed value, which can be a time value within 3 seconds, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 1 minute, 2 minutes, 5 minutes, or 10 minutes. According to some preferred embodiments, it is preferably a time value within 30 seconds. The measurement period T1 is a fixed value and can be 2.5 seconds, 5 seconds, 15 seconds, 30 seconds, 1 minute, 2.5 minutes, 5 minutes, 10 minutes, or 30 minutes, preferably 30 seconds. According to some preferred embodiments, the sum of each measurement period T1 and each recharging period t2 is a fixed value. According to some preferred embodiments, each recharging potential difference V2 has a fixed voltage value, and each recharging period t2 is dynamically adjusted according to the amount of AgCl consumed each time (such as Figure 5AAs shown. According to some preferred embodiments, each of the output physiological parameters is obtained by calculating the physiological signals at a single measurement time point during each measurement period T1. According to some preferred embodiments, each of the output physiological parameters is obtained by calculating a mathematical operation value of multiple physiological signals at multiple measurement time points during each measurement period T1. The aforementioned mathematical operation value is, for example, an accumulated value, an average value, a median value, an average of median values, etc. According to some preferred embodiments, by controlling each charge amount to be equal to or not equal to (including approximately similar, greater than or less than) each consumption amount, the AgCl amount on the counter electrode is controlled within the safety inventory range, so that a stable proportional relationship is maintained between the next physiological signal and the next physiological parameter obtained in the next measurement step. According to some preferred embodiments, the step of removing each measurement potential difference V1 is to open the circuit configured to connect the working electrode and the counter electrode, or set each measurement potential difference V1 to 0. In other words, power can be cut off to make the measurement circuit in an open circuit state; or, a 0-volt voltage can be applied between the working electrode and the counter electrode, and the operation time of any one of the two operations is 0.01 to 0.5 seconds. The step of removing the measurement potential difference V1 can avoid the generation of Λ-shaped physiological signals. According to some preferred embodiments, the step of removing each recharge potential difference V2 is to open the circuit configured to connect the working electrode and the counter electrode, or set each recharge potential difference V2 to 0.

[0090] According to some preferred embodiments, after the sensor is implanted into the human body, a warm-up time is required to enable the sensor to reach equilibrium and stability in the body so as to stably present a physiological signal that is positively correlated with the analyte concentration. Therefore, during the measurement step (S901), the measurement voltage is continuously applied until the end of the measurement period T1, and the measurement period T1 is controlled so that a stable proportional relationship is achieved between the physiological signal and the physiological parameter of the analyte. Therefore, the measurement period T1 can be a variable value or a combination of a variable value and a fixed value (for example, variable value + fixed value, the variable value can be 1 hour, 2 hours, 3 hours, 6 hours, 12 hours or 24 hours, and the fixed value can be, for example, 30 seconds).

[0091] Please refer to Figure 5A -F, Figure 8A -D and Figure 9, the present invention measures the reaction current of the counter electrode R / C by applying a voltage to the counter electrode R / C, and obtains the initial capacity of AgCl by performing mathematical operations on the reaction current during a period. For example, the initial capacity of AgCl is defined by calculating the area under the reaction current curve, also known as the initial amount or initial Coulomb amount (Cinitial), and hereinafter will be described in terms of amount. The counter electrode R / C contains Ag and AgCl. When the percentage of AgCl (X% AgCl) is known, the percentage of Ag (Y% Ag = 100% - X% AgCl) can be calculated. In each measurement step (S901), the consumption amount of AgCl each time (denoted as Cconsume) is defined by calculating the area under the current curve of the working electrode W. The AgCl of the counter electrode R / C has a consumption amount Cconsume corresponding to the physiological signal Ia, that is, Cconsume = Ia * T1. In each recharge step (S902), the recharge amount of AgCl each time (denoted as Creplenish) is defined by calculating the area under the current curve of the counter electrode R / C, that is, Creplenish = Ib * t2, where t2 ranges from 0 to T2.

[0092] The following describes the calculation method of the safety inventory of AgCl. In some preferred embodiments, the safety inventory range is presented in the ratio of Ag to AgCl, and the present invention uses the Coulomb amount (C) measured at the counter electrode to reflect the ratio relationship between Ag and AgCl. In some preferred embodiments, the ratio of Ag to AgCl is 99.9%:0.1%, 99%:1%, 95%:5%, 90%:10%, 70%:30%, 50%:50%, 40%:60%, or 30:70%, so that a certain amount of AgCl is present on the counter electrode and will not be completely consumed, enabling each physiological signal measurement step to be stably executed. The remaining amount of AgCl is the sum of the recharge amount and the initial amount minus the consumption amount. In some preferred embodiments, the remaining amount of AgCl varies within a range, that is, the remaining amount of AgCl is controlled within the range of the initial amount plus or minus a specific value (X value), that is, (Creplenish + Cinitial) - Cconsume = Cinitial ± X, where 0 < X < 100% Cinitial, 10% Cinitial < X ≤ 90% Cinitial, or 0.5% Cinitial < X ≤ 50% Cinitial. In some preferred embodiments, the remaining amount of AgCl can gradually decrease, gradually increase, or vary smoothly or arbitrarily within the range but still within the range.

[0093] Please refer to Figure 10, which shows a method for measuring an analyte according to another embodiment of the present invention. Through this method, not only can the service life of the micro-biosensor be extended, but also the usage amounts of silver and silver halide materials for the counter electrode can be reduced. The micro-biosensor can be, for example, Figures 2A to 3 the micro-biosensor shown, which is used for subcutaneous implantation to measure a physiological signal of a physiological parameter associated with the analyte in a biological fluid (such as interstitial fluid). The electrode material of the counter electrode of the micro-biosensor includes silver and silver halide. In Figure 10 the embodiment, the analyte can be glucose in interstitial fluid, the physiological parameter is the glucose value in the human body, and the physiological signal is the current value measured by the micro-biosensor. Only one cycle of this embodiment will be described below. The method of this embodiment starts with the following steps: applying a measurement voltage to drive the working electrode to measure the physiological signal for obtaining the physiological parameter, where a specific amount of silver halide is consumed (hereinafter abbreviated as the consumption amount) (S1001).

[0094] Then, stop applying the measurement voltage (S1002), and use the obtained physiological signal to obtain the physiological parameter (S1003). After obtaining the physiological parameter, apply a recharge voltage between the counter electrode and the working electrode to drive the counter electrode, so that the amount of silver halide is recharged by a recharge amount (S1004), where the sum of the recharge amount and the initial amount minus the consumption amount (i.e., the remaining amount described above) is controlled within the range of the initial amount plus or minus a specific value. The above control step is achieved by controlling the recharge amount to be equal to or not equal to (including approximately similar, greater than or less than) the consumption amount to maintain the amount of silver halide within the safety inventory range. According to the reaction formula, the increase or decrease in the number of moles of silver halide corresponds to the increase or decrease in the number of moles of silver. Therefore, for the sake of convenience in description, the consumption amount of silver halide corresponds to the simulated increase amount of silver. In some preferred embodiments, the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the sum of the amount of silver and the amount of silver halide (AgCl / Ag + AgCl) is greater than 0 and less than 1, that is, there is an amount of silver halide on the counter electrode, preferably between 0.01 - 0.99, between 0.1 - 0.9, between 0.2 - 0.8, between 0.3 - 0.7, or between 0.4 - 0.6. Stop applying the recharge voltage when the recharge amount is reached (S1005). Then recycle to step S1001 to execute the next cycle.

[0095] The following describes a specific embodiment of the present invention. Taking the requirement that the service life of a biosensor must reach 16 days as an example, a method for calculating the size of the Ag / AgCl material in the electrode signal sensing section is provided. For example, the average measurement current of the analyte to be measured each time is 30 nA, the measurement period (T1) is 30 seconds, and the recharge period (t2) is 30 seconds. The daily consumption of AgCl (Cconsume / day) = 1.3 mC / day. Assuming that the requirement for the service life of the sensor is 16 days, the consumption of AgCl required for 16 days of use is 1.3 x 16 = 20.8 mC.

[0096] For example, the length of the counter electrode is 2.5 mm, and its corresponding initial amount of AgCl, Cinitial = 10 mC;

[0097] (1) In the case of not performing the recharge of AgCl, for a sensor service life of 16 days, the length required for the counter electrode is at least:

[0098] C16day / Cconsume / day = 20.8 mC / 1.3 mg / day = 16 mm

[0099] (2) Therefore, in the case of not using the AgCl recharge method of the present invention, the length of the counter electrode needs to exceed 16 mm to enable the sensor to have a service life of 16 days.

[0100] In this embodiment, in the case of not using the AgCl recharge technology of the present invention, a relatively large size of Ag / AgCl material needs to be configured in the counter electrode signal sensing section to achieve a sensor service life of 16 days. Through the AgCl recharge method of the present invention, the AgCl recharge step is performed between two measurement steps. The consumption and recharge of AgCl can be repeatedly cycled in a short time (i.e., recharge immediately when in use). Therefore, the amount of Ag / AgCl material in the sensor can be reduced, and thus the sensor can be miniaturized. Therefore, it is not necessary to prepare the capacity of AgCl for 16 days for consumption in the counter electrode signal sensing section material. For example, preparing the capacity of AgCl for about 1 - 2 days can enable the sensor to be used for 16 days, thereby achieving the effect of extending the service life of the sensor. The capacity of AgCl for 1 - 2 days also refers to the initial amount of AgCl, which is, for example, between about 1.3 - 2.6 mC, that the counter electrode has before leaving the factory or before performing the first measurement. This initial amount can also be other smaller or larger ranges. In other embodiments, different AgCl capacities such as 1 - 5 days, 1 - 3 days, 6 - 24 hours, 6 - 12 hours, etc. can also be prepared. The material size of the counter electrode signal sensing section only needs to have the capacity to enable each glucose measurement step to be stably performed and make the measurement current show a positive correlation with the glucose concentration in the body.

[0101] Without using the silver chloride recharge technology of the present invention, the prior art would increase the electrode length / area to meet the required number of days for the sensor. Taking the prior art as an example, the length of the implanted end of the sensor is about 12 mm. Due to the long implanted length, in order to avoid implanting deep into the subcutaneous tissue, it needs to be implanted subcutaneously at an oblique angle, resulting in a larger implantation wound. Another example is that the capacity of AgCl for 1 - 2 days is between about 1.3 - 2.6 mC. Converting this to the counter electrode length for 1 - 2 days is 2.5 - 5 mm, which is much shorter than the 16 - mm counter electrode length required without using the silver halide recharge method of the present invention, further highlighting that the present invention can effectively reduce the required counter electrode size. Through the silver halide recharge method of the present invention, the implanted end length can be shortened, for example, reduced to no more than 10 mm. In the present invention Figures 2A-2C The lower half of the connection region 117 to the second end 114 of the micro - biosensor 100 disclosed in the present invention belongs to the short implanted end 118 (as Figure 2A and 2B shown), and the implantation depth of the short implanted end 118 needs to at least meet the depth where tissue fluid glucose can be measured in the dermis. Through the silver halide recharge method of the present invention, the longest side of the short implanted end 118 is no more than 6 mm, so that the micro - biosensor 100 can be partially implanted under the organism's epidermis perpendicular to the organism's epidermis. The longest side of the short implanted end 118 is preferably no more than 5 mm, 4.5 mm, 3.5 mm, or 2.5 mm. The short implanted end 118 of the present invention includes the signal sensing section 132 of the counter electrode, and the longest side of its signal sensing section 132 is no more than 6 mm, preferably 2 - 6 mm, 2 - 5 mm, 2 - 4.5 mm, 2 - 3.5 mm, 0.5 - 2 mm, 0.2 - 1 mm.

[0102] Therefore, compared with the situation without using the silver halide recharge technology of the present invention, through the silver halide recharge method of the present invention, the service life of the sensor can be effectively extended, and the use of Ag / AgCl material on the counter electrode can be significantly reduced, so that the size of the signal sensing section of the counter electrode can be reduced. Due to the reduction in the use of Ag / AgCl material on the counter electrode, the sensor can be miniaturized and the biological toxicity can be reduced. In addition, the reduction in electrode size especially refers to shortening the implanted end length of the sensor, so the implantation pain of the user can be reduced.

[0103]

Symbol Explanation

[0104] 10: Physiological signal measurement device

[0105] 100: Micro - biosensor

[0106] 110: Substrate

[0107] 111: Surface

[0108] 112: Opposite surface

[0109] 113: First end

[0110] 114: Second end

[0111] 115: Signal output area

[0112] 116: Sensing area

[0113] 117: Connection area

[0114] 120: Working electrode

[0115] 121: Signal output section

[0116] 122: Signal sensing section

[0117] 130: Counter electrode

[0118] 131: Signal output section

[0119] 132: Signal sensing section

[0120] 140: Chemical reagent

[0121] 20: User device

[0122] 200: Sensing unit

[0123] 210: Processor

[0124] 220: Power supply

[0125] 230: Circuit switching unit

[0126] 240: Temperature sensing unit

[0127] 250: Communication unit

[0128] Steps of S901, S902, S1001, S1002, S1003, S1004, S1005

Claims

1. A method for measuring an analyte that can extend the service life of a micro biosensor, the biosensor being used for subcutaneous implantation to measure a physiological signal of a physiological parameter associated with the analyte in a biological fluid, the biosensor including a working electrode and a counter electrode, the working electrode being at least partially covered by a chemical reagent and being used to generate an electrochemical reaction with the analyte, the electrode material of the counter electrode including silver and silver chloride, the method including the following cyclic steps: a) Perform a first measurement step, including: i. Apply a first measurement potential difference between the working electrode and the counter electrode during a first measurement period, such that the voltage of the working electrode is higher than the voltage of the counter electrode, so that a first oxidation reaction occurs at the working electrode, and an electrochemical reaction is carried out with the chemical reagent and the analyte to output a first physiological signal. At the same time, the silver chloride of the counter electrode has a first consumption amount, which is calculated by the area under the current curve of the first physiological signal during the first measurement period; And ii. Remove the first measurement potential difference, stop the first measurement step, and the first physiological signal is output as a first physiological parameter after being calculated; b) Perform a first recharge step, including: i. Apply a first recharge potential difference between the counter electrode and the working electrode during a first recharge period, such that the voltage of the counter electrode is higher than the voltage of the working electrode, so that a second oxidation reaction occurs on the silver of the counter electrode, and the silver chloride has a first recharge amount, which is calculated by the area under the current curve of the counter electrode during the first recharge period, wherein the first recharge amount corresponds to the first consumption amount, so that the amount of silver chloride on the counter electrode is controlled within a safety inventory range, and a stable proportional relationship is maintained between the next physiological signal and the next physiological parameter obtained in the next measurement step; and wherein the first recharge potential difference has a fixed voltage value and the time of the first recharge period is dynamically adjusted based on the first consumption amount, or the time of the first recharge period has a fixed time value and the first recharge potential difference is dynamically adjusted based on the first consumption amount, so that the first recharge amount is close to the first consumption amount or within a specific range of the first consumption amount; and ii. Remove the first recharge potential difference, stop the first recharge step; c) Perform a second measurement step identical to step a) to obtain the second physiological signal and output the second physiological parameter; d) Perform a second recharge step identical to step b); and e) Sequentially and repeatedly perform the Nth measurement step and the Nth recharge step in a cycle.

2. The method according to claim 1, wherein: Each of the measurement potential differences is applied during a measurement time, and each of the recharge potential differences is applied during a recharge time; Each of the measurement times has a fixed measurement time value or a variable measurement time value.

3. The method according to claim 2, wherein the sum of each of the measurement times and each of the recharge times is a fixed time.

4. The method according to claim 2, wherein each of the recharge potential differences has a fixed voltage value, and each of the recharge times is dynamically adjusted according to each of the consumption amounts of the silver chloride.

5. The method according to claim 2, wherein each of the recharge times is a fixed time value, and the value of each of the recharge potential differences is dynamically adjusted according to each of the consumption amounts of the silver chloride.

6. The method according to claim 2, wherein each of the fixed measurement time values can be selected from time values within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes.

7. The method according to claim 1, wherein each of the output physiological parameters is obtained by operating on the physiological signals at a single measurement time point during each of the measurement periods, and the amount of the silver chloride of the pair of electrodes is controlled within a safety inventory range so that a stable proportional relationship is maintained between the next physiological signal obtained in the next measurement step and the next physiological parameter, by controlling each of the recharge amounts to be approximately similar to or equal to each of the consumption amounts.

8. The method according to claim 1, wherein each of the output physiological parameters is obtained by operating on the mathematical operation values of the plurality of physiological signals at a plurality of measurement time points during each of the measurement periods, and the amount of the silver chloride of the pair of electrodes is controlled within a safety inventory range so that a stable proportional relationship is maintained between the next physiological signal obtained in the next measurement step and the next physiological parameter, by controlling each of the recharge amounts to be greater than each of the consumption amounts.

9. The method according to claim 1, wherein the amount of the silver chloride of the pair of electrodes is controlled within a safety inventory range so that a stable proportional relationship is maintained between the next physiological signal obtained in the next measurement step and the next physiological parameter, by controlling each of the recharge amounts to be less than each of the consumption amounts, and the values of each of the recharge times and each of the recharge potential differences are dynamically adjusted according to each of the consumption amounts of the silver chloride.

10. The method according to claim 1, wherein the amount of the silver chloride of the pair of electrodes is controlled within a safety inventory range so that a stable proportional relationship is maintained between the next physiological signal obtained in the next measurement step and the next physiological parameter, by controlling each of the recharge amounts to be not equal to each of the consumption amounts.

11. The method according to claim 1, wherein the step of removing each of the measurement potential differences and each of the recharge potential differences is to open a circuit configured to connect the working electrode and the pair of electrodes, or to set each of the measurement potential differences and each of the recharge potential differences to 0.

12. A method for measuring an analyte that can extend the service life of a biosensor, the biosensor being used for subcutaneous implantation to measure physiological signals of physiological parameters associated with the analyte, and including a working electrode and a pair of electrodes, the working electrode being at least partially covered by a chemical reagent, the electrode material of the pair of electrodes including silver and silver halide, the silver halide having an initial amount, the method including the following steps: Applying a measurement voltage during a measurement period to drive the working electrode to measure the physiological signal and to obtain the physiological parameter, and the silver halide is consumed by a specific amount, the specific amount being calculated by the area under the current curve of the physiological signal during the measurement period; Stopping applying the measurement voltage; and Whenever a physiological parameter is obtained, a recharge voltage is applied during the recharge period to drive the pair of electrodes, so that the amount of silver halide is recharged to a recharge amount, which is calculated by the area under the current curve of the pair of electrodes during the recharge period. wherein the sum of each recharge amount and the initial amount minus the value of each consumed amount is controlled within the range of the initial amount plus or minus a specific value; and wherein the recharge voltage has a fixed voltage value and the time of the recharge period is dynamically adjusted based on the consumed amount, or the time of the recharge period has a fixed time value and the recharge voltage is dynamically adjusted based on the consumed amount, so that the recharge amount approaches each consumed amount or is within a specific range of each consumed amount.

13. The method according to claim 12, wherein the specific value is X, and X satisfies the following condition: 0 < X < 100% of the initial amount.

14. The method according to claim 12, wherein controlling the sum of each recharge amount and the initial amount minus the value of each consumed amount to be within the range of the initial amount plus or minus a specific value is achieved by controlling each recharge amount to be approximately similar to or equal to, greater than, less than, or not equal to each consumed amount of the silver halide, so as to maintain the amount of the silver halide within a safety inventory range and make the amount greater than 0.

15. An implantable micro-biosensor for implanting subcutaneously to measure a physiological signal associated with an analyte in a living body, the biosensor comprising: a substrate; a chemical reagent; a working electrode disposed on the substrate, at least partially covered by the chemical reagent, and driven to undergo a first oxidation reaction during the measurement period to measure the physiological signal and generate the physiological parameter; a counter electrode disposed on the substrate, the electrode material of the counter electrode comprising silver and silver halide, wherein the silver halide has an initial amount and is consumed by a specific amount during the measurement period, and the specific amount is calculated by the area under the current curve of the physiological signal during the measurement period; and whenever a physiological parameter is obtained, during a recharge period, the counter electrode is driven so that the silver halide of the driven counter electrode is recharged to a recharge amount, which is calculated by the area under the current curve of the counter electrode during the recharge period, wherein the sum of each recharge amount and the initial amount minus the value of each consumed amount is controlled within the range of the initial amount plus or minus a specific value; and wherein the recharge voltage has a fixed voltage value and the time of the recharge period is dynamically adjusted based on the consumed amount, or the time of the recharge period has a fixed time value and the recharge voltage is dynamically adjusted based on the consumed amount, so that the recharge amount approaches each consumed amount or is within a specific range of each consumed amount.

16. The implantable micro-biosensor according to claim 15, wherein the ratio of the sum of each recharge amount and the initial amount minus the value of each consumed amount to the sum of the amount of the silver halide and the amount of the silver plus the amount of the silver halide is greater than 0 and less than 1.

17. The biosensor according to claim 15, wherein the biosensor has a short implant end with a length not greater than 6 mm.

18. The implantable micro-biosensor according to claim 15, wherein the surface of the pair of electrodes is partially covered by a conductive material.

19. The implantable micro-biosensor according to claim 15, wherein the conductive material is carbon.

20. The implantable micro-biosensor according to claim 15, wherein the pair of electrodes is at least partially covered by the chemical reagent.

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