WO2021180229A1 - Procédé de restauration de biocapteur et dispositif utilisant ledit procédé - Google Patents

Procédé de restauration de biocapteur et dispositif utilisant ledit procédé Download PDF

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Publication number
WO2021180229A1
WO2021180229A1 PCT/CN2021/080609 CN2021080609W WO2021180229A1 WO 2021180229 A1 WO2021180229 A1 WO 2021180229A1 CN 2021080609 W CN2021080609 W CN 2021080609W WO 2021180229 A1 WO2021180229 A1 WO 2021180229A1
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Prior art keywords
measurement
electrode
recharge
silver halide
counter electrode
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PCT/CN2021/080609
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English (en)
Chinese (zh)
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黄椿木
陈界行
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华广生技股份有限公司
华广美国公司
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Publication of WO2021180229A1 publication Critical patent/WO2021180229A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements

Definitions

  • the present invention relates to a biosensor and a method for determining the size of its counter electrode, in particular to a biosensor for measuring the physiological signal represented by the physiological parameter associated with the object to be measured, and for prolonging the service life of the biosensor method.
  • CGM continuous glucose monitoring
  • the biochemical reaction signal that depends on the concentration of the analyte is converted into a measurable physical signal, such as an optical or electrochemical signal.
  • a measurable physical signal such as an optical or electrochemical signal.
  • an electrochemical reaction such as glucose oxidase (GOx) catalyzes the reaction of glucose to produce Gluconolactone and reduced enzymes. The subsequent reduced enzymes will interact with the oxygen in the biological fluids in the body. The transfer then generates the product hydrogen peroxide (H 2 O 2 ), and finally the glucose concentration is quantified by the oxidation reaction of the catalyzed product H 2 O 2.
  • the reaction formula is as follows.
  • FAD Fevin Adenine Dinucleotide
  • the basic structure of CGM includes: (a) Biosensor, used to measure physiological signals corresponding to human glucose concentration; and (b) Transmitter, used to transmit these physiological signals.
  • the biosensor can be a two-electrode system or a three-electrode system. In the three-electrode system biosensor, 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).
  • the counter electrode also functions as a reference electrode, so it is sometimes called a counter/reference electrode (R/C).
  • the suitable material for the reference electrode in the three-electrode system biosensor and the counter electrode as the reference electrode in the two-electrode system biosensor for stable measurement of glucose concentration is silver/silver chloride (Ag/AgCl).
  • the corresponding reference electrode (RE) or reference/counter electrode (R/C) undergoes a reduction reaction to make the silver chloride
  • the reduction to silver causes the silver chloride to be consumed.
  • the silver chloride on the reference electrode will be lost due to the dissociation of silver chloride in the body fluid, which will cause the problem of drifting to the reference voltage.
  • the reference/counter electrode (R/C) of the two-electrode system due to the reaction of the reference/counter electrode (R/C) of the two-electrode system, the consumption of silver chloride is even higher than that of the three-electrode system. Therefore, the service life of the sensor is limited by the silver chloride content on the counter electrode and/or reference electrode.
  • the consumption of the counter electrode is about 1.73 millicoulombs (mC) per day at an average sensing current of 20 nanoamperes (nA).
  • mC millicoulombs
  • nA nanoamperes
  • the length, width and height of the counter electrode are 3.3 mm, 0.25 mm
  • the electrode capacity (Capacity) of the original design is only 6mC at 0.01 mm
  • the stable measurement state can be maintained for about one day at most.
  • the capacity of the electrode must be at least 27.68mC.
  • the current technology does not change the width and thickness.
  • the length of the counter electrode may need to be as long as 15.2 mm. Therefore, the prior art attempts to extend the length of the counter electrode to more than 10 mm, and in order to avoid implanting deep into the subcutaneous tissue, these biosensors need to be implanted at an oblique angle. Therefore, it causes problems such as a larger implantation wound and a higher risk of infection to the patient, and due to the long implantation length, the pain during implantation is also more pronounced.
  • US 8,620,398 describes a biosensor, which is mainly a three-electrode system.
  • the reference electrode basically does not participate in the chemical reaction, the silver chloride is still gradually consumed in the internal environment, but the consumption rate is slower than that of the two-electrode system, which is disclosed in the article.
  • the step of determining depletion includes determining that the output current of the transmitter is noisy. Will be activated to restore AgCl to the amount required for enough measurements. Then until the next time the noise occurs again, AgCl needs to be recharged again. It can be understood that although US 8,620,398 considers that AgCl will be consumed in the measurement and AgCl recharge is performed when the biosensor fails.
  • the measured value at the time of failure is no longer credible. It is necessary to wait for the biosensor to complete the AgCl refilling procedure to obtain the correct measured value, temporarily adopt the blood sampling method, or skip this measurement directly. This problem is for the patient or People who need to know the blood glucose concentration at the time are always troubled.
  • this type of biosensor since this type of biosensor has to cope with at least several consecutive or even multiple measurements over several days, a large amount of AgCl must be prepared, but it will inevitably cause the problem of a longer implantation length of the biosensor. It has not been proposed that real-time AgCl refilling can be used to provide uninterrupted measurement, a biosensor with a shorter implant length and a longer service life.
  • US9,351,677 is mainly a two-electrode system.
  • the reference/counter electrode (R/C) participates in the chemical reaction, so silver chloride is consumed by the electrochemical reaction.
  • the article proposes an analyte sensor with increased AgCl capacity, which uses H 2 O 2 regenerates the AgCl on the reference electrode, but because H 2 O 2 is easily reduced to H 2 O or oxidized to O 2 , it is not easy to exist stably in the human body. Therefore, during regeneration/recharging, the concentration of H 2 O 2 in the body may not be sufficient to stably recharge enough AgCl, and the biosensor needs to be equipped with a larger AgCl electrode size, and its implanted end is also long. Up to 12mm.
  • the service life of the biosensor depends on the amount of silver halide present in the counter electrode.
  • the size of the counter electrode also depends on the amount of silver halide. The longer the life of the biosensor, the greater the amount of silver halide. The larger the amount of silver halide, the larger the size of the counter electrode. The larger the size of the counter electrode, the longer the implantation length into the patient. The longer the implant length for the patient, the greater the discomfort suffered by the patient.
  • the present disclosure provides a solution to reduce the size of the counter electrode, provides a method for quantifying the initial amount of silver halide required on the counter electrode, and provides a method for intelligently starting the refill halogenation when needed.
  • the silver method and device do not need to wait for the silver halide depletion signal to appear (for example, physiological signal noise) before performing silver halide recharging.
  • an appropriate range can be selected as the threshold interval to control the inventory level of silver halide to be maintained here.
  • the present invention provides a biosensor capable of providing uninterrupted measurement, stable refilling of AgCl, prolonging its service life, and miniaturizing the effect of the small size of the implanted end, which can further reduce the cost of the product. Manufacturing costs, and these effects can solve the aforementioned problems that are difficult to overcome by the known technology.
  • the size of the counter electrode signal sensing section in the micro biosensor of the present invention can be reduced, thereby reducing biological toxicity and enabling the micro biosensor to have a prolonged service life.
  • the reduced size of the electrode can shorten the length of the implanted end of the sensor, thus reducing the pain of implantation for the user.
  • the refilling technology of the present invention is used to control the timing and amount of refilling of silver chloride. Therefore, even when the user's glucose concentration fluctuates greatly, the micro sensor of the present invention can still recharge in real time and automatically. Charge the consumed silver chloride to maintain the inventory of silver chloride within a predetermined interval. Therefore, the obtained physiological signals and physiological parameters maintain a stable proportional relationship.
  • the recharging rate of silver chloride does not have to be completely positively correlated with the decrease rate of silver chloride during the measurement, and it also includes the recharging of silver chloride immediately after each measurement. Charging method.
  • One of the objectives of this case is to provide a method for controlling the recharge of silver halide material in a biosensor that is implanted under the skin to measure the physiological parameters associated with the analyte in the biological fluid.
  • the biosensor at least includes a first electrode and a counter electrode
  • the counter electrode includes a silver halide material and a silver material
  • the silver halide material has an inventory level in the silver halide material and the silver material
  • the refill control method includes the following steps: after a measurement operation, a measurement value of the physiological signal is obtained, wherein the inventory level decreases after the measurement operation; If the condition is met, calculate the variation value of the inventory level during the predetermined number of times, and start the first refill operation to refill the variation value of the inventory level, and the predetermined number of times is a positive integer , Wherein the inventory level substantially changes between the first threshold and the second threshold.
  • One of the objectives of this case is to provide a physiological signal measuring device that can control the inventory level of the silver halide material of the biosensor.
  • the silver halide material has an initial inventory, and the inventory level represents the current
  • the inventory is used to make the physiological signal measurement device perform a refill operation to restore the silver halide material to the inventory level
  • the physiological signal measurement device includes: the biosensor, includes: a first electrode, and The first pair of electrodes includes the silver halide material and the silver material; and a transmission unit, which is coupled to the biosensor, and includes a processor, configured to reduce the consumption of the inventory when the measurement operation is started.
  • the processor controls the inventory level to basically change between a first threshold and a second threshold .
  • the biosensor includes a first electrode and a counter electrode.
  • the counter electrode includes a silver halide material and a silver material.
  • the silver halide material has a stock.
  • the method includes the following steps: after the measuring operation, calculating the change in the inventory level; and activating the first A refill operation is performed to refill the variation value of the inventory level, wherein the inventory level is controlled to vary substantially between a first threshold and a second threshold.
  • FIG. 1 is a schematic diagram of a physiological signal measuring device according to an embodiment of the present invention.
  • FIG. 2A is a schematic front view of the micro biosensor of the present invention.
  • FIG. 2B is a schematic diagram of the back of the micro biosensor of the present invention.
  • FIG. 2C is a schematic cross-sectional view along the line A-A' in Fig. 2A of the present invention.
  • FIG. 2D is a schematic cross-sectional view of the second embodiment of the micro biosensor of the present invention.
  • FIG. 3A is a flowchart of a method for recharging silver halide material in a biosensor according to an embodiment of the present invention.
  • FIG. 3B is a flowchart of a method for recharging silver halide material in a biosensor according to another embodiment of the present invention.
  • FIG. 3C is a flowchart of a method for recharging silver halide material in a biosensor according to another embodiment of the present invention.
  • FIG. 3D is a flowchart of a method for recharging silver halide material in a biosensor according to another embodiment of the present invention.
  • FIG. 3E is a flowchart of a method for recharging silver halide material in a biosensor according to another embodiment of the present invention.
  • FIG. 4A] to [FIG. 4H] are schematic diagrams of the inventory level of various embodiments of the present invention.
  • FIG. 5A is the constant voltage circuit in the measurement mode in the present invention.
  • FIG. 5B is the constant voltage circuit in the recharging mode in the present invention.
  • FIG. 6A is a schematic diagram of the variation curve of the inventory level according to an embodiment of the present invention.
  • FIG. 6B is a schematic diagram of the variation curve of the inventory level according to another embodiment of the present invention.
  • FIG. 6C is a schematic diagram of the variation curve of the inventory level according to another embodiment of the present invention.
  • FIG. 6D is a schematic diagram of the variation curve of the inventory level according to another embodiment of the present invention.
  • FIG. 6E is a schematic diagram of the variation curve of the inventory level according to another embodiment of the present invention.
  • FIG. 7A is a current schematic diagram of the constant voltage circuit of the present invention in the first mode alternately performing the measurement mode and the recharge mode.
  • FIG. 7B is a schematic diagram of the current of the constant voltage circuit of the present invention in the second mode alternately performing the measurement mode and the recharge mode.
  • FIG. 7C is a current schematic diagram of the constant voltage circuit of the present invention in the third mode alternately performing the measurement mode and the recharge mode.
  • FIG. 7D is a current schematic diagram of the constant voltage circuit of the present invention in the fourth mode alternately performing the measurement mode and the recharge mode.
  • FIG. 7E is a current schematic diagram of the constant voltage circuit of the present invention in the fifth mode alternately performing the measurement mode and the recharge mode.
  • FIG. 7F is a current schematic diagram of the constant voltage circuit of the present invention in the sixth mode alternately performing the measurement mode and the recharge mode.
  • FIG. 8A The constant current circuit with step-switching in the measurement mode of the present invention.
  • FIG. 8B The constant current circuit with step-switching in the recharge mode of the present invention.
  • FIG. 9A The constant current circuit with stepless switching in the measurement mode of the present invention.
  • FIG. 9B The constant current circuit with stepless switching in the recharge mode in the present invention.
  • FIG. 10A is a voltage schematic diagram of the constant current circuit of the present invention in the first mode alternately performing the measurement mode and the recharge mode.
  • FIG. 10B is a voltage schematic diagram of the constant current circuit of the present invention in the second mode alternately performing the measurement mode and the recharge mode.
  • FIG. 10C is a voltage schematic diagram of the constant current circuit of the present invention in the third mode alternately performing the measurement mode and the recharge mode.
  • FIG. 10D is a schematic diagram of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in the third mode.
  • Figure 11 is a method for determining an analyte according to an embodiment of the present invention.
  • FIG. 12 is a method for determining an analyte according to another embodiment of the present invention.
  • FIG. 13A is a schematic front view of the first embodiment of the micro biosensor of the present invention.
  • FIG. 13B is a schematic back view of the first embodiment of the micro biosensor of the present invention.
  • FIG. 13C is a schematic cross-sectional view taken along the line A-A' in Figure 2A of the present invention.
  • FIG. 14A is a schematic cross-sectional view of the second embodiment of the micro biosensor of the present invention.
  • FIG. 14B is a schematic cross-sectional view of the third embodiment of the micro biosensor of the present invention.
  • FIG. 14C is a schematic cross-sectional view of the fourth embodiment of the micro biosensor of the present invention.
  • FIG. 14D is a schematic cross-sectional view of the fifth embodiment of the micro biosensor of the present invention.
  • FIG. 14E is a schematic cross-sectional view of the sixth embodiment of the micro biosensor of the present invention.
  • FIG. 14F is a schematic cross-sectional view of the seventh embodiment of the micro biosensor of the present invention.
  • FIG. 14G is a schematic cross-sectional view of the eighth embodiment of the micro biosensor of the present invention.
  • FIG. 15A is the constant voltage circuit in the measurement mode in the present invention.
  • FIG. 15B is the constant voltage circuit in the recharging mode in the present invention.
  • FIG. 16A The constant current circuit with step-switching in the measurement mode of the present invention.
  • FIG. 16B The constant current circuit with step-switching in the recharge mode in the present invention.
  • FIG. 17A The constant current circuit with stepless switching in the measurement mode of the present invention.
  • FIG. 17B The constant current circuit with stepless switching in the recharge mode in the present invention.
  • FIG. 18A is a schematic front view of the first embodiment of the micro biosensor of the present invention.
  • FIG. 18B is a schematic back view of the first embodiment of the micro biosensor of the present invention.
  • FIG. 18C is a schematic cross-sectional view taken along the line A-A' in Fig. 2A of the present invention.
  • FIG. 19A is a schematic cross-sectional view of the second embodiment of the micro biosensor of the present invention.
  • FIG. 19B is a schematic cross-sectional view of the third embodiment of the micro biosensor of the present invention.
  • FIG. 19C is a schematic cross-sectional view of the fourth embodiment of the micro biosensor of the present invention.
  • FIG. 20A It is a constant voltage circuit that can execute the measurement mode and the recharge mode according to the first method of the present invention.
  • FIG. 20B is a constant voltage circuit that can perform measurement mode and recharge mode according to the second method of the present invention.
  • FIG. 20C is a constant voltage circuit that can perform measurement mode and recharge mode according to the third method of the present invention.
  • FIG. 21 It is a constant current circuit that can perform stepwise switching between the measurement mode and the recharge mode in the present invention.
  • FIG. 22 is a constant current circuit that can perform stepless switching between the measurement mode and the recharge mode in the present invention.
  • FIG. 23A is a schematic diagram of the constant current or constant voltage circuit of the present invention in a measurement mode and a recharge mode according to an embodiment.
  • FIG. 23B is a schematic diagram of the constant current or constant voltage circuit of the present invention in the measurement mode and the recharge mode according to another embodiment.
  • FIG. 24 is a flowchart according to an embodiment of the present invention.
  • amount refers to the capacity of silver halide (AgX) or silver chloride (AgCl) in the counter electrode, and is preferably measured in microcoulomb ( ⁇ C), millicoulomb (mC) or coulomb (C ) Is expressed in units of, but not limited to, expressed in terms of weight percentage concentration wt%, number of moles, molar concentration, etc.
  • curves or straight lines schematically shown in the drawings do not necessarily represent their true shapes.
  • a straight line or a curve may have fluctuations along the normal direction of the line, or may have various possible turns; or
  • the distance, length or height shown in does not represent an absolute measure, unless explicitly stated.
  • FIG. 1 is a schematic diagram of the physiological signal measuring device of the present invention.
  • the physiological signal measuring device 10 of the present invention can be used to be implanted under the skin to measure the physiological signal of the physiological parameter associated with the analyte in the biological fluid.
  • the physiological signal measurement device 10 of the present invention includes a micro biosensor 100 and a transmission unit 200, wherein the transmission unit 200 is electrically connected to the micro biosensor 100, and has a processor 210, a power supply 220, a voltage application unit 230, a temperature sensing unit 240 and Communication unit 250.
  • the power supply 220 controls the voltage applying unit 230 through the processor 210 to provide voltage to the micro biosensor 100 for measuring the physiological signal, and the temperature sensing unit 240 measures the temperature of the biological body, so the temperature measurement signal and the physiological signal measured by the micro biosensor 100
  • the signal is transmitted to the processor 210, and the processor 210 calculates the physiological signal into a physiological parameter.
  • the communication unit 250 may perform wired or wireless transmission with the user device 20.
  • the transmission unit 200 may optionally include a timer 260 coupled to the processor 210, for example, within 5 seconds, within 15 seconds, within 30 seconds, within one minute, and ten minutes. Timekeeping at a fixed time interval such as within one hour, within two hours, within four hours, within one day, within one week, or within one month.
  • the timer 260 can also be set to send a signal to the processor 210 at one or more settable time points.
  • FIGS. 2A and 2B are schematic diagrams of the front and back 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 surrounding the working electrode 120 and the counter electrode 130 (as shown in FIG. 2C).
  • the material of the substrate 110 can be any material that is known to be suitable for use in electrode substrates and preferably has flexibility and insulation properties, such as but not limited to polymer materials such as polyester and polyimide.
  • the aforementioned polymer materials can be used singly or in combination of multiple types.
  • the substrate 110 has a surface 111 (that is, the first surface), an opposite surface 112 (that is, the second surface) opposite to the surface 111, a first end 113 and a second end 114, and the substrate 110 is divided into 3 regions, which are respectively close to The signal output area 115 of the first end 113, the sensing area 116 close to the second end 114, and the connection area 117 between the signal output area 115 and the sensing area 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 section 121 located in the signal output area 115 of the substrate 110 and a signal sensing section 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, a mixture of the foregoing elements, or derivatives of the foregoing elements (such as alloys, oxides or metal compounds, etc.).
  • the material of the working electrode 120 is a noble metal, a derivative of noble metal, or a combination of the foregoing, more preferably Ground, the working electrode 120 is a platinum-containing material.
  • 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 section 131 located in the signal output area 115 of the substrate 110 and a signal sensing section 132 located in the sensing area 116 of the substrate 110.
  • the material on the surface of the counter electrode 130 includes silver and silver halide, and the silver halide is preferably silver chloride or silver iodine, so that the counter electrode 130 also functions 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, so that the working electrode 120 is smoothly connected to ensure that the electrochemical reaction occurs on the working electrode 120; and (2) provide a stable relative potential as Reference potential.
  • the working electrode 120 and the counter electrode 130 of the present invention form a two-electrode system.
  • the silver/silver halide can be mixed with carbon.
  • the silver/silver halide is mixed with carbon glue, and the silver halide content only needs to make the counter electrode 130 stable. Just execute the set measurement action.
  • the surface of the counter electrode 130 can also be covered with a conductive material to prevent silver halide from dissolution, thereby protecting the counter electrode 130.
  • the conductive material is mainly a conductive material that does not affect the measurement performance of the working electrode, such as conductive material. It is Carbon.
  • the biosensor is not limited to a wire-type or stacked-type electrode structure.
  • the initial amount of silver halide may be zero before the biosensor is ready to be shipped out of the factory for sale. In this case, there is no silver halide on the counter electrode 130 of the biosensor. After the biosensor is subcutaneously implanted in the patient and during the initial recharge period before the first measurement, the silver coated on the counter electrode 130 through oxidation can be recharged with the initial amount of silver halide on the counter electrode 130 .
  • 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 other words, 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 so that the signal sensing section 122 of the working electrode 120 measures the physiological signal associated with the analyte in the biological fluid, and the physiological signal will be transmitted to the signal output of the working electrode 120 In section 121, the signal output section 121 is sent to the processor 210 to obtain physiological parameters. In addition to obtaining the physiological parameters from the transmission unit 200, the physiological parameters may also be transmitted to the user device 20 via wireless/wired communication, such as a smart phone, a physiological signal receiver, or a blood glucose meter.
  • FIG. 2C is a schematic cross-sectional view along the line AA' in FIG.
  • the working electrode 120 is disposed on the surface 111 of the substrate 110
  • the counter electrode 130 is disposed on the opposite side surface 112 of the substrate 110
  • the surfaces of the working electrode 120 and the counter electrode 130 are covered with a chemical reagent 140.
  • 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 the measurement step during the measurement period, and performs the recharge step during the recharge (ie regeneration) period.
  • the voltage of the working electrode 120 is higher than the voltage of the counter electrode 130, so that the current flows from the working electrode 120 to the direction of the counter electrode 130, so that the working electrode 120 undergoes an oxidation reaction (that is, the working electrode 120, the chemical reagent 140)
  • the electrochemical reaction between the analyte and the analyte) is used to measure the physiological signal, and a reduction reaction occurs on the counter electrode 130, so that the silver halide in the counter electrode 130 is consumed and dissociated into silver (Ag) and halide ions (X ⁇ ). Since the silver halide in the counter electrode 130 is consumed, the silver halide in the counter electrode 130 needs to be recharged to perform the next measurement step.
  • the voltage of the counter electrode 130 is higher than the voltage of the working electrode 120, so that the current flows from the counter electrode 130 to the direction of the working electrode 120, and the counter electrode 130 is oxidized to cause the silver to react with the halide ions in the living body. Or AgCl oxidized (or dissociated) Cl - combined to recharge the silver halide.
  • the detailed measurement steps and recharge steps are shown in Figure 11.
  • the working electrode 120 and the counter electrode 130 of the present invention may 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, such as Shown in Figure 2D.
  • the measurement step when the measurement step is performed, current flows from the working electrode 120 to the counter electrode 130, and the working electrode 120 is oxidized to measure physiological signals.
  • the silver halide in the counter electrode 130 is consumed and dissociated into silver ( Ag) and halogen ions (X -).
  • the recharging step current flows from the counter electrode 130 to the working electrode 120, so that the counter electrode 130 undergoes an oxidation reaction to combine silver and halide ions to recharge the silver halide.
  • a layer of conductive material such as carbon
  • a conductive layer such as silver
  • the impedance of the output end makes the counter electrode 130 of the present invention form a conductive layer, a carbon layer, and a silver/silver halide layer in sequence starting from the opposite surface 112 of the substrate 110.
  • the silver halide of the counter electrode material is not excluded as silver chloride or silver sulfide, or other electrode materials based on silver redox reaction, such as silver acetate, phosphoric acid.
  • Silver (silver phosphate) the method for restoring the inventory level of electrode materials of the present invention is not limited to the above-mentioned materials. For example, all other electrodes with similar features can be applied to the method of restoring the biosensor and the device using this method.
  • the present invention proposes a physiological signal measuring device 10 that can control the inventory level of silver halide materials of the micro biosensor 100.
  • the silver halide material has an initial inventory I 0 .
  • the inventory level represents the inventory of silver halide materials at the time and is used to make the physiological signal measurement device perform a refill operation to restore the inventory level of the silver halide material.
  • the physiological signal measurement device 10 includes: a biosensor 100, including: a first electrode and The counter electrode 130, in a two-electrode system, the first electrode is the working electrode 120, and the counter electrode 130 includes a silver halide material and a silver material; and a transmission unit 200, coupled to the micro biosensor 100, and includes: a processor 210 , Is configured to reduce the consumption of inventory when the measurement operation is started, and increase the inventory when the refill operation is started, and calculate the inventory level.
  • the processor controls the inventory level to basically vary between the first threshold and the second threshold. In other embodiments, it can also be implemented in the electrode system as shown in FIG. 13C or FIG. 14A-F.
  • 3A-3E are flowcharts of methods for recharging silver halide materials in biosensors according to different embodiments of the present invention.
  • 3A is a flowchart of a method for recharging silver halide material in a biosensor according to an embodiment of the present invention.
  • the silver halide material has an inventory level, and the inventory level changes with the measurement and refilling operations: in the measurement operation, the inventory level will decrease; and in the refilling operation, the inventory level will increase .
  • the recharging method of the present invention includes step S11: the processor 210 receives the measurement instruction; step S12: the power supply 220 controls the voltage applying unit 230 through the processor 210 to provide voltage to the biosensor 100 to measure the physiological signal and obtain the measured value; Step S13: The processor determines the operating conditions for recharging according to the measured value. For example, it determines the application time and the magnitude of the recharging voltage according to the accumulated consumption to start the recharging, and stops the recharging when the time is reached.
  • Step S14 Perform refilling according to the operating conditions of refilling;
  • Step S15 Calculate the current inventory level during the refilling operation;
  • Step S16 The processor performs the refill according to different preset thresholds (Th1, Th2, Th3, Th4, predetermined value S, etc.), determine whether the inventory level is between the first threshold and the second threshold: if not, continue the current refill operation, or go to step S11 to wait for the next measurement instruction to proceed to the next measurement and Refill cycle; if so, stop refilling and go to step S11 to receive the measurement instruction again, or go directly to step S12 for the next measurement and refill cycle.
  • Th1, Th2, Th3, Th4, predetermined value S, etc. The processor performs the refill according to different preset thresholds (Th1, Th2, Th3, Th4, predetermined value S, etc.), determine whether the inventory level is between the first threshold and the second threshold: if not, continue the current refill operation, or go to step S11 to wait for the next measurement instruction to proceed to the next measurement and Refill cycle; if so, stop refilling
  • the refill time and refill amount of the inventory level when the processor performs the refill operation can be calculated based on a consumption of each measurement operation performed, such as total consumption, partial consumption or average consumption, and a period of execution.
  • a consumption of each measurement operation performed such as total consumption, partial consumption or average consumption, and a period of execution.
  • One or a combination of the cumulative amount of consumption of each measurement operation in the measurement operation, the natural consumption of the electrode, or a combination thereof is dynamically adjusted.
  • the calculation of the refill inventory can also be matched with the user’s glucose concentration index factor. The higher the glucose concentration, the more the consumption of silver halide materials, so that the reduction rate of silver halide materials during the measurement operation does not have to be the same as that of silver halide materials.
  • the generation rate is positively correlated, and the timing and amount of regeneration of the silver halide material can be controlled by the charging method.
  • the inventory level is based on the percentage of the silver halide material in the counter electrode in the silver halide material and the silver material, or the cumulative value of the consumption of the silver halide material in each measurement operation and each recharge operation. The difference between the cumulative value of the silver halide material refilling amount is used as the calculation method.
  • the inventory level can also be a unit amount of the silver halide material in the counter electrode between the silver halide material and the silver material, for example, in coulombs. The number is presented, but is not limited to the weight percentage concentration wt%, the number of moles, and the concentration of moles.
  • other mathematical methods or electrical units can also be used to calculate the inventory level.
  • 3B is a flowchart of a method for recharging silver halide materials in a biosensor according to another embodiment of the present invention, using the difference as the inventory level as the judgment parameter to be applied to the physiological signal measuring device to perform the recharging operation .
  • the difference here is replaced with the inventory level, it can also be applied in Figure 3B.
  • the silver halide material has an inventory.
  • the recharging method includes step S21: the processor 210 receives the measurement instruction; step S22: the power supply 220 controls the voltage applying unit 230 through the processor 210 to provide voltage to the biosensor 100 for physiological signal measurement , Obtain the measured value, and convert the current consumption of the silver halide material; Step S23: The processor calculates the silver halide inventory level (the proportion of silver halide, or the cumulative value of each consumption and the accumulation of each recharge Step S24: Determine whether the current proportion (or difference) satisfies the recharge condition: if not, wait for the next measurement instruction; if yes, then Step S25: start the recharge operation; measure and measure Measurement step S26: Determine whether the proportion (or difference) meets the conditions for stopping recharging, if not, continue the current rechar
  • FIG. 3C is a flowchart of a method for recharging silver halide materials in a biosensor according to another embodiment of the present invention.
  • Step S33 Calculate the proportion of the inventory (or a difference between the cumulative value of each consumption and the cumulative value of each refill).
  • Step S34 Determine whether one of the inventory level, the difference value, and the cumulative value of the measurement times meets the refilling condition, if not, wait for the next measurement instruction; if yes, then step S35: start the refill operation; step S36: Calculate the gradually increasing inventory level in the refilling operation; step S37: determine whether the inventory level meets the refilling stop condition: if not, continue the current refilling operation; if so, stop the refilling and wait for the next measurement instruction.
  • Step S38 The cumulative value of the number of measurements is reset to zero. After the measurement instruction is received again, step S31 is entered again.
  • 3D is a flowchart of a method for recharging silver halide material in a biosensor according to another embodiment of the present invention. Please refer to FIG. 3D, steps S44 to S47 are similar to steps S34 to S37 of FIG. 3C.
  • This method can be controlled after each measurement (of course, it can also be after each measurement, such as after a single measurement operation that consumes too much, or the cumulative consumption of multiple measurement operations. Large time) start a recharge operation.
  • step S51 receiving measurement instructions
  • step S52 measuring and obtaining the measured value
  • step S53 calculating the current consumption and cumulative consumption (if it is the first measurement, the cumulative consumption is the current Consumption)
  • step S54 Determine whether the accumulated consumption satisfies the recharge condition: if not, wait for the next measurement instruction; if it is, then Step S55: Determine the operating condition for recharge.
  • the size and/or time of the applied recharge voltage is determined according to the amount of accumulated consumption, or different threshold values (Th1, Th2, Th3, Th4, predetermined value S, etc.) are given.
  • Step S56 Start the refilling operation; Step S57: Calculate the gradually increasing inventory level during the refilling operation; Step S58: Determine whether the inventory level meets the conditions for stopping the refilling: If not, continue the current refilling operation; if so, then Stop refilling and wait for the next measurement instruction. After the measurement instruction is received again, step S51 is entered again.
  • FIGS. 4A-4H are schematic diagrams of the variation curve of the inventory level of various embodiments of the present invention, in which FIGS. 4A-4D and 4H are schematic diagrams of the variation of the inventory level that may occur when only the method of FIG. 3B, 3C or 3D is used .
  • the inventory quantity starts from the initial inventory quantity I 0.
  • the refill operation is initiated until the inventory level reaches the second threshold. Stop recharging operation at Th2.
  • a predetermined value S can be set between the first threshold Th1 and the second threshold Th2 as another threshold.
  • the refill operation is stopped.
  • the predetermined value S is set equal to the initial inventory I 0 to replace the second threshold Th2. Therefore, after the refill operation is started, the refill operation is stopped when the inventory level reaches the initial inventory level I 0.
  • the predetermined value S is set to be greater than the initial inventory I 0 and less than the second threshold Th2. Therefore, after the refill operation is initiated, the inventory level rises to a predetermined value S greater than the initial inventory I 0 and then the refill operation is stopped.
  • the predetermined value S is set to be less than the initial inventory amount and greater than the first threshold Th1. Therefore, after the refill operation is started, the inventory level rises to a predetermined value S less than the initial inventory I 0 and then the refill operation is stopped.
  • FIGS. 3B to 3D are schematic diagrams of possible changes in inventory levels when the method of FIG. 3A or 3E is combined with one of the methods of FIGS. 3B to 3D.
  • FIG. 4F after one or more determination operations have been initiated and the first refill operation of the method shown in FIG. 3A or 3E has been started once or more times, when the inventory level gradually rises to be greater than or equal to the second threshold Th2, The second recharging operation as shown in FIGS. 3B to 3D will not be started, and the second recharging operation will not be started until the inventory level is less than or equal to the first threshold Th1.
  • Fig. 6A is a schematic diagram of an inventory level curve implemented in conjunction with the refilling method of Figs. 3B and 3X. Please refer to Figure 6A.
  • the vertical axis in the above figure is the proportion of AgCl
  • the vertical axis in the middle figure is the applied measured voltage (V1) and the recharge voltage (V2)
  • the vertical axis in the figure below is the condition of applying a constant voltage.
  • the horizontal axis is the same time, and the vertical dashed line indicates the same point in time. If the proportion of AgCl is initially 50%, the measurement voltage of V1 is applied in the first measurement, and the proportion of AgCl gradually decreases until the measurement operation stops.
  • the recharging operation Since the proportion of AgCl at this time is not less than or equal to the first threshold Th1, the recharging operation will not be started yet. Until after several measurement operations, the proportion of AgCl is less than (or equal to) the first threshold Th1, the recharging operation is started, and the recharging operation is stopped when the proportion of AgCl reaches (slightly greater than or equal to) the second threshold Th2.
  • Fig. 6B is a schematic diagram of another inventory level curve implemented in conjunction with the refilling method of Figs. 3B and 3X. Please refer to Figure 6B.
  • the vertical axis in the above graph is the difference between the accumulated consumption of AgCl and the accumulated recharge (the difference is initially 0), and the vertical axis in the middle graph is the applied measured voltage (V1) and the recharge voltage (V2), the vertical axis of the figure below is the measured current (area without diagonal lines) and the recharge current (area with diagonal lines) under the condition of applying a constant voltage.
  • the horizontal axis is the same time, and the vertical dashed line indicates the same time point. In the first measurement, the measurement voltage of V1 was applied, and the difference gradually decreased until the measurement operation was stopped.
  • the recharging operation Since the difference at this time is not less than or equal to the first threshold Th1, the recharging operation will not be started yet. Until after several determination operations, the difference is less than (or equal to) the first threshold Th1, the recharging operation is started, and the recharging operation is stopped when the difference reaches (slightly greater than or equal to) the second threshold Th2.
  • Another embodiment of the present invention hopes to control the inventory level between Th1 and Th2, and calculate the current fluctuation amount after each measurement and immediately reclaim the secondary fluctuation amount, but the current recharge amount is not necessarily It is exactly equal to the current change amount, so there will be a change amount between each measurement and the inventory before and after each refill. However, if the single consumption is too large and is less than or equal to another lower limit threshold Th3, the inventory level can be greatly increased to Th2.
  • FIGS. 3A and 3B are graphs showing the inventory level in accordance with the embodiment of the refilling method of FIGS. 3A and 3B.
  • the curve of Fig. 6C can be controlled by the method of Fig. 3A as the main axis, Th1 and Th2 are set so that the inventory level is controlled between them, and the method shown in Fig. 3B is used, so that in case the inventory level is suddenly large When the consumption is lower than Th3, the inventory level can be effectively kept away from Th3 in the subsequent refill operation; or when the inventory level is instantly higher than Th4 due to sudden and large consumption, it can be temporarily terminated afterwards
  • the refilling operation or reducing the refilling amount of the refilling operation effectively keeps the inventory level away from Th4.
  • the vertical axis is the AgCl inventory level
  • the horizontal axis is time
  • the refilled inventory level is initially the initial inventory level.
  • the first refilling method shown in Figure 3A is used. After the first measurement (M1), the first refill is initiated and the first refill (R1) is implemented. The subsequent inventory The amount level has not reached S.
  • the inventory level (for example, the proportion in FIG. 3B) is lower than Th3.
  • the inventory level can be increased to between Th2 and Th4.
  • other conditions that can also allow the biosensor to maintain the measurement accuracy can be selected as the default value.
  • S the inventory level
  • the inventory level will fluctuate like the curve of M7-M8-R7-M9. If not designed in this way, the inventory level curve after M7 (not shown as M7-M9 in Figure 6C) can be similar to the change in inventory level between R1-M6, and the change in inventory level is smoother.
  • FIG. 6D is roughly similar to FIG. 6C, except that the predetermined value S is set between I 0 and Th2.
  • the inventory level can be changed between Th1 and Th2, but it is more gentle than the latter curve (M6-M9) shown in Figure 3C.
  • the inventory level in addition to using the calculation method of the proportion or the difference, can also be calculated by setting the threshold value (ie, the upper and lower limit) of the coulomb number of the silver halide.
  • the inventory level is calculated based on the coulomb amount.
  • the proportion, the difference or the coulomb amount or a combination thereof can be applied to the inventory level as a measurement parameter.
  • Th3 and Th4 may also include: when the processor confirms that the inventory level exceeds Th3 and Th4, it gives an abnormal signal, and the system can determine that the biosensor is suspended or ends the measurement operation.
  • the transmission unit may optionally include a timer 260
  • the method of the present invention further includes the following steps: every time the fixed time interval of each measurement operation is satisfied, another recharging operation is initiated, wherein the fixed time The interval is within 15 seconds, within 30 seconds, within one minute, within ten minutes, within one hour, within two hours, within four hours, within one day, within one week or within one month.
  • the first threshold Th1 when the inventory level is the proportion of silver halide materials in the proportion of silver halide materials and silver materials, the first threshold Th1 is selected from 1% to 98%, and the second threshold Th2 is selected from 2. % To 99%.
  • the second threshold Th2 when the first threshold Th1 is 1%, the second threshold Th2 can be a value from 2%, 3%, 4%, 5%, ... to 99%; or, when the second threshold Th2 is 99% , The second threshold Th2 can be a value of 98%, 97%, 96%, 95%, ...
  • the second threshold Th2 up to 1%, or selected from the first threshold Th1 at 20%, and the second threshold Th2 at 80%, or selected from The first threshold Th1 is at 30%, the second threshold Th2 is 70%, or the first threshold Th1 is at 40%, the second threshold Th2 is 60%, or the first threshold Th1 is at 50%, the second threshold Th2 Is 60%.
  • the first threshold Th1 is -1% to -99 of the initial inventory
  • a value between% and the second threshold Th2 is a value between 1% and 99% of the initial inventory.
  • the cumulative consumption may be a single consumption after only one measurement, or may be the cumulative consumption after multiple measurements.
  • the recharge control of the biosensor of the present invention and the method for restoring a biosensor to a proper working state can not only be applied to a biosensor having an electrode structure with a working electrode and a counter electrode, but also can be applied to a biosensor with a working electrode and a counter electrode.
  • the biosensor with the electrode structure of the counter electrode and one auxiliary electrode it can also be applied to the biosensor with the electrode structure of one working electrode, two counter electrodes and one auxiliary electrode; or it can also be applied to the biosensor with two working electrodes and two A biosensor of the electrode structure of the counter electrode.
  • the recharge control method of the biosensor of the present invention also covers the requirement of raising the inventory during the warm-up period. For example, before performing the refilling operation, it further includes the following steps: the physiological signal measuring device forcibly executes the refilling operation, and stopping the refilling operation when the inventory level increases to be greater than or equal to the second threshold Th1.
  • the application of the recharge voltage is implemented by applying a fixed potential difference or a fixed current value.
  • the fixed potential difference or a fixed current value is essentially dynamically adjusted according to the change in AgCl consumption.
  • Detailed implementation Please refer to Figure 5 to Figure 10 for the mechanism.
  • the present invention also provides a method for restoring a biosensor to a proper working state.
  • the biosensor includes a first electrode and a counter electrode.
  • the counter electrode includes a silver halide material and a silver material.
  • the silver halide material has a stock
  • the method of the present invention includes the following steps: after the measurement operation, the change in the inventory level is calculated; and the first refill operation is initiated to recover The variation value of the replenishment inventory level, wherein the inventory level is controlled to fluctuate between the first threshold Th1 and the second threshold Th2.
  • the first refill operation is started to refill the consumed silver halide material, so that the inventory level is increased to the first threshold Th1 and higher than the first threshold Th1 A predetermined value between the second threshold Th2.
  • the method of the present invention further includes at least one of the following steps: each time the predetermined number of measurement operations is met, calculating the change value of the inventory level during the predetermined number of times, and starting The first refill operation (that is, another refill operation) is to refill the change value of the inventory level; and every time the fixed time interval of each measurement operation is met, the second refill operation is started.
  • data related to the inventory level can also be transmitted to the remote control system.
  • the remote control system monitors the inventory level, and provides update instructions to the physiological signal measurement device when necessary to perform refilling conditions. renew.
  • Figures 5A-5B and 7A-7D show the constant voltage circuit in the measurement mode and the recharge mode of the present invention.
  • Figures 7A-7D show the constant voltage circuit alternately in different ways.
  • the measurement mode can be started and stopped by applying the measurement potential difference V1 and removing the measurement potential difference V1, respectively, and the corresponding current is represented by Ia.
  • the measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C during the measurement period T1, so that the voltage of the working electrode W is higher than the voltage of the counter electrode R/C.
  • the switches S1 and S4 are in the closed state at this time, while the switches S2 and S3 are in the open state, the working electrode W is +Vl, and the counter electrode R/C is grounded, so that the working electrode W undergoes oxidation reaction, and The chemical reagent and the analyte are electrochemically reacted to output a physiological signal Ia, and at the same time, the AgCl of the counter electrode R/C has a consumption corresponding to the physiological signal Ia.
  • T1 between the plurality of measurement periods T1 is a period T2 during which no measurement is performed. In some preferred embodiments, T2 is a fixed value.
  • the recharging mode can be started and stopped by applying the recharging gap V2 and removing the recharging gap 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.
  • the recharge mode apply the recharge potential V2 between the working electrode W and the counter electrode R/C for the recharge period t2 (t2 is between 0 and T2), so that the voltage of the counter electrode R/C is higher than The voltage of the working electrode W.
  • the switches S1 and S4 are in the open state at this time, while the switches S2 and S3 are in the closed state, the working electrode W is grounded, and the counter electrode R/C is +V2, so that the Ag on the counter electrode R/C The oxidation reaction proceeds, and the AgCl on the counter electrode R/C is recharged to a recharge.
  • the recharge potential V2 in the constant voltage circuit is a fixed voltage, and the measured output current is Ib.
  • the present invention defines the capacity of AgCl by calculating the area under the current curve (Capacity, unit coulomb, represented by the symbol "C"), so the consumption of AgCl in the measurement mode is Ia*Tl, and the recharge of AgCl in the recharge mode The amount is Ib*t2.
  • the recharge amount of AgCl can be controlled by regulating the application time t2 of the recharge potential V2.
  • the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption.
  • the horizontal axis in FIGS. 7A-7D represents time, 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.
  • V2 and T2 are both fixed values, and the application time t2 of V2 (that is, the recharging period) is a variable value.
  • the recharge period t2 is dynamically adjusted from 0 to T2 based on the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in FIG. 7A, t2 can be t2', t2', or t2''.... In other words, the recharge period t2 can be changed according to the consumption of AgCl.
  • the consumption of AgCl is large, it can be recharged for a longer period of time to keep the AgCl on the counter electrode R/C within the safe inventory.
  • the amount of AgCl recharged during t2'' will be greater than the amount of AgCl recharged during t2'.
  • T2 1/2 of T2, 2/5 T2, 3/5 T2, etc.
  • FIGS. 7E and 7F 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.
  • the horizontal axis is time and the vertical axis is current
  • the curve represents the physiological parameter value curve converted from the measured physiological signal Ia.
  • V2 and T2 are fixed values, and t2 during the recharge period is a variable value.
  • the white area under the curve represents the AgCl consumption in the measurement mode (Ia*Tl)
  • the oblique area represents the AgCl recharge in the recharge mode (Ib*t2).
  • the recharge period t2 is based on the measured physiological signal Ia and the measurement period T1 and is set between 0 and T2. Dynamic adjustment between time. According to needs, the recharging mode can be selected in the front part (as shown in FIG. 7E) or the back part (as shown in FIG. 7F) of the period (T2) in which the measurement mode is not performed.
  • Figures 8A-8B and Figures 10A-10C show the constant current circuit in the measurement mode and the recharge mode of the present invention
  • Figures 10A-10C show the constant current circuit of the present invention.
  • the current circuit alternately performs three voltage schematic diagrams of measurement mode and recharge mode in different ways.
  • the measurement mode can be started and stopped by applying the measurement potential difference V1 and removing the measurement potential difference V1, respectively, and the corresponding current is represented by Ia.
  • the measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C for the measurement period T1.
  • the switches S1 and S4 are in the closed state at this time, while the other switches are in the open state.
  • the working electrode W is +V1, and the counter electrode R/C is grounded, so that the working electrode W undergoes oxidation reaction and interacts with The chemical reagent and the analyte undergo an electrochemical reaction to output a physiological signal Ia, and at the same time, the AgCl of the counter electrode R/C has a consumption corresponding to the physiological signal Ia.
  • T1 between the plurality of measurement periods T1 is a period T2 during which no measurement is performed.
  • T2 is a fixed value.
  • the recharging mode can be started and stopped by applying the recharging gap V2 (V2 is a variable value) and removing the recharging gap V2, and the corresponding current is represented by Ib.
  • V2 is a variable value
  • Ib the recharging current
  • the recharging level difference V2 is applied between the working electrode W and the counter electrode R/C for the recharging period t2 (t2 is between 0 and T2).
  • switches S1 and S4 are in an open state, and at least one switch corresponding to S2 and I_F1 to I_Fn is in a closed state (the figure exemplarily shows that the switches corresponding to I_F1 and I_F3 are in a closed state), and work
  • the electrode W is grounded, and the counter electrode R/C is +V2, so that the Ag on the counter electrode R/C is oxidized, and then AgCl is recharged.
  • At least one switch corresponding to I_F1 to I_Fn can be selected to output a fixed current Ib, and the AgCl can be controlled by regulating the application time t2 of the potential difference V2 The amount of recharge.
  • the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption.
  • FIGS. 9A-9B and FIGS. 10A-10C show the stepless switching constant current circuit in the measurement mode and the recharge mode in the present invention.
  • the measurement mode and recharge mode of this embodiment are similar to those in Figs. 8A-8B, so they will not be repeated here.
  • the difference from the embodiment of Figs. 8A-8B is only when the embodiment is in the recharge mode, according to the physiological signal Ia
  • a fixed current Ib is output by the control of a digital-to-analog converter (DAC), and the recharge amount of AgCl is controlled by adjusting the application time t2 of the potential difference V2.
  • the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption.
  • 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
  • the line of V2 represents the application and removal of the recharge potential V2.
  • T2 is a fixed value
  • the application time t2 of V2 and V2 (that is, the recharging period) is a variable value.
  • the recharge period t2 is dynamically adjusted from 0 to T2 based on the physiological signal Ia measured in the measurement mode and the measurement period T1.
  • t2 can be t2', t2'', or t2'''...
  • the recharge period t2 can be changed according to the consumption of AgCl. If the consumption of AgCl is large, it can be recharged for a longer period of time to keep the AgCl on the counter electrode R/C within the safe inventory.
  • V2 is a variable value
  • V2 is dynamically adjusted according to the consumption of AgCl in the physiological signal measurement step (that is, in the measurement mode).
  • One example of the dynamic adjustment method is as follows. For example, the above-mentioned constant current circuit with segment switching is used. The circuit has n fixed current sources and n switches, and each fixed current source corresponds to a switch.
  • At least one of the n switches is selected to be turned on (even if the switch is in a closed state) to output a fixed current value.
  • the recharge period t2 is a fixed value
  • the recharge amount of AgCl can be controlled by selecting different fixed current outputs.
  • V2 is a variable value
  • the measurement mode and the recharge mode are seamlessly alternated, and the period during which no measurement is performed is the recharge period.
  • a constant current circuit with segment switching can control multiple current paths through multiple switches, and can recharge with a segmented constant current according to the amount of current required.
  • the method is more power-efficient and can reduce costs.
  • the potential difference can come from a DC power supply or an AC power supply.
  • FIGS. 7A to 10C describe the alternate cycle of the measurement step and the refilling step. That is, there is an AgCl refilling step between each measurement step. This method can better ensure that AgCl is kept safe. Within inventory. However, in some preferred embodiments, Y times of AgCl recharge can also be selectively matched during N measurements, where Y ⁇ N, so that the cumulative recharge of AgCl can still be kept within the safety stock range. .
  • the measurement step and the refilling step do not necessarily need to be performed in an alternating cycle, and the refilling step may be performed again after several measurement steps, or the refilling step may be performed only after a predetermined measurement time. For example, the refilling step can be performed again after 10 measurements, or the refilling step can be performed only after the cumulative measurement time reaches 1 hour.
  • FIG. 10D shows a schematic diagram of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in a manner similar to FIG. 10C.
  • the curve represents the physiological parameter value curve converted from the measured physiological signal Ia, and is similar to Fig. 10C, T2 and t2 are both fixed values, and V2 is a variable value.
  • the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the slanted area represents the recharge volume of AgCl in the recharge mode (Ib*t2). 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 position difference V2 is dynamically adjusted according to the consumption of AgCl.
  • each physiological parameter value is not limited to the output when the measurement is completed or during the recharge period.
  • the AgCl refilling step is not limited to being executed after each physiological parameter is output or after the physiological signal is obtained.
  • FIG. 11 shows a method for determining an analyte according to an embodiment of the present invention, by which the service life of the micro biosensor can be prolonged.
  • the miniature biosensor may be, for example, the miniature biosensor shown in FIGS. 2A-2D, which is implanted subcutaneously to measure the physiological signal of the physiological parameter associated with the analyte in the biological fluid (for example, tissue fluid).
  • the analyte may be glucose in the tissue fluid
  • the physiological parameter is the glucose value in the human body
  • the physiological signal is the current value measured by the micro biosensor.
  • the method for measuring the analyte includes repeatedly executing the measuring step (S901) and the refilling step (S902).
  • the measurement step (S901) includes using the aforementioned constant voltage or constant current circuit to perform the aforementioned measurement mode during the measurement period T1 to output a physiological signal (ie, current value), and at the same time, the AgCl of the counter electrode has a consumption corresponding to the current value.
  • the measuring step (S901) further includes stopping the measuring step by stopping the aforementioned measuring mode, and the current value is calculated to output a physiological parameter (ie, a glucose value).
  • 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, so that the AgCl on the counter electrode
  • the amount is controlled within the safety stock range.
  • the potential difference between the working electrode and the counter electrode can be kept stable, so that 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 proportional. It may also be an inverse relationship). In other words, it is possible to maintain a stable proportional relationship between the next current value obtained in the next measurement step and the next glucose value.
  • the recharging step (S902) also includes stopping the recharging step by stopping the aforementioned recharging mode. After the refilling step (S902) is finished, loop back to perform the measurement step (S901) until the measurement step (S901) and the refilling step (S902) are executed N times.
  • the positive potential on the counter electrode 130 promotes the following oxidation reaction on the counter electrode 130:
  • the human body can obtain chloride ions and iodide ions through iodine-doped table salt, so the available halide ions include at least chloride ions and iodide ions, which are used to recharge the silver halide.
  • each measurement potential difference V1 is applied during the measurement period T1
  • each recharge level difference V2 is applied during the recharge period t2
  • the measurement period T1 is a fixed value, which can be within 3 seconds, 5 seconds Within, within 10 seconds, within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes.
  • the time value is preferably 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.
  • each measurement period T1 plus each recharge period t2 is a fixed value.
  • each recharge level difference V2 has a fixed voltage value, and each recharge period t2 is dynamically adjusted according to each consumption of AgCl (as shown in FIG. 7A).
  • the output physiological parameters are obtained by calculating the physiological signals at a single measurement time point in each measurement period T1.
  • the output physiological parameters are obtained through a mathematical operation of a plurality of physiological signals at a plurality of measurement time points in each measurement period T1.
  • the aforementioned mathematical operation value is, for example, the accumulated value, the average value, the median, the average value of the median, and so on.
  • the amount of each refill to be equal to or not equal to (including approximately similar, greater than or less than) each consumption, and controlling the amount of AgCl of the counter electrode within the safety stock interval, the lower
  • the next physiological signal obtained in a determination step maintains a stable proportional relationship with the next physiological parameter.
  • the step of removing each measured potential difference V1 is to disconnect the circuit that connects the working electrode and the counter electrode, or set each measured potential difference V1 to zero.
  • the power can be turned off to make the measuring circuit have an open state; or, a 0 volt voltage can be applied between the working electrode and the counter electrode, wherein the operation time of either of the two operations is 0.01 to 0.5 seconds.
  • Removing the step of measuring the potential difference V1 can avoid the generation of ⁇ -shaped physiological signals.
  • the step of removing each regenerative level difference V2 is to disconnect the circuit that connects the working electrode and the counter electrode, or set each regenerative level difference V2 to zero.
  • the measurement period T1 can be a variable value or a combination of a variable value and a fixed value (for example, a variable value + a fixed value.
  • the variable value can be 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, or 24 hours.
  • the fixed value may be, for example, 30 seconds).
  • the present invention uses voltage applied to the counter electrode R/C to measure the reaction current of the counter electrode in a period, and the reaction current in the period is calculated by mathematical operation. Knowing the initial capacity of AgCl, for example, by calculating the area under the reaction current curve to define the initial capacity of AgCl, also known as the initial amount or initial coulombic amount (C initial ), the following are all explained by the amount.
  • each measurement step (S901) the consumption of AgCl (expressed as C consume ) is defined by calculating the area under the current curve of the working electrode W.
  • the safety stock interval is represented by the ratio of Ag to AgCl.
  • the present invention uses the coulombic amount (C) measured on the counter electrode to reflect the ratio of Ag to AgCl.
  • 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 AgCl has a certain amount of AgCl on the counter electrode without being exhausted, so that each physiological signal measurement step can be performed stably.
  • the remaining amount of AgCl is the sum of the refill amount and the initial amount minus the consumption.
  • the remaining amount of AgCl may gradually decrease, gradually increase, or change steadily or arbitrarily within an interval, but still within the interval.
  • FIG. 12 shows a method for determining an analyte according to another embodiment of the present invention.
  • the miniature biosensor may be, for example, the miniature biosensor shown in FIGS. 2A-2D, which is implanted subcutaneously to measure the physiological signal of the physiological parameter associated with the analyte in the biological fluid (for example, tissue fluid).
  • the electrode material of the counter electrode of the micro biosensor includes silver and silver halide.
  • the analyte can be glucose in tissue fluid
  • the physiological parameter is the glucose value in the human body
  • the physiological signal is the micro biosensor. The measured current value.
  • the method of this embodiment starts with the following steps: applying a measuring voltage to drive the working electrode to measure a physiological signal for obtaining a physiological parameter, in which a specific amount of silver halide is consumed (hereinafter referred to as a consumption amount) (S1001).
  • the value of the deconsumption amount (that is, the remaining amount mentioned above) is controlled within the range of the initial amount plus or minus a specific value.
  • the above-mentioned control steps are achieved by controlling the refilling amount to be equal to or not equal to (including approximately similar, greater than or less than) the consumption, so as to maintain the amount of silver halide within the safety stock range.
  • the increase or decrease of the number of moles of silver halide corresponds to the increase or decrease of the number of moles of silver, so for the convenience of explanation, the consumption of silver halide corresponds to the increase of simulated silver.
  • the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the amount of silver plus the amount of silver halide (AgCl/Ag+AgCl) is greater than 0 and less than 1, also That is, there is only one amount of silver halide in 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- Between 0.6.
  • the application of the recharge voltage is stopped (S1005). Then it loops to step S1001 to execute the next loop.
  • a method for calculating the size of the Ag/AgCl material of the electrode signal sensing section is taken as an example with a biosensor service life of 16 days.
  • the average measured current of the analyte for each measurement is 30 nA
  • the measurement period (T1) is 30 seconds
  • the recharge period (t2) is 30 seconds.
  • the daily consumption of AgCl (C consume/day ) 1.3mC/day.
  • the service life requirement of the sensor is 16 days
  • the required length of the counter electrode is at least:
  • the length of the counter electrode needs to exceed 16 mm in order to make the sensor life up to 16 days.
  • the counter electrode signal sensing section needs to be equipped with a correspondingly larger Ag/AgCl material size to achieve the sensor life of 16 days.
  • the silver halide recharging step is performed between the two measurement steps.
  • the consumption and recharging of the silver halide can be repeated in a short period of time (recharge when used), so it can be reduced
  • the amount of Ag/AgCl material in the sensor further miniaturizes the sensor, so there is no need to prepare 16 days of AgCl capacity for the electrode signal sensing section material for consumption.
  • the senor by preparing the capacity of AgCl for about 1 to 2 days, the sensor can be used for 16 days, thereby achieving the effect of extending the service life of the sensor.
  • the capacity of AgCl for 1 to 2 days also refers to the initial amount of AgCl in the counter electrode before leaving the factory or before performing the first measurement, for example, between about 1.3 and 2.6 mC.
  • the initial amount can also be other smaller Or a larger range.
  • different AgCl capacities may be prepared for 1 to 5 days, 1 to 3 days, 6 to 24 hours, and 6 to 12 hours.
  • the material size of the signal sensing section of the counter electrode only needs to have the capacity to enable the stable execution of each glucose measurement step and the positive correlation between the measurement current and the glucose concentration in the body.
  • the prior art will increase the electrode length/area so that the sensor can meet the required number of days.
  • the length of the implanted end of the sensor is about 12mm. Because of the long implantation length, in order to avoid implanting deep into the subcutaneous tissue, it needs to be implanted under the skin at an oblique angle, and the implantation wound is relatively large.
  • the capacity of AgCl for 1 to 2 days is about 1.3 to 2.6 mC
  • the length of the counter electrode for 1 to 2 days is 2.5 to 5 mm, which is compared with that without the silver halide of the present invention.
  • the present invention can effectively reduce the size of the required counter electrode.
  • the length of the implanted end can be shortened, for example, the length is reduced to no more than 10 mm.
  • the lower half of the connecting area 117 to the second end 114 of the micro biosensor 100 disclosed in FIGS. 2A-2B of the present invention belong to the short implanted end 118 (as shown in FIGS. 2A and 2B), and the short implanted end 118 is implanted
  • the penetration depth must at least meet the depth of the tissue fluid glucose that can be measured in the dermis.
  • the longest side of the short implant end 118 is not greater than 6 mm, so that the micro biosensor 100 can be perpendicular to the biological
  • the method of the body surface is partially implanted under the surface of the living body.
  • the longest side of the short implant end 118 is preferably no greater than 5 mm, 4.5 mm, 3.5 mm, or 2.5 mm.
  • the short implant end 118 of the present invention includes the signal sensing section 132 of the counter electrode, and the longest side of the signal sensing section 132 is not greater than 6mm, preferably 2-6mm, 2-5mm, 2-4.5mm, 2- 3.5mm, 0.5-2mm, 0.2-1mm.
  • the silver halide recharging method of the present invention can effectively extend the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode, so that The size of the counter electrode signal sensing section can be reduced.
  • the sensor can be miniaturized and biological toxicity can be reduced.
  • the reduction of the electrode size particularly refers to shortening the length of the implanted end of the sensor, thus reducing the pain of implantation of the user.
  • FIGS. 13A and 13B are schematic diagrams of the front and back of the first embodiment of the micro biosensor of the present invention.
  • the micro biosensor 300 of the present invention includes a substrate 310, a working electrode 320 disposed on the substrate 310, a counter electrode 330 and an auxiliary electrode 340, and a chemical reagent 350 surrounding the working electrode 320, the counter electrode 330 and the auxiliary electrode 340 (as shown in FIG. 13C Shown).
  • the material of the substrate 310 can be any material that is known to be suitable for use in electrode substrates and preferably has flexibility and insulation properties, such as but not limited to polymer materials such as polyester and polyimide. The aforementioned polymer materials can be used singly or in combination of multiple types.
  • the substrate 310 has a surface 311 (that is, the first surface), an opposite surface 312 (that is, the second surface) opposite to the surface 311, a first end 313 and a second end 314, and the substrate 310 is divided into 3 regions, which are respectively close to The signal output area 315 of the first end 313, the sensing area 316 close to the second end 314, and the connection area 317 between the signal output area 315 and the sensing area 316.
  • the working electrode 320 is disposed on the surface 311 of the substrate 310 and extends from the first end 313 to the second end 314 of the substrate 310.
  • the working electrode 320 includes a signal output section 321 located in the signal output area 315 of the substrate 310 and located on the substrate 310 The signal sensing section 322 of the sensing area 316.
  • the counter electrode 330 and the auxiliary electrode 340 are disposed on the opposite side surface 312 of the substrate 310 and extend from the first end 313 to the second end 314 of the substrate 310.
  • the counter electrode 330 includes a signal sensing section 332 located in the sensing area 316 of the substrate 310 and the auxiliary electrode 340 includes a signal sensing section 342 located in the sensing area 316 of the substrate 310.
  • the sensing area 316 of the micro biosensor 300 can be implanted subcutaneously so that the signal sensing section 322 measures the physiological signal associated with the analyte in the biological fluid.
  • the physiological signal will be transmitted to the signal output section 321, and then the signal output section 321 is transmitted to the processor 210 to obtain physiological parameters.
  • the physiological parameters may also be transmitted to the user device 20 via wireless/wired communication, such as a smart phone, a physiological signal receiver, or a blood glucose meter.
  • the material on the surface of the counter electrode 330 includes silver and silver halide, and the silver halide is preferably silver chloride (Silver Chloride) or silver iodide (Silver Iodine), so that the counter electrode 330 also functions as a reference electrode That is, the counter electrode 330 of the present invention can (1) form an electronic circuit with the working electrode 320, so that the working electrode 320 is smoothly connected to ensure that the oxidation reaction occurs on the working electrode 320; and (2) provide a stable relative potential as a reference Potential. Therefore, the working electrode 320 and the counter electrode 330 of the present invention form a two-electrode system.
  • the silver halide is preferably silver chloride (Silver Chloride) or silver iodide (Silver Iodine)
  • the counter electrode 330 of the present invention can (1) form an electronic circuit with the working electrode 320, so that the working electrode 320 is smoothly connected to ensure that the oxidation reaction occurs on the working electrode 320; and (2) provide a
  • the silver/silver halide can be mixed with carbon.
  • the silver/silver halide is mixed with carbon glue, and the silver halide content only needs to make the counter electrode 330 stable. Just execute the set measurement action.
  • the outermost surface of the counter electrode 330 can also be covered with a conductive material to prevent silver halide from dissolution, thereby protecting the counter electrode 330.
  • the conductive material is mainly selected from conductive materials that do not affect the measurement performance of the working electrode, such as The conductive material is Carbon.
  • the biosensor is not limited to a wire-type or stacked-type electrode structure.
  • the initial amount of silver halide may be zero before the biosensor is ready to be shipped out of the factory for sale. In this case, there is no silver halide on the counter electrode 330 of the biosensor. After the biosensor is subcutaneously implanted in the patient and during the initial recharge period before the first measurement, the silver coated on the counter electrode 330 through oxidation can be recharged with the initial amount of silver halide on the counter electrode 330 .
  • the auxiliary electrode 340 forms an electronic circuit with the counter electrode 330 during the recharging step, so that the counter electrode 330 is smoothly powered to ensure that the oxidation reaction occurs on the counter electrode 320.
  • the electrode material is selected from the same material as the working electrode 320 or the same material as the working electrode 320
  • the working electrode 320 has a lower sensitivity to hydrogen peroxide than a material, such as carbon.
  • the chemical reagent 350 covers at least the signal sensing sections 322, 332, and 342 of each electrode. In another embodiment, the chemical reagent 350 covers at least the signal sensing section 322 of the working electrode 320 (not shown in the figure). In other words, the counter electrode 330 may not be covered by the chemical reagent 350.
  • the sensing area 316 of the micro biosensor 300 can be implanted subcutaneously so that the signal sensing section 322 of the working electrode 320 measures the physiological signal associated with the analyte in the biological fluid, and the physiological signal will be transmitted to the signal output of the working electrode 320
  • the signal output section 321 transmits to the processor 210 to obtain physiological parameters. In addition to obtaining the physiological parameters from the transmission unit 200, the physiological parameters may also be transmitted to the user device 20 via wireless/wired communication for obtaining.
  • FIG. 13C is a schematic cross-sectional view along the line AA' in FIG.
  • the working electrode 320 is disposed on the surface 311 of the substrate 310
  • the counter electrode 330 and the auxiliary electrode 340 are disposed on the opposite surface 312 of the substrate 310
  • the surfaces of the working electrode 320, the counter electrode 330 and the auxiliary electrode 340 are covered with chemical reagents. 350.
  • the chemical reagent 350 covers at least a part of the surface of the working electrode 320.
  • the micro biosensor 300 of the present invention performs the measurement step during the measurement period, and performs the refill step during the refill period.
  • the voltage of the working electrode 320 is higher than the voltage of the counter electrode 330, causing the current to flow from the working electrode 320 to the direction of the counter electrode 330, thereby causing the working electrode 320 to undergo an oxidation reaction (that is, the working electrode 320, the chemical reagent 350 and an electrochemical reaction between the analyte) is measured physiological signals, reduction reaction of the electrode 330, the counter electrode 330 so that the silver halide (AgX) consumption dissociate into silver (Ag) and a halide ion (X -) . Since the silver halide in the counter electrode 330 is consumed, the silver halide in the counter electrode 330 needs to be recharged to perform the next measurement step.
  • an oxidation reaction that is, the working electrode 320, the chemical reagent 350 and an electrochemical reaction between the analyte
  • the voltage of the counter electrode 330 is higher than the voltage of the auxiliary electrode 340, so that the current flows from the counter electrode 330 to the direction of the auxiliary electrode 340, and the counter electrode 330 is oxidized to cause the silver to react with the halide ions in the living body. Or combined and refilled with silver halide, the detailed measurement steps and refilling steps are shown in Figure 11.
  • FIG. 14A is a schematic cross-sectional view of the second embodiment of the micro biosensor of the present invention.
  • the working electrode 320 and the auxiliary electrode 340 of the present invention may be disposed on the surface 311 of the substrate 310, the counter electrode 330 is disposed on the opposite surface 312 of the substrate 310, and the working electrode 320, the counter electrode 330 and the auxiliary electrode The surface of 340 is covered with a chemical reagent 350.
  • the current flows from the working electrode 320 to the counter electrode 330, and the working electrode 320 is oxidized to measure the physiological signal.
  • the silver halide in the counter electrode 330 is consumed and dissociated.
  • FIG. 14B is a schematic cross-sectional view of the third embodiment of the micro biosensor of the present invention.
  • the micro biosensor 300 of the present invention may have two working electrodes, which are a first working electrode 323 and a second working electrode 324, respectively, and the second working electrode 324 replaces the auxiliary electrode.
  • the first working electrode 323 and the second working electrode 324 are provided on the surface 311 of the substrate 310
  • the counter electrode 330 is provided on the opposite side surface 312 of the substrate 310
  • the first working electrode 323, the second working electrode 324 and the opposite The surface of the electrode 330 is covered with a chemical reagent 350.
  • the first working electrode 323 or the second working electrode 324 can be selected to measure physiological signals, and in the recharging step, the first working electrode 323 or the second working electrode 324 helps to recharge the electrode 330 with silver halide . Therefore, in this embodiment, when the measurement step is performed, the current flows from the first working electrode 323 or the second working electrode 324 to the counter electrode 330, so that the first working electrode 323 or the second working electrode 324 is oxidized. The physiological signal is measured in response, and the silver halide in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁇ ).
  • FIG. 14C is a schematic cross-sectional view of the fourth embodiment of the micro biosensor of the present invention.
  • the micro biosensor 300 of the present invention may have two working electrodes, which are a first working electrode 323 and a second working electrode 324, respectively, and the second working electrode 324 replaces the auxiliary electrode.
  • the first working electrode 323 is provided on the surface 311 of the substrate 310
  • the counter electrode 330 and the second working electrode 324 are provided on the opposite side surface 312 of the substrate 310
  • the surface of the electrode 330 is covered with a chemical reagent 350.
  • the area of the first working electrode 323 can be increased as the electrode for measurement, and the area of the second working electrode 324 can be reduced as the electrode for recharging. Therefore, in the measurement step, the first working electrode 323 is used as the electrode. The physiological signal is measured, and during the recharging step, the second working electrode 324 helps the electrode 330 to recharge the silver halide. Therefore, in this embodiment, when the measurement step is performed, the current flows from the first working electrode 323 to the counter electrode 330, so that the first working electrode 323 undergoes an oxidation reaction to measure physiological signals, and the halogenation in the counter electrode 330 silver is dissociated into silver (Ag) and a halide ion (X -) solution consumption. When the recharging step is performed, current flows from the counter electrode 330 to the second working electrode 324, so that the counter electrode 330 undergoes an oxidation reaction to combine silver with halide ions to recharge the silver halide.
  • FIG. 14D is a schematic cross-sectional view of the fifth embodiment of the micro biosensor of the present invention.
  • the fifth embodiment is the first embodiment with one more working electrode. That is, in the fifth embodiment, the micro biosensor 300 of the present invention has two working electrodes, the first working electrode 323 and the second working electrode 324, respectively. One counter electrode 330 and one auxiliary electrode 340.
  • FIG. 14D is a schematic cross-sectional view of the fifth embodiment of the micro biosensor of the present invention.
  • the fifth embodiment is the first embodiment with one more working electrode. That is, in the fifth embodiment, the micro biosensor 300 of the present invention has two working electrodes, the first working electrode 323 and the second working electrode 324, respectively. One counter electrode 330 and one auxiliary electrode 340.
  • FIG. 14D is a schematic cross-sectional view of the fifth embodiment of the micro biosensor of the present invention.
  • the first working electrode 323 and the second working electrode 324 are disposed on the surface 311 of the substrate 310, the counter electrode 330 and the auxiliary electrode 340 are disposed on the opposite surface 312 of the substrate 310, and the first working electrode 323 and the second working electrode
  • the surface of the electrode 324, the counter electrode 330, and the auxiliary electrode 340 are covered with a chemical reagent 350.
  • the first working electrode 323 or the second working electrode 324 can be selected to measure the physiological signal
  • the auxiliary electrode 340 helps the electrode 330 to be recharged with silver halide.
  • the current flows from the first working electrode 323 or the second working electrode 324 to the counter electrode 330, so that the first working electrode 323 or the second working electrode 324 is oxidized.
  • the physiological signal is measured in response, and the silver halide in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁇ ).
  • the recharging step is performed, current flows from the counter electrode 330 to the auxiliary electrode 340, so that the counter electrode 330 undergoes an oxidation reaction to combine silver with halide ions to recharge the silver halide.
  • FIG. 14E is a schematic cross-sectional view of the sixth embodiment of the micro biosensor of the present invention.
  • the micro biosensor 300 of the present invention may have three working electrodes, which are a first working electrode 323, a second working electrode 324, and a third working electrode 325, and the third working electrode 325 replaces the auxiliary electrode.
  • the third working electrode 325 replaces the auxiliary electrode.
  • the first working electrode 323 and the second working electrode 324 are provided on the surface 311 of the substrate 310
  • the counter electrode 330 and the third working electrode 325 are provided on the opposite side surface 312 of the substrate 310
  • the first working electrode 323 and the second working electrode The surfaces of the second working electrode 324, the third working electrode 325, and the counter electrode 330 are covered with a chemical reagent 350.
  • the first working electrode 323, the second working electrode 324, or the third working electrode 325 can be selected to measure physiological signals, and in the recharging step, the first working electrode 323 and the second working electrode 324 can also be selected.
  • the third working electrode 325 helps to recharge the electrode 330 with silver halide.
  • the current flows from the first working electrode 323, the second working electrode 324, or the third working electrode 325 to the counter electrode 330, so that the first working electrode 323, the second working electrode
  • the second working electrode 324 or the third working electrode 325 undergoes an oxidation reaction to measure physiological signals, and the silver halide in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁇ ).
  • the current flows from the counter electrode 330 to the first working electrode 323, the second working electrode 324, or the third working electrode 325, so that the counter electrode 330 undergoes an oxidation reaction and the silver and halide ions are combined and returned. Filled with silver halide.
  • FIG. 14F is a schematic cross-sectional view of the seventh embodiment of the micro biosensor of the present invention.
  • the seventh embodiment is a variation of the electrode configuration of the sixth embodiment.
  • the first working electrode 323, the second working electrode 324, and the third working electrode 325 are all disposed on the surface 311 of the substrate 310, and the counter electrode 330 is disposed on the opposite surface 312 of the substrate 310.
  • the surfaces of the first working electrode 323, the second working electrode 324, the third working electrode 325, and the counter electrode 330 are covered with a chemical reagent 350.
  • the first working electrode 323, the second working electrode 324, or the third working electrode 325 can be selected to measure physiological signals, and in the recharging step, the first working electrode 323 and the second working electrode 324 can also be selected. Or the third working electrode 325 helps to recharge the electrode 330 with silver halide.
  • the current flows from the first working electrode 323, the second working electrode 324, or the third working electrode 325 to the counter electrode 330, so that the first working electrode 323, the second working electrode
  • the second working electrode 324 or the third working electrode 325 undergoes an oxidation reaction to measure physiological signals, and the silver halide in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁇ ).
  • the current flows from the counter electrode 330 to the first working electrode 323, the second working electrode 324, or the third working electrode 325, so that the counter electrode 330 undergoes an oxidation reaction and the silver and halide ions are combined and returned. Filled with silver halide.
  • FIG. 14G is a schematic cross-sectional view of the eighth embodiment of the micro biosensor of the present invention.
  • the difference is that the second working electrode 324 is U-shaped.
  • the first working electrode 323 and the second working electrode 324 are disposed on the surface 311 of the substrate 310, and the second working electrode 324 is adjacent to
  • the counter electrode 330 and the auxiliary electrode 340 are disposed on the opposite side surface 312 of the substrate 310 and are arranged around the side of the first working electrode 323.
  • the current flows from the first working electrode 323 to the counter electrode 330, so that the first working electrode 323 undergoes an oxidation reaction to measure physiological signals, and the silver halide in the counter electrode 330 is consumed dissociate into silver (Ag) and a halide ion (X -).
  • the recharging step is performed, current flows from the counter electrode 330 to the auxiliary electrode 340 or the second working electrode 324, so that the counter electrode 330 undergoes an oxidation reaction to combine silver with halide ions to recharge the silver halide.
  • the substrate 310 of the present invention is an insulator.
  • the electrode materials of the working electrode 320 and the first working electrode 323 of the present invention include but are 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 working electrode 320 and the first working electrode 323
  • the material is precious metal, precious metal derivative or a combination of the foregoing.
  • the working electrode 320 and the first working electrode 323 are made of platinum-containing materials.
  • the second working electrode 324 and the third working electrode 325 can also use the elements or their derivatives as exemplified in the above-mentioned working electrode 320 and the first working electrode 323.
  • the electrode materials of the second working electrode 324 and the third working electrode 325 are selected from materials having a lower sensitivity to hydrogen peroxide than the first working electrode 323, such as carbon.
  • the electrode material of the counter electrode 330 of the present invention includes silver and silver halide (Ag/AgX), it has the functions of a well-known counter electrode and a reference electrode at the same time, that is, the counter electrode 330 of the present invention can be (1) formed with the working electrode 320
  • the electronic circuit enables the working electrode 320 to be energized smoothly to ensure that the electrochemical reaction occurs on the working electrode 320; (2) to form an electronic circuit with the auxiliary electrode 340 to make the counter electrode 330 to be energized smoothly to ensure that the oxidation reaction occurs on the counter electrode 330 And (3) provide a stable relative potential as a reference potential. Therefore, the working electrode 320, the counter electrode 330 and the auxiliary electrode 340 of the present invention form a three-electrode system which is different from the traditional three-electrode system.
  • the auxiliary electrode 340 of the present invention can also be used as an electrode for measuring physiological signals.
  • a layer of conductive material such as carbon
  • a conductive layer such as silver
  • the impedance of the output end makes the counter electrode 330 of the present invention form a conductive layer, a carbon layer, and a silver/silver halide layer in order from the opposite surface 312 of the substrate 310.
  • Figures 15A-15B and 7A-7D respectively show the constant voltage circuit in the measurement mode and the recharge mode of the present invention.
  • Figures 7A-7D show the constant voltage circuit alternately in different ways. Schematic diagram of current in measurement mode and recharge mode.
  • the measurement mode can be started and stopped by applying the measurement potential difference V1 and removing the measurement potential difference V1, respectively, and the corresponding current is represented by Ia.
  • the measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C during the measurement period T1, so that the voltage of the working electrode W is higher than the voltage of the counter electrode R/C.
  • the switches S1 and S4 are in the closed state at this time, while the switches S2 and S3 are in the open state, the working electrode W is +Vl, the counter electrode R/C is grounded, and the auxiliary electrode Aux is in an open state to make the work
  • the electrode W undergoes an oxidation reaction, and electrochemically reacts with the chemical reagent and the analyte to output a physiological signal Ia, and at the same time, the AgCl of the electrode R/C has a consumption amount corresponding to the physiological signal Ia.
  • T2 is a fixed value.
  • the recharging mode can be started and stopped by applying the recharging gap V2 and removing the recharging gap 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.
  • the recharge mode apply the recharge potential V2 between the counter electrode R/C and the auxiliary electrode Aux for the recharge period t2 (t2 is between 0 and T2), so that the voltage of the counter electrode R/C is higher than The voltage of the auxiliary electrode Aux.
  • the switches S1 and S4 are in an open state at this time, while the switches S2 and S3 are in a closed state, the working electrode W is in an open state, the counter electrode R/C is +V2, and the auxiliary electrode Aux is grounded to make the counter electrode
  • the Ag on the R/C undergoes an oxidation reaction, and the AgCl on the counter electrode R/C is recharged to a recharge.
  • the recharge potential V2 in the constant voltage circuit is a fixed voltage
  • the measured output current is Ib.
  • the present invention defines the capacity of AgCl by calculating the area under the current curve (Capacity, unit coulomb, represented by the symbol "C"), so the consumption of AgCl in the measurement mode is Ia*Tl, and the recharge of AgCl in the recharge mode The amount is Ib*t2. Therefore, the recharge amount of AgCl can be controlled by regulating the application time t2 of the recharge potential 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.
  • the horizontal axis in FIGS. 7A-7D represents time, 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.
  • V2 and T2 are both fixed values, and the application time t2 of V2 (that is, the recharging period) is a variable value.
  • the recharge period t2 is dynamically adjusted from 0 to T2 based on the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in FIG. 7A, t2 can be t2', t2', or t2''.... In other words, the recharge period t2 can be changed according to the consumption of AgCl.
  • the consumption of AgCl is large, it can be recharged for a longer time to keep the AgCl on the counter electrode R/C within the safe inventory.
  • the amount of AgCl recharged during t2'' will be greater than the amount of AgCl recharged during t2'.
  • T2 1/2 of T2, 2/5 T2, 3/5 T2, etc.
  • FIGS. 7E and 7F 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.
  • the horizontal axis is time and the vertical axis is current
  • the curve represents the physiological parameter value curve converted from the measured physiological signal Ia.
  • V2 and T2 are fixed values
  • t2 during recharging is a variable value.
  • the white area under the curve represents the AgCl consumption in the measurement mode (Ia*Tl)
  • the oblique area represents the AgCl recharge in the recharge mode (Ib*t2).
  • the recharge period t2 is based on the measured physiological signal Ia and the measurement period T1 and is set between 0 and T2. Dynamic adjustment between time. According to needs, the recharging mode can be selected in the front part (as shown in FIG. 7E) or the back part (as shown in FIG. 7F) of the period (T2) in which the measurement mode is not performed.
  • Figures 8A-8B and Figures 10A-10C show the constant current circuit in the measurement mode and the recharge mode of the present invention
  • Figures 10A-10C show the constant current circuit of the present invention.
  • the current circuit alternately performs three voltage schematic diagrams of measurement mode and recharge mode in different ways.
  • the measurement mode can be started and stopped by applying the measurement potential difference V1 and removing the measurement potential difference V1, respectively, and the corresponding current is represented by Ia.
  • the measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C for the measurement period T1.
  • the switches S1 and S4 are in the closed state at this time, and the other switches are in the open state, the working electrode W is +V1, the counter electrode R/C is grounded, and the auxiliary electrode Aux is in the open state, so that the working electrode W undergoes an oxidation reaction, and electrochemically reacts with the chemical reagent and the analyte to output a 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.
  • T1 between the plurality of measurement periods T1 is a period T2 during which no measurement is performed. In some preferred embodiments, T2 is a fixed value.
  • the recharging mode can be started and stopped by applying the recharging gap V2 (V2 is a variable value) and removing the recharging gap V2, and the corresponding current is represented by Ib.
  • V2 is a variable value
  • Ib the recharging current
  • the recharging level difference V2 is applied between the auxiliary electrode Aux and the counter electrode R/C for the recharging period t2 (t2 is between 0 and T2).
  • switches S1 and S4 are in an open state, and at least one switch corresponding to S2 and I_F1 to I_Fn is in a closed state (the figure exemplarily shows that the switches corresponding to I_F1 and I_F3 are in a closed state), and work
  • the electrode W is in an open state
  • the auxiliary electrode Aux is grounded
  • the counter electrode R/C is +V2, so that the Ag on the counter electrode R/C is oxidized, and then AgCl is recharged.
  • At least one switch corresponding to I_F1 to I_Fn can be selected to output a fixed current Ib, and the AgCl can be controlled by regulating the application time t2 of the potential difference V2 The amount of recharge.
  • the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption.
  • FIGS. 9A-9B and FIGS. 10A-10C show the stepless switching constant current circuit in the measurement mode and the recharge mode in the present invention.
  • the measurement mode and recharge mode of this embodiment are similar to those in Figs. 8A-8B, so they will not be repeated here.
  • the difference between the embodiments of Figs. 8A-8B is only when the embodiment is in the recharge mode, according to the physiological signal Ia,
  • the fixed current Ib is output by the control of the digital-to-analog converter (DAC), and the recharge amount of AgCl is controlled by adjusting the application time t2 of the potential difference V2.
  • the recharge amount can be made equal to or not equal to (including approximately similar, greater than or less than) the consumption.
  • 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
  • the line of V2 represents the application and removal of the recharge potential V2.
  • T2 is a fixed value
  • the application time t2 of V2 and V2 (that is, the recharging period) is a variable value.
  • the recharge period t2 is dynamically adjusted from 0 to T2 based on the physiological signal Ia measured in the measurement mode and the measurement period T1.
  • t2 can be t2', t2'', or t2'''...
  • the recharge period t2 can be changed according to the consumption of AgCl. If the consumption of AgCl is large, it can be recharged for a longer period of time to keep the AgCl on the counter electrode R/C within the safe inventory.
  • V2 is a variable value
  • V2 is dynamically adjusted according to the consumption of AgCl in the physiological signal measurement step (that is, in the measurement mode).
  • One example of the dynamic adjustment method is as follows. For example, the above-mentioned constant current circuit with segment switching is used. The circuit has n fixed current sources and n switches, and each fixed current source corresponds to a switch.
  • At least one of the n switches is selected to be turned on (even if the switch is in a closed state) to output a fixed current value.
  • the recharge period t2 is a fixed value
  • the recharge amount of AgCl can be controlled by selecting different fixed current outputs.
  • V2 is a variable value
  • the measurement mode and the recharge mode are seamlessly alternated, and the period during which no measurement is performed is the recharge period.
  • a constant current circuit with segment switching can control multiple current paths through multiple switches, and can recharge with a segmented constant current according to the amount of current required.
  • the method is more power-efficient and can reduce costs.
  • the potential difference can come from a DC power source or an AC power source, preferably from a DC power source.
  • Figures 7A-7F, Figures 8A-8B, Figures 9A-9B, and Figures 10A-10C all describe the alternate cycle of the measurement step and the refilling step, that is, there is an AgCl return between each measurement step.
  • this method can better ensure that AgCl remains within the safety stock.
  • Y times of AgCl recharge can also be selectively matched during N measurements, where Y ⁇ N, so that the cumulative recharge of AgCl can still be kept within the safety stock range.
  • the measurement step and the refilling step do not necessarily need to be performed in an alternating cycle, and the refilling step may be performed again after several measurement steps, or the refilling step may be performed only after a predetermined measurement time. For example, the refilling step can be performed again after 10 measurements, or the refilling step can be performed only after the cumulative measurement time reaches 1 hour.
  • FIG. 10D shows a schematic diagram of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in a manner similar to FIG. 10C.
  • the curve represents the physiological parameter value curve converted from the measured physiological signal Ia, and is similar to Fig. 10C, T2 and t2 are both fixed values, and V2 is a variable value.
  • the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the slanted area represents the recharge of AgCl in the recharge mode (Ib*t2). 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 position difference V2 is dynamically adjusted according to the consumption of AgCl.
  • each physiological parameter value is not limited to the output when the measurement is completed or during the recharge period.
  • the AgCl refilling step is not limited to being executed after each physiological parameter is output or after the physiological signal is obtained.
  • the working electrode W In a two-electrode system including a working electrode W and a counter electrode R/C, the working electrode W must constantly switch between performing an oxidation reaction and performing a reduction reaction. In the chemical reaction environment of the electrode, the switching between oxidation and reduction reactions must go through a stabilization period, such as several seconds or minutes.
  • the loop between the working electrode W and the counter electrode R/C can be used to perform the measurement step, and then the auxiliary electrode Aux
  • the circuit between the counter electrode R/C and the counter electrode R/C is recharged, thereby avoiding the disadvantage that the working electrode W needs a stabilization period, that is, the recharging step can be performed immediately after the measurement step.
  • FIG. 11 shows a method for determining an analyte according to an embodiment of the present invention, by which the service life of the micro biosensor can be prolonged.
  • the miniature biosensor may be, for example, the miniature biosensor shown in FIGS. 13A-14, which is implanted subcutaneously to measure the physiological signal of the physiological parameter associated with the analyte in the biological fluid (for example, tissue fluid).
  • the analyte may be glucose in the tissue fluid
  • the physiological parameter is the glucose value in the human body
  • the physiological signal is the current value measured by the micro biosensor.
  • the method for measuring the analyte includes repeatedly executing the measuring step (S901) and the refilling step (S902).
  • the measurement step (S901) includes using the aforementioned constant voltage or constant current circuit to perform the aforementioned measurement mode during the measurement period T1 to output a physiological signal (ie, current value), and at the same time, the AgCl of the counter electrode has a consumption corresponding to the current value.
  • the measuring step (S901) further includes stopping the measuring step by stopping the aforementioned measuring mode, and the current value is calculated to output a physiological parameter (ie, a glucose value).
  • each measurement potential difference V1 is applied during the measurement period T1
  • each recharge level difference V2 is applied during the recharge period t2
  • the measurement period T1 is a fixed value, which can be within 3 seconds, 5 seconds Within, within 10 seconds, within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes.
  • the time value is preferably 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.
  • each measurement period T1 plus each recharge period t2 is a fixed value.
  • each recharge level difference V2 has a fixed voltage value, and each recharge period t2 is dynamically adjusted according to each consumption of AgCl (as shown in FIG. 7A).
  • the output physiological parameters are obtained by calculating the physiological signals at a single measurement time point in each measurement period T1.
  • the output physiological parameters are obtained through a mathematical operation of a plurality of physiological signals at a plurality of measurement time points in each measurement period T1.
  • the aforementioned mathematical operation value is, for example, the accumulated value, the average value, the median, the average value of the median, and so on.
  • the amount of each refill to be equal to or not equal to (including approximately similar, greater than or less than) each consumption, and controlling the amount of AgCl of the counter electrode within the safety stock interval, the lower
  • the next physiological signal obtained in a determination step maintains a stable proportional relationship with the next physiological parameter.
  • the step of removing each measured potential difference V1 is to disconnect the circuit that connects the working electrode and the counter electrode, or set each measured potential difference V1 to zero.
  • the power can be turned off to make the measurement circuit open; or, a voltage of 0 volts can be applied between the working electrode and the counter electrode, and the operating time of either of the two operations is 0.01 to 0.5 seconds.
  • Removing the step of measuring the potential difference V1 can avoid the generation of ⁇ -shaped physiological signals.
  • the step of removing each regenerative level difference V2 is to disconnect the circuit configured to connect the auxiliary electrode and the counter electrode, or to set each regenerative level difference V2 to zero.
  • the measurement period T1 can be a variable value or a combination of a variable value and a fixed value (for example, a variable value + a fixed value.
  • the variable value can be 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, or 24 hours.
  • the fixed value may be, for example, 30 seconds).
  • the present invention uses voltage applied to the counter electrode R/C to measure the reaction current of the counter electrode in a period, and the reaction current in the period is calculated by mathematical operation. Knowing the initial capacity of AgCl, for example, by calculating the area under the reaction current curve to define the initial capacity of AgCl, also known as the initial amount or initial coulombic amount (C initial ), the following are all explained by the amount.
  • each measurement step (S901) the consumption of AgCl (expressed as C consume ) is defined by calculating the area under the current curve of the working electrode W.
  • the safety stock interval is represented by the ratio of Ag to AgCl.
  • the present invention uses the coulombic amount (C) measured on the counter electrode to reflect the ratio of Ag to AgCl.
  • 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 AgCl has a certain amount of AgCl on the counter electrode without being exhausted, so that each physiological signal measurement step can be performed stably.
  • the remaining amount of AgCl is the sum of the refill amount and the initial amount minus the consumption.
  • the remaining amount of AgCl may gradually decrease, gradually increase, or change steadily or arbitrarily within an interval, but still within the interval.
  • FIG. 11 shows a method for determining an analyte according to another embodiment of the present invention, by which the service life of the micro biosensor can be prolonged and the amount of silver and silver halide materials for the counter electrode can be reduced.
  • the miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 13A-13C and 14A-14G, which is implanted subcutaneously to measure the physiological parameters associated with the analyte in the biological fluid (for example, tissue fluid). Signal.
  • the electrode material of the counter electrode of the micro biosensor includes silver and silver halide.
  • the analyte can be glucose in tissue fluid
  • the physiological parameter is the glucose value in the human body
  • the physiological signal is the micro biosensor. The measured current value.
  • the method of this embodiment starts with the following steps: applying a measuring voltage to drive the working electrode to measure a physiological signal for obtaining a physiological parameter, in which a specific amount of silver halide is consumed (hereinafter referred to as a consumption amount) (S1001).
  • the increase or decrease of the number of moles of silver halide corresponds to the increase or decrease of the number of moles of silver, so for the convenience of explanation, the consumption of silver halide corresponds to the increase of simulated silver.
  • the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the amount of silver plus the amount of silver halide (AgCl/Ag+AgCl) is greater than 0 and less than 1, also That is, there is only one amount of silver halide in 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- Between 0.6.
  • the application of the recharge voltage is stopped (S1005). Then it loops to step S1001 to execute the next loop.
  • a method for calculating the size of the Ag/AgCl material of the electrode signal sensing section is taken as an example with a biosensor service life of 16 days.
  • the average measured current of the analyte for each measurement is 30 nA
  • the measurement period (T1) is 30 seconds
  • the recharge period (t2) is 30 seconds.
  • the daily consumption of AgCl (C consume/day ) 1.3mC/day.
  • the service life requirement of the sensor is 16 days
  • the required length of the counter electrode is at least:
  • the length of the counter electrode needs to exceed 16 mm in order to make the sensor life up to 16 days.
  • the counter electrode signal sensing section needs to be equipped with a correspondingly larger Ag/AgCl material size to achieve the sensor life of 16 days.
  • the silver halide recharging step is performed between the two measurement steps.
  • the consumption and recharging of the silver halide can be repeated in a short period of time (recharge when used), so it can be reduced
  • the amount of Ag/AgCl material in the sensor further miniaturizes the sensor, so there is no need to prepare 16 days of AgCl capacity for the electrode signal sensing section material for consumption.
  • the senor by preparing the capacity of AgCl for about 1 to 2 days, the sensor can be used for 16 days, thereby achieving the effect of extending the service life of the sensor.
  • the capacity of AgCl for 1 to 2 days also refers to the initial amount of AgCl in the counter electrode before leaving the factory or before performing the first measurement, for example, between about 1.3 and 2.6 mC.
  • the initial amount can also be other smaller Or a larger range.
  • different AgCl capacities may be prepared for 1 to 5 days, 1 to 3 days, 6 to 24 hours, and 6 to 12 hours.
  • the material size of the signal sensing section of the counter electrode only needs to have the capacity to enable the stable execution of each glucose measurement step and the positive correlation between the measurement current and the glucose concentration in the body.
  • the prior art will increase the electrode length/area to make the sensor reach the required number of days.
  • the sensor implantation end length is about 12mm.
  • the implantation length is long, and in order to avoid implanting deep into the subcutaneous tissue, it needs to be implanted under the skin at an oblique angle, and the implantation wound is relatively large.
  • the capacity of AgCl for 1 to 2 days is about 1.3 to 2.6 mC
  • the length of the counter electrode for 1 to 2 days is 2.5 to 5 mm, which is compared with that without the silver halide of the present invention.
  • the present invention can effectively reduce the size of the required counter electrode.
  • the length of the implanted end can be shortened, for example, the length is reduced to no more than 10 mm.
  • the lower half of the connection area 317 to the second end 314 belong to the short implant end 318 (as shown in FIGS.
  • the dermis layer can measure the depth of tissue fluid glucose, so the longest side of the short implanted end 318 is not greater than 6 mm, so that the micro biosensor 300 can be partially implanted under the epidermis of the organism in a manner perpendicular to the epidermis of the organism.
  • the longest side of the short implant end 318 is preferably no more than 5 mm, 4.5 mm, 3.5 mm, or 2.5 mm.
  • the short implanted end of the present invention includes the signal sensing section 332 of the counter electrode 330, and the longest side of the signal sensing section 332 is not greater than 6mm, preferably 2-6mm, 2-5mm, 2-4.5mm or 2-3.5 mm, 0.5-2mm, 0.2-1mm.
  • the silver halide recharging method of the present invention can effectively extend the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode, so that The size of the counter electrode signal sensing section can be reduced.
  • the sensor can be miniaturized and biological toxicity can be reduced.
  • the reduction of the electrode size particularly refers to shortening the length of the implanted end of the sensor, thus reducing the pain of implantation of the user.
  • FIGS. 18A and 18B are schematic diagrams of the front and back of the first embodiment of the micro biosensor of the present invention.
  • the micro biosensor 400 of the present invention includes a substrate 410, a first working electrode 420, a second working electrode 430, a first pair of electrodes 440 and a second pair of electrodes 450, and surrounding the first working electrode 420, a
  • the two working electrodes 430, the first pair of electrodes 440 and the second pair of electrodes 450 are chemical reagents 460 (as shown in FIG. 18C).
  • the material of the substrate 410 can be any material that is known to be suitable for use in electrode substrates and preferably has flexibility and insulation properties, such as but not limited to polymer materials such as polyester and polyimide.
  • the aforementioned polymer materials can be used singly or in combination of multiple types.
  • the substrate 410 has a surface 411 (that is, the first surface), an opposite surface 412 (that is, the second surface) opposite to the surface 411, a first end 413 and a second end 414, and the substrate 410 is divided into 3 regions, which are respectively close to The signal output area 415 of the first end 413, the sensing area 416 close to the second end 414, and the connection area 417 between the signal output area 415 and the sensing area 416.
  • the first working electrode 420 and the second working electrode 430 are disposed on the surface 411 of the substrate 410 and extend from the first end 413 to the second end 414 of the substrate 410.
  • the first working electrode 420 includes a first signal output section 421 located in the signal output area 415 of the substrate 410 and a first signal sensing section 422 located in the sensing area 416 of the substrate 410.
  • the second working electrode 430 includes a second signal output section 431 located in the signal output area 415 of the substrate 410 and a second signal sensing section 432 located in the sensing area 416 of the substrate 410.
  • the first pair of electrodes 440 and the second pair of electrodes 450 are disposed on the opposite side surface 412 of the substrate 410 and extend from the first end 413 to the second end 414 of the substrate 410.
  • the first pair of electrodes 440 includes a third signal output section 441 located in the signal output area 415 of the substrate 410, and a third signal sensing section 442 located in the sensing area 416 of the substrate 410
  • the second pair of electrodes 450 includes a third signal output section 441 located on the substrate 410.
  • the fourth signal output section 451 of the signal output area 415 and the fourth signal sensing section 452 of the sensing area 416 of the substrate 410 are located.
  • the materials on the surfaces of the first pair of electrodes 440 and the second pair of electrodes 450 include silver and silver halide, and the silver halide is preferably silver chloride (Silver Chloride) or silver iodide (Silver Iodine).
  • the counter electrode 440 and the second pair of electrodes 450 both have the functions of reference electrodes, that is, the first pair of electrodes 440 and the second pair of electrodes 450 of the present invention can (1) form an electronic circuit with the first working electrode 420 or the second working electrode 430 , Enabling the first working electrode 420 or the second working electrode 430 to be smoothly energized to ensure that the oxidation reaction occurs on the first working electrode 420 or the second working electrode 430; and (2) providing a stable relative potential as a reference potential. Therefore, the first working electrode 420, the second working electrode 430, the first pair of electrodes 440, and the second pair of electrodes 450 of the present invention form a four-electrode system.
  • the silver/silver halide can be mixed with carbon.
  • the silver/silver halide is mixed into the carbon glue, and the silver halide content is as long as the first pair of electrodes 440 And the second pair of electrodes 450 can perform the set measurement operation stably.
  • the surface of the first pair of electrodes 440 and the second pair of electrodes 450 may also be covered with conductive materials to prevent silver halide from dissolution, thereby protecting the first pair of electrodes 440 and the second pair of electrodes 450, wherein the conductive material is
  • the conductive material that does not affect the measurement performance of the working electrode is mainly selected, for example, the conductive material is Carbon.
  • the biosensor is not limited to a wire-type or stacked-type electrode structure.
  • the initial amount of silver halide may be zero before the biosensor is ready to be shipped out of the factory for sale. In this case, there is no silver halide on the first pair of electrodes 440 and/or the second pair of electrodes 450 of the biosensor.
  • the silver coated on the first pair of electrodes 440 and/or the second pair of electrodes 450 through oxidation may be in the first pair of electrodes.
  • the pair of electrodes 440 and/or the second pair of electrodes 450 are refilled with the initial amount of silver halide.
  • the chemical reagent 460 at least covers the first signal sensing section 422 of the first working electrode 420. In another embodiment, the chemical reagent 460 covers at least the first signal sensing section 422 and the second signal sensing section 432 of the first working electrode 420 and the second working electrode 430. In another embodiment, the chemical reagent 460 covers the signal sensing sections 422, 432, 442, and 452 of all electrodes. In another embodiment, the first pair of electrodes 440 and/or the second pair of electrodes 450 may not be covered by the chemical reagent 460.
  • the sensing area 416 of the micro biosensor 400 can be implanted subcutaneously so that the first signal sensing section 422 and the second signal sensing section 432 perform the determination of the physiological signals associated with the analyte in the biological fluid, and the physiological signals will be transmitted separately
  • the first output section 421 and the second output section 431 of the signal are transmitted to the processor 210 from the first output section 421 and the second output section 431 to obtain physiological parameters.
  • the physiological parameters may also be transmitted to the user device 20 via wireless/wired communication, such as a smart phone, a physiological signal receiver, or a blood glucose meter.
  • FIG. 18C is a schematic cross-sectional view along the line AA' in FIG.
  • the first working electrode 420 and the second working electrode 430 are disposed on the surface 411 of the substrate 410
  • the first pair of electrodes 440 and the second pair of electrodes 450 are disposed on the opposite surface 412 of the substrate 410
  • the first working electrode 420 The surfaces of the second working electrode 430, the first pair of electrodes 440 and the second pair of electrodes 450 are covered with a chemical reagent 460.
  • the chemical reagent 460 covers at least a part of the surface of a working electrode.
  • the micro biosensor 400 of the present invention will perform the measurement step during the measurement period and perform the refill step during the refill period.
  • the first working electrode 420 or the second working electrode 430 can be selected to measure physiological signals, and in the recharging step, the first working electrode 420 or the second working electrode 430 helps the first pair of electrodes 440 or the second electrode Two pairs of electrodes 450 are recharged with silver halide. Therefore, in this embodiment, when the measurement step is performed, the voltage of the first working electrode 420 or the second working electrode 430 is higher than the voltage of the first pair of electrodes 440 or the second pair of electrodes 450, so that the current flows from the first working electrode.
  • the first working electrode 420 or the second working electrode 430 flows in the direction of the first pair of electrodes 440 or the second pair of electrodes 450, thereby causing the first working electrode 420 or the second working electrode 430 to undergo an oxidation reaction (that is, the first working electrode 420 or the second working electrode 430).
  • the electrochemical reaction between the electrode 430, the chemical reagent 460 and the analyte) to measure the physiological signal the first pair of electrodes 440 or the second pair of electrodes 450 undergo a reduction reaction, so that the first pair of electrodes 440 or the second pair of electrodes 450 silver halide consumed dissociate into silver (Ag) and a halide ion (X -).
  • the silver halide in the first pair of electrodes 440 or the second pair of electrodes 450 is consumed, it is necessary to recharge the silver halide in the first pair of electrodes 440 or the second pair of electrodes 450 to perform the next measurement step.
  • the voltage of the first pair of electrodes 440 or the second pair of electrodes 450 is higher than the voltage of the first working electrode 420 or the second working electrode 430, so that the current flows from the first pair of electrodes 440 or the second pair of electrodes 450 Flow in the direction of the first working electrode 420 or the second working electrode 430, and then cause the first pair of electrodes 440 or the second pair of electrodes 450 to oxidize to combine silver and halide ions to recharge the silver halide.
  • Detailed measurement steps and recharge The steps are illustrated in Figure 12.
  • FIG. 19A is a schematic cross-sectional view of the second embodiment of the micro biosensor of the present invention.
  • the second embodiment is a change of the electrode configuration of the first embodiment.
  • the first working electrode 420 and the first pair of electrodes 440 of the micro biosensor 400 of the present invention are disposed on the surface 411 of the substrate 410, and the second working electrode 430 and the second pair of electrodes 450
  • the opposite side surface 412 of the substrate 410 is provided, and the surface of the first working electrode 420, the second working electrode 430, the first pair of electrodes 440, or the second pair of electrodes 450 is covered with a chemical reagent 460.
  • the first working electrode 420 or the second working electrode 430 can be selected to measure physiological signals, and in the recharging step, the first working electrode 420 or the second working electrode 430 can also be selected to help The pair of electrodes 440 or the second pair of electrodes 450 are backfilled with silver halide.
  • the current flows from the first working electrode 420 or the second working electrode 430 to the first pair of electrodes 440 or the second pair of electrodes 450, so that the first working electrode 420 Or the second working electrode 430 undergoes an oxidation reaction to measure physiological signals, and the first pair of electrodes 440 or the second pair of electrodes 450 undergo a reduction reaction, so that the silver halide in the first pair of electrodes 440 or the second pair of electrodes 450 is consumed and dissociated into silver (Ag) and a halide ion (X -).
  • the current flows from the first pair of electrodes 440 or the second pair of electrodes 450 to the direction of the first working electrode 420 or the second working electrode 430, thereby causing the first pair of electrodes 440 or the second pair of electrodes 450 to generate
  • the oxidation reaction combines silver and halide ions to recharge the silver halide.
  • FIG. 19B is a schematic cross-sectional view of the third embodiment of the micro biosensor of the present invention.
  • the first working electrode 420 of the micro biosensor 400 of the present invention is arranged on the surface 411 of the substrate 410, and the second working electrode 430, the first pair of electrodes 440, and the second pair of electrodes 450 are arranged on the surface of the substrate 410.
  • the side surface 412, and the surface of the first working electrode 420, the second working electrode 430, the first pair of electrodes 440, or the second pair of electrodes 450 are covered with a chemical reagent 460.
  • the second working electrode 430 can be arranged between the two opposite electrodes, and can also be arranged at the leftmost or rightmost position (not shown in the figure).
  • the first working electrode 420 or the second working electrode 430 can be selected to measure physiological signals
  • the first working electrode 420 or the second working electrode can also be selected 430 helps to recharge the first pair of electrodes 440 or the second pair of electrodes 450 with silver halide.
  • FIG. 19C is a schematic cross-sectional view of the fourth embodiment of the micro biosensor of the present invention.
  • the first working electrode 420 and the second working electrode 430 of the micro biosensor 400 of the present invention are disposed on the surface 411 of the substrate 410, and the second working electrode 430 is U-shaped and is adjacently disposed and surrounds the first working electrode.
  • the first pair of electrodes 440 and the second pair of electrodes 450 are disposed on the opposite side surface 412 of the substrate 410, and the first working electrode 420, the second working electrode 430, the first pair of electrodes 440 and the second The surfaces of the two pairs of electrodes 450 are covered with a chemical reagent 460.
  • the first working electrode 420 or the second working electrode 430 can be selected to measure physiological signals, and in the recharging step, the first working electrode 420 or the second working electrode 430 can also be selected. It helps to recharge the first pair of electrodes 440 or the second pair of electrodes 450 with silver halide.
  • FIGS. 18C-19C basically cover the surface of the first working electrode 420 with the chemical reagent 460 at least.
  • the materials of the first working electrode 420 and the second working electrode 430 include but are 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 first work
  • the materials of the electrode 420 and the second working electrode 430 are precious metals, derivatives of precious metals, or a combination of the foregoing.
  • the first working electrode 420 and the second working electrode 430 are platinum-containing materials.
  • the electrode material of the second working electrode 430 is selected from a material having a lower sensitivity to hydrogen peroxide than that of the first working electrode 420, such as carbon.
  • any of the above embodiments in order to prevent the silver electrode material from being disconnected due to excessive chlorination, it is also possible to add one between the opposite side surface 412 of the substrate 410 and the silver of the first pair of electrodes 440 and the second pair of electrodes 450.
  • Layer of conductive material such as carbon
  • the resistance at the switch will be too high. Therefore, a layer of conductive material can be added between the carbon conductive material and the opposite surface 412 of the substrate 410.
  • the layer such as silver is used to reduce the impedance of the signal output terminal, so that the first pair of electrodes 440 and the second pair of electrodes 450 of the present invention start from the opposite side surface 412 of the substrate 410 as a conductive layer, a carbon layer, and a silver/silver halide layer in order .
  • the micro biosensor 400 of the present invention can use, for example, the first working electrode 420 and the first pair of electrodes 440 to perform the measurement step while using the second working electrode. 430 and the second pair of electrodes 450 perform a recharging step. Or, for example, the first working electrode 420 is used to continuously perform the measurement step, while the second working electrode 430 is used to help the first pair of electrodes 440 or the second pair of electrodes 450 perform the recharging step.
  • FIGS. 20A-20C respectively show the constant voltage circuit in the present invention that can perform the measurement mode and the recharge mode according to different methods.
  • the measurement mode can be started and stopped by applying the measurement potential difference V1 and removing the measurement potential difference V1, respectively, and the corresponding current is represented by Ia.
  • the first working electrode W1 is controlled by switch S1
  • the first pair of electrodes R/C1 is controlled by switches S5 and S6
  • the second working electrode W2 is controlled by switches S2 and S7
  • the second The counter electrode R/C2 is controlled by switches S3 and S4.
  • the measurement potential difference V1 is applied between the first working electrode W1 and the first pair of electrodes R/C1 during the measurement period T1, so that the voltage of the first working electrode W1 is higher than that of the first pair of electrodes. Voltage of electrode R/C1.
  • the switches S1 and S6 are in the closed state, and the switch S5 is in the open state.
  • the first working electrode W1 is +Vl, and the first pair of electrodes R/C1 is grounded, so that the first working electrode W1 undergoes oxidation reaction and reacts with chemical reagents.
  • the recharging mode it can be started and stopped by applying the recharging gap V2 and removing the recharging gap 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.
  • the recharge mode apply the recharge potential V2 between the second working electrode W2 and the second pair of electrodes R/C2 for the recharge period t2, so that the voltage of the second pair of electrodes R/C2 is higher than that of the second working electrode The voltage of W2.
  • the switches S4 and S7 are in the open state, and the switches S2 and S3 are in the closed state.
  • the second pair of electrodes R/C2 is +V2, and the second working electrode W2 is grounded, so that the Ag on the second pair of electrodes R/C2 The oxidation reaction is carried out, and the AgCl on the second pair of electrodes R/C2 is recharged to a recharge amount.
  • the recharge potential V2 in the constant voltage circuit is a fixed voltage, and the measured output current is Ib.
  • the present invention defines the capacity of AgCl by calculating the area under the current curve (Capacity, unit coulomb, represented by the symbol "C"), so the consumption of AgCl in the measurement mode is Ia*Tl, and the recharge of AgCl in the recharge mode The amount is Ib*t2. Therefore, the recharge amount of AgCl can be controlled by regulating the application time t2 of the recharge potential V2. In other words, under the premise that the AgCl on the first or second pair of electrodes R/C1 or R/C2 is kept within the safety inventory, the recharge amount can be equal to or not equal to (including approximately similar, greater than or less than) consumption quantity.
  • Figure 20A illustrates that the timing of the simultaneous measurement mode and the timing of the recharge mode overlap.
  • the above-mentioned switch control can also be changed to other forms of circuits to have a variety of flexible operation modes.
  • the measurement The mode sequence and the recharge mode sequence can be carried out at the same time, and can also be partially overlapped or not overlapped.
  • Figures 20B-20C are similar to Figure 20A, the only difference is that Figure 20B shows an embodiment using W2 and R/C2 for measurement and W1 and R/C1 for refilling; and Figure 20C shows an embodiment using W1 and R /C2 is measured and W2 and R/C1 are used for refilling.
  • the constant voltage circuit alternately switches to FIG. 20A and FIG. 20B and repeats the cycle.
  • the constant voltage circuit alternately switches to FIG. 20A and FIG. 20C and repeats the cycle.
  • the first pair of electrodes R/C1 and the second pair of electrodes R/C2 can be consumed and recharged in turn, so that the AgCl on the two pairs of electrodes can be kept within the safe inventory.
  • the constant voltage circuit may have a third voltage source to control the recharge voltage difference to be different from the measured voltage difference.
  • the constant voltage circuit shown in Figs. 20A-20C can also alternately perform the measurement mode and the recharge mode.
  • 7A-7D respectively show the current schematic diagrams of the constant voltage circuit alternately performing the measurement mode and the recharge mode in different ways.
  • T1 between a plurality of measurement periods T1 is a period T2 during which no measurement is performed.
  • T2 is a fixed value.
  • the horizontal axis in FIG. 7A7D represents time, 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 FIG. 7A.
  • V2 and T2 are both fixed values, and the application time t2 of V2 (that is, the recharging period) is a variable value.
  • the recharge period t2 is dynamically adjusted from 0 to T2 based on the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in FIG. 7A, t2 can be t2', t2', or t2''.... In other words, the recharge period t2 can be changed according to the consumption of AgCl. If the consumption of AgCl is large, it can be recharged for a longer time to keep the AgCl on the first pair of electrodes R/C1 within the safe inventory. For example, the amount of AgCl recharged during t2'' will be greater than the amount of AgCl recharged during t2'.
  • T2 1/2 of T2, 2/5 T2, 3/5 T2, etc.
  • FIGS. 7E and 7F 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.
  • the horizontal axis is time and the vertical axis is current
  • the curve represents the physiological parameter value curve converted from the measured physiological signal Ia.
  • V2 and T2 are fixed values, and t2 during the recharge period is a variable value.
  • the white area under the curve represents the AgCl consumption in the measurement mode (Ia*Tl)
  • the oblique area represents the AgCl recharge in the recharge mode (Ib*t2).
  • the refill period t2 is based on the measured physiological signal Ia and the measurement period T1 and is set between 0 and T2. Dynamic adjustment between time. According to needs, the recharging mode can be selected in the front part (as shown in FIG. 7E) or the back part (as shown in FIG. 7F) of the period (T2) in which the measurement mode is not performed.
  • FIG. 21 shows a constant current circuit capable of segmented switching between the measurement mode and the recharge mode in the present invention.
  • the method of the constant current circuit with segment switching to repeat the measurement mode and the recharge mode is similar to that of FIG. 20A, so it will not be repeated here.
  • the main difference is that the recharging mode can be started and stopped by applying the recharging gap V2 (V2 is a variable value) and removing the recharging gap V2, and the corresponding current is represented by Ib.
  • the recharging potential V2 is applied between the second working electrode W2 and the second pair of electrodes R/C2 for the recharging period t2 .
  • the switches S2 and S3 are in the closed state
  • the switch S2 and at least one switch corresponding to I_F1 to I_Fn in the partial constant current circuit 61 are in the closed state
  • the second working electrode W2 is grounded
  • the second pair of electrodes R/C2 is + V2, so that the Ag on the second pair of electrodes R/C2 undergoes an oxidation reaction, and AgCl is backfilled.
  • the constant current circuit with segment switching in this embodiment can selectively switch to I_F1, I_F2, I_F3...I_Fn by controlling multiple switches corresponding to I_F1 to I_Fn to adjust the required recharge level difference V2 and output the current Ib.
  • the recharging amount of AgCl can be controlled by adjusting the recharging level difference V2 and its application time t2 according to the magnitude of the physiological signal Ia and the measurement period T1.
  • the recharge amount can be equal to or not equal to (including approximately similar, greater than or less than) consumption quantity.
  • part of the constant current circuit 61 may be configured to connect to the second pair of electrodes R/C2.
  • FIG. 22 shows a constant current circuit capable of stepless switching between the measurement mode and the recharge mode in the present invention.
  • the measurement mode of the constant current circuit with stepless switching is similar to that of Figs. 20A-20C, and the recharging mode is similar to that of Fig. 21, so it will not be repeated here.
  • the difference between the embodiment of FIG. 22 and FIG. 21 is only that in the constant current circuit of FIG. 22, the part of the constant current circuit 71 with stepless switching is controlled by a digital-to-analog converter (DAC) to output a fixed current Ib.
  • DAC digital-to-analog converter
  • FIGS. 10A-10C show the voltage schematic diagrams of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in different ways.
  • the horizontal axis in FIGS. 10A-10C represents time
  • the line of V1 represents the application and removal of the measured potential difference V1
  • the line of V2 represents the application and removal of the recharge potential difference V2.
  • T2 is a fixed value
  • the application time t2 of V2 and V2 (that is, the recharging period) is a variable value.
  • the recharge period t2 is dynamically adjusted from 0 to T2 based on the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in FIG.
  • t2 can be t2', t2'', or t2'''...
  • the recharge period t2 can be changed according to the consumption of AgCl. If the consumption of AgCl is large, it can be recharged for a longer time to keep the AgCl on the first pair of electrodes R/C1 within the safe inventory.
  • V2 is a variable value
  • V2 is dynamically adjusted according to the consumption of AgCl in the physiological signal measurement step (that is, in the measurement mode).
  • One example of the dynamic adjustment method is as follows. For example, the above-mentioned constant current circuit with segment switching is used. The circuit has n fixed current sources and n switches, and each fixed current source corresponds to a switch.
  • At least one of the n switches is selected to be turned on (even if the switch is in a closed state) to output a fixed current value.
  • the recharge period t2 is a fixed value
  • the recharge amount of AgCl can be controlled by selecting different fixed current outputs.
  • V2 is a variable value
  • the measurement mode and the recharge mode are seamlessly alternated, and the period during which no measurement is performed is the recharge period.
  • a constant current circuit with segment switching can control multiple current paths through multiple switches, and can recharge with a segmented constant current according to the amount of current required.
  • the method is more power-efficient and can reduce costs.
  • the potential difference can come from a DC power source or an AC power source, preferably a DC power source.
  • Figures 7A-7F, Figures 21-22, and Figures 10A-10C all describe the alternate cycle of the measurement step and the refilling step, that is, there is an AgCl refilling step between each measurement step.
  • This method It can better ensure that AgCl remains within the safety stock.
  • Y times of AgCl recharge can also be selectively matched during N measurements, where Y ⁇ N, so that the cumulative recharge of AgCl can still be kept within the safety stock range.
  • the measurement step and the refilling step do not necessarily need to be performed in an alternating cycle, and the refilling step may be performed again after several measurement steps, or the refilling step may be performed only after a predetermined measurement time. For example, the refilling step can be performed again after 10 measurements, or the refilling step can be performed only after the cumulative measurement time reaches 1 hour.
  • FIG. 10D shows a schematic diagram of the constant current circuit of the present invention alternately performing the measurement mode and the recharge mode in a manner similar to FIG. 10C.
  • the curve represents the physiological parameter value curve converted into the measured physiological signal Ia, and similar to FIG. 10C, T2 and t2 are both fixed values, and V2 is a variable value.
  • the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the slanted area represents the recharge volume of AgCl in the recharge mode (Ib*t2). 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 position difference V2 is dynamically adjusted according to the consumption of AgCl.
  • each physiological parameter value is not limited to the output when the measurement is completed or during the recharge period.
  • the AgCl refilling step is not limited to being executed after each physiological parameter is output or after the physiological signal is obtained.
  • the working electrodes used in the measurement mode and the recharge mode can be the first working electrode W1 and the second working electrode W1.
  • the counter electrode used in the measurement mode can also be either the first pair of electrodes R/C1 and the second pair of electrodes R/C2, but the counter electrode used in the recharge mode Preferably, it is the counter electrode used in the previous measurement mode. Two exemplary embodiments are described below.
  • Example 1 is carried out in chronological order: (a) use W1/W2 (representing one of W1 and W2) and R/C1 measurement, (b) use the other W1/W2 and R/C1 recharge, (c) Use one of W1/W2 and R/C2 to measure, (d) use the other W1/W2 and R/C2 to recharge, repeat steps (a)-(d).
  • steps (a), (b), (a), (b), (c), (d), (c), (d) are repeatedly executed in chronological order.
  • FIGS. 23A and 23B show schematic diagrams of different embodiments in which the constant current or constant voltage circuit of the present invention performs the measurement mode and the recharge mode at the same time.
  • the horizontal axis in FIGS. 23A and 23B is time, 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. Since there are two counter electrodes and two working electrodes in the present invention, the measuring step and the recharging step can be performed at the same time.
  • FIG. 23A and 23B show schematic diagrams of different embodiments in which the constant current or constant voltage circuit of the present invention performs the measurement mode and the recharge mode at the same time.
  • the first combination formed by the first working electrode W1 and the first pair of electrodes R/C1 and the second combination formed by the second working electrode W2 and the second pair of electrodes R/C2 alternately perform measurement and return. Filling steps. That is, when the first combination is used for the measurement step, the second combination is used for the refill step, and vice versa.
  • the first working electrode W1 is fixed for the measuring step
  • the second working electrode W2 is fixed for the recharging step
  • the two counter electrodes are used alternately between the measuring step and the recharging step.
  • multiple T1s do not overlap with each other.
  • multiple t2s do not overlap with each other.
  • T1 and t2 overlap (meaning that they start and end at the same time) or partially overlap.
  • Figures 23A and 23B show that the first measurement (using R/C1) is not accompanied by the refilling step, and the second measurement (using R/C2) is performed at the same time (refilling R/C1). However, it can also be accompanied by the refilling step (refilling R/C2) at the first measurement (using R/C1).
  • FIG. 11 shows a method for determining an analyte according to an embodiment of the present invention, by which the service life of the micro biosensor can be prolonged.
  • the miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 18A-18C and 19A-19C, which is used to be implanted subcutaneously to measure the physiological parameters associated with the analyte in the biological fluid (for example, tissue fluid). Signal.
  • the analyte may be glucose in tissue fluid
  • the physiological parameter is the glucose value (or concentration) in the human body
  • the physiological signal is the current value measured by the micro biosensor.
  • the method for measuring the analyte includes repeatedly executing the measuring step (S901) and the refilling step (S902).
  • the measurement step (S901) includes using the aforementioned constant voltage or constant current circuit to perform the aforementioned measurement mode during the measurement period T1 to output a physiological signal (i.e., current value), and at the same time, the AgCl of the counter electrode has a consumption amount corresponding to the current value.
  • the measurement step (S901) also includes stopping the measurement mode as described above.
  • each measurement potential difference V1 is applied during the measurement period T1
  • each recharge level difference V2 is applied during the recharge period t2
  • the measurement period T1 is a fixed value, which can be within 3 seconds, 5 seconds Within, within 10 seconds, within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes.
  • the time value is preferably 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 .
  • each measurement period T1 plus each recharge period t2 is a fixed value.
  • each recharge level difference V2 has a fixed voltage value, and each recharge period t2 is dynamically adjusted according to each consumption of AgCl (as shown in FIG. 7A).
  • the output physiological parameters are obtained by calculating the physiological signals at a single measurement time point in each measurement period T1.
  • the output physiological parameters are obtained through a mathematical operation of a plurality of physiological signals at a plurality of measurement time points in each measurement period T1.
  • the aforementioned mathematical operation value is, for example, the accumulated value, the average value, the median, the average value of the median, and so on.
  • the amount of each refill to be equal to or not equal to (including approximately similar, greater than or less than) each consumption, and controlling the amount of AgCl of the counter electrode within the safety stock interval, the lower
  • the next physiological signal obtained in a determination step maintains a stable proportional relationship with the next physiological parameter.
  • the step of removing each measured potential difference V1 is to disconnect the circuit that connects the working electrode and the counter electrode, or set each measured potential difference V1 to zero.
  • the power can be turned off to make the measuring circuit have an open state; or, a 0 volt voltage can be applied between the working electrode and the counter electrode, wherein the operation time of either of the two operations is 0.01 to 0.5 seconds.
  • Removing the step of measuring the potential difference V1 can avoid the generation of ⁇ -shaped physiological signals.
  • the step of removing each regenerative level difference V2 is to disconnect the circuit that connects the working electrode and the counter electrode, or set each regenerative level difference V2 to zero.
  • the measurement period T1 can be a variable value or a combination of a variable value and a fixed value (for example, a variable value + a fixed value.
  • the variable value can be 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, or 24 hours.
  • the fixed value may be, for example, 30 seconds).
  • the present invention uses voltage applied to the counter electrode R/C to measure the reaction current of the counter electrode in a period, and the reaction current in the period is calculated by mathematical operation. Knowing the initial capacity of AgCl, for example, by calculating the area under the reaction current curve to define the initial capacity of AgCl, also known as the initial amount or initial coulombic amount (C initial ), the following are all explained by the amount.
  • each measurement step (S901) the consumption of AgCl (expressed as C consume ) is defined by calculating the area under the current curve of the working electrode W.
  • the safety stock interval is represented by the ratio of Ag to AgCl.
  • the present invention uses the coulombic amount (C) measured on the counter electrode to reflect the ratio of Ag to AgCl.
  • 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 AgCl has a certain amount on the counter electrode without being exhausted, so that each physiological signal measurement step can be performed stably.
  • the remaining amount of AgCl is the sum of the refill amount and the initial amount minus the consumption.
  • the remaining amount of AgCl may gradually decrease, gradually increase, or change steadily or arbitrarily within an interval, but still within the interval.
  • FIG. 12 shows a method for determining an analyte according to another embodiment of the present invention.
  • the miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 18A-18C and 19A-19C, which is used to be implanted subcutaneously to measure the physiological parameters associated with the analyte in the biological fluid (for example, tissue fluid). Signal.
  • the electrode material of the counter electrode of the micro biosensor includes silver and silver halide.
  • the analyte can be glucose in tissue fluid
  • the physiological parameter is the glucose value in the human body
  • the physiological signal is the micro biosensor.
  • the measured current value Only 2 cycles of this embodiment are described below.
  • the method of this embodiment starts with the following steps: during the first measurement period, the measurement voltage is applied to drive the first or second working electrode W1/W2 to measure the physiological signal used to obtain the physiological parameter, wherein the first or second pair of electrodes
  • the silver halide of R/C1 or R/C2 (assuming the first pair of electrodes R/C1) is consumed by a consumption amount (S1101).
  • the application of the measurement voltage is stopped (S1102), and the obtained physiological signal is used to obtain the physiological parameter (S1103).
  • the recharge voltage is applied during the first recharge period to drive the counter electrode used in S1101 with the consumption (ie the first pair of electrodes R/C1), so that the amount of silver halide is recharged.
  • the recharge amount (S1104) wherein the value of the sum of the recharge amount and the initial amount minus the consumption amount (that is, the remaining amount mentioned above) is controlled within the range of the initial amount plus or minus a specific value.
  • control steps are achieved by controlling the refilling amount to be equal to or not equal to (including approximately similar, greater than or less than) the consumption, so as to maintain the amount of silver halide within the safety stock range.
  • the increase or decrease of the number of moles of silver halide corresponds to the increase or decrease of the number of moles of silver, so for the convenience of explanation, the consumption of silver halide corresponds to the increase of simulated silver.
  • the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the amount of silver plus the amount of silver halide (AgCl/Ag+AgCl) is greater than 0 and less than 1, also That is, there is only one amount of silver halide in 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- Between 0.6.
  • the application of the recharge voltage is stopped (S1105). Then return to step S1101.
  • the measurement voltage is applied to drive the first or second working electrode W1/W2 to measure another physiological signal for obtaining another physiological parameter, and the other counter electrode (ie The silver halide of the second pair of electrodes R/C2) is consumed by a consumption amount. Then, the application of the measurement voltage is stopped (S1102), and the obtained physiological signal is used to obtain the physiological parameter (S1103). After the physiological parameters are obtained, the recharge voltage is applied during the second recharge period to drive the counter electrode used in S1101 with the consumption (ie the second pair of electrodes R/C2), so that the amount of silver halide is recharged. Recharge amount (S1104). Then it loops to step S1001 to execute the next loop.
  • a method for calculating the size of the Ag/AgCl material of the electrode signal sensing section is taken as an example with a biosensor service life of 16 days.
  • the average measured current of the analyte for each measurement is 30 nA
  • the measurement period (T1) is 30 seconds
  • the recharge period (t2) is 30 seconds.
  • the daily consumption of AgCl (C consume/day ) 1.3mC/day.
  • the service life requirement of the sensor is 16 days
  • the required length of the counter electrode is at least:
  • the length of the counter electrode needs to exceed 16 mm in order to make the sensor life up to 16 days.
  • the counter electrode signal sensing section needs to be equipped with a correspondingly larger Ag/AgCl material size to achieve the sensor life of 16 days.
  • the silver halide recharging step is performed between the two measurement steps.
  • the consumption and recharging of the silver halide can be repeated in a short period of time (recharge when used), so it can be reduced
  • the amount of Ag/AgCl material in the sensor further miniaturizes the sensor, so there is no need to prepare 16 days of AgCl capacity for the electrode signal sensing section material for consumption.
  • the senor by preparing the capacity of AgCl for about 1 to 2 days, the sensor can be used for 16 days, thereby achieving the effect of extending the service life of the sensor.
  • the capacity of AgCl for 1 to 2 days also refers to the initial amount of AgCl in the counter electrode before leaving the factory or before performing the first measurement, for example, between about 1.3 and 2.6 mC.
  • the initial amount can also be other smaller Or a larger range.
  • different AgCl capacities may be prepared for 1 to 5 days, 1 to 3 days, 6 to 24 hours, and 6 to 12 hours.
  • the material size of the signal sensing section of the counter electrode only needs to have the capacity to enable the stable execution of each glucose measurement step and the positive correlation between the measurement current and the glucose concentration in the body.
  • the prior art will increase the electrode length/area so that the sensor can meet the required number of days.
  • the length of the implanted end of the sensor is about 12mm. Due to the long implantation length, in order to avoid implanting deep into the subcutaneous tissue, it needs to be implanted under the skin at an oblique angle, and the implantation wound is relatively large.
  • the capacity of AgCl for 1 to 2 days is about 1.3 to 2.6 mC
  • the length of the counter electrode for 1 to 2 days is 2.5 to 5 mm, which is compared with that without the silver halide of the present invention.
  • the present invention can effectively reduce the size of the required counter electrode.
  • the length of the implanted end can be shortened, for example, the length is reduced to no more than 10 mm.
  • the lower half of the connection area 417 of the micro biosensor 400 disclosed in FIGS. 18A-18C of the present invention to the second end 414 belong to the short implanted end 418 (as shown in FIGS. 18A and 18B), and the short implanted end 418 is implanted
  • the penetration depth must be at least the depth of the tissue fluid glucose that can be measured in the dermis.
  • the longest side of the short implant end 418 is not more than 6 mm, so that the micro biosensor 400 can be perpendicular to the biological
  • the method of the body surface is partially implanted under the surface of the living body.
  • the longest side of the short implant end 418 is preferably no greater than 5 mm, 4.5 mm, 3.5 mm, or 2.5 mm.
  • the short implanted end 418 of the present invention includes a third signal sensing section 442 and a fourth signal sensing section 452, and the longest side of the third signal sensing section 442 and the fourth signal sensing section 452 is not greater than 6 mm, which is relatively Preferably they are 2-6mm, 2-5mm, 2-4.5mm, 2-3.5mm, 0.5-2mm, 0.2-1mm.
  • the silver halide recharging method of the present invention can effectively extend the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode, so that The size of the counter electrode signal sensing section can be reduced.
  • the sensor can be miniaturized and biological toxicity can be reduced.
  • the reduction of the electrode size particularly refers to shortening the length of the implanted end of the sensor, thus reducing the pain of implantation of the user.
  • the device of the present invention including four electrodes since measurement and recharging can be performed at the same time, it can have a shorter counter electrode size and a more flexible and efficient operation mode than a device including two electrodes or three electrodes.
  • the amount of silver halide on the counter electrode can be minimized to an initial amount sufficient to support at least one measurement of the biosensor.
  • the size of the counter electrode is quantified based on the initial amount of silver halide, which is sufficient to process at least one determination of the physiological signal of the physiological parameter related to the analyte in the patient. After the first measurement, the silver halide that was consumed during the refill period was refilled. Therefore, the present invention provides a method for determining the size of the counter electrode of a biosensor and for extending the lifespan of the biosensor.
  • Fig. 24 is a flowchart according to an embodiment of the present invention.
  • the method includes the following steps: Step a: Define a required consumption range of the silver halide during the measurement period performed by the biosensor at least once; Step b: According to the required consumption range An upper limit plus a buffer amount determines the initial amount, so that a required recharge amount range of the silver halide during the regeneration period is controlled to be sufficient to maintain an amount of the silver halide within a safety stock interval To ensure that a second physiological signal obtained during a second measurement period after the regeneration period maintains a stable proportional relationship with a second physiological parameter; step c: converting the initial quantity to the size of the pair of electrodes; Step d: Make the pair of electrodes contain at least the initial amount of the silver halide; Step e: Measure the physiological signal during the measurement period and the silver halide is consumed by a consumption amount; and Step f: During the regeneration period the silver halide It is recharged once.
  • an initial amount of silver halide is prepared before the biosensor is ready to be sold out of the factory.
  • the silver halide layer can be printed with an initial amount on the counter electrode or a silver layer coated on the counter electrode via halogenation so that it has an initial amount of silver halide.
  • the initial amount of silver halide may be zero before the biosensor is ready to be shipped out of the factory for sale. In this case, there is no silver halide on the counter electrode of the biosensor. After the biosensor is subcutaneously implanted in the patient's body and during the initial recharging period before the first measurement, the silver coated on the counter electrode through oxidation can be recharged with the initial amount of silver halide on the counter electrode.
  • the biosensor when a biosensor is implanted in a patient, the possible trauma to the skin and/or subcutaneous tissue sometimes causes the signal monitored by the sensor to be unstable.
  • the biosensor before using the biosensor, the biosensor must be completely "moistened” or hydrated to achieve a balance with the analyte in the patient (for example, glucose in the biological fluid). Therefore, after the biosensor is implanted in the organism, the user must wait for a warm-up period before the initial measurement of the biosensor in order to obtain an accurate reading of the analyte concentration. In this case, since the biosensor needs a warm-up period before measuring the analyte after being implanted in the organism, the initial recharge period can be performed in the warm-up period without delaying any required measurement.
  • a predetermined upper limit of the detected glucose concentration is selected as the reference, for example, it is performed once when the glucose concentration is 600 mg/dL Physiological signal measurement to obtain the required consumption current is 100nA per second. If the measurement period lasts for 30 seconds, the required consumption of silver chloride during a measurement period is 3000nC (or 0.003mC), which is 100nA multiplied by 30 seconds acquired.
  • the upper limit of the consumption of silver chloride required for one measurement can be selected to be greater than or equal to 0.003 mC. In other embodiments, other concentration values can be selected for the upper limit value.
  • the analyte concentration of different patients or the concentration of the same patient at different times may fluctuate to a large extent and the internal environment is variable, it is recommended to use a larger range of silver halide consumption (that is, the need Larger initial amount), so the required silver halide consumption range must also be added with a buffer amount to cope with the fluctuation of the analyte concentration in the patient's body so as to keep the silver halide in a safe inventory at the counter electrode during the measurement process. Changes within the interval, so that the measured physiological signals and physiological parameters maintain a stable proportional relationship.
  • the amount of buffering can be greater than 0, and can be adjusted based on the predetermined period of use of the biosensor.
  • the time of the scheduled use period can be any multiple of the time of the measurement period, such as 1, 2, 4, 10, 100 times, etc., or an appropriate scheduled use period is selected according to the sensor, such as 1 hour, 2 hours, 6 hours , 1 day, 2 days, 3 days, 5 days, etc. to prepare a sufficient but small initial amount.
  • the arithmetic mean, geometric mean, or median of the required consumption range can also be used to replace the upper limit of the required consumption range to determine the initial amount, which depends on the biosensor's possibility.
  • the required silver halide consumption range and buffer amount can be adjusted based on the predetermined use period of the biosensor.
  • the time of the scheduled use period can be any multiple of the time of the measurement period, such as 1, 2, 4, 10, 100 times, etc., or an appropriate scheduled use period is selected according to the sensor, such as 1 hour, 2 hours, 6 hours , 1 day, 2 days, 3 days, 5 days, etc. to prepare a sufficient but small initial amount.
  • a buffer can also be added to cope with fluctuations in the analyte concentration in the patient's body.
  • the amount of buffering can be greater than 0, and can be adjusted based on the predetermined period of use of the biosensor.
  • the required consumption can be adjusted according to multiple measurement times during the predetermined use period of the biosensor.
  • the initial amount can be determined based on the upper limit of the required consumption range and the sum of the buffer amount to ensure that the required recharge amount of silver halide during the recharge period is sufficient to keep the amount of silver halide within a safe inventory range to safely Ensure that the next physiological signal and the next physiological parameter are successfully obtained during the next measurement period and maintain a stable proportional relationship between the two.
  • the buffering amount may be zero.
  • the initial amount of silver chloride on the counter electrode can be determined as 1.5mC, which is the sum of 1mC and 0.5mC . Therefore, the required recharge amount range can be greater than zero, greater than 1.5 mC, or less than 1.5 mC.
  • At least the first measurement can be made. After performing the first measurement, perform the first recharge to recharge the consumed silver halide.
  • the size of the counter electrode is related to the total volume of silver and silver halide on the counter electrode.
  • the initial amount of silver halide can be converted into the total volume of silver halide on the counter electrode.
  • the total volume of silver and silver halide can be simply defined by the arithmetic product of the width, length, and thickness of silver and silver halide on the counter electrode. Any of the width, length, and thickness can be adjusted to change the volume of silver and silver halide.
  • the width and thickness of the silver and silver halide on the counter electrode are predetermined to meet the constraints of design and manufacturing capabilities.
  • the volume of silver and silver halide on the counter electrode can be reduced by reducing the length of the silver and silver halide on the counter electrode, which means that the length of the counter electrode can be shortened. Therefore, by using the method for determining the initial amount of silver halide provided by the present invention, a biosensor with a prolonged service life and a shorter counter electrode can be realized. Therefore, the patient's pain and discomfort for the implanted biosensor will be greatly reduced, and there is no need to frequently purchase new biosensors to replace old biosensors.
  • the unit amount (or unit capacity) of silver halide depending on the characteristics of the biosensors of different manufacturers is 300 mC/mm 3
  • the required silver halide volume is 0.005 mm 3
  • the width of the counter electrode is 0.3 mm and the thickness of the silver halide is 0.01 mm
  • the length of the silver halide on the counter electrode is 1.67 mm.
  • the length of the silver halide that is, the length of the counter electrode is about 6mm
  • the counter electrode The length is about 10mm. Because the length of the counter electrode can be shortened, the length of the biosensor implanted in the patient can be correspondingly shortened, and the biosensor can also be implanted vertically in the patient to minimize damage to the patient. Therefore, not only can the life of the biosensor be prolonged due to the recharge period provided by the present invention, but also the pain and discomfort caused to the patient can be reduced due to the shortened length of the counter electrode.
  • reducing the volume of silver and silver halide can be achieved by changing at least one of the length, width, and thickness of silver and silver halide. All the above modifications are still within the scope of the present invention.
  • the silver halide can be performed without waiting for the silver halide depletion signal to appear (for example, when the physiological signal appears noise) Recharge to control the inventory level of silver halide within this threshold range.
  • the use of the predetermined value S can further help control the inventory level after silver halide refilling within a specific range of preference.
  • the recharging rate of silver chloride does not have to be completely positively correlated with the decrease rate of silver chloride during the measurement, and it is not necessary to refill the silver chloride immediately after each measurement.
  • the present invention is also applicable to biosensors with any number of counter electrodes and any number of working electrodes, such as a biosensor with one working electrode, one auxiliary electrode and one counter electrode, and a biosensor with two working electrodes and one counter electrode. , Or a biosensor with two working electrodes and two counter electrodes. If the biosensor has two or more counter electrodes, all counter electrodes may have the same size and/or the same initial amount of silver halide.
  • the silver halide recharging method of the present invention can effectively extend the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode, so that The size of the counter electrode signal sensing section can be reduced.
  • the sensor can be miniaturized and biological toxicity can be reduced.
  • the reduction of the electrode size particularly refers to shortening the length of the implanted end of the sensor, thus reducing the pain of implantation of the user.
  • connection area 117, 317, 417: connection area
  • Th1, Th3 the first threshold
  • Th2 second threshold

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Abstract

Procédé de restauration d'un biocapteur (100) vers un état de travail approprié. Le biocapteur (100) comprend une première électrode (120) et une contre-électrode (130), la contre-électrode (130) comprend un matériau d'halogénure d'argent et un matériau d'argent, le matériau d'halogénure d'argent présente un niveau de stock et, dans une opération de mesure, le niveau de stock du matériau d'halogénure d'argent est consommé. Le procédé comprend les étapes suivantes : après l'opération de mesure, le calcul d'un changement du niveau de stock ; et le lancement d'une première opération de renouvellement permettant de renouveler la valeur de fluctuation du niveau de stock, le niveau de stock étant contrôlé pour fluctuer fondamentalement entre un premier seuil (Th1) et un second seuil (Th2).
PCT/CN2021/080609 2020-03-12 2021-03-12 Procédé de restauration de biocapteur et dispositif utilisant ledit procédé WO2021180229A1 (fr)

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Citations (6)

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US20090294306A1 (en) * 2008-06-02 2009-12-03 Feldman Benjamin J Reference electrodes having an extended lifetime for use in long term amperometric sensors
CN107743584A (zh) * 2015-06-15 2018-02-27 豪夫迈·罗氏有限公司 电化学检测体液样品中至少一种被分析物的方法和测试元件
KR20190002136A (ko) * 2017-06-29 2019-01-08 주식회사 아이센스 CGMS 센서용 AgCl 보충시스템 및 보충방법
CN109946362A (zh) * 2017-12-19 2019-06-28 恩德莱斯和豪瑟尔分析仪表两合公司 参比电极以及参比电极的制造方法
CN110268099A (zh) * 2017-02-08 2019-09-20 西门子股份公司 参照开路电势进行脉冲式电解
CN112294322A (zh) * 2019-08-02 2021-02-02 华广生技股份有限公司 生物传感器及用于决定其对电极尺寸和延长其寿命的方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090294306A1 (en) * 2008-06-02 2009-12-03 Feldman Benjamin J Reference electrodes having an extended lifetime for use in long term amperometric sensors
CN107743584A (zh) * 2015-06-15 2018-02-27 豪夫迈·罗氏有限公司 电化学检测体液样品中至少一种被分析物的方法和测试元件
CN110268099A (zh) * 2017-02-08 2019-09-20 西门子股份公司 参照开路电势进行脉冲式电解
KR20190002136A (ko) * 2017-06-29 2019-01-08 주식회사 아이센스 CGMS 센서용 AgCl 보충시스템 및 보충방법
CN109946362A (zh) * 2017-12-19 2019-06-28 恩德莱斯和豪瑟尔分析仪表两合公司 参比电极以及参比电极的制造方法
CN112294322A (zh) * 2019-08-02 2021-02-02 华广生技股份有限公司 生物传感器及用于决定其对电极尺寸和延长其寿命的方法

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