TWI770871B - Method for recovering biological sensor and device using same - Google Patents

Abstract

The present disclosure provides a method for recovering a biosensor to a properly working state, the biosensor including a first electrode and a conouter electrode, the counter electrode including a silver halide material anda silver material, the silver halide material including an amount level, and during an measurement operation, the amount level of the silver halide material is consumed. The method including the following steps: after the measurement operation, calculating a change of the amount level; and activating a first replenishment operation to replenish the change of the amount level, wherein the amount level is controlled to essentially vary between a first threshold value and a second threshold value.

Description

Method of restoring biosensor and device using the same

The present invention relates to a biosensor and a method for determining the size of its counter electrode, in particular to a method for measuring a physiological signal represented by a physiological parameter associated with a test object, and for extending the use of the biosensor method of life.

With the rapid growth of the diabetic patient population, the need to monitor the changes of glucose (Glucose) in the body has become increasingly emphasized. Therefore, many researches have begun to develop systems that can be implanted in the body for continuous glucose monitoring (CGM) to solve the problem of patients' daily glucose monitoring. The inconvenience of life caused by repeated blood collection and testing.

In the field of CGM systems for enzyme-based biosensors, in which biochemical reaction signals depending on analyte concentration are converted into measurable physical signals, such as optical or electrochemical signals. For glucose measurement, the electrochemical reaction, such as glucose oxidase (GOx), catalyzes the reaction of glucose to generate gluconolactone (Gluconolactone) and a reduced enzyme, and the subsequent reduced enzyme will react with the oxygen in the biological fluid in the body. The electron transfer then generates the product hydrogen peroxide (H ₂ O ₂ ), and finally the glucose concentration is quantified by catalyzing the oxidation reaction of the product H ₂ O ₂ . The reaction formula is as follows.

Glucose+GOx(FAD)→GOx(FADH ₂ )+Gluconolactone

GOx(FADH ₂ )+O ₂ →GOx(FAD)+H ₂ O ₂ In the above reaction, FAD (Flavin Adenine Dinucleotide) is the active center of GOx.

Users usually wear CGM for a long time, such as more than 14 days, so it is an inevitable trend to miniaturize it. The basic structure of CGM includes: (a) a biosensor (Biosensor) for measuring physiological signals corresponding to the glucose concentration of the human body; and (b) a sensor (Transmitter) for transmitting these physiological signals. The biosensor can be a two-electrode system or a three-electrode system. In a three-electrode system biosensor, there is 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), wherein the counter electrode also functions as a reference electrode, so it is sometimes called counter/reference electrode (R/C). A suitable material for the stable measurement of glucose concentration is silver/silver chloride (Ag/AgCl) for the reference electrode in the biosensor of the three-electrode system and the counter electrode as the reference electrode in the biosensor of the two-electrode system. However, after the sensor is implanted in a living body, when the working electrode undergoes a redox reaction to measure the glucose concentration, the corresponding reference electrode (RE) or reference/counter electrode (R/C) undergoes a reduction reaction, making chlorine Silver chloride is consumed by reduction of silver chloride to silver. In addition, if the sensor implanted in the living body is a sensor of a two- or three-electrode system, due to the dissociation of silver chloride in the body fluid, the silver chloride on the reference electrode will be depleted, which will cause a decrease in the reference voltage. Drift problem. However, due to the participation of the reference/counter electrode (R/C) in the two-electrode system, the consumption of silver chloride is even higher than that of the three-electrode system. The lifetime of the sensor is therefore limited by the amount of silver chloride on the counter and/or reference electrodes.

There are also many inventions proposed for the service life of biosensors. Taking a two-electrode system as an example, at an average sense current of 20 nanoamperes (nA) The consumption of the lower counter electrode is about 1.73 millicoulombs (mC) per day. Assuming that the length, width and height of the counter electrode are 3.3 mm, 0.25 mm and 0.01 mm respectively, and the originally designed electrode capacity (Capacity) is only 6mC, its The state of stable measurement lasts about one day at most. However, if the service life is to be extended, if the biosensor is to be implanted subcutaneously for 16 consecutive days of glucose monitoring, the capacity of the counter electrode must be at least 27.68mC. The counter electrode length may need to be up to 15.2mm. Therefore, the prior art attempts to lengthen the length of the counter electrode to more than 10 mm, and in order to avoid implantation deep into the subcutaneous tissue, these biosensors need to be implanted at an oblique angle. Therefore, problems such as larger implantation wounds and higher infection risks are caused to patients, and because of the long implantation length, the pain during implantation is also significant.

US 8,620,398 describes a biosensor, which is mainly a three-electrode system. Although the reference electrode basically does not participate in chemical reactions, silver chloride is still gradually and naturally consumed in the in vivo environment, but the consumption rate is slower than that of the two-electrode system. It does not regenerate until the AgCl will be exhausted. The step of determining the exhaustion includes determining that the sensor output current has noise, that is to say, when the measurement signal is unstable, that is, the measured signal is already noisy, recharge the AgCl. The procedure is then activated to return the AgCl to the amount required to have enough measurements. Then until the next 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 during measurement, AgCl is recharged when the biosensor fails. However, the measurement value at the time of failure is unreliable. It is necessary to wait for the biosensor to complete the AgCl recharge procedure to obtain the correct measurement value, temporarily adopt the method of blood sampling, or directly skip this measurement. This problem is always troublesome for patients or those who need to know the blood glucose concentration at that time. In addition, since this kind of biosensor has to deal with multiple measurements at least several times in a row or even several days, it is necessary to prepare more AgCl capacity, but also Inevitably, the biosensor has a long implant length, and it does not propose that instant AgCl recharge can be used to provide uninterrupted measurement, have a shorter implant length, and have Longer life biosensors.

US 9,351,677 is mainly a two-electrode system, the reference/counter electrode (R/C) participates in the chemical reaction, so the silver chloride is consumed with the electrochemical reaction. An analyte sensor with increased AgCl capacity is proposed, which uses H ₂ O ₂ is used to regenerate AgCl on the reference electrode, but since 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/ _recharge , the concentration of _H2O2 in the body may not be sufficient to recharge a sufficient amount of AgCl stably, and its biosensor needs to be configured with a relatively large AgCl electrode size, and its implanted end Also up to 12mm long.

The lifetime of the biosensor depends on the amount of silver halide present in the counter electrode. However, 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 implant length into the patient. The longer the implant length to the patient, the more discomfort the patient suffers. The present disclosure provides a solution for reducing the size of the counter electrode, provides a method of quantifying the initial amount of silver halide required on the counter electrode, and provides a method of intelligently initiating recharging of silver halide when needed The method and device do not need to wait until the silver halide depletion signal appears (such as noise in physiological signals) before performing silver halide recharging, but can select an appropriate range as a threshold interval to control the inventory level of silver halide to maintain the threshold interval Inside. Therefore, the present invention provides a biosensor capable of providing uninterrupted measurement, stably recharging AgCl, prolonging its service life, and miniaturizing the small size of the implanted end, which can reduce the The manufacturing cost of the product, and these effects can solve the problems that are difficult to overcome by the prior art.

In view of the deficiencies in the prior art, the applicant of this case, after careful experimentation and research, and a spirit of perseverance, finally conceived of this case, which can overcome the deficiencies of the prior art. The following is a brief description of the case.

Through the recharging technique of the present invention, the size of the sensing section of the counter electrode signal in the micro biosensor of the present invention can be reduced, thereby reducing the biological toxicity and making the micro biosensor have a prolonged service life. In addition, the reduction in the size of the electrodes can shorten the length of the implanted end of the sensor, thus reducing the pain of the user during implantation. In particular, the recharging timing and recharging amount of silver chloride are regulated by the recharging technology of the present invention, so even when the user's glucose concentration fluctuates greatly, the micro-sensor of the present invention can still be instantly and automatically The silver chloride consumed by ground recharging keeps the silver chloride inventory within a predetermined range, so the obtained physiological signals and physiological parameters maintain a stable proportional relationship. Through the recharging method of the present invention, the recharging rate of silver chloride does not need to be positively correlated with the decreasing rate of silver chloride during the measurement period, and the present invention also provides a method that does not need to be recharged immediately after each measurement. The method of recharging silver chloride.

One of the objectives of the present application is to provide a method for recharging a silver halide material in a biosensor that is implanted subcutaneously to measure an analyte associated with an analyte in a biological fluid. A physiological signal of a physiological parameter, the biosensor includes at least a first electrode and a pair of electrodes, the pair of electrodes includes a silver halide material and a silver material, the silver halide material is between the silver halide material and the silver There is an inventory level in the material, and the recharge control method includes the following steps: after a measurement operation, obtaining a measurement value of the physiological signal, wherein the inventory level decreases after the measurement operation; A predetermined number of measurement operations is satisfied Under the condition, a change value of the inventory level in a period of the predetermined number of times is calculated, and a first refill operation is started to recharge the change value of the inventory level, and the predetermined number of times is a positive integer, wherein the The inventory level varies substantially between a first threshold value and a second threshold value.

Another object of the present application is to provide a physiological signal measuring device capable of controlling an inventory level of a silver halide material in a biosensor. The silver halide material has an initial inventory, and the inventory level represents the current inventory level. An inventory of silver halide material is used to make the physiological signal measurement device perform a recharge operation to restore the inventory level of the silver halide material, and the physiological signal measurement device includes: the biological sensor, including: a first electrode, and a first pair of electrodes, including the silver halide material and a silver material; and a sensing unit, coupled to the biosensor, and including: a processor configured to initiate execution During a measuring operation, the inventory is decreased by a consumption amount, and when the recharging operation is started, the inventory is increased by a recharging amount, and the inventory level is calculated, wherein the processor controls the inventory level to substantially varies between a first threshold and a second threshold.

Another object of the present application is to provide a method for restoring a biosensor to a proper working state, the biosensor includes a first electrode and a pair of electrodes, the pair of electrodes includes a silver halide material and a silver material, The silver halide material has an inventory level, and in a measurement operation, the inventory level of the silver halide material is depleted, the method comprising the steps of: after the measurement operation, calculating an amount of the inventory level a change; and initiating a first refill operation to refill the changed value of the inventory level, wherein the inventory level is controlled to vary substantially between a first threshold value and a second threshold value.

10: Physiological signal measurement device

20: User device

61: Partial constant current circuit with segment switching

71: Partial constant current circuit with stepless switching

100, 300, 400: Tiny Biosensors

110, 310, 410: substrate

111, 311, 411: Surface

112, 312, 412: Opposite side surfaces

113, 313, 413: The first end

114, 314, 414: second end

115, 315, 415: Signal output area

116, 316, 416: Sensing area

117, 317, 417: Connection area

120, 320: working electrode

121, 321: Signal output section

122, 322, 332, 342: Signal sensing segment

130, 330: Counter electrode

131: Signal output section

132: Signal sensing segment

140, 350, 460: chemical reagents

200: Sensing unit

210: Processor

220: Power

230: Voltage application unit

240: Temperature Sensing Unit

250: Communication unit

260: Timer

318, 418: Short implant end

323, 420: the first working electrode

324, 430: the second working electrode

325: Third working electrode

340: auxiliary electrode

321: The first signal output section

322: The first signal sensing segment

431: The second signal output section

432: The second signal sensing segment

440: The first pair of electrodes

441: The third signal output section

442: The third signal sensing segment

450: Second pair of electrodes

451: Fourth signal output section

452: Fourth signal sensing segment

I ₀ : initial amount

N: number of measurements

P; predetermined number of times

S: predetermined value

S1, S2, S3, S4, S5, S6, S11, S12, S13, S14, S15, S16, S17, S21, S22, S23, S24, S25, S26, S31, S32, S33, S34, S35, S36, S37, S38, S901, S902, S1001, S1002, S1003, S1004, S1005: Steps

Th1, Th3: the first threshold value

Th2, Th4: the second threshold value

The above objects and advantages of the present invention will become more immediately apparent to those of ordinary skill in the art upon review of the following detailed description and accompanying drawings.

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 miniature biosensor of the present invention.

[ FIG. 2B ] is a schematic diagram of the backside of the miniature biosensor of the present invention.

[Fig. 2C] is a schematic cross-sectional view taken 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 materials in a biosensor according to an embodiment of the present invention.

[ FIG. 3B ] is a flowchart of a method for recharging the silver halide material in the biosensor according to another embodiment of the present invention.

[ FIG. 3C ] is a flowchart of a method for recharging the silver halide material in a biosensor according to another embodiment of the present invention.

[ FIG. 3D ] is a flowchart of a method for recharging the silver halide material in a biosensor according to still another embodiment of the present invention.

[ FIG. 3E ] is a flowchart of a method for recharging the silver halide material in a biosensor according to still another embodiment of the present invention.

[FIG. 4A] to [FIG. 4H] are schematic diagrams of curves of inventory levels in 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 recharge mode in the present invention.

[ FIG. 6A ] is a schematic diagram of a variation curve of an inventory level according to an embodiment of the present invention.

[ FIG. 6B ] is a schematic diagram of a variation curve of the inventory level according to another embodiment of the present invention.

[ Fig. 6C ] is a schematic diagram of a variation curve of the inventory level according to another embodiment of the present invention.

[FIG. 6D] is a schematic diagram of a variation curve of the inventory level according to still another embodiment of the present invention.

[ FIG. 6E ] is a schematic diagram of a variation curve of the inventory level according to still another embodiment of the present invention.

[ FIG. 7A ] is a schematic diagram of the current in which the constant voltage circuit of the present invention performs the measurement mode and the recharge mode alternately in the first manner.

[ FIG. 7B ] is a schematic diagram of the current in which the constant voltage circuit of the present invention performs the measurement mode and the recharge mode alternately in the second manner.

[ FIG. 7C ] is a schematic diagram of the current in which the constant voltage circuit of the present invention performs the measurement mode and the recharge mode alternately in the third manner.

[ FIG. 7D ] is a schematic diagram of the current in which the constant voltage circuit of the present invention performs the measurement mode and the recharge mode alternately in the fourth manner.

[ FIG. 7E ] is a schematic diagram of the current in which the constant voltage circuit of the present invention performs the measurement mode and the recharge mode alternately in the fifth manner.

[ FIG. 7F ] is a schematic diagram of the current in which the constant voltage circuit of the present invention performs the measurement mode and the recharge mode alternately in the sixth manner.

[FIG. 8A] The constant current circuit with step switching in the measurement mode in the present invention.

[FIG. 8B] The constant current circuit with step switching in the recharge mode in the present invention.

[FIG. 9A] The constant current circuit of the present invention is in the measurement mode without step switching.

[FIG. 9B] The constant current circuit of the present invention is in the recharge mode without step switching.

[ FIG. 10A ] is a schematic diagram of the voltage of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in the first manner.

[ FIG. 10B ] is a schematic diagram of the voltage of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in the second manner.

[ FIG. 10C ] is a schematic diagram of the voltage of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in the third manner.

[ FIG. 10D ] is a schematic diagram of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in the third manner.

[ FIG. 11 ] is a method for measuring an analyte according to an embodiment of the present invention.

[Fig. 12] is a method for measuring an analyte according to another embodiment of the present invention.

[ FIG. 13A ] is a schematic front view of the first embodiment of the miniature biosensor of the present invention.

[ FIG. 13B ] is a schematic view of the back 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 Fig. 2A of the present invention.

[FIG. 14A] is a cross-sectional view of the second embodiment of the micro biosensor of the present invention intention.

[ 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 miniature biosensor of the present invention.

[ FIG. 14E ] is a schematic cross-sectional view of the sixth embodiment of the miniature 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 recharge mode in the present invention.

[FIG. 16A] The constant current circuit with step switching in the measurement mode in the present invention.

[FIG. 16B] The constant current circuit with step switching in the recharge mode in the present invention.

[FIG. 17A] A constant-current circuit with stepless switching in the measurement mode in the present invention.

[FIG. 17B] The constant current circuit of the present invention is in the stepless switching mode in the recharge mode.

[ FIG. 18A ] is a schematic front view of the first embodiment of the miniature biosensor of the present invention.

[FIG. 18B] is a back view of the first embodiment of the micro biosensor of the present invention intention.

[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 ] is a constant voltage circuit that can execute a measurement mode and a recharge mode according to the first method of the present invention.

[ FIG. 20B ] is a constant voltage circuit according to the second aspect of the present invention that can perform a measurement mode and a recharge mode.

[FIG. 20C] is a constant voltage circuit according to the third aspect of the present invention that can perform a measurement mode and a recharge mode.

[FIG. 21] is a constant current circuit capable of switching between measurement mode and recharge mode in stages according to 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 performing the measurement mode and the recharge mode according to an embodiment.

[ FIG. 23B ] is a schematic diagram of the constant current or constant voltage circuit of the present invention performing the measurement mode and the recharge mode according to another embodiment.

[FIG. 24] is a flowchart according to an embodiment of the present invention.

The invention proposed in this case can be fully understood by the following examples, so that those with ordinary knowledge in the technical field can complete it accordingly. However, the implementation of this case is not limited by the following examples. Those with ordinary knowledge in the art can still deduce other embodiments according to the spirit of the disclosed embodiments, and these embodiments should all belong to the scope of the present invention.

Unless otherwise limited in a specific example, the following definitions apply to terms used throughout the specification.

The term "amount" or "stock amount" refers to the capacity (Capacity) of silver halide (AgX) or silver chloride (AgCl) in the counter electrode, and is preferably expressed in microcoulombs (μC), millicoulombs (mC) or coulombs (C ), but is not limited to be expressed in terms of weight percent concentration wt%, molar number, molar concentration, etc.

The curves or straight lines schematically shown in the drawings do not necessarily represent their real shapes. For example, straight lines or curves may have fluctuations along the normal direction of the line, or have various possible turning points; Distances, lengths or heights shown do not represent absolute measurements unless explicitly stated.

Please refer to FIG. 1 , which 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 for subcutaneous implantation to measure the physiological signal of the physiological parameter associated with the analyte in the biological fluid. The physiological signal measuring device 10 of the present invention includes a miniature biosensor 100 and a sensing unit 200 , wherein the sensing unit 200 is electrically connected to the miniature biosensor 100 and has a processor 210 , a power source 220 and a voltage applying unit 230 , a temperature sensing unit 240 and a communication unit 250 . power supply 220 is controlled by the processor 210 to control the voltage applying unit 230 to provide voltage to the micro biosensor 100 to measure the physiological signal, and the temperature sensing unit 240 to measure the biological body temperature, so the temperature measurement signal and the micro biosensor The physiological signal measured by 100 is sent to the processor 210, and the processor 210 calculates the physiological signal into a physiological parameter. The communication unit 250 can perform wired or wireless transmission with the user device 20 .

Please continue to refer to FIG. 1 , the sensing unit 200 may optionally include a timer 260 coupled to the processor 210 for, for example, within 5 seconds, within 15 seconds, within 30 seconds, within one minute, within ten seconds Timing of a fixed time interval of a time value within minutes, within one hour, within two hours, within four hours, within one day, within one week, or within one month, etc. The timer 260 may also be configured to send a signal to the processor 210 at one or more configurable time points.

Please refer to FIGS. 2A and 2B , which are schematic views of the front and the back of the miniature biosensor of the present invention. The miniature 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 known suitable material for electrode substrates, and preferably has flexibility and insulation properties, such as but not limited to: polyester (Polyester), polyimide (Polyimide) and other polymer materials, The aforementioned polymer materials may be used alone or in combination of two or more. The substrate 110 has a surface 111 (ie, a first surface), an opposite surface 112 (ie, a second surface) opposite to the surface 111 , a first end 113 and a second end 114 , and the substrate 110 is divided into three regions, which are close to each other. The signal output area 115 of the first end 113 , the sensing area 116 near the second end 114 , and the connection area 117 located 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 base The signal output section 121 of the signal output area 115 of the board 110 and the signal sensing section 122 of the sensing area 116 of the substrate 110 are provided. Materials of the working electrode 120 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 aforementioned elements, or derivatives of the aforementioned elements (such as alloys, oxides or metal compounds, etc.), preferably, the material of the working electrode 120 is noble metals, derivatives of noble metals or combinations of the aforementioned, more preferably Ground, the working electrode 120 is a platinum-containing material.

The counter electrode 130 is disposed on the opposite side surface 112 of the substrate 110 and extends from the first end 113 to the second end 114 of the substrate 110 . The counter electrode 130 includes a signal output segment 131 located in the signal output area 115 of the substrate 110 and a signal sensing segment 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, wherein the silver halide is preferably silver chloride (Silver Chloride) or silver iodide (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 current on the working electrode 120 is smooth, so as to ensure that the electrochemical reaction occurs on the working electrode 120; and (2) provide a stable relative potential as reference potential. Therefore, the working electrode 120 and the counter electrode 130 of the present invention form a two-electrode system. In order to further reduce the cost and improve the biocompatibility of the biosensor of the present invention, the silver/silver halide can be mixed with carbon. 130 can stably perform the set measurement action. A portion of the surface of the counter electrode 130 can also be covered with a conductive material to prevent the dissociation of the silver halide, thereby protecting the counter electrode 130, wherein the conductive material is mainly a conductive material that does not affect the measurement performance of the working electrode, such as a conductive material For carbon (Carbon).

In another embodiment, the biosensor is not limited to wire type or stack type electrode structure.

In another embodiment of the invention, 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. During the initial recharge period after subcutaneous implantation of the biosensor into the patient and before the first measurement is taken, the counter electrode 130 can be recharged with an initial amount of silver halide.

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 in the sensing region 116 . In another embodiment, the chemical reagent 140 covers at least the signal sensing section 122 (not shown) of the working electrode 120 . That is, the counter electrode 130 may not be covered by the chemical reagent 140 . The sensing area 116 of the miniature biosensor 100 can be implanted subcutaneously so that the signal sensing section 122 of the working electrode 120 can measure the physiological signal associated with the analyte in the biological fluid, and the physiological signal will be transmitted to the working electrode 120 The signal output section 121 is sent to the processor 210 by the signal output section 121 to obtain the physiological parameters. In addition to being obtained from the sensing unit 200, the physiological parameter can also be obtained by transmitting it to the user device 20 through wireless/wired communication, such as a commonly used user device 20 such as a smart phone, a physiological signal receiver or a blood glucose meter.

Please refer to FIG. 2C , which is a schematic cross-sectional view along the line AA′ in FIG. 2A , wherein the line AA′ is a section line from the sensing area 116 of the micro biosensor 100 . In FIG. 2C , the working electrode 120 is disposed on the surface 111 of the substrate 110 , the counter electrode 130 is disposed on the opposite surface 112 of the substrate 110 , and the surfaces of the working electrode 120 and the counter electrode 130 are covered with chemical reagents 140 . Basically, the chemical reagent 140 covers at least part of the surface of the working electrode 120 . The micro biosensor 100 of the present invention performs the measurement step during the measurement and the recharge step during the recharge (ie regeneration). When the measurement step is performed, 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, thereby causing the working electrode 120 to undergo an oxidation reaction (ie, the working electrode 120, chemical reagents, etc.). 140 and the analyte) to measure physiological signals, the counter electrode 130 undergoes a reduction reaction, and 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, it is necessary to recharge the silver halide in the counter electrode 130 for the next measurement step. When the recharging step is performed, 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 working electrode 120, and then the counter electrode 130 is oxidized to cause the silver to interact with the halide ions in the living body. Or AgCl oxidized (or dissociated) after Cl ^- is combined to recharge silver halide. The detailed measurement steps and recharge steps are illustrated in Figure 11 .

In another embodiment, 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. Similarly, when the measurement step is performed, the current flows from the working electrode 120 to the counter electrode 130, so that the working electrode 120 undergoes an oxidation reaction to measure the physiological signal, and the silver halide in the counter electrode 130 is consumed and dissociated into silver (Ag) and halide ions (X ^- ). When the recharging step is performed, the 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 with halide ions to recharge the silver halide.

The detailed electrode stacks in FIGS. 2C-2D above are omitted, and only the electrode positions are shown.

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

In other embodiments, the silver halide of the counter electrode material is not excluded to be silver chloride or silver sulfide, or other electrode materials based on silver redox reaction, such as silver acetate, phosphoric acid. Silver (silver phosphate). In other embodiments, the method for restoring the inventory level of the electrode material of the present invention is not limited to the above-mentioned materials, for example, other electrodes with similar aspects can be applied to the method of restoring the biosensor and the device using the method.

1, 2C or 2D, and 5A-5B, the present invention provides a physiological signal measuring device 10 capable of controlling the inventory level of the silver halide material of the miniature biosensor 100. The silver halide material has an initial inventory amount I ₀ , the inventory level represents the inventory of the silver halide material at that time and is used to make the physiological signal measurement device perform a recharge 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 a counter electrode 130, in a two-electrode system, the first electrode is the working electrode 120, and the counter electrode 130, including silver halide material and silver material; and a sensing unit 200, coupled to the micro biosensing The device 100 includes: a processor 210 configured to decrease the consumption of the inventory when starting the measurement operation, increase the inventory to the recharge and calculate the inventory level when starting the recharging operation. The processor controls the inventory level to vary substantially between the first threshold and the second threshold. In other embodiments, it can also be implemented in the electrode system as described in FIG. 13C or FIGS. 14A-F.

3A-3E are halogenated halogens in biosensors according to different embodiments of the present invention. The flow chart of the recharge method of silver material. 3A is a flowchart of a method for recharging the silver halide material in a biosensor according to an embodiment of the present invention. Referring to Figure 3A, the silver halide material has an inventory level that varies during the measurement and recharge operations: during the measurement operation, the inventory level decreases; during the recharge operation, the inventory level will increase. The recharging method of the present invention includes step S11: the processor 210 receives a measurement instruction; step S12: the power source 220 controls the voltage applying unit 230 by the processor 210 to provide a voltage to the biosensor 100 to measure the physiological signal, and Obtain the measured value; Step S13 : The processor determines the recharge operation condition according to the measured value, for example, determines the applied recharge voltage and/or time according to the accumulated consumption. Step S14: perform recharging according to the recharging operating conditions; Step S15: calculate the current inventory level during the recharging operation; Step S16: according to different threshold values (Th1, Th2, Th3, Th4, predetermined value S etc.), determine whether the inventory level satisfies the stop recharging condition: if not, continue the current recharging operation, or go to step S11 to wait for the next measurement instruction or go to step S12 to perform the next measurement and recharging cycle; , then stop recharging and wait for the next measurement instruction, then proceed to step S11 to receive the measurement instruction again, or directly proceed to step S12 to perform the next measurement and recharging cycle.

The recharge time and recharge amount of the inventory level when the processor performs the recharge operation can be calculated according to a consumption amount each time the measurement operation is performed, such as the total consumption amount, the partial consumption amount or the average consumption amount. One of the cumulative consumption of each measurement operation during the period, the natural consumption of the electrode, or a combination thereof is dynamically adjusted. The calculation of the recharge inventory can also be matched with the user's glucose concentration index factor. The higher the glucose concentration, the more silver halide material is consumed, so that the reduction rate of the silver halide material during the measurement operation does not need to be related to the silver halide material. The generation rate of is in positive phase The timing and amount of regeneration of the silver halide material can be controlled by the charging method.

In the present invention, the inventory level is first 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 of the accumulated value of the recharge amount of the silver halide material in the counter electrode is used as the calculation method. In other embodiments, the inventory level can also be a unit amount of the silver halide material in the counter electrode in the silver halide material and the silver material, for example, in coulombs Numbers are presented, but not limited to weight percent concentration wt%, molar number, molar concentration. The inventory level can also be calculated by using other mathematical methods or electrical units, which will not be repeated here.

3B is a flow chart of a method for recharging silver halide materials in a biosensor according to another embodiment of the present invention. The difference value is used as the inventory level as a judgment parameter to be applied to the physiological signal measuring device to perform the recharging process. charging operation. Of course, if the difference here is replaced by the inventory level, it can also be applied in Figure 3B.

Referring to FIG. 3B , the silver halide material has an inventory. When the biosensor is shipped from the factory, the inventory is the initial inventory, and the inventory decreases or increases with the measurement and recharging operations. The recharging method according to an embodiment of the present invention includes step S21 : the processor 210 receives a measurement instruction; step S22 : the power supply 220 controls the voltage applying unit 230 by the processor 210 to provide a voltage to the biosensor 100 to perform physiological signals Step S23: The processor calculates the inventory level of silver halide (the proportion of silver halide, or the cumulative value of each consumption and the cumulative value of each consumption) step S24: determine whether the current proportion (or difference) satisfies the recharge condition: if not, wait for the next measurement instruction; if so, step S25: start recharging Operation; Step S26: determine whether the proportion (or difference) satisfies the stop recharging condition, if not, continue the current recharging recharge, or go to step S21 to wait for a new measurement instruction; if so, stop recharging and wait for the next measurement instruction, go to step S21 to receive the measurement instruction again, or directly go to step S22 to perform the next measurement with recharge cycle. The recharging operation shown in FIG. 3B stops when the recharging amount approximately equal to the variation value is reached. For convenience of distinction, this recharging operation may be referred to as the first recharging operation.

In the method for restoring a biosensor of the present invention as described above, other judgment parameters may also be added. For example, a recharge operation can be additionally activated under certain specific conditions, please refer to FIG. 3C . 3C is a flowchart of a method for recharging silver halide material in a biosensor according to still another embodiment of the present invention. Step S31: After receiving the measurement instruction, step S32 not only obtains the measurement value, but also calculates the cumulative value of the measurement times N. For example, after the first measurement, such as the calculation of computer language, at this time N=N +1, that is, N increases from 0 to 1. Step S33: Calculate the proportion of the inventory (or a difference between the cumulative value of each consumption and the cumulative value of each recharge). Step S34: Determine whether one of the inventory level, the difference value, and the cumulative value of the measurement times meets the recharge condition, if not, wait for the next measurement instruction; if so, step S35: start the recharge operation; step S36: Calculate the gradually increasing inventory level during the recharging operation; Step S37: Determine whether the inventory level satisfies the stop recharging condition: if not, continue the current recharging operation; if so, stop the recharging and wait for the next measurement instruct. Step S38: Return the accumulated value of the measurement times to zero. After receiving the measurement instruction again, go to step S31.

In addition to the method of restoring a biosensor of the present invention as described above, other judgment parameters may be used independently or in combination. For example, according to another embodiment of the present invention, if this recovery method is implemented alone, the fluctuation of the inventory level can be controlled within a small (that is, relatively stable) range until the inventory level is too low. When the level reaches a certain lower limit, increase the recharge potential, recharge current or recharge time to increase the larger single recharge amount. 3D is a flowchart of a method for recharging the silver halide material in the biosensor according to another embodiment of the present invention. Referring to FIG. 3D , steps S44 to S47 are similar to steps S34 to S37 of FIG. 3C . Step S42: Measure to obtain the measurement value, and calculate the number of measurements (N=N+1), under the condition that the number of measurement operations N reaches the predetermined number of times P (that is, when N=P and P is a predetermined positive value) Integer), calculate the cumulative measurement value from N=0 to N=P, or the change in inventory level (for example, the difference (or its absolute value) of the inventory from N=0 to N=P), and also It is the accumulated consumption between N=0 and N=P, then step S43 : start the first recharging operation to recharge the recharging amount approximately equal to the variable value. After the recharging is stopped, step S48: the measurement times N is reset to zero. After receiving the measurement instruction again, go to step S41.

This method can be controlled after each measurement (of course, it can also be accumulated after each measurement, for example, after a single measurement operation with excessive consumption, or in multiple measurement operations. When the consumption is too large) start a recharge operation.

If this recharging method is implemented in combination with the method of FIG. 3A , 3B or 3C described above, in case the measured physiological parameter changes too much and may cause the expectation of exceeding the parameter setting value of the biosensor, It is thus possible to prevent the problem of failing the biosensor sooner or later as the inventory level continues to rise or fall.

3E is a flowchart of a method for recharging the silver halide material in the biosensor according to another embodiment of the present invention. Please refer to FIG. 3E, step S51: receiving the measurement instruction; step S52: measuring and obtaining the measurement value; step S53: calculating the current consumption and the cumulative consumption (if it is the first measurement, the cumulative consumption is the current cancellation step S54: determine whether the accumulated consumption satisfies the recharge condition: if not, wait for the next measurement instruction; if so, step S55: determine the recharge operation condition. For example, the size and/or time of the applied recharge voltage is determined according to the amount of accumulated consumption, or according to different threshold values (Th1, Th2, Th3, Th4, predetermined value S, etc.). Step S56: Start the recharging operation; Step S57: Calculate the gradually increased inventory level during the recharging operation; Step S58: Determine the inventory level according to different threshold values (Th1, Th2, Th3, Th4, predetermined value S, etc.) Whether the recharging stop condition is met: if not, continue the current recharging operation; if so, stop recharging and wait for the next measurement instruction. After receiving the measurement instruction again, go to step S51.

4A-4H are schematic diagrams of variation curves of inventory levels according to various embodiments of the present invention, wherein FIGS. 4A-4D and 4H are schematic diagrams of possible changes in inventory levels when only the method of FIGS. 3B, 3C or 3D is used. Referring to FIG. 4A, the inventory starts from the initial inventory I _0. After several measurement operations, when the inventory level gradually decreases to less than or equal to the first threshold Th1, the recharging operation is started until the inventory level reaches the first threshold Th1. When the threshold value Th2 is reached, the recharging operation is stopped. In addition, a predetermined value S may be set between the first threshold value Th1 and the second threshold value Th2 as another threshold value, and when the inventory level reaches S, the recharging operation is stopped. FIG. 4A shows the situation when Th2=S.

Referring to FIG. 4B , at this time, the predetermined value S is set equal to the initial inventory amount I ₀ instead of the second threshold value Th2. Therefore, after the recharging operation is started, the recharging operation is stopped when the inventory level reaches the initial inventory I ₀ .

Referring to FIG. 4C , at this time, the predetermined value S is set to be greater than the initial inventory amount I ₀ and less than the second threshold value Th2. Therefore, after the recharging operation is started, the recharging operation is stopped after the inventory level rises to a predetermined value S greater than the initial inventory I ₀ .

Referring to FIG. 4D , at this time, the predetermined value S is set to be smaller than the initial stock amount and larger than the first threshold value Th1 . Therefore, after the recharging operation is started, the recharging operation is stopped after the inventory level rises to a predetermined value S smaller than the initial inventory I ₀ .

Figures 4E-4H are schematic diagrams of the variation curves of inventory levels that may occur when the method of Figure 3A or 3E is implemented in combination with one of the methods of Figures 3B to 3D. Referring to FIG. 4E , the inventory starts from the initial inventory I ₀ , and after one or more measurement operations and the first recharging operation of the method as shown in FIG. 3A or 3E has been initiated one or more times, the inventory level gradually decreases When it is less than or equal to the first threshold Th1, start the recharging operation as shown in Figures 3B to 3D (referred to as the second recharging operation), and stop the recharging until the inventory level reaches the second threshold Th2 (or S=Th2). charging operation.

Referring to FIG. 4F , after one or more measurement operations and one or more first recharging operations of the method as shown in FIG. 3A or 3E have been initiated, the inventory level gradually increases 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 initiated, and the second recharging operation will not be initiated until the inventory level is less than or equal to the first threshold Th1 .

Please refer to FIGS. 4G and 4H , the difference between the two figures lies in the size of the range between the first threshold value Th1 and the second threshold value Th2 . If the range is large, as shown in FIG. 4G , a second recharging operation is initiated when the inventory level gradually decreases to less than or equal to the first threshold Th1 during the measurement operation and after another recharging operation. If this range is small, as shown in FIG. 4H , a second recharging operation may be initiated after each measurement operation, ignoring the first recharging operation. It can also be considered that the first recharging operation is started after each measurement operation, while the second recharging operation is ignored, and whichever of the two recharging operations takes precedence.

FIG. 6A is a schematic diagram of an inventory level curve implemented in conjunction with the recharging methods of FIGS. 3B and 3X . Please refer to FIG. 6A , the vertical axis in the upper figure is the proportion of AgCl, the vertical axis in the middle figure is the applied measurement voltage (V1) and the recharge voltage (V2), and the vertical axis in the lower figure is the applied constant voltage. The measured current (without the slashed area) and the recycle current (with the slashed area) under the condition. The horizontal axis is the same time, and the vertical dotted line represents the same time point. 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 is stopped. Since the proportion of AgCl at this time has not been less than or equal to the first threshold value Th1, the recharging operation will not be started yet. 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 is stopped when the proportion of AgCl reaches (slightly greater than or equal to) the second threshold Th2 operate.

FIG. 6B is a schematic diagram of another inventory level curve implemented in conjunction with the recharging methods of FIGS. 3B and 3X . Please refer to FIG. 6B , the vertical axis in the upper figure is the difference between the cumulative consumption of AgCl and the cumulative recharge (the difference is initially 0), and the vertical axis in the middle figure is the applied measurement voltage (V1) and recharge Voltage (V2), the vertical axis of the figure below is the measured current (without the slashed area) and the recycle current (with the slashed area) under the condition of applying a constant voltage. The horizontal axis is the same time, and the vertical dotted line represents 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. Since the difference at this time has not been smaller than or equal to the first threshold value Th1, the recharging operation will not be started yet. After several measurement 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.

In another embodiment of the present invention, it is desirable to control the inventory level between Th1 and Th2, and after each measurement, the current change will be calculated and immediately returned as the next change, but the current return is not seen. It is exactly equal to the current change, so there will be a change between each measurement and the inventory before and after each recharge. However, if the single consumption is too large and is less than or equal to another lower threshold Th3, the inventory level can be greatly increased to Th2.

FIGS. 6C to 6E are schematic diagrams of another inventory level implemented in conjunction with the recharging method of FIGS. 3A and 3B . For example, the control of the curve of FIG. 6C can be based on the method of FIG. 3A, set Th1 and Th2, so that the inventory level is controlled in between, and supplemented by the method of FIG. 3B, so that in case the inventory level is suddenly consumed in large quantities When the instantaneous or natural consumption is lower than Th3, the inventory level can be effectively kept away from Th3 in the subsequent recharging operation; or when the inventory level is instantaneously higher than Th4 due to sudden and large consumption, it can be Then temporarily terminate the recharge operation or reduce the recharge amount of the recharge operation, effectively keeping the inventory level away from Th4.

Referring to FIG. 6C, the vertical axis is the AgCl inventory level, the horizontal axis is time, S=Th2, and another lower threshold Th3 and another upper threshold Th4 are set. The recharge inventory level is initially the initial inventory. Using the first recharge method in Figure 3A, after the first measurement (M1), the first recharge is started and the first recharge (R1) is implemented. Inventory levels did not reach S. After the second measurement (M2), the second recharging (R2), and the sixth measurement (M6), the inventory level (eg, the proportion in FIG. 3B ) is lower than Th3. Inventory levels between R1-M6 appear to be on a downward trend. In this case, the method according to Figure 3B is suitable, A second recharging operation is initiated to directly raise the inventory level to S(S=Th2).

In addition, if the preset value S of FIG. 3B is set to a value between Th2 and Th4, the inventory level can be increased to be between Th2 and Th4. In other embodiments, other conditions that can also enable the biosensor to maintain the measurement accuracy can be selected as the default value.

Alternatively, in the method of FIG. 3B , it can be set that when the inventory level reaches Th2, after forcing the next measurement (for example, M7), if the inventory level does not reach Th3, the first step of FIG. 3A is not performed. Recharging (not shown in the figure), therefore, the next step is to execute M8. If the inventory level is less than or equal to Th3, the second recharging operation is forced to start again, so that the inventory level is directly increased to S (S=Th2). Inventory levels will follow the M7-M8-R7-M9 curve. If not designed in this way, the inventory level curve after M7 (as shown by M7-M9 in Fig. 6C ) can be similar to the change in the inventory level between R1-M6, and the change in the inventory level is smoother.

Please refer to FIG. 6D, which is substantially similar to FIG. 6C, except that the predetermined value S is set to be between I0 and Th2. The same can be done to vary the inventory level between Th1 and Th2, but more moderately than the latter curve (M6-M9) shown in Figure 3C.

Referring to Figure 6E, the inventory level between R3-M7 seems to be on an upward trend. However, due to the setting of thresholds Th1 and Th2, it also effectively prevents the inventory level from exceeding the upper limit.

In another embodiment, in addition to using the calculation method of the ratio or the difference, the inventory level can also be calculated by setting the threshold value (ie, the upper and lower limit values) of the coulomb number of the silver halide. Referring to FIGS. 3C to 3E again, the inventory level is calculated based on coulombs. In the case of performing a recharge operation after each measurement operation, such as From the curve between M1-M9, it can be clearly seen that with the method of the present invention, even though there may be an increasing or decreasing trend during this period, the inventory level can be stably controlled between Th1 and Th2. Therefore, percentages, differences or coulombs, or a combination thereof, can be applied to inventory levels as a measure.

Regarding the threshold application of Th3 and Th4, it can also include: when the processor confirms that the inventory level exceeds Th3 and Th4, an abnormal signal is given, and the system can determine that the biosensor suspends or ends the measurement operation.

Referring to FIG. 1 , when the sensing unit can optionally include a timer 260, the method of the present invention further includes the following steps: starting another recharging operation every time the condition of the fixed time interval of each measuring operation is satisfied, The fixed time interval is a time value 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.

Regarding the selection of each threshold value, when the inventory level is the ratio of silver halide material to silver halide material and silver material, the first threshold value Th1 is selected from the ratio of 1% to 98%, and the second threshold value Th2 Selected from 2% to 99%. For example, when the first threshold value Th1 is 1%, the second threshold value Th2 may be one of 2%, 3%, 4%, 5%, . . . up to 99%; or, when the second threshold value Th2 When Th2 is 99%, the second threshold Th2 can be one of 98%, 97%, 96%, 95%, ... up to 1%, or selected from the first threshold Th1 at 20%, the second The threshold Th2 is 80%, or the first threshold Th1 is 30%, the second threshold Th2 is 70%, or the first threshold Th1 is 40%, and the second threshold Th2 is 60%, or The first threshold value Th1 is 50%, and the second threshold value Th2 is 60%.

When the inventory level is the difference between the cumulative recharge amount of silver halide material after each recharge operation minus the cumulative consumption of silver halide material after each measurement operation, the first The threshold Th1 is a value between -1% and -99% of the initial inventory, 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 a cumulative consumption after multiple measurements.

The recharge control of the biosensor and the method for restoring a biosensor to a proper working state of the present invention can be applied to a biosensor with an electrode structure of one working electrode and one counter electrode, and can also be applied to A biosensor with an electrode structure of one working electrode, one counter electrode and one auxiliary electrode; it can also be applied to a biosensor with an electrode structure of one working electrode, two counter electrodes and one auxiliary electrode; or Suitable for biosensors with electrode structures with two working electrodes and two counter electrodes.

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 recharging operation, the following steps are further included: the physiological signal measuring device forcibly performs the recharging operation, and stopping the recharging operation when the inventory level increases to be greater than or equal to the second threshold Th1.

According to an embodiment of the present invention, applying the recharge voltage is implemented by applying a fixed potential difference or a fixed current value, and the fixed potential difference or the fixed current value is essentially dynamically adjusted according to the change of AgCl consumption. For the detailed implementation mechanism, please refer to 5 to 10 illustrate.

According to an embodiment of the present invention, 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, and the silver halide material has an inventory level, and in the measurement operation, the inventory level of silver halide material is consumed, this The method of the invention includes the steps of: after the measuring operation, calculating the change in the inventory level; and initiating a first refill operation to recharge the change in the inventory level, wherein the inventory level is controlled to be substantially at a first threshold The value Th1 varies between the second threshold value Th2. When the inventory level changes to less than or equal to the first threshold Th1, a first recharging operation is initiated to recharge 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 threshold value Th1 and the second threshold value Th2.

According to an embodiment of the present invention, the method of the present invention further includes at least one of the following steps: calculating the variation value of the inventory level during the predetermined number of times under the condition that each predetermined number of measurement operations is satisfied, and starting the In the first recharging operation (ie, another recharging operation), the variation value of the recharging inventory level is used to recharge; and the second recharging operation is started under the condition that the fixed time interval after each measurement operation is satisfied.

According to the method for restoring silver halide of the present invention, the data of the relevant inventory level can also be transmitted to the remote control system, and the remote control system monitors the inventory level, and if necessary, provides an update instruction to the physiological signal measuring device to perform the recharging condition. 's update.

Constant voltage circuit switching application

Please refer to FIGS. 5A-5B and 7A-7D, wherein FIG. 5A and FIG. 5B respectively illustrate the constant voltage circuit in the measurement mode and the recharge mode of the present invention, and FIGS. 7A-7D respectively illustrate the constant voltage circuit in different ways Current schematic diagram of alternately performing measurement mode and recharge mode. The measurement mode can be started and stopped by applying and removing the measurement potential difference V1, respectively, and the corresponding current is denoted by Ia. In the measurement mode, 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 working electrode W and the counter electrode R/C are The voltage of the working electrode W is higher than the voltage of the opposing electrode R/C. As shown in FIG. 5A , switches S1 and S4 are in a closed state at this time, while switches S2 and S3 are in an open state, the working electrode W is +V1, and the counter electrode R/C is grounded, so that the working electrode W undergoes an oxidation reaction, and Electrochemical reaction with chemical reagent and analyte is performed to output physiological signal Ia, and AgCl of the counter electrode R/C has a consumption corresponding to the physiological signal Ia. As shown in FIGS. 7A-7D, between the plurality of measurement periods T1 is a period T2 in which no measurement is performed. In some preferred embodiments, T2 is a fixed value.

The recharge mode can be started and stopped by applying the recharge potential V2 and removing the recharge potential V2, respectively, and the corresponding current is denoted by Ib. V2 is a fixed value between 0.1V and 0.8V, preferably between 0.2V and 0.5V. In the recharge mode, the recharge potential difference V2 is applied between the working electrode W and the counter electrode R/C for a continuous recharge period t2 (t2 is between 0 and T2), so that the voltage of the counter electrode R/C is higher than the working electrode R/C The voltage of electrode W. As shown in Figure 5B, at this time, switches S1 and S4 are in an open state, while switches S2 and S3 are in a closed state, the working electrode W is grounded, and the counter electrode R/C is +V2, so that the Ag on the counter electrode R/C is in a closed state. The oxidation reaction is carried out, and the AgCl on the counter electrode R/C is recharged to a recharge amount. The recharge potential difference 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 symbol "C"), so the consumption of AgCl in the measurement mode is Ia*Tl, and the return of AgCl in the recharge mode is The charge is Ib*t2. Therefore, the recharge amount of AgCl can be controlled by adjusting the application time t2 of the recharge potential difference V2. In other words, on the premise that the AgCl on the counter electrode R/C is kept within the safety stock, the recharge amount can be made equal to or not equal to (including approximately similar, greater or less than) consumption.

In FIGS. 7A-7D, the horizontal axis is time, the line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the recharge potential difference V2. Please Referring to FIG. 7A , in a preferred embodiment, both V2 and T2 are fixed values, and the application time t2 of V2 (ie, the recharging period) is a variable value. The recharging period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in Figure 7A, t2 may 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 long time to keep the AgCl on the counter electrode R/C within the safety stock. For example, the amount of AgCl recharged during t2'' will be greater than the amount of AgCl recharged during t2'.

Referring to FIG. 7B, in another preferred embodiment, V2, T2 and t2 are all fixed values, where t2=T2. That is to say, the measurement mode and the recharge mode alternate seamlessly, and the period when no measurement is performed is the recharge period. 7C and 5D, in some preferred embodiments, V2, T2 and t2 are all fixed values, wherein t2 is a fixed value greater than 0 and less than T2, such as T2, 2/5 when t2=1/2 of T2, 3/5 of T2, etc. The difference between Fig. 7C and Fig. 7D is that in Fig. 7C, after each measurement mode ends, after a buffer time (buffer time = T2-t2), the recharge mode starts; in Fig. 7D, each measurement mode ends The recharge mode starts immediately without buffering time, and there is a period of time between the end of each recharge mode and the start of the next measurement mode. In certain preferred embodiments, t2 is less than T2, and t2 can be any time period during T2.

Please refer to FIGS. 7E and 7F , which are schematic diagrams of currents in which the constant voltage circuit of the present invention alternately performs the measurement mode and the recharge mode in different ways. In FIGS. 7E and 7F , the horizontal axis is time, the vertical axis is current, and the curve represents the physiological parameter value curve converted from the measured physiological signal Ia. In these two embodiments, similar to FIG. 7A, V2 and T2 are fixed values, and t2 is a fluctuating value during the recharging period. In Figures 7E and 7F, the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the area of the slanted line represents the recharged amount of AgCl in the recharge mode (Ib*t2). As can be seen from the figure, in order to make Ib*t2 close to Ia*T1 or within a certain range of Ia*T1, the recharge period t2 is dynamically adjusted between 0 and T2 according to the measured physiological signal Ia and the measurement period T1. According to needs, the recharge mode can be selected to be performed in the first stage (as shown in FIG. 7E ) or the latter stage (as shown in FIG. 7F ) during the period (T2) when the measurement mode is not executed.

Constant current circuit switching application with segment switching

Please refer to FIGS. 8A-8B and FIGS. 10A-10C, wherein FIG. 8A and FIG. 8B respectively show the constant current circuit with segment switching in the measurement mode and the recharge mode of the present invention, and FIGS. 10A-10C show the Three voltage schematic diagrams of the constant current circuit alternately performing measurement mode and recharge mode in different ways. The measurement mode can be started and stopped by applying and removing the measurement potential difference V1, respectively, and the corresponding current is denoted by Ia. In the measurement mode, the measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C for the measurement period T1. As shown in FIG. 8A , switches S1 and S4 are in a closed state at this time, while other switches are in an open state, the working electrode W is +V1, and the counter electrode R/C is grounded, so that the working electrode W is oxidized and reacted with The chemical reagent and the analyte undergo electrochemical reaction to output the physiological signal Ia, and the AgCl of the counter electrode R/C has a consumption corresponding to the physiological signal Ia. As shown in FIGS. 10A-10C , between the plurality of measurement periods T1 is a period T2 in which no measurement is performed. In some preferred embodiments, T2 is a fixed value.

The recharge mode can be started and stopped by applying the recharge potential V2 (V2 is a variable value) and removing the recharge potential V2, respectively, and the corresponding current is represented by Ib. In the recharge mode, a recharge potential difference V2 is applied between the working electrode W and the counter electrode R/C for a recharge period t2 (t2 is between 0 and T2). As shown in FIG. 8B , at this time, 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 switches corresponding to I_F1 and I_F3 are exemplarily shown in the figure in a 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 is oxidized and then recharged with AgCl. In the recharge mode, according to the magnitude of the physiological signal Ia and the measurement period T1, at least one switch corresponding to I_F1 to I_Fn can be selectively switched to output a fixed current Ib, and AgCl can be controlled by regulating the application time t2 of the potential difference V2 the recharge amount. In other words, on the premise that the AgCl on the counter electrode R/C is kept within the safety stock, the recharge amount can be made equal to or not equal to (including approximately similar, greater or less than) consumption.

Constant current circuit switching application of stepless switching

Please refer to FIGS. 9A-9B and FIGS. 10A-10C, wherein FIG. 9A and FIG. 9B respectively illustrate the stepless switching constant current circuit in the measurement mode and the recharge mode according to the present invention. The measurement mode and the 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 this embodiment is in the recharge mode, which can be based on the physiological signal. Ia, outputs a fixed current Ib under the control of a digital-to-analog converter (DAC), and controls the recharge amount of AgCl by regulating the application time t2 of the potential difference V2. In other words, on the premise that the AgCl on the counter electrode R/C is kept within the safety stock, the recharge amount can be made equal to or not equal to (including approximately similar, greater or less than) consumption.

10A-10C, the horizontal axis is time, and the vertical axis is current, wherein the line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the recharge potential difference V2. Referring to FIG. 10A , in a preferred embodiment, T2 is a fixed value, and the application time t2 of V2 and V2 (ie, the recharging period) is a variable value. The recharging period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in Figure 10A, t2 may 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 If it is large, it can be recharged for a longer time to keep the AgCl on the counter electrode R/C within the safety stock.

Please refer to FIG. 10B , in another preferred embodiment, V2 is a variable value, T2 and t2 are fixed values, and t2 is a fixed value greater than 0 and less than T2, such as T2, 2/ T2 of 5, T2 of 3/7, etc. In this embodiment, V2 is dynamically adjusted according to the consumption of AgCl in the physiological signal measurement step (ie, 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, and the circuit has n fixed current sources and n switches, and each fixed current source corresponds to one switch respectively. In the recharge mode, according to the consumption of AgCl, at least one switch among the n switches is selected to be turned on (even if the switch is in a closed state) to output a fixed current value. When the recharge period t2 is a fixed value, the recharge amount of AgCl can be controlled by selecting different fixed current outputs.

Referring to FIG. 10C , in another preferred embodiment, V2 is a variable value, and both T2 and t2 are fixed values, where t2=T2. That is to say, the measurement mode and the recharge mode alternate seamlessly, and the period when no measurement is performed is the recharge period.

Compared with the constant current circuit with stepless switching, the constant current circuit with step switching can control multiple current paths through multiple switches, so that it can be recharged with a segmented constant current according to the required current. The method is more energy-saving and can reduce the cost. In addition, whether it is a constant voltage circuit or a constant current circuit, the potential difference can come from a DC power source or an AC power source.

The embodiments of FIGS. 7A to 10C all describe the operation mode of alternating cycles of the measurement step and the recharging step, that is, there is an AgCl recharging step between each measurement step, which can better ensure that the AgCl remains within the safety stock. However, in some preferred embodiments, Y times can also be selectively matched during the N times of measurement. , where Y≦N, so that the accumulated amount of AgCl can still be kept within the safety stock range. The measurement step and the recharging step do not necessarily need to be performed in an alternate cycle, and a recharging step can be performed after several measurement steps, or a recharging step is performed only after a predetermined measurement time. . For example, a recharging step can be performed after 10 measurements, or a recharging step can be performed after the accumulated measurement time reaches 1 hour.

Please refer to FIG. 10D , which is a schematic diagram of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in a manner similar to FIG. 10C . In FIG. 10D , the curve represents the physiological parameter value curve converted from the measured physiological signal Ia, and similar to FIG. 10C , T2 and t2 are fixed values, and V2 is a variable value. In Fig. 10D, the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the area of the oblique line represents the recharged amount of AgCl in the recharge mode (Ib*t2). As can be seen from the figure, in order to make Ib*t2 close to Ia*T1 or within a certain range of Ia*T1, the recharge potential difference V2 is dynamically adjusted according to the consumption of AgCl.

In addition, in FIGS. 7E , 7F and 10D , although the output timing of each physiological parameter value output after each execution of the physiological signal measurement step is not shown, the physiological parameter value is not limited to output when the measurement is completed or during the recharge period output, and the AgCl recharging step is not limited to be performed after each physiological parameter is output or after a physiological signal is obtained.

Please refer to FIG. 11 , which shows a method for measuring an analyte according to an embodiment of the present invention, through which the service life of the micro biosensor can be extended. The miniature biosensor may be, for example, the miniature biosensor shown in FIGS. 2A-2D for implantation subcutaneously to measure physiological parameters associated with the analyte in biological fluids (eg, interstitial fluid). physiological signals. In the embodiment of FIG. 11 , the analyte may be glucose in the tissue fluid, the physiological parameter is the glucose value in the human body, and the physiological signal The current value measured by the micro biosensor. In this embodiment, the method for measuring the analyte includes repeatedly and cyclically performing the measuring step ( S901 ) and the recharging 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, a current value), while the AgCl of the electrode has a consumption corresponding to the current value quantity. 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, the glucose value).

葡萄糖酸內酯(Gluconolactone)+氧化型葡萄糖氧化酶(FADH₂) In the measurement step (S901), the chemical reaction formula is as follows: the following oxidation reaction is performed on the working electrode 120: glucose (Glucose) + reduced glucose oxidase (Glucose oxidase, Gox) (FAD)

Gluconolactone + oxidative glucose oxidase (FADH ₂ )

還原型葡萄糖氧化酶(FAD)+H₂O₂ Oxidative glucose oxidase (FADH ₂ )+O ₂

Reduced glucose oxidase (FAD)+H ₂ O ₂

2H⁺+O₂+2e^-於對電極130進行以下還原反應：2AgCl+2e^-

2Ag+2Cl^- H ₂ O ₂

2H ⁺ +O ₂ +2e ^- performs the following reduction reaction on the counter electrode 130: 2AgCl+2e ^-

2Ag+2Cl ^-

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 has a recharging amount corresponding to the consumption. The amount is controlled within the safety stock range. Therefore, 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 in a proportional relationship. may be inversely proportional). In other words, the next current value obtained in the next measurement step can be compared with the next The glucose value maintains a stable proportional relationship. The recharging step ( S902 ) further includes stopping the recharging step by stopping the recharging mode as described above. After the recharging step ( S902 ) ends, the cycle goes back to the measuring step ( S901 ) until N times of the measuring step ( S901 ) and N times of the recharging step ( S902 ) are performed.

葡萄糖酸內酯(Gluconolactone)+氧化型葡萄糖氧化酶(FADH₂) In the recharging step (S902), the chemical reaction formula is as follows: the following reduction reaction is performed on the working electrode 120: glucose (Glucose) + reduced glucose oxidase (Glucose oxidase) (FAD)

Gluconolactone + oxidative glucose oxidase (FADH ₂ )

還原型葡萄糖氧化酶(FAD)+H₂O₂ Oxidative glucose oxidase (FADH ₂ )+O ₂

Reduced glucose oxidase (FAD)+H ₂ O ₂

H₂O H ₂ O ₂ +2H ⁺ +2e ^-

H ₂ O

2H₂O於對電極130的正電位促使對電極130進行以下氧化反應：2Ag

2Ag⁺+2Cl^-

2AgCl+2e^-其中對電極上的Ag氧化成Ag⁺，與來自生物體內Cl^-或AgCl氧化(或解離)後的Cl^-結合而成AgCl，使得於量測期間T1內被消耗的部分或全部AgCl被回充到對電極上。 O ₂ +4H ⁺ +4e ^-

The positive potential of 2H ₂ O on the counter electrode 130 causes the counter electrode 130 to undergo the following oxidation reaction: 2Ag

2Ag ⁺ +2Cl ^-

2AgCl+2e ^- in which Ag on the counter electrode is oxidized to Ag ⁺ , which is combined with Cl ^- from the biological body or after the oxidation (or dissociation) ^of AgCl to form AgCl, so that part or all of it is consumed during the measurement period T1 AgCl was backcharged onto the counter electrode.

The human body can obtain chloride ions and iodide ions through iodine-doped salt, so the halide ions that can be obtained include at least chloride ions and iodide ions for recharging silver halide.

The following embodiment is for the cycle of N measurement steps ( S901 ) and N recharging steps ( S902 ), wherein the physiological parameter mentioned is preferably the glucose value, and the physiological signal mentioned is preferably the current value. According to some preferred embodiments, each measurement potential difference V1 is applied during the measurement period T1, and each recharge potential difference V2 is applied during the recharge period t2 applied, and the measurement period T1 is a fixed value, which can be within 3 seconds, within 5 seconds, within 10 seconds, within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes a time value. According to some preferred embodiments, a time value within 30 seconds is preferred. The measurement period T1 is a fixed value, and can be 2.5 seconds, 5 seconds, 15 seconds, 30 seconds, 1 minute, 2.5 minutes, 5 minutes, 10 minutes or 30 minutes, preferably 30 seconds. According to some preferred embodiments, each measurement period T1 plus each recharging period t2 is a fixed value. According to some preferred embodiments, each recharge potential 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 ). According to some preferred embodiments, each outputted physiological parameter is obtained by calculating each physiological signal at a single measurement time point in each measurement period T1. According to some preferred embodiments, each outputted physiological parameter is 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, an accumulated value, an average value, a median, an average of medians, and the like. According to some preferred embodiments, by controlling the amount of each recharge to be equal to or not equal to (including approximately similar, greater or less than) each consumption amount, the AgCl amount of the counter electrode is controlled to be within the safety stock range, so that the lower The next physiological signal obtained during a measurement step maintains a stable proportional relationship with the next physiological parameter. According to some preferred embodiments, the step of removing each measurement potential difference V1 is to disconnect the circuit configured to connect the working electrode and the counter electrode, or to set each measurement potential difference V1 to zero. In other words, the power can be turned off, so that the measurement circuit has an open state; or, a voltage of 0 volts can be applied between the working electrode and the counter electrode, and the operation time of any of the two operations is 0.01~0.5 seconds. . Removing the step of measuring the potential difference V1 can prevent the A-shaped physiological signal from being generated. According to some preferred embodiments, the step of removing each recycle potential difference V2 is to disconnect the circuit configured to connect the working electrode and the counter electrode, or set each recycle potential difference V2 to 0.

According to some preferred embodiments, after the sensor is implanted in the human body, a warm-up time is required so that the sensor reaches equilibrium and stability in the body so as to stably present a physiological signal that is positively correlated with the concentration of the analyte. Therefore, in the measurement step ( S901 ), the measurement voltage is continuously applied until the measurement period T1 ends, and the measurement period T1 is controlled so that the physiological signal and the physiological parameter of the analyte achieve a stable proportional relationship. Therefore, 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).

Please refer to FIGS. 7A-7F , FIGS. 10A-10D and FIG. 11 , in the present invention, the reaction current of the counter electrode is measured by applying a voltage to the counter electrode R/C in a period, and the reaction current in the period is calculated by mathematical operation. To know 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 coulomb (C _initial ), the following are all described in terms of amount. The counter electrode R/C contains Ag and AgCl. When the percentage of AgCl (X%AgCl) is known, the percentage of Ag can be calculated (Y% Ag=100%-X% AgCl). In each measurement step ( S901 ), the consumption of AgCl (represented by C _consume ) is defined by calculating the area under the current curve of the working electrode W. The AgCl of the counter electrode R/C has a consumption amount C _consume corresponding to the physiological signal Ia, that is, C _consume =Ia*T1. In each recharging step (S902), the amount of AgCl recharging each time (represented by C _replenish ) is defined by calculating the area under the current curve of the counter electrode R/C, that is, C _replenish =Ib*t2, and t2 is between Between 0 and T2.

The calculation method of the AgCl safety stock amount is described below. In some preferred embodiments, the safety stock interval is represented by the ratio of Ag to AgCl. The present invention uses the coulomb (C) measured by the counter electrode to reflect the ratio of Ag to AgCl. In some preferred embodiments, the ratio of Ag to AgCl is 99.9%: 0.1%, 99%: 1%, 95%: 5%, 90%: 10%, 70%: 30%, 50%: 50% , 40%: 60% or 30: 70%, so that AgCl has a certain amount on the counter electrode without being consumed, so that each physiological signal measurement step can be performed stably. The remaining amount of AgCl is the sum of the recharged amount and the initial amount minus the consumption amount. In some preferred embodiments, the remaining amount of AgCl varies within an interval, that is, the remaining amount of AgCl is controlled within the range of the initial amount plus or minus a specific value (X value), that is, (C _replenish +C _initial ) -C _consume =C _initial ±X, where 0<X<100% C _initial , 10% C _initial <X≦90% C _initial , or 0.5% C _initial <X≦50% C _initial . In some preferred embodiments, the remaining amount of AgCl may gradually decrease, gradually increase, or fluctuate smoothly or arbitrarily within a range but still within the range.

Please refer to FIG. 12 , which shows a method for measuring an analyte according to another embodiment of the present invention. Through this method, the service life of the miniature biosensor can be prolonged and the amount of silver and silver halide materials used in the counter electrode can be reduced. . The miniature biosensor may be, for example, the miniature biosensor shown in FIGS. 2A-2D for implantation subcutaneously to measure the physiological parameters of the analyte associated with the analyte in biological fluids (eg, interstitial fluid). signal. The electrode material of the counter electrode of the micro biosensor includes silver and silver halide. In the embodiment of FIG. 12 , the analyte can be glucose in tissue fluid, the physiological parameter is the glucose value in the human body, and the physiological signal is micro The current value measured by the biosensor. Only one cycle of this embodiment is described below. The method of this embodiment begins with the step of applying a measurement voltage to drive the working electrode to measure a physiological signal for obtaining a physiological parameter, wherein the silver halide is consumed in a specific amount (hereinafter abbreviated as consumption) (S1001).

Then stop applying the measurement voltage (S1002), and use the obtained physiological signal to obtain physiological parameters (S1003). After obtaining physiological parameters, apply recharge A voltage is applied between the counter electrode and the working electrode to drive the counter electrode, so that the amount of silver halide is recharged by a recharge amount (S1004), wherein the sum of the recharge amount and the initial amount minus the consumption amount (that is, the preceding The remaining amount) is controlled within the range of the initial amount plus or minus a specific value. The above control step is achieved by controlling the recharge amount to be equal to or not equal to (including approximately similar, greater or less than) the consumption amount, so as to maintain the amount of silver halide within the safety stock range. According to the reaction formula, the increase or decrease of the molar number of silver halide corresponds to the increase or decrease of the molar number of silver, so for convenience of explanation, the consumption of silver halide corresponds to the increase of simulated silver. In certain preferred embodiments, the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the sum of the amount of silver plus the amount of silver halide (AgCl/Ag+AgCl) is greater than 0 and less than 1, also That is to say, the amount of silver halide in the counter electrode is only one amount, preferably between 0.01-0.99, between 0.1-0.9, between 0.2-0.8, between 0.3-0.7 or between 0.4 -0.6. When the recharge amount is reached, the application of the recharge voltage is stopped (S1005). Then it loops back to step S1001 to execute the next loop.

A specific embodiment of the present invention is described below, taking the lifespan of the biosensor reaching 16 days as an example to calculate the required size of the Ag/AgCl material in the sensing section of the electrode signal, such as the average amount of the analyte measured each time The measurement current was 30 nA, the measurement period (T1) was 30 seconds, and the recharge period (t2) was 30 seconds. The consumption of AgCl required per day (C _consume/day )=1.3mC/day. Assuming that the sensor lifetime requirement is 16 days, the consumption of AgCl required for 16 days is 1.3 x 16=20.8mC.

For example, the length of the counter electrode is 2.5mm, which corresponds to the initial amount of AgCl C _intial =10mC;

(1) In the case of no AgCl recharging, for a sensor service life of 16 days, the required length of the counter electrode is at least: C _16day /C _consume/day =20.8mC/1.3mg/day=16mm

(2) Therefore, without the use of the silver halide recharging method of the present invention, the length of the counter electrode needs to exceed 16 mm to make the life of the sensor reach 16 days.

In this embodiment, without using the silver halide recharge technology of the present invention, the counter electrode signal sensing segment needs to be configured with a correspondingly larger Ag/AgCl material size to achieve a sensor life of 16 days. Through the silver halide recharging method of the present invention, 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 immediately after use), so it can be The amount of Ag/AgCl material in the sensor is reduced, and the sensor is miniaturized. Therefore, the material for the sensing section of the electrode signal does not need to prepare 16 days' worth of AgCl for consumption. For example, the sensor can be used for 16 days by preparing the capacity of AgCl for about 1-2 days, thereby achieving the effect of prolonging the service life of the sensor. The capacity of AgCl for 1 to 2 days also refers to the initial amount of AgCl that is between about 1.3 to 2.6 mC in the counter electrode before leaving the factory or before the first measurement is performed, and the initial amount can also be other more. small or larger range. In other embodiments, different AgCl capacities such as 1 to 5 days, 1 to 3 days, 6 to 24 hours, and 6 to 12 hours can also be prepared. The size of the material of the counter electrode signal sensing segment only needs to have a capacity that allows each glucose measurement step to be performed stably and that the measurement current can be positively correlated with the glucose concentration in the body.

Without the recharge technique using the silver chloride of the present invention, the prior art would allow the sensor to reach the required number of days by increasing the electrode length/area. Taking the prior art as an example, the length of the implanted end of the sensor is about 12 mm. Due to the long implantation length, in order to avoid implanting deep into the subcutaneous tissue, it needs to be implanted subcutaneously at an oblique angle, and the implantation wound is large. For another example, the capacity of AgCl for 1~2 days is about 1.3~2.6mC, and the length of the counter electrode for 1~2 days is 2.5~5mm. In the case of the silver halide recharging method, a counter electrode length of 16 mm is required, which further highlights that the present invention can effectively reduce the required counter electrode size. Through the silver halide recharging method of the present invention, the length of the implanted end can be shortened, for example, the length can be shortened to not more than 10 mm. The lower half of the connection region 117 to the second end 114 of the miniature biosensor 100 disclosed in FIGS. 2A-2C of the present invention belong to the short implanted end 118 (as shown in FIGS. 2A and 2B ), and the short implanted end The implantation depth of 118 should at least meet the depth where the dermis layer can measure the tissue fluid glucose. Through the silver halide recharging method of the present invention, the longest side of the short implantation end 118 is not greater than 6 mm, so that the micro biosensor 100 can be used. It is 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 118 is preferably no greater than 5mm, 4.5mm, 3.5mm or 2.5mm. The short implanted end 118 of the present invention includes a signal sensing segment 132 of the counter electrode, and the longest side of the signal sensing segment 132 is not greater than 6 mm, preferably 2-6 mm, 2-5 mm, 2-4.5 mm, 2-3.5 mm mm, 0.5-2mm, 0.2-1mm.

Therefore, compared with the recharge technology without the silver halide of the present invention, the recharge method of the silver halide of the present invention can effectively prolong the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode. Therefore, the size of the counter electrode signal sensing segment can be reduced. The sensor can be miniaturized and biotoxicity can be reduced by reducing the use of Ag/AgCl material on the counter electrode. In addition, the reduction of the electrode size especially refers to the shortening of the length of the implantation end of the sensor, thus reducing the pain of the user during implantation.

Example II

Please refer to FIGS. 13A and 13B , which are schematic views of the front and the back of the first embodiment of the miniature biosensor of the present invention. The miniature 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 (eg 13C). The material of the substrate 310 can be any known suitable material The material used for the electrode substrate preferably has flexibility and insulation properties, such as but not limited to: polyester (Polyester), polyimide (Polyimide) and other polymer materials, the aforementioned polymer materials can be used alone or mixed. Multiple uses. The substrate 310 has a surface 311 (ie, a first surface), an opposite surface 312 (ie, a second surface) opposite to the surface 311 , a first end 313 and a second end 314 , and the substrate 310 is divided into three regions, which are close to each other. The signal output area 315 of the first end 313 , the sensing area 316 near the second end 314 , and the connection area 317 located 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 segment 322 of the sensing region 316 of the .

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 segment 332 located in the sensing region 316 of the substrate 310 and the auxiliary electrode 340 includes a signal sensing segment 342 located in the sensing region 316 of the substrate 310 . The sensing area 316 of the miniature biosensor 300 can be implanted subcutaneously so that the signal sensing section 322 can measure the physiological signal associated with the analyte in the biological fluid, and the physiological signal will be transmitted to the signal output section 321, and then sent to the signal output section 321. The signal output section 321 is sent to the processor 210 to obtain physiological parameters. In addition to being obtained from the sensing unit 200, the physiological parameter can also be obtained by transmitting it to the user device 20 through wireless/wired communication, such as a commonly used user device 20 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, wherein the silver halide is preferably silver chloride (Silver Chloride) or silver iodide (Silver Iodine), so that the counter electrode 330 can also function as a reference electrode ,Right now The counter electrode 330 of the present invention can (1) form an electronic circuit with the working electrode 320, so that the current on the working electrode 320 is smooth 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. In order to further reduce the cost and improve the biocompatibility of the biosensor of the present invention, the silver/silver halide can be mixed with carbon. The 330 can stably perform the set measurement action. The outermost surface of the part of the counter electrode 330 can also be covered with a conductive material to prevent the silver halide from dissociating, thereby protecting the counter electrode 330, wherein the conductive material is mainly selected from the conductive material that does not affect the measurement performance of the working electrode, such as The conductive material is carbon.

In another embodiment, the biosensor is not limited to a wire-type or stacked-type electrode structure.

In another embodiment of the invention, 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. During the initial recharge period after subcutaneous implantation of the biosensor into the patient and before the first measurement is taken, the counter electrode 330 can be recharged with an initial amount of an initial amount of silver coated on the counter electrode 330 via oxidation silver halide.

The auxiliary electrode 340 forms an electronic circuit with the counter electrode 330 during the recharging step, so that the current on the counter electrode 330 is smooth, so as to ensure that the oxidation reaction occurs on the counter electrode 320. The working electrode 320 has a lower sensitivity to hydrogen peroxide than materials such as carbon.

The chemical reagent 350 covers at least the signal sensing segments 322, 332, and 342 of each electrode. In another embodiment, the chemical reagent 350 covers at least the working electrode 320 The signal sensing segment 322 (not shown in the figure). That is, the counter electrode 330 may not be covered by the chemical reagent 350 . The sensing area 316 of the miniature biosensor 300 can be implanted subcutaneously so that the signal sensing section 322 of the working electrode 320 can measure the physiological signal associated with the analyte in the biological fluid, and the physiological signal will be transmitted to the working electrode 320 The signal output section 321 is sent to the processor 210 by the signal output section 321 to obtain the physiological parameters. In addition, the physiological parameters can also be obtained from the user device 20 through wireless/wired communication in addition to being obtained from the sensing unit 200 .

Please refer to FIG. 13C , which is a schematic cross-sectional view along line AA′ in FIG. 13A , where line AA′ is a section line from the sensing region 316 of the micro biosensor 300 . In FIG. 13C , 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 side surface 312 of the substrate 310 , and the surfaces of the working electrode 320 , the counter electrode 330 and the auxiliary electrode 340 are covered with chemical reagents 350. Substantially the chemical reagent 350 covers at least part of the surface of the working electrode 320 . The micro biosensor 300 of the present invention performs the measurement step during the measurement and the recharge step during the recharge. When the measurement step is performed, the voltage of the working electrode 320 is higher than the voltage of the counter electrode 330, so that the current flows from the working electrode 320 to the direction of the counter electrode 330, thereby causing the working electrode 320 to undergo an oxidation reaction (ie, the working electrode 320, chemical reagents 350 and the electrochemical reaction between the analyte) to measure the physiological signal, the counter electrode 330 undergoes a reduction reaction, the silver halide (AgX) in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁻ ). Since the silver halide in the counter electrode 330 is consumed, it is necessary to recharge the silver halide in the counter electrode 330 for the next measurement step. When the recharging step is performed, 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 auxiliary electrode 340, and then the counter electrode 330 is oxidized to cause the silver to react with the halide ions in the living body. Or combined to recharge silver halide, the detailed measurement steps and recharge steps are shown in Figure 11.

Please refer to FIG. 14A , which is a schematic cross-sectional view of the second embodiment of the miniature biosensor of the present invention. In FIG. 14A , the working electrode 320 and the auxiliary electrode 340 of the present invention can be arranged on the surface 311 of the substrate 310 , the counter electrode 330 is arranged 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 chemical reagent 350. In this embodiment, when the measurement step is performed, the current flows from the working electrode 320 to the direction of the counter electrode 330, so that the working electrode 320 undergoes an oxidation reaction to measure the physiological signal, and the silver halide in the counter electrode 330 is consumed to Dissociated into silver (Ag) and halide ions (X ^- ). When performing the recharging step, the current flows from the counter electrode 330 to the direction of 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.

Please refer to FIG. 14B , which is a schematic cross-sectional view of the third embodiment of the miniature biosensor of the present invention. In this embodiment, 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. In FIG. 14B, 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 is disposed on the opposite side surface 312 of the substrate 310, and 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 . During the measuring step, the first working electrode 323 or the second working electrode 324 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 323 or the second working electrode 324 helps to recharge the electrode 330 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 direction of the opposite electrode 330 , thereby causing the first working electrode 323 or the second working electrode 324 to generate The oxidation reaction is used to measure the physiological signal, and the silver halide in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁻ ). When performing the recharging step, the current flows from the counter electrode 330 to the first working electrode 323 or the second working electrode 324 , and then the counter electrode 330 undergoes an oxidation reaction to combine silver with halide ions to recharge the silver halide.

Please refer to FIG. 14C , which is a schematic cross-sectional view of the fourth embodiment of the miniature biosensor of the present invention. In this embodiment, 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. In FIG. 14C, the first working electrode 323 is disposed on the surface 311 of the substrate 310, the counter electrode 330 and the second working electrode 324 are disposed on the opposite side surface 312 of the substrate 310, and 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 . In this embodiment, the area of the first working electrode 323 can be increased to serve as the measurement electrode, and the area of the second working electrode 324 can be decreased to serve as the recharge electrode. Therefore, in the measurement step, the first working electrode is 323 to measure the physiological signal, and during the recharging step, the second working electrode 324 helps the electrode 330 to recharge with silver halide. Therefore, in this embodiment, when the measurement step is performed, the current flows from the first working electrode 323 to the direction of the counter electrode 330 , thereby causing the first working electrode 323 to undergo an oxidation reaction to measure physiological signals. The silver halide is consumed and dissociated into silver (Ag) and halide ions (X ^- ). When the recharging step is performed, the current flows from the counter electrode 330 to the direction of 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.

Please refer to FIG. 14D , which is a schematic cross-sectional view of the fifth embodiment of the miniature biosensor of the present invention. The fifth embodiment adds one working electrode to the first embodiment, that is, in the fifth embodiment, the micro biosensor 300 of the present invention has two working electrodes, which are the first working electrode 323 and the second working electrode respectively. 324 , a counter electrode 330 and an auxiliary electrode 340 . In FIG. 14D, 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 side surface 312 of the substrate 310, and the first working electrode 323 and the second working electrode The surfaces of the electrode 324 , the counter electrode 330 and the auxiliary electrode 340 are covered with a chemical reagent 350 . During the measuring step, the first working electrode 323 or the second working electrode 324 can be selected to measure the physiological signal, and during the recharging step, the auxiliary electrode 340 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 direction of the opposite electrode 330 , thereby causing the first working electrode 323 or the second working electrode 324 to generate The oxidation reaction is used to measure the physiological signal, and the silver halide in the counter electrode 330 is consumed and dissociated into silver (Ag) and halide ions (X ⁻ ). When performing the recharging step, the current flows from the counter electrode 330 to the direction of 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.

Please refer to FIG. 14E , which is a schematic cross-sectional view of the sixth embodiment of the miniature biosensor of the present invention. In this embodiment, the micro biosensor 300 of the present invention may have three working electrodes, namely 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. In FIG. 14E , 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 third working electrode 325 are disposed on the opposite surface 312 of the substrate 310 , and the first working electrode 323 , the second working electrode 325 The surfaces of the second working electrode 324 , the third working electrode 325 and the counter electrode 330 are covered with chemical reagents 350 . During the measurement step, the first working electrode 323, the second working electrode 324 or the third working electrode 325 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 323, the second working electrode 323 and the second working electrode can also be selected. Electrode 324 or third working electrode 325 assists in recharging electrode 330 with silver halide. Therefore, in this embodiment, when the measurement step is performed, the current flows from the first working electrode 323 , the second working electrode 324 or the third working electrode 325 to the direction of the opposite electrode 330 , thereby causing the first working electrode 323 , 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 ⁻ ). When the recharging step is performed, current flows from the counter electrode 330 to the direction of 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 to combine silver and halide ions to return Filled with silver halide.

Please refer to FIG. 14F , which is a schematic cross-sectional view of the seventh embodiment of the miniature biosensor of the present invention. The seventh embodiment is a modification of the electrode configuration of the sixth embodiment. In this embodiment, as shown in FIG. 14F , 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 side surface 312 of the substrate 310 . , and 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 . During the measurement step, the first working electrode 323, the second working electrode 324 or the third working electrode 325 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 323, the second working electrode 323 and the second working electrode can also be selected. Electrode 324 or third working electrode 325 assists in recharging electrode 330 with silver halide. Therefore, in this embodiment, when the measurement step is performed, the current flows from the first working electrode 323 , the second working electrode 324 or the third working electrode 325 to the direction of the opposite electrode 330 , thereby causing the first working electrode 323 , 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 ⁻ ). When the recharging step is performed, current flows from the counter electrode 330 to the direction of 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 to combine silver and halide ions to return Filled with silver halide.

Please refer to FIG. 14G , which is a schematic cross-sectional view of the eighth embodiment of the miniature biosensor of the present invention. The difference compared to FIG. 14D is that the second working electrode 324 is U-shaped. In this eighth embodiment, 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 disposed around the side of the first working electrode 323 . In this embodiment, when the measurement step is performed, the current flows from the first working electrode 323 to the direction of 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 consumed and dissociated into silver (Ag) and halide ions (X ⁻ ). When performing the recharging step, the current flows from the counter electrode 330 to the direction of 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 detailed electrode stacks in FIGS. 13C-14G above are omitted, and only the electrode positions are shown.

In any of the above embodiments, 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 aforementioned elements, or derivatives of the aforementioned elements (such as alloys, oxides or metal compounds, etc.), preferably, the working electrode 320 and the first working electrode 323 The materials are precious metals, derivatives of precious metals or combinations of the foregoing. More preferably, the working electrode 320 and the first working electrode 323 are platinum-containing materials. The second working electrode 324 and the third working electrode 325 can also use the elements or derivatives thereof exemplified as the working electrode 320 and the first working electrode 323 described above. In another embodiment, the electrode materials of the second working electrode 324 and the third working electrode 325 are selected from materials with lower sensitivity to hydrogen peroxide than that of the first working electrode 323, such as carbon.

Since 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 conventional counter electrode and a reference electrode at the same time, that is, the counter electrode 330 of the present invention can (1) and the working electrode 320 An electronic circuit is formed to make the current flow on the working electrode 320 to ensure that the electrochemical reaction occurs on the working electrode 320; (2) an electronic circuit is formed with the auxiliary electrode 340 to make the current flow on the counter electrode 330 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 different from the conventional three-electrode system.

When the electrode material of the auxiliary electrode 340 of the present invention is covered with platinum, the auxiliary electrode 340 can also be used as an electrode for measuring physiological signals.

In any of the above embodiments, in order to prevent wire breakage due to excessive chlorination of the silver electrode material, a layer of conductive material (such as carbon) may also be added between the opposite surface 312 of the substrate 310 and the silver of the counter electrode 330 . However, if the bottom layer of the counter electrode 330 is carbon, the resistance at the switch will be too high. Therefore, a conductive layer, such as silver, can be added between the carbon conductive material and the opposite surface 312 of the substrate 310 to reduce the signal output. The impedance of the terminals makes the counter electrode 330 of the present invention sequentially form a conductive layer, a carbon layer and a silver/silver halide layer from the opposite side surface 312 of the substrate 310 .

Constant voltage circuit switching application

Please refer to FIGS. 15A-15B and 7A-7D, wherein FIG. 15A and FIG. 15B respectively illustrate the constant voltage circuit in the measurement mode and the recharge mode of the present invention, and FIGS. 7A-7D respectively illustrate the constant voltage circuit in different ways Current schematic diagram of alternately performing measurement mode and recharge mode. The measurement mode can be started and stopped by applying and removing the measurement potential difference V1, respectively, and the corresponding current is denoted by Ia. in measurement mode During the measurement period T1, a measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C, so that the voltage of the working electrode W is higher than the voltage of the counter electrode R/C. As shown in FIG. 15A, at this time, switches S1 and S4 are in a closed state, while switches S2 and S3 are in an open state, the working electrode W is +V1, the counter electrode R/C is grounded, and the auxiliary electrode Aux is in an open state, so that the work The electrode W performs oxidation reaction, and performs electrochemical reaction with chemical reagents and analytes to output a physiological signal Ia, and the AgCl of the electrode R/C has a consumption corresponding to the physiological signal Ia. As shown in FIGS. 7A-7D, between the plurality of measurement periods T1 is a period T2 in which no measurement is performed. In some preferred embodiments, T2 is a fixed value.

The recharge mode can be started and stopped by applying the recharge potential V2 and removing the recharge potential V2, respectively, and the corresponding current is denoted by Ib. V2 is a fixed value between 0.1V and 0.8V, preferably between 0.2V and 0.5V. In the recharge mode, the recharge potential difference V2 is applied 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 auxiliary electrode Aux Voltage of electrode Aux. As shown in Figure 15B, at this time, switches S1 and S4 are in an open state, while switches S2 and S3 are in a closed state, the working electrode W is in an open state, the counter electrode R/C is +V2, and the auxiliary electrode Aux is grounded, so that the counter electrode is in an open state. The Ag on the R/C undergoes an oxidation reaction, and the AgCl on the counter electrode R/C is recharged to a recharge amount. The recharge potential difference 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 symbol "C"), so the consumption of AgCl in the measurement mode is Ia*Tl, and the return of AgCl in the recharge mode is The charge is Ib*t2. Therefore, the recharge amount of AgCl can be controlled by adjusting the application time t2 of the recharge potential difference V2. In other words, on the premise that the AgCl on the counter electrode R/C is kept within the safety stock, the recharge amount can be made equal to or not equal to (including approximately similar, greater or less than) consumption.

In FIGS. 7A-7D, the horizontal axis is time, the line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the recharge potential difference V2. Referring to FIG. 7A , in a preferred embodiment, both V2 and T2 are fixed values, and the application time t2 of V2 (ie, the recharging period) is a variable value. The recharging period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in Figure 7A, t2 may 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 long time to keep the AgCl on the counter electrode R/C within the safety stock. For example, the amount of AgCl recharged during t2'' will be greater than the amount of AgCl recharged during t2'.

Referring to FIG. 7B, in another preferred embodiment, V2, T2 and t2 are all fixed values, where t2=T2. That is to say, the measurement mode and the recharge mode alternate seamlessly, and the period when no measurement is performed is the recharge period. 7C and 7D, in some preferred embodiments, V2, T2 and t2 are all fixed values, wherein t2 is a fixed value greater than 0 and less than T2, such as T2, 2/5 when t2=1/2 of T2, 3/5 of T2, etc. The difference between Fig. 7C and Fig. 7D is that in Fig. 7C, after each measurement mode ends, after a buffer time (buffer time = T2-t2), the recharge mode starts; in Fig. 7D, each measurement mode ends The recharge mode starts immediately without buffering time, and there is a period of time between the end of each recharge mode and the start of the next measurement mode. In certain preferred embodiments, t2 is less than T2, and t2 can be any time period during T2.

Please refer to FIGS. 7E and 7F , which are schematic diagrams of currents in which the constant voltage circuit of the present invention alternately performs the measurement mode and the recharge mode in different ways. In FIGS. 7E and 7F , the horizontal axis is time, the vertical axis is current, and the curve represents the physiological parameter value curve converted from the measured physiological signal Ia. In these two embodiments, similar to FIG. 7A, V2 and T2 are fixed values, and t2 is a fluctuating value during the recharging period. In Figures 7E and 7F, white under the curve The colored area represents the consumption of AgCl in the measurement mode (Ia*Tl), and the area of the diagonal line represents the recharged amount of AgCl in the recharge mode (Ib*t2). As can be seen from the figure, in order to make Ib*t2 close to Ia*T1 or within a certain range of Ia*T1, the recharge period t2 is between 0 and T2 according to the measured physiological signal Ia and the measurement period T1. Dynamic adjustment between. According to needs, the recharge mode can be selected to be performed in the first stage (as shown in FIG. 7E ) or the latter stage (as shown in FIG. 7F ) during the period (T2) when the measurement mode is not executed.

Constant current circuit switching application with segment switching

Please refer to FIGS. 8A-8B and FIGS. 10A-10C, wherein FIG. 8A and FIG. 8B respectively show the constant current circuit with segment switching in the measurement mode and the recharge mode of the present invention, and FIGS. 10A-10C show the Three voltage schematic diagrams of the constant current circuit alternately performing measurement mode and recharge mode in different ways. The measurement mode can be started and stopped by applying and removing the measurement potential difference V1, respectively, and the corresponding current is denoted by Ia. In the measurement mode, the measurement potential difference V1 is applied between the working electrode W and the counter electrode R/C for the measurement period T1. As shown in FIG. 8A , switches S1 and S4 are in a closed state at this time, while other switches are in an open state, the working electrode W is +V1, the counter electrode R/C is grounded, and the auxiliary electrode Aux is in an open state, so that the working electrode is in an open state. W carries out oxidation reaction, and carries out electrochemical reaction with chemical reagent and analyte to output physiological signal Ia, meanwhile, AgCl of counter electrode R/C has consumption corresponding to the physiological signal Ia. As shown in FIGS. 110A-10C, between the plurality of measurement periods T1 is a period T2 in which no measurement is performed. In some preferred embodiments, T2 is a fixed value.

The recharge mode can be started and stopped by applying the recharge potential V2 (V2 is a variable value) and removing the recharge potential V2, respectively, and the corresponding current is represented by Ib. In the recharge mode, the recharge potential difference V2 is applied between the auxiliary electrode Aux and the counter electrode R/C for the recharge period t2 (t2 is between 0 and T2). As shown in Figure 8B, at this time the switch S1 and S4 are in the open state, at least one switch corresponding to S2 and I_F1 to I_Fn is in the closed state (the switches corresponding to I_F1 and I_F3 are exemplarily shown in the closed state in the figure), the working electrode W is in the open state, and the auxiliary electrode Aux is in the open state. For grounding, the counter electrode R/C is +V2, so that the Ag on the counter electrode R/C is oxidized, and then AgCl is recharged. In the recharge mode, according to the magnitude of the physiological signal Ia and the measurement period T1, at least one switch corresponding to I_F1 to I_Fn can be selectively switched to output a fixed current Ib, and AgCl can be controlled by regulating the application time t2 of the potential difference V2 the recharge amount. In other words, on the premise that the AgCl on the counter electrode R/C is kept within the safety stock, the recharge amount can be made equal to or not equal to (including approximately similar, greater or less than) consumption.

Constant current circuit switching application of stepless switching

Please refer to FIGS. 9A-9B and FIGS. 10A-10C, wherein FIG. 9A and FIG. 9B respectively illustrate the stepless switching constant current circuit in the measurement mode and the recharge mode according to the present invention. The measurement mode and the 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 this embodiment is in the recharge mode, which can be based on the physiological signal Ia , through the control of a digital-to-analog converter (DAC) to output a fixed current Ib, and to control the recharge amount of AgCl by regulating the application time t2 of the potential difference V2. In other words, on the premise that the AgCl on the counter electrode R/C is kept within the safety stock, the recharge amount can be made equal to or not equal to (including approximately similar, greater or less than) consumption.

10A-10C, the horizontal axis is time, and the vertical axis is current, wherein the line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the recharge potential difference V2. Referring to FIG. 10A , in a preferred embodiment, T2 is a fixed value, and the application time t2 of V2 and V2 (ie, the recharging period) is a variable value. The recharging period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in Figure 10A, t2 may be t2', t2'', or t2'''.... Change 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 long time to keep the AgCl on the counter electrode R/C within the safety stock.

Please refer to FIG. 10B , in another preferred embodiment, V2 is a variable value, T2 and t2 are fixed values, and t2 is a fixed value greater than 0 and less than T2, such as T2, 2/ T2 of 5, T2 of 3/7, etc. In this embodiment, V2 is dynamically adjusted according to the consumption of AgCl in the physiological signal measurement step (ie, 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, and the circuit has n fixed current sources and n switches, and each fixed current source corresponds to one switch respectively. In the recharge mode, according to the consumption of AgCl, at least one switch among the n switches is selected to be turned on (even if the switch is in a closed state) to output a fixed current value. When the recharge period t2 is a fixed value, the recharge amount of AgCl can be controlled by selecting different fixed current outputs.

Referring to FIG. 10C , in another preferred embodiment, V2 is a variable value, and both T2 and t2 are fixed values, where t2=T2. That is to say, the measurement mode and the recharge mode alternate seamlessly, and the period when no measurement is performed is the recharge period.

Compared with the constant current circuit with stepless switching, the constant current circuit with step switching can control multiple current paths through multiple switches, so that it can be recharged with a segmented constant current according to the required current. The method is more energy-saving and can reduce the cost. In addition, whether it is a constant voltage circuit or a constant current circuit, the potential difference can be derived from a DC power source or an AC power source, preferably a DC power source.

7A-7F, FIGS. 8A-8B, FIGS. 9A-9B, and FIGS. 10A-10C are all descriptions of the operation mode of alternating cycles of measurement steps and recharge steps, that is, there is a cycle between each measurement step. AgCl recharge step, this method can better ensure the AgCl Stay within safety stock levels. However, in some preferred embodiments, Y times of AgCl recharge can also be selectively matched during the N times of measurement, where Y≦N, so that the accumulated recharge amount of AgCl can still be kept within the safety stock range Inside. The measurement step and the recharging step do not necessarily need to be performed in an alternate cycle, and a recharging step can be performed after several measurement steps, or a recharging step is performed only after a predetermined measurement time. . For example, a recharging step can be performed after 10 measurements, or a recharging step can be performed after the accumulated measurement time reaches 1 hour.

Please refer to FIG. 10D , which is a schematic diagram of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in a manner similar to FIG. 10C . In FIG. 10D , the curve represents the physiological parameter value curve converted from the measured physiological signal Ia, and similar to FIG. 10C , T2 and t2 are fixed values, and V2 is a variable value. In Fig. 10D, the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the area of the oblique line represents the recharged amount of AgCl in the recharge mode (Ib*t2). As can be seen from the figure, in order to make Ib*t2 close to Ia*T1 or within a certain range of Ia*T1, the recharge potential V2 is dynamically adjusted according to the consumption of AgCl.

In addition, in FIGS. 7E , 7F and 10D , although the output timing of each physiological parameter value output after each execution of the physiological signal measurement step is not shown, the physiological parameter value is not limited to output when the measurement is completed or during the recharge period output, and the AgCl recharging step is not limited to be performed after each physiological parameter is output or after a physiological signal is obtained.

In a two-electrode system including a working electrode W and a counter electrode R/C, the working electrode W must be constantly cyclically switched 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. In contrast, in a three-electrode system comprising the working electrode W, the counter electrode R/C and the auxiliary electrode Aux, the available The measurement step is performed on the circuit between the working electrode W and the counter electrode R/C, and then the recharging step is performed through the circuit between the auxiliary electrode Aux and the counter electrode R/C, thereby avoiding the need for the working electrode W to return to the stable period. The disadvantage is that the recharging step can be carried out immediately after the measuring step.

Please refer to FIG. 11 , which shows a method for measuring an analyte according to an embodiment of the present invention, through which the service life of the micro biosensor can be extended. The miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 13A-14G for implantation subcutaneously to measure the physiological parameters associated with the analyte in biological fluids (eg, interstitial fluid). physiological signals. In the embodiment of FIG. 11 , the analyte may be glucose in the tissue fluid, the physiological parameter is the glucose value in the human body, and the physiological signal is the current value measured by the micro biosensor. In this embodiment, the method for measuring the analyte includes repeatedly and cyclically performing the measuring step ( S901 ) and the recharging 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, a current value), while the AgCl of the electrode has a consumption corresponding to the current value quantity. 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, the glucose value).

葡萄糖酸內酯(Gluconolactone)+氧化型葡萄糖氧化酶(FADH₂) In the measurement step (S901), the chemical reaction formula is as follows: the following oxidation reaction is performed on the working electrode 320: glucose (Glucose) + reduced glucose oxidase (Glucose oxidase, Gox) (FAD)

Gluconolactone + oxidative glucose oxidase (FADH ₂ )

還原型葡萄糖氧化酶(FAD)+H₂O₂ Oxidative glucose oxidase (FADH ₂ )+O ₂

Reduced glucose oxidase (FAD)+H ₂ O ₂

2H⁺+O₂+2e^-於對電極330進行以下還原反應：2AgCl+2e^-

2Ag+2Cl^- H ₂ O ₂

2H ⁺ +O ₂ +2e ^- performs the following reduction reaction on the counter electrode 330: 2AgCl+2e ^-

2Ag+2Cl ^-

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 has a recharging amount corresponding to the consumption. The amount is controlled within the safety stock range. Therefore, 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 in a proportional relationship. may be inversely proportional). In other words, a stable proportional relationship between the next current value and the next glucose value obtained in the next measurement step can be maintained. The recharging step ( S902 ) further includes stopping the recharging step by stopping the recharging mode as described above. After the recharging step ( S902 ) ends, the cycle goes back to the measuring step ( S901 ) until N times of the measuring step ( S901 ) and N times of the recharging step ( S902 ) are performed.

葡萄糖酸內酯(Gluconolactone)+氧化型葡萄糖氧化酶(FADH₂) In the recharging step (S902), the chemical reaction formula is as follows: the following reduction reaction is performed on the auxiliary electrode: glucose (Glucose) + reduced glucose oxidase (Glucose oxidase) (FAD)

Gluconolactone + oxidative glucose oxidase (FADH ₂ )

還原型葡萄糖氧化酶(FAD)+H₂O₂ Oxidative glucose oxidase (FADH ₂ )+O ₂

Reduced glucose oxidase (FAD)+H ₂ O ₂

H₂O H ₂ O ₂ +2H ⁺ +2e ^-

H ₂ O

2H₂O於對電極330的正電位促使對電極330進行以下氧化反應： 2Ag

2Ag⁺+2Cl^-

2AgCl+2e^- O ₂ +4H ⁺ +4e ^-

The positive potential of 2H ₂ O on the counter electrode 330 causes the counter electrode 330 to undergo the following oxidation reaction: 2Ag

2Ag ⁺ +2Cl ^-

2AgCl+2e ^-

Among them, Ag on the counter electrode is oxidized to Ag ⁺ , which combines with Cl ^- or Cl ^- after AgCl oxidation (or dissociation) in the organism to form AgCl, so that part or all of the AgCl consumed in the measurement period T1 is recharged to the counter electrode.

The human body can obtain chloride ions and iodide ions through iodine-doped salt, so the halide ions that can be obtained include at least chloride ions and iodide ions for recharging silver halide.

The following embodiment is for the cycle of N measurement steps ( S901 ) and N recharging steps ( S902 ), wherein the physiological parameter mentioned is preferably the glucose value, and the physiological signal mentioned is preferably the current value. According to some preferred embodiments, each measurement potential difference V1 is applied in the measurement period T1, each recharge potential difference V2 is applied in the recharge period t2, and the measurement period T1 is a fixed value, which can be within 3 seconds, 5 A time value within seconds, within 10 seconds, within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes. According to some preferred embodiments, a time value within 30 seconds is preferred. The measurement period T1 is a fixed value, and can be 2.5 seconds, 5 seconds, 15 seconds, 30 seconds, 1 minute, 2.5 minutes, 5 minutes, 10 minutes or 30 minutes, preferably 30 seconds. According to some preferred embodiments, each measurement period T1 plus each recharging period t2 is a fixed value. According to some preferred embodiments, each recharge potential 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 ). According to some preferred embodiments, each outputted physiological parameter is obtained by calculating each physiological signal at a single measurement time point in each measurement period T1. According to some preferred embodiments, each outputted physiological parameter is 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, an accumulated value, an average value, a median, an average of medians, and the like. According to some preferred embodiments, by controlling the amount of each recharge to be equal to or not equal to (including approximately similar, greater or less than) each The consumption is controlled, and the AgCl amount of the counter electrode is controlled within the safety stock range, so that the next physiological signal obtained in the next measurement step and the next physiological parameter maintain a stable proportional relationship. According to some preferred embodiments, the step of removing each measurement potential difference V1 is to disconnect the circuit configured to connect the working electrode and the counter electrode, or to set each measurement potential difference V1 to zero. In other words, the power can be turned off, so that the measurement circuit has an open state; or, a voltage of 0 volts can be applied between the working electrode and the counter electrode, and the operation time of any of the two operations is 0.01~0.5 seconds. . Removing the step of measuring the potential difference V1 can prevent the A-shaped physiological signal from being generated. According to some preferred embodiments, the step of removing each recycle potential difference V2 is to disconnect the circuit configured to communicate with the auxiliary electrode and the counter electrode, or to set each recycle potential difference V2 to 0.

According to some preferred embodiments, after the sensor is implanted in the human body, a warm-up time is required so that the sensor reaches equilibrium and stability in the body so as to stably present a physiological signal that is positively correlated with the concentration of the analyte. Therefore, in the measurement step ( S901 ), the measurement voltage is continuously applied until the measurement period T1 ends, and the measurement period T1 is controlled so that the physiological signal and the physiological parameter of the analyte achieve a stable proportional relationship. Therefore, 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).

Please refer to FIGS. 7A-7F , FIGS. 10A-10D and FIG. 11 , in the present invention, the reaction current of the counter electrode is measured by applying a voltage to the counter electrode R/C in a period, and the reaction current in the period is calculated by mathematical operation. To know 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 coulomb (C _initial ), the following are all described in terms of amount. The counter electrode R/C contains Ag and AgCl. When the percentage of AgCl (X%AgCl) is known, the percentage of Ag can be calculated (Y% Ag=100%-X% AgCl). In each measurement step ( S901 ), the consumption of AgCl (represented by C _consume ) is defined by calculating the area under the current curve of the working electrode W. The AgCl of the counter electrode R/C has a consumption amount C _consume corresponding to the physiological signal Ia, that is, C _consume =Ia*T1. In each recharging step (S902), the amount of AgCl recharging each time (represented by C _replenish ) is defined by calculating the area under the current curve of the counter electrode R/C, that is, C _replenish =Ib*t2, and t2 is between Between 0 and T2.

The calculation method of the AgCl safety stock amount is described below. In some preferred embodiments, the safety stock interval is represented by the ratio of Ag to AgCl. The present invention uses the coulomb (C) measured by the counter electrode to reflect the ratio of Ag to AgCl. In some preferred embodiments, the ratio of Ag to AgCl is 99.9%: 0.1%, 99%: 1%, 95%: 5%, 90%: 10%, 70%: 30%, 50%: 50% , 40%: 60% or 30: 70%, so that AgCl has a certain amount on the counter electrode without being consumed, so that each physiological signal measurement step can be performed stably. The remaining amount of AgCl is the sum of the recharged amount and the initial amount minus the consumption amount. In some preferred embodiments, the remaining amount of AgCl varies within an interval, that is, the remaining amount of AgCl is controlled within the range of the initial amount plus or minus a specific value (X value), that is, (C _replenishe +C _initial ) -C _consume =C _initial ±X, where 0<X<100% C _initial , 10% C _initial <X≦90% C _initial , or 0.5% C _initial <X≦50% C _initial . In some preferred embodiments, the remaining amount of AgCl may gradually decrease, gradually increase, or fluctuate smoothly or arbitrarily within a range but still within the range.

Please refer to FIG. 12 , which shows a method for measuring an analyte according to another embodiment of the present invention, through which the service life of the miniature biosensor can be prolonged and the amount of silver and silver halide materials used in the counter electrode can be reduced. The miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 13A-13C and 14A-14G for implantation Subcutaneously to measure physiological signals of physiological parameters associated with the analyte in biological fluids (eg, interstitial fluid). The electrode material of the counter electrode of the micro biosensor includes silver and silver halide. In the embodiment of FIG. 12 , the analyte can be glucose in tissue fluid, the physiological parameter is the glucose value in the human body, and the physiological signal is micro The current value measured by the biosensor. Only one cycle of this embodiment is described below. The method of this embodiment begins with the step of applying a measurement voltage to drive the working electrode to measure a physiological signal for obtaining a physiological parameter, wherein the silver halide is consumed in a specific amount (hereinafter abbreviated as consumption) (S1001).

Then stop applying the measurement voltage (S1002), and use the obtained physiological signal to obtain physiological parameters (S1003). After obtaining the physiological parameters, a recharge voltage is applied between the counter electrode and the auxiliary electrode to drive the counter electrode, so that the amount of silver halide is recharged by a recharge amount (S1004), wherein the sum of the recharge amount and the initial amount is reduced. The value of the de-consumption amount (ie, the remaining amount described above) is controlled within the range of the initial amount plus or minus a specific value. The above control step is achieved by controlling the recharge amount to be equal to or not equal to (including approximately similar, greater or less than) the consumption amount, so as to maintain the amount of silver halide within the safety stock range. According to the reaction formula, the increase or decrease of the molar number of silver halide corresponds to the increase or decrease of the molar number of silver, so for convenience of explanation, the consumption of silver halide corresponds to the increase of simulated silver. In certain preferred embodiments, the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the sum of the amount of silver plus the amount of silver halide (AgCl/Ag+AgCl) is greater than 0 and less than 1, also That is to say, the amount of silver halide in the counter electrode is only one amount, preferably between 0.01-0.99, between 0.1-0.9, between 0.2-0.8, between 0.3-0.7 or between 0.4 -0.6. When the recharge amount is reached, the application of the recharge voltage is stopped (S1005). Then it loops back to step S1001 to execute the next loop.

A specific embodiment of the present invention is described below, taking the lifespan of the biosensor reaching 16 days as an example to calculate the required size of the Ag/AgCl material in the sensing section of the electrode signal, such as the average amount of the analyte measured each time The measurement current was 30 nA, the measurement period (T1) was 30 seconds, and the recharge period (t2) was 30 seconds. The consumption of AgCl required per day (C _consume/day )=1.3mC/day. Assuming that the sensor lifetime requirement is 16 days, the consumption of AgCl required for 16 days is 1.3 x 16=20.8mC.

For example, the length of the counter electrode is 2.5mm, which corresponds to the initial amount of AgCl C _intial =10mC;

(3) In the case of no AgCl recharging, for a sensor service life of 16 days, the required length of the counter electrode is at least: C _16day /C _consume/day =20.8mC/1.3mg/day=16mm

(4) Therefore, without the use of the silver halide recharging method of the present invention, the length of the counter electrode needs to exceed 16 mm in order to make the life of the sensor reach 16 days.

In this embodiment, without using the silver halide recharge technology of the present invention, the counter electrode signal sensing segment needs to be configured with a correspondingly larger Ag/AgCl material size to achieve a sensor life of 16 days. Through the silver halide recharging method of the present invention, 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 immediately after use), so it can be The amount of Ag/AgCl material in the sensor is reduced, and the sensor is miniaturized. Therefore, the material for the sensing section of the electrode signal does not need to prepare 16 days' worth of AgCl for consumption. For example, the sensor can be used for 16 days by preparing the capacity of AgCl for about 1-2 days, thereby achieving the effect of prolonging the service life of the sensor. The capacity of AgCl for 1 to 2 days also refers to the initial amount of AgCl that is between about 1.3 to 2.6 mC in the counter electrode before leaving the factory or before the first measurement is performed, and the initial amount can also be other more. small or larger range. Also in other embodiments Different AgCl capacities such as 1~5 days, 1~3 days, 6~24 hours, and 6~12 hours can be prepared. The size of the material of the counter electrode signal sensing segment only needs to have a capacity that allows each glucose measurement step to be performed stably and that the measurement current can be positively correlated with the glucose concentration in the body.

Without the use of the silver chloride recharge technology of the present invention, the prior art would increase the electrode length/area to make the sensor reach the required number of days. Taking the prior art as an example, the length of the implanted end of the sensor is about It is 12mm, because the implantation length is long, and in order to avoid implantation deep into the subcutaneous tissue, it needs to be implanted subcutaneously in an oblique way, and the implantation wound is large. For another example, the capacity of AgCl for 1~2 days is about 1.3~2.6mC, and the length of the counter electrode for 1~2 days is 2.5~5mm. In the case of the charging method, a counter electrode length of 16 mm is required, which further highlights that the present invention can effectively reduce the required counter electrode size. Through the silver halide recharging method of the present invention, the length of the implanted end can be shortened, for example, the length can be shortened to not more than 10 mm. The lower half of the connecting region 317 to the second end 314 of the miniature biosensor 300 of the present invention belongs to the short implant end 318 (as shown in FIGS. 13A and 13B ), and the implant depth of the short implant end 318 needs to be at least The depth of the tissue fluid glucose can be measured to the dermis layer, so the longest side of the short implantation end 318 is not greater than 6 mm, so that the micro biosensor 300 can be partially implanted in the living body in a manner perpendicular to the living body epidermis under the epidermis. The longest side of the short implanted end 318 is preferably no greater than 5mm, 4.5mm or 3.5mm or 2.5mm. The short implanted end of the present invention includes the signal sensing segment 332 of the counter electrode 330, and the longest side of the signal sensing segment 332 is not greater than 6mm, preferably 2-6mm, 2-5mm, 2-4.5mm or 2-3.5mm , 0.5-2mm, 0.2-1mm.

Therefore, compared with the recharging technology without the silver halide of the present invention, the recharging method of the silver halide of the present invention can effectively prolong the service life of the sensor, In addition, the use of Ag/AgCl material on the counter electrode can be greatly reduced, so that the size of the counter electrode signal sensing section can be reduced. The sensor can be miniaturized and biotoxicity can be reduced by reducing the use of Ag/AgCl material on the counter electrode. In addition, the reduction of the electrode size especially refers to the shortening of the length of the implantation end of the sensor, thus reducing the pain of the user during implantation.

Example III

Please refer to FIGS. 18A and 18B , which are schematic views of the front and the back of the first embodiment of the miniature biosensor of the present invention. The miniature 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 disposed on the substrate 410 , and surrounding the first working electrode 420 , the chemical reagent 460 of the second working electrode 430 , the first pair of electrodes 440 and the second pair of electrodes 450 (as shown in FIG. 18C ). The material of the substrate 410 can be any known material suitable for use as an electrode substrate, and preferably has flexibility and insulation properties, such as but not limited to: polyester (Polyester), polyimide (Polyimide) and other polymer materials, The aforementioned polymer materials may be used alone or in combination of two or more. The substrate 410 has a surface 411 (ie, a first surface), an opposite surface 412 (ie, a second surface) opposite to the surface 411 , a first end 413 and a second end 414 , and the substrate 410 is divided into three regions, which are close to each other. 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 located 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 segment 421 located in the signal output area 415 of the substrate 410 , and a first signal sensing segment 422 located in the sensing area 416 of the substrate 410 . The second working electrode 430 includes a second signal output segment 431 located in the signal output region 415 of the substrate 410 and a second signal sensing segment 432 located in the sensing region 416 of the substrate 410 .

The first pair of electrodes 440 and the second pair of electrodes 450 are disposed on the opposite side surfaces 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 segment 441 located in the signal output area 415 of the substrate 410 and a third signal sensing segment 442 located in the sensing area 416 of the substrate 410 , and the second pair of electrodes 450 includes a third signal output segment 442 located in the substrate 410 The fourth signal output section 451 of the signal output area 415 of the 410 and the fourth signal sensing section 452 located in the sensing area 416 of the substrate 410 . Materials on the surfaces of the first pair of electrodes 440 and the second pair of electrodes 450 include silver and silver halide, wherein the silver halide is preferably silver chloride or silver iodine, so that the first The counter electrode 440 and the second counter electrode 450 also function as reference electrodes, that is, the first counter electrode 440 and the second counter electrode 450 of the present invention can (1) form an electronic circuit with the first working electrode 420 or the second working electrode 430 , making the first working electrode 420 or the second working electrode 430 flow current 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. In order to further reduce the cost and improve the biocompatibility of the biosensor of the present invention, the silver/silver halide can be mixed with carbon. It is sufficient that the counter electrode 440 and the second counter electrode 450 can stably perform the set measurement operation. Parts of the surfaces of the first pair of electrodes 440 and the second pair of electrodes 450 may also be covered with conductive materials to prevent the silver halide from dissociating, thereby protecting the first pair of electrodes 440 and the second pair of electrodes 450, wherein the conductive materials are selected The conductive material that does not affect the measurement performance of the working electrode is mainly used, for example, the conductive material is carbon.

In another embodiment, the biosensor is not limited to wire type or stack type electrode structure.

In another embodiment of the invention, 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. During the initial recharge period after subcutaneous implantation of the biosensor into the patient and prior to taking the first measurement, the silver coated on the first pair of electrodes 440 and/or the second pair of electrodes 450 via oxidation, may An initial amount of silver halide is recharged on the first pair of electrodes 440 and/or the second pair of electrodes 450 .

The chemical reagent 460 covers at least the first signal sensing segment 422 of the first working electrode 420 . In another embodiment, the chemical reagent 460 covers at least the first signal sensing segment 422 and the second signal sensing segment 432 of the first working electrode 420 and the second working electrode 430 . In another embodiment, the chemical reagent 460 coats the signal sensing segments 422, 432, 442, 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 miniature biosensor 400 can be implanted subcutaneously so that the first signal sensing segment 422 and the second signal sensing segment 432 can measure the physiological signal associated with the analyte in the biological fluid, and the physiological signal will The signals are respectively sent to the first output section 421 and the second output section 431, and then sent to the processor 210 by the first output section 421 and the second output section 431 to obtain the physiological parameters. In addition to being obtained from the sensing unit 200, the physiological parameter can also be obtained by transmitting it to the user device 20 through wireless/wired communication, such as a commonly used user device 20 such as a smart phone, a physiological signal receiver or a blood glucose meter.

Please refer to FIG. 18C , which is a schematic cross-sectional view taken along the line AA′ in FIG. 18A , wherein the line AA′ is a section line from the sensing region 416 of the micro biosensor 400 . In FIG. 18C , 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 side surface 412 of the substrate 410 , and 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 chemical reagents 460 . Substantially the chemical reagent 460 covers at least a portion of the surface of one working electrode. The micro biosensor 400 of the present invention performs the measurement step during the measurement and the recharge step during the recharge. During the measurement step, the first working electrode 420 or the second working electrode 430 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 420 or the second working electrode 430 helps the first pair of electrodes 440 Or the second pair of electrodes 450 is 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 420 or the second pair of electrodes 450 The 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 (ie, the first working electrode 420 or the second working electrode 430). The electrochemical reaction between the working 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 undergo a reduction reaction. The silver halide in 450 is consumed and dissociated into silver (Ag) and halide ions (X ⁻ ). Since 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 for the next measurement step. When the recharging step is performed, the voltage of the first pair of electrodes 440 or the second pair of electrodes 450 is higher than the voltage of the first pair of electrodes 420 or the second pair of electrodes 430, so that 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 undergo an oxidation reaction to combine silver and halide ions to recharge the silver halide. The detailed measurement steps and return The charging steps are shown in Figure 12.

Please refer to FIG. 19A , which is a schematic cross-sectional view of the second embodiment of the miniature biosensor of the present invention. The second embodiment is a variation of the electrode configuration of the first embodiment. In this embodiment, as shown in FIG. 19A , the first working electrode 420 and the first pair of electrodes 440 of the miniature biosensor 400 of the present invention are disposed on the surface 411 of the substrate 410 , the second working electrode 430 and the second pair of electrodes The electrode 450 is disposed on the opposite side surface 412 of the substrate 410 , 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 . Similarly, during the measurement step, the first working electrode 420 or the second working electrode 430 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 420 or the second working electrode 430 can also be selected to help The first pair of electrodes 440 or the second pair of electrodes 450 is recharged with silver halide. Therefore, in this embodiment, when the measurement step is performed, the current flows from the first working electrode 420 or the second working electrode 430 to 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 undergoes an oxidation reaction to measure physiological signals, and the first pair of electrodes 440 or the second pair of electrodes 450 undergoes 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 halide ions (X ^- ). When the recharging step is performed, 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 recharges the silver halide by combining the silver with the halide ions.

Please refer to FIG. 19B , which is a schematic cross-sectional view of the third embodiment of the miniature biosensor of the present invention. In the third embodiment, the first working electrode 420 of the miniature biosensor 400 of the present invention is disposed 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 disposed on the substrate 410 the opposite side surface 412 of the first working electrode 420, the second working electrode 430, the first pair of electrodes 440 or The surfaces of the second pair of electrodes 450 are covered with chemical reagents 460 . The second working electrode 430 is not only disposed between the two opposite poles, but also can be disposed at the leftmost or rightmost position (not shown in the figure). In this embodiment, during the measurement step, the first working electrode 420 or the second working electrode 430 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 420 or the second working electrode can also be selected. The working electrode 430 assists in recharging the first pair of electrodes 440 or the second pair of electrodes 450 with silver halide.

Please refer to FIG. 19C , which is a schematic cross-sectional view of the fourth embodiment of the miniature biosensor of the present invention. In the fourth embodiment, 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 adjacent to and surrounding On the side of the first working electrode 420 , 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 , and the first pair of electrodes 440 and the surface of the second pair of electrodes 450 is covered with chemical reagent 460 . In this embodiment, during the measurement step, the first working electrode 420 or the second working electrode 430 can be selected to measure the physiological signal, and during the recharging step, the first working electrode 420 or the second working electrode can also be selected Electrode 430 assists in recharging first pair of electrodes 440 or second pair of electrodes 450 with silver halide.

The detailed electrode stacks in FIGS. 18C-19C above are omitted, and only the electrode positions are shown. 18C-19C above substantially cover the surface of at least a portion of the first working electrode 420 with the chemical reagent 460 .

In any of the above embodiments, 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, or derivatives of the foregoing such as alloys, oxides, or gold metal compounds, etc.), preferably, the materials of the first working electrode 420 and the second working electrode 430 are noble metals, derivatives of noble metals or a combination of the foregoing, more preferably, the first working electrode 420 and the second working electrode 430 are Platinum containing material. In another embodiment, the electrode material of the second working electrode 430 is a material with lower sensitivity to hydrogen peroxide than that of the first working electrode 420 , such as carbon.

In any of the above embodiments, in order to prevent wire breakage due to excessive chlorination of the silver electrode material, a layer of silver may also be added between the opposite surface 412 of the substrate 410 and the silver of the first pair of electrodes 440 and the second pair of electrodes 450 Conductive material (eg carbon). However, if the bottom layers of the first pair of electrodes 440 and the second pair of electrodes 450 are made of carbon, the resistance at the switch will be too high. Therefore, a conductive layer can be added between the carbon conductive material and the opposite surface 412 of the substrate 410 For example, silver is used to reduce the impedance of the signal output end, so that the first pair of electrodes 440 and the second pair of electrodes 450 of the present invention are sequentially formed from the opposite surface 412 of the substrate 410 as a conductive layer, a carbon layer and a silver/silver halide layer.

Since the miniature biosensor 400 of the present invention has two working electrodes and two counter electrodes, the miniature biosensor 400 can use, for example, the first working electrode 420 and the first pair of electrodes 440 to perform the measurement step while performing the measurement step. The recharging step is performed using the second working electrode 430 and the second counter electrode 450 . Or use the second working electrode 430 to help the first pair of electrodes 440 or the second pair of electrodes 450 to perform the recharging step while continuously performing the measurement step, eg, using the first working electrode 420 .

Constant voltage circuit switching application

Please refer to FIGS. 20A-20C , which respectively illustrate the constant voltage circuits in the present invention that can perform the measurement mode and the recharge mode in different ways. The measurement mode can be started and stopped by applying and removing the measurement potential difference V1, respectively, and the corresponding current is denoted by Ia. In the constant voltage circuit, the first working electrode W1 is switched by Controlled by 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, and the second pair of electrodes R/C2 is controlled by switches S3 and S4. Through the control of the above-mentioned switches, there can be various flexible operation modes, which are described in the following examples.

As shown in FIG. 20A , in the measurement mode, a 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 working electrode W1. The voltage of a pair of electrodes R/C1. At this time, the switches S1 and S6 are in a closed state, while the switch S5 is in an open state, the first working electrode W1 is +V1, and the first pair of electrodes R/C1 is grounded, so that the first working electrode W1 is oxidized and reacted with chemical reagents. Electrochemical reaction is performed with the analyte to output the physiological signal Ia, and the AgCl of the first pair of electrodes R/C1 has a consumption corresponding to the physiological signal Ia. In the recharge mode, it can be started and stopped by applying the recharge potential V2 and removing the recharge potential V2, respectively, and the corresponding current is denoted by Ib. V2 is a fixed value between 0.1V and 0.8V, preferably between 0.2V and 0.5V. In the recharge mode, a recharge potential difference V2 is applied between the second working electrode W2 and the second pair of electrodes R/C2 for a continuous recharge period t2, so that the voltage of the second pair of electrodes R/C2 is higher than that of the second working electrode W2 voltage. At this time, the switches S4 and S7 are in the open circuit state, while the switches S2 and S3 are in the closed circuit 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 is grounded. 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 difference 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 symbol "C"), so the consumption of AgCl in the measurement mode is Ia*Tl, and the return of AgCl in the recharge mode is The charge is Ib*t2. Therefore, the recharge amount of AgCl can be controlled by adjusting the application time t2 of the recharge potential difference V2. In other words, in On the premise that the AgCl on the first or second pair of electrodes R/C1 or R/C2 is kept within the safety stock, the recharge amount can be equal to or not equal to (including approximately similar, greater or less than) consumption. FIG. 20A illustrates the overlapping of the timing of the simultaneous measurement mode and the timing of the recharge mode. The control of the above-mentioned switches can also be converted into other forms of circuits to have a variety of flexible operation modes. In some preferred embodiments, the measurement The mode timing and the recharging mode timing may be partially overlapped or non-overlapping in addition to being performed at the same time.

Figures 20B-20C are similar to Figure 20A, except that Figure 20B shows an embodiment using W2 and R/C2 for measurement and W1 and R/C1 for recharging; and Figure 20C shows an embodiment using W1 and R/C1 Example of R/C2 for measurement and recharge with W2 and R/C1. In some preferred embodiments, the constant voltage circuit alternately switches to FIG. 20A and FIG. 20B and repeats the cycle. In some preferred embodiments, the constant voltage circuit alternately switches to FIG. 20A and FIG. 20C and repeats the cycle. In the manner described above, the first pair of electrodes R/C1 and the second pair of electrodes R/C2 can be consumed and recharged alternately so that the AgCl on both pairs of electrodes can be kept within the safety stock. In some preferred embodiments, the constant voltage circuit may have a third voltage source to control the recharge voltage difference to be different from the measurement voltage difference.

By controlling the application of the voltage difference and the switching of the switches, the constant voltage circuit shown in FIGS. 20A-20C can also alternately perform the measurement mode and the recharge mode. 7A-7D are schematic diagrams of currents in which the constant voltage circuit alternately performs the measurement mode and the recharge mode in different ways. As shown in the figure, between the plurality of measurement periods T1 is a period T2 in which no measurement is performed. In some preferred embodiments, T2 is a fixed value. In FIGS. 7A-7D, the horizontal axis is time, the line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the recharge potential difference V2. Referring to FIG. 7A, in a preferred embodiment, V2 and T2 are both fixed values, and the application time t2 of V2 (ie, the recharge period) is variable value. The recharging period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in Figure 7A, t2 may 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 long time to keep the AgCl on the first pair of electrodes R/C1 within the safety stock. For example, the amount of AgCl recharged during t2'' will be greater than the amount of AgCl recharged during t2'.

Referring to FIG. 7B, in another preferred embodiment, V2, T2 and t2 are all fixed values, where t2=T2. That is to say, the measurement mode and the recharge mode alternate seamlessly, and the period when no measurement is performed is the recharge period. 7C and 5D, in some preferred embodiments, V2, T2 and t2 are all fixed values, wherein t2 is a fixed value greater than 0 and less than T2, such as T2, 2/5 when t2=1/2 of T2, 3/5 of T2, etc. The difference between Fig. 7C and Fig. 7D is that in Fig. 7C, after each measurement mode ends, after a buffer time (buffer time = T2-t2), the recharge mode starts; in Fig. 7D, each measurement mode ends The recharge mode starts immediately without buffering time, and there is a period of time between the end of each recharge mode and the start of the next measurement mode. In certain preferred embodiments, t2 is less than T2, and t2 can be any time period during T2.

Please refer to FIGS. 7E and 7F , which are schematic diagrams of currents in which the constant voltage circuit of the present invention alternately performs the measurement mode and the recharge mode in different ways. In FIGS. 7E and 7F , the horizontal axis is time, the vertical axis is current, and the curve represents the physiological parameter value curve converted from the measured physiological signal Ia. In these two embodiments, similar to FIG. 7A, V2 and T2 are fixed values, and t2 is a fluctuating value during the recharging period. In Figures 7E and 7F, the white area under the curve represents the consumption of AgCl in the measurement mode (Ia*Tl), and the area of the slanted line represents the recharged amount of AgCl in the recharge mode (Ib*t2). As can be seen from the figure, in order to make Ib*t2 close to Ia*T1 or within a certain range of Ia*T1, the recharge period t2 is based on the measured physiological signal. The number Ia and the measurement period T1 are dynamically adjusted between 0 and T2. According to needs, the recharge mode can be selected to be performed in the first stage (as shown in FIG. 7E ) or the latter stage (as shown in FIG. 7F ) during the period (T2) when the measurement mode is not executed.

Constant current circuit switching application with segment switching

Please refer to FIG. 21 , which shows a constant current circuit capable of switching between the measurement mode and the recharge mode according to the present invention. The manner in which the constant current circuit with segment switching repeats the cycle to perform the measurement mode and the recharge mode is similar to that shown in FIG. 20A , so it is not repeated here. The main difference is that the recharge mode can be started and stopped by applying the recharge potential V2 (V2 is a variable value) and removing the recharge potential V2, respectively, and the corresponding current is denoted by Ib. Taking the recharge mode performed on the second working electrode W2 and the second pair of electrodes R/C2 as an example, the recharge potential difference V2 is applied between the second working electrode W2 and the second pair of electrodes R/C2 for the recharge period t2. At this time, the switches S2 and S3 are in the closed circuit 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 circuit state, the second working electrode W2 is grounded, and the second pair of electrodes R/C2 is + V2, so that Ag on the second pair of electrodes R/C2 is oxidized, and AgCl is recharged. In this embodiment, the constant current circuit with stage switching can selectively switch to I_F1, I_F2, I_F3...I_Fn by controlling a plurality of switches corresponding to I_F1 to I_Fn to adjust the required regenerative charge level difference V2 and output the current Ib . In the recharge mode, the recharge amount of AgCl can be controlled by adjusting the recharge potential difference V2 and the application time t2 according to the magnitude of the physiological signal Ia and the measurement period T1. In other words, on the premise that the AgCl on the first or second pair of electrodes R/C1 or R/C2 is kept within the safety stock, the recharge amount can be equal to or not equal to (including approximately similar, greater or less than) consumption quantity. In another embodiment, part of the constant current circuit 61 may be configured to connect the second pair of electrodes R/C2.

Constant current circuit switching application of stepless switching

Please refer to FIG. 22 , which shows a constant current circuit capable of continuously switching between the measurement mode and the recharge mode in the present invention. The measurement mode of the stepless switching constant current circuit is similar to that of FIGS. 20A-20C, and the recharge mode is similar to that of FIG. 21, so it is not repeated here. The difference between the embodiment of FIG. 22 and the embodiment of 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.

Please refer to FIGS. 10A-10C , which are schematic diagrams of voltages in which the constant current circuit of the present invention alternately performs the measurement mode and the recharge mode in different ways. In FIGS. 10A-10C , the horizontal axis is time, the line of V1 represents the application and removal of the measurement potential difference V1 , and the line of V2 represents the application and removal of the recharge potential difference V2 . Referring to FIG. 10A , in a preferred embodiment, T2 is a fixed value, and the application time t2 of V2 and V2 (ie, the recharging period) is a variable value. The recharging period t2 is dynamically adjusted between 0 and T2 according to the physiological signal Ia measured in the measurement mode and the measurement period T1. As shown in Figure 10A, t2 may 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 long time to keep the AgCl on the first pair of electrodes R/C1 within the safety stock.

Please refer to FIG. 10B , in another preferred embodiment, V2 is a variable value, T2 and t2 are fixed values, and t2 is a fixed value greater than 0 and less than T2, such as T2, 2/ T2 of 5, T2 of 3/7, etc. In this embodiment, V2 is dynamically adjusted according to the consumption of AgCl in the physiological signal measurement step (ie, 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, and the circuit has n fixed current sources and n switches, and each fixed current source corresponds to one switch respectively. In the recharge mode, according to the consumption of AgCl, at least one switch among the n switches is selected to be turned on (even if the switch is in a closed state) to output the A fixed current value is output. When the recharge period t2 is a fixed value, the recharge amount of AgCl can be controlled by selecting different fixed current outputs.

Referring to FIG. 10C , in another preferred embodiment, V2 is a variable value, and both T2 and t2 are fixed values, where t2=T2. That is to say, the measurement mode and the recharge mode alternate seamlessly, and the period when no measurement is performed is the recharge period.

Compared with the constant current circuit with stepless switching, the constant current circuit with step switching can control multiple current paths through multiple switches, so that it can be recharged with a segmented constant current according to the required current. The method is more energy-saving and can reduce the cost. In addition, whether it is a constant voltage circuit or a constant current circuit, the potential difference can come from a DC power source or an AC power source, preferably a DC power source.

7A-7F, FIGS. 8A-8B, FIGS. 9A-9B, and FIGS. 10A-10C are all descriptions of the operation mode of alternating cycles of measurement steps and recharge steps, that is, there is a cycle between each measurement step. The AgCl recharge step, this method can preferably ensure that the AgCl is kept within the safety stock. However, in some preferred embodiments, Y times of AgCl recharge can also be selectively matched during the N times of measurement, where Y≦N, so that the accumulated recharge amount of AgCl can still be kept within the safety stock range Inside. The measurement step and the recharging step do not necessarily need to be performed in an alternate cycle, and a recharging step can be performed after several measurement steps, or a recharging step is performed only after a predetermined measurement time. . For example, a recharging step can be performed after 10 measurements, or a recharging step can be performed after the accumulated measurement time reaches 1 hour.

Please refer to FIG. 10D , which is a schematic diagram of the constant current circuit of the present invention performing the measurement mode and the recharge mode alternately in a manner similar to FIG. 10C . In FIG. 10D , the curve represents the physiological parameter value curve converted from the measured physiological signal Ia, and similar to FIG. 10C , T2 and t2 are fixed values, and V2 is a variable value. In Figure 10D, the lower part of the curve is white The colored area represents the consumption of AgCl in the measurement mode (Ia*Tl), and the area of the diagonal line represents the recharged amount of AgCl in the recharge mode (Ib*t2). As can be seen from the figure, in order to make Ib*t2 close to Ia*T1 or within a certain range of Ia*T1, the recharge potential V2 is dynamically adjusted according to the consumption of AgCl.

In addition, in FIGS. 7E , 7F and 10D , although the output timing of each physiological parameter value output after each execution of the physiological signal measurement step is not shown, the physiological parameter value is not limited to output when the measurement is completed or during the recharge period output, and the AgCl recharging step is not limited to be performed after each physiological parameter is output or after a physiological signal is obtained.

In the aforementioned embodiment using the constant current or constant voltage circuit of the present invention to alternately perform the measurement mode and the recharge mode, the working electrodes used in both the measurement mode and the recharge mode can be the first working electrode W1 and the first working electrode W1 and the second working electrode. Either of the two working electrodes W2, 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 The counter electrode is preferably the counter electrode used in the previous measurement mode. Two exemplary embodiments are described below. Example 1 was carried out chronologically: (a) using W1/W2 (representing one of W1 and W2) and R/C1 measurement, (b) using the other W1/W2 and R/C1 recharging, (c) ) Use one of W1/W2 and R/C2 to measure, (d) use the other W1/W2 and R/C2 to recharge, and repeat steps (a)-(d). Example 2: Steps (a), (b), (a), (b), (c), (d), (c), (d) are repeatedly executed chronologically.

Please refer to FIGS. 23A and 23B, which are schematic diagrams illustrating different embodiments of the present invention in which the constant current or constant voltage circuit performs the measurement mode and the recharge mode simultaneously. The horizontal axis in FIGS. 23A and 23B is time, the line of V1 represents the application and removal of the measurement potential difference V1, and the line of V2 represents the application and removal of the 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. Row. In the embodiment of FIG. 23A, 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 are alternately measured and recharge steps. That is, when the first combination is used for the measurement step, the second combination is used for the recharge step, and vice versa. In the embodiment of FIG. 23B , the first working electrode W1 is fixed for the measurement step, the second working electrode W2 is fixed for the recharge step, and the two counter electrodes are used alternately between the measurement step and the recharge step . In some preferred embodiments, the plurality of T1s do not overlap each other. In some preferred embodiments, the plurality of t2 do not overlap each other. In some preferred embodiments, T1 and t2 overlap (meaning 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 a recharge step, and the second measurement (using R/C2) is performed simultaneously (recharging R/C1). ). However, the first measurement (using R/C1) can also be accompanied by a recharge step (recharge R/C2).

Please refer to FIG. 11 , which shows a method for measuring an analyte according to an embodiment of the present invention, through which the service life of the micro biosensor can be extended. The miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 18A-18C and 19A-19C for implantation subcutaneously to measure the association of the analyte in biological fluids (eg, interstitial fluid) Physiological signals of physiological parameters. In the embodiment of FIG. 9 , the analyte may be glucose in tissue fluid, the physiological parameter is the glucose value (or concentration) in the human body, and the physiological signal is the current value measured by the micro biosensor. In this embodiment, the method for measuring the analyte includes repeatedly and cyclically performing the measuring step ( S901 ) and the recharging 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, a current value), while the AgCl of the electrode has a consumption corresponding to the current value quantity. The measurement step ( S901 ) further includes stopping the measurement by stopping the aforementioned measurement mode step, and the current value is calculated to output a physiological parameter (ie, the glucose value).

葡萄糖酸內酯(Gluconolactone)+氧化型葡萄糖氧化酶(FADH₂) In the measurement step (S901), the chemical reaction formula is as follows: the following oxidation reaction is performed on the first working electrode 420 or the second working electrode 430: glucose (Glucose) + reduced glucose oxidase (Glucose oxidase, Gox) (FAD)

Gluconolactone + oxidative glucose oxidase (FADH ₂ )

還原型葡萄糖氧化酶(FAD)+H₂O₂ Oxidative glucose oxidase (FADH ₂ )+O ₂

Reduced glucose oxidase (FAD)+H ₂ O ₂

2H⁺+O₂+2e^-於第一對電極440或第二對電極450進行以下還原反應：2AgCl+2e^-

2Ag+2Cl^- H ₂ O ₂

2H ⁺ +O ₂ +2e ^- The following reduction reaction is performed on the first pair of electrodes 440 or the second pair of electrodes 450: 2AgCl+2e ^-

2Ag+2Cl ^-

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 has a recharging amount corresponding to the consumption. The amount is controlled within the safety stock range. Therefore, 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 in a proportional relationship. may be inversely proportional). In other words, a stable proportional relationship between the next current value and the next glucose value obtained in the next measurement step can be maintained. The recharging step ( S902 ) further includes stopping the recharging step by stopping the recharging mode as described above. After the recharging step ( S902 ) ends, the cycle goes back to the measuring step ( S901 ) until N times of the measuring step ( S901 ) and N times of the recharging step ( S902 ) are performed. In some preferred embodiments, the measuring step (S901) and the recharging step (S902) are performed simultaneously, not simultaneously, or partially overlapping. In some preferred embodiments, the N measurement steps do not overlap each other. in some relatively In a preferred embodiment, the N recharging steps do not overlap each other.

葡萄糖酸內酯(Gluconolactone)+氧化型葡萄糖氧化酶(FADH₂) In the recharging step (S902), the chemical reaction formula is as follows: the following reduction reaction is performed on the first working electrode 420 or the second working electrode 430: glucose (Glucose) + reduced glucose oxidase (Glucose oxidase) (FAD)

Gluconolactone + oxidative glucose oxidase (FADH ₂ )

還原型葡萄糖氧化酶(FAD)+H₂O₂ Oxidative glucose oxidase (FADH ₂ )+O ₂

Reduced glucose oxidase (FAD)+H ₂ O ₂

H₂O H ₂ O ₂ +2H ⁺ +2e ^-

H ₂ O

2H₂O於第一對電極440或第二對電極450的正電位促使第一對電極440或第二對電極450進行以下氧化反應：2Ag

2Ag⁺+2Cl^-

2AgCl+2e^-其中對電極上的Ag氧化成Ag⁺，與來自生物體內Cl^-或AgCl氧化(或解離)後的Cl^-結合而成AgCl，使得於量測期間T1內被消耗的部分或全部AgCl被回充到對電極上。 O ₂ +4H ⁺ +4e ^-

The positive potential of 2H ₂ O on the first pair of electrodes 440 or the second pair of electrodes 450 causes the first pair of electrodes 440 or the second pair of electrodes 450 to undergo the following oxidation reaction: 2Ag

2Ag ⁺ +2Cl ^-

2AgCl+2e ^- in which Ag on the counter electrode is oxidized to Ag ⁺ , which is combined with Cl ^- from the biological body or after the oxidation (or dissociation) ^of AgCl to form AgCl, so that part or all of it is consumed during the measurement period T1 AgCl was backcharged onto the counter electrode.

The human body can obtain chloride ions and iodide ions through iodine-doped salt, so the halide ions that can be obtained include at least chloride ions and iodide ions for recharging silver halide.

The following embodiment is for the cycle of N measurement steps ( S901 ) and N recharging steps ( S902 ), wherein the physiological parameter mentioned is preferably the glucose value, and the physiological signal mentioned is preferably the current value. According to some preferred embodiments, each measurement potential difference V1 is applied in the measurement period T1, each recharge potential difference V2 is applied in the recharge period t2, and the measurement period T1 is a fixed value, which can be within 3 seconds, 5 Within seconds, within 10 seconds, within 15 seconds, within 30 seconds, within 1 minute, within 2 minutes, within 5 minutes, or within 10 minutes between values. According to some preferred embodiments, a time value within 30 seconds is preferred. According to some preferred embodiments, 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 second. According to some preferred embodiments, each measurement period T1 plus each recharging period t2 is a fixed value. According to some preferred embodiments, each recharge potential 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 ). According to some preferred embodiments, each outputted physiological parameter is obtained by calculating each physiological signal at a single measurement time point in each measurement period T1. According to some preferred embodiments, each outputted physiological parameter is 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, an accumulated value, an average value, a median, an average of medians, and the like. According to some preferred embodiments, by controlling the amount of each recharge to be equal to or not equal to (including approximately similar, greater or less than) each consumption amount, the AgCl amount of the counter electrode is controlled to be within the safety stock range, so that the lower The next physiological signal obtained during a measurement step maintains a stable proportional relationship with the next physiological parameter. According to some preferred embodiments, the step of removing each measurement potential difference V1 is to disconnect the circuit configured to connect the working electrode and the counter electrode, or to set each measurement potential difference V1 to zero. In other words, the power can be turned off, so that the measurement circuit has an open state; or, a voltage of 0 volts can be applied between the working electrode and the counter electrode, and the operation time of any of the two operations is 0.01~0.5 seconds. . Removing the step of measuring the potential difference V1 can prevent the A-shaped physiological signal from being generated. According to some preferred embodiments, the step of removing each recycle potential difference V2 is to disconnect the circuit configured to connect the working electrode and the counter electrode, or set each recycle potential difference V2 to 0.

According to some preferred embodiments, a warm-up time is required after the sensor is implanted in the human body, so that the sensor can reach equilibrium and stability in the body before it can stably display and analyte concentration Physiological signals that are positively correlated. Therefore, in the measurement step ( S901 ), the measurement voltage is continuously applied until the measurement period T1 ends, and the measurement period T1 is controlled so that the physiological signal and the physiological parameter of the analyte achieve a stable proportional relationship. Therefore, 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).

Please refer to FIGS. 7A-7F , FIGS. 10A-10D and FIG. 11 , in the present invention, the reaction current of the counter electrode is measured by applying a voltage to the counter electrode R/C in a period, and the reaction current in the period is calculated by mathematical operation. To know 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 coulomb (C _initial ), the following are all described in terms of amount. The counter electrode R/C contains Ag and AgCl. When the percentage of AgCl (X%AgCl) is known, the percentage of Ag can be calculated (Y% Ag=100%-X% AgCl). In each measurement step ( S901 ), the consumption of AgCl (represented by C _consume ) is defined by calculating the area under the current curve of the working electrode W. The AgCl of the counter electrode R/C has a consumption amount C _consume corresponding to the physiological signal Ia, that is, C _consume =Ia*T1. In each recharging step (S902), the amount of AgCl recharging each time (represented by C _replenish ) is defined by calculating the area under the current curve of the counter electrode R/C, that is, C _replenish =Ib*t2, and t2 is between Between 0 and T2.

The calculation method of the AgCl safety stock amount is described below. In some preferred embodiments, the safety stock interval is represented by the ratio of Ag to AgCl. The present invention uses the coulomb (C) measured by the counter electrode to reflect the ratio of Ag to AgCl. In some preferred embodiments, the ratio of Ag to AgCl is 99.9%: 0.1%, 99%: 1%, 95%: 5%, 90%: 10%, 70%: 30%, 50%: 50% , 40%: 60% or 30: 70%, so that AgCl has a certain amount on the counter electrode without being consumed, so that each physiological signal measurement step can be performed stably. The remaining amount of AgCl is the sum of the recharged amount and the initial amount minus the consumption amount. In some preferred embodiments, the remaining amount of AgCl varies within an interval, that is, the remaining amount of AgCl is controlled within the range of the initial amount plus or minus a specific value (X value), that is, (C _replenish +C _initial ) -C _consume =C _initial ±X, where 0<X<100% C _initial , 10% C _initial <X≦90% C _initial , or 0.5% C _initial <X≦50% C _initial . In some preferred embodiments, the remaining amount of AgCl may gradually decrease, gradually increase, or fluctuate smoothly or arbitrarily within a range but still within the range.

Please refer to FIG. 12 , which shows a method for measuring an analyte according to another embodiment of the present invention. Through this method, the service life of the miniature biosensor can be prolonged and the amount of silver and silver halide materials used in the counter electrode can be reduced. . The miniature biosensor can be, for example, the miniature biosensor shown in FIGS. 18A-18C and 19A-19C for implantation subcutaneously to measure the association of the analyte in biological fluids (eg, interstitial fluid) Physiological signals of physiological parameters. The electrode material of the counter electrode of the micro biosensor includes silver and silver halide. In the embodiment of FIG. 12 , the analyte can be glucose in tissue fluid, the physiological parameter is the glucose value in the human body, and the physiological signal is micro The current value measured by the biosensor. Only 2 cycles of this example are described below. The method of this embodiment begins with the following steps: applying a measurement voltage to drive the first or second working electrodes W1/W2 during a first measurement period to measure a physiological signal for obtaining a physiological parameter, wherein the first or second working electrode W1/W2 The silver halide of the two pairs of electrodes R/C1 or R/C2 (assuming the first pair of electrodes R/C1) is consumed by a consumption amount (S1101).

Then stop applying the measurement voltage (S1102), and use the obtained physiological signal to obtain physiological parameters (S1103). After obtaining the physiological parameters, a recharging voltage is applied during the first recharging period to drive the pair used in S1101 and having the consumption electrode (ie the first pair of electrodes R/C1), so that the amount of silver halide is recharged by a recharge amount (S1104), wherein the sum of the recharge amount and the initial amount minus the value of the consumption amount (that is, the aforementioned The remaining amount) is controlled within the range of the initial amount plus or minus a specific value. The above control step is achieved by controlling the recharge amount to be equal to or not equal to (including approximately similar, greater or less than) the consumption amount, so as to maintain the amount of silver halide within the safety stock range. According to the reaction formula, the increase or decrease of the molar number of silver halide corresponds to the increase or decrease of the molar number of silver, so for convenience of explanation, the consumption of silver halide corresponds to the increase of simulated silver. In certain preferred embodiments, the value of the remaining amount is controlled such that the ratio of the amount of silver halide to the sum of the amount of silver plus the amount of silver halide (AgCl/Ag+AgCl) is greater than 0 and less than 1, also That is to say, the amount of silver halide in the counter electrode is only one amount, preferably between 0.01-0.99, between 0.1-0.9, between 0.2-0.8, between 0.3-0.7 or between 0.4 -0.6. When the recharge amount is reached, the application of the recharge voltage is stopped (S1105). Then go back to step S1101, and apply a measurement voltage to drive the first or second working electrodes W1/W2 during the second measurement period to measure another physiological signal used to obtain another physiological parameter, wherein the other pair of The silver halide of the electrodes (ie the second pair of electrodes R/C2) is consumed by a consumption amount. Then stop applying the measurement voltage (S1102), and use the obtained physiological signal to obtain physiological parameters (S1103). After obtaining the physiological parameters, a recharging voltage is applied during the second recharging period to drive the counter electrode (ie, the second counter electrode R/C2) with the consumption used in S1101, so that the amount of silver halide is recharged by one. Recharge amount (S1104). Then it loops back to step S1001 to execute the next loop.

A specific embodiment of the present invention is described below, taking the lifespan of the biosensor reaching 16 days as an example to calculate the required size of the Ag/AgCl material in the sensing section of the electrode signal, such as the average amount of the analyte measured each time The measurement current was 30 nA, the measurement period (T1) was 30 seconds, and the recharge period (t2) was 30 seconds. The consumption of AgCl required per day (C _consume/day )=1.3mC/day. Assuming that the sensor lifetime requirement is 16 days, the consumption of AgCl required for 16 days is 1.3 x 16=20.8mC.

For example, the length of the counter electrode is 2.5mm, which corresponds to the initial amount of AgCl C _intial =10mC;

(5) In the case of no AgCl recharging, for a sensor service life of 16 days, the required length of the counter electrode is at least: C _16day /C _consume/day =20.8mC/1.3mg/day=16mm

(6) Therefore, without the use of the silver halide recharging method of the present invention, the length of the counter electrode needs to exceed 16 mm to make the life of the sensor reach 16 days.

In this embodiment, without using the silver halide recharge technology of the present invention, the counter electrode signal sensing segment needs to be configured with a correspondingly larger Ag/AgCl material size to achieve a sensor life of 16 days. Through the silver halide recharging method of the present invention, 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 immediately after use), so it can be The amount of Ag/AgCl material in the sensor is reduced, and the sensor is miniaturized. Therefore, the material for the sensing section of the electrode signal does not need to prepare 16 days' worth of AgCl for consumption. For example, the sensor can be used for 16 days by preparing the capacity of AgCl for about 1-2 days, thereby achieving the effect of prolonging the service life of the sensor. The capacity of AgCl for 1 to 2 days also refers to the initial amount of AgCl that is between about 1.3 to 2.6 mC in the counter electrode before leaving the factory or before the first measurement is performed, and the initial amount can also be other more. small or larger range. In other embodiments, different AgCl capacities such as 1 to 5 days, 1 to 3 days, 6 to 24 hours, and 6 to 12 hours can also be prepared. As long as the material size of the electrode signal sensing segment is sufficient, each glucose measurement step can be performed stably, so that the measurement current can be positively correlated with the glucose concentration in the body sexual capacity.

Without the recharge technique using the silver chloride of the present invention, the prior art would allow the sensor to reach the required number of days by increasing the electrode length/area. Taking the prior art as an example, the length of the implanted end of the sensor is about 12 mm. Due to the long implantation length, in order to avoid implanting deep into the subcutaneous tissue, it needs to be implanted subcutaneously at an oblique angle, and the implantation wound is large. For another example, the capacity of AgCl for 1~2 days is about 1.3~2.6mC, and the length of the counter electrode for 1~2 days is 2.5~5mm. In the case of the charging method, a counter electrode length of 16 mm is required, which further highlights that the present invention can effectively reduce the required counter electrode size. Through the silver halide recharging method of the present invention, the length of the implanted end can be shortened, for example, the length can be shortened to not more than 10 mm. The lower half of the connection region 417 to the second end 414 of the miniature biosensor 400 disclosed in FIGS. 18A-18C of the present invention belong to the short implant end 418 (as shown in FIGS. 18A and 18B ), and the short implant end The implantation depth of 418 should at least meet the depth where the dermis layer can measure the interstitial fluid glucose. Through the silver halide refilling method of the present invention, the longest side of the short implantation end 418 is not greater than 6mm, so that the micro biosensor 400 can be It is 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 418 is preferably no greater than 5mm, 4.5mm, 3.5mm or 2.5mm. The short implanted end 418 of the present invention includes a third signal sensing segment 442 and a fourth signal sensing segment 452, and the longest sides of the third signal sensing segment 442 and the fourth signal sensing segment 452 are not greater than 6 mm, preferably 2-6mm, 2-5mm, 2-4.5mm, 2-3.5mm, 0.5-2mm, 0.2-1mm.

Therefore, compared with the recharge technology without the silver halide of the present invention, the recharge method of the silver halide of the present invention can effectively prolong the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode. Therefore, the size of the counter electrode signal sensing segment can be reduced. Due to the reduction in the use of Ag/AgCl material on the counter electrode, the The detector can be miniaturized and can reduce biological toxicity. In addition, the reduction of the electrode size especially refers to the shortening of the length of the implantation end of the sensor, thus reducing the pain of the user during implantation. In the device comprising four electrodes of the present invention, 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 compared to devices comprising two or three electrodes.

Reduce the size of the counter electrode

To reduce the size of the counter electrode, 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 an initial amount of silver halide sufficient to process at least one measurement of a physiological signal of a physiological parameter associated with the analyte in the patient. After the first measurement, a recharge period was performed to recharge the consumed silver halide. Accordingly, the present invention provides a method for sizing a counter electrode of a biosensor and for extending the useful life of the biosensor.

FIG. 24 is a flowchart according to an embodiment of the present invention. As shown in FIG. 24, 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 An upper limit of the amount range plus a buffer amount determines the initial amount so that a desired recharge amount range of the silver halide during the regeneration period is controlled to be sufficient to maintain an amount of the silver halide at a safe level within the inventory interval to ensure that a second physiological signal obtained during a second measurement period after the regeneration period and a second physiological parameter maintain a stable proportional relationship; step c: convert the initial amount into the pair of electrodes step d: make the pair of electrodes have the silver halide containing at least the initial amount; step e: measure the physiological signal during the measurement and the silver halide is consumed by a consumption amount; and step f: in During the regeneration The silver halide is recharged once.

According to one embodiment of the present invention, an initial amount of silver halide is prepared before the biosensor is ready to be shipped for sale. The silver halide layer can be made to have an initial amount of silver halide via printing on the counter electrode with an initial amount of silver halide or via halide coating of a silver layer on the counter electrode.

In another embodiment of the invention, 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. During the initial recharge period after subcutaneous implantation of the biosensor into the patient and before the first measurement is taken, the counter electrode can be recharged with an initial amount of silver halide via oxidation of the silver coated on the counter electrode .

Typically, when a biosensor is implanted in a patient, possible trauma to the skin and/or subcutaneous tissue can sometimes cause instability in the signal monitored by the sensor. Additionally, the biosensor must be fully "wetted" or hydrated to equilibrate with the analyte in the patient (eg, glucose in biological fluids) prior to use. Therefore, after implanting the biosensor into a living body, the user must wait for a warm-up period to be ready to obtain an accurate reading of the analyte concentration before the initial measurement of the biosensor. In this case, since the biosensor requires a warm-up period after implantation into the organism before measuring the analyte, the initial recharge period can be performed during the warm-up period without delaying any desired measurements .

In order to understand how to determine the initial amount of silver halide, the following is an example of a calculation method. The required consumption range of silver halide is defined by performing at least one physiological signal measurement period on the physiological sensor. The required consumption range is Associated with this physiological parameter of the analyte, measured as glucose in the human body and halogenated For example, silver chloride is silver chloride, and a predetermined upper limit of glucose concentration is selected as the benchmark. For example, when the glucose concentration is 600mg/dL, a physiological signal measurement is performed to obtain the required current consumption of 100nA per second. If The measurement period lasts for 30 seconds, and the consumption of silver chloride required for one measurement period is 3000 nC (or 0.003 mC), which is obtained by multiplying 100 nA by 30 seconds. In this case, the upper limit of the consumption of silver chloride required for one measurement may be selected to be greater than or equal to 0.003 mC. In other embodiments, the upper limit value can be selected from other concentration values.

Since analyte concentrations in different patients or at different times in the same patient may fluctuate to a large extent and the in vivo environment is variable, it is recommended to use a wider range of required silver halide consumption (i.e. Larger initial amount), so the required consumption range of silver halide must also add a buffer amount to cope with the fluctuation of the analyte concentration in the patient to keep the silver halide in a safety stock at the counter electrode during the measurement process Changes within the interval, so that the measured physiological signal and physiological parameters maintain a stable proportional relationship. The amount of buffering can be greater than 0 and can be adjusted based on a predetermined period of use of the biosensor. The time of the predetermined use period can be any multiple of the time of a measurement period, such as 1, 2, 4, 10 and 100 times, etc., or an appropriate predetermined use period can be 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.

In addition, in addition to selecting one measurement as the calculation basis for the required consumption range, it is also possible to select multiple measurement periods to adjust the required consumption range according to the predetermined use period of the biosensor, and the corresponding buffer volume also follows the required consumption range. Adjust according to the consumption range, and then adjust the initial amount of silver halide required.

In another embodiment of the present invention, the arithmetic mean, geometric mean, or median of the desired consumption range may also be used in place of the desired consumption range The upper limit of the range to determine the initial amount depends on the actual situation the biosensor may face. For example, it is known that the average current of the physiological signal measured by the biosensor in one measurement is 20nA per second. If the measurement period lasts for 30 seconds, the average consumption of silver chloride required in one measurement period is 600nC (or 0.0006mC), which is obtained by multiplying 20nA by 30 seconds. In this case, the average consumption of silver chloride required for one measurement can be determined to be 0.0006mC.

Since it is also necessary to consider factors such as the analyte concentration of different patients or the concentration of the same patient at different times, and the factors such as in vivo environmental variables, it is recommended to use a wider range of required silver halide consumption ( That is, a larger initial amount is required), for example, if the measurement period is performed every 1 minute, and a measurement lasts for 30 seconds, 1440 measurements are required in a day, so the required consumption of silver chloride is 0.864mC , which is obtained by multiplying 0.0006mC by 1440 times a day, and its value is close to 1mC, so a value within 1mC can be selected as the buffer amount to determine the initial amount of silver chloride.

In the above-mentioned embodiment, the required consumption range and buffering amount of silver halide can be adjusted based on the predetermined usage period of the biosensor. The time of the predetermined use period can be any multiple of the time of a measurement period, such as 1, 2, 4, 10 and 100 times, etc., or an appropriate predetermined use period can be 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.

Since the current required for each biosensor to perform a measurement depends on the design and characteristics of biosensors produced by different manufacturers, the required consumption range of silver halide also depends on different biosensors. Therefore, it is understood that any modification of the required consumption is within the scope of the present invention.

In addition to the required consumption range of silver halide, it is also possible to consider adding a buffer Impulse to cope with fluctuations in analyte concentration in the patient. The amount of buffering can be greater than 0 and can be adjusted based on a predetermined period of use of the biosensor. The required consumption can be adjusted based on a number of measured times during the predetermined period of use of the biosensor.

The initial amount can be determined based on the sum of the upper limit of the required consumption range and the buffer amount to ensure that the required recharge of silver halide during the recharge 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 in the next measurement period and keep a stable proportional relationship between the two. In the case where the recharge amount of silver halide is controlled to be sufficient to support the consumption in the next measurement, the buffer amount can be zero.

If the upper limit of the desired silver chloride consumption range is chosen to be 1 mC, and the buffer amount is chosen to be 0.5 mC, the initial amount of silver chloride on the counter electrode can be determined to be 1.5 mC, which is the sum of 1 mC and 0.5 mC . Therefore, the required recharge range can be greater than zero, greater than 1.5mC, or less than 1.5mC.

Based on the initial amount of silver halide, at least a first measurement can be made. After the first measurement is performed, a first recharge is performed to recharge the consumed silver halide.

After the initial amount is determined, the desired size of the counter electrode is thus determined. 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 to 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. Typically, the width and thickness of silver and silver halide on the counter electrode are predetermined to meet design and fabrication capability constraints. Therefore, the 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 volume, which means that the length of the counter electrode can be shortened. Therefore, with the method of determining the initial amount of silver halide provided by the present invention, a biosensor with an extended service life and a shorter counter electrode can be realized. Therefore, the pain and discomfort experienced by the patient to the implanted biosensor will be greatly reduced, and there is no need to frequently purchase a new biosensor to replace the old biosensor.

According to one embodiment of the present invention, when the initial amount of silver halide for one day is 1.5 mC, the unit amount (or unit capacity) of silver halide depending on the characteristics of biosensors of different manufacturers is ³⁰⁰ mC/mm In this case, the silver halide volume required is 0.005 mm ³ . When 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. Proportionally, if the initial amount of silver halide required requires an amount of 3.6 days, the length of the silver halide, that is, the length of the counter electrode is about 6 mm, and if the initial amount of silver halide required requires an amount of 6 days, the length of 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 harm to the patient. Therefore, not only the service life of the biosensor can be extended due to the recharge period provided by the present invention, but also the pain and discomfort to the patient can be reduced due to the shortened length of the counter electrode.

Of course, reducing the volume of silver and silver halide can be accomplished by changing at least one of the length, width, and thickness of the silver and silver halide. All of the above modifications are still within the scope of the present invention.

Through the recharging method of the present invention and the setting values of the first threshold and the second threshold are selected in an appropriate interval, the silver halide recharge can be performed without waiting for the occurrence of a silver halide depletion signal (such as noise in a physiological signal). charge to control Inventory levels of manufactured silver halide remain within this threshold range. The use of the predetermined value S can further help the inventory level of the silver halide recharged to be controlled within a preferred specific range. Moreover, through the recharging method of the present invention, the recharging rate of silver chloride does not need to be positively correlated with the decreasing rate of silver chloride during the measurement period, and the present invention also provides a method that does not need to be immediately after each measurement. The method of recharging the silver chloride immediately.

The invention is also applicable to biosensors with any number of counter electrodes and any number of working electrodes, such as biosensors with one working electrode, one auxiliary electrode and one counter electrode, two working electrodes and one counter electrode An electrode biosensor, 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.

Therefore, compared with the recharge technology without the silver halide of the present invention, the recharge method of the silver halide of the present invention can effectively prolong the service life of the sensor, and can greatly reduce the use of Ag/AgCl material on the counter electrode. Therefore, the size of the counter electrode signal sensing segment can be reduced. The sensor can be miniaturized and biotoxicity can be reduced by reducing the use of Ag/AgCl material on the counter electrode. In addition, the reduction of the electrode size especially refers to the shortening of the length of the implantation end of the sensor, thus reducing the pain of the user during implantation.

While the present invention has been described in terms of what are presently considered to be the most practical and preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. On the contrary, the intention is to cover various modifications and similar arrangements included within the spirit and scope of the appended claims, which are to be accorded the broadest interpretation to cover all such modifications and similar arrangements structure.

S11, S12, S13, S14, S15, S16, S17: Steps

Claims (23)

A refill control method for a silver halide material in a biosensor for subcutaneous implantation to measure a physiological parameter associated with an analyte in a biological fluid A signal, the biosensor at least includes a first electrode and a pair of electrodes, the pair of electrodes includes a silver halide material and a silver material, and the silver halide material has an initial inventory amount in the silver halide material and the silver material and an inventory level, the recharge control method includes the following steps: after a measurement operation, obtaining a measurement value of the physiological signal, wherein the inventory level decreases after the measurement operation; after each measurement Under a condition that a predetermined number of operations are satisfied, calculate a change value of the inventory level during a period of the predetermined number of times, and start a first refill operation to recharge the change value of the inventory level, the The predetermined number of times is a positive integer, wherein the inventory level basically varies between a first threshold value and a second threshold value. The recharging control method according to claim 1, further comprising the steps of: starting a second recharging operation when the inventory level is less than or equal to the first threshold value, until the inventory level increases to the A predetermined value between the first threshold value or the second threshold value greater than the first threshold value. The recharge control method according to claim 2, further comprising the following steps: when the inventory level is greater than or equal to the second threshold value, The second recharging operation is not performed again or the number of times or a recharging amount of the second recharging operation is reduced until the inventory level is reduced to the predetermined value. The recharging control method according to claim 2, further comprising the step of: starting the second recharging operation every time a condition is satisfied after a fixed time interval of each measurement operation. The recharge control method according to claim 4, wherein the fixed time 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 A time value within a month or within a month. The recharge control method of claim 1, wherein when the inventory level is a ratio of the silver halide material to the silver halide material and the silver material, the first threshold value is selected from 1% to 98 A proportion between %, and the second threshold value is selected from a proportion between 2% and 99%. The recharge control method of claim 1, wherein the inventory level is an accumulated recharge amount of the silver halide material after each of the recharge operations minus an accumulated amount of the silver halide material after each of the measurement operations When there is a difference in consumption, the first threshold is a value between -1% and -99% of the initial inventory, and the second threshold is a value between 1% and 99% of the initial inventory. a value between. The recharge control method of claim 1, wherein the recharge method is implemented by applying a recharge voltage between the pair of electrodes and the first electrode, and the first electrode is a working electrode, or The biosensor includes An auxiliary electrode is implemented by applying a recharge voltage between the pair of electrodes and the auxiliary electrode. The recharge control method of claim 8, wherein applying the recharge voltage is performed by applying a fixed potential difference or a fixed current value. The recharging control method according to claim 1, further comprising the following steps before executing the recharging operation: forcibly executing the recharging operation by a physiological signal measuring device; and when the inventory level increases to greater than or equal to Stop the recharging operation when it is equal to the second threshold value. A physiological signal measuring device capable of controlling an inventory level of a silver halide material in a biosensor, the silver halide material has an initial inventory, and the inventory level represents an inventory of the silver halide material at that time and is applied to make the physiological signal measuring device perform a recharging operation to restore the stock level of the silver halide material. The physiological signal measuring device includes: the biosensor, including: a first electrode, and a The first pair of electrodes includes the silver halide material and a silver material; and a sensing unit, coupled to the biosensor, and including: a processor configured to enable the execution of a measurement operation when initiating a measurement operation. The inventory is reduced by one consumption, and when the recharging operation is started, the inventory is increased A recharge is added, and the inventory level is calculated, wherein the processor controls the inventory level to substantially vary between a first threshold and a second threshold. The physiological signal measuring device of claim 11, wherein when the processor determines that the inventory level is less than or equal to a first threshold, the processor causes the physiological signal measuring device to perform the recharging operation, so that The inventory level increases to a predetermined value between the first threshold value and a second threshold value greater than the first threshold value. The physiological signal measuring device of claim 12, wherein when the processor determines that the inventory level is greater than or equal to the second threshold value, it no longer performs or reduces the number of recharging operations or the recharging amount until the The inventory level is reduced to a predetermined value between a first threshold value and the second threshold value. The physiological signal measuring device according to claim 11, further comprising a voltage applying unit, which is controlled by the processor to perform the measurement operation on the biosensor to obtain the physiological signal, and perform the recharging operation to obtain the physiological signal. Reply to this inventory level. The physiological signal measuring device of claim 14, wherein the recharging operation is performed by applying a recharging voltage between the first pair of electrodes and the first electrode by the voltage applying unit, and the first The electrode is a working electrode. The physiological signal measuring device of claim 14, wherein the biosensor further comprises an auxiliary electrode, and the recharging operation is performed by the The voltage applying unit applies a recharge voltage between the first pair of electrodes and the auxiliary electrode. The physiological signal measurement device of claim 14, wherein the biosensor further comprises a second pair of electrodes and a second electrode, and the measurement operation is performed by applying a measurement voltage to the voltage applying unit. between one of the first electrode and a second working electrode and one of the first pair of electrodes and the second pair of electrodes, and the recharging operation is performed by applying a recharging voltage by the voltage applying unit It is implemented between the other one of the first pair of electrodes and the second pair of electrodes and the other one of the first electrode and a second electrode. The physiological signal measuring device according to any one of claims 15-17, wherein applying the recharge voltage is performed by applying a fixed potential difference or a fixed current value, and the fixed potential difference or the fixed current value is Essentially dynamically adjusted according to a consumption change. The physiological signal measuring device as claimed in claim 11, wherein a recovery time and a recovery amount of the inventory level when the processor performs the recharging operation can be based on a total consumption amount each time the measurement operation is performed Or an average consumption, a cumulative consumption of each measurement operation in a period, and a natural consumption of the silver halide material, or a combination thereof, are dynamically adjusted. The physiological signal measurement device of claim 11, wherein the biosensor is subcutaneously implanted into a living body. A method for restoring a biosensor to a proper working state, the biosensor comprises a first electrode and a pair of electrodes, the pair of electrical The electrode includes a silver halide material and a silver material, the silver halide material has an inventory level, and in a measurement operation, the inventory level of the silver halide material is depleted, the method includes the following steps: in the After the measuring operation, calculating a variation value of the inventory level; and initiating a first recharging operation to recharge the variation value of the inventory level, wherein the inventory level is controlled to be substantially at a first The threshold value varies between a second threshold value. The method of claim 21, when the inventory level changes to less than or equal to a first threshold value, initiating a recovery operation to recharge the consumed silver halide material, thereby increasing the inventory level to A predetermined value between the first threshold value and a second threshold value higher than the first threshold value. The method of claim 21, further comprising at least one of the following steps: calculating the inventory level in a period of the predetermined number of times under a condition that each predetermined number of times of each measurement operation is satisfied , start the first recharging operation to recharge the fluctuating value of the inventory level; and start a second recharging every time a condition is satisfied after a fixed time interval of each measurement operation charging operation.

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