TW573123B - Biosensor provided with multi-stage applied voltages and a method thereof - Google Patents

Description

573123 V. Description of the invention (1) [Technical field to which the invention belongs] The present invention relates to a biosensor and a method thereof; in particular, to a biosensor with a multi-stage bias adjustment and a method thereof. 2. [Previous Technology] In recent years, various biosensors using specific enzymes to catalyze reactions have been developed for use in medical applications. One use of this type of biosensor is for the treatment of diabetes to help diabetic patients control their own blood glucose content (glucose concentration in blood) within a normal range. For in-patients with diabetes, they can control their gold content within the normal range under the supervision of a doctor. But for non-patients with diabetes, without the direct supervision of a doctor, the patient's own ability to control blood glucose levels becomes very important. Self-control of blood glucose levels can be achieved through diet, exercise, and medication :: These treatments are usually used simultaneously under the supervision of a doctor. When diabetes :: itself can detect whether its blood glucose level is within the normal range, it can help patients to control their blood glucose level more effectively. Calculate the crystal picture 2 2 糖 物 意 2 1 blood is shown 1 piece of the solution of the plate separation volume containing a piece-shaped, sugar sugar structure 4 blood blood 2 1 2 measurement 1 — ^ 1 —_ test piece 1 layer of supply crystals 2 should be from one thing 2 the other and produce 1 problem ο Department cover cover 1, the electrode cover can indicate the electricity type of the singles, one previous attempt to have 1 display two settings 2 show the main end 2 Refer to the previous 1 for a picture.包 部 第 包包 2 包 极其 1 Its electricity f J71J ο 573123 V. Description of the invention (2) 6 and a cover plate 1 2 8 The electrode portion 1 2 2 1 is provided with an operation electrode χ 222 and a corresponding electrode 1 224 surrounding the operation electrode 1222. The operating electrode 1 2 2 2 and the corresponding electrode 1 2 2 4 are electrically connected to a wire 1 2 2 6 and a wire i 2 2 8 at the tail end of the strip substrate 1 2 2 and cover the electrode part 1 2 2 1 The reaction layer 1 2 4 contains potassium ferricyanide and oxidase, such as glucose oxidase. Before using the above blood glucose meter, the biochip 12 is inserted into the main test unit 10 first. Then, the patient can prick his skin with a tick to bleed the drip, and then drip the dripped blood directly on the end of the biochip 12 inserted into the main test unit 丄. The blood droplet is sucked into the reaction layer 1 2 4 located above the electrode portion 1 2 2 1, and the reaction layer 1 2 4 is dissolved to perform an enzyme-catalyzed reaction, as shown in the following reaction formula: D-Glucosc + 2Fc (CN ) 63 * + Η20

Gluconic acid + 2H ++ 2Fe (CN) 64 '

Fe (CN) 64-Fe (CN), + e · A pre-quantified amount of ferrous cyanide (PotaSium ferroCyanide) is produced according to the glucose concentration in the blood sample. After a predetermined period of time, an applied voltage Vref is applied to the biochip 12 to electrochemically oxidize potassium ferrocyanide to release electrons, and a corresponding reaction current is generated through the operating electrode 1 2 2 2 . This reaction current is proportional to the enzyme catalysis

573123 V. Description of the invention (3) The concentration of potassium ferrocyanide produced by the reaction may be proportional to the concentration of grapes in the blood sample. By measuring this reaction current, the sugar concentration in the blood sample can be obtained. ^ The third diagram is a schematic diagram of the control circuit of the blood glucose meter shown in the first diagram, the electrode part of the biochip 12 in 1; [2 2 i can be regarded as a resistor R, and the operating voltage Vrei can be supplied by a battery. A s reaction stream I produced by the biochip 丄 2 is gradually attenuated with time and forms a corresponding blood sample; a signal curve of glucose concentration over time. Furthermore, the response current 1 of each time-varying signal curve is converted into an output voltage Vout through a current / voltage converter 3 with an amplifier resistor Rf. In this way, this time-varying signal curve becomes a voltage-time discharge curve. The output voltage VQut corresponding to each sampling time in this discharge curve is output to an analog digital converter 3 2: to convert it into a group of digital signals. A microprocessor (miccrocmputer) 3 4 continuously reads the digital signal from the analog digital converter 32 with time, and obtains the glucose concentration value in the blood sample based on the read digital signal. This glucose concentration value is displayed via a display such as a liquid crystal display 36 for patient reference. The fourth graph is a voltage-time discharge curve with a rising time (r i s i ng t i) tr of the glucose concentration in the corresponding blood sample. At this rising time tr is a peak value of the corresponding discharge curve. Generally, the discharge curve of different glucose concentrations in the gray liquid has different rise time t, which

573123 V. Description of the invention (4) It is prolonged by increasing the degree of glucose in the blood of the system I1. However, when the applied voltage V re of the application wafer 12 is too high, oxygen in the air or its substance is easily adsorbed on the electrode portion 1 2 2 1 of the bio wafer 12. Reagents on the biochip 12 such as potassium ferricyanide or components in the sample such as glucose are easily combined with oxygen or other impurities, causing the discharge curve to shift or be disturbed, such as the first As shown in the four figures, after the elapse of the rise time ^, the discharge curve is now shifted and noisy. As a result, it will be difficult to determine the glucose concentration in the blood based on the measured discharge line. Lvlai According to this, the above-mentioned conventional blood glucose meter and its measurement method need to be modified to overcome its shortcomings. The main purpose of the present invention is to provide a multi-segment bias adjustment sensing method, and a method thereof, which is to provide a biological sample on a biological wafer of a specimen, and first to a comparative sample. A high applied voltage is applied to the biochip, so that when the% of tritium is provided on the biochip, it can promote a specific component in the specimen and the two reagents extracted in a short time to complete the reaction quickly to prevent the reagent or This: the two components react with oxygen or other impurities in the air, thereby improving the biosensing; the accuracy of the measurement. 2. Another object of the present invention is to provide a biosensor with multi-stage bias adjustment and a method thereof, before a specimen is provided on its biochip '

Page 573123 V. Description of the invention (5) A higher applied voltage is applied to the biochip first, so that when the specimen is provided on the biochip, it can promote a specific component in the specimen and the reagent of the biochip. Quick response is complete in a short time to prevent the reagent or this specific component from reacting with oxygen or other impurities in the air to reduce noise interference. Still another object of the present invention is to provide a biosensor with multi-stage bias adjustment and a method thereof, which can reduce the operating voltage in different periods as the detection time increases to reduce the power consumption of the biosensor. According to the object described above, the present invention provides a biosensor with a multi-stage bias adjustment and a method thereof. The biological sensor with multi-stage bias adjustment of the present invention includes a bio-chip, an adjustable bias generator, a current / voltage converter and a microprocessor. When an applied voltage is applied to a biochip, the biochip is a specific component in a specimen correspondingly provided thereon, generating a response current that changes with time. An adjustable bias generator is used to supply the applied voltage to the biochip, and a current / voltage converter is used to convert the time-dependent response current into an output voltage that changes over time. This time-varying output voltage forms a discharge curve. The microprocessor is used to control the adjustable bias generator to provide different applied voltages to the biochip at different time periods, and to determine the concentration value of this specific component in the specimen according to the time-varying output voltage. . The _ invention of the biosensor with multi-stage bias adjustment is the one provided on the biochip by the specimen, and the 5-cycle bias generator can first apply a first applied voltage to the biofilm, and A signal threshold for detecting this particular component in the corresponding specimen

573123 V. Description of the invention (6) After the first response time has passed (threshold response signal), the adjustable bias generator reduces the first response voltage to a second response voltage. Then, a time-varying output voltage curve of the specific component in the corresponding sample is obtained, and a concentration value of the specific component in the sample is determined based on the time-varying output voltage curve. The biosensor with multi-stage bias adjustment of the present invention is to 'apply a higher applied voltage to the biochip before providing the specimen to its biochip. When the specimen is provided to the biochip, this higher effect is provided. The voltage can promote the specific reaction between the specific component in the sample and the reagent on the biochip in a short time to completely complete the reaction to prevent the reagent on the biochip or the specific component in the sample from combining with the oxygen or other impurities in the air reference gas. . In this way, the measured signal to noise ratio of the discharge curve can be improved, and the measurement accuracy of the concentration value of the specific component in the sample can be improved. Furthermore, the present invention is to reduce this higher applied voltage after the first period of application time has elapsed, so the power consumption of the biosensor can be reduced. The purpose and many advantages of the present invention will be made clear by the following detailed description of specific embodiments and with reference to the accompanying drawings. 4. [Embodiment] ® The present invention provides a biosensor with multi-stage bias adjustment and its method, which can apply different applied voltages to the biosensor's biochip at different time stages. Biological sense with multi-stage bias adjustment of the present invention

Page 11 573123 V. Description of the invention (7) The detector is used on a wafer before a specimen is provided on a biochip. When the sample is applied to the biological crystal with a higher voltage, it can promote a specific reaction between the specific salt and biological Γ reagent in the sample in a short time to complete the reaction, and prevent the test 戍 = filial detecting the specific component in the corresponding sample A signal threshold (si, after Λ a first period of action, that is, in the reagent and a sample: so-come, ... step to prevent unreacted specific-components-and-Shi Hao-ί = impurities to combine Response, and can reduce biosensory ▲ = ϊ. In addition to the same applied voltage Vref, the biosensor with multi-stage bias adjustment of the present invention creates a large neighbor / bias to generate theft to provide a non-biosensor The components are the same. The first part depends on the type of enzyme of the biosensor. "The specific circuit to be detected." Chip, with a different amplifier 5 1 0 and an amplifier resistor & gt iib, λ, generator R n ^, a current / voltage conversion of electricity 1 κ, an adjustable bias generator 5 5 9 ^ rt xm u. ~ Analog digital conversion 2, a micro processing state 5 3 and a display, ☆ 丨 l, Guang Yue Tendon-5 4. When an applied voltage v is applied in this life / as if a liquid crystal display is not stolen ^ Block ref on this biochip, this biocrystal

573123 V. Description of the invention (8) The film will generate a response electricity that changes with time according to the concentration of the specific component to be detected in the specimen. A: The reaction current changes at any time! The system gradually declines with time; 'The adjustable bias generator 5 1 is under the control of the microprocessor 5 3 at different time stages to apply different operating voltages on the biochip U voltage converter 5 0 system This time-varying reaction current I is converted into a time-varying output voltage v time-varying discharge curve. The time-varying output voltage v is: ,,,, microprocessor 5 3 performs further processing. The microprocessor 53 determines the concentration value of the specific component in the specimen according to the time discharge. The number of terms of this density value is displayed on the liquid crystal display 54. The adjustable bias generator 51 controlled by the microprocessor 53 is applied with a voltage in the range of 500 millivolts to 52 millivolts before supplying the specimen to the biochip! On a biochip. Then, after providing the M 2 on the tablet, the threshold voltage (Vth) of this specific component in the corresponding specimen will be detected, as shown in the ninth figure, after a first period of action time In about one second, the adjustable bias generator adjusts the first applied voltage to a second applied voltage with a voltage range of m% volts to 320 millivolts. The t-pressure value l represents that the pressure system is significantly higher than the second action a, so ^ middle = ΐ 成 = reagent on the biochip for a period of action. Corresponding peak value in the discharge curve

Page 13 573123 V. Description of the invention (9) A rise time tr of the value) can be, and after the rise time tr has passed, the first applied voltage and the second applied voltage of the biosensor with multi-stage bias adjustment A discharge curve not shown in the nine figures. In the present invention, the biochip with a multi-stage bias adjustment is first given a higher level. When a specimen is provided on the biochip, the specific component in the body is combined with the biochip to prevent the combination of reagents or other impurities on the biochip from occurring. reaction. In addition, adjusting to the second working pressure after the action time can prevent oxygen or other impurities in the air from preventing unreacted reactions on the biochip from reacting to reduce the noise. The discharge curve measured by the sensor is positive. The quasi-two-acting voltage of the specific component concentration value measured in the biological chip can be reduced to the ground potential after a voltage is applied. The second paragraph depends on the concentration of this particular component. The integrated biosensor can reduce its power. The sixth figure is that the adjustable bias of the present invention quickly reaches the electrical curve within a certain period of time, that is, rapidly decays. The sequence of the present invention can be obtained after being applied to the biochip at different time stages. For example, the biosensor is used to provide the specimen with an applied voltage on the biochip, and this higher applied voltage can promote the reagent on the test. The rapid reaction is complete, and the specific component and oxygen in the air or its first applied voltage passes through the first stage of voltage. This lower second-acting electrolyte is adsorbed onto the biochip, and this specific component and reagent can be incorporated into them. Therefore, the accuracy of the multi-stage bias adjustment of the present invention can be improved, and the accuracy can be increased. On the other hand, from the administration of the second period of action time, the second period of action time is about 5 to 30 seconds, and the visual inspection is painful. Therefore, the present invention has a multi-stage bias adjustment consumption. An example of electricity generation by generating 5 1

573123 V. Description of the invention (ίο) Road schematic diagram. The adjustable bias generator 5 includes a bias regulator 5 1 1, a first resistor Ri, a current amplifier 5 丄 2, a second resistor R 2, a voltage source VDD, a third resistor r 3 and a Fourth resistor R4. The bias regulator 5 1 1 can provide different voltage outputs. One end of the first resistor Ri is connected to the bias regulator 5 1 1 so that a first current I b flows through the first

Resistor R !. The current amplifier 5 1 2 has an input terminal, an output terminal, and a ground terminal. The input terminal is connected to the other terminal of the first resistor 1 to receive the first current I b and then output a second current from its output terminal. I c. One end of the second resistor R is connected to the output terminal of the current amplifier 5 i 2 to receive the second current I c, and the other end of the second resistor r is used as a voltage output terminal to provide an applied voltage V ref to Biochip. The current amplifier 5 1 2 may be formed by a common-emitter PNP diode transistor (i common_emitter ^ polar transistor), where a base of the common-emitter PNP diode transistor is connected to the first resistor Ri, and its emitter The pole system is connected to the sensor and its collector system is connected to the second resistor R2. The third resistor Ra is connected between the power source Vdd and a node 5 1 4. This node 5 丄 4 is connected to the voltage output terminal of the second resistor R 2. One end of the fourth resistor R4 is connected to the node 14 and the other end thereof is connected to the ground terminal 513. power source

Figure, the second current Ic can be shown in the circuit of the Ipjj bias generator 51: The current of the PNP diode transistor /) 18 table ^, Zhongwan is a common shot by the bias regulator 5 " Thunder rate two: The magnitude of stream 18 can be determined by the voltage y 丄 r. Therefore, Tian Yu > U can be determined by Vref = Ic, where v 『_Vdd {w

573123 V. Description of the invention (11) Therefore, the bias regulator 5 1 1 can control the magnitude of the operating voltage Vref applied to the biochip. Another aspect of the present invention is a method for measuring a specific component in a specimen in the form of a device. The seventh diagram is a one-step flowchart of the method of the present invention and the eighth diagram is a time relationship diagram of the applied voltage applied to the biochip by the present invention. In step 7 丨, after inserting a biochip into the biosensor of the present invention, a first applied voltage vref l is applied to the biochip. The voltage of the first applied voltage V ref, i ranges from about 500 millivolts to about 520 millivolts. In step 72, a specimen is provided on the biochip. In step 73, when a threshold signal Vth corresponding to a specific component in the specimen is detected, after a first period of application time t, such as about one second, the first application voltage Vref is adjusted. Reduced to a second applied voltage v ref '2. The second applied voltage V W, 2 can be maintained for a second period of operation time 72, H5 to 30 seconds, and then decreased to the ground potential V ref 3. Then in step 74, the signal curve of the specific component in the specimen over time changes to nine; the household ... the bar value of the wave value of the specific component in the corresponding specimen = the two 5 'according to this time varying signal The curve determines the concentration value of a particular component. One of the concentration values of this specific component in the specimen is "alue", and the root; one: i, the signal curve is nine-point-value (_Ping table) to determine the specific pairing table on the # this specific component in the sample Concentration value of the concentration value of the Jade Temple Hachiman ingredients. In addition, the signal curve obtained by the transformation obtains a peak, and the steps may include changing from time to time and according to a peak-this specific composition rule

573123 V. Description of the invention (12) Mapping table of grid signal curve (prescribed curve), obtain the corresponding standard signal curve, and then determine the concentration value of this specific component according to this standard signal curve. The above are only specific embodiments of the present invention, and are not intended to limit the scope of patent application for the present invention; all other equivalent changes or modifications made without departing from the spirit disclosed by the present invention should be included in the following Within the scope of patent application.

Page 17 573123 Brief description of the drawings V. [Simplified illustration of the drawings] The first diagram is a schematic diagram of the appearance of a traditional blood glucose meter; the second diagram is an exploded diagram of the biochip of the traditional blood glucose meter of the first diagram; the third diagram is The first diagram is a schematic diagram of a control circuit of a conventional blood glucose meter; the fourth diagram is a schematic diagram of a discharge curve of the glucose concentration in a corresponding blood sample measured by a traditional blood glucose meter; the fifth diagram is a schematic diagram of a control circuit of the biosensor of the present invention; the sixth diagram An example circuit diagram of the adjustable bias generator of the present invention; the seventh diagram is a flowchart of the steps of the method of the present invention; the eighth diagram is a time relationship diagram of the applied voltage of the present invention; and the ninth diagram is measured by the method of the present invention Get a schematic diagram of the discharge curve. The main part of the symbol: 10 main test unit

Page 18 573123 Brief description of the drawings 1 2 Biochip 1 2 2 Strip substrate 1 2 4 Reaction layer 1 2 6 Spacer 1 2 8 Cover 1 2 2 1 Electrode section 1 2 2 2 Operating electrode 1 2 2 4 Correspondence Electrode 1 2 2 6, 1 2 2 8 Lead 3 0 Current / Voltage converter 3 2 Analog to digital converter 3 4 Microprocessor 3 6 LCD monitor voltage conversion / galvanic power ο 5 voltage converter器 器 器 Positioning device shows a large-scale mathematical display and adjustment of the end-to-end ratio at the crystal calculation pressure location can be similar to the micro-fluid transport partial electrical connection 0 12 3 4 IX 0 ^-00 4 ~ IX IX IX IX 1 ± 555 555 555 page 19

Claims (1)

573123 VI. Scope of patent application 1. A method for measuring the concentration of a specific component of a specimen with a multi-segment bias adjustment biosensor, comprising: applying a first applied voltage to a biochip of the biosensor A specimen is provided on the biochip, and the biochip generates a time-varying signal corresponding to a specific component in the specimen during the application of the first applied voltage; to be detected in the corresponding specimen A signal threshold for a specific component starts · After a first period of application time, the first application voltage is reduced to a second application voltage; a time-dependent signal ® curve corresponding to the specific composition in the sample is obtained ; And determining a concentration value of the specific component in the specimen based on the time-varying signal curve. 2. The method for measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, which further includes passing from the application of the second applied voltage to the biochip After a second period of application time, the second application voltage is reduced to the ground potential. 3. The method for measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, wherein the above-mentioned first applied voltage is about 500 millivolts to 5 2 0 Millivolts. Page 20 573123 VI. Application for Patent Scope 4 · As described in item 1 of the scope of patent application, the method for adjusting the concentration of a specific component of a specimen with a multi-stage bias is used to measure the concentration of a specific component of a specimen, wherein the first applied voltage is about 300 millivolts to 350 millivolts. The method of measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, wherein the first stage of the above-mentioned action period is about one second. …, 6 · The method of measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, wherein the second stage of the above-mentioned action period is about 5 seconds to 30 seconds . 7. The method for measuring the concentration of a specific component of a specimen with a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, wherein the above step of determining the concentration of the specific component in the specimen includes The signal curve that changes with time obtains a peak value, and determines a concentration value of the specific component according to a peak value-map of the concentration of the specific component. 8. The method for measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, wherein the step of determining the concentration value of the specific component in the specimen includes the step of The signal curve that changes with time obtains a peak value, and according to a peak value ~ the specific component specification signal curve mapping table to determine the concentration value of the specific component. Page 21 573123 6. Application scope of patent 9. As described in item 1 of the scope of application for patent, the method for measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor, wherein the above-mentioned specimen is intended to be The specific component detected depends on an enzyme of the biochip. 10. The method for measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 1 of the scope of the patent application, wherein the time-varying signal is a time-varying response current. . 11. The method for measuring the concentration of a specific component of a specimen by using a multi-stage bias adjustment biosensor as described in item 10 of the scope of the patent application, wherein the signal curve of time-varying 0 is a time-varying signal. Discharge curve. 1 2. —A biosensor with multi-stage bias adjustment, comprising: a biochip, which is applied to a specific voltage in a specimen provided on the biochip when an applied voltage is applied to the biochip Components to generate a response current that changes with time; an adjustable bias generator to provide the applied voltage to the biochip; a current / voltage converter that responds to the response that changes with time φ The current is converted into a time-varying output voltage; and a microprocessor is used to control the adjustable bias generator to provide different applied voltages to the biochip at different time periods, and according to the time-varying output Voltage to determine one of the specific components in the specimen Page 573123 6. The concentration range of the patent application; wherein the adjustable bias generator applies a first applied voltage to the biochip before the sample is provided on the biochip, and the corresponding sample is detected at & A signal threshold of the specific component has passed a first period of action time, and the adjustable bias generator reduces the first action voltage to a second action voltage. 1 3 · If the biosensor of the scope of the patent application, wherein the first and second periods of action time have passed, the applied voltage drops to a ground potential. One of the operating voltages with multi-stage bias adjustment described in item 2 is applied to the biochip. The adjustable bias generator generates the second 14 · Ru Shengu patent scope item i 2 ^ #, a, i As mentioned above, the biosensor theft with multi-stage bias adjustment described above can be used. The above-mentioned value can be used to generate a bias-type bias generator including: Twist μ 电阻 a resistor, for different voltage output; a first resistor, one end of which is connected to the first current flowing through the first resistor to the bias regulator, so that the current amplifier, and- Yu Ruqi selects Shi Li ^ Le in, an output terminal and a ground. Cang ;, recognize one of the zero resistance and the other to receive the first current, and output a silver from the 4 round output terminal to receive a second Resistor, one end of the instrument is twisted to an electric end, and the other end is to receive the second current, so that = electricity: the output of the amplifier is shielded from the mountain * one of the second end of the second resistor is used for a voltage output & amp 'In order to provide the field preparation and capture the " applied voltage on the biochip. 573123 VI. Application for patent scope 1 5. The biosensor with multi-stage bias adjustment as described in item 14 of the scope of patent application, wherein the current amplifier mentioned above includes a common emitter PNP diode transistor, where the A base of a common-emitter PNP diode transistor is connected to the first resistor, an emitter thereof is grounded, and a collector thereof is connected to the second resistor. 16 · The biosensor with multi-stage bias adjustment as described in item 14 of the scope of patent application, further comprising: a voltage source; a third resistor connected between the voltage source and a node, The node is connected to the voltage output terminal of the second resistor; and a fourth resistor, one end of which is connected to the node and the other end of which is grounded. 17 · The biosensor with multi-stage bias adjustment as described in item 15 of the scope of patent application, further comprising: a voltage source; a third resistor connected between the voltage source and a node, The node is connected to the voltage output terminal of the second resistor; and a fourth resistor, one end of which is connected to the node and the other end of which is grounded. 18 · The biosensor with multi-stage bias adjustment as described in item 12 of the scope of patent application, wherein the specific component to be detected in the above-mentioned specimen is Page 24 573123 6. Scope of patent application-It depends on an enzyme of the biochip. 19 · The biosensor with multi-stage bias adjustment as described in item 12 of the scope of the patent application, wherein the first applied voltage is about 500 millivolts to 5200 millivolts. 2 0. The biosensor with multi-stage bias adjustment as described in item 12 of the scope of the patent application, wherein the second applied voltage is about 300 millivolts to 3 2 0 ′ millivolts. Page 25