WO2019083206A1 - Biosensor robust against coffee ring effect - Google Patents

Biosensor robust against coffee ring effect

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Publication number
WO2019083206A1
WO2019083206A1 PCT/KR2018/012068 KR2018012068W WO2019083206A1 WO 2019083206 A1 WO2019083206 A1 WO 2019083206A1 KR 2018012068 W KR2018012068 W KR 2018012068W WO 2019083206 A1 WO2019083206 A1 WO 2019083206A1
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WO
WIPO (PCT)
Prior art keywords
slot
width
reaction
electrode
biosensor
Prior art date
Application number
PCT/KR2018/012068
Other languages
French (fr)
Korean (ko)
Inventor
김진구
오인돈
김효정
윤광현
장제영
Original Assignee
주식회사 비바이오
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 비바이오 filed Critical 주식회사 비바이오
Priority to RU2019118420A priority Critical patent/RU2713587C1/en
Priority to CN201880004858.1A priority patent/CN110073206A/en
Publication of WO2019083206A1 publication Critical patent/WO2019083206A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3272—Test elements therefor, i.e. disposable laminated substrates with electrodes, reagent and channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3273—Devices therefor, e.g. test element readers, circuitry

Definitions

  • the present invention relates to an electrochemical biosensor, and more particularly, to an electrochemical biosensor having a characteristic strong against a coffee ring effect generated when a reaction material for causing an electrochemical reaction with a target biomaterial is coated on an electrode of the biosensor. .
  • an electrochemical biosensor is an electrochemical biosensor that uses an electrode coated with a biologically specific reactant such as an enzyme, an antigen, an antibody, a hormone, and the like, Means an apparatus that outputs an electrical signal according to a chemical reaction. That is, an electrochemical biosensor is a device that provides specific information about a bio material as a current value or a voltage value. Recently, as these biosensors have been applied to blood glucose measurement systems and various kinds of precision medical diagnosis systems, there is a growing interest and demand for techniques for improving the accuracy and reproducibility of measured values measured by a biosensor.
  • a reaction material for an electrochemical reaction with a target biomaterial is fixed to an electrode of a biosensor
  • the reactant particles are dispersed in the reactive material application region due to the coffee ring effect generated in the drying process.
  • the amount and density of biased particles are different for each biosensor as well as the accuracy and reproducibility of the measurement value using the biosensor are deteriorated and the reliability of the measurement value can not be guaranteed .
  • the present invention has been made in view of the above problems, and it is an object of the present invention to provide a biosensor that improves the accuracy and reproducibility of measured values using a biosensor and ensures the reliability of measured values, .
  • a biosensor robust against a coffee ring effect includes: a substrate; At least one working electrode and at least one reference electrode patterned on a surface of the substrate, respectively, with a conductive material; Wherein the working electrode and the reference electrode are coated with a predetermined area on one surface of the substrate on which the working electrode and the reference electrode are patterned and a part of the working electrode is stacked on a part of the working electrode, A layer of reactive material deposited on a portion; And a film layer stacked on one surface of the substrate on which the working electrode and the reference electrode are patterned and having a slot having a predetermined width so as to expose the reactive material layer, A terminal portion located in an outer region of the slot; A plurality of spaced-apart reaction slots spaced apart from the sidewalls of the slots, each slot having a predetermined width and extending in a widthwise direction of the slots, part; And a connection part having a narrower width than the reaction part and extending from the reaction part and connected to the terminal part.
  • the biosensor is configured such that when the width of the slot is Ws and the distance between the longitudinal end of the reaction part facing the sidewall of the slot and the sidewall is d, .
  • the biosensor may be configured to satisfy the following equation (2) when the width of the reaction part is Wr and the width of the connection part is Wc.
  • the working electrode and the reference electrode each further include an extension having the same width as the connection portion and extending from the reaction portion and having an end located in an outer region of the slot, May be configured to extend in the width direction of the slot in the reaction part, respectively, and extend in opposite directions to each other in the reaction part.
  • the biosensor may be configured to satisfy Equation (3) below when the width of the slot is Ws and the length of the extension is Le.
  • the width of the slot may be configured to correspond to a range of 1.5 mm to 3 mm.
  • a reaction part of an electrode to which a reactive material is applied is located in an area of a slot of a biosensor into which a target biomaterial is introduced, a reaction part which is spaced apart from the sidewalls of the slot, It is possible to improve the accuracy and reproducibility of the measurement value using the biosensor in spite of the coffee ring effect that the reactant particles are unevenly distributed along the edge of the reactive substance applied to the electrode, Reliability can be assured.
  • an extension part extending in the width direction of the slot in the reaction part of the electrode and connected to the terminal part of the electrode is provided in the reaction part of the electrode so as to extend in the direction opposite to the connection part, ,
  • the area of the electrode located in the slot area can be kept constant even when tolerance is generated in the width direction of the slot in the process of laminating the film layer having the slot on the substrate. As a result, And reproducibility can be further improved.
  • the reproducibility of the measurement value using the biosensor can be maintained at a high level without applying new materials or materials
  • By providing an optimized numerical range it is possible to facilitate the design of the biosensor and reduce the time and cost required for manufacturing the biosensor.
  • FIG. 1 is a perspective view illustrating a biosensor robust to a coffee ring effect according to an embodiment of the present invention.
  • FIG. 2 is an exploded perspective view showing the biosensor of FIG.
  • FIG 3 is a view illustrating an electrode structure of a biosensor according to an embodiment of the present invention.
  • FIG. 4 is a view showing a reactive material layer applied to electrodes of a general structure.
  • FIG. 5 is a view illustrating a layer of a reactive material applied to an electrode of a biosensor according to an embodiment of the present invention.
  • FIG. 6 is a view showing an example in which a film layer is laminated on a substrate on which electrodes having no extension portion are patterned.
  • FIG. 7 is a view showing another example in which a film layer is laminated on a substrate on which an electrode not including an extension portion is patterned.
  • FIG. 8 is a view showing an example in which a film layer is laminated on a substrate on which an electrode including an extended portion is patterned.
  • FIG. 9 is a view showing another example in which a film layer is laminated on a substrate on which an electrode including an extension portion is patterned.
  • 10 is a graph showing the coefficient of variation of the biosensor according to the interval between the reaction part of the slot side wall and the electrode.
  • 11 is a graph showing the coefficient of variation of the biosensor according to the connection width of the electrode.
  • FIG. 1 is a perspective view of a biosensor 100 resistant to a coffee-ring effect according to an embodiment of the present invention.
  • a biosensor 100 includes a substrate 110, electrodes 120 and 130, a reactive material layer 140 and a film layer 150, , An outer film layer 160 according to an embodiment, and the like.
  • the biosensor 100 may have a stacked structure in which electrodes 120 and 130, a reactive material layer 140, a film layer 150, and an outer film layer 160 are stacked on one surface of a substrate 110 .
  • a slot 152 into which the target bio material to be analyzed is inputted is provided in the film layer 150 stacked on the substrate 110.
  • the outer film layer 160 laminated on the film layer 150 may be provided with a discharge port 162 for discharging the air inside the slot 152 as the target biomaterial enters the slot 152.
  • a reactive material layer 140 including a substance that causes an electrochemical reaction with a target biomaterial is applied and laminated to a portion of the substrate corresponding to the inner area of the slot 152 of the entire substrate 110.
  • the target biomaterial may be a biological material such as blood, saliva, a cell, a gene, or the like, a biochemical material, or a biomaterial or a material derived from a biochemical material.
  • FIG. 2 is an exploded perspective view of the biosensor 100 of FIG.
  • the substrate 110 corresponds to a base layer of the biosensor 100, and may be formed of an insulating material. At least one working electrode 120 and at least one reference electrode 130 are patterned on a surface of the substrate 110 with a conductive material. For example, the working electrode 120 and the reference electrode 130 may be formed on one side of the substrate 110 through a screen printing process using carbon ink.
  • the reactive material layer 140 includes a material that causes an electrochemical reaction with the target biomaterial and is applied on one surface of the substrate 110 on which the working electrode 120 and the reference electrode 130 are patterned, A portion is deposited on a portion of the working electrode 120 and another portion is deposited on a portion of the reference electrode 130.
  • the film layer 150 is stacked on one surface of the substrate 110 on which the working electrode 120 and the reference electrode 130 are patterned and has a predetermined width to expose the reactive material layer 140, Respectively.
  • the slot 152 is constituted by a U-shaped groove recessed in the horizontal direction of the film layer 150 and having a certain opening at the edge of the film layer 150 and a certain width toward the center of the film layer 150 .
  • the order of lamination between the reactive material layer 140 and the film layer 150 may be appropriately changed according to the embodiment.
  • the outer film layer 160 is configured to laminate to the film layer 150 to protect the inner space of the slot 152 in which the reactive material layer 140 is located.
  • the discharge port 162 formed in the outer film layer 160 is formed in the slot 152 so that the internal air of the slot 152 is discharged to the outside as the target bio material is introduced into the internal space of the slot 152 by capillary phenomenon, As shown in FIG.
  • the outer film layer 160 may be made of a hydrophilic material. When the outer film layer 160 is made of a hydrophilic material, the introduction of the target biomaterial containing water can be facilitated.
  • the measurement system for measuring the characteristics of the target biomaterial using the biosensor 100 described above can quantitatively measure the characteristics of the target biomaterial by applying amperometry among the electrochemical techniques. That is, the measurement system applies a voltage of a certain magnitude to the working electrode 120 of the biosensor 100 and controls the biosensor 100 in proportion to the concentration or content of the target biosensor input to the biosensor 100 By measuring the magnitude of the oxidation-reduction current that is generated, a quantified measurement of the target biomaterial can be provided.
  • the reactive material layer 140 may include an enzyme such as a glucose oxidase (GOx) or a glucose dehydrogenase (GDH) And an electron transfer mediator which is reduced by receiving an electron upon an enzyme reaction, and the like.
  • an enzyme such as GOx or GDH, which reacts with the sugar to supply electrons to the medium, is contained at a concentration of 1000 to 5000 U / ml, and serves as an electron transfer mediator between the enzyme and the working electrode 120 Of ferricyanide, ruthenium, or osmium based on 100 to 500 mM of the compound.
  • Triton X-100 or Tween-100 which contains BSA (Bovine serum albumin) in an amount of 0.1 to 10 wt% and maintains the activity of the enzyme
  • BSA Bovine serum albumin
  • a fixing agent such as polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), or agarose to aid in fixing the reaction material
  • PEG polyethyleneglycol
  • PVP polyvinylpyrrolidone
  • agarose agarose
  • the blood glucose measurement system using the biosensor 100 does not directly measure the electrons generated due to the reaction of the glucose and the enzyme in the biosensor 100,
  • the blood glucose level is measured by measuring the magnitude of the generated oxidation-reduction current, that is, the magnitude of the current output through the working electrode 120 of the biosensor 100.
  • the current value i (t) of the biosensor applying amperometry over time can be calculated through the Cottrell's equation as follows.
  • n is the number of electrons involved in the electrochemical reaction
  • F is the Faraday constant
  • A is the electrode area
  • D is the diffusion coefficient
  • C 0 is the initial concentration of the material (reduced medium) .
  • the current value of the biosensor is determined by taking the number (n) of electrons participating in the reaction and the area (A) of the electrode as factors, respectively. Accordingly, in order to improve the accuracy and reproducibility of the measurement value using the biosensor, it is necessary to prevent the edge portion of the reaction material layer 140, which is unpredictably biased due to the coffee ring effect, from participating in the electrochemical reaction On the other hand, it is necessary to keep the area of the electrode used in the electrochemical reaction constant.
  • the working electrode 120 and the reference electrode 130 of the biosensor 100 may include the terminal portions 122 and 132, the reaction portions 124 and 134, 136, and may further include extensions 128, 138, depending on the embodiment.
  • the terminal portions 122 and 132 are located in an outer region of the slot 152 formed in the film layer 150 stacked on the substrate 110 and are configured to be electrically connected to an external circuit.
  • the shapes of the terminal portions 122 and 132 can be variously modified.
  • the reaction parts 124 and 134 are positioned in the inner region of the slot 152 and have a constant width and extend by a predetermined length in the width direction of the slot 152, And spaced apart from the sidewalls of the slots 152 that face each other.
  • connection portions 126 and 136 are configured to be narrower than the reaction portions 124 and 134 and extend from the reaction portions 124 and 134 to be connected to the terminal portions 122 and 132. In this case, one end of each of the connection portions 126 and 136 is located in the inner region of the slot 152, and the other end of the connection portions 126 and 136 is located in the outer region of the slot 152.
  • the extension portions 128 and 138 have the same width as the connection portions 126 and 136, , 134 so that the distal end is located in the outer region of the slot 152.
  • the connection portions 126 and 136 and the extension portions 128 and 138 are configured to extend in the width direction of the slots 152 in the reaction portions 124 and 134, respectively, and extend in opposite directions to each other.
  • FIG 3 shows an electrode structure of the biosensor 100 according to an embodiment of the present invention.
  • the reaction units 124 and 134 of each of the electrodes 120 and 130 are located in the inner region of the slot 152 and have a constant width and have a predetermined length in the width direction of the slot 152 And spaced from each other by a predetermined distance d1, d2 from the side wall of the slot 152, which is opposite in the width direction of the slot 152, at both ends in the longitudinal direction.
  • the spaces d1 and d2 between the reaction parts 124 and 134 and the side walls of the slots 152 are set such that the edge portions of the reactive material layer 140,
  • the area of the reaction parts 124 and 134 should not be too small, while not directly contacting the reaction parts 124 and 134.
  • the distance between the longitudinal ends of the reaction parts 124 and 134, which face the side wall of the slot 152, and the corresponding side wall can be determined within a range satisfying the following equation (1).
  • Ws is the width of the slot 152
  • d is the distance between the longitudinal end of the reacting portions 124 and 134 and the corresponding sidewall facing the sidewall of the slot 152.
  • the width Ws of the slot 152 may have a size corresponding to a range of 1.5 mm or more and 3 mm or less.
  • d1 and d2 have a size corresponding to a range of 0.075 Ws to 0.2 Ws, respectively.
  • d1 and d2 are smaller than 0.075 Ws, the edge portions of the reactant material layer 140, which are ununiformly biased due to the coffee ring effect, contact the reactive portions 124 and 134, Participate in the oxidation-reduction reaction, and the reproducibility of the measurement value using the biosensor 100 is lowered.
  • d1 and d2 are larger than 0.2 Ws, the area of the reaction parts 124 and 134 becomes excessively small, so that the output current of the biosensor 100 decreases. As a result, the measured values of the biosensor 100 Rather it will degrade accuracy.
  • connection portions 126 and 136 of the electrodes 120 and 130 are extended from the reaction portions 124 and 134 to the terminal portions 122 and 132 with a narrower width than the reaction portions 124 and 134, As shown in FIG.
  • the width Wc of the connection portions 126 and 136 should be determined within a range that minimizes the contact area with the edge portion of the reactive material layer 140, and is easy to implement and does not cause disconnection.
  • the width Wc of the connecting portions 126 and 136 can be determined within a range satisfying the following equation (2).
  • Wr is the width of the reacting portions 124 and 134
  • Wc is the width of the connecting portions 126 and 136.
  • the width of the reaction part 124 of the working electrode 120 may range from 0.2 mm to 3 mm
  • the width of the reaction part 134 of the reference electrode 130 may be 0.2 mm or more and 4.5 mm.
  • the width Wc of the connecting portion 126 has a size corresponding to a range of 0.2 Wr or more and 0.5 Wr or less.
  • the width Wc of the connecting portion 126 is smaller than 0.2 Wr, actual implementation is difficult, resulting in manufacturing defects or disconnection.
  • the width Wc of the connection portion 126 is larger than 0.5 Wr, the contact area between the edge portion of the reactive material layer 140 and the connection portion 126 increases, and the measured value of the biosensor 100 The reproducibility is degraded.
  • the working electrode 120 and the reference electrode 130 further include extensions 128 and 138 extending in the direction opposite to the connecting portions 126 and 136 in the reaction portions 124 and 134
  • the portions 128 and 138 may be configured to have the same width as the connecting portions 126 and 136.
  • Figure 4 shows a layer of reactive material 16 applied to electrodes 12, 14 of general construction.
  • the reactant solution coated on the electrodes 12 and 14 having the general structure formed on the substrate 10 is dried to form the reactive material layer 16 Due to the effect of the coffee ring effect, the reactant particles are unevenly distributed along the edge of the reactive material layer 16, and the amount and density of the biased particles are also different for each biosensor. Since the electrodes 12 and 14 of the general structure have a large area of the portions x1 to x4 contacting the edge portions of the reactive material layer 16, And thus the accuracy and reproducibility of the measurement value using the biosensor are deteriorated and the reliability of the measurement value can not be guaranteed.
  • FIG. 5 is a view illustrating a reactive material layer 140 applied to electrodes 120 and 130 of a biosensor according to an embodiment of the present invention.
  • the working electrode 120 and the reference electrode 130 patterned on the substrate 110 of the biosensor according to the embodiment of the present invention have the same width as the connecting portions 126 and 136, respectively And may further include extension portions 128 and 138 extending from the reaction portions 124 and 134 and configured to be positioned at the outer region of the slot 152.
  • the connecting portions 126 and 136 and the extending portions 128 and 138 may be configured to extend in the width direction of the slots 152 in the reaction portions 124 and 134, respectively, and extend in opposite directions to each other.
  • the reason why the electrodes 120 and 130 of the biosensor 100 are provided with the extensions 128 and 138 is that when the film layer 150 having the slots 152 is laminated on the substrate 110, In order to further improve the accuracy and reproducibility of the measurement value using the biosensor by keeping the area of the electrode located in the inner region of the slot 152 constant even when a tolerance is generated in the direction of the width Ws of the biosensor 152 to be.
  • the length Le of the extensions 128 and 138 may be determined to satisfy the following equation (3).
  • Ws is the width of the slot 152 and Le is the length of the extensions 128 and 138.
  • the length Le of the extension portions 128, 138 should be at least longer than 0.2 Ws, which is the maximum value of d1 or d2.
  • the length Le does not need to be longer than 0.4 Ws which is the maximum value of d1 + d2.
  • the connecting portion 126 of the working electrode 120 should be formed to be longer than the extending portion 138 of the reference electrode 130 without being shorter than the extending portion 128 thereof. Also, the connection portion 136 of the reference electrode 130 should be formed not to be shorter than the extension portion 138 thereof.
  • FIG. 6 shows an example in which a film layer 150a is laminated on a substrate 110a on which an electrode 120a not including an extended portion is patterned.
  • FIG. 7 shows another example in which the film layer 150a is laminated on the substrate 110a on which the electrode 120a not including the extension part is patterned.
  • the electrode area used for the electrochemical reaction differs from one biosensor to another because of the tolerance generated in manufacturing the biosensor.
  • FIG. 8 shows an example in which a film layer 150 is laminated on a substrate 110 on which an electrode 120 including an extension part 128 is patterned.
  • FIG 9 shows another example in which the film layer 150 is laminated on the substrate 110 on which the electrodes 120 including the extending portions 128 are patterned.
  • the film layer 150 is formed on the substrate 110 on which the electrode 120 including the terminal portion 122, the reaction portion 124, the connection portion 126, and the extension portion 128 is patterned,
  • the area S2 of the connection part 126 located in the slot internal area of the film layer 150 is narrowed but the area S2 of the film layer 150 is located inside the slot of the film layer 150
  • the area S1 of the extension portion 128 becomes wider. Since the connection portion 126 and the extension portion 128 have the same width, the electrode area used in the electrochemical reaction is kept constant despite the tolerances.
  • an electrode 120 including a terminal portion 122, a reaction portion 124, a connection portion 126, and an extension portion 128 is formed on a substrate 110 patterned with a film layer
  • the area S2 'of the connection part 126 located in the slot internal area of the film layer 150 is widened in the process of stacking the film layers 150.
  • the area S1 'of the extension portion 128 located at the end portion becomes narrow. Since the connection portion 126 and the extension portion 128 have the same width, the electrode area used in the electrochemical reaction is kept constant despite the tolerances.
  • the electrode of the biosensor includes the above-described extension, the electrode area used for the electrochemical reaction is kept constant in all the biosensors, regardless of the tolerance generated in manufacturing the biosensor, It is possible to ensure the reproducibility of the measured values using a high level.
  • the coefficient of variation indicates the standard deviation of the population consisting of blood glucose values measured by the biosensor as a percentage of the average value of the population, and the smaller the size, the higher the reproducibility.
  • a biosensor having a structure as shown in FIG. 2 as a whole and using a biosensor constructed as a blood glucose sensor was used.
  • Hypoglycemia blood having a blood glucose level of 119 mg / dL and high blood glucose blood glucose having a blood glucose level of 299 mg / dL were used as a target biomaterial.
  • FIG. 10 is a graph showing the variation coefficient of the biosensor according to the interval between the side wall of the slot and the reaction part of the electrode.
  • the hypoglycemia blood having a blood sugar level of 119 mg / dL was administered 30 times with a blood glucose level of 299 mg / Blood was measured 20 times for blood.
  • the coefficient of variation has a value within 4% and shows a high level of reproducibility.
  • the coefficient of variation has a value within 3% and a relatively higher level of reproducibility .
  • the intervals d1 and d2 are larger than 0.2 Ws, the area of the reaction area of the electrode is excessively reduced, and the reproducibility is rather lowered.
  • FIG. 11 is a graph showing the coefficient of variation of the biosensor according to the connection width of the electrode.
  • 30 times for hypoglycemic blood having a blood glucose level of 119 mg / dL while maintaining the reaction width Wr of the electrode constant for each biosensor and changing the width Wc of the connecting portion and the extension portion of the electrode, The blood glucose level was measured 20 times for hyperglycemic blood having a blood sugar level of 299 mg / dL.
  • the width Wc of the connecting portion and the extending portion is reduced to 0.5 Wr or less with respect to the width Wr of the reaction portion, the coefficient of variation of measured values is within 4% for hyperglycemic blood as well as hypoglycemic blood Value and high level of reproducibility.
  • the width (Wc) of the connecting portion and the extending portion is less than 0.2 Wr, it is difficult to realize the actual implementation, resulting in manufacturing failure and disconnection.
  • a reaction part of an electrode to which a reactive material is applied is located in a region of a slot of a biosensor into which a target biomolecule flows, and the reaction part of the electrode is spaced apart from the sidewalls of the slot, so that the accuracy and reproducibility of the measured value using the biosensor can be improved in spite of the coffee ring effect in which the reactant particles are unevenly biased along the edge of the reactive substance applied to the electrode And the reliability of the measured value can be guaranteed.
  • an extension part extending in the width direction of the slot in the reaction part of the electrode and connected to the terminal part of the electrode is provided in the reaction part of the electrode so as to extend in the direction opposite to the connection part, ,
  • the area of the electrode located in the slot area can be kept constant even when tolerance is generated in the width direction of the slot in the process of laminating the film layer having the slot on the substrate. As a result, And reproducibility can be further improved.
  • the reproducibility of the measurement value using the biosensor can be maintained at a high level without applying new materials or materials
  • By providing an optimized numerical range it is possible to facilitate the design of the biosensor and reduce the time and cost required for manufacturing the biosensor.

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Abstract

A biosensor robust against a coffee ring effect is disclosed. The biosensor robust against the coffee ring effect includes: a substrate; a work electrode and a reference electrode patterned on one surface of the substrate; a reactive material layer applied to the one surface of the substrate such that one portion thereof is layered on one part of the work electrode, and another portion thereof is layered on one part of the reference electrode; and a film layer, which is layered on the one surface of the substrate and has a slot having a predetermined width and extending such that the reactive material layer is exposed, wherein each of the work electrode and the reference electrode includes: a terminal part positioned in an external area of the slot; a reaction part positioned in an internal area of the slot, having a predetermined width, extending in the widthwise direction of the slot at a predetermined length, and having both longitudinal ends respectively spaced apart from slot side walls, which face each other in the widthwise direction of the slot, at a predetermined interval; and a connection part having a width narrower than that of the reaction part, and extending from the reaction part so as to be connected to the terminal portion.

Description

커피링 효과에 강인한 바이오센서Robust biosensor with coffee ring effect
본 출원은 2017년 10월 23일에 출원된 한국 특허출원 제10-2017-0137669호를 기초로 한 우선권 주장을 수반하며, 해당 특허출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.This application is a priority claim based on Korean Patent Application No. 10-2017-0137669 filed on October 23, 2017, the disclosure of which is incorporated herein by reference in its entirety.
본 발명은 전기화학 바이오센서에 관한 것으로서, 더 상세하게는, 타깃 바이오 물질과의 전기화학 반응을 일으키기 위한 반응 물질이 바이오센서의 전극에 코팅될 때 발생하는 커피링 효과에 강인한 특성을 가지는 바이오센서에 관한 것이다.BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an electrochemical biosensor, and more particularly, to an electrochemical biosensor having a characteristic strong against a coffee ring effect generated when a reaction material for causing an electrochemical reaction with a target biomaterial is coated on an electrode of the biosensor. .
일반적으로, 전기화학 바이오센서(electrochemical biosensor)는 효소, 항원, 항체, 호르몬 등과 같이 생물학적 특이성을 가진 반응 물질이 코팅된 전극(electrode)을 이용하여, 분석 타깃이 되는 바이오 물질과 상기 반응 물질 간의 전기화학 반응에 따른 전기적 신호를 출력하는 장치를 말한다. 즉, 전기화학 바이오센서는 바이오 물질에 관한 특정 정보를 전류값 또는 전압값으로 제공하는 장치이다. 최근, 이러한 바이오센서가 혈당 측정 시스템이나 각종 정밀 의료 진단 시스템 등에 적용되면서, 바이오센서를 통해 측정되는 측정값의 정확성과 재현성을 개선하는 기술에 대한 관심과 요청이 급증하고 있다.Generally, an electrochemical biosensor is an electrochemical biosensor that uses an electrode coated with a biologically specific reactant such as an enzyme, an antigen, an antibody, a hormone, and the like, Means an apparatus that outputs an electrical signal according to a chemical reaction. That is, an electrochemical biosensor is a device that provides specific information about a bio material as a current value or a voltage value. Recently, as these biosensors have been applied to blood glucose measurement systems and various kinds of precision medical diagnosis systems, there is a growing interest and demand for techniques for improving the accuracy and reproducibility of measured values measured by a biosensor.
그러나, 한국 공개특허공보 제10-2004-0028437호, 한국 공개특허공보 제10-2014-0005156호 등에 개시된 바와 같이, 타깃 바이오 물질과의 전기화학 반응을 위한 반응 물질을 바이오센서의 전극에 고정하여 사용하는 기존 기술은, 실제 제조시 액상의 반응 물질을 전극 상에 도포한 후 건조하는 공정을 거치기 때문에, 건조 과정에서 발생하는 커피링 효과(coffee ring effect)로 인해 반응 물질 입자들이 반응 물질 도포 영역의 가장자리 부분에 불균일하게 편중됨은 물론, 편중되는 입자의 양이나 밀도 등도 바이오센서마다 상이하게 되어, 바이오센서를 이용한 측정값의 정확성과 재현성을 떨어뜨리고, 측정값의 신뢰성을 보장할 수 없게 되는 문제가 있다.However, as disclosed in Korean Patent Laid-Open Nos. 10-2004-0028437 and 10-2014-0005156, a reaction material for an electrochemical reaction with a target biomaterial is fixed to an electrode of a biosensor In the conventional technology, since the liquid material is applied on the electrode in the actual manufacturing process and then dried, the reactant particles are dispersed in the reactive material application region due to the coffee ring effect generated in the drying process. The amount and density of biased particles are different for each biosensor as well as the accuracy and reproducibility of the measurement value using the biosensor are deteriorated and the reliability of the measurement value can not be guaranteed .
본 발명이 해결하고자 하는 기술적 과제는, 바이오센서의 실제 제조 과정에서 발생하는 커피링 효과나 제조 공차에 불구하고 바이오센서를 이용한 측정값의 정확성과 재현성을 개선하고 측정값의 신뢰성을 보장하는 바이오센서를 제공하는 것이다.SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to provide a biosensor that improves the accuracy and reproducibility of measured values using a biosensor and ensures the reliability of measured values, .
본 발명의 일 실시예에 따른 커피링 효과에 강인한 바이오센서는, 기판; 상기 기판의 일면에 각각 도전성 소재로 패터닝된 적어도 하나의 작업 전극과 적어도 하나의 기준 전극; 타깃 바이오 물질과 전기화학 반응을 일으키는 물질을 포함하며, 상기 작업 전극과 기준 전극이 패터닝된 상기 기판의 일면에 일정 면적으로 도포되어 일부분이 상기 작업 전극의 일부에 적층되고 다른 일부분이 상기 기준 전극의 일부에 적층되는 반응 물질층; 및 상기 작업 전극과 기준 전극이 패터닝된 상기 기판의 일면에 적층되며, 상기 반응 물질층이 노출되도록 일정 폭을 가지며 연장된 슬롯을 구비하는 필름층을 포함하고, 상기 작업 전극 및 상기 기준 전극은 각각, 상기 슬롯의 외부 영역에 위치하는 단자부; 상기 슬롯의 내부 영역에 위치하고, 일정 폭을 가지며 상기 슬롯의 폭 방향으로 일정 길이만큼 연장되되 길이 방향 양측 말단이 각각 상기 슬롯의 폭 방향으로 대향하고 있는 상기 슬롯의 측벽과 일정 간격을 두고 이격된 반응부; 및 상기 반응부보다 좁은 폭을 가지며 상기 반응부에서 연장되어 상기 단자부에 연결된 연결부를 포함한다.A biosensor robust against a coffee ring effect according to an embodiment of the present invention includes: a substrate; At least one working electrode and at least one reference electrode patterned on a surface of the substrate, respectively, with a conductive material; Wherein the working electrode and the reference electrode are coated with a predetermined area on one surface of the substrate on which the working electrode and the reference electrode are patterned and a part of the working electrode is stacked on a part of the working electrode, A layer of reactive material deposited on a portion; And a film layer stacked on one surface of the substrate on which the working electrode and the reference electrode are patterned and having a slot having a predetermined width so as to expose the reactive material layer, A terminal portion located in an outer region of the slot; A plurality of spaced-apart reaction slots spaced apart from the sidewalls of the slots, each slot having a predetermined width and extending in a widthwise direction of the slots, part; And a connection part having a narrower width than the reaction part and extending from the reaction part and connected to the terminal part.
일 실시예에 있어서, 상기 바이오센서는, 상기 슬롯의 폭이 Ws이고 상기 슬롯의 측벽과 대향하는 상기 반응부의 길이 방향 말단과 상기 측벽 간의 간격이 d일 때, 아래의 수학식 1을 만족하도록 구성될 수 있다.In one embodiment, the biosensor is configured such that when the width of the slot is Ws and the distance between the longitudinal end of the reaction part facing the sidewall of the slot and the sidewall is d, .
[수학식 1][Equation 1]
0.075Ws ≤ d ≤ 0.2Ws0.075Ws? D? 0.2Ws
일 실시예에 있어서, 상기 바이오센서는, 상기 반응부의 폭이 Wr이고 상기 연결부의 폭이 Wc일 때, 아래의 수학식 2를 만족하도록 구성될 수 있다.In one embodiment, the biosensor may be configured to satisfy the following equation (2) when the width of the reaction part is Wr and the width of the connection part is Wc.
[수학식 2]&Quot; (2) "
0.2Wr ≤ Wc ≤ 0.5Wr0.2 Wr? Wc? 0.5 Wr
일 실시예에 있어서, 상기 작업 전극 및 상기 기준 전극은 각각, 상기 연결부와 동일한 폭을 가지며 상기 반응부에서 연장되어 말단이 상기 슬롯의 외부 영역에 위치하는 연장부를 더 포함하고, 상기 연결부와 상기 연장부는, 상기 반응부에서 각각 상기 슬롯의 폭 방향으로 연장되되 서로 반대 방향으로 연장되도록 구성될 수 있다.In one embodiment, the working electrode and the reference electrode each further include an extension having the same width as the connection portion and extending from the reaction portion and having an end located in an outer region of the slot, May be configured to extend in the width direction of the slot in the reaction part, respectively, and extend in opposite directions to each other in the reaction part.
일 실시예에 있어서, 상기 바이오센서는, 상기 슬롯의 폭이 Ws이고 상기 연장부의 길이가 Le일 때, 아래의 수학식 3을 만족하도록 구성될 수 있다.In one embodiment, the biosensor may be configured to satisfy Equation (3) below when the width of the slot is Ws and the length of the extension is Le.
[수학식 3]&Quot; (3) "
0.2Ws < Le ≤ 0.4Ws0.2Ws <Le? 0.4Ws
일 실시예에 있어서, 상기 슬롯의 폭은, 1.5 mm 이상 3 mm 이하의 범위에 해당하도록 구성될 수 있다.In one embodiment, the width of the slot may be configured to correspond to a range of 1.5 mm to 3 mm.
본 발명에 따르면, 타깃 바이오 물질이 유입되는 바이오센서의 슬롯 내부 영역에 위치하여 반응 물질이 도포되는 전극의 반응부가, 슬롯의 측벽들과 일정 간격을 두고 이격되어 슬롯의 측벽 근처에 위치하는 반응 물질의 가장자리 부분과 접촉하지 않도록 구성됨으로써, 전극에 도포되는 반응 물질의 가장자리를 따라 반응 물질 입자들이 불균일하게 편중되는 커피링 효과에 불구하고 바이오센서를 이용한 측정값의 정확성과 재현성을 개선하고 측정값의 신뢰성을 보장할 수 있다.According to the present invention, a reaction part of an electrode to which a reactive material is applied is located in an area of a slot of a biosensor into which a target biomaterial is introduced, a reaction part which is spaced apart from the sidewalls of the slot, It is possible to improve the accuracy and reproducibility of the measurement value using the biosensor in spite of the coffee ring effect that the reactant particles are unevenly distributed along the edge of the reactive substance applied to the electrode, Reliability can be assured.
또한, 전극의 반응부에서 슬롯의 폭 방향으로 연장되어 전극의 단자부에 연결되는 연결부와 함께, 전극의 반응부에서 상기 연결부와 반대 방향으로 연장되어 말단이 슬롯의 외부 영역에 위치하는 연장부가 마련됨으로써, 슬롯을 가진 필름층을 기판에 적층하는 과정에서 슬롯의 폭 방향으로 공차가 발생하는 경우에도 슬롯 내부 영역에 위치하는 전극의 면적을 일정하게 유지할 수 있으며, 그 결과 바이오센서를 이용한 측정값의 정확성과 재현성을 더욱 개선할 수 있다.In addition, an extension part extending in the width direction of the slot in the reaction part of the electrode and connected to the terminal part of the electrode is provided in the reaction part of the electrode so as to extend in the direction opposite to the connection part, , The area of the electrode located in the slot area can be kept constant even when tolerance is generated in the width direction of the slot in the process of laminating the film layer having the slot on the substrate. As a result, And reproducibility can be further improved.
또한, 바이오센서의 슬롯과 전극 간의 구조적 상관관계와, 전극의 반응부, 연결부 및 연장부 간의 구조적 상관관계에 대하여, 새로운 자재나 물질의 적용 없이 바이오센서를 이용한 측정값의 재현성을 높은 수준으로 유지할 수 있는 최적화된 수치 범위가 제공됨으로써, 바이오센서의 설계를 용이하게 하고 바이오센서의 제조에 요구되는 시간과 비용을 절감할 수 있다.Further, regarding the structural correlation between the slot and the electrode of the biosensor and the structural correlation between the electrode reaction part, the connection part and the extension part, the reproducibility of the measurement value using the biosensor can be maintained at a high level without applying new materials or materials By providing an optimized numerical range, it is possible to facilitate the design of the biosensor and reduce the time and cost required for manufacturing the biosensor.
나아가, 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자라면, 본 발명에 따른 다양한 실시예들이 상기 언급되지 않은 여러 기술적 과제들을 해결할 수 있음을 이하의 설명으로부터 자명하게 이해할 수 있을 것이다.It will be apparent to those skilled in the art that various embodiments of the present invention can be accomplished without departing from the spirit and scope of the present invention.
도 1은 본 발명의 일 실시예에 따른 커피링 효과에 강인한 바이오센서를 나타낸 사시도이다.1 is a perspective view illustrating a biosensor robust to a coffee ring effect according to an embodiment of the present invention.
도 2는 도 1의 바이오센서를 나타낸 분해 사시도이다.2 is an exploded perspective view showing the biosensor of FIG.
도 3은 본 발명의 일 실시예에 따른 바이오센서의 전극 구조를 나타낸 도면이다.3 is a view illustrating an electrode structure of a biosensor according to an embodiment of the present invention.
도 4는 일반적 구조의 전극에 도포된 반응 물질층을 나타낸 도면이다.4 is a view showing a reactive material layer applied to electrodes of a general structure.
도 5는 본 발명의 일 실시예에 따른 바이오센서의 전극에 도포된 반응 물질층을 나타낸 도면이다.5 is a view illustrating a layer of a reactive material applied to an electrode of a biosensor according to an embodiment of the present invention.
도 6은 연장부를 포함하지 않은 전극이 패터닝된 기판에 필름층을 적층한 일례를 나타낸 도면이다.6 is a view showing an example in which a film layer is laminated on a substrate on which electrodes having no extension portion are patterned.
도 7은 연장부를 포함하지 않은 전극이 패터닝된 기판에 필름층을 적층한 다른 일례를 나타낸 도면이다.7 is a view showing another example in which a film layer is laminated on a substrate on which an electrode not including an extension portion is patterned.
도 8은 연장부를 포함한 전극이 패터닝된 기판에 필름층을 적층한 일례를 나타낸 도면이다.8 is a view showing an example in which a film layer is laminated on a substrate on which an electrode including an extended portion is patterned.
도 9는 연장부를 포함한 전극이 패터닝된 기판에 필름층을 적층한 다른 일례를 나타낸 도면이다.9 is a view showing another example in which a film layer is laminated on a substrate on which an electrode including an extension portion is patterned.
도 10은 슬롯 측벽과 전극의 반응부 간 간격에 따른 바이오센서의 변동계수를 나타낸 그래프이다.10 is a graph showing the coefficient of variation of the biosensor according to the interval between the reaction part of the slot side wall and the electrode.
도 11은 전극의 연결부 폭에 따른 바이오센서의 변동계수를 나타낸 그래프이다.11 is a graph showing the coefficient of variation of the biosensor according to the connection width of the electrode.
이하, 본 발명의 기술적 과제에 대한 해결 방안을 명확화하기 위해 첨부도면을 참조하여 본 발명의 실시예들을 상세하게 설명한다. 다만, 본 발명을 설명함에 있어서 관련 공지기술에 관한 설명이 오히려 본 발명의 요지를 불명료하게 하는 경우 그에 관한 설명은 생략하기로 한다. 또한, 본 명세서에서 사용되는 용어들은 본 발명에서의 기능을 고려하여 정의된 용어들로서 이들은 설계자, 제조자 등의 의도 또는 관례 등에 따라 달라질 수 있을 것이다. 그러므로 후술되는 용어들의 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다.Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings in order to clarify solutions for technical problems of the present invention. In the following description of the present invention, however, the description of related arts will be omitted if the gist of the present invention becomes obscure. In addition, terms used in this specification are defined in consideration of the functions of the present invention, and they may vary depending on the intention or custom of a designer, a manufacturer, and the like. Therefore, the definitions of the following terms should be based on the contents throughout this specification.
도 1에는 본 발명의 일 실시예에 따른 커피링 효과에 강인한 바이오센서(100)가 사시도로 도시되어 있다.FIG. 1 is a perspective view of a biosensor 100 resistant to a coffee-ring effect according to an embodiment of the present invention.
도 1에 도시된 바와 같이, 본 발명의 일 실시예에 따른 바이오센서(100)는 기판(110), 전극(120, 130), 반응 물질층(140) 및 필름층(150) 등을 포함하며, 실시예에 따라 외부 필름층(160) 등을 더 포함할 수 있다. 이러한 바이오센서(100)는 기판(110)의 일면에 전극(120, 130), 반응 물질층(140), 필름층(150), 외부 필름층(160) 등이 적층된 적층 구조를 가질 수 있다.1, a biosensor 100 according to an exemplary embodiment of the present invention includes a substrate 110, electrodes 120 and 130, a reactive material layer 140 and a film layer 150, , An outer film layer 160 according to an embodiment, and the like. The biosensor 100 may have a stacked structure in which electrodes 120 and 130, a reactive material layer 140, a film layer 150, and an outer film layer 160 are stacked on one surface of a substrate 110 .
기판(110)에 적층되는 필름층(150)에는 분석 대상인 타깃 바이오 물질이 입력되는 슬롯(slot)(152)이 마련된다. 또한, 필름층(150)에 적층되는 외부 필름층(160)에는 타깃 바이오 물질이 슬롯(152)에 유입됨에 따라 슬롯(152)의 내부 공기를 배출하는 배출구(162)가 마련될 수 있다. 타깃 바이오 물질과 전기화학 반응을 일으키는 물질을 포함하는 반응 물질층(140)은, 전체 기판(110) 중 슬롯(152)의 내부 영역에 대응하는 기판 부분에 도포되어 적층된다.A slot 152 into which the target bio material to be analyzed is inputted is provided in the film layer 150 stacked on the substrate 110. The outer film layer 160 laminated on the film layer 150 may be provided with a discharge port 162 for discharging the air inside the slot 152 as the target biomaterial enters the slot 152. A reactive material layer 140 including a substance that causes an electrochemical reaction with a target biomaterial is applied and laminated to a portion of the substrate corresponding to the inner area of the slot 152 of the entire substrate 110. [
한편, 본 명세서에서 ‘바이오 물질’은, 전기화학적 테크닉들 중 암페로메트리(amperometry)를 적용하여 그 특성을 정량적으로 측정할 수 있는 모든 바이오 물질을 포함하는 의미이다. 예컨대, 타깃 바이오 물질은 혈액, 타액, 세포, 유전자 등과 같은 생체 물질이거나, 생화학 물질이거나, 생체 물질 또는 생화학 물질로부터 유래된 물질일 수 있다.In the present specification, 'biomaterial' is meant to include all biomaterials capable of quantitatively measuring the characteristics of amorphometry applied to electrochemical techniques. For example, the target biomaterial may be a biological material such as blood, saliva, a cell, a gene, or the like, a biochemical material, or a biomaterial or a material derived from a biochemical material.
도 2에는 도 1의 바이오센서(100)가 분해 사시도로 도시되어 있다.2 is an exploded perspective view of the biosensor 100 of FIG.
도 2에 도시된 바와 같이, 기판(110)은 바이오센서(100)의 기저층에 해당하는 것으로서, 절연성 소재로 구성될 수 있다. 이러한 기판(110)의 일면에 적어도 하나의 작업 전극(120)과 적어도 하나의 기준 전극(130)이 도전성 소재로 패터닝된다. 예컨대, 작업 전극(120)과 기준 전극(130)은 탄소잉크를 사용하는 스크린 프린트 공정을 통해 기판(110)의 일면에 형성될 수 있다.As shown in FIG. 2, the substrate 110 corresponds to a base layer of the biosensor 100, and may be formed of an insulating material. At least one working electrode 120 and at least one reference electrode 130 are patterned on a surface of the substrate 110 with a conductive material. For example, the working electrode 120 and the reference electrode 130 may be formed on one side of the substrate 110 through a screen printing process using carbon ink.
반응 물질층(140)은, 타깃 바이오 물질과 전기화학 반응을 일으키는 물질을 포함하며, 작업 전극(120)과 기준 전극(130)이 패터닝된 기판(110)의 일면에 일정 면적으로 도포되어, 그 일부분이 작업 전극(120)의 일부에 적층되고 다른 일부분이 기준 전극(130)의 일부에 적층된다.The reactive material layer 140 includes a material that causes an electrochemical reaction with the target biomaterial and is applied on one surface of the substrate 110 on which the working electrode 120 and the reference electrode 130 are patterned, A portion is deposited on a portion of the working electrode 120 and another portion is deposited on a portion of the reference electrode 130.
필름층(150)은, 작업 전극(120)과 기준 전극(130)이 패터닝된 기판(110)의 일면에 적층되며, 반응 물질층(140)이 노출되도록 일정 폭을 가지며 연장된 슬롯(152)을 구비한다. 이 경우, 슬롯(152)은 필름층(150)의 수평 방향 단면상, 필름층(150)의 가장자리에 개구를 가지고 필름층(150)의 중심부 측으로 일정 폭을 가지면 만입된 ‘U’자형 홈으로 구성될 수 있다. 반응 물질층(140)과 필름층(150) 간의 적층 순서는 실시예에 따라 적절히 변경될 수 있다.The film layer 150 is stacked on one surface of the substrate 110 on which the working electrode 120 and the reference electrode 130 are patterned and has a predetermined width to expose the reactive material layer 140, Respectively. In this case, the slot 152 is constituted by a U-shaped groove recessed in the horizontal direction of the film layer 150 and having a certain opening at the edge of the film layer 150 and a certain width toward the center of the film layer 150 . The order of lamination between the reactive material layer 140 and the film layer 150 may be appropriately changed according to the embodiment.
외부 필름층(160)은, 필름층(150)에 적층되어 반응 물질층(140)이 위치한 슬롯(152)의 내부 공간을 보호하도록 구성된다. 외부 필름층(160)에 형성된 배출구(162)는, 타깃 바이오 물질이 모세관 현상 등에 의해 슬롯(152)의 내부 공간으로 유입됨에 따라 슬롯(152)의 내부 공기가 외부로 배출되도록, 슬롯(152)의 말단부와 연통되는 위치에 형성될 수 있다. 이러한 외부 필름층(160)은 친수성 소재로 구성될 수 있다. 외부 필름층(160)이 친수성 소재로 구성되는 경우, 수분을 함유한 타깃 바이오 물질의 유입을 용이하게 할 수 있다.The outer film layer 160 is configured to laminate to the film layer 150 to protect the inner space of the slot 152 in which the reactive material layer 140 is located. The discharge port 162 formed in the outer film layer 160 is formed in the slot 152 so that the internal air of the slot 152 is discharged to the outside as the target bio material is introduced into the internal space of the slot 152 by capillary phenomenon, As shown in FIG. The outer film layer 160 may be made of a hydrophilic material. When the outer film layer 160 is made of a hydrophilic material, the introduction of the target biomaterial containing water can be facilitated.
상술한 바이오센서(100)를 이용하여 타깃 바이오 물질의 특성을 측정하는 측정 시스템은, 전기화학적 테크닉들 중 암페로메트리(amperometry)를 적용하여 타깃 바이오 물질의 특성을 정량적으로 측정할 수 있다. 즉, 상기 측정 시스템은 바이오센서(100)의 작업 전극(120)에 일정한 크기의 전압을 인가하고, 바이오센서(100)에 입력된 타깃 바이오 물질의 농도나 함량 등에 비례하여 바이오센서(100)에서 발생하는 산화-환원 전류의 크기를 측정함으로써, 타깃 바이오 물질에 대한 정량화된 측정값을 제공할 수 있다.The measurement system for measuring the characteristics of the target biomaterial using the biosensor 100 described above can quantitatively measure the characteristics of the target biomaterial by applying amperometry among the electrochemical techniques. That is, the measurement system applies a voltage of a certain magnitude to the working electrode 120 of the biosensor 100 and controls the biosensor 100 in proportion to the concentration or content of the target biosensor input to the biosensor 100 By measuring the magnitude of the oxidation-reduction current that is generated, a quantified measurement of the target biomaterial can be provided.
예컨대, 바이오센서(100)가 혈당 측정 시스템에 이용되는 혈당 센서로 구성되는 경우, 반응 물질층(140)은 혈액에 포함된 당과 반응하는 GOx(glucose oxidase)나 GDH(glucose dehydrogenase) 등의 효소와, 효소 반응시 전자를 받아 환원되는 전자 전달 매개체 등이 혼합된 반응 물질로 구성될 수 있다. 이 경우, 반응 물질에는 당과 반응하여 매개체에 전자를 공급하는 역할을 하는 GOx나 GDH 등의 효소가 1000~5000 U/ml 농도로 포함되고, 효소와 작업 전극(120) 간의 전자 전달 매개체 역할을 하는 페리시아나이드(ferricyanide), 루테늄(ruthenium) 또는 오스뮴(osmium) 계열의 화합물이 100~500 mM 포함될 수 있다. 또한, 반응 물질에는 효소의 활성도를 유지해주는 BSA(Bovine serum albumin)가 0.1~10 wt%로 포함되고, 액상의 반응 물질이 전극(120, 130) 위에 잘 퍼지도록 도와주는 TritonX-100나 Tween-20 등의 계면활성제가 0.1~2 wt%로 포함되고, 반응 물질의 고정을 도와주는 PEG(Polyethyleneglycol), PVP(Polyvinylpyrrolidone), 또는 아가로스(Agarose) 등과 같은 고정제가 0.1~1 wt%로 포함될 수 있다.For example, when the biosensor 100 is constituted by a glucose sensor used in a blood glucose measurement system, the reactive material layer 140 may include an enzyme such as a glucose oxidase (GOx) or a glucose dehydrogenase (GDH) And an electron transfer mediator which is reduced by receiving an electron upon an enzyme reaction, and the like. In this case, an enzyme such as GOx or GDH, which reacts with the sugar to supply electrons to the medium, is contained at a concentration of 1000 to 5000 U / ml, and serves as an electron transfer mediator between the enzyme and the working electrode 120 Of ferricyanide, ruthenium, or osmium based on 100 to 500 mM of the compound. In addition, Triton X-100 or Tween-100, which contains BSA (Bovine serum albumin) in an amount of 0.1 to 10 wt% and maintains the activity of the enzyme, And 0.1 to 2 wt% of a fixing agent such as polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), or agarose to aid in fixing the reaction material may be contained in an amount of 0.1 to 1 wt% have.
상술한 바이오센서(100)를 이용한 혈당 측정 시스템은, 바이오센서(100)에서 혈당과 효소의 반응으로 인해 발생되는 전자들을 직접 측정하는 것이 아니라, 해당 전자들을 받아 환원된 전자 전달 매개체가 다시 산화되면서 발생하는 산화-환원 전류의 크기, 즉 바이오센서(100)의 작업 전극(120)을 통해 출력되는 전류의 크기를 측정함으로써 혈당량을 측정하게 된다.The blood glucose measurement system using the biosensor 100 does not directly measure the electrons generated due to the reaction of the glucose and the enzyme in the biosensor 100, The blood glucose level is measured by measuring the magnitude of the generated oxidation-reduction current, that is, the magnitude of the current output through the working electrode 120 of the biosensor 100.
한편, 암페로메트리를 적용한 바이오센서의 시간별 전류값 i(t)은, 아래와 같은 코트렐 식(Cottrell's equation)을 통해 산출될 수 있다.On the other hand, the current value i (t) of the biosensor applying amperometry over time can be calculated through the Cottrell's equation as follows.
[코트렐 식][Cotrel type]
i(t) ＝ (nFAD1/2C0) / (πt)1/2 i (t) = (nFAD 1/2 C 0 ) / (tt) 1/2
코트렐 식에서, n은 전기화학 반응에 참여하는 전자 수, F는 패러데이 상수, A는 전극 면적, D는 확산 계수, C0는 물질(환원된 매개체)의 초기 농도, π는 원주율, t는 시간이다.In the Coctrel equation, n is the number of electrons involved in the electrochemical reaction, F is the Faraday constant, A is the electrode area, D is the diffusion coefficient, C 0 is the initial concentration of the material (reduced medium) .
코트렐 식에 나타난 바와 같이, 바이오센서의 전류값은 반응에 참여하는 전자의 수(n)와 전극의 면적(A)을 각각 인자로 하여 결정된다. 따라서, 바이오센서를 이용한 측정값의 정확성과 재현성을 개선하기 위해서는, 커피링 효과로 인해 반응 물질 입자가 예측 불가능하게 편중되는 반응 물질층(140)의 가장자리 부분이 전기화학 반응에 참여하는 것을 방지하는 한편, 전기화학 반응에 사용되는 전극의 면적을 일정하게 유지할 필요가 있다.As shown in the Coctrel equation, the current value of the biosensor is determined by taking the number (n) of electrons participating in the reaction and the area (A) of the electrode as factors, respectively. Accordingly, in order to improve the accuracy and reproducibility of the measurement value using the biosensor, it is necessary to prevent the edge portion of the reaction material layer 140, which is unpredictably biased due to the coffee ring effect, from participating in the electrochemical reaction On the other hand, it is necessary to keep the area of the electrode used in the electrochemical reaction constant.
이를 위해, 본 발명의 일 실시예에 따른 바이오센서(100)의 작업 전극(120)과 기준 전극(130)은 각각, 단자부(122, 132), 반응부(124, 134) 및 연결부(126, 136)를 포함하며, 실시예에 따라 연장부(128, 138)를 더 포함할 수 있다.The working electrode 120 and the reference electrode 130 of the biosensor 100 according to an embodiment of the present invention may include the terminal portions 122 and 132, the reaction portions 124 and 134, 136, and may further include extensions 128, 138, depending on the embodiment.
단자부(122, 132)는, 기판(110)에 적층된 필름층(150)에 형성되어 있는 슬롯(152)의 외부 영역에 위치하며, 외부 회로와 전기적으로 연결되도록 구성된다. 단자부(122, 132)의 형상은 다양하게 변형될 수 있다.The terminal portions 122 and 132 are located in an outer region of the slot 152 formed in the film layer 150 stacked on the substrate 110 and are configured to be electrically connected to an external circuit. The shapes of the terminal portions 122 and 132 can be variously modified.
반응부(124, 134)는, 상기 슬롯(152)의 내부 영역에 위치하고, 일정 폭을 가지며 슬롯(152)의 폭 방향으로 일정 길이만큼 연장되되 길이 방향 양측 말단이 각각 슬롯(152)의 폭 방향으로 대향하고 있는 슬롯(152)의 측벽과 일정 간격을 두고 이격되도록 구성된다.The reaction parts 124 and 134 are positioned in the inner region of the slot 152 and have a constant width and extend by a predetermined length in the width direction of the slot 152, And spaced apart from the sidewalls of the slots 152 that face each other.
연결부(126, 136)는, 반응부(124, 134)보다 좁은 폭을 가지며 상기 반응부(124, 134)에서 연장되어 단자부(122, 132)에 연결되도록 구성된다. 이 경우, 연결부(126, 136)의 일 단부는 슬롯(152)의 내부 영역에 위치하게 되고, 연결부(126, 136)의 타 단부는 슬롯(152)의 외부 영역에 위치하게 된다.The connection portions 126 and 136 are configured to be narrower than the reaction portions 124 and 134 and extend from the reaction portions 124 and 134 to be connected to the terminal portions 122 and 132. In this case, one end of each of the connection portions 126 and 136 is located in the inner region of the slot 152, and the other end of the connection portions 126 and 136 is located in the outer region of the slot 152.
작업 전극(120)과 기준 전극(130)이 각각, 연장부(128, 138)를 더 포함하는 경우, 연장부(128, 138)부는 연결부(126, 136)와 동일한 폭을 가지며 반응부(124, 134)에서 연장되어 말단이 슬롯(152)의 외부 영역에 위치하도록 구성된다. 이 경우, 연결부(126, 136)부와 연장부(128, 138)부는, 반응부(124, 134)에서 각각 슬롯(152)의 폭 방향으로 연장되되 서로 반대 방향으로 연장되도록 구성된다.When the working electrode 120 and the reference electrode 130 further include the extension portions 128 and 138, the extension portions 128 and 138 have the same width as the connection portions 126 and 136, , 134 so that the distal end is located in the outer region of the slot 152. In this case, the connection portions 126 and 136 and the extension portions 128 and 138 are configured to extend in the width direction of the slots 152 in the reaction portions 124 and 134, respectively, and extend in opposite directions to each other.
도 3에는 본 발명의 일 실시예에 따른 바이오센서(100)의 전극 구조가 도시되어 있다.3 shows an electrode structure of the biosensor 100 according to an embodiment of the present invention.
도 3에 도시된 바와 같이, 각 전극(120, 130)의 반응부(124, 134)는, 슬롯(152)의 내부 영역에 위치하며, 일정 폭을 가지며 슬롯(152)의 폭 방향으로 일정 길이만큼 연장되되, 그 길이 방향 양측 말단이 각각 슬롯(152)의 폭 방향으로 대향하고 있는 슬롯(152)의 측벽과 일정 간격(d1, d2)을 두고 이격되도록 구성된다.3, the reaction units 124 and 134 of each of the electrodes 120 and 130 are located in the inner region of the slot 152 and have a constant width and have a predetermined length in the width direction of the slot 152 And spaced from each other by a predetermined distance d1, d2 from the side wall of the slot 152, which is opposite in the width direction of the slot 152, at both ends in the longitudinal direction.
이 경우, 반응부(124, 134)와 슬롯(152)의 측벽 간의 간격(d1, d2)은, 슬롯(152)의 내부 영역에 도포되어 건조되는 반응 물질층(140)의 가장자리 부분이 반응부(124, 134)와 직접 접촉하지 않으면서도, 반응부(124, 134)의 면적이 지나치게 작아지지 않는 범위에서 결정되어야 한다. 이를 위해, 슬롯(152)의 측벽과 대향하는 반응부(124, 134)의 길이 방향 말단과 해당 측벽 간의 간격은, 아래의 수학식 1을 만족하는 범위 내에서 결정될 수 있다.In this case, the spaces d1 and d2 between the reaction parts 124 and 134 and the side walls of the slots 152 are set such that the edge portions of the reactive material layer 140, The area of the reaction parts 124 and 134 should not be too small, while not directly contacting the reaction parts 124 and 134. For this, the distance between the longitudinal ends of the reaction parts 124 and 134, which face the side wall of the slot 152, and the corresponding side wall can be determined within a range satisfying the following equation (1).
[수학식 1][Equation 1]
0.075Ws ≤ d ≤ 0.2Ws [mm]0.075Ws? D? 0.2Ws [mm]
수학식 1에서, Ws는 슬롯(152)의 폭, d는 슬롯(152)의 측벽과 대향하는 반응부(124, 134)의 길이 방향 말단과 해당 측벽 간의 간격이다. 이 경우, 슬롯(152)의 폭(Ws)은, 1.5 mm 이상 3 mm 이하의 범위에 해당하는 크기를 가질 수 있다.In Equation 1, Ws is the width of the slot 152, and d is the distance between the longitudinal end of the reacting portions 124 and 134 and the corresponding sidewall facing the sidewall of the slot 152. In this case, the width Ws of the slot 152 may have a size corresponding to a range of 1.5 mm or more and 3 mm or less.
도 3에서, d1과 d2는 각각, 0.075Ws 이상 0.2Ws 이하 범위에 해당하는 크기를 가진다. d1과 d2가 0.075Ws보다 작은 경우, 커피링 효과로 인해 반응 물질 입자가 불균일하게 편중된 반응 물질층(140)의 가장자리 부분이, 반응부(124, 134) 상에 접촉하여 타깃 바이오 물질과의 산화환원 반응에 참여하게 됨으로써, 바이오센서(100)를 이용한 측정값의 재현성을 떨어뜨리게 된다. 또한, d1과 d2가 0.2Ws보다 큰 경우, 반응부(124, 134)의 면적이 지나치게 작아져 바이오센서(100)의 출력 전류가 감소하게 되고, 그 결과 바이오센서(100)를 이용한 측정값의 정확도를 오히려 떨어뜨리게 된다.In Fig. 3, d1 and d2 have a size corresponding to a range of 0.075 Ws to 0.2 Ws, respectively. When d1 and d2 are smaller than 0.075 Ws, the edge portions of the reactant material layer 140, which are ununiformly biased due to the coffee ring effect, contact the reactive portions 124 and 134, Participate in the oxidation-reduction reaction, and the reproducibility of the measurement value using the biosensor 100 is lowered. When d1 and d2 are larger than 0.2 Ws, the area of the reaction parts 124 and 134 becomes excessively small, so that the output current of the biosensor 100 decreases. As a result, the measured values of the biosensor 100 Rather it will degrade accuracy.
앞서 언급한 바와 같이, 전극(120, 130)의 연결부(126, 136)는, 반응부(124, 134)에서 상기 반응부(124, 134)보다 좁은 폭을 가지며 연장되어 단자부(122, 132)에 연결되도록 구성된다.The connection portions 126 and 136 of the electrodes 120 and 130 are extended from the reaction portions 124 and 134 to the terminal portions 122 and 132 with a narrower width than the reaction portions 124 and 134, As shown in FIG.
이 경우, 연결부(126, 136)의 폭(Wc)은, 반응 물질층(140)의 가장자리 부분과의 접촉 면적을 최소화하면서도, 구현이 용이하고 단선이 발생하지 않는 범위에서 결정되어야 한다. 이를 위해, 연결부(126, 136)의 폭(Wc)은 아래의 수학식 2를 만족하는 범위 내에서 결정될 수 있다.In this case, the width Wc of the connection portions 126 and 136 should be determined within a range that minimizes the contact area with the edge portion of the reactive material layer 140, and is easy to implement and does not cause disconnection. For this purpose, the width Wc of the connecting portions 126 and 136 can be determined within a range satisfying the following equation (2).
[수학식 2]&Quot; (2) &quot;
0.2Wr ≤ Wc ≤ 0.5Wr [mm]0.2 Wr? Wc? 0.5 Wr [mm]
수학식 2에서, Wr은 반응부(124, 134)의 폭, Wc는 연결부(126, 136)의 폭이다. 이 경우, 작업 전극(120)의 반응부(124) 폭은 0.2 mm 이상 3 mm 이하의 범위에 해당하는 크기를 가질 수 있으며, 기준 전극(130)의 반응부(134) 폭은 0.2mm 이상 4.5 mm 이하의 범위에 해당하는 크기를 가질 수 있다.In Equation (2), Wr is the width of the reacting portions 124 and 134, and Wc is the width of the connecting portions 126 and 136. In this case, the width of the reaction part 124 of the working electrode 120 may range from 0.2 mm to 3 mm, and the width of the reaction part 134 of the reference electrode 130 may be 0.2 mm or more and 4.5 mm. &lt; / RTI &gt;
도 3에서, 연결부(126)의 폭(Wc)은 0.2Wr 이상 0.5Wr 이하의 범위에 해당하는 크기를 가진다. 연결부(126)의 폭(Wc)이 0.2Wr보다 작은 경우, 실제 구현이 곤란하고 제조 불량이나 단선을 초래하게 된다. 또한, 연결부(126)의 폭(Wc)이 0.5Wr보다 큰 경우, 반응 물질층(140)의 가장자리 부분과 연결부(126) 사이의 접촉 면적이 증가하여, 바이오센서(100)를 이용한 측정값의 재현성을 떨어뜨리게 된다.3, the width Wc of the connecting portion 126 has a size corresponding to a range of 0.2 Wr or more and 0.5 Wr or less. When the width Wc of the connecting portion 126 is smaller than 0.2 Wr, actual implementation is difficult, resulting in manufacturing defects or disconnection. When the width Wc of the connection portion 126 is larger than 0.5 Wr, the contact area between the edge portion of the reactive material layer 140 and the connection portion 126 increases, and the measured value of the biosensor 100 The reproducibility is degraded.
한편, 작업 전극(120)과 기준 전극(130)이 각각, 반응부(124, 134)에서 연결부(126, 136)와 반대 방향으로 연장된 연장부(128, 138)를 더 포함하는 경우, 연장부(128, 138)는 연결부(126, 136)와 동일한 폭을 가지도록 구성될 수 있다.On the other hand, in the case where the working electrode 120 and the reference electrode 130 further include extensions 128 and 138 extending in the direction opposite to the connecting portions 126 and 136 in the reaction portions 124 and 134, The portions 128 and 138 may be configured to have the same width as the connecting portions 126 and 136.
도 4는 일반적 구조의 전극(12, 14)에 도포된 반응 물질층(16)이 도시되어 있다.Figure 4 shows a layer of reactive material 16 applied to electrodes 12, 14 of general construction.
도 4에 도시된 바와 같이, 기판(10)에 형성된 일반적 구조의 전극(12, 14) 위에 도포된 반응 물질 용액이 건조되어 반응 물질층(16)이 형성되는 경우, 건조 과정에서 발생하는 커피링 효과(coffee ring effect)로 인해 반응 물질 입자들이 반응 물질층(16)의 가장자리를 따라 불균일하게 편중되고, 편중되는 입자의 양이나 밀도 등도 바이오센서마다 상이하게 된다. 일반적 구조의 전극(12, 14)은 이러한 반응 물질층(16)의 가장자리 부분과 접촉하는 부분들(x1 내지 x4)의 면적이 크기 때문에, 반응 물질층(16)의 가장자리 부분이 타깃 바이오 물질과의 전기화학 반응 또는 산화환원 반응에 상당한 비율로 참여하게 되고, 그 결과, 바이오센서를 이용한 측정값의 정확성과 재현성을 떨어뜨리고, 측정값의 신뢰성을 보장할 수 없게 된다.As shown in FIG. 4, when the reactant solution coated on the electrodes 12 and 14 having the general structure formed on the substrate 10 is dried to form the reactive material layer 16, Due to the effect of the coffee ring effect, the reactant particles are unevenly distributed along the edge of the reactive material layer 16, and the amount and density of the biased particles are also different for each biosensor. Since the electrodes 12 and 14 of the general structure have a large area of the portions x1 to x4 contacting the edge portions of the reactive material layer 16, And thus the accuracy and reproducibility of the measurement value using the biosensor are deteriorated and the reliability of the measurement value can not be guaranteed.
도 5에는 본 발명의 일 실시예에 따른 바이오센서의 전극(120, 130)에 도포된 반응 물질층(140)을 나타낸 도면이다.FIG. 5 is a view illustrating a reactive material layer 140 applied to electrodes 120 and 130 of a biosensor according to an embodiment of the present invention.
도 5에 도시된 바와 같이, 본 발명의 경우, 기판(110)에 도포된 반응 물질 입자들이 커피링 효과로 인해 반응 물질층(140)의 가장자리를 따라 불균일하게 편중되더라도, 반응 물질층(140)의 가장자리 부분과 접촉하는 연결부(126, 136)와 연장부(128, 138)의 부분들(y1 내지 y4)의 면적이 작기 때문에, 타깃 바이오 물질과의 산화환원 반응에는 주로 전극(120, 130)의 반응부(124, 134)와 접촉하는 반응 물질층(140)의 중심 부분이 참여하게 되고, 반응 물질층(140)의 가장자리 부분은 측정값에 영향을 주지 않는 매우 낮은 비율로 참여하게 된다. 따라서, 본 발명에 따르면, 바이오센서를 이용한 측정값의 정확성과 재현성을 개선하고, 측정값의 신뢰성을 보장할 수 있다.5, in the present invention, even though the reactant particles applied to the substrate 110 are unevenly biased along the edges of the reactive material layer 140 due to the coffee ring effect, Since the areas of the connecting portions 126 and 136 and the portions y1 to y4 of the extension portions 128 and 138 that contact the edge portions of the electrodes 120 and 130 are small, The center portion of the reactive material layer 140 that is in contact with the reaction portions 124 and 134 of the reactive material layer 140 is involved and the edge portions of the reactive material layer 140 participate at a very low rate that does not affect the measured value. Therefore, according to the present invention, it is possible to improve the accuracy and reproducibility of the measurement value using the biosensor and ensure the reliability of the measurement value.
다시 도 3을 참조하면, 본 발명의 일 실시예에 따른 바이오센서의 기판(110)에 패터닝된 작업 전극(120)과 기준 전극(130)은 각각, 연결부(126, 136)와 동일한 폭을 가지며 반응부(124, 134)에서 연장되어 말단이 슬롯(152)의 외부 영역에 위치하도록 구성된 연장부(128, 138)를 더 포함할 수 있다. 이 경우, 연결부(126, 136)부와 연장부(128, 138)는, 반응부(124, 134)에서 각각 슬롯(152)의 폭 방향으로 연장되되 서로 반대 방향으로 연장되도록 구성될 수 있다.3, the working electrode 120 and the reference electrode 130 patterned on the substrate 110 of the biosensor according to the embodiment of the present invention have the same width as the connecting portions 126 and 136, respectively And may further include extension portions 128 and 138 extending from the reaction portions 124 and 134 and configured to be positioned at the outer region of the slot 152. In this case, the connecting portions 126 and 136 and the extending portions 128 and 138 may be configured to extend in the width direction of the slots 152 in the reaction portions 124 and 134, respectively, and extend in opposite directions to each other.
이와 같이 바이오센서(100)의 전극(120, 130)에 연장부(128, 138)를 마련하는 이유는, 슬롯(152)을 가진 필름층(150)을 기판(110)에 적층하는 과정에서 슬롯(152)의 폭(Ws) 방향으로 공차가 발생하는 경우에도 슬롯(152)의 내부 영역에 위치하는 전극의 면적을 일정하게 유지하여, 바이오센서를 이용한 측정값의 정확성과 재현성을 더욱 개선하기 위함이다.The reason why the electrodes 120 and 130 of the biosensor 100 are provided with the extensions 128 and 138 is that when the film layer 150 having the slots 152 is laminated on the substrate 110, In order to further improve the accuracy and reproducibility of the measurement value using the biosensor by keeping the area of the electrode located in the inner region of the slot 152 constant even when a tolerance is generated in the direction of the width Ws of the biosensor 152 to be.
이를 위해, 연장부(128, 138)의 길이(Le)는, 아래의 수학식 3의 범위를 만족하도록 결정될 수 있다.To this end, the length Le of the extensions 128 and 138 may be determined to satisfy the following equation (3).
[수학식 3]&Quot; (3) &quot;
0.2Ws < Le ≤ 0.4Ws [mm]0.2Ws <Le? 0.4Ws [mm]
수학식 3에서, Ws는 슬롯(152)의 폭, Le는 연장부(128, 138)의 길이이다.In Equation (3), Ws is the width of the slot 152 and Le is the length of the extensions 128 and 138.
기판(110)에 필름층(150)을 적층하는 과정에서 슬롯(152)의 폭(Ws) 방향으로 공차가 발생하는 경우에도, 슬롯(152)의 내부 영역에 위치하는 전극의 면적을 일정하게 유지하기 위해서는, 연장부(128, 138)가 슬롯(152)의 외부 영역에 일정 길이(l0)의 마진을 가지고 있어야 한다. 따라서, 연장부(128, 138)의 길이(Le)는, 적어도 d1 또는 d2의 최대치인 0.2Ws보다 길어야 한다. 또한, 필름층(150) 적층 시의 공차는 전극(120, 130)의 반응부(124, 134)가 슬롯(152)의 내부 영역에 위치하는 경우에만 허용되는 것이므로, 연장부(128, 138)의 길이(Le)는 d1+d2의 최대치인 0.4Ws보다 길 필요는 없다.Even when a tolerance is generated in the direction of the width Ws of the slot 152 in the process of laminating the film layer 150 on the substrate 110, the area of the electrode located in the inner region of the slot 152 is kept constant The extensions 128 and 138 must have a margin of a certain length l 0 in the outer region of the slot 152. Therefore, the length Le of the extension portions 128, 138 should be at least longer than 0.2 Ws, which is the maximum value of d1 or d2. Since the tolerances in the lamination of the film layers 150 are allowed only when the reaction portions 124 and 134 of the electrodes 120 and 130 are located in the inner region of the slot 152, The length Le does not need to be longer than 0.4 Ws which is the maximum value of d1 + d2.
한편, 도 3에서, 작업 전극(120)의 연결부(126)는 그 연장부(128)보다 짧지 않으면서 기준 전극(130)의 연장부(138)보다 길게 형성되어야 한다. 또한, 기준 전극(130)의 연결부(136)도 그 연장부(138)보다 짧지 않게 형성되어야 한다.3, the connecting portion 126 of the working electrode 120 should be formed to be longer than the extending portion 138 of the reference electrode 130 without being shorter than the extending portion 128 thereof. Also, the connection portion 136 of the reference electrode 130 should be formed not to be shorter than the extension portion 138 thereof.
도 6에는 연장부를 포함하지 않은 전극(120a)이 패터닝된 기판(110a)에 필름층(150a)을 적층한 일례가 도시되어 있다.FIG. 6 shows an example in which a film layer 150a is laminated on a substrate 110a on which an electrode 120a not including an extended portion is patterned.
도 7에는 연장부를 포함하지 않은 전극(120a)이 패터닝된 기판(110a)에 필름층(150a)을 적층한 다른 일례가 도시되어 있다.7 shows another example in which the film layer 150a is laminated on the substrate 110a on which the electrode 120a not including the extension part is patterned.
도 6에 도시된 바와 같이, 단자부(122a), 반응부(124a) 및 연결부(126a) 만으로 구성된 전극(120a)이 패터닝된 기판(110a)에, 필름층(150a)이 적층되는 과정에서 좌측으로 공차가 발생하는 경우, 필름층(150)의 슬롯 내부 영역에 위치하는 연결부(126a)의 면적(Sa)이 좁아져서, 전기화학 반응에 사용되는 전극 면적이 감소하게 된다.6, when the film layer 150a is laminated on the substrate 110a on which the electrode 120a composed of only the terminal portion 122a, the reaction portion 124a and the connection portion 126a is patterned, When the tolerance occurs, the area Sa of the connection portion 126a located in the slot region of the film layer 150 is narrowed, so that the electrode area used in the electrochemical reaction is reduced.
반면, 도 7에 도시된 바와 같이, 단자부(122a), 반응부(124a) 및 연결부(126a) 만으로 구성된 전극(120a)이 패터닝된 기판(110a)에, 필름층(150a)이 적층되는 과정에서 우측으로 공차가 발생하는 경우, 필름층(150)의 슬롯 내부 영역에 위치하는 연결부(126a)의 면적(Sa')이 넓어져서, 전기화학 반응에 사용되는 전극 면적이 증가하게 된다.7, in the process of stacking the film layer 150a on the substrate 110a on which the electrode 120a composed of only the terminal portion 122a, the reaction portion 124a and the connection portion 126a is patterned, When a tolerance occurs to the right, the area Sa 'of the connection portion 126a located in the slot region of the film layer 150 is widened, and the electrode area used for the electrochemical reaction increases.
이와 같이, 바이오센서의 전극이 상술한 연장부를 포함하지 않는 경우, 바이오센서의 제조시 발생하는 공차로 인해 전기화학 반응에 사용되는 전극 면적이 바이오센서마다 달라진다.When the electrode of the biosensor does not include the extension portion, the electrode area used for the electrochemical reaction differs from one biosensor to another because of the tolerance generated in manufacturing the biosensor.
도 8에는 연장부(128)를 포함한 전극(120)이 패터닝된 기판(110)에 필름층(150)을 적층한 일례가 도시되어 있다.8 shows an example in which a film layer 150 is laminated on a substrate 110 on which an electrode 120 including an extension part 128 is patterned.
도 9에는 연장부(128)를 포함한 전극(120)이 패터닝된 기판(110)에 필름층(150)을 적층한 다른 일례가 도시되어 있다.9 shows another example in which the film layer 150 is laminated on the substrate 110 on which the electrodes 120 including the extending portions 128 are patterned.
도 8에 도시된 바와 같이, 단자부(122), 반응부(124), 연결부(126), 및 연장부(128)를 포함한 전극(120)이 패터닝된 기판(110)에, 필름층(150)이 적층되는 과정에서 좌측으로 공차가 발생하는 경우, 필름층(150)의 슬롯 내부 영역에 위치하는 연결부(126)의 면적(S2)은 좁아지지만, 필름층(150)의 슬롯 내부 영역에 위치하는 연장부(128)의 면적(S1)은 넓어지게 된다. 연결부(126)와 연장부(128)는 동일한 폭을 가지므로, 전기화학 반응에 사용되는 전극 면적은 공차에 불구하고 일정하게 유지된다.The film layer 150 is formed on the substrate 110 on which the electrode 120 including the terminal portion 122, the reaction portion 124, the connection portion 126, and the extension portion 128 is patterned, The area S2 of the connection part 126 located in the slot internal area of the film layer 150 is narrowed but the area S2 of the film layer 150 is located inside the slot of the film layer 150 The area S1 of the extension portion 128 becomes wider. Since the connection portion 126 and the extension portion 128 have the same width, the electrode area used in the electrochemical reaction is kept constant despite the tolerances.
또한, 도 9에 도시된 바와 같이, 단자부(122), 반응부(124), 연결부(126), 및 연장부(128)를 포함한 전극(120)이 패터닝된 기판(110)에, 필름층(150)이 적층되는 과정에서 우측으로 공차가 발생하는 경우, 필름층(150)의 슬롯 내부 영역에 위치하는 연결부(126)의 면적(S2')은 넓어지지만, 필름층(150)의 슬롯 내부 영역에 위치하는 연장부(128)의 면적(S1')은 좁아지게 된다. 연결부(126)와 연장부(128)는 동일한 폭을 가지므로, 전기화학 반응에 사용되는 전극 면적은 공차에 불구하고 일정하게 유지된다.9, an electrode 120 including a terminal portion 122, a reaction portion 124, a connection portion 126, and an extension portion 128 is formed on a substrate 110 patterned with a film layer The area S2 'of the connection part 126 located in the slot internal area of the film layer 150 is widened in the process of stacking the film layers 150. However, The area S1 'of the extension portion 128 located at the end portion becomes narrow. Since the connection portion 126 and the extension portion 128 have the same width, the electrode area used in the electrochemical reaction is kept constant despite the tolerances.
이와 같이, 바이오센서의 전극이 상술한 연장부를 포함하는 경우, 바이오센서의 제조시 발생하는 공차에 불구하고, 전기화학 반응에 사용되는 전극 면적이 모든 바이오센서에서 일정하게 유지되며, 그 결과 바이오센서를 이용한 측정값의 재현성을 높은 수준으로 보장할 수 있게 된다.In this way, when the electrode of the biosensor includes the above-described extension, the electrode area used for the electrochemical reaction is kept constant in all the biosensors, regardless of the tolerance generated in manufacturing the biosensor, It is possible to ensure the reproducibility of the measured values using a high level.
이하, 변동계수(coefficient of variation) 측정 실험 결과를 참조하여, 본 발명의 일 실시예에 따른 바이오센서의 재현성 개선 효과를 검증한다.Hereinafter, the reproducibility improvement effect of the biosensor according to one embodiment of the present invention will be verified with reference to the experimental results of the measurement of the coefficient of variation.
변동계수는, 바이오센서로 측정된 혈당값들로 이루어진 모집단의 표준편차를 모집단의 평균치에 대한 백분율로 나타낸 것으로서, 그 크기가 작을수록 재현성이 높다는 것을 의미한다.The coefficient of variation indicates the standard deviation of the population consisting of blood glucose values measured by the biosensor as a percentage of the average value of the population, and the smaller the size, the higher the reproducibility.
변동계수 측정 실험에서는, 전체적으로 도 2와 같은 구조를 가지며 혈당 센서로서 구성된 바이오센서들을 사용하였으며, 타깃 바이오 물질로서 혈당량 119 mg/dL의 저혈당 혈액과 혈당량 299 mg/dL의 고혈당 혈액을 사용하였다.In the experiment of measuring the coefficient of variation, a biosensor having a structure as shown in FIG. 2 as a whole and using a biosensor constructed as a blood glucose sensor was used. Hypoglycemia blood having a blood glucose level of 119 mg / dL and high blood glucose blood glucose having a blood glucose level of 299 mg / dL were used as a target biomaterial.
도 10에는 슬롯의 측벽과 전극의 반응부 간 간격에 따른 바이오센서의 변동계수가 그래프로 도시되어 있다. 도 10과 관련된 실험에서는, 바이오센서별로 슬롯의 폭(Ws)을 일정하게 유지하고 전극의 반응부 길이를 변경하면서, 혈당량 119 mg/dL의 저혈당 혈액에 대해서는 30회씩, 혈당량 299 mg/dL의 고혈당 혈액에 대해서는 20회씩 혈당량 측정을 진행하였다.FIG. 10 is a graph showing the variation coefficient of the biosensor according to the interval between the side wall of the slot and the reaction part of the electrode. In the experiment related to Fig. 10, while maintaining the width Ws of the slot for each biosensor constantly and changing the length of the reaction part of the electrode, the hypoglycemia blood having a blood sugar level of 119 mg / dL was administered 30 times with a blood glucose level of 299 mg / Blood was measured 20 times for blood.
도 10에 도시된 바와 같이, 슬롯의 측벽과 전극의 반응부 사이의 간격(d1, d2)이 슬롯의 폭(Ws)에 대하여 0.05Ws 이상으로 커지면, 고혈당 혈액은 물론 저혈당 혈액에 대해서도 측정값들의 변동계수가 4% 이내의 값을 가지며 높은 수준의 재현성을 나타냄을 알 수 있다. 특히, 상기 간격(d1, d2)이 슬롯(152)의 폭(Ws)에 대하여 0.075Ws 이상 0.2Ws 이하 범위에 해당하는 경우, 변동계수가 3% 이내의 값을 가지며 상대적으로 더 높은 수준의 재현성을 나타냄을 알 수 있다. 다만, 상기 간격(d1, d2)이 0.2Ws보다 커지면 전극의 반응부 면적이 지나치게 감소되어 재현성이 오히려 떨어짐을 알 수 있다.As shown in FIG. 10, when the intervals d1 and d2 between the sidewalls of the slots and the reacting portions of the electrodes become larger than the width Ws of the slot by 0.05 Ws or more, It can be seen that the coefficient of variation has a value within 4% and shows a high level of reproducibility. Particularly, when the intervals d1 and d2 fall within the range of 0.075 Ws to 0.2 Ws with respect to the width Ws of the slots 152, the coefficient of variation has a value within 3% and a relatively higher level of reproducibility . &Lt; / RTI &gt; However, if the intervals d1 and d2 are larger than 0.2 Ws, the area of the reaction area of the electrode is excessively reduced, and the reproducibility is rather lowered.
도 11에는 전극의 연결부 폭에 따른 바이오센서의 변동계수를 나타낸 그래프이다. 도 11과 관련된 실험에서는, 바이오센서별로 전극의 반응부 폭(Wr)을 일정하게 유지하고 전극의 연결부와 연장부의 폭(Wc)을 변경하면서, 혈당량 119 mg/dL의 저혈당 혈액에 대해서는 30회씩, 혈당량 299 mg/dL의 고혈당 혈액에 대해서는 20회씩 혈당량 측정을 진행하였다.11 is a graph showing the coefficient of variation of the biosensor according to the connection width of the electrode. In the experiment related to Fig. 11, 30 times for hypoglycemic blood having a blood glucose level of 119 mg / dL, while maintaining the reaction width Wr of the electrode constant for each biosensor and changing the width Wc of the connecting portion and the extension portion of the electrode, The blood glucose level was measured 20 times for hyperglycemic blood having a blood sugar level of 299 mg / dL.
도 11에 도시된 바와 같이, 연결부와 연장부의 폭(Wc)이 반응부 폭(Wr)에 대하여 0.5Wr 이하로 작아지면, 고혈당 혈액은 물론 저혈당 혈액에 대해서도 측정값들의 변동계수가 4% 이내의 값을 가지며 높은 수준의 재현성을 나타냄을 알 수 있다. 다만, 연결부와 연장부의 폭(Wc)이 0.2Wr보다 작아지면, 실제 구현이 곤란하고 제조 불량이나 단선을 초래하게 된다. As shown in FIG. 11, if the width Wc of the connecting portion and the extending portion is reduced to 0.5 Wr or less with respect to the width Wr of the reaction portion, the coefficient of variation of measured values is within 4% for hyperglycemic blood as well as hypoglycemic blood Value and high level of reproducibility. However, if the width (Wc) of the connecting portion and the extending portion is less than 0.2 Wr, it is difficult to realize the actual implementation, resulting in manufacturing failure and disconnection.
상술한 바와 같이, 본 발명에 따르면, 타깃 바이오 물질이 유입되는 바이오센서의 슬롯 내부 영역에 위치하여 반응 물질이 도포되는 전극의 반응부가, 슬롯의 측벽들과 일정 간격을 두고 이격되어 슬롯의 측벽 근처에 위치하는 반응 물질의 가장자리 부분과 접촉하지 않도록 구성됨으로써, 전극에 도포되는 반응 물질의 가장자리를 따라 반응 물질 입자들이 불균일하게 편중되는 커피링 효과에 불구하고 바이오센서를 이용한 측정값의 정확성과 재현성을 개선하고 측정값의 신뢰성을 보장할 수 있다.As described above, according to the present invention, a reaction part of an electrode to which a reactive material is applied is located in a region of a slot of a biosensor into which a target biomolecule flows, and the reaction part of the electrode is spaced apart from the sidewalls of the slot, So that the accuracy and reproducibility of the measured value using the biosensor can be improved in spite of the coffee ring effect in which the reactant particles are unevenly biased along the edge of the reactive substance applied to the electrode And the reliability of the measured value can be guaranteed.
또한, 전극의 반응부에서 슬롯의 폭 방향으로 연장되어 전극의 단자부에 연결되는 연결부와 함께, 전극의 반응부에서 상기 연결부와 반대 방향으로 연장되어 말단이 슬롯의 외부 영역에 위치하는 연장부가 마련됨으로써, 슬롯을 가진 필름층을 기판에 적층하는 과정에서 슬롯의 폭 방향으로 공차가 발생하는 경우에도 슬롯 내부 영역에 위치하는 전극의 면적을 일정하게 유지할 수 있으며, 그 결과 바이오센서를 이용한 측정값의 정확성과 재현성을 더욱 개선할 수 있다.In addition, an extension part extending in the width direction of the slot in the reaction part of the electrode and connected to the terminal part of the electrode is provided in the reaction part of the electrode so as to extend in the direction opposite to the connection part, , The area of the electrode located in the slot area can be kept constant even when tolerance is generated in the width direction of the slot in the process of laminating the film layer having the slot on the substrate. As a result, And reproducibility can be further improved.
또한, 바이오센서의 슬롯과 전극 간의 구조적 상관관계와, 전극의 반응부, 연결부 및 연장부 간의 구조적 상관관계에 대하여, 새로운 자재나 물질의 적용 없이 바이오센서를 이용한 측정값의 재현성을 높은 수준으로 유지할 수 있는 최적화된 수치 범위가 제공됨으로써, 바이오센서의 설계를 용이하게 하고 바이오센서의 제조에 요구되는 시간과 비용을 절감할 수 있다.Further, regarding the structural correlation between the slot and the electrode of the biosensor and the structural correlation between the electrode reaction part, the connection part and the extension part, the reproducibility of the measurement value using the biosensor can be maintained at a high level without applying new materials or materials By providing an optimized numerical range, it is possible to facilitate the design of the biosensor and reduce the time and cost required for manufacturing the biosensor.
나아가, 본 발명에 따른 실시예들은, 당해 기술 분야는 물론 관련 기술 분야에서 본 명세서에 언급된 내용 이외의 다른 여러 기술적 과제들을 해결할 수 있음은 물론이다.Furthermore, it should be understood that the embodiments according to the present invention can solve various technical problems other than those mentioned in the specification in the related technical field as well as the related art.
지금까지 본 발명에 대해 구체적인 실시예들을 참고하여 설명하였다. 그러나 당업자라면 본 발명의 기술적 범위에서 다양한 변형 실시예들이 구현될 수 있음을 명확하게 이해할 수 있을 것이다. 그러므로 앞서 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 할 것이다. 즉, 본 발명의 진정한 기술적 사상의 범위는 청구범위에 나타나 있으며, 그와 균등범위 내에 있는 모든 차이점은 본 발명에 포함되는 것으로 해석되어야 할 것이다.The present invention has been described with reference to specific embodiments. It will be apparent, however, to one skilled in the art that various modifications may be practiced within the technical scope of the invention. Therefore, the above-described embodiments should be considered from an illustrative point of view, not from a restrictive viewpoint. That is, the scope of the true technical idea of the present invention is shown in the claims, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (6)

  1. 기판; 상기 기판의 일면에 각각 도전성 소재로 패터닝된 적어도 하나의 작업 전극과 적어도 하나의 기준 전극; 타깃 바이오 물질과 전기화학 반응을 일으키는 물질을 포함하며, 상기 작업 전극과 기준 전극이 패터닝된 상기 기판의 일면에 일정 면적으로 도포되어 일부분이 상기 작업 전극의 일부에 적층되고 다른 일부분이 상기 기준 전극의 일부에 적층되는 반응 물질층; 및 상기 작업 전극과 기준 전극이 패터닝된 상기 기판의 일면에 적층되며, 상기 반응 물질층이 노출되도록 일정 폭을 가지며 연장된 슬롯을 구비하는 필름층을 포함하고,Board; At least one working electrode and at least one reference electrode patterned on a surface of the substrate, respectively, with a conductive material; Wherein the working electrode and the reference electrode are coated with a predetermined area on one surface of the substrate on which the working electrode and the reference electrode are patterned and a part of the working electrode is stacked on a part of the working electrode, A layer of reactive material deposited on a portion; And a film layer laminated on one surface of the substrate on which the working electrode and the reference electrode are patterned and having a slot having a predetermined width so as to expose the reactive material layer,
    상기 작업 전극 및 상기 기준 전극은 각각,Wherein the working electrode and the reference electrode each comprise:
    상기 슬롯의 외부 영역에 위치하는 단자부;A terminal portion located in an outer region of the slot;
    상기 슬롯의 내부 영역에 위치하고, 일정 폭을 가지며 상기 슬롯의 폭 방향으로 일정 길이만큼 연장되되 길이 방향 양측 말단이 각각 상기 슬롯의 폭 방향으로 대향하고 있는 상기 슬롯의 측벽과 일정 간격을 두고 이격된 반응부; 및A plurality of spaced-apart reaction slots spaced apart from the sidewalls of the slots, each slot having a predetermined width and extending in a widthwise direction of the slots, part; And
    상기 반응부보다 좁은 폭을 가지며 상기 반응부에서 연장되어 상기 단자부에 연결된 연결부를 포함하는 커피링 효과에 강인한 바이오센서.And a connection portion extending from the reaction portion and connected to the terminal portion, the connection portion being narrower in width than the reaction portion.
  2. 제1항에 있어서The method of claim 1, wherein
    상기 슬롯의 폭이 Ws이고, 상기 슬롯의 측벽과 대향하는 상기 반응부의 길이 방향 말단과 상기 측벽 간의 간격이 d일 때, 아래의 수학식 1을 만족하는 것을 특징으로 하는 커피링 효과에 강인한 바이오센서.When the width of the slot is Ws and the distance between the longitudinal end of the reaction part facing the side wall of the slot and the sidewall is d, the following equation (1) is satisfied: .
    [수학식 1][Equation 1]
    0.075Ws ≤ d ≤ 0.2Ws0.075Ws? D? 0.2Ws
  3. 제1항에 있어서,The method according to claim 1,
    상기 반응부의 폭이 Wr이고, 상기 연결부의 폭이 Wc일 때, 아래의 수학식 2를 만족하는 것을 특징으로 하는 커피링 효과에 강인한 바이오센서.Wherein a width of the reaction part is Wr and a width of the connection part is Wc, the following formula (2) is satisfied.
    [수학식 2]&Quot; (2) &quot;
    0.2Wr ≤ Wc ≤ 0.5Wr0.2 Wr? Wc? 0.5 Wr
  4. 제1항에 있어서,The method according to claim 1,
    상기 작업 전극 및 상기 기준 전극은 각각, 상기 연결부와 동일한 폭을 가지며 상기 반응부에서 연장되어 말단이 상기 슬롯의 외부 영역에 위치하는 연장부를 더 포함하고,Wherein the working electrode and the reference electrode each include an extension portion having the same width as the connection portion and extending in the reaction portion and having an end located in an outer region of the slot,
    상기 연결부와 상기 연장부는, 상기 반응부에서 각각 상기 슬롯의 폭 방향으로 연장되되 서로 반대 방향으로 연장된 것을 특징으로 하는 커피링 효과에 강인한 바이오센서.Wherein the connection portion and the extension portion extend in the width direction of the slot in the reaction portion and extend in opposite directions to each other in the reaction portion.
  5. 제4항에 있어서,5. The method of claim 4,
    상기 슬롯의 폭이 Ws이고, 상기 연장부의 길이가 Le일 때, 아래의 수학식 3을 만족하는 것을 특징으로 하는 커피링 효과에 강인한 바이오센서.Wherein when the width of the slot is Ws and the length of the extended portion is Le, the following expression (3) is satisfied.
    [수학식 3]&Quot; (3) &quot;
    0.2Ws < Le ≤ 0.4Ws0.2Ws <Le? 0.4Ws
  6. 제1항에 있어서,The method according to claim 1,
    상기 슬롯의 폭은, 1.5 mm 이상 3 mm 이하의 범위에 해당하는 것을 특징으로 하는 커피링 효과에 강인한 바이오센서.Wherein the width of the slot corresponds to a range of 1.5 mm or more and 3 mm or less.
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