KR20160063900A - Sensor for Measuring blood glucose and Manufacturing Methods thereof - Google Patents

Abstract

The present invention relates to a blood glucose sensor for measuring blood glucose and a manufacturing method thereof, wherein the method includes the steps of: forming a micro needle array in a blood sensing area on a substrate; and growing carbon nanotubes on the micro needle array to form electrodes and to electrically plate platinum nanoparticles, and more includes a electrode forming step of dividing the blood sensing area into a working electrode area and a counter electrode area which are separated from each other and forming a working electrode (WE), a counter electrode (CE) and a reference electrode (RE) corresponding to the working electrode area, the counter electrode area and a reference electrode area on the micro needle array, thereby minimizing pain to a user due to a needle, performing non-enzymatic measurement not requiring an enzymatic process, and manufacturing a blood gathering unit and a test strip in an integrated type to provide a more convenient blood glucose sensor.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a blood glucose sensor,

The present invention relates to a blood glucose sensor for blood glucose measurement and a method of manufacturing the same.

Diabetes is a type of metabolic disease that lacks insulin secretion or does not function normally. It causes various symptoms and signs due to hyperglycemia, which increases blood glucose level. Many diseases, including diabetes, can detect abnormalities in health through blood sugar, so many of the medical diagnoses often involve blood glucose measurement.

Blood glucose measurement is mainly performed by photometric and electrochemical methods. The photometric method utilizes the oxidation reaction of sugar by peroxidase and peroxidase, and determines the amount of blood glucose using the difference in color after reaction. The electrochemical method is a principle for determining the concentration of blood glucose by measuring the flow of electrons transferred by the continuous redox reaction between the glucose oxidase and the electron acceptor to an electrode built in the glucose sensor. The electrochemical method is a method recently selected mainly because it can reduce the error caused by other substances in the blood as compared with the photometric method, shortens the measurement time of the blood glucose, and is easy to operate.

1 is a view showing a conventional blood glucose sensor 10 used for blood glucose measurement. 1, the conventional blood glucose sensor 10 includes an electrode unit 30 formed on a substrate 40, and an electrode unit 30 such as glucose oxidase (GOX) and ferrocene And a coating film 50 is formed. As shown in FIG. 1, when the blood 20 collected by a separate blood collecting tool is dropped on the coating film 50, the blood glucose oxidizing enzyme is sequentially supplied to the blood vessel 20 and the medium such as ferrocene in the coating film 50 And the oxidation and reduction are repeated. The current generated by the electrochemical process can be measured through the electrode unit 30. Since the amount of the current depends on the blood sugar concentration, the blood glucose concentration can be measured by measuring the amount of current by inserting the blood glucose sensor 10 into the measuring instrument 60.

Although the conventional blood glucose sensor as described above is not shown in the drawing, a separate blood collection tool for blood collection is needed. A commonly used blood collecting tool has a needle having a diameter of several millimeters at its tip, and a needle is pushed out from the blood collecting tool instantaneously by a spring and a button, and a hole is made in the skin of the human body to collect blood. However, these blood collecting tools cause pain and fear to the users, which is causing great pain for the diabetic patients who need to check blood glucose from time to time. In addition, since such a blood collecting tool must be provided separately from the blood glucose sensor, there is a disadvantage that the blood glucose measurement process is cumbersome.

In addition, the conventional blood glucose sensor is an enzyme-based blood glucose sensor coated with an enzyme such as a glucose oxidase. The activity of the enzyme is greatly affected by environmental conditions such as temperature, humidity and pH, Storage and quality control in mass production is difficult, which limits its commercialization.

Therefore, there is a need for a blood glucose sensor that can minimize pain and pain to users, has a convenient blood glucose measurement process, is excellent in stability of characteristics, and is suitable for mass production.

SUMMARY OF THE INVENTION The present invention has been made to solve the problems of the prior art, and it is an object of the present invention to provide a blood glucose sensor capable of minimizing a user's suffering due to blood collection during a blood glucose measurement process.

It is another object of the present invention to provide a blood glucose sensor that is easy to use because it is not necessary to separately provide a blood collecting tool.

It is another object of the present invention to provide a blood glucose sensor that is excellent in stability of characteristics and is suitable for mass production.

According to an aspect of the present invention, there is provided a blood glucose sensor including a micro needle array in which a plurality of micro needles are arranged in a blood sensing area of a substrate, And a working electrode (WE) and a counter electrode (CE) formed on the microneedle array corresponding to the working electrode region and the counter electrode region, respectively.

The reference electrode region may further include a reference electrode region spaced apart from the working electrode region and the counter electrode region, and may include a reference electrode RE formed on the array of the microneedles corresponding to the reference electrode region.

At this time, the working electrode and the counter electrode may include a carbon nanotube forest (CNT forest) grown on the microneedle array, and platinum nanoparticles may be formed on the carbon nanotube forest surface.

Further, it may further comprise an operation connecting electrode, a counter connection electrode, and a reference connection electrode extending from the working electrode, the counter electrode, and the reference electrode, respectively, on the substrate.

According to another aspect of the present invention, there is provided a method of manufacturing a blood glucose sensor, including: forming a micro needle array in which a plurality of micro needles are arranged in a blood sensing area of a substrate; forming a micro needle array in the blood sensing area, And forming an electrode (WE) and a counter electrode (CE) on the array of micro-needles, which are divided into electrode regions and correspond to the working electrode region and the counter electrode region, respectively.

The electrode forming step may include: an electrode area dividing step of dividing the blood sensing area into a working electrode area and a counter electrode area spaced apart from each other; growing carbon nanotubes in the microneedle array corresponding to the working electrode area and the counter electrode area; Forming a carbon nanotube forest (CNT Forest) by depositing platinum nanoparticles on the carbon nanotube forest, and depositing platinum nanoparticles on the working electrode region and the counter electrode region, respectively, . ≪ / RTI >

At this time, the electrode forming step may include forming an iron catalyst as a catalyst layer for growing carbon nanotubes on the surface of the microneedle array corresponding to the working electrode region and the counter electrode region, prior to the carbon nanotube- And forming the second electrode.

The electrode forming step may further include the step of separating the working electrode region and the reference electrode region separated from the counter electrode region in the electrode region dividing step and forming a reference electrode in the array of microneedles corresponding to the reference electrode region And a reference electrode forming step of forming a reference electrode. At this time, the step of forming the reference electrode may include forming silver chloride (AgCl) on the silver surface after depositing silver (Ag).

The step of forming the micro-needle array may include the steps of: forming a mask pattern with a photoresist film in a region where the plurality of micro needles are to be formed; dry-etching the substrate using the mask pattern; And wet etching the substrate.

The method may further include forming a connection electrode extending from the working electrode, the counter electrode, and the reference electrode on the substrate, a counter connection electrode, and a reference connection electrode.

According to the present invention, the blood glucose sensor is provided with a fine microneedle array having a micrometer-level tip, thereby minimizing the user's pain due to blood collection.

Further, according to the present invention, since the micro needle array for collecting blood is integrally provided in the blood glucose sensor, there is no need to provide a separate blood collecting tool, which is convenient to use.

In addition, the present invention uses electrodes having a structure in which a carbon nanotube forest and platinum nanoparticles are formed on a microneedle array, thereby maximizing the surface area of the electroactive region and measuring blood glucose with high sensitivity without enzymes, And is suitable for mass production.

1 is a view showing a conventional blood glucose sensor.
2 is a perspective view of a blood glucose sensor according to the present invention.
3 is a manufacturing flow chart for forming a microneedle array.
4 is a manufacturing flow chart for forming electrodes on a microneedle array.
5 is a scanning electron micrograph of a microneedle array according to an embodiment of the present invention.
6 is a photograph of a surface of a microneedle array and electrodes according to an embodiment of the present invention.
7 is a result of X-ray diffraction analysis of a platinum nanoparticle-plated carbon nanotube forest according to an embodiment of the present invention.
8 is a result of an atomic force microscope analysis of a platinum nanoparticle-plated carbon nanotube forest according to an embodiment of the present invention.
9 is a graph showing a current density response characteristic of a blood glucose sensor according to an embodiment of the present invention.
10 is a graph of current density according to blood glucose concentration of a blood glucose sensor according to an embodiment of the present invention.

The preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings, but the present invention is not limited to or limited by the embodiments. In describing the various embodiments of the present invention, corresponding elements are denoted by the same names and the same reference numerals.

2 is a perspective view of the blood glucose sensor 100 according to the present invention. 2, the blood glucose sensor 100 according to the present invention includes a substrate 110, a microneedle array 150 formed in a blood sensing region of the substrate 110, A working electrode (WE) 200, a counter electrode (CE) 300, a reference electrode (RE) 400, and electrodes (200, 300, 400) And connection electrodes 210, 310, and 410 connected to the substrate 110 and extending to one side of the substrate 110.

The substrate 110 supports the micro needle array 150 and the electrodes 200, 300 and 400 and forms a body of the blood glucose sensor 100. The substrate 110 may have a rectangular plate shape as shown in FIG. The material of the substrate 110 is not particularly limited, but it is preferable to use a silicon (Si) substrate so that the microneedle array 150 can be easily formed using a semiconductor manufacturing process.

The microneedle array 150 is formed on at least a portion of the substrate 110 and has a plurality of sharp micro-needles arranged therein. The microneedle array 150 is configured to penetrate the stratum corneum of the skin and collect blood using the microneedles. The diameter of the distal end of each micro needle can be formed to be very fine in the micrometer range to enable blood collection without pain.

The working electrode 200, the counter electrode 300, and the reference electrode 400 are spaced apart from each other on the upper part of the micro needle array 150 so that the collected blood is not transferred to another blood glucose sensor, So that the blood glucose can be measured. The working electrode 200 and the counter electrode 300 include a carbon nanotube forest and metal nanoparticles coated thereon grown on the microneedle array 150. The metal nanoparticles are platinum Pt, Nanoparticles. In this case, the carbon nanotubes are preferably multi-walled carbon nanotubes, but the present invention is not limited thereto, and single-walled carbon nanotubes may be used. An insulating layer for insulating the electrodes 200, 300, and 400 from the substrate 110 and a catalyst layer for growing the carbon nanotubes may be formed between the micro needle array 150 and the carbon nanotubes. The insulating layer may include a silicon oxide layer, and the catalyst layer may include iron (Fe).

The reference electrode 400 may be spaced apart from the working electrode 200 and the counter electrode 300 and may include a stacked structure of silver (Ag) and silver chloride (AgCl). The silver chloride (AgCl) may be a structure formed on the silver (Ag) layer in the form of nanoparticles. Further, another layer, for example, a titanium (Ti) layer may be further formed between the silver (Ag) layer and the substrate 110.

The connection electrodes 210, 310, and 410 are electrically connected to the electrodes 200, 300, and 400 to extend to one side of the substrate 110. The electrodes 200, 300, To the meter of the meter. The working connection electrode 210 is electrically connected to the working electrode 200 and the counter connection electrode 310 is electrically connected to the counter electrode 300 and the reference connection electrode 410 is electrically connected to the reference electrode 400. The connection electrodes 210, 310, and 410 may be formed of copper (Cu) or gold (Au), but are not limited thereto.

Since the blood glucose sensor 100 according to the present invention having such a structure can form a micro needle array 150 having a fine tip and perform blood collection through it, it is possible to minimize the pain of the user due to blood collection . Further, since the micro needle array for collecting blood is integrally provided in the blood glucose sensor, it is not necessary to provide a separate blood collecting tool, which is convenient to use. Further, by using an electrode having a structure in which carbon nanotube forest and platinum nanoparticles are formed on the elongated micro needle array 150, the surface area of the electroactive area of the electrode is maximized, Can be measured.

Although the reference electrode 400 is shown in FIG. 2, the reference electrode 400 should be understood as an optional configuration. That is, when a two-electrode system is used without using a three-electrode system, only the working electrode 200 and the counter electrode 300 may be formed without the reference electrode 400.

According to the blood glucose sensor 100 of the present invention, the blood collected by the micro needle array 150 directly contacts the electrodes 200, 300, and 400, and the blood glucose concentration in the blood depends on the measurement current value The blood glucose concentration is measured. Such a working principle is well known in the art, so detailed description is omitted.

A method of manufacturing a blood glucose sensor according to the present invention will be described with reference to FIGS. 3 and 4. FIG. FIG. 3 is a manufacturing flow chart for explaining a method of forming the microneedle array 150, and FIG. 4 is a flow chart for explaining a method of forming the electrodes 200, 300, 400 on the microneedle array 150. FIG. to be. 3 and 4 conceptually show only the portion of the blood glucose sensor 100 where the microneedle array 150 and the electrodes 200, 300 and 400 are formed. In the case of using a silicon (Si) substrate as a substrate, .

3, a silicon (Si) wafer is prepared as a substrate 110, and a photoresist (PR) film is applied to the surface of the wafer. The photoresist film may be formed by spin coating and may be subjected to hexamethyldisilane (HMDS) priming treatment to improve the adhesion between the silicon wafer and the photoresist film prior to application of the photoresist.

After the photoresist film is applied, an exposure process for pattern formation is performed. After the exposure process, a photoresist pattern is formed by developing using a developer (c). A soft-baked process for evaporating the solvent in the photoresist film before the exposure process can be performed. In addition, a hard-baked process for removing the solvent, water, etc., absorbed in the photoresist film may be performed after the development process.

Thereafter, the dry etching process of the silicon wafer is performed using the formed photoresist pattern as an etching mask (d). The dry etching process can use a plasma etching process, and the ions formed by the plasma are vertically incident on the surface of the silicon wafer, so that a columnar silicon columnar array having a long columnar shape in the vertical direction as shown in FIG. 3 (d) can be formed. At this time, the rectangular silicon pillars can be formed to have a width of about 100 탆 x 100 탆 and a length of several hundred 탆.

Then, the photoresist film remaining on the silicon pillar array formed through the dry etching is removed (e), and the wet etching process is performed (f). As the wet etching solution, a mixture of hydrofluoric acid (HF) and nitric acid (HNO ₃ ) can be used. In the wet etching process, unlike the dry etching, there is no directionality of the etching, and the etching rate at the corner portion of the silicon column is relatively larger, so that a sharp and sharp needle-like array as shown in FIG. 3 (f) can be formed. The tip diameter of each microneedle formed at this time may be several 占 퐉 or less.

Next, a process of forming an electrode for blood glucose sensing on the microneedle array 150 will be described with reference to FIG. First, an insulating film is deposited on the silicon substrate on which the microneedle array 150 is formed to insulate the substrate 110 from the electrodes 200, 300, and 400 and the electrodes (a). At this time, a silicon oxide film (SiO ₂ ) can be used as an insulating film.

Next, as shown in FIG. 4B, a catalyst layer for growing carbon nanotubes is formed on the microneedle array 150 using a shadow mask in which only the region where the working electrode 200 and the counter electrode 300 are to be formed is opened . The catalyst layer may be an iron (Fe) catalyst layer and may be formed through vacuum electron beam evaporation to a thickness of 5 nm. The catalyst layers formed in the regions of the working electrode 200 and the counter electrode 300 by the shadow mask can be formed to be separated from each other.

The carbon nanotube forests formed in the working electrode 200 and the counter electrode 300 are separated from each other by selective growth on the catalyst layer. The carbon nanotube forming process may be a known process, and is not limited to the specific process in the present invention. After forming the carbon nanotube forest, metal nanoparticles are formed on the surface of the carbon nanotube forest (c). The metal nanoparticles may be platinum nanoparticles and may be formed by electroplating using hexachloroplatinic acid hydrate (H ₂ PtCl ₆ ). In this case, the platinum nanoparticles formed on the surface of the carbon nanotube forest can be formed with a diameter ranging from 50 to 100 nm.

In the case of the three-electrode blood glucose sensor including the reference electrode 400, the reference electrode forming step of FIG. 4D is further performed. The reference electrode forming step may be performed using a shadow mask in which only the reference electrode forming region in which the working electrode 200 and the counter electrode 300 are formed is spaced apart from the reference electrode forming region as shown in FIG. . As a reference electrode, silver (Ag) / silver chloride (AgCl) can be used. First, a 300 nm thick silver (Ag) layer is deposited through a shadow mask having a pattern corresponding to a reference electrode, (AgCl) can be formed on the silver (Ag) surface. Chloride treatment can be performed, for example, by flowing a predetermined current in a 1 M KCl / HCl buffer solution, and silver chloride (AgCl) nanoparticles can be formed on silver (Ag) surfaces in this manner. Further, an adhesion layer such as a titanium (Ti) layer or a chromium (Cr) layer of about 100 nm thick may be further deposited to improve the adhesion of the silver (Ag) layer to the substrate before the silver (Ag) layer is deposited.

In FIG. 4, the reference electrode 400 is formed after the working electrode 200 and the counter electrode 300 are formed. However, the order may be changed. Although not shown in FIG. 4, an operation connecting electrode 210, which is electrically connected to the working electrode 200, the counter electrode 300, and the reference electrode 400 on the substrate and extends to the surface of the substrate 110, The relative connection electrode 310 and the reference connection electrode 410 may be formed. The connection electrodes 210, 310, and 410 may not be formed after the electrodes 200, 300, and 400 are formed, but may be formed beforehand.

In order to eliminate the possibility that the carbon nanotube forest grown vertically on the microneedle array 150 is peeled off from the surface of the microneedle array to be lost into the body in the course of blood collection through the stratum corneum of the skin, The carbon nanotube forest may be collapsed by immersing the electrode forming part in the ethanol after the step of forming the counter electrode 200 and the counter electrode 300.

Hereinafter, the specific structure of the blood glucose sensor according to the present invention and the blood glucose sensing characteristics will be described as examples.

<Examples>

The blood glucose sensor was manufactured according to the manufacturing method of the present invention and the structures of the micro needle array 150 and the electrodes were analyzed by a scanning electron microscope (SEM) and a transmission electron microscope (TEM). 5 (a) is an SEM photograph of a silicon column array after dry etching the silicon substrate, and FIG. 5 (b) is an SEM photograph of the microneedle array 150 after wet etching. From the SEM image of FIG. 5, after the dry etching, a rectangular column was formed. However, it was confirmed that the wet etching was performed to form a very sharp and sharp micro needle array 150. The tip diameter of each micro needle was a very fine shape smaller than 1 mu m.

6 (a) is a TEM photograph of a multi-walled carbon nanotube formed on a microneedle array 150, and FIG. 6 (b) is a SEM photograph of a multi-walled carbon nanotube forest grown on a tip of a microneedle. to be. FIG. 6 (c) is an SEM photograph of the platinum nanoparticles formed on the surface of the carbon nanotube forest. It was confirmed that the platinum nanoparticles of about 50 to 100 nm size were uniformly formed. 6 (d) is an SEM image of silver chloride (AgCl) nanoparticles formed on the silver (Ag) reference electrode surface. It was confirmed that silver chloride nanoparticles having a size of about 260 nm were uniformly formed.

The crystal structure of the platinum nanoparticle-plated carbon nanotube forest was analyzed by X-ray diffraction (XRD), and the results of the analysis are shown in FIG. (111), (200) and (220) plane diffraction peaks were observed at about 39.68, 46.4 and 67.7 degrees, respectively, and the (002) plane of carbonized carbon at 26 degrees Can be confirmed.

Atomic Force Microscope (AFM) analysis was performed to analyze the average surface roughness of the carbon nanotube forest formed with platinum nanoparticles, and the results of the analysis are shown in FIG. Analysis of AFM data showed that the average surface roughness of the carbon nanotube forest with platinum nanoparticles was 150 ± 16 nm. This roughness largely differs from the roughness of the platinum surface deposited on the plane of 0.493 + - 0.3 nm, and it can be seen that the surface area of the electrode portion is greatly increased by the constitution of the present invention.

9 and 10 show the current density response characteristics of the ineffective glucose sensor manufactured according to the embodiment of the present invention. FIG. 9 is a graph obtained through a cronoamperometry which is a current density response measurement method. In FIG. 9, 3 mM of glucose is added to 0.01 M PBS (Phosphate Buffered Saline; Ph 7.4) solution containing an electrode portion of a glucose sensor It is the result of measuring the current density in the concentration range of 3 ~ 20mM. As a result, the measurement current increased linearly with each addition of blood glucose.

FIG. 10 shows the result of calculating the current response characteristic according to the blood glucose concentration after repeating the experiment of FIG. 9 several times. Referring to FIG. 10, it can be seen that the current density linearly increases with blood glucose concentration in the range of 3 to 20 mm, and the sensitivity was 17.73 ± 3 μA / mM-cm ² . This high sensitivity is achieved by the unique configuration of the present invention in which a carbon nanotube forest and platinum nanoparticles are formed in a microneedle array, and can be expected only when using only platinum nanoparticles or using carbon nanotubes and platinum nanoparticles. No result.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention. Accordingly, the scope of protection of the present invention should be determined by the description of the claims and their equivalents.

10, 100: blood sugar sensor
20: blood
30:
40, 110: substrate
150: Micro needle array
200: working electrode
210: Working connection electrode
300: counter electrode
310: Relative connecting electrode
400: reference electrode
410: Reference connecting electrode

Claims (13)

A microneedle array forming step of forming a microneedle array in which a plurality of microneedles are arranged in a blood sensing area of a substrate; And
The blood sensing region is divided into a working electrode region and a counter electrode region which are spaced apart from each other,
And an electrode forming step of forming a working electrode (WE) and a counter electrode (CE) on the microneedle array corresponding to the working electrode area and the counter electrode area, respectively. The method according to claim 1,
The electrode forming step may include:
An electrode region dividing step of dividing the blood sensing region into a working electrode region and a counter electrode region which are spaced apart from each other;
Forming a carbon nanotube forest (CNT forest) by growing carbon nanotubes on the microneedle array corresponding to the working electrode region and the counter electrode region; And
Depositing platinum nanoparticles on the carbon nanotube forest and depositing platinum nanoparticles on the working electrode region and the counter electrode region, respectively;
Wherein the blood glucose sensor is a blood glucose sensor. 3. The method of claim 2,
The electrode forming step may include:
Forming an iron catalyst as a catalyst layer for growing carbon nanotubes on the surface of the microneedle array corresponding to the working electrode region and the counter electrode region before the step of forming the carbon nanotubes Wherein the blood glucose sensor is a blood glucose sensor. 3. The method of claim 2,
The electrode forming step may include:
In the electrode region dividing step, the reference electrode region spaced apart from the working electrode region and the counter electrode region is further divided,
And forming a reference electrode on the array of microneedles corresponding to the reference electrode region. The method according to claim 1,
The microneedle array forming step may include:
Forming a mask pattern with a photoresist film in a region where the plurality of microneedles are formed;
Dry-etching the substrate using the mask pattern;
Removing the mask pattern; And
Wet etching the substrate;
Wherein the blood glucose sensor is a blood glucose sensor. 5. The method of claim 4,
Wherein forming the reference electrode comprises:
And forming silver chloride (AgCl) on the silver surface after depositing silver (Ag). 3. The method according to claim 1 or 2,
Further comprising a connection electrode forming step of forming an operation connection electrode and a counter connection electrode extending from the working electrode and the counter electrode on the substrate, respectively. 5. The method of claim 4,
Further comprising forming a connection electrode extending from the working electrode, the counter electrode, and the reference electrode on the substrate, a counter connection electrode, and a reference connection electrode, respectively. A micro needle array in which a plurality of micro needles are arranged in a blood sensing area of a substrate; And
Wherein the blood sensing area includes a working electrode area and a counter electrode area spaced from each other,
A working electrode (WE) and a counter electrode (CE) formed on the microneedle array corresponding to the working electrode region and the counter electrode region, respectively;
. 10. The method of claim 9,
Further comprising a reference electrode region spaced apart from the working electrode region and the counter electrode region,
Further comprising a reference electrode (RE) formed on the array of micro-needles corresponding to the reference electrode region. 10. The method of claim 9,
Wherein the working electrode and the counter electrode are electrically connected to each other,
And a carbon nanotube forest (CNT Forest) grown on the microneedle array. 12. The method of claim 11,
And platinum nanoparticles are formed on the surface of the carbon nanotube forest. 11. The method of claim 10,
Further comprising: an operation connection electrode, a counter connection electrode, and a reference connection electrode extending from the working electrode, the counter electrode and the reference electrode on the substrate, respectively.

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