JP2007000483A - Needle-integrated biosensor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a needle-integrated biosensor capable of efficiently feeding the blood collected after the puncture into the biosensor. <P>SOLUTION: The biosensor is composed of the biosensor with electrodes and a spacer disposed in the space formed between two electrical insulating substrates, and a puncture needle disposed inside the biosensor for puncturing the skin of a subject to collect the bodily fluid, which are integrated with each other via a puncture needle support body. In the biosensor, a puncture blood collection port at the tip of the puncture needle is sealed with a soft material which can be punctured, and the gap between the two substrates and the puncture needle support body in the rear of the puncture needle is sealed with an elastic material, so that the interior of the biosensor is retained under the negative pressure. The needle-integrated biosensor sucks and collects blood and measures the detected component of the blood as the puncture needle receives the driving from outside to puncture both the soft material and the skin at the same time. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a needle-integrated biosensor. More particularly, the present invention relates to a needle-integrated biosensor having a configuration in which a puncture needle for piercing the skin to obtain blood and a biosensor for collecting and analyzing body fluid taken on the surface of the skin are integrated.

Conventionally, a diabetic patient himself collects blood and measures a blood glucose level which is a glucose level in blood. In this case, the patient uses a blood collection device called a lancet to attach and detach the blood collection needle, collect blood by inserting a blood collection needle into his / her fingertip or arm, etc., and transfer the collected blood to a blood glucose analyzer to measure the blood glucose level. is doing. In such a measurement method, the patient must carry a set of measuring instruments consisting of several points such as a blood glucose analyzer, a lancet, a blood collection needle and an analytical element, and combine them when necessary to perform the measurement. However, it takes a lot of training and it takes a considerable amount of time before the patient can make reliable measurements. Actually, measurements at sites other than the fingertip and forearm (abdominal wall, earlobe, etc.) are difficult even for a skilled person. In recent years, biosensors that can be measured with a sample volume of 1 μl or less have been developed due to the need for less invasive specimen supply with less pain. The work of supplying accurately becomes very difficult. As a result, the measurement fails, and the patient who is the subject has the inconvenience of having to puncture again and replacing the biosensor and restart the measurement.
JP-A-9-266898 Japanese Patent Publication No. 8-20412

Thus, several needle-integrated biosensors have been devised. First, in the needle-integrated biosensor disclosed in Patent Document 3, the puncture needle and the biosensor are placed in different positions in a pen-type (two-color ballpoint pen-like) measuring device equipped with a puncture needle drive unit. The blood glucose is measured by placing the tip of the pen-like measuring device against the skin of the subject and puncturing it, exposing the biosensor to the tip, and collecting blood. However, in this method, the troublesomeness of setting the needle and the biosensor in the measuring device has not been solved.
JP 2000-217804 A

Further, in the needle integrated biosensor disclosed in Patent Document 4, the puncture needle is entrusted to external drive, and the puncture needle moves in parallel along the longitudinal direction of the elongated piece-like biosensor. Have taken. However, in this type, the puncture needle is exposed from the biosensor, so a cover that protects the tip of the puncture needle is necessary, and in order to send blood collected after puncture to the biosensor, only capillary action is used. It was.
Republished 2002-056769

  Furthermore, the conventional needle-integrated biosensor has a complicated structure, has a large amount of blood collected as a sample solution, and has an influence such as entering a useless space.

  An object of the present invention is to provide a needle-integrated biosensor capable of efficiently feeding blood after puncture into a biosensor.

  The object of the present invention is to collect a body fluid by piercing the biosensor provided with electrodes and spacers in a space between two electrically insulating substrates, and the skin of the subject placed in the biosensor. In the biosensor in which the puncture needle to be integrated with the puncture needle support is formed, the puncture blood collection port at the tip of the puncture needle is sealed with a puncturable soft material, and the rear portion of the puncture needle Uses a stretchable material to seal the gap between the two substrates and the puncture needle support, while keeping the inside of the biosensor at a negative pressure, and the puncture needle is driven from the outside to remove both the soft material and the skin. This is achieved by a needle-integrated biosensor that is characterized by sucking blood and measuring a detected component by piercing at the same time.

  Since the needle-integrated biosensor according to the present invention uses a suction means in addition to capillary action when feeding blood into the biosensor, it can efficiently feed blood after puncture into the biosensor. it can. Moreover, since the puncture needle is contained in the biosensor, a cover for protecting the tip is not necessary, and the safety is excellent. Further, when the puncture needle is arranged in parallel with the long axis direction of the electrode, the puncture needle is contaminated with the reagent because the contact between the reagent layer formed on the electrode and the puncture needle can be avoided. It is possible to avoid problems such as.

  As the substrate, it is sufficient if it is electrically insulating, for example, plastic, biodegradable material, paper or the like is used, and preferably two sheets of polyethylene terephthalate are used.

  The electrode is formed on the substrate by a screen printing method, a vapor deposition method, a sputtering method, a foil pasting method, a plating method, etc., and the materials include carbon, silver, silver / silver chloride, platinum, gold, nickel, copper, Examples include palladium, titanium, iridium, lead, tin oxide, and platinum black. Here, as the carbon, carbon nanotubes, carbon microcoils, carbon nanohorns, fullerenes, dendrimers, or derivatives thereof can be used.

  The electrode may be a two-pole method formed by a working electrode and a counter electrode or a three-pole method formed by a working electrode and a counter electrode, a reference electrode, or an electrode method having more poles. Here, when the three-pole method is adopted, in addition to the electrochemical measurement of the measurement target substance, it is possible to measure the moving speed of the blood sample introduced into the conveyance path, thereby measuring the hematocrit value. Moreover, you may be comprised by 2 or more sets of electrode systems. These electrodes are formed on a single substrate or separately on two substrates.

  A reagent layer (electrode reaction part) can be formed on the substrate on which the electrode is formed. The reagent layer is formed by a screen printing method or a dispenser method, and the reagent layer can be immobilized on the electrode surface or the substrate surface by an adsorption method involving drying or a covalent bonding method. Examples of the reagent disposed in the electrode reaction part of the biosensor include those containing glucose oxidase as an oxidase and potassium ferricyanide as a mediator when configured for blood glucose measurement. When the reagent is dissolved by the blood, the enzyme reaction is started. As a result, potassium ferricyanide coexisting in the reaction layer is reduced and potassium ferrocyanide, which is a reduced electron carrier, is accumulated. The amount is proportional to the substrate concentration, ie the glucose concentration in the blood. The reduced electron carrier accumulated for a certain time is oxidized by an electrochemical reaction. An electronic circuit in the measurement apparatus main body, which will be described later, calculates and determines a glucose concentration (blood glucose level) from the anode current measured at this time, and displays it on a display unit arranged on the surface of the main body.

  In addition, a surfactant and lipid can be applied around the blood collection port and on the surface of the electrode or reagent layer (electrode reaction part). By applying a surfactant or lipid, the sample can be moved smoothly.

  Here, there is a possibility that the puncture needle contained in the inside of the sample conveyance path is contaminated by the application of the reagent layer, surfactant or lipid into the sample transport path. In order to prevent such contamination, it is preferable not to apply these reagents around the tip of the puncture needle.

  In the biosensor in which the reagent layer is provided on the electrode filled with the above blood collection, the blood collection and the reagent react when the blood collected from the blood collection port contacts the reagent layer on the electrode. This reaction is monitored as an electrical change at the electrode.

  These electrodes may be defined by a resist layer. The resist is not particularly limited as long as it does not react or dissolve with the substrate, and examples thereof include ultraviolet curable vinyl / acrylic resins, urethane acrylate resins, and polyester acrylate resins. The purpose of using the resist is mainly to clarify the electrode pattern and to clarify the definition of the electrode area, but there are other purposes such as insulating the sample transport path where no reagent layer is present. In order to achieve the latter purpose, the resist layer is preferably provided on a substrate on which an electrode is formed. Further, by providing the resist layer thicker than the electrode, contact between the puncture needle and the electrode can be suppressed. Such a resist layer can be formed by a screen printing method or the like. For example, the resist layer is formed with a thickness of about 5 to 500 μm, preferably about 10 to 100 μm, using any of the above materials, and the resist layer is used as a spacer. Also works.

  The two substrates are bonded via an adhesive such as an acrylic resin adhesive to constitute a biosensor. Such an adhesive layer can also be formed by a screen printing method, and is formed with a thickness of about 5 to 500 μm, preferably about 10 to 100 μm, and such an adhesive layer acts as a spacer as well as a resist layer. In addition, the said reagent can also be contained in an adhesive bond layer. The adhesive layer may be either the same pattern as the resist layer or a different pattern.

  In the sample transport path of the biosensor, for example, a puncture needle for puncturing the subject's skin and collecting body fluid is arranged in parallel with the long axis direction of the electrode.

  About the puncture needle for collecting body fluid from the skin of the subject, it is necessary to penetrate the soft material described later and further puncture the subject. In order to suppress pain during puncture, a thin puncture needle is preferable. Specifically, a 21-33 gauge thing by Terumo company is used. The puncture needle may be a hollow needle or a rod-like needle as long as it can penetrate the subject's skin. Furthermore, since the puncture needle needs to be hygienicly stored in the biosensor until it is used, a photocatalytic function effective for antibacterial and antiviral effects may be imparted to the needle tip surface. In that case, a film of titanium oxide or titanium dioxide is desirable.

  The puncture blood collection port of the biosensor having the above configuration is covered with a soft material such as silicone rubber, soft polyurethane, polyvinyl chloride, or polystyrene foam, and on the puncture driving side, two substrates and a puncture needle constituting the biosensor The support is configured to be sealed with an elastic material (elastic material) such as natural rubber. When such a biosensor is manufactured, the inside of the biosensor sample conveyance path is set to a negative pressure rather than an external pressure by sealing the inside of the sensor under a negative pressure condition, preferably a vacuum condition, than the outside air. The Thus, in the needle-integrated biosensor according to the present invention, in order to smoothly collect blood after puncturing, the suction means is used in combination with the movement of blood collection into the sample transport path in addition to the capillary phenomenon. At this time, immediately after the puncture, the puncture needle is further pulled in the direction opposite to the puncture direction, so that the stretchable material is stretched and the negative pressure inside can be further increased to suck the blood sample.

  The needle-integrated biosensor according to the present invention is desirably set in a measuring device equipped with a puncture drive to perform a series of operations of puncture, blood collection, and measurement. In this case, for example, it is desirable that the puncture drive has a mechanism in which the needle penetrates the soft material of the biosensor and breaks through the skin of the subject, and a mechanism that quickly returns to the original position immediately after the puncture.

  Furthermore, the puncture drive system in the measuring device can be further improved in order to increase the suction force during blood collection by the needle-integrated biosensor. That is, by using a mechanism for returning the puncture needle to its original position immediately after puncture, the stretchable material is extended as described above by further pulling the puncture needle in the direction opposite to the puncture direction, and the internal negative pressure is further increased. It can also be made stronger.

  As a measuring device for a needle-integrated biosensor, a measuring device that uses operability and durability to ensure repeatable and reliable measurement using a needle-integrated biosensor and is easy to carry is used. Insert the needle-integrated biosensor into the introduction part at the bottom so that the puncture needle support is facing upward, and the terminal of the biosensor is connected to the connector of the measuring device, so that measurement is possible. The preparation for the measurement is completed by pulling the trigger to give the puncture drive to the inside of the needle integrated biosensor, and then the puncture, blood collection, and measurement are automatically activated by pressing the puncture start button switch. A system that finally leads to measurement results is used.

  An example of the structural features of the measuring device will be described in more detail. In this measurement apparatus, the puncture needle drive unit and the measurement apparatus unit are integrated, and the puncture needle drive unit includes a trigger unit, a puncture start button unit, and a drive unit using an elastic body such as a spring. On the other hand, for the measuring device section, the sensor introduction section, the connector, the electrochemical measurement circuit, the memory section, the operation panel, the measurement section that measures the electrical values at the electrodes of the biosensor, and the display that displays the measurement values at the measurement section Further, a radio wave, for example, Bluetooth (registered trademark) can be mounted as a wireless means. With such a slide structure, since the puncture drive is received while the needle-integrated biosensor is securely held, the strength of the entire measuring apparatus can be increased.

  The puncture drive of the measuring device is preferably a mechanism that returns quickly after tapping the upper part of the needle-integrated biosensor in the vertical direction, and preferably has a mechanism that can adjust the depth at which the skin of the subject is punctured.

  The measuring device must have voice guidance and voice recognition functions for visual impairment caused by diabetes, measurement data management functions using the built-in radio clock, communication functions for medical data such as measurement data, and charging functions. Can do.

  A measurement method in the measurement unit of the measurement apparatus is not particularly limited, and potential step chronoamperometry, coulometry, cyclic voltammetry, or the like can be used.

As described above, the needle-integrated biosensor of the present invention does not limit the user, that is, can handle a universal project.

  The needle-integrated biosensor according to the embodiment of the present invention will be described in detail with reference to the drawings. However, the present invention is not limited to the following examples unless it exceeds the gist.

  FIG. 1 shows an assembly example of the needle-integrated biosensor of the present invention. FIGS. 1a) to e) are examples of manufacturing a needle-integrated biosensor, i) and iii) are constituent materials required for manufacturing the needle-integrated biosensor, and ii) shows a molded body thereof. FIG. 1a) shows a plate member and a resist layer 6 on which a conductor 7 is formed on the surface of the lower substrate 1 of the biosensor. The resist layer 6 serves not only as a spacer 2 but also to define the electrode area and to prevent contact between the electrode surface and the puncture needle. Therefore, the through-hole 4 is provided in the resist 6 layer. Here, the lower substrate 1 and the upper substrate 9 can be used safely by rounding the corners. FIG. 1 b) shows how the adhesive layer 5 is formed on the resist layer 6. Here, since the adhesive layer 5 is also provided between the plate members of the lower substrate 1 and the upper substrate 9, it plays the role of the spacer 2 like the resist layer 6. Further, FIG. 1b) ii) shows an electrode 10 and its electrode reaction part 13 whose area is defined by the resist layer 6 and the adhesive layer 5. FIG. 1 c) shows a state in which the stretchable material 16 is provided so as to cover the lower part of the adhesive layer 5. The elastic member 16 bonds the puncture needle portion 14 and the lower substrate 1 as shown in FIG. 1d), and the upper substrate 9 is covered in this state, so that the puncture needle portion 14 and the upper substrate 16 are covered as shown in FIG. 1e). The substrates 9 are bonded to each other, and finally the inside of the puncture needle passage 8 forming the sample transport path is shut off from the outside air. As shown in FIG. 1 d) i), the puncture needle portion 14 is composed of a puncture needle 20, a support 19 that supports the puncture needle 20, and an external drive connection portion 17. The external drive connection portion 17 is a measurement device equipped with a puncture drive. By being connected, it is possible to obtain a puncture drive from the measuring device. Further, FIG. 1 d) shows that the puncture needle portion 14 is arranged in parallel with the long axis direction of the electrode 10. As shown in this figure, the puncture needle portion 14 has a structure in which contact with the electrode surface 10 can be avoided by forming the resist layer 6. Further, in FIG. 1e), a layer of a soft material 15 is formed in the vicinity of the puncture blood collection port 12 of the needle-integrated biosensor 3, thereby maintaining the airtightness inside the sensor.

  FIG. 2 is a cross-sectional view showing a configuration example of the needle-integrated biosensor 3 shown in FIG. FIG. 2b) shows a longitudinal section through the center line shown in FIG. 2a). As shown in this figure, a puncture needle portion 14 is arranged on the surface of a pattern provided on the lower substrate 1 of the biosensor. Further, the puncture needle portion 14 is fixed to the lower substrate 1 and the upper substrate 9 by an adhesive member 23 by an elastic material 16. FIG. 2c) shows a cross-sectional view along B-B 'shown in FIG. 2a). A puncture needle portion 14 is disposed at the center of the lower substrate 1 and the upper substrate 9.

  FIG. 3 shows an example of use of the needle-integrated biosensor 3 shown in FIGS. In FIG. 3, steps a) to d) are shown. In i) and ii), the state of the needle-integrated biosensor 3 at that time is shown in i), and ii) is a needle-integrated biosensor shown in i). It is shown in a centerline longitudinal section of the sensor. FIG. 3a) shows a state before use of the needle-integrated biosensor 3 connected to a measuring device with a puncture drive. At this time, the skin as the subject is in close contact with the soft material 15 provided in the puncture blood sampling port 12 of the needle-integrated biosensor 3. FIG. 3 b) shows the state of puncture, and shows the state where the puncture needle 20 penetrates the soft material 15. Although not shown, the puncture needle 20 also pierces the skin at this time. Further, it can be seen that the elastic material 16 is contracted. FIG. 3c) shows a state where the puncture needle portion 14 has returned to its original position after puncturing. Here, the soft material 15 penetrated by the puncture needle 20 is shown. In this state, the negative pressure in the biosensor is applied to the punctured skin. FIG. 3d) shows a state in which the blood collection 24 from the punctured skin is subsequently sucked by the internal negative pressure (ii-1). 3d) In ii) -2, the puncture needle portion of the needle-integrated biosensor 3 in the state of ii-1 is held by pressing and fixing both sides of the needle-integrated biosensor 3 with the pressing tool 25 of the measuring device. 14 can be pulled in a direction opposite to the puncturing direction, and the inside of the sensor is further under negative pressure. At this time, it can be seen that the elastic material 16 is stretched.

  FIG. 4 shows an example of a measurement device 26 with a puncture drive to which the needle integrated biosensor of the present invention can be attached. FIG. 4 a) shows a state before the needle-integrated biosensor 3 is introduced into the measuring device 26. The measurement apparatus will be described with reference to this figure. The measuring device 26 includes an introduction part 27 of the needle-integrated biosensor 3, a trigger part 28 for puncture driving, an operation panel 29, and a puncture start button 33. A display unit 30 and operation buttons 31 are provided on the operation panel 29, and a non-slip tool 34 is provided on the puncture start button 33. FIG. 4B shows a state in which the sensor 3 is introduced into the measuring device 26 and the trigger 28 at the top is pulled to turn on the measuring device and enter the measurement mode. FIG. 4C shows the state after the sensor 3 is introduced into the measuring device 26 from the side. As shown in the figure, a hook 35 is provided on the back side of the display unit so that the measuring device main body can be easily stored in a breast pocket or an inner pocket. 4D shows a state when the sensor 3 and the measuring device 26 are viewed from below. FIG. 4E shows a case where the sensor 3 is inserted into the measuring device 26 from below. The sensor 3 is the one shown in FIG.

It is a figure which shows the assembly example of the needle-integrated biosensor according to the present invention. It is a figure which shows one structural example of the needle-integrated biosensor according to the present invention. It is a figure which shows the usage example of the needle | hook integrated biosensor which concerns on this invention. It is a figure which shows one structural example of the measuring apparatus with a puncture drive for the needle | hook integrated biosensor which concerns on this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Lower substrate 2 Spacer 3 Needle-integrated biosensor 4 Through hole 5 Adhesive layer 6 Resist layer 7 Conductor 8 Sample transport path / puncture needle path 9 Upper substrate 10 Electrode 11 Terminal 12 Puncture blood sampling port 13 Electrode reaction part (reagent layer) )
14 Puncture needle part 15 Soft material 16 Stretch material 17 External drive connection part 19 Puncture needle support body 20 Puncture needle 23 Adhesion part 24 Blood collection 25 Presser 26 Puncture drive built-in measuring device 27 Needle integrated biosensor introduction part 28 Trigger part 29 Operation Panel 30 Display unit 31 Operation button 33 Puncture start button 34 Non-slip tool 35 Hook

Claims (14)

A biosensor provided with electrodes and spacers in a space sandwiched between two electrically insulating substrates, and a puncture needle for puncturing the skin of a subject placed in the biosensor and collecting body fluid In the biosensor configured integrally through the puncture needle support,
The puncture blood collection port at the tip of the puncture needle is sealed with a puncturable soft material, and the rear part of the puncture needle seals the gap between the two substrates and the puncture needle support with a stretchable material, and the biosensor Keep the inside negative pressure,
A needle-integrated biosensor characterized in that the puncture needle is driven from the outside to pierce both the soft material and the skin at the same time to collect blood by suction and measure a detected component.   The needle-integrated biosensor according to claim 1, wherein a reagent layer is provided on and / or around the electrode.   The needle-integrated biosensor according to claim 1, wherein the spacer is composed of a resist layer and / or an adhesive layer.   The needle-integrated biosensor according to claim 3, wherein the resist layer is formed thicker than the electrode.   The needle-integrated biosensor according to claim 1 or 2, wherein the puncture needle is installed in the biosensor in parallel with the major axis direction of the electrode.   The needle-integrated biosensor according to claim 1 or 2, wherein the soft material is a gel, an elastic material, or a foamable material.   The needle-integrated biosensor according to claim 6, wherein the elastic material is silicone rubber.   The needle-integrated biosensor according to claim 1 or 2, wherein the stretchable material is natural rubber.   Immediately after puncturing, by pulling the puncture needle support in the direction opposite to the puncture direction, the stretchable material provided between the rear part of the puncture needle, the biosensor substrate and the cover is extended, and further the negative pressure inside the biosensor The needle-integrated biosensor according to claim 1 or 2, wherein   The needle-integrated biosensor according to any one of claims 1 to 9, wherein a series of operations of puncturing, blood collection, and measurement are automatically performed by a measuring device for a needle-integrated biosensor having a puncture drive. .   The needle-integrated biosensor according to any one of claims 1 to 10, a needle-integrated biosensor introduction section for inserting and setting the biosensor, a connector section for capturing an electrical signal at an electrode of the biosensor, Measuring unit for measuring electrical values via a connector unit, operation panel unit for measurement, display unit for displaying measured values in the measuring unit, memory unit for storing measured values, driving unit for puncture needle, driving unit A measuring device for a needle-integrated biosensor provided with a trigger start button and a puncture start button for starting puncturing with a puncture needle.   The measurement device for a needle-integrated biosensor according to claim 11, further comprising a puncture drive and an extension mechanism for an elastic material that connects the puncture needle and the biosensor.   The measurement device for a needle-integrated biosensor according to claim 11 or 12, wherein a potential step chronoamperometry method, a coulometry method, or a cyclic voltammetry method is applied as a measurement method in the measurement unit. The needle according to any one of claims 11 to 13, comprising at least one of a voice guide function and a voice recognition function, a measurement data management function using a built-in radio clock, a communication function of measurement data to a medical institution, and a charging function. Integrated biosensor measuring device.

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