JP2013088298A - Sensor chip - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sensor chip having high durability capable of monitoring an analysis object with high accuracy over a long period in a sensor chip used to measure or monitor the analysis object in a living body by using an optical technique.SOLUTION: The durability of the sensor chip can be improved because the formation of projecting parts 11 on a solid support 13 can eliminate contact between a sensor surface and a living tissue, further a member used when the sensor chip 10 is embedded in a living body.

Description

  The present invention relates to a sensor chip used for measuring or monitoring an analyte in vivo using optical techniques.

  The sensor chip is particularly suitable for use when high durability performance is required because it is necessary to accurately measure or monitor an analysis object over a long period of time.

  In managing diabetes, it is essential to measure glucose in blood regularly to ensure accurate insulin administration. Furthermore, in the long-term care of diabetic patients, better management of blood glucose levels can help prevent retinopathy, circulatory system diseases and other degenerative diseases often associated with diabetes. Even if the onset cannot be prevented, it can be delayed. That is, there is a strong demand from diabetic patients for reliable and accurate self-monitoring of blood glucose levels.

  At present, blood glucose is monitored by diabetic patients themselves using commercially available color test strips or electrochemical biosensors (such as enzyme electrodes). It is necessary to collect an appropriate amount of blood using a lancet. Many diabetics measure blood glucose levels twice a day. However, the National Institutes of Health recommends that blood glucose measurements be made at least four times per day, and such recommendations are supported by the American Diabetes Association. For diabetics, such frequent blood collection is an economic burden as well as physical pain. As a result, many diabetics seek a better long-term glucose monitoring system without blood collection.

  In recent years, many proposals have been made on a glucose measurement method that does not require blood collection from the patient. For example, a device using a needle or a catheter as an enzyme biosensor electrode and inserting it into a blood vessel or percutaneously has been reported (Non-patent Document 1, Patent Document 1).

  However, the sensor continues to insert a needle or catheter into a blood vessel or percutaneously, and there is a risk of infection. The patient is always injured, painful and uncomfortable. Therefore, it is not suitable for continuous use. Secondly, since this type of sensor, the sensor itself, has the tip of a needle or catheter, it may cause thrombosis to be peeled and put into the patient's circulatory system, which is extremely serious. Risk of danger.

  An apparatus for in-situ monitoring of low molecular weight compounds in blood by optical means has already been reported (Patent Document 2, Non-Patent Document 2). These devices are designed to be inserted into a blood vessel or placed percutaneously and require optical coupling with an external light source and an external detector. Again, since the device is placed in the blood vessel, it can form a thrombus and is at risk of infection.

  As a less invasive glucose monitoring method, for example, a method using surface-enhanced Raman or other surface excitation sensitization spectroscopy using a sensor chip embedded in a living body has been proposed. (Non-patent document 3).

  In such an approach, the sensor chip is completely embedded in the living body, and when an object is to be measured, the light is radiated from the outside, and the analyte is measured or monitored without any pain. be able to.

Special table 2009-519106 gazette US Pat. No. 4,344,438

E. Wilkins, P.M. Atanasov, Med. Eng. Pys. (1966) 18: 273-288 D. L. Mansouri, J. et al. S. Schultz, Anal. Chim. Acta. (1993) 280: pp21-30 J. et al. M.M. Yuen, N .; C. Shah et. al. , Anal. Chem. (2010) 82: 8382-8385

  However, in the conventional configuration, the adhesion between the metal layer that can induce surface plasmon waves formed on the surface of the sensor chip and the solid substrate is weak, and the functional thin film formed on the metal layer is very Because it is fragile, it is necessary to be careful not to touch the sensor surface when embedding the sensor chip in the living body, and even after embedding in the living body, the metal on the sensor surface is contacted with the living tissue. There is a problem that the sensor chip is damaged due to the separation of the fine particles, and the functional thin film is damaged.

  An object of the present invention is to solve the above-mentioned conventional problems, and to provide a sensor chip having high durability that can accurately monitor a substance to be analyzed over a long period of time.

  In order to solve the above-described conventional problems, the sensor chip of the present invention is a sensor chip in which a metal layer capable of inducing surface plasmon waves is formed on a solid support, and has a protrusion shape on the surface of the sensor chip. .

  It is preferable that an aspect ratio of the protrusion shape is 0.4 or more and 5.2 or less, and a height of the protrusion shape is 5 μm or more and 150 μm or less.

  It is preferable that the protrusion shape is periodically formed in the first direction, or periodically formed in the first direction and the second direction, and is a columnar shape formed periodically. preferable.

  The protrusion shape is preferably the same material as the solid support.

  The solid support is preferably a silicon compound, and the surface of the solid support is preferably covered with a biocompatible material.

  The metal layer is preferably gold.

  With this configuration, it is possible to eliminate contact between the surface of the sensor chip and a member used when a biological tissue or sensor is embedded.

  According to the sensor chip of the present invention, when the sensor chip is embedded in the living body, and even after being embedded, the living tissue and the sensor surface do not come into contact, so there is no risk of damage to the sensor surface and damage to the sensor surface. In the living body, it is possible to obtain high durability performance that can maintain the function of the sensor chip for a long time.

Sectional drawing of the sensor chip in embodiment of this invention The top view of the sensor chip in an embodiment of the invention Process drawing which shows the manufacturing method of the protrusion shape on the solid support body in embodiment of this invention Process drawing which shows the manufacturing method of the metal layer which can induce the surface plasmon wave on the solid support body which has the protrusion shape in embodiment of this invention

  Hereinafter, the configuration of the sensor chip in the embodiment of the present invention will be described with reference to the drawings.

  FIG. 1 is a cross-sectional view of a sensor chip 10 according to an embodiment of the present invention. In FIG. 1, the solid support 13 of the sensor chip in the present embodiment includes a silicon substrate, a glass substrate, a ceramic substrate, and a plastic film.

  On the solid support 13, a protruding shape 11 is provided. The protrusion shape 11 on the surface of the solid support 13 may be a material different from that of the solid support 13, but the same material is preferable in manufacturing.

  When the solid support 13 and the protrusion shape 11 are made of the same material, the protrusion shape 11 can be formed by combining, for example, a photolithography method and an etching method.

  An example of a method for forming a protrusion shape on the solid support 13 will be described with reference to the drawings. As shown in FIG. 3, first, a resist film 31 is formed on a solid support by using a spin coat method or the like (FIG. 3A). The resist film is selectively exposed (FIG. 3B) and developed to form a resist pattern 32 having a predetermined shape (FIG. 3C). Thereafter, by etching the solid support portion having no resist film so as to have a predetermined depth, a projection shape 11 as shown in FIG. 3D can be formed.

  For the etching method, for example, one or more of physical etching methods such as plasma etching, reactive ion etching, beam etching, and light-assisted etching, and chemical etching methods such as wet etching are combined. Can be used.

  Further, when the solid support is a plastic film, a production method using a support having fine irregularities produced by a molding method is also possible. Thereby, a fine protrusion shape pattern can be formed precisely.

  The thickness (W4) of the solid support 13 is not particularly limited, and is appropriately selected in consideration of the place of implantation in the living body. Specifically, the thickness of the solid support is preferably in the range of 5 μm to 1000 μm, more preferably in the range of 100 μm to 500 μm. If the thickness of the solid support is 5 μm or less, the solid support 13 may be damaged or deformed. Further, when the thickness of the solid support is 1000 μm or more, the load on the human body is increased when the solid support is embedded in the living body.

  When the solid support 13 is not a biocompatible material, the surface of the solid support 13 can be coated with a biocompatible polymer. As the biocompatible polymer, a known material can be used, and it is appropriately selected in consideration of embedding in the living body. For example, polyurethane, silicone resin, PMMA, parylene and the like can be mentioned.

  As a coating method of the biocompatible polymer on the solid support, a method that can uniformly coat the protrusion shape formed on the solid support 13 such as a spin coating method, an ink jet method, a dipping method, or a vacuum polymerization method. It can be selected as appropriate.

  The aspect ratio of the protrusion shape of the present invention is preferably 0.4 or more and 5.2 or less. When the thickness is 0.4 or less, the metal layer 12 formed in the recess on the solid support shown below comes into contact with the living tissue, and thus the metal layer is peeled off or damaged. When the aspect ratio of the protrusion shape is 5.2 or more, there is a risk of breakage or breakage of the edge portion of the protrusion shape.

  Here, the aspect ratio is a cross-sectional shape obtained by cutting the linearly formed protrusion shape perpendicularly to the substrate and perpendicularly to the linear protrusion shape when the protrusion shape is linear. The value obtained by dividing the height (W1) of the protrusion shape by the width (W2) of the recess. When there are a plurality of types of cross-sectional shapes of the protrusions, the maximum value is set.

  When the protrusion shape is columnar, the aspect ratio is calculated by the same method as described above, using a cross-sectional shape cut perpendicularly to the columnar protrusion pattern and at right angles to the protrusion pattern. Similarly, when there are a plurality of types of cross-sectional shapes of the protrusion-shaped pattern, the maximum value is set.

  The height (W1) of the protrusion shape in FIG. 1 is preferably in the range of 5 μm to 150 μm, and the width W2 of the recess is preferably in the range of 0.9 μm to 375 μm.

  Further, the width W3 of the protrusion shape is not particularly limited, but in consideration of processing accuracy, breakage of the protrusion shape, and the area for forming the metal layer 12 that can induce surface plasmon waves, the width W3 may be in a range of 2 μm to 1000 μm. preferable.

  A metal layer 12 capable of inducing surface plasmon waves is formed in the recess of the solid support 13.

  An example of a method for forming the metal layer 12 capable of inducing surface plasmon waves on the solid support 13 will be described with reference to the drawings. As shown in FIG. 4, first, a metal thin film 41 is deposited on the solid support 13 having a protruding shape by a sputtering method or a vapor deposition method. An electron beam resist 42 is formed thereon by spin coating or the like (FIG. 4A). Next, exposure is performed with an electronic drawing device to obtain a resist pattern 43 after development (FIG. 4B). Thereafter, an unnecessary metal thin film is etched, the resist is removed, and a metal layer 12 having an arbitrary shape can be formed (FIG. 4C).

  In addition to the electron beam lithography apparatus described above, the metal pattern layer can be formed by a patterning method using a focused ion beam processing apparatus, an X-ray exposure apparatus, or an EUV exposure apparatus.

  FIG. 2 is a plan view showing an example of the sensor chip 10 of the present invention. FIG. 2A shows a sensor formed on a solid support and having a protrusion shape 21 periodically formed in the first direction, and a recess of each protrusion shape pattern having a metal layer 12 capable of inducing surface plasmon waves. Chip.

  FIG. 2B shows a sensor chip formed on a solid support and having a protrusion shape 21 formed in the first direction and a protrusion shape 22 formed in the second direction. Indicates a columnar protrusion shape 23 periodically formed on the solid support. The columnar protrusion shape 23 may be a cylinder, a quadrangular column, or a hexagonal column, and is not particularly limited. The method of arranging the columnar protrusions may be square, triangular, or hexagonal, and there is no particular limitation as long as they are regularly arranged.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

(Example)
A resist material is applied on a 525 μm thick silicon wafer by spin coating to form a 1 μm thick resist film, and this resist film is pre-baked and then selectively exposed, developed, and post-baked on the resist film. To form a resist pattern having a predetermined shape. Thereafter, a portion of the silicon wafer where the resist pattern was not formed was selectively dry-etched, and then the resist pattern was removed. As a result, a solid support having a protrusion shape in a first direction having a protrusion-shaped height W1 and a recess width W2 shown in Table 1 on a silicon wafer was produced. The protrusion-shaped width W3 was 20 μm.

  Next, a gold thin film having a film thickness of 30 μm was formed on the solid support having a protruding shape by a sputtering method. An electron beam resist (PMMA) was spin-coated on the gold thin film and patterned by an electron beam drawing apparatus, and a gold layer capable of inducing surface plasmon waves was formed using the resist as a mask.

  On these sensor chips, a human three-dimensional cultured epidermis (LabCyte EPI-MODEL: manufactured by Japan Tissue Engineering Co., Ltd.), in which human normal epidermal cells were layered, was placed and allowed to stand for 2 hours, and then 0.3 kg / cm 2. A scratch test was performed on the sensor surface under the load of. Then, peeling, breakage, and damage of the gold thin film pattern in the concave portions on the sensor surface were confirmed under a microscope. The case where there was no peeling or damage of the gold thin film pattern was evaluated as ◯, and the case where a change due to peeling or damage was confirmed in the gold thin film pattern was evaluated as x.

  As is clear from Table 1, the sensor chip of the example was not contacted by a living tissue, and therefore the gold film layer that could induce surface plasmon waves did not change. On the other hand, as shown in the comparative example, peeling or damage of the metal thin film was confirmed when the aspect ratio was 0.4 or less.

  In addition, a sensor chip having a protrusion shape in the first direction and the second direction on the solid support, and a sensor chip having a cylindrical protrusion shape of φ30 μm on the solid support are manufactured. As a result of forming a gold thin film layer capable of inducing the surface plasmon wave in the same manner and trying the same test, the results were in agreement with Table 1.

  Since the sensor chip according to the present invention has a protruding shape on the surface thereof, it is useful as a sensor chip that does not come into contact with a living tissue and can maintain high durability characteristics. In addition, since the sensor surface can be protected, handling properties of various sensor chips that are relatively easily damaged can be improved.

DESCRIPTION OF SYMBOLS 10 Sensor chip 11 Protrusion shape 12 Metal layer 13 Solid support body
W1 Height of protrusion shape
W2 width of recess
W3 Protrusion width 21 Protrusion shape formed in the first direction 22 Protrusion shape formed in the second direction 23 Columnar protrusion shape 31 Resist film 32 Resist pattern 41 Metal thin film 42 Electron beam resist 43 Electron beam resist pattern

Claims (9)

  A sensor chip in which a metal layer capable of inducing surface plasmon waves is formed on a solid support, the sensor chip having a protrusion shape on the surface of the sensor chip.   2. The sensor chip according to claim 1, wherein an aspect ratio of the protrusion shape is 0.4 or more and 5.2 or less, and a height of the protrusion shape is 5 μm or more and 150 μm or less.   The sensor chip according to claim 1, wherein the protrusion shape is periodically formed in a first direction.   The sensor chip according to claim 1, wherein the protrusion shape is periodically formed in a first direction and a second direction.   The sensor chip according to claim 1, wherein the protruding shape is a columnar shape formed periodically.   The sensor chip according to claim 1, wherein the protrusion shape is made of the same material as that of the solid support.   The sensor chip according to claim 1, wherein the solid support is made of a silicon-based compound.   The sensor chip according to claim 1, wherein a surface of the solid support is covered with a biocompatible material.   The sensor chip according to claim 1, wherein the metal layer includes gold.

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