JP2009198467A - Sensor element using nano structure, analytical chip, analytical apparatus, and method for manufacturing sensor element - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sensor chip having a nano structure exposed in a flow channel, which can be formed simply with a high reliability. <P>SOLUTION: A silicon nano wire 3 is exposed, at least a part thereof, in a groove part 5 and is configured as one unit with a substrate 2. Also. a source semiconductor region formed on the substrate forms a part of the one side of the sidewall of the groove part 5 and a drain semiconductor region forms a part of the other side of the sidewall of the groove part 5. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a sensor element using a nanostructure, and more particularly to a sensor element using a silicon nanowire, a manufacturing method thereof, and the like.

  A nanostructure such as a nanowire constitutes a transistor by being disposed between electrodes and is used for a sensor or the like. For example, in Patent Document 1, a nanowire is formed on a substrate, and a PDMS (polymethylsiloxane) substrate on which a channel for flowing a sample is formed is attached to the substrate, thereby arranging the nanowire in the channel. A biosensor is disclosed.

Such a nanowire manufacturing method is roughly divided into two, and one is a bottom-up manufacturing method in which a nanowire is grown using a metal catalyst or the like, and placed on a substrate using a coating and alignment technique. The other is a top-down manufacturing method in which nanowires are formed on a silicon substrate or SOI substrate using a semiconductor microfabrication technique.
Special Table 2004-515782 (released May 27, 2004)

  However, in the above-described sensor using nanowires, when nanowires are formed by a bottom-up manufacturing method, nanowires are formed by growth and placed between electrodes using coating or alignment techniques. It is difficult to arrange with high accuracy. That is, it is difficult to perform arrangement control at a fine level. Further, when exposed to the flow path, when the nanowire is cross-linked between the electrodes, the nanowire is easily distorted or broken due to the influence of the sample flow, and the durability is low. Further, the degree of freedom of position control in the flow path is low. That is, it can only be attached to the substrate. Therefore, a highly reliable label-free sensor cannot be provided.

  On the other hand, even when a top-down manufacturing method is used, a flow path is formed in a cover layer such as PDMS, which is a silicon-based resin, and a sensor chip is created by artificial bonding. It is difficult to control accurately.

  Therefore, it is difficult to create a high-performance sensor by any method.

  Furthermore, in the bottom-up manufacturing method, it is difficult to realize a differential detection system using a reference detection unit due to large variations in nanowire characteristics. Also in the top-down manufacturing method, PDMS having a flow path is artificially aligned and bonded onto the nanowire, so that there is a large variation in characteristics and it is difficult to realize a differential detection system.

  The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a sensor element having a nanostructure exposed in a flow path, which can be easily formed with high reliability. is there.

  In order to solve the above-described problems, a sensor element according to the present invention includes a substrate having a surface provided with a groove, a nanostructure that is at least partially exposed in the groove and is configured integrally with the substrate. And a nanostructure connection region formed of the same material as the nanostructure, connected to the nanostructure, and formed on the substrate so as to form part of both side walls of the groove portion, It is characterized by having.

  According to the said structure, the said nanostructure is exposed in the groove part of a board | substrate, and is comprised integrally with the board | substrate. That is, the nanostructure is formed by processing the substrate, and is formed inseparably from the substrate. Further, a nanostructure connection region made of the same material as the nanostructure is formed so as to be connected to the nanostructure and to form part of both side walls of the groove. Therefore, the nanostructure connection region can also be formed simultaneously with the groove and the nanostructure. This nanostructure connection region can be used as a region connected to the source electrode and the drain electrode.

  Here, the channel can be formed by simply attaching a flat cover layer that does not form the groove on the surface of the substrate provided with the groove, and the nanostructure is exposed and disposed in the channel. Can be made. The flow path is a passage for flowing a solution such as a sample.

  Therefore, according to the said structure, it becomes possible to arrange | position a nanostructure to a predetermined position of a flow path with a fine level with high precision. Further, since the nanostructure and the substrate are integrated, there is no problem such as displacement or peeling of the nanostructure due to the flow of the solution flowing in the flow path, and durability is improved. Therefore, the sensor element of the present invention can provide a highly reliable sensor element.

  Here, the nanostructure and the substrate may be made of a semiconductor. In particular, the nanostructure and the substrate may be made of silicon.

  In the sensor element according to the present invention, in addition to the above-described configuration, the nanostructure may be disposed across both side walls of the groove. As described above, the nanostructures are arranged over the both side walls of the groove portion of the substrate, so that the durability is enhanced by being connected and fixed to the both side walls. Furthermore, as described later, when the nanostructure is fixed to the bottom surface, the durability becomes higher.

  The nanostructure may be arranged perpendicular to the extending direction of the groove. Thus, arranging the nanostructure perpendicularly to the extending direction of the groove portion means arranging the nanostructure perpendicularly to the flow direction of the flow path. With such an arrangement, the ligand solution is allowed to flow through the flow channel, so that the ligand can be immobilized evenly over the entire nanostructure and can be reacted efficiently with the target molecule.

  A plurality of the nanostructures may be formed in the groove. By forming a plurality of nanostructures in the groove, a plurality of nanostructures are arranged in the flow path. Therefore, target molecules that cannot be caught by some nanostructures in the flow channel can be detected uniformly by catching the target molecules by a plurality of nanostructures in the flow channel, which is more reliable. A sensor can be provided. That is, it is preferable that a plurality of nanostructures are arranged, so that the target molecules distributed as a whole can be caught by the plurality of nanostructures and averaged and evaluated.

  In the sensor element according to the present invention, in addition to the above-described configuration, the nanostructure may be disposed via an insulator from the bottom surface of the groove.

  Since the nanostructure is disposed at the bottom of the groove portion via an insulator, the nanostructure is not easily affected by damage such as a sample flowing through the channel including the groove portion, and the flow of the solution It can be prevented from being distorted or broken. Therefore, the durability of the nanostructure can be increased, and a higher quality sensor element can be provided.

  In addition, the sensor element according to the present invention may include the two groove portions provided with the nanostructure. Since the nanostructures integrated with the substrates respectively provided in the two groove portions are arranged in a uniform size and with high accuracy as described above, a sensor element that can be used in a differential analysis system is provided. be able to.

The analysis chip according to the present invention has any one of the above sensor elements. An analysis apparatus according to the present invention includes the analysis chip, fixes a ligand to the nanostructure, and detects a target molecule by measuring a change in electrical characteristics of the nanostructure.
Therefore, by using these analysis chips and analyzers, target molecules can be analyzed and detected with high accuracy.

  In addition, the differential analysis chip according to the present invention includes a sensor element having two of the groove portions provided with the nanostructure, and the nanostructure in one of the two groove portions includes the sensor element. It is characterized in that the ligand is modified and used as a detection part, and the ligand is not fixed to the nanostructure in the other groove part and used as a reference detection part.

  Here, since the sample solution contains molecules that affect the impedance change of the electrode, such as ions, only the change in impedance due to the binding of the target molecule to the ligand immobilized on the nanostructure is measured. In order to do this, it is necessary to provide a reference detector. The sensor element according to the present invention can form a nano-structure having a uniform size by forming the nano-structure integrally with the substrate, so that a differential sensor element can be realized. . Therefore, the differential analysis chip using the differential sensor element and the analyzer having this differential analysis chip measure the impedance change of the detection unit and the reference detection unit, and detect the reference from the impedance change amount of the detection unit. By subtracting the impedance change amount of the part, it becomes possible to detect the target molecule more accurately.

  In order to solve the above problems, a method for manufacturing a sensor element according to the present invention includes a substrate having a surface provided with a groove, a nanostructure formed integrally with the substrate, and the same quality as the nanostructure. And a nanostructure connection region formed on the substrate so as to form a part of both side walls of the groove and to be connected to the nanostructure. And forming the groove, the nanostructure, and the nanostructure connection region at the same time so that at least a part of the nanostructure is exposed in the groove. .

  According to the above method, the groove, the nanostructure, and the nanostructure connection region are formed simultaneously. The groove is a portion where a flow path is formed by being covered with a cover layer. Therefore, it is possible to manufacture a sensor element in which the nanostructure is accurately arranged at a predetermined position in the flow path. In addition, nanostructures with uniform sizes can be manufactured. Therefore, a highly reliable and high-performance sensor element can be easily created.

As described above, the sensor element according to the present invention includes a substrate having a surface provided with a groove, a nanostructure that is at least partially exposed in the groove and is configured integrally with the substrate, and A nanostructure connection region formed of the same material as the nanostructure, connected to the nanostructure, and formed on the substrate so as to form part of both side walls of the groove;
have.

  According to the said structure, the said nanostructure is exposed in the groove part of a board | substrate, and is comprised integrally with the board | substrate. That is, the nanostructure is formed by processing the substrate, and is formed inseparably from the substrate. Further, a nanostructure connection region made of the same material as the nanostructure is formed so as to be connected to the nanostructure and to form part of both side walls of the groove. Therefore, the nanostructure connection region can also be formed simultaneously with the groove and the nanostructure. This nanostructure connection region can be used as a region connected to the source electrode and the drain electrode.

  Here, the channel can be formed by simply attaching a flat cover layer that does not form the groove on the surface of the substrate provided with the groove, and the nanostructure is exposed and disposed in the channel. Can be made. The flow path is a passage for flowing a solution such as a sample.

  Therefore, according to the said structure, it becomes possible to arrange | position a nanostructure to a predetermined position of a flow path with a fine level with high precision. Further, since the nanostructure and the substrate are integrated, there is no problem such as displacement or peeling of the nanostructure due to the flow of the solution flowing in the flow path, and durability is improved. Therefore, the sensor element of the present invention can provide a highly reliable sensor element.

  The best mode for carrying out the present invention will be described below in detail with reference to the drawings.

[Embodiment 1]
<Sensor structure>
First, the structure of the sensor element according to the present invention will be described. FIG. 1 is a perspective view showing the vicinity of a silicon nanowire 3 included in the sensor element 1 of the present embodiment. 2A is a top view of the sensor element 1, and FIGS. 2B and 2C are views showing the AA ′ section and the BB ′ section of FIG. 2A, respectively.

  As shown in FIG. 1, the sensor element 1 includes a substrate 2 having a surface provided with a groove portion 5, a source electrode and a drain electrode provided on the substrate 2, and a groove portion 5. It has silicon nanowires 3 that are connected nanostructures. The silicon nanowire 3 is at least partially exposed in the groove 5 and is configured integrally with the substrate 2, the source electrode forms part of the side wall on one side of the groove 5, and the drain electrode It forms part of the other side wall of the groove 5. The cover layer 4 is bonded to the substrate 2 and a flow path is formed from the groove 5 and the lower surface of the cover layer. In the present embodiment, the nanostructure is a silicon nanowire, but may be a gallium nitride nanowire, a gallium arsenide nanowire, a zinc oxide nanowire, or the like, and any semiconductor material can be applied.

  Specifically, in the sensor element 1, the flow path is configured in a plane where the substrate 2 and the cover layer 4 are bonded together. In the present embodiment, the cover layer 4 that is a layer forming the upper surface of the flow path is made of PDMS. In addition, the substrate 2 forming the groove portion 5 which becomes the bottom surface and the side surface of the flow path is formed from an SOI (Silicon On Insulator) substrate.

  Here, in FIG. 2, in order to explain the side surface of the groove portion in the cross-sectional view, the groove portion 5 serving as the flow path has a U-shaped shape from the top surface, but may be, for example, a straight shape.

  The silicon nanowire 3 supported by an insulator is exposed in the groove portion 5 serving as a flow path, and the sensor element 1 can measure a sample (sample) flowing through the flow path using the silicon nanowire 3.

  The detection part which the silicon nanowire 3 comprises is demonstrated using Fig.2 (a)-(c). The arrows in FIG. 2A indicate the flow of the sample in the flow path. Silicon nanowires 3 are formed in the flow path composed of the groove portions 5. Semiconductor regions to be a source electrode and a drain electrode are formed on both ends (both walls) of the silicon nanowire 3, and each semiconductor region is electrically connected to the metal electrode 6 on the side opposite to the silicon nanowire and further wired. . In this embodiment, the flow path other than the part where the silicon nanowire, the source semiconductor region (nanostructure connection region) and the drain semiconductor region (nanostructure connection region) are formed is formed of an insulating film (silicon oxide film). Has been. The silicon nanowire 3, the source semiconductor region, and the drain semiconductor region are formed of a semiconductor (silicon). Since the metal electrode 6 is formed on the opposite side to the silicon nanowire 3 in each source semiconductor region and drain semiconductor region, the metal electrode 6 can be formed without facing the flow path. Therefore, it is possible to provide a highly reliable sensor free from the problem of corrosion of the metal electrode 6 and short circuit due to facing the flow path.

  Furthermore, the silicon nanowire 3 is exposed in the flow path and is configured integrally with the SOI substrate which is the substrate 2, that is, the silicon nanowire is processed by processing a semiconductor film (SOI film) on the insulating film of the SOI substrate. It is formed and inseparably formed. Further, the insulating film supporting the silicon nanowire 3 is also formed by processing the insulating film of the SOI substrate, and is formed inseparably. Therefore, it is possible to accurately control the placement of the silicon nanowire 3 at a predetermined level in the flow path. Therefore, since the silicon nanowire 3 and the substrate 2 are integrated, there is no problem of deviation or peeling due to the flow of the solution flowing in the flow path, and durability is increased. Furthermore, since the base of the silicon nanowire 3 is supported by the insulating film, the durability is very high.

  Note that the conductivity types of the impurities in the silicon nanowire 3 and the source semiconductor region and the drain semiconductor region may have the same conductivity type, and the conductivity types of the source semiconductor region and the drain semiconductor region are different from those of the silicon nanowire 3. It may be.

<Sensor manufacturing method>
Next, the manufacturing method of the sensor element 1 of this embodiment is demonstrated in order using FIG. 3 (a1), 3 (b1)... And 4 (a1), 4 (b1)... Are diagrams for explaining the AA ′ cross section of the sensor element shown in FIG. 3 (a2), 3 (b2), and FIGS. 4 (a2), 4 (b2),... Are views for explaining the BB ′ cross section shown in FIG.

  First, as shown in FIGS. 3A1 and 3A2, a silicon nitride film 24 is deposited on the substrate 2 which is an SOI substrate by CVD (Chemical Vapor Deposition). Since the silicon nitride film 24 is used as a stopper in a CMP (Chemical Mechanical Polishing) process, which is a subsequent process, the silicon nitride film 24 may have a film thickness sufficient as a stopper. Therefore, the silicon nitride film 24 may be deposited by about 100 nm, for example. Then, a resist 25 is formed using a photolithography technique so as to cover the source semiconductor region, the drain semiconductor region, the flow path including the silicon nanowire (SiNW) portion, and the metal formation portion. Next, the silicon nitride film 24 is patterned in the same shape as the resist 25 by etching the silicon nitride film 24 using the resist 25 as a mask.

  For the silicon film on the insulating film (SOI film), it is preferable to use, for example, a substrate doped with a p-type conductivity type at a high concentration. This is because by using such a substrate, a suitable connection can be obtained in a later metal forming step. Moreover, since the impurity concentration of the source semiconductor region and the drain semiconductor region and the silicon nanowire 3 can be appropriately adjusted by separately performing the impurity implantation in the metal formation step, the impurity concentration of the silicon nanowire more suitable for detection can be adjusted. preferable.

  Next, as shown in FIGS. 3B1 and 3B2, the silicon film (SOI film) 23 on the insulating film of the substrate 2 is etched using the resist 25 as a mask so as to have the same shape as the resist 25 and the silicon nitride film 24. The SOI film 23 is patterned. In addition, since the film thickness of the SOI film 23 affects the height of the flow path to be formed thereafter, it may be appropriately adjusted in the range of about 10 μm to 1000 μm according to the required flow path height. In this embodiment, the SOI film thickness is 50 μm. In addition, by this patterning, the SOI film 23 must be etched by 10 μm or more, which is necessary for the channel height. Accordingly, if fine etching such as that used in a normal semiconductor manufacturing process is performed, it takes a considerable amount of time. Therefore, it is preferable to perform etching using a deep silicon etching apparatus such as an ICP etching apparatus. Thereafter, the resist 25 is peeled off. Note that after etching the silicon nitride film 24 using the resist 25 as a mask, the resist 25 may be peeled off and the SOI film 23 may be etched using the silicon nitride film 24 as a mask.

  Next, as shown in FIGS. 3C1 and 3C2, a silicon oxide film 26 is deposited using CVD. For this deposition, it is preferable to use a TEOS-CVD apparatus optimized for thick film formation. A silicon oxide film having a thickness of 10 μm or more can be formed by a TEOS-CVD apparatus. Further, by repeating the CVD deposition process of an amorphous silicon film or episilicon film of 5 μm or less and the thermal oxidation process of the amorphous silicon film or episilicon film, the formation of the thick silicon oxide film can be completed earlier. Can do.

  Next, as shown in FIGS. 3D1 and 3D2, CMP is performed using the silicon nitride film 24 as a stopper. Thereafter, the remaining silicon nitride film 24 is removed by selective wet etching using phosphoric acid or the like.

  Thereafter, as shown in FIGS. 4A1 and 4A2, a resist 27 is formed on the SOI film 23 by using a photolithography technique. The resist 27 defines a region for forming the silicon nanowire and the source / drain semiconductor region, and is patterned so that the resist 27 remains in the silicon nanowire and the source / drain semiconductor region.

  Next, as shown in FIGS. 4B1 and 4B2, anisotropic etching is performed by wet etching using KOH, and the SOI film 23 is etched. By using KOH, anisotropic etching based on the plane orientation becomes possible, so that fine fine lines of silicon can be formed. In this step, in addition to the above, by performing anisotropic etching by dry etching using RIE, fine silicon fine lines corresponding to the shape of the resist 27 can be formed.

  Next, as shown in FIGS. 4C1 and 4C2, a silicon nitride film 28 is deposited using CVD. Then, the resist 29 is patterned using a photolithography technique so as to cover the source / drain semiconductor regions. Next, the silicon nitride film 28 is etched using the resist 29 as a mask, and the silicon nitride film 28 is patterned in the same shape as the resist 29.

  Next, as shown in FIGS. 4D1 and 4D2, the portion of the silicon exposed by using the resist 29 as a mask is anisotropically etched by dry etching using RIE to reduce the thickness. This step is for ensuring a sufficient channel height even at the silicon nanowire forming portion. Similar to the SOI film etching step, a sufficient height for the flow path is necessary, and therefore, silicon etching of 10 μm or more is desirably performed. Similar to the SOI film etching step, etching may be performed using a silicon deep etching apparatus such as an ICP etching apparatus. Thereafter, the resist 29 is removed.

  Next, as shown in FIGS. 4E1 and 4E2, using the silicon nitride film 28 as an oxidation resistant film, the exposed portion of silicon is thermally oxidized to form an oxide film 30 on the exposed portion of silicon. By the thermal oxidation process, the silicon nanowire 3 can be further thinned. Because of the use of thermal oxidation, it is possible to control the silicon nanowire diameter, which is fine, at the level of several nanometers. Furthermore, the size variation of the silicon nanowire can be suppressed. This is for the following reason. It is known that when the thinned silicon is thermally oxidized, stress generated in the silicon due to the formation of the oxide film concentrates on the silicon, and the oxidation rate of the silicon decreases, so that it cannot be oxidized finally. It is known that silicon having a size of about 5 nm to 15 nm (diameter in the case of a thin line) remains without being oxidized, although it varies depending on the shape or the oxidation method. Therefore, by utilizing this principle, it is possible to form a thin silicon nanowire 3 having a uniform diameter by suppressing variation in diameter by thermal oxidation.

  Next, as shown in FIGS. 4F1 and 4F2, the oxide film 30 is removed using a buffered hydrofluoric acid (BHF) solution whose concentration is adjusted to be sufficiently thin. Here, in order to make adjustment so that the underlying oxide film of the silicon nanowire 3 is not removed, it is preferable to use a BHF solution having a sufficiently low concentration. Moreover, it is preferable to use a BHF solution in order to keep the surface of the silicon nanowire 3 well, that is, without roughness. In addition to using wet etching, this process can also use oxide film selective RIE dry etching. In that case, since the underlying oxide film of the silicon nanowire 3 is not removed, it can be etched sufficiently.

  Then, a metal formation process is performed. Specifically, the metal electrode 6 is formed so as to be electrically connected to the source / drain semiconductor region. In the present embodiment, the metal electrode 6 is formed without facing the flow path because the metal formation region is already formed on the opposite side of the silicon nanowire 3 of each source / drain semiconductor region by etching. Can do. Therefore, it is possible to provide a highly reliable sensor element free from the problem of metal corrosion and short circuit due to facing the flow path.

  In the present embodiment, two silicon nanowires 3 are formed in one flow path, but may be one or three or more.

  As described above, in this embodiment, since the groove 5 (the portion where the flow path is formed by being covered with the cover layer) and the silicon nanowire 3 are formed at the same time, the silicon nanowire is moved to a predetermined position in the flow path. It becomes possible to accurately control the arrangement at a fine level. In addition, silicon nanowires having a uniform diameter can be formed.

  In addition, in the bottom-up manufacturing technology, nanowires are formed by bridging electrodes, so that when exposed to a flow path, fine nanowires are distorted or broken by the influence of the flow, and the durability is weak. However, according to the present embodiment, since the base of the silicon nanowire 3 is supported by the insulating film 22, the durability is very high.

  In addition, the degree of freedom of position control such as the height of the silicon nanowire 3 in the groove 5 can only be attached to the substrate or the electrode by the bottom-up manufacturing technique, but in this embodiment, the height and the flow direction can be freely adjusted. The position and the like can be designed, and the accuracy becomes higher. Therefore, a highly reliable label free sensor can be provided.

  On the other hand, the top-down manufacturing method (manufacturing method of nanowires on the substrate using a microfabrication technique) formed channels by using a cover layer such as PDMS, and created the chip by artificial bonding. It was difficult to accurately control the position control. However, in this embodiment, since the flow path is not formed in the cover layer 4, it is not necessary to perform the alignment system with the substrate 2, so that the sensor can be easily created.

<Usage example of sensor element>
(Immobilization of ligand)
Next, a method for immobilizing a ligand on the silicon nanowire 3 of the sensor element 1 will be described. First, the surface of the silicon nanowire 3 is modified by flowing a silane coupling agent through the flow path. Here, it is desirable to use a silane coupling agent whose terminal is a functional group modified with COOH, NH2, OH, CHO, or SH groups. Next, the functional group on the surface of the silicon nanowire 3 is activated. Thereafter, a ligand solution that specifically recognizes and binds to the target molecule is introduced, and the ligand is immobilized on the surface of the silicon nanowire 3 by covalent bonding. Examples of the ligand include antibodies, peptides, DNA, RNA, aptamers, receptors, cells and the like. After immobilization of the ligand, activated functional groups that are not bound to the ligand are inactivated. Thereafter, the substrate is washed with a buffer to immobilize the ligand on the surface of the silicon nanowire 3. A photocrosslinking agent can also be used in the ligand immobilization method. The immobilization method is merely an example and is not limited to the above.

(Sample measurement)
Next, measurement of a sample using the sensor element of this embodiment will be described. A substrate 2 that is an SOI substrate having a groove portion 5 in which silicon nanowires 3 are formed, and a cover layer 4 that is a PDMS substrate provided with an inlet and an outlet for injecting a sample solution and a reagent solution are, for example, 100 W, Oxygen plasma treatment is performed under conditions of an oxygen flow rate of 30 sccm and 60 seconds to activate and bond the substrate 2 and the cover layer 4 together. It is not always necessary to perform oxygen plasma treatment to bond the substrate 2 and the cover layer 4, and the cover layer 4 can be bonded to the substrate 2 using the natural adhesion of PDMS. By covering the groove 5 with the cover layer 4, a flow path including silicon nanowires is formed.

  After a ligand that specifically recognizes and binds to a target molecule is immobilized on the surface of the silicon nanowire 3, blocking is performed to prevent the target molecule from adsorbing nonspecifically to the surface of the silicon nanowire 3. For example, blocking may be performed using a bovine serum albumin (BSA) solution. As the blocking agent, a polymer or protein can be used in addition to BSA. After blocking, a sample solution (sample) containing the target molecule is introduced into the channel. The target molecules in the introduced sample solution bind to the silicon nanowires 3 and cause a change in electrical characteristics between the source electrode and the drain electrode. In addition, after introducing the sample solution, a buffer solution may be injected to wash away target molecules that are not bound to the ligand immobilized on the surface of the silicon nanowire. The change in the impedance between the source electrode and the drain electrode (the impedance of the silicon nanowire) changes in proportion to the concentration of the target molecule contained in the sample solution. Therefore, it is possible to calibrate the target molecule in the sample solution by measuring the change in impedance between the source electrode and the drain electrode.

(Measurement of multiple target molecules)
In the above, one groove portion 5 where the silicon nanowire 3 is exposed is formed on the substrate 2, but a plurality of groove portions 5 where the silicon nanowire 3 is exposed may be formed. Different ligands specifically recognizing different target molecules are immobilized on the surfaces of the silicon nanowires 3 formed in the flow paths composed of the plurality of grooves 5 by the ligand immobilization method, respectively. By introducing a sample solution containing a plurality of target molecules into the plurality of flow paths, a plurality of target molecules can be measured simultaneously. In this case, in order to fix different ligands, each of the plurality of flow paths has an independent inlet and is connected to different inlets. The inlet is an inlet for injecting the solution into the flow path.

  Further, different ligands are introduced from the respective inlets into a plurality of flow paths connected to different inlets. When a ligand that specifically recognizes a target molecule is immobilized on the surface of each formed silicon nanowire 3, the target molecules contained in different sample solutions can be measured simultaneously. It is also possible to simultaneously measure a plurality of target molecules in a sample solution containing a plurality of target molecules.

[Embodiment 2]
First, a method for measuring a target molecule by immobilizing a ligand that specifically recognizes and binds to a target molecule to a silicon nanowire in the flow channel and introducing a sample solution containing the target molecule into the flow channel is as follows. Due to the influence of nonspecific adsorption of ions and target molecules in the sample solution on the silicon nanowire, variation in the impedance of the silicon nanowire becomes large. Therefore, it is necessary to measure the same sample solution as a negative control using a silicon nanowire that does not immobilize a ligand that specifically recognizes and binds to a target molecule.

  Therefore, in this embodiment, as shown in FIG. 6, a differential sensor element in which two different groove portions 5 are formed on a substrate and silicon nanowires 3 are formed in the respective groove portions 5 will be described. The manufacturing method of the groove 5 and the silicon nanowire 3 in the differential sensor element is the same as the method described in the first embodiment. Further, the channel is formed by covering the groove 5 with the cover layer 4 as in the first embodiment.

  In the differential sensor element, a ligand that specifically recognizes and binds to a target molecule is immobilized on the silicon nanowire 3 in the flow path formed by one of the grooves 5 and used as the detection unit 60. The fixing method is the same as in the first embodiment. A ligand is not immobilized on the silicon nanowire 3 in the flow path formed by the other groove portion 5, and the reference detection portion 61 is used. However, the reference detection unit 61 is blocked on the surface of the silicon nanowire using a BSA solution. As described above, since the ligand is fixed to the silicon nanowire 3 in one channel and the ligand is not fixed to the other channel, the two channels are connected to different inlets. In addition, the two flow paths may be one as shown in FIG. 6 in the downstream (absorption part or discharge side) that has passed through the detection part of the silicon nanowire 3.

  When the sample solution containing the target molecule is introduced into the flow path composed of the groove portion 5, the sample solution flows into the two flow paths, and in the detection unit 60, the target molecule in the sample solution is immobilized on the silicon nanowire. And the impedance of the silicon nanowire changes. On the other hand, in the reference detection unit 61, since the ligand is not fixed, the impedance of the silicon nanowire does not change due to specific binding with the target molecule. Therefore, the target molecule can be detected more accurately by subtracting the impedance change amount of the reference detection unit 61 from the impedance change amount of the detection unit 60.

  Conventionally, with a bottom-up manufacturing technology, it has been difficult to realize a differential sensor due to large variations in nanowire characteristics. Further, in the top-down manufacturing method, since the flow path is formed in the cover layer, the characteristic variation is large and it is difficult to realize a differential sensor.

  However, in the present embodiment, similarly to the first embodiment, silicon nanowires having a uniform size can be arranged with high accuracy by simultaneously forming silicon nanowires and grooves to be flow paths on the substrate. A differential sensor can be realized.

[Embodiment 3]
In this embodiment, an analysis chip using the sensor element described in Embodiment 1 will be described with reference to FIG.

  The micro-analysis chip of this embodiment is composed of a cover layer 40 whose front view is shown in FIG. 5A and an analysis substrate 20 whose front view is shown in FIG.

  The cover layer 40 preferably has high transparency and processability, and glass, quartz, polymer resin (such as thermosetting resin or thermoplastic resin), film, or the like can be used. Among these, silicon resins, acrylic resins, styrene resins, and the like are preferable. In this embodiment, PDMS that is a silicon resin is used. The cover layer 40 is provided with an injection port 50 therethrough so that a liquid can be injected into the liquid reservoir 51 of the analysis substrate 20.

  The size of the injection port 50 is not particularly limited. When the injection port 50 has such a size that the capillary force does not work, the liquid can be injected into the liquid reservoir 51 even if the injection port 50 has hydrophobicity. When the injection port 50 has such a size that the capillary force works, the liquid can be injected into the liquid reservoir 51 by the capillary force by making the injection port 50 hydrophilic.

  Moreover, the inlet 50 should just be open | released by air | atmosphere. The liquid can also be injected by connecting a cartridge filled with the liquid to the injection port 50 in advance. Even in that case, it is preferable that the cartridge is open to the atmosphere at the connection port with the injection port 50 or other part so that the liquid can be sufficiently discharged at the time of liquid injection.

  The analysis substrate 20 uses an SOI substrate as a material capable of forming silicon nanowires, electrodes and the like. In the analysis substrate 20, the detection unit 60 having the silicon nanowire 3 and the liquid reservoir 51 can be formed on the same substrate at the same time. The analysis substrate 20 is provided with a liquid reservoir 51, a detection unit 60, and an absorption unit 54 with the upper surface opened. The absorber 54 is filled with an absorber from the opened space. And these opening parts are sealed by the cover layer 40, and an upper surface is sealed and a space is formed. The analysis substrate 20 is provided with an external connection terminal 55.

  The liquid reservoir 51 accumulates the solution injected from the injection port 50, and preferably has a size that allows capillary force to work. In this case, the height direction may be designed to be sufficiently small. When the liquid reservoir 51 is filled with the solution, it flows toward the detection unit 60.

  For the detection unit 60, the sensor element 1 described in the first embodiment is used. Here, the substrate 2 of the sensor element 1 is a part of the analysis board 20 and is integrated with the analysis board 20, and the cover layer 4 of the sensor element is a part of the cover layer 40, Integrated with layer 40. Moreover, the groove part 5 is linear. The detection unit 60 can directly detect the target substance (target molecule). Since it is the structure which can detect a to-be-detected substance directly, it can be set as the structure which does not have a reaction part which performs an antigen antibody reaction separately, for example.

  The absorption part 54 is filled with an absorber that is a substance that absorbs liquid, and the absorber uses a polymer absorber, a porous substance, a hydrophilic mesh, a sponge, cotton, filter paper, and other capillary forces. Any substance that absorbs liquid can be used. In order that the liquid can be efficiently absorbed by the absorption part 54, the connection part between the absorption part 54 and the detection part 60 or the other part should be open to the atmosphere (in contact with the atmosphere). .

  The external connection terminal 55 is a conductive terminal for inputting an electrical control signal to the detection unit 60 and other electrically controlled members and outputting a detection signal from the detection unit 60. For example, it is preferable to use a gold electrode because it can be used in combination with a detection electrode and the like and the process is simplified. Alternatively, a conductive material containing a material such as platinum, aluminum, or copper may be used.

  As shown in FIG. 5, the detection part 60 which has a silicon nanowire, and the external connection terminal 55 are electrically connected. Further, when a valve is provided in a liquid reservoir or the like and this is electrically controlled, the valve is connected to the external connection terminal 55. The external connection terminal 55 is connected to an external control circuit or integrated circuit (not shown). With this configuration, the micro analysis chip itself does not need to be provided with a control circuit such as a power supply or an IC, and therefore a chip with excellent cost performance can be provided.

  In the present embodiment, the case of having one injection port has been described, but two or more injection ports may be appropriately formed to form a liquid reservoir accordingly. The flow of the solution from the liquid reservoir may be controlled by a valve or the like. These can be formed by a known method.

  As described above, in the analysis chip of the present embodiment, the analysis substrate 20 is made of an SOI substrate, and the detection silicon nanowires, the grooves serving as the flow paths in which the detection silicon nanowires are arranged, and the like can all be formed on the same substrate at the same time. . Therefore, the controllability of the arrangement is possible at the nano level, and it is possible to form an analysis chip having a sensor using silicon nanowires with extremely high accuracy as compared with the case of bottom-up formation. In the analysis chip of this embodiment, label-free detection using the silicon nanowire 3 can be performed.

[Embodiment 4]
Next, a handy type microanalyzer, which is an embodiment of a microanalyzer using an analysis element according to the present invention, will be described with reference to FIG.

  FIG. 7 is a diagram showing a configuration of a microanalyzer (analyzer) 100 of the present embodiment. The microanalyzer 100 is a portable handheld microanalyzer.

A chip connection port 2303 which is a connection port of the micro analysis chip (analysis chip) 2302 which is the analysis chip described in the third embodiment is provided below the handy device 2301. An external input / output terminal (not shown) that can be electrically connected to the external connection terminal 2306 of the micro analysis chip 2302 is provided in the back of the chip connection port 2303 in the handy device 2301. By inserting the chip 2302, the external input / output terminal in the handy device 2301 and the external connection terminal 2306 of the micro analysis chip 2302 are electrically connected. In addition, the handy device can display a display unit 2304 that can display the measurement result of the substance to be detected, and can start and stop measurement, and input various data for specifying measurement parameters. An input unit 2305 is provided. In addition, although not shown, an information processing system such as a CPU that can process data and an I / O logic circuit that processes input information and output information is built in the handy device.
A micro analysis chip is connected to a handy device, various data are input, and a measurement start button is pressed, so that a measurement start state is established, and a sample (sample) is injectable from an injection port 2307 and measurement is possible.

  When the measurer injects the sample into the inlet 2307, the sample flows in the flow path provided in the microanalysis chip 2302 toward the absorber 2308 provided at the end of the flow path by capillary action. Then, an electrical signal corresponding to the amount of the substance to be detected detected by the detection unit 2309 made of silicon nanowires is output from the external connection terminal 2306 of the micro analysis chip. By analyzing the electrical signal input from the external input / output terminal of the handy device, the amount or type of the substance to be detected can be specified.

  The micro analysis chip can be provided with a valve for stopping the flow of the sample into the flow path. By doing so, the measurer can inject the sample from the injection port in advance. Then, by connecting the micro analysis chip to the handy device and starting the measurement, a certain electric signal is given from the handy device to the valve of the micro analysis chip via the external input / output terminal and the external connection terminal 2306 of the micro analysis chip. As a result, the valve is opened to start the flow of the sample into the flow path. Therefore, measurement can be performed more easily.

  The handy device 2301 can be, for example, a portable electronic device such as a mobile phone or a PDA. Here, a mobile phone will be described as an example. The mobile phone can be operated as a handy device by activating a circuit capable of analyzing an electrical change of the micro analysis chip 2302 and data processing analysis software. That is, a mobile phone is used as a handy device by a dedicated circuit and software. That is, the mobile phone is virtually used as a handy device by dedicated software. The external connection terminal 2306 of the micro analysis chip 2302 may be configured to be connectable to an external input / output terminal of a mobile phone.

  The micro analysis chip 2302 is connected to a mobile phone, various data are input by using buttons on the mobile phone, and a button set as a measurement start button is pressed to enter a measurement start state. As a result, an electric signal corresponding to the amount of the substance to be detected detected in the detection unit is output from the external connection terminal 2306 of the micro analysis chip, and is electrically connected to the external connection terminal 2306 of the micro analysis chip in the mobile phone. By processing the electric signal input from the external input / output terminal, the amount or type of the substance to be detected can be specified. Then, the measurement result is displayed on the display screen of the mobile phone. In addition, in the case where a valve is provided in the micro analysis chip 2302, the measurement of the mobile phone starts the inflow of a reagent or sample (sample) that has been prepared in advance in the micro analysis chip 2302 and stopped flowing in the valve. When the button is pressed, the operation is sequentially started, and as a result, an electric signal corresponding to the amount of the substance to be detected detected by the detection unit is output from the external connection terminal 2306 of the micro analysis chip, and the micro analysis chip 2302 of the mobile phone is output. By processing an electric signal input from an external input / output terminal electrically connected to the external connection terminal 2306, the amount or type of the substance to be detected can be specified. Then, the measurement result is displayed on the display screen of the mobile phone.

  By using the handy device 2301 as a mobile phone, a microanalyzer with excellent cost performance can be provided. Users can also take measurements wherever they need it. Many mobile users can enjoy the benefits when the mobile phone ownership rate rises and mobile phones become sufficiently widespread for the measurers (users). That is, the cost of the handheld device of the mobile phone holder is unnecessary. However, the cost of an electric circuit and data processing analysis software that can be operated on a mobile phone instead is required, but the measurer can download the data processing analysis software on the network, An electric circuit can be mounted in advance by increasing the functionality of the mobile phone. The user can use the mobile phone as a handy device at low cost. As described above, the cellular phone holder can easily prepare the handy device 2301, and after preparing the handy device, the sample (sample) can be analyzed only with the cost of the micro analysis chip 2302.

[Embodiment 5]
Furthermore, an independent microanalyzer, which is another embodiment of the microanalyzer using the analytical element according to the present invention, will be described with reference to FIG.

  FIG. 8 is a diagram showing a configuration of a microanalyzer (analyzer) 200 of the present embodiment. The microanalyzer 200 is an independent microanalyzer capable of collecting a sample (sample), analyzing detection data, and outputting independently. As shown in FIG. 8, the microanalyzer 200 includes a sample collection unit 2401, a liquid channel unit 2402, a drive analysis processing unit 2403, an input / output logic processing unit 2404, and an input / output unit 2405. The respective parts are sequentially stacked or combined to form the microanalyzer 200.

  The sample collection unit 2401 is provided with a needle that penetrates a capillary tube, and collects blood, a sample, or the like by inserting or introducing a needle into a subject or a sample body. Note that the sample collecting unit 2401 may be directly provided with a needle or a hole for fixing the needle.

  The needle is preferably a minimally invasive microprobe because pain can be alleviated when a needle is inserted into a subject and a body fluid such as blood is extracted. Further, instead of a needle, it may be an absorbent body that collects saliva, tears, urine, and the like in a sweat mouth on a non-invasive skin surface.

  Next, in the liquid flow path portion 2402, the flow path structure of the micro analysis chip described in the third embodiment is formed. The capillary tube of the sample collection unit 2401 is connected to the liquid reservoir 2414 of the liquid flow path unit 2042, and is configured such that the sample flows into the liquid reservoir 2414 by capillary action of a capillary provided on the needle.

  The liquid channel portion 2042 can also form a plurality of channel structures. In addition, the detection unit 60 may have a differential configuration as shown in the second embodiment. Furthermore, a plurality of detection units 60 can be formed. In FIG. 8, the absorber 54 filled with the absorber is separated by the left and right channel structures, but one absorber 54 can be shared by the left and right channel structures. Thereby, space can be reduced.

  The drive analysis processing unit 2403 is provided with a CPU 24031, a memory, and a battery 24032. The drive analysis processing unit 2403 is connected to a detection unit of the liquid flow path unit 2042, an I / O logic circuit described later, and the like, and supports various measurements. Valve control, measurement data processing, input / output control, etc. are possible. When the measurement is started, valve inflow of reagents and samples (samples) that have been stopped inflow by a valve (not shown) is sequentially started, and as a result, according to the amount of the detected substance detected by the detection unit 60 By processing the electrical signal by the CPU 24031, the amount or type of the substance to be detected can be specified. Data can be output to an I / O logic circuit 24041 connected to the CPU 24031 described below, and the measurement result can be displayed on the input / output unit 2405.

  The input / output logic processing unit 2404 has an I / O logic circuit 24041 connected to the CPU 24031. An electrical connection line connected to the I / O logic circuit 24041 is connected to each button 24052 of the input / output unit 2405, the display unit 24051, or the like, and can cooperate with the CPU 24031 to appropriately process I / O data. it can. In other words, the I / O logic circuit 24041 cooperates with the CPU 24031, and when various data and measurement start signals input by the input / output unit 2405 are input, the I / O logic circuit 24041 becomes a non-detected substance of the sample detected by the liquid channel unit 2402. In response to this, the output electric signal is processed, the amount and type of the substance to be detected are specified, and the information is displayed on the display unit 24051 of the input / output unit 2405.

  The input / output unit 2405 is provided with various data input buttons 24052 and a display unit 24051.

  As the display portion 24051, a liquid crystal display module, an organic EL display module, or the like can be used. The display portion 24051 can perform a display operation by driving a driver circuit (not shown) in cooperation with the I / O logic circuit and the CPU. The display can also be displayed with a time-dependent change using a numerical value display format or a graph. It can also be displayed in a format such as positive or negative.

  Furthermore, although not shown, the input / output unit 2045 can be provided with a terminal for processing input / output with the outside or a wireless transceiver. By doing so, it is possible to connect to a personal computer, a PDA terminal, and the like, and to process, analyze, and store measurement data. Further, since it is possible to connect to a network, bidirectional information exchange can be performed. In this way, by exchanging information in both directions, health information obtained from the measurement results of the measurer can be networked with hospitals and health management centers, etc., so that information can be provided in both directions. The measurer can enjoy advice, diagnosis, and treatment directly related to advanced medical care, and the medical provider can make appropriate diagnosis and treatment from abundant health information.

  The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.

  INDUSTRIAL APPLICABILITY The present invention can be used for a target detection apparatus such as a biosensor or a chemical sensor that detects various targets using a nanostructure and qualifies and quantifies these targets.

It is the perspective view which expanded the silicon nanowire vicinity in the sensor element of one Embodiment of this invention. (A) is a top view of the sensor element, (b) is an AA ′ sectional view of the sensor element of (a), and (c) is a BB ′ sectional view of the sensor element of (a). (A1)-(d1) is a figure explaining the AA 'cross section of the sensor element of Fig.2 (a) in order of a manufacturing process, (a2)-(d2) is BB of the sensor element of Fig.2 (a). 'It is a figure explaining a section in order of a manufacturing process. (A1)-(f1) is a figure explaining the AA 'cross section of the sensor element of Fig.2 (a) in order of a manufacturing process, (a2)-(f2) is BB of the sensor element of Fig.2 (a). 'It is a figure explaining a section in order of a manufacturing process. (A), (b) is a block diagram of the analysis chip using a sensor element. It is a figure which shows the differential type sensor element of other embodiment of this invention. It is a block diagram of the handy type microanalyzer of other embodiments of the present invention. It is a block diagram of the independent type | mold microanalyzer of other embodiment of this invention.

Explanation of symbols

1 sensor element 2 substrate 3 silicon nanowire (nanostructure)
4 Cover Layer 5 Groove 20 Substrate 40 Cover Layer 50 Inlet 51 Liquid Reservoir 54 Absorber 55 External Connection Terminal 60 Detector 61 Reference Detector 100, 200 Micro Analyzer (Analyzer)
2302 Micro analysis chip (analysis chip)

Claims (13)

A substrate having a surface provided with a groove;
A nanostructure that is at least partially exposed in the groove and configured integrally with the substrate;
A nanostructure connection region formed of the same material as the nanostructure, connected to the nanostructure, and formed on the substrate so as to form part of both side walls of the groove;
The sensor element characterized by having.   The sensor element according to claim 1, wherein the nanostructure and the substrate are made of a semiconductor.   The sensor element according to claim 1, wherein the nanostructure and the substrate are made of silicon.   The sensor element according to any one of claims 1 to 3, wherein the nanostructure is disposed over both side surfaces of the groove.   The sensor element according to any one of claims 1 to 4, wherein the nanostructure is disposed perpendicular to the extending direction of the groove.   The sensor element according to any one of claims 1 to 5, wherein a plurality of the nanostructures are formed in the groove.   The sensor element according to any one of claims 1 to 6, wherein the nanostructure is disposed via an insulator from a bottom surface of the groove.   The sensor element according to any one of claims 1 to 7, wherein the sensor element has two of the groove portions provided with the nanostructures.   An analysis chip comprising the sensor element according to claim 1.   The sensor element according to claim 8, wherein the nanostructure in one of the two grooves is modified with a ligand and used as a detector, and the ligand in the nanostructure in the other groove A differential analysis chip, wherein the differential detection chip is used as a reference detection unit without being fixed.   An analysis device comprising the analysis chip according to claim 9, wherein a ligand is immobilized on the nanostructure, and a target molecule is detected by measuring a change in electrical characteristics of the nanostructure.   An analysis apparatus comprising the differential analysis chip according to claim 10. A substrate having a surface provided with a groove, a nanostructure integrally formed with the substrate, a material of the same quality as the nanostructure, connected to the nanostructure, and of the groove A nanostructure connection region formed on the substrate so as to form a part of each side wall,
A step of forming the groove, the nanostructure, and the nanostructure connection region at the same time so that at least a part of the nanostructure is exposed in the groove. Production method.

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