JP2007003234A - Detection method of substance to be detected using cantilever and cantilever sensor system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a detection method of a substance to be detected using a cantilever capable of detecting the substance to be detected in a shorter time than before, and also to provide a cantilever sensor system. <P>SOLUTION: A specimen is brought into contact with the cantilever 3A which is bent if the substance to be detected is present in the specimen in the case brought into contact with the specimen and, after the point of time when the specimen is brought into contact with the cantilever 3A but before the point of time when the time required for completely bending the cantilever 3A is elapsed in a case that the substance to be detected is contained in the specimen, the displacement quantities of the cantilever 3A are measured at the first and second points of time and the displacement quantity of the cantilever 3A measured at the first point of time is compared with that of the cantilever 3A measured at the second point of time. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a detection method for a detection target substance using a cantilever and a cantilever sensor system used therefor.

  In recent years, various developments have been made on sensors using cantilevers (hereinafter referred to as “cantilever sensors” as appropriate). The principle of operation of this cantilever sensor is to detect a change in surface stress caused by the interaction between the detection target and the cantilever surface based on the deflection amount (displacement amount) of the cantilever.

  Examples of such cantilever sensors include a DNA hybridization detection sensor (Non-Patent Document 1), an antigen-antibody reaction detection sensor (Non-Patent Document 2), a microcantilever biosensor (Patent Document 1), and the like. In the measurement using these cantilever sensors, the detection target substance is detected by measuring how much the displacement of the cantilever changes before and after the cantilever is brought into contact with the specimen.

  However, a change in the amount of cantilever displacement caused by contact between the specimen and the cantilever requires a certain reaction time. Therefore, the specific measurement is performed when the change in the displacement amount of the cantilever caused by the contact between the specimen and the cantilever stops after a certain period of time and the displacement amount of the cantilever shows a constant value. The detection target substance is detected by measuring the displacement amount and comparing the displacement amount with the displacement amount of the cantilever before contact with the specimen.

International Publication No. WO 98/50773 Pamphlet Science, Vol.288 (2000), pp.316-318 Sensors and Actuators B, Vol.79 (2001), pp.115-126

  However, in conventional measurement methods such as those described in Patent Document 1 and Non-Patent Documents 1 and 2, after the cantilever is brought into contact with the specimen, the change in the displacement amount of the cantilever due to the interaction between the specimen and the cantilever is a certain time. There was a problem that the measurement could not be finished until it stopped after the lapse and the displacement amount of the cantilever showed a constant value. In particular, when the time until the change in displacement of the cantilever stops after being brought into contact with the specimen is long (for example, several hours or several tens of hours), this measurement method takes a long time to complete the measurement and is practical. is not.

  The present invention was devised in view of the above problems, and provides a detection method of a detection target substance using a cantilever and a cantilever sensor system that enables detection of the detection target substance in a shorter time than in the past. The purpose is to do.

  As a result of intensive studies to solve the above-described problems, the inventors of the present invention have found that two time points in a time range (hereinafter referred to as “specific time range” as appropriate) before the cantilever bends after contacting the specimen with the cantilever. It was found that how much the displacement of the cantilever changes in the sample is closely related to the interaction between the detection target substance in the sample and the cantilever. In other words, when the interaction is small, the change in the cantilever displacement is small, and when the interaction is large, the change in the cantilever displacement is large, but this relationship indicates that the displacement of the cantilever changes within a specific time range. It holds even while continuing.

  Furthermore, when the change in the amount of displacement of the cantilever due to the interaction between the detection target substance and the cantilever continues in the specific time range, the change over time in the amount of displacement can be approximated by a straight line, a polynomial, an exponential function, etc. In addition, it was also found that the slope of the straight line, the polynomial, and the coefficient of the exponential function are closely related to the interaction between the detection target substance and the cantilever. That is, the absolute values of the slope of the straight line, the polynomial and the exponential function are small when the interaction is small and large when the interaction is large.

  Here, the specific time range means the time required for the cantilever to bend after the sample is brought into contact with the cantilever, that is, the time required for the cantilever to bend, that is, the cantilever is the sample. This refers to a time range before the point in time when the change in the amount of displacement of the cantilever due to the interaction between the specimen and the cantilever stops and the amount of displacement of the cantilever shows a constant value after the contact.

  Based on the above findings, the inventors of the present invention do not compare the amount of cantilever displacement before and after the time point at which the specimen is brought into contact with the cantilever as in the prior art, but within a specific time range after the contact, By measuring how much the displacement of the cantilever has changed, it has been found that even if the change in the displacement of the cantilever is slow, accurate detection can be performed in a short time. Completed.

  That is, the gist of the present invention is a method for detecting a detection target substance using a cantilever that generates deflection when the detection target substance is present in the specimen when the specimen is brought into contact with the specimen. And a first time point before the time point required for the cantilever to bend when the sample contains a detection target substance after the time point when the sample is brought into contact with the cantilever. The displacement amount of the cantilever is measured at the second time point, and the detection target substance is detected by comparing the displacement amount of the cantilever measured at the first time point with the displacement amount of the cantilever measured at the second time point. The present invention resides in a method for detecting a substance to be detected using a cantilever (claim 1). This makes it possible to perform accurate detection in a shorter time than in the past. This is because the detection target substance can be detected before the change in the displacement amount of the cantilever due to the interaction between the specimen and the cantilever stops within the specific time range. Furthermore, conventionally, since the time required for detection becomes long, it is required that the output of the measuring device used for measuring the displacement amount is stabilized for a long time, and an expensive measuring device is required. If the above detection method is used, there is no risk of such an increase in cost.

  Another gist of the present invention is a cantilever that generates a deflection when a detection target substance is present in the specimen when it is brought into contact with the specimen, and a deflection that does not depend on the presence or absence of the detection target substance in the specimen. A method for detecting a detection target substance using the resulting correction cantilever, wherein the specimen is brought into contact with the cantilever and the correction cantilever, and the specimen is brought into contact with the specimen after the point in time when the specimen is brought into contact with the cantilever. Measure the displacement of each of the cantilever and the correction cantilever at the first time point and the second time point before the time point required for the cantilever to bend when the substance is contained. Then, the displacement amount of the cantilever is corrected by the displacement amount of the correction cantilever, and the cantilever measured at the first time point after correction is corrected. A detection target substance detection method using a cantilever, wherein the detection target substance is detected by comparing the displacement amount of the bar with the displacement amount of the cantilever measured at the second time point. ). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past. In addition, the correction cantilever has no interaction with the detection target substance, and outputs displacement due to environmental changes such as temperature changes. Therefore, correction is performed to calculate the difference between the displacement amount of the cantilever and the displacement amount of the correction cantilever. Thus, the influence of environmental changes on the measurement result can be reduced, and more accurate detection can be performed.

  Further, another aspect of the present invention is a method for detecting a detection target substance using a cantilever that generates deflection when the detection target substance is present in the specimen when the specimen is brought into contact with the specimen. After the time when the specimen is brought into contact with the cantilever and the specimen is brought into contact with the cantilever and before the time when the cantilever needs to bend when the specimen contains a detection target substance, Between the first time point and the second time point, the displacement amount of the cantilever is measured, the displacement amount of the cantilever is linearly approximated with respect to time, and the detection target substance is detected by the slope of the straight line obtained by the linear approximation. The present invention resides in a method for detecting a detection target substance using a cantilever (claim 3). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  Further, another aspect of the present invention is a cantilever that generates a deflection when a detection target substance is present in the specimen when brought into contact with the specimen, and a deflection that does not depend on the presence or absence of the detection target substance in the specimen. A method for detecting a detection target substance using the resulting correction cantilever, wherein the specimen is brought into contact with the cantilever and the correction cantilever, and the specimen is brought into contact with the cantilever after the specimen is brought into contact with the cantilever. The amount of displacement of each of the cantilever and the correction cantilever between the first time point and the second time point before the time when the time required for the cantilever to deflect is included is included. Measure and correct the displacement amount of the cantilever with the displacement amount of the correction cantilever, and calculate the displacement amount of the cantilever after the correction. Linear approximation to between, and detects the detection target by the slope of the line obtained by the linear approximation resides in the detection method of the detection target substance using a cantilever (claim 4). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past. Furthermore, by performing correction with the correction cantilever, it is possible to reduce the influence of environmental changes on the measurement result and perform more accurate detection.

  Furthermore, still another aspect of the present invention is a method for detecting a detection target substance using a cantilever that generates deflection when the detection target substance is present in the specimen when the specimen is brought into contact with the specimen. After the time when the specimen is brought into contact with the cantilever and the specimen is brought into contact with the cantilever and before the time when the cantilever needs to bend when the specimen contains a detection target substance, Between the first time point and the second time point, the displacement amount of the cantilever is measured, the displacement amount of the cantilever is approximated by a polynomial with respect to time, and the detection target substance is detected by the coefficient of the polynomial obtained by the approximation. The present invention resides in a method of detecting a substance to be detected using a cantilever (claim 5). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  Further, another aspect of the present invention is a cantilever that generates a deflection when a detection target substance is present in the specimen when brought into contact with the specimen, and a deflection that does not depend on the presence or absence of the detection target substance in the specimen. A method for detecting a detection target substance using the resulting correction cantilever, wherein the specimen is brought into contact with the cantilever and the correction cantilever, and the specimen is brought into contact with the specimen after the point in time when the specimen is brought into contact with the cantilever. Displacement amount of each of the cantilever and the correction cantilever between the first time point and the second time point before the time point required for the cantilever to bend when the substance is contained. , And the displacement amount of the cantilever is corrected by the displacement amount of the correction cantilever, and the displacement of the cantilever after correction is measured. It was approximated by a polynomial with respect to time, and detecting the detection target by a factor of the resulting polynomial by the approximation consists in the detection method of the detection target substance using a cantilever (claim 6). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past. Furthermore, by performing correction with the correction cantilever, it is possible to reduce the influence of environmental changes on the measurement result and perform more accurate detection.

  Furthermore, still another aspect of the present invention is a method for detecting a detection target substance using a cantilever that generates deflection when the detection target substance is present in the specimen when the specimen is brought into contact with the specimen. After the time when the specimen is brought into contact with the cantilever and the specimen is brought into contact with the cantilever and before the time when the cantilever needs to bend when the specimen contains a detection target substance, From the first time point to the second time point, the displacement amount of the cantilever is measured, the displacement amount of the cantilever is approximated by an exponential function with respect to time, and the detection target substance is obtained by the exponential function coefficient obtained by the approximation. The present invention resides in a method for detecting a substance to be detected using a cantilever (claim 7). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  Further, another aspect of the present invention is a cantilever that generates a deflection when a detection target substance is present in the specimen when brought into contact with the specimen, and a deflection that does not depend on the presence or absence of the detection target substance in the specimen. A method for detecting a detection target substance using the resulting correction cantilever, wherein the specimen is brought into contact with the cantilever and the correction cantilever, and the specimen is brought into contact with the specimen after the point in time when the specimen is brought into contact with the cantilever. Displacement amount of each of the cantilever and the correction cantilever between the first time point and the second time point before the time point required for the cantilever to bend when the substance is contained. , And the displacement amount of the cantilever is corrected by the displacement amount of the correction cantilever, and the displacement of the cantilever after correction is measured. The method of detecting a detection target substance using a cantilever is characterized in that the detection target substance is detected by a coefficient of the exponential function obtained by the above approximation. ). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past. Furthermore, by performing correction with the correction cantilever, it is possible to reduce the influence of environmental changes on the measurement result and perform more accurate detection.

Furthermore, it is preferable that a specific substance capable of interacting with the detection target substance is immobilized on the surface of the cantilever (claim 9).
Moreover, it is preferable to use a sugar chain as the specific substance.
Furthermore, it is preferable to detect at least one of a virus and a bacterium as the detection target substance.

  Further, another aspect of the present invention is a cantilever that causes deflection when a substance to be detected is present in the specimen when the specimen is brought into contact with the specimen, a specimen contact section that brings the specimen into contact with the cantilever, and the cantilever After the time when the specimen is brought into contact with the cantilever, when the specimen contains the detection target substance, the amount of displacement before the time when the time required for the cantilever to sag is passed. A displacement amount measuring unit that measures the displacement amount of the cantilever at the first time point and a second time point, a displacement amount of the cantilever measured at the first time point, and a displacement amount of the cantilever measured at the second time point The present invention resides in a cantilever sensor system having a displacement amount comparison unit for comparison. This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  Further, another aspect of the present invention is a cantilever that causes deflection when a substance to be detected is present in the specimen when the specimen is brought into contact with the specimen, a specimen contact section that brings the specimen into contact with the cantilever, and the cantilever After the time point when the sample is brought into contact with the sample, the first time point to the second time point before the time point required for the cantilever to bend if the sample contains the detection target substance. Output a displacement amount measuring unit for measuring the displacement amount of the cantilever, a displacement amount approximating portion for approximating the displacement amount of the cantilever with respect to time, and a slope of the straight line obtained by the linear approximation. The cantilever sensor system includes an inclination output unit that performs the above-described operation (claim 13). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  Furthermore, another gist of the present invention is a cantilever that causes deflection when a substance to be detected is present in the specimen when brought into contact with the specimen, a specimen contact section that brings the specimen into contact with the cantilever, and the cantilever After the time point when the sample is brought into contact with the sample, the first time point to the second time point before the time point required for the cantilever to bend if the sample contains the detection target substance. The displacement amount measuring unit for measuring the displacement amount of the cantilever, the displacement amount approximating portion for approximating the displacement amount of the cantilever with a polynomial with respect to time, and the coefficient of the polynomial obtained by the linear approximation The present invention resides in a cantilever sensor system comprising a coefficient output unit for outputting. This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  Further, another aspect of the present invention is a cantilever that causes deflection when a substance to be detected is present in the specimen when the specimen is brought into contact with the specimen, a specimen contact section that brings the specimen into contact with the cantilever, and the cantilever After the time point when the sample is brought into contact with the sample, the first time point to the second time point before the time point required for the cantilever to bend if the sample contains the detection target substance. The displacement amount measurement unit for measuring the displacement amount of the cantilever, the displacement amount approximation unit for approximating the displacement amount of the cantilever with an exponential function with respect to time, and the exponential function obtained by the linear approximation A cantilever sensor system comprising a coefficient output unit that outputs a coefficient (claim 15). This also makes it possible to perform accurate measurement in a shorter time than in the past, and to perform detection without using an expensive measurement device as in the past.

  According to the detection method of a detection target substance using the cantilever and the cantilever sensor system of the present invention, it becomes possible to detect the detection target substance in a shorter time than in the past.

  Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments, and can be arbitrarily modified and implemented without departing from the gist of the present invention.

[1. Substances to be detected]
First, a detection target substance to be detected by using a detection target substance detection method using the cantilever of the present invention (hereinafter simply referred to as “the detection method of the present invention” as appropriate) will be described.
The type and state of the detection target substance are not particularly limited, but are usually used for detection in a state dissolved or dispersed in the specimen. In addition, one type of detection target substance may be detected alone, or two or more types may be detected in any combination. Note that the specimen here is an object to be analyzed whether or not it contains a detection target substance, and is usually subjected to analysis in a gas or liquid state. In the following embodiments, the case where the sample is a liquid sample liquid will be described, but the same can be applied to the case where the sample is in a gas state.

  The detection target substance is usually a substance that interacts specifically with a certain substance such as a biological substance (hereinafter referred to as “specific substance” as appropriate) (hereinafter referred to as “active substance” as appropriate). Here, the “interaction” between the specific substance and the active substance is not particularly limited, but is usually a covalent bond, a hydrophobic bond, a hydrogen bond, a van der Waals bond, or an electrostatic force bond. The effect | action by the force which acts between the substances which arise from at least one is shown. However, the term “interaction” in the present specification should be interpreted in the broadest sense, and should not be limitedly interpreted in any way. The covalent bond contains a coordinate bond. In addition, electrostatic coupling includes electric repulsion in addition to electrostatic coupling. In addition, a binding reaction, a synthesis reaction, and a decomposition reaction resulting from the above action are also included in the interaction.

  Specific examples of interactions include binding and dissociation between antigen and antibody, binding and dissociation between protein receptor and ligand, binding and dissociation between adhesion molecule and partner molecule, between enzyme and substrate Binding and dissociation, binding and dissociation between apoenzyme and coenzyme, binding and dissociation between nucleic acid and nucleic acid or protein binding to it, binding and dissociation between proteins in information transmission system, glycoprotein and Examples include binding and dissociation between proteins, and binding and dissociation between sugar chains and microorganisms such as proteins, viruses, and bacteria, but are not limited to this range.

Further, examples of detection target substances include immunoglobulins and derivatives thereof such as F (ab ′) ₂ , Fab ′, Fab, receptors and enzymes and derivatives thereof, nucleic acids, natural or artificial peptides, artificial polymers, sugars Quality, lipid, inorganic substance or organic ligand, virus, cell, drug and the like.

  Of these, viruses and bacteria are suitable for detection by the detection method of the present invention. In general, there is a protein that binds to the sugar chain on the surface of the virus or bacterium (hereinafter referred to as “binding protein”), and this binding protein binds to the sugar chain on the cell surface. This infects cells with viruses and bacteria. Therefore, if detection by a cantilever is performed using this infection mechanism, these viruses and cells can be detected with high sensitivity.

  Specific examples of bacteria that can be detected by the detection method of the present invention include Escherichia coli, Vibrio cholerae, Staphylococcus, Bacillus anthracis, Neisseria gonorrhoeae, Plasmodium pestis, Legionella, Shigella, Salmonella typhi, Helicobacter pylori, Mycobacterium tuberculosis, and Botulinum. Examples include fungi, tetanus, and diphtheria.

  Specific examples of viruses that can be detected by the detection method of the present invention include hepatitis B virus, hepatitis C virus, reovirus, encephalomyocarditis virus, AIDS virus, rotavirus, coronavirus, parvovirus, Sendai virus, Newcastle disease virus, herpes type 1 virus, proboscis virus, influenza virus and the like. Examples of influenza viruses include human influenza viruses and avian influenza viruses.

[2. Cantilever]
Next, the cantilever used in the detection method of the present invention will be described.
In the detection method of the present invention, a detection cantilever functioning as a sensor (cantilever sensor) for detecting a detection target substance (hereinafter referred to as “detection cantilever” as appropriate) is used. In addition, a correction cantilever is used in order to appropriately improve the detection accuracy of the detection cantilever.

[2-1. Cantilever for detection]
The detection cantilever is not particularly limited as long as it can bend by contact with the specimen when the substance to be detected is present in the specimen. A specific substance that can interact with the surface is immobilized on the surface. In this detection cantilever, when a specimen containing a detection target substance corresponding to a specific substance comes into contact with the detection cantilever, the detection target substance and the specific substance interact with each other, and surface stress is applied to the surface of the detection cantilever. A change occurs and the detection cantilever bends. Therefore, the amount, concentration, type, etc. of the detection target substance can be detected by measuring the magnitude of this deflection (hereinafter referred to as “displacement amount” as appropriate).

Hereinafter, the configuration of the detection cantilever will be described with reference to the drawings.
FIG. 19 is a schematic perspective view showing the main part of an example of a detection cantilever, and FIG. 20 is a cross-sectional view schematically showing the vicinity of the surface of an example of a detection cantilever. As shown in FIGS. 19 and 20, the detection cantilever 100 usually has a cantilever main body 101 and a specific substance 102 fixed on the surface of the cantilever main body 101. The specific substance 102 may be directly fixed to the cantilever body 101 or may be indirectly fixed. Normally, as shown in FIG. 20, the metal film 103 formed on the surface of the cantilever main body 101 and the organic molecule 104 fixed on the metal film 103 are immobilized on the organic molecule 104. As a result, the specific substance 102 is indirectly fixed to the cantilever main body 101. In FIG. 19, the specific substance 102 is not shown. Further, in FIG. 19, it is assumed that a portion (hereinafter, appropriately referred to as “interaction portion”) 105 to which the specific substance 102 is immobilized is formed on the upper surface of the detection cantilever 100 in the drawing.

There is no limitation on the cantilever main body 101 used for the detection cantilever 100, and a known cantilever can be arbitrarily used.
For example, the material of the cantilever main body 101 is not limited and any material can be used, but usually a flexible material is used. Specific examples of the material of the cantilever main body 101 include silicon and silicon nitride.

  Although the shape of the cantilever body 101 is not limited, the cantilever body 101 is usually formed as a rectangular parallelepiped member having a free end and a fixed end. As another example, a shape having one side of a triangle as a fixed end, and a shape obtained by punching the inside of the triangle are also possible. Note that the specific substance 102, the metal film 103 and the organic molecules 104 that are used as appropriate, and the like are formed as very thin films, so that the shape of the cantilever body 101 can be regarded as the shape of the detection cantilever 100 itself. In the present embodiment, the cantilever main body 101 will be described as a member that extends from the support member 106 into a rectangular parallelepiped shape as shown in FIG.

  Further, although the size of the cantilever main body 101 is not limited, normally, the length L (that is, the distance from the free end to the fixed end) is a deflection caused by the interaction between the surface of the detection cantilever 100 and the detection target substance. It is preferable that the length is long enough to reliably measure. As an example of dimensions, when the cantilever body 101 is formed in a rectangular parallelepiped shape, the length L is usually set in a range of 10 μm to 1000 μm, the width W is set in a range of 5 μm to 500 μm, and the thickness T is set in a range of 0.1 μm to 5 μm. It is preferable.

Moreover, there is no restriction | limiting in the production method of the cantilever main body 101, A well-known method can be used arbitrarily. For example, it can be produced in the same manner as a cantilever used in an AFM (Atomic Force Microscope) by an existing semiconductor process.
By the way, when the cantilever main body 101 is manufactured using a semiconductor formation process, even if it is manufactured under the same conditions, the film thickness and the material can be changed between manufacturing lots, between wafers, and between locations in the same wafer. Differences can occur. This can also occur in technologies other than the semiconductor formation process.

  The difference in film thickness and material described above becomes smaller if they are the same production lot, and becomes smaller if they are taken out from the same wafer. Furthermore, the difference is even smaller the closer the location where it is removed, even within the same wafer. Using this, the cantilever bodies 101 of the plurality of detection cantilevers 100 used in the same measurement are preferably manufactured from the same wafer, and more preferably manufactured at adjacent positions on the wafer.

  It is also preferable to use a plurality of detection cantilevers 100 used in the same measurement as one piece without being separated from each other. By not separating, it is clearly shown that measurement is performed by combining the plurality of detection cantilevers 100, and the mounting operation of the plurality of cantilevers is simplified.

Since the detection cantilever 100 and the cantilever main body 101 are very small, they are usually supported by some kind of support member 106. The support member 106 may be prepared separately from the cantilever body 101 and the detection cantilever 100 and the cantilever body 101 may be fixed later. However, when the cantilever main body 101 is manufactured using the semiconductor formation process as described above, the portion where the cantilever main body 101 of the same wafer is formed becomes the detection cantilever 100 or the cantilever main body 101, and the other portions of the wafer are A support member 106 is formed. Therefore, when the detection cantilevers 100 formed on the same wafer as described above are used without being separated, the detection cantilevers 100 are supported by the common support member 106.
Further, since the support member 106 is larger and stronger than the detection cantilever 100 and the cantilever main body 101, the support member 106 is usually fixed with a support and the detection cantilever 100 is attached to the analyzer. Yes.

  Further, it is preferable to form a concavo-convex pattern 107 on the surface of the detection cantilever 100 as shown in FIG. Thereby, the detection sensitivity at the time of detecting a detection target substance can be raised. When the uneven pattern 107 is formed on the surface of the detection cantilever 100, the surface of the cantilever body 101 may be formed in an uneven shape, and the metal layer 103 formed on the cantilever body 101 is formed in an uneven shape. Alternatively, other methods may be used.

Further, the detection cantilever 100 normally has a specific substance in the interaction unit 105 so that the detection cantilever 100 is bent by the interaction between the detection target substance and the specific substance as described above.
As the specific substance, any substance can be used according to the purpose. Specific examples include enzymes, antibodies, lectins, receptors, protein A, protein G, protein A / G, avidin, streptavidin, neutravidin, glutathione-S-transferase, glycoproteins, peptides, amino acids, hormones Nucleic acids, sugars, oligosaccharides, polysaccharides, sialic acid derivatives, sugar chains such as sialylated sugar chains, lipids, low molecular weight compounds, macromolecular organic substances other than those mentioned above, inorganic substances, or fusions thereof, or viruses, Or biomolecules, such as a molecule | numerator which comprises a cell, are mentioned. In addition, substances other than biomolecules such as cells can be used as the specific substance. These specific substances serve as target substances when measuring the interaction (binding property, etc.) between the detection target substance and the specific substance in the specimen.

  Further, among the examples of the specific substance, the protein may be the full length of the protein or a partial peptide including a binding active site. Further, the protein may be a protein whose amino acid sequence and its function are known or unknown. These can also be used as target substances, such as synthesized peptide chains, proteins purified from living bodies, or proteins that have been translated from a cDNA library or the like using an appropriate translation system and purified. The synthesized peptide chain may be a glycoprotein having a sugar chain bound thereto. Of these, a purified protein is preferable.

  Furthermore, there is no restriction | limiting in particular as a nucleic acid, In addition to DNA and RNA, nucleobases, such as an aptamer, and peptide nucleic acids, such as PNA, can also be used. The nucleic acid may be a known nucleic acid or an unknown nucleic acid. Preferably, a protein having a binding ability and having a known nucleic acid function and base sequence, or one that has been cleaved and isolated from a genomic library or the like using a restriction enzyme or the like can be used.

The sugar chain may be either a known sugar chain or an unknown sugar chain. Preferably, a sugar chain that has already been separated and analyzed and whose sugar sequence or function is known is used.
Further, the low molecular compound is not particularly limited as long as it has the ability to interact. Although those with unknown functions or those with already known ability to bind to proteins can be used, drug candidate compounds and the like are preferably used.

Among the specific substances described above, it is particularly preferable to use a sugar chain because it is possible to detect a detection target substance that is difficult to detect by other methods, such as viruses and bacteria, with high sensitivity.
The sugar chain is composed of monosaccharides such as glucose, galactose, mannose, fucose, xylose, N-acetylglucosamine, N-acetylgalactosamine, sialic acid, and derivatives thereof. At this time, it is preferable that sialic acid or substituted sialic acid is contained in at least one monosaccharide constituting the sugar chain. An example of a substituted sialic acid is fluorinated sialic acid, and a specific example is 3-fluorosialic acid. As a result, there is an advantage that sugar chains are hardly decomposed by an enzyme or the like contained in the specimen.

  Moreover, it is preferable that the glucoside bond part of a sugar chain is a nitrogen atom, a carbon atom, or a sulfur atom instead of an oxygen atom. As a result, there is an advantage that sugar chains are hardly decomposed by an enzyme or the like contained in the specimen.

Specific examples of the sugar chain include sialyllacto type I and type II sugar chains having the structure [NeuAcα2-6 (3) Galβ1-4 (3) GlcNAcβ1-], [NeuAcα2-6 (3) Galβ1-4 (3 ) A sialylganglio sugar chain having a GalNAcβ1-] structure, a sialyl lactose sugar chain having a [NeuAcα2-6 (3) Galβ1-4 (3) Glcβ1-] structure, and the like. Not. Usually, since a sugar chain can be artificially synthesized, it is possible to design and synthesize a structure with high selectivity to a target substance to be detected.
In addition, a specific substance may be used individually by 1 type, and may use 2 or more types together by arbitrary combinations and a ratio.

  Furthermore, since the interaction unit 105 of the detection cantilever 100 usually only needs to bend by the interaction with the detection target substance, the synthetic chemical substance that interacts with the detection target substance is immobilized. In some cases, the detection cantilever 100 may be in a state in which no substance is particularly immobilized.

There is no limitation on the method of fixing the specific substance on the surface of the cantilever main body 101 to form the interaction part 105. For example, the fixation can be performed by the following fixing method.
When the detection cantilever 100 is manufactured by immobilizing a specific substance on the surface of the cantilever body 101, as shown in FIG. 20, a metal film 103 is formed on the surface of the cantilever body 101, and organic molecules are formed on the formed metal film 103. The specific substance 102 can be immobilized on the organic molecule 104 by immobilizing 104. As a result, the interaction unit 105 includes the metal film 103 formed on the surface of the cantilever body 101, the organic molecules 104 fixed on the metal film 103, and the specific substance 105 fixed on the organic molecules 104. It is formed as a part having In FIG. 20, the organic molecules 104 are drawn as a layer in which the organic molecules 104 are gathered instead of drawing them individually for the sake of explanation.

The metal film 103 is not particularly limited as long as the organic molecules 104 can be fixed on the surface thereof, and can be formed of any material.
In addition, the metal film 103 may be a single-layer film in which only one layer is formed alone, or may be a film in which two or more layers are stacked in any combination and thickness.
However, the outermost layer of the metal film 103 is preferably formed of gold. That is, when the metal film 103 has a single layer structure, the metal film 103 itself is formed of gold. When the metal film 103 has a stacked structure, the outermost layer to which the organic molecules 104 are fixed is formed of gold. It is preferred that Thereby, organic molecules can be easily fixed to the metal film 103.

  Further, when the metal film 103 has a laminated structure, the metal film 103 preferably has a layer made of chromium between the surface of the cantilever body 101 and the outermost layer of the metal film 103. Thereby, the advantage that the adhesive force of the metal film 103 and the surface of the cantilever main body 101 improves is acquired.

  The thickness of the metal film 103 is not limited and is arbitrary, but is usually 1 nm or more, preferably 10 nm or more, and usually 10 μm or less, preferably 5 μm or less. If the lower limit of this range is not reached, the organic molecules 104 may not be fixed sufficiently, and if the upper limit is exceeded, a good metal film 103 may not be formed.

Furthermore, there is no restriction | limiting in the formation method of said metal film 103, Although a well-known method can be used arbitrarily, Usually, it forms by sputtering, vapor deposition, etc.
If the cantilever body 101 itself is made of metal, the surface of the cantilever body 101 can be used as the metal film 103.

  On the metal film 103, organic molecules 104 are fixed. The organic molecule 104 can be fixed to the metal film 103, and the type of the organic molecule 104 is not limited as long as the specific substance 102 can be fixed on the organic molecule 104. Any appropriate substance can be used depending on the type of the specific substance 102 to be immobilized from the molecule 104.

  However, the organic molecule 104 preferably has a mercapto group (—SH group) at its end. In this case, since the organic molecule 104 is fixed to the metal film 103 by a stable “sulfur atom-metal bond”, the organic molecule 104 can be firmly fixed to the metal film 103.

Specific examples of the organic molecule 104 include 16-mercaptohexadecanoic acid.
In addition, the organic molecule 104 may be used individually by 1 type, and may use 2 or more types together by arbitrary combinations and a ratio.
Furthermore, the amount of the organic molecules 104 to be fixed is arbitrary, but it is usually preferable to fix them at a high density. Thereby, there is an advantage that the film thickness of the fixed organic molecule 104 layer can be made uniform.

Further, the organic molecules 104 may be fixed two-dimensionally on the surface of the metal film 103, but may be configured to be three-dimensionally stacked. Further, when the organic molecule 104 is formed as a layer, it may have a single layer structure or a laminated structure. However, it is usually desirable to have a single layer structure. This is because it is easier to control the film thickness of the organic molecule 104 in the single-layer structure than in the case of a plurality of layers. Note that FIG. 20 shows an example in which the organic molecules 104 are formed in a single layer.
Furthermore, there is no restriction | limiting in the fixing method of the organic molecule 104, Although a well-known method can be used arbitrarily, Usually, it fix | immobilizes by a "sulfur atom-metal bond."

  In addition, the specific substance 102 is immobilized on the organic molecule 104, whereby the specific substance 102 is immobilized on the surface of the cantilever body 101 via the metal film 103 and the organic molecule 104, and the interaction unit 105 is fixed. A detection cantilever 100 having a specific substance 102 is formed.

  Here, the specific substance 102 may be immobilized on the organic molecule 104 by any bond, but it is usually desirable that the specific substance 102 be immobilized by a covalent bond. Thereby, the specific substance 102 can be firmly fixed to the organic molecule 104. In such a case, it is desirable that the specific substance 102 is immobilized through, for example, an ester bond, an amide bond, a —C═N— bond, an ether bond, a thioether bond, a bond with a carbon atom, or the like. The specific substance 102 may be fixed by one type of bond, or may be fixed by any two or more types of bonds.

The specific substance 102 may have a functional group for immobilization.
Furthermore, when immobilizing the specific substance 102 on the organic molecule 104, the specific operation is arbitrary. Usually, the specific substance 102 is immobilized on the organic molecule 104 by bringing the solution of the specific substance 102 into contact with the organic molecule 104. In this case, the solvent or dispersion medium for diluting the specific substance 102 is preferably adjusted in consideration of the activity of the specific substance 102, the stability of the structure, and the like.

In the detection method of the present invention, the amount of displacement of the detection cantilever 100 is measured. In this case, a member for measuring the amount of displacement is appropriately attached to the detection cantilever 100 according to the displacement amount measurement method. Make it.
For example, when the amount of displacement of the detection cantilever 100 is measured by an optical method, the reflection surface 108 is usually formed on the detection cantilever 100. In this case, the reflective surface 108 is subjected to a surface treatment so that light used for measuring the amount of displacement can be effectively reflected. Specific surface treatment is optional, but for example, treatment such as forming a metal film on the reflective surface 108 is performed. At this time, the metal film 103 provided for immobilizing the specific substance 102 on the detection cantilever 100 can be used as the metal film for reflection. In the configuration of FIG. 19, it is assumed that the reflection surface 108 is provided on the surface opposite to the interaction portion 105 of the detection cantilever 100.

  Further, for example, when the amount of deflection of the detection cantilever 100 is measured electrically, usually, a piezoelectric resistance element (not shown) is patterned on the surface (usually one side) of the detection cantilever 100. There is no restriction | limiting in the material of a piezoresistive element part, a pattern shape, a dimension, etc., A well-known thing can be used arbitrarily.

[2-2. Correction cantilever]
When the detection target substance is detected using the detection cantilever, it is also possible to perform detection using a plurality of cantilevers simultaneously. Although it is possible to use a plurality of detection cantilevers, the detection accuracy of the detection cantilever can be improved by using at least one correction cantilever.

  The correction cantilever is a cantilever used for the purpose of measuring a correction value for adding a correction to the displacement amount of the detection cantilever in order to eliminate the influence of the deflection caused by the environmental change or the like. In other words, the cantilever, including the detection cantilever and the correction cantilever, is displaced by changes in the environment such as temperature and pressure in addition to changes in the surface stress caused by the interaction between the detection target substance and the specific substance. The amount varies. Therefore, when measuring the amount of displacement, it is desirable to measure only the amount of displacement caused by the interaction between the target substance to be detected and the specific substance, eliminating the influence of deflection due to environmental changes. The correction cantilever is used to eliminate the displacement due to the environmental change.

  It is desirable that the correction cantilever be formed such that no deflection due to interaction occurs, and that deflection due to factors other than interaction such as environmental changes occurs. Therefore, in order to realize this, a specific substance is not normally immobilized on the correction cantilever. That is, the entire surface of the correction cantilever is formed as a non-immobilized portion where the specific substance is not immobilized.

  Further, it is more preferable that the correction cantilever be formed in the same manner as possible with the detection cantilever to be corrected except that the specific substance is not immobilized. Specifically, it is preferable that dimensions and materials are as equal as possible. As a result, when the same environmental change is applied to each of the detection cantilever and the correction cantilever, the deflection due to the environmental change can be caused in both by the same displacement amount. Therefore, the deflection amount of the detection cantilever is the sum of the displacement amount due to the interaction and the displacement amount due to the environmental change, while the displacement amount of the correction cantilever is only the deflection amount due to the environmental change. This makes it possible to accurately measure the amount of displacement due to the interaction.

  Depending on the application of the correction cantilever, the correction cantilever surface has a metal layer, organic molecules, or a specific substance fixed to the detection cantilever. Material (hereinafter referred to as “reference material”) or the like may be immobilized. Even in this case, it may be possible to perform more appropriate correction using the correction cantilever. Examples of the reference substance include the same substances as the specific substance.

  Among these, it is preferable to fix the reference substance to the correction cantilever. In this case, when a metal layer or an organic molecule is used to immobilize a specific substance on the detection cantilever, a metal layer similar to the detection cantilever is used to immobilize the reference substance on the correction cantilever. It is more preferable to use organic molecules. This is because the detection accuracy can be further increased.

  That is, for example, when an appropriate reference material that does not interact with the detection target substance is immobilized on the correction cantilever, the correction cantilever causes a deflection very close to the deflection caused by the environmental change that occurs in the detection cantilever. This makes it possible to more accurately measure the amount of deflection due to the interaction generated in the detection cantilever.

  Further, in order to measure the deflection amount of the correction cantilever, it is desirable that the correction cantilever be formed with a displacement measuring member such as a reflective surface or a piezoresistive element in the same manner as the detection cantilever. At this time, if a reflective surface is also formed on the correction cantilever, the reflective surface of the correction cantilever is preferably subjected to surface treatment in the same manner as the reflective surface of the detection cantilever.

  However, at this time, it is more preferable to form a metal film so that a metal that is difficult to fix a specific substance as a reflective film of the correction cantilever, specifically, a metal such as aluminum, copper, or silver is the outermost layer. . Normally, when a metal other than gold is used, the binding force between the organic molecule and the metal is weaker than when gold is used. Therefore, the ability of the correction cantilever to immobilize a specific substance is that of the detection cantilever. It becomes smaller than the ability to immobilize a specific substance. Therefore, even when the correction cantilever is in the vicinity of the detection cantilever when the specific substance is fixed to the detection cantilever, the specific substance is not fixed to the correction cantilever, and the detection cantilever and the correction cantilever are simply Can be produced.

[2-3. Other configurations]
As described above, in the detection method of the present invention, the number of cantilevers to be used is not limited. Accordingly, one detection cantilever and one correction cantilever may be used alone, or two or more maytilevers may be used.

  In general, when two or more detection cantilevers are used, different specific substances are immobilized on each detection cantilever so that more detection target substances can be detected by one analysis operation. It is desirable to configure. That is, by using a plurality of detection cantilevers in which different specific substances are immobilized, it is possible to detect a plurality of detection target substances by a single analysis operation by comparing the reactions to a plurality of types of specific substances. Is obtained. In such a case, the number of cantilevers to be used can be appropriately selected according to the number of detection target substances, but is, for example, 5 to 10 from the viewpoint of downsizing the apparatus and reducing the amount of specimen.

[3. First Embodiment]
Hereinafter, a first embodiment of the present invention will be described with reference to the drawings.
1 to 4 illustrate a first embodiment of the present invention, and FIG. 1 is a perspective view schematically showing an outline of a cantilever sensor system according to the first embodiment of the present invention. FIG. 2 illustrates one embodiment of the present invention, and FIG. 2 (a) is a diagram schematically showing the state of the detection cantilever before the specific substance and the detection target substance interact, FIG. 2B is a diagram schematically showing a state of the detection cantilever when the deflection is caused by the interaction between the specific substance and the detection target substance. FIG. 3 is a cross-sectional view schematically showing a main part of the cantilever sensor system according to the first embodiment of the present invention. FIG. 4 is a graph schematically showing an example of the relationship between the time and displacement when the detection cantilever 3A is bent.

  The cantilever sensor system used in the detection method of the present embodiment measures the displacement amount of the detection cantilever using an optical method. As shown in FIG. 1, the light source 1, the condensing means 2, and the detection cantilever 3A. A light receiving element 4, a displacement measuring unit 51, and a displacement comparing unit 52. The displacement measuring unit 51 and the displacement comparing unit 52 are configured by causing the computer 5 to read a program for causing the computer 5 to function as the displacement measuring unit 51 and the displacement comparing unit 52 in terms of hardware. Is. Furthermore, in the cantilever sensor system of this embodiment, the detection cantilever 3A is assumed to be mounted on a transparent container 6 as a specimen contact portion. In FIG. 1, the symbol I indicates light used for detection.

[3-1. light source]
The light source 1 irradiates light toward the detection cantilever 3A. Any light source can be used as long as the effects of the present invention are not significantly impaired, but it is usually preferable to use a laser beam irradiation apparatus.
The laser irradiation device is not particularly limited as long as it can emit laser light. For example, a gas laser irradiation device, a semiconductor laser irradiation device, or the like is used, but it is preferable to use a semiconductor laser irradiation device because it is cheaper. Also in this embodiment, it is assumed that a semiconductor laser irradiation apparatus is used as the light source 1.

[3-2. Condensing means]
It is desirable that the light emitted from the light source 1 to the detection cantilever 3A is condensed on the surface (specifically, the reflection surface) of the detection cantilever 3A. Therefore, in the optical cantilever sensor system, it is desirable to provide the light condensing means 2 for condensing the light emitted from the light source 1.

  Although there is no restriction | limiting in the condensing means 2, For example, it can comprise by combining the rod lens 21 and the cylindrical lenses 22 and 23. FIG. That is, as shown in FIG. 1, the light emitted from the light source 1 is first spread in a predetermined direction by the rod lens 21, and the spread light is converted into parallel light by the cylindrical lens 22. This parallel light is light that travels in parallel (that is, in the same direction) at any position with respect to the predetermined direction. Then, the parallel light is collected by the cylindrical lens 23. The condensed light is collected so as to be collected on the surface of the detection cantilever 3A.

  For example, as the condensing means 2, a cylindrical concave mirror can be used instead of the cylindrical lenses 22 and 23 in the configuration exemplified above. In addition, for example, a cylindrical convex mirror can be used instead of the rod lens 21. However, when the spot light size of the light emitted from the light source 1 is sufficiently large to obtain a desired detection accuracy, the light from the light source 1 is appropriately transmitted by one cylindrical lens 23 without using the rod lens 21 or the like. It is also possible to irradiate the detection cantilever 3A simply by condensing.

  In the present embodiment, the light emitted from the light source 1 is linearly collected on the detection cantilever 3 </ b> A by the condensing means 2 that combines the rod lens 21 and the cylindrical lenses 22 and 23, and passes through the transparent container 6. It is assumed that the detection cantilever 3A is irradiated.

[3-3. Cantilever for detection]
The cantilever sensor system of the present embodiment is provided with a detection cantilever 3A. The detection cantilever 3A is irradiated with light emitted from the light source 1, and can further reflect the irradiated light. ing.
Further, the detection cantilever 3A according to the present embodiment is formed as a rectangular parallelepiped cantilever extending from the support member 31A.

  Further, in this detection cantilever 3A, a specific substance (not shown in FIG. 1) is fixed to the lower surface in the figure via a metal layer (not shown in FIG. 1) and organic molecules (not shown in FIG. 1). It has become. Further, the upper surface 32A in the drawing is subjected to a surface treatment so that the irradiated light can be effectively reflected, and these surfaces function as reflecting surfaces. Hereinafter, this surface 32A will be referred to as a reflective surface as appropriate.

  Therefore, as shown in FIGS. 2A and 2B, the detection cantilever 3A according to the present embodiment has a detection target substance S that can interact with the specific substance T immobilized on the detection cantilever 3A. In the case where it is contained, the deflection due to the interaction between the specific substance T and the detection target substance S occurs in the detection cantilever 3A. That is, even if the detection cantilever 3A is not bent as shown in FIG. 2A before the interaction occurs, the specific substance T and the detection target substance S interact (bond in FIG. 2). By doing so, the deflection occurs as shown in FIG. 2 (b).

  By the way, as described above, the light emitted from the light source 1 is condensed by the condensing means 2, and the light applied to the detection cantilever 3A is linear. Here, of the light emitted from the light source 1, the light irradiated to the position where the detection cantilever 3 </ b> A does not exist is not reflected, so that only the light corresponding to the detection cantilever 3 </ b> A is reflected toward the light receiving element 4. It is like that.

[3-4. Transparent container]
In the present embodiment, the detection cantilever 3A is mounted and used in the transparent container 6, whereby the detection cantilever 3A is detachably provided to the cantilever sensor system. Specifically, a transparent container 6 for storing a specimen as shown in FIG. 3 is provided at a site where the light source 1 emits light, and a support (cantilever mounting portion) 61 formed in the transparent container 6. By fixing the support member 31A of the detection cantilever 3A to the detection cantilever 3A, the detection cantilever 3A can be held in the transparent container 6 and mounted on the cantilever sensor system.

In the present embodiment, the transparent container 6 can transmit light emitted from the light source 1. Accordingly, the incident light collected by the condensing means 2 and the reflected light reflected by the detection cantilever 3A are not prevented from advancing by the transparent container 6.
Furthermore, the specimen can be injected and discharged into the transparent container 6 through holes 62 and 63 formed in the transparent container 6. Therefore, the specimen can be brought into contact with the detection cantilever 3A by injecting the specimen from the holes 62 and 63 and filling the transparent container 6 with the specimen.

In the present embodiment, the support 61 is formed on the ceiling surface 64 of the transparent container 6, and the detection cantilever 3 </ b> A is mounted by sandwiching the support member 31 </ b> A between the support 61 and the ceiling surface 64. Suppose that
In FIG. 1, the transparent container 6 is indicated by a two-dot chain line. Moreover, in FIG. 3, the arrow shows light.

[3-5. Light receiving element]
The light receiving element 4 receives the light reflected by the detection cantilever 3A. In addition, the light receiving element 4 is configured to send information of the received position (hereinafter referred to as “light receiving position” as appropriate) to the displacement measuring unit 51 of the computer 5. In addition, the site | part which has received light on the light receiving element 4 is hereafter called the light reception part 41A suitably.

  There is no restriction | limiting in the kind of light receiving element 4, For example, PSD (position detection element), CCD (charge-coupled element), a CMOS light receiving element, etc. are used. Note that one of these light receiving elements 4 may be used alone, or two or more of them may be used in combination. In this embodiment, it is assumed that a CCD is used as the light receiving element 4.

[3-6. Displacement measurement unit]
The displacement measuring unit 51 receives the information on the light receiving position of the light receiving element 4, detects the amount of movement of the light receiving position corresponding to the detection cantilever 3A, and detects the detection cantilever 3A from the detected amount of movement of the light receiving position. The amount of displacement is measured. That is, if the detection cantilever 3A is deflected, the light receiving position of the light receiving element 4 is moved. Therefore, by using the information on the movement distance, the displacement measuring unit 51 is deflected in the detection cantilever 3A. The size of can be calculated. It should be noted that the position of the light receiving part 41A of the light receiving element 4 to be used as the light receiving position used for measuring the displacement amount may be determined as appropriate. For example, the center position of the light receiving part 41A is used as the light receiving position. Can do.

  Further, the displacement amount measuring unit 51 has elapsed after at least the time required for the detection cantilever 3A to bend when the detection target substance is included in the sample after the sample is brought into contact with the detection cantilever 3A. It is only necessary to measure the displacement amount of the detection cantilever 3A at the first time point and the second time point within the time range before the time point (hereinafter referred to as “specific time range” as appropriate).

An example will be described. FIG. 4 is a graph schematically showing an example of the relationship between the time and the amount of displacement when the detection cantilever 3A causes deflection.
In FIG. 4, the time point when the specimen is brought into contact with the detection cantilever 3A is represented by the symbol “T ₁ ”. Usually, before this time T ₁ , the standard solution not containing the detection target substance fills the transparent container 6, no interaction occurs, and the displacement does not change. At this point T _1, the standard solution of the transparent container 6 is discharged, the sample solution is injected.
In FIG. 4, the time required for the detection cantilever 3 </ b> A to bend when the detection target substance is contained in the specimen is represented by the symbol “T ₀ ”. However, it is assumed that this time T ₀ is known in advance by tests, documents, and the like. If the time T ₀ is unknown, a predicted value can be used as appropriate.

Further, in FIG. 4, the point in time when the time T ₀ required for the detection cantilever 3 </ _b > A to bend when the detection target substance is contained in the specimen is represented by the symbol “T ₂ ”. At this time point T ₂ , the interaction between the specific substance and the detection target substance is completely advanced. Therefore, the detection cantilever 3 A is not further bent after the time point T _{2, and} the detection cantilever 3 A is displaced by the interaction. The change in quantity stops.

Therefore, in the example of FIG. 4, the time range after the time point T _{1 and} before the time point T ₂ is the specific time range. Also, this particular time range, later than time T _1, it is also possible that the time range, before the time T ₀ from the time T ₁ is passed.
In such a case, the displacement amount measurement unit 51 detects at least at _two time points after the time point T _{1 and} before the time point T ₂ , that is, at the first time point t ₁ and the second time point t ₂ . The amount of displacement of the cantilever 3A only needs to be measured. In other words, this is the displacement at the start point (that is, the first time point t ₁ ) and the end point (that is, the second time point t ₂ ) of the predetermined time range within the specific time range (hereinafter referred to as “predetermined time range” as appropriate). Represents measuring a quantity. It is assumed that the first time point t ₁ is earlier than the second time point t ₂ .

However, since the detection cantilever 3A itself is often not stable immediately after the specimen and the detection cantilever 3A are brought into contact with each other, the first time point t ₁ is usually greater than 0 minutes after the time point T _1. Is within a time range in which a time of 5 minutes or more, usually 30 minutes or less, preferably 20 minutes or less has elapsed. On the other hand, the second time point t ₂ is within the time range after the time point T ₁ , usually 10 minutes or more, preferably 20 minutes or more, and usually 120 minutes or less, preferably 60 minutes or less. It is desirable.

In this embodiment, the displacement amount measuring unit 51 always measures the displacement amount of the detection cantilever 3A. Therefore, from the time T ₁ before the sample is brought into contact with the detection cantilever 3A, the first time t through _1, to the second time point t _2, and are made to measure the displacement amount of the detection cantilever 3A. The first time point t ₁ and the second time point t ₂ are indicated by the displacement amount measurement unit 51 and the displacement amount comparison unit 52 when the operator instructs the computer 5 through an interface (not shown) such as a keyboard. It is assumed that it is set by reading. Further, the measured displacement amount is sent to the displacement amount comparison unit 52.

[3-7. Displacement comparison unit]
Displacement amount comparing unit 52, among the amount of displacement is the displacement amount measuring unit 51 to measure the displacement amount of the detection cantilever 3A measured at the first time point t _1, detection cantilever measured at second time t ₂ The displacement amount of 3A is compared.

Specifically, the difference between the displacement amount measured at the first time point t ₁ and the displacement amount measured at the second time point t ₂ is calculated, and when the difference occurs (that is, the absolute value of the difference is 0). If it is larger) it is determined that the detection target substance is present in the sample, and if there is no difference (that is, the absolute value of the difference is 0), the detection target substance is present in the sample. Judge that there is no. The above difference represents a change in the amount of displacement that has occurred within a predetermined time range. When such a change appears, the above-mentioned detection target substance and the specific substance interact with each other. Therefore, it can be determined that the detection target substance is present in the sample.

  Further, a predetermined threshold value is set in advance, and if the absolute value of the difference is equal to or greater than the threshold value, it is determined that the detection target substance exists, and if the absolute value of the difference is less than the threshold value, the detection target substance does not exist. You may make it determine. This is to prevent erroneous detection due to noise during displacement measurement. Note that this threshold value is arbitrarily set according to the measurement accuracy of the measurement apparatus, the type of specimen, and the like.

  Further, the magnitude of the absolute value of the difference includes information on the amount and concentration of the detection target substance in the sample. That is, in general, the greater the amount or concentration of the detection target substance in the specimen, the greater the deflection of the detection cantilever 3A. Therefore, it can be determined that the greater the absolute value of the difference, the greater the amount or concentration of the detection target substance. Therefore, it is also possible to measure the amount and concentration based on the difference. In this case, information such as a table indicating correspondence between the difference and the concentration of the detection target substance is recorded in advance in a recording unit (not shown) in the computer 5, and the concentration is calculated from the difference based on the information. A computing unit (not shown) for outputting such information may be provided in the computer 5.

In this embodiment, the displacement amount comparison unit 52 detects the detection target substance by determining whether or not the absolute value of the difference between the displacement amounts is equal to or greater than a predetermined threshold value. It shall be.
Further, the result of the comparison, that is, the presence / absence of the detection target substance and the difference value are output to an output device (not shown). Further, it is assumed that the operator recognizes information such as the concentration of the detection target substance in the sample based on the output difference.

[3-8. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, the detection cantilever 3A is mounted on the support 61 and the detection can be performed from the light source 1. The specimen is brought into contact with the detection cantilever 3A while irradiating the cantilever 3A with light. Then, measuring the displacement amount of the detection cantilever 3A at least a first time point t ₁ of the second time point t ₂ Prefecture. Thereafter, the detection target substance is detected by comparing the displacement amount of the detection cantilever 3A measured at the first time point t ₁ with the displacement amount of the detection cantilever 3A measured at the second time point t ₂ .
This will be described in detail below.

First, the detection cantilever 3 </ b> A is attached to the support 61 so that the support member 31 </ b> A is sandwiched between the support 61 and the ceiling surface 64 of the transparent container 6. In addition, as conditions used for detection, information on the first time point t ₁ and the second time point t ₂ and information on threshold values used by the displacement amount comparison unit 52 are input to the displacement amount measurement unit 51 and the displacement amount comparison unit 52 in advance. Keep it.

And after filling the transparent container 6 with the standard solution which does not contain a detection target substance, light is irradiated from the light source 1 to the detection cantilever 3A. The irradiated light is reflected by the reflecting surface 32A of the detection cantilever 3A and is irradiated toward the light receiving element 4. At this time, if the light reflected by the detection cantilever 3A is not received by the light receiving element 4, the position and inclination of the detection cantilever 3A and the light receiving element 4 are adjusted so that the light is reliably received as described above. Make initial adjustments. The standard solution is for this initial adjustment.
The light irradiated to the light receiving element 4 is received by the light receiving portion 41 </ b> A of the light receiving element 4. In addition, the light receiving element 4 sends information on the light receiving position to the displacement measuring unit 51.

In this embodiment, in such a state, after the standard solution in the transparent container 6 is discharged, the specimen is injected into the transparent container 6 and the detection cantilever 3A and the specimen are brought into contact with each other. This time is time T ₁ .
When the detection cantilever 3A and the specimen come into contact with each other, when the detection target substance that can interact with the specific substance immobilized on the detection cantilever 3A is contained in the specimen, the mutual relation between the specific substance and the detection target substance Deflection due to the action occurs in the detection cantilever 3A.

  When deflection occurs in the detection cantilever 3A, the traveling direction of the light reflected by the detection cantilever 3A varies according to the amount of displacement of the detection cantilever 3A. If it does so, the advancing direction of the light to the light receiving element 4 will also fluctuate, and this will also move the light reception site | part 41A on the light receiving element 4, and, therefore, the light receiving position will also move.

  Information on the light receiving position corresponding to the detection cantilever 3 </ b> A is sent to the displacement measuring unit 51. The displacement measuring unit 51 receives information on the light receiving position of the light receiving element 4, detects the amount of movement of the light receiving position, and measures the amount of displacement of the detection cantilever 3A from the detected amount of movement of the light receiving position.

Here, in the present embodiment, the displacement amount measuring unit 51 always measures the displacement amount. Therefore, when the first time point t ₁ is reached, the displacement amount measuring unit 51 measures the displacement amount at the first time point t ₁ , and the second time point. When the time point t ₂ is reached, the displacement amount at the second time point t ₂ is measured. The measured displacement amount of the detection cantilever 3 </ b> A including the measurement results at the first time point t ₁ and the second time point t ₂ is sent to the displacement amount comparison unit 52.

In the displacement amount comparison unit 52, the displacement amount of the detection cantilever 3A measured at the first time point t ₁ according to the condition given by the operator from the displacement amount sent from the displacement amount measurement unit 51, and the second time point comparing the displacement amount of the detection cantilever 3A measured at t _2, by the difference between the amount of displacement to determine whether or larger than the threshold, to detect the detection target substance in a sample.
As a result of the displacement amount comparison unit 52, the presence / absence of the detection target substance and the difference value are output to an output device (not shown). Further, based on the output difference value, the operator detects the presence and concentration of the detection target substance in the sample.

[3-9. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art. In particular, in many conventional sensors, the time required for detection has been relatively short, and thus attention has not been paid to shortening the time required for detection. However, the detection method using a cantilever sensor requires a long time for detection, which is efficient. There was a point to be improved. In contrast, as in the present embodiment, without waiting for detection cantilever 3A Kiru deflection (i.e., before the time T ₂₎ by brief by which enables accurate detection, the detection Efficiency can be realized. Furthermore, since an expensive measuring device is unnecessary, the cost required for detection can be reduced.

  Further, since the specific substance is immobilized on the surface of the detection cantilever 3A, if the detection target substance capable of interacting with the specific substance is contained in the sample, the detection target substance can be reliably detected. For example, when a sugar chain is used as the specific substance, it is possible to detect viruses and bacteria that have been difficult to detect.

[4. Second Embodiment]
Next, a second embodiment of the present invention will be described with reference to the drawings.
FIG. 5 is a perspective view schematically showing an outline of a cantilever sensor system according to a second embodiment of the present invention. In FIG. 5, parts similar to those in FIGS. 1 to 4 are denoted by the same reference numerals as in FIGS. 1 to 4.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the first embodiment. However, in this embodiment, the displacement amount of the detection cantilever is corrected using the correction cantilever 3B. For this reason, in addition to the configuration of the first embodiment, the correction displacement amount measurement unit 53 and The displacement amount correction unit 54 is provided.

  That is, as shown in FIG. 5, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a light collecting means 2, a detection cantilever 3A, a correction cantilever 3B, a light receiving element 4, and a displacement. An amount measuring unit 51, a corrected displacement amount measuring unit 53, a displacement amount correcting unit 54, and a displacement amount comparing unit 52 are provided. The displacement measuring unit 51, the corrected displacement measuring unit 53, the displacement correcting unit 54, and the displacement comparing unit 52 are the same in hardware as the computer 5, and the computer 5 is replaced with the displacement measuring unit 51 and the corrected displacement measuring. It is configured by reading a program for functioning as the unit 53, the displacement amount correction unit 54, and the displacement amount comparison unit 52. Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A and the correction cantilever 3B are mounted on a transparent container 6 as a specimen contact portion.

[4-1. light source]
As the light source 1, the thing similar to 1st Embodiment can be used.
In the present embodiment, the light source 1 irradiates not only the detection cantilever 3A but also the correction cantilever 3B. Therefore, as the light source 1, a separate light source 1 may be used for each of the detection cantilever 3A and the correction cantilever 3B. However, from the viewpoint of more accurately comparing the displacement amounts of the detection cantilever 3A and the correction cantilever 3B, it is preferable to use the common light source 1 for the detection cantilever 3A and the correction cantilever 3B.
Also in this embodiment, it is assumed that a semiconductor laser irradiation device common to the detection cantilever 3A and the correction cantilever 3B is used as the light source 1.

[4-2. Condensing means]
The light emitted from the light source 1 to the detection cantilever 3A and the correction cantilever 3B is collected on the surface (specifically, the reflection surface) of the detection cantilever 3A and the correction cantilever 3B as in the first embodiment. It is desirable to make it light. As the condensing means 2 used at this time, the same thing as 1st Embodiment can be used.

  However, in the present embodiment, the light condensing means 2 should condense light on the surfaces of both the detection cantilever 3A and the correction cantilever 3B, and therefore, the detection cantilever 3A and the correction cantilever 3B. The installation position of 3B should be appropriately set according to the configuration of the light collecting means 2.

  In the present embodiment, it is assumed that the cylindrical lens 23 collects light emitted from the light source 1 in a straight line along a predetermined direction. It is assumed that the detection cantilever 3A and the correction cantilever 3B are arranged in a line in a predetermined direction and juxtaposed so that the detection cantilever 3A and the correction cantilever 3B can be irradiated with light uniformly.

[4-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first embodiment.

[4-4. Correction cantilever]
The cantilever sensor system of this embodiment is provided with a correction cantilever 3B. The correction cantilever 3B is configured in the same manner as the detection cantilever 3A except that a reference substance is immobilized instead of the specific substance.

That is, the correction cantilever 3B is irradiated with the light emitted from the light source 1 and can reflect the emitted light in the same manner as the detection cantilever 3A. Therefore, the shape of the part 33B irradiated with light (that is, the irradiated part) 33B of the correction cantilever 3B is on the line segment, but the light reflected from the irradiated part 33A is received by the light receiving element 4. In some cases, it is spot-like.
Further, the correction cantilever 3B according to the present embodiment is formed as a rectangular parallelepiped cantilever extending from the support member 31B.

  Further, in this correction cantilever 3B, a reference substance (not shown in FIG. 5) is fixed to the lower surface in the figure via a metal layer (not shown in FIG. 5) and organic molecules (not shown in FIG. 5). It has become. Further, the upper surface 32B in the drawing is subjected to a surface treatment so that the irradiated light can be effectively reflected, and these surfaces function as a reflecting surface. Hereinafter, this surface 32B will be appropriately referred to as a reflective surface.

  Therefore, the correction cantilever 3B according to the present embodiment does not cause a deflection due to an interaction even when it comes into contact with the specimen, but detects a deflection that does not depend on the presence or absence of a detection target substance in the specimen due to an environmental change or the like, for example. The size is the same as that of the cantilever 3A.

[4-5. Transparent container]
Also in this embodiment, the transparent container 6 is provided in the cantilever sensor system. As shown in FIG. 3, the transparent container 6 is the same as the first embodiment except that a correction cantilever 3B can be mounted in addition to the detection cantilever 3A. The correction cantilever 3B is mounted on the transparent container 6 in the same manner as the detection cantilever 3A, and can be measured for the amount of displacement by light transmitted through the transparent container 6 in contact with the specimen.
In FIG. 5, the transparent container 6 is indicated by a two-dot chain line.

[4-6. Light receiving element]
The light receiving element 4 used in the present embodiment receives light reflected by the correction cantilever 3B in addition to the detection cantilever 3A, and sends information on the light reception position to the displacement measuring unit 51 of the computer 5. Other than that, the second embodiment is the same as the first embodiment. Hereinafter, the part on the light receiving element 4 that receives the light reflected by the correction cantilever 3B will be referred to as a light receiving part 41B.

[4-7. Displacement measurement unit]
The displacement measuring unit 51 according to the present embodiment is the same as the first embodiment except that the measured displacement of the detection cantilever 3A is sent to the displacement correcting unit 54. Therefore, since the displacement amount measuring unit 51 measures the displacement amount of constantly detecting cantilever 3A, if the first time point t ₁ and the second time point t _2, the displacement at each time point t _1, t ₂ It comes to measure.

In the present embodiment as well, as in the first embodiment, the information on the first time point t ₁ and the second time point t ₂ and the threshold value information used by the displacement amount comparison unit 52 are displayed on an interface such as a keyboard ( When the operator instructs the computer 5 by (not shown), the instruction content is set by reading the displacement amount measuring unit 51, the corrected displacement amount measuring unit 53, the displacement amount correcting unit 54, and the displacement amount comparing unit 52. It is assumed that

[4-8. Corrected displacement measurement unit]
The correction displacement amount measuring unit 53 receives the information on the light receiving position of the light receiving element 4 in the same manner as the displacement amount measuring unit 51, and detects and detects the movement amount of the light receiving position corresponding to the correction cantilever 3B. The displacement of the correction cantilever 3B is measured from the amount of movement of the light receiving position.

Therefore, in the present embodiment, the correction displacement amount measurement unit 53 always measures the displacement amount of the correction cantilever 3B. Therefore, from the time T ₁ before the specimen is brought into contact with the detection cantilever 3A, It is assumed that the displacement amount of the correction cantilever 3B is measured from one time point t ₁ to the second time point t ₂ .
Further, the measured displacement amount of the correction cantilever 3 </ b> B is sent to the displacement amount correction unit 54.

[4-9. Displacement correction unit]
The displacement amount correction unit 54 corrects the displacement amount of the detection cantilever 3A with the displacement amount of the correction cantilever 3B, and removes the displacement amount caused by factors other than the interaction between the specific substance and the detection target substance. In the present embodiment, the displacement amount correction unit 54 is configured so that the correction displacement amount measurement unit 53 determines the displacement amount of the detection cantilever 3A measured by the displacement amount measurement unit 51 for each of the first time point t ₁ and the second time point t _2. The measured displacement amount of the correction cantilever 3B is subtracted and the corrected displacement amount of the detection cantilever 3A is sent to the displacement amount comparison unit 52.

  That is, the displacement amount of the detection cantilever 3 </ b> A measured by the displacement amount measurement unit 51 includes a deflection caused by the interaction and a deflection caused by other than the interaction. On the other hand, the displacement amount of the correction cantilever 3B measured by the correction displacement amount measurement unit 53 includes only deflection due to other than the interaction. Therefore, if the displacement amount of the correction cantilever 3B measured by the correction displacement amount measurement unit 53 is subtracted from the displacement amount of the detection cantilever 3A measured by the displacement amount measurement unit 51, the displacement amount caused by the interaction is obtained. Can be obtained more accurately.

[4-10. Displacement comparison unit]
In the present embodiment, the displacement amount comparing unit 52 uses the displacement amount of the detection cantilever 3A after correction sent from the displacement amount correction section 54, and the displacement amount of the detection cantilever 3A measured at the first time t ₁ The displacement amount of the detection cantilever 3A measured at the second time point t ₂ is compared. Instead of the displacement amount measured by the displacement amount measurement unit 51, the displacement amount of the detection cantilever 3A corrected by the displacement amount correction unit 54 is used, which is the same as in the first embodiment.
In the present embodiment, the determination result, that is, the presence / absence of the detection target substance and the difference value are output to an output device (not shown). Further, it is assumed that the operator recognizes information such as the concentration of the detection target substance in the sample based on the output difference.

[4-11. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, in a state where the detection cantilever 3A and the correction cantilever 3B are attached to the support 61, The specimen is brought into contact with the detection cantilever 3A and the correction cantilever 3B while irradiating light from the light source 1 to the detection cantilever 3A and the correction cantilever 3B. Then, measuring the displacement amount of the detection cantilever 3A and correction cantilever 3B at least a first time point t ₁ of the second time point t ₂ Prefecture. Next, at least at each of the first time point t ₁ and the second time point t ₂ , the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B. After that, by comparing the corrected displacement amount of the detection cantilever 3A at the first time point t ₁ with the corrected displacement amount of the detection cantilever 3A measured at the second time point t ₂ , The substance is detected.
This will be described in detail below.

  First, the detection cantilever 3A and the correction cantilever 3B are mounted on the support 61 such that the support member 31A and the support member 31B are sandwiched between the support 61 and the ceiling surface 64 of the transparent container 6. At this time, in order to perform correction more accurately, the detection cantilever 3A and the correction cantilever 3B are installed as close as possible. Further, in order to uniformly irradiate the light used for measuring the amount of displacement, the detection cantilever 3A and the correction cantilever 3B are arranged in a line in the predetermined direction along the light linearly collected by the light collecting means 7. Furthermore, they are juxtaposed so as to be parallel to each other and extend in the same direction.

Further, as conditions used for detection, information on the first time point t ₁ and the second time point t ₂ and information on the threshold value used by the displacement amount comparison unit 52 are preliminarily used as the displacement amount measurement unit 51, the corrected displacement amount measurement unit 53, This is input to the displacement correction unit 54 and the displacement comparison unit 52 in advance.
Then, after filling the transparent container 6 with the standard solution not containing the detection target substance, the light source 1 irradiates the detection cantilever 3A and the correction cantilever 3B with light. The irradiated light is reflected by the reflection surface 32A of the detection cantilever 3A and the reflection surface 32B of the correction cantilever 3B, and is irradiated toward the light receiving element 4.

  At this time, as described above, the detection cantilever 3A and the correction cantilever 3B are juxtaposed in a row in the predetermined direction, and are juxtaposed so as to be parallel to each other and extend in the same direction. Therefore, the light condensed by the light condensing means 7 is linear when irradiated to the detection cantilever 3A and the correction cantilever 3B. However, the light collected in this way is linear. However, it is possible to uniformly irradiate the reflecting surfaces 32A and 32B on the detection cantilever 3A and the correction cantilever 3B and reflect them on the reflecting surfaces 32A and 32B. That is, it is possible to irradiate light to the detection cantilever 3A and the correction cantilever 3B using an optical system having a simple configuration as in this embodiment.

  The light irradiated to the light receiving element 4 is received by the light receiving portions 41 </ b> A and 41 </ b> B of the light receiving element 4. As in the first embodiment, when the light reflected by the detection cantilever 3A or the correction cantilever 3B is not received by the light receiving element 4, the positions of the detection cantilever 3A, the correction cantilever 3B, the light receiving element 4, etc. The initial adjustment is performed so that light is reliably received as described above. Further, the light receiving element 4 sends information on the light receiving position to each of the displacement amount measuring unit 51 and the corrected displacement amount measuring unit 53.

In this embodiment, in such a state, after the standard solution in the transparent container 6 is discharged, the specimen is injected into the transparent container 6, and the detection cantilever 3A, the correction cantilever 3B and the specimen are brought into contact with each other. This time is time T ₁ .
When the detection cantilever 3A and the specimen come into contact with each other, the detection target substance that can interact with the specific substance immobilized on the detection cantilever 3A is contained in the specimen as described in the first embodiment. Similarly, deflection occurs in the detection cantilever 3 </ b> A, and this displacement amount is measured by the displacement amount measurement unit 51 using the light receiving element 4. Further, the displacement amount of the detection cantilever 3 </ b> A measured here includes a cause due to a factor other than the interaction.

  On the other hand, when the correction cantilever 3B comes into contact with the specimen, a deflection having the same magnitude as the deflection generated in the detection cantilever 3A due to factors other than the interaction also occurs in the correction cantilever 3B. The displacement of the deflection is measured by the correction displacement measuring unit 53 using the light receiving element 4 in the same manner as the detection cantilever 3A. The displacement amount of the correction cantilever 3B measured here is due to factors other than the interaction.

  The displacement amount of the detection cantilever 3 </ b> A measured by the displacement amount measurement unit 51 and the displacement amount of the correction cantilever 3 </ b> B measured by the correction displacement amount measurement unit 53 are sent to the displacement amount correction unit 54. Then, the displacement correction unit 54 subtracts the displacement amount of the correction cantilever 3B from the displacement amount of the detection cantilever 3A, thereby removing the displacement amount caused by factors other than the interaction from the displacement amount of the detection cantilever 3A. Is done. Further, the corrected correction amount of the detection cantilever 3 </ b> A is sent to the displacement amount comparison unit 52.

In the displacement comparison unit 52, the detection cantilever measured at the first time point t ₁ according to the condition given by the operator with respect to the displacement of the corrected detection cantilever 3A sent from the displacement correction unit 53. and displacement of the 3A, by comparing the displacement amount of the detection cantilever 3A measured at the second time point t _2, the difference between the two displacement to determine whether or larger than the threshold, the detection target substance in a sample Is detected.
As a result of the displacement measuring unit 52, the presence / absence of the detection target substance and the difference value are output to an output device (not shown). Further, based on the output difference value, the operator detects the presence and concentration of the detection target substance in the sample.

[4-12. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.

Further, according to the detection method of the present embodiment, the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B, and therefore, due to factors other than the interaction between the specific substance and the detection target substance. It is possible to eliminate the influence of deflection and perform more accurate detection.
Furthermore, the same advantages as those of the first embodiment can be obtained.

[5. Third Embodiment]
The third embodiment of the present invention will be described below with reference to the drawings.
FIG. 6 is a perspective view schematically showing an outline of a cantilever sensor system according to a third embodiment of the present invention. FIG. 7 is a graph schematically showing an example of the relationship between the time and the displacement when the detection cantilever 3A is bent. 6 and 7, the same parts as those in FIGS. 1 to 5 are denoted by the same reference numerals as those in FIGS. 1 to 5.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the first embodiment. However, in this embodiment, the displacement amount of the detection cantilever 3A is linearly approximated with respect to time, and the detection target substance is detected based on the slope of the straight line obtained by the linear approximation. Therefore, instead of the displacement amount comparison unit 52, a displacement amount linear approximation unit (displacement amount approximation unit) 55 and an inclination output unit 56 are provided.

  That is, as shown in FIG. 6, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a condensing means 2, a detection cantilever 3A, a light receiving element 4, a displacement measuring unit 51, A displacement amount linear approximation unit 55 and an inclination output unit 56 are provided. The displacement amount measuring unit 51, the displacement amount linear approximation unit 55, and the inclination output unit 56 are the same in hardware as the computer 5, and the computer 5 is replaced with the displacement amount measurement unit 51, the displacement amount linear approximation unit 55, and the inclination output unit 56. It is configured by loading a program for functioning as Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A is mounted on the transparent container 6 as the specimen contact portion.

[5-1. light source]
In the present embodiment, the light source 1 is the same as that in the first embodiment.

[5-2. Condensing means]
In the present embodiment, the light collecting means 2 is the same as that in the first embodiment.

[5-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first and second embodiments.

[5-4. Transparent container]
In the present embodiment, the transparent container 6 is the same as that in the first embodiment.
In FIG. 6, the transparent container 6 is indicated by a two-dot chain line.

[5-5. Light receiving element]
In the present embodiment, the light receiving element 4 is the same as that in the first embodiment.

[5-6. Displacement measurement unit]
Similar to the first embodiment, the displacement measuring unit 51 according to the present embodiment receives information on the light receiving position of the light receiving element 4 and measures the displacement of the detection cantilever 3A.
However, in the present embodiment, at least the displacement amount measurement unit 51 measures the displacement amount of the detection cantilever 3A within a predetermined time range from the first time point t ₁ to the second time point t _2. It has become.

That is, after time T ₁ when the specimen is brought into contact with the detection cantilever 3A, from time T ₂ when a time T ₀ required for the detection cantilever 3A to bend when the specimen contains a detection target substance. In addition, the displacement amount of the detection cantilever 3A is measured within a predetermined time range from the first time point t ₁ to the second time point t ₂ within the previous specific time range. Note that it is usually desirable to always measure the amount of displacement during a predetermined time range from the first time point t ₁ to the second time point t ₂ described above, but the displacement amount should be measured at a frequency at which desired detection accuracy can be obtained. If it can be measured, it is not always necessary to measure at all times.

In the present embodiment, similarly to the first embodiment, the displacement amount measuring unit 51 constantly measures the displacement amount of the detection cantilever 3A. Therefore, during the period from the first time point t ₁ to the second time point t ₂ , The displacement amount of the detection cantilever 3A at each time point is always measured.

Also in the present embodiment, as in the first embodiment, the first time point t ₁ and the second time point t ₂ are determined by an operator instructing the computer 5 through an interface (not shown) such as a keyboard. It is assumed that the instruction content is set by reading the displacement amount measurement unit 51, the displacement amount linear approximation unit 55, and the inclination output unit 56. Further, the measured displacement amount of the detection cantilever 3 </ b> A is sent to the displacement amount linear approximation unit 55.

[5-7. Displacement straight line approximation part]
The displacement linear approximation unit 55 according to the present embodiment linearly approximates the displacement of the detection cantilever 3A with respect to time. Specifically, the displacement amount of the detection cantilever 3A in the predetermined time range from the first time point t ₁ to the second time point t ₂ sent from the displacement amount measurement unit 51 is received, approximated, and time A function representing a displacement amount is obtained as a linear function for.

For example, if the transition of the displacement amount as indicated by a two-dot chain line in FIG. 7 was measured by displacement measuring unit 51, the displacement amount linear approximation unit 55, predetermined from the first time point t ₁ to the second time point t ₂ The approximate amount of displacement measured in the time range is linearly approximated to obtain an approximate straight line VII representing the change in the amount of displacement in the predetermined time range. As estimated by the present inventors, this approximate straight line VII is a change over time in the displacement amount in a partial time range (that is, a predetermined time range) in the entire time range in which the deflection of the detection cantilever 3A is proceeding. Represents. That is, the data measured over time of the amount of displacement of the detection cantilever 3A in the cantilever sensor is accurate enough to obtain sufficiently high detection accuracy even if it is linearly approximated with respect to time. It can represent a change in quantity over time.

At this time, the specific approximation method is not limited and is arbitrary as long as the effects of the present invention are not significantly impaired. For example, a least square method or the like can be used. As for the least square method, “Standard Mathematical Tables and Formulae (30th edition), pp. 680-682, CRC Press, Inc., 1996” can be referred to.
In the present embodiment, it is assumed that the displacement amount linear approximation unit 55 performs linear approximation using the least square method.
In addition, information about the obtained approximate straight line is sent to the inclination output unit 56.

[5-8. Tilt output section]
The gradient output unit 56 according to the present embodiment outputs the gradient of the approximate line obtained by the linear approximation of the displacement amount linear approximation unit 55. Specifically, information on the approximate line sent from the displacement amount straight line approximation unit 55 is taken in, and the inclination of the approximate line is output to an output device (not shown).

  As described above, the approximate straight line obtained by the displacement straight line approximating unit 55 is in a partial time range (that is, a predetermined time range) in the entire time range in which the deflection of the detection cantilever 3A proceeds. This represents a change with time of the displacement amount. However, as estimated by the present inventors, the inclination of the approximate straight line includes information on the change of the displacement amount in the entire time range in which the deflection of the detection cantilever 3A proceeds. That is, the slope of the approximate line is closely related to the interaction between the detection target substance and the detection cantilever 3A. When the interaction is small, the absolute value of the slope of the approximate line is small and the interaction is large. In this case, since the absolute value of the inclination of the approximate straight line becomes large, if this is used, the detection target substance in the specimen is measured in the same manner as when the displacement is measured over the entire time range in which the deflection of the detection cantilever 3A is progressing. Can be detected.

  Therefore, when the absolute value of the inclination of the approximate straight line output from the inclination output unit 56 is 0, the displacement amount of the detection cantilever 3A does not change, and therefore, the detection target substance does not exist in the sample. Can be determined. On the other hand, when the absolute value of the slope is larger than 0, the displacement amount of the detection cantilever 3A is changed. When such a change appears, the detection target substance is identified. It is possible to determine that the detection target substance is present in the specimen because an interaction with the substance has occurred.

  In addition, a predetermined threshold value is set in advance, and if the absolute value of the slope is equal to or greater than the threshold value, it is determined that the detection target substance is present, and if it is less than the threshold value, the detection target substance is not present. You may make it determine. This is to prevent erroneous detection due to noise during displacement measurement. Note that this threshold value is arbitrarily set according to the measurement accuracy of the measurement apparatus, the type of specimen, and the like.

  Further, the magnitude of the inclination includes information on the amount and concentration of the detection target substance in the specimen. That is, in general, the greater the amount or concentration of the detection target substance in the sample, the greater the deflection of the detection cantilever 3A. Therefore, it can be determined that the greater the absolute value of the slope, the greater the amount or concentration of the detection target substance. Therefore, it is possible to measure the above-mentioned amounts and concentrations by inclination. In this case, information such as a table indicating the correspondence between the inclination of the approximate straight line and the concentration of the detection target substance is recorded in advance in a recording unit (not shown) in the computer 5, and the above inclination is determined based on the information. A computing unit (not shown) that outputs information such as density may be provided in the computer 5.

  In the present embodiment, the inclination value output from the inclination output unit 56 is output to an output device (not shown). Further, based on this inclination, it is assumed that the operator recognizes information such as the presence / absence and concentration of the detection target substance in the sample.

[5-9. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, the detection cantilever 3A is mounted on the support 61 and the detection can be performed from the light source 1. The specimen is brought into contact with the detection cantilever 3A while irradiating the cantilever 3A with light. Then, at least from the time point t ₁ to the second time point t ₂ , the displacement amount of the detection cantilever 3A is measured. Thereafter, the displacement amount of the detection cantilever 3A is linearly approximated with respect to time, and the detection target substance is detected based on the slope of the straight line obtained by the linear approximation.
This will be described in detail below.

First, as in the first embodiment, the detection cantilever 3 </ b> A is mounted on the support 61 so that the support member 31 </ b> A is sandwiched between the support 61 and the ceiling surface 64 of the transparent container 6. In addition, as conditions used for detection, information on the first time point t ₁ and the second time point t ₂ is input in advance to the displacement amount measurement unit 51 and the displacement amount straight line approximation unit 55.

  And after filling the transparent container 6 with the standard solution which does not contain a detection target substance, light is irradiated from the light source 1 to the detection cantilever 3A. The irradiated light is reflected by the reflecting surface 32A of the detection cantilever 3A, irradiated toward the light receiving element 4, and received by the light receiving portion 41A of the light receiving element 4. At this time, if the light reflected by the detection cantilever 3A is not received by the light receiving element 4, the position and inclination of the detection cantilever 3A and the light receiving element 4 are adjusted so that the light is reliably received as described above. Make initial adjustments. Based on the information on the light receiving position, the displacement measuring unit 51 measures the displacement of the detection cantilever 3A in the same manner as in the first embodiment.

In this embodiment, in such a state, after the standard solution in the transparent container 6 is discharged, the specimen is injected into the transparent container 6 and the detection cantilever 3A and the specimen are brought into contact with each other. This time is time T ₁ .
When the detection cantilever 3A and the specimen come into contact with each other, when the detection target substance that can interact with the specific substance immobilized on the detection cantilever 3A is contained in the specimen, the mutual relation between the specific substance and the detection target substance Deflection due to the action occurs in the detection cantilever 3A. This displacement amount is measured by the displacement amount measuring unit 51 as described above.

Here, in the present embodiment, since the displacement amount measuring unit 51 always measures the displacement amount, the displacement amount from the first time point t ₁ to the second time point t ₂ is also measured. Therefore, the measured displacement amount of the detection cantilever 3 </ _b > A including the measurement results from the first time point t ₁ to the second time point t ₂ is sent to the displacement amount linear approximation unit 55.

In the displacement amount linear approximation unit 55, the displacement amount sent from the displacement amount measurement unit 51 was measured in a predetermined time range from the first time point t ₁ to the second time point t ₂ according to the condition given by the operator. The displacement amount of the detection cantilever 3A is approximated by a straight line, and an approximate straight line representing the change with time of the displacement amount is obtained.

  Then, the information on the approximate line is sent to the inclination output unit 56, and the information on the inclination of the approximate line is taken in by the inclination output unit 56. The inclination value captured by the inclination output unit 56 is output to an output device (not shown), and based on the output value, the operator detects the presence / absence and concentration of the detection target substance in the sample.

[5-10. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.
It is also possible to measure the amount and concentration of the detection target substance from the magnitude of the inclination of the approximate line.
Further, the same advantages as those of the first embodiment can be obtained except by comparing the difference in displacement.

[6. Fourth Embodiment]
Next, a fourth embodiment of the present invention will be described with reference to the drawings.
FIG. 8 is a perspective view schematically showing an outline of a cantilever sensor system according to a fourth embodiment of the present invention. In FIG. 8, the same parts as those in FIGS. 1 to 7 are denoted by the same reference numerals as those in FIGS.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the third embodiment. However, in the present embodiment, the displacement amount of the detection cantilever is corrected using the correction cantilever 3B as in the second embodiment. For this reason, in addition to the configuration of the third embodiment, A correction cantilever 3B, a corrected displacement amount measuring unit 53, and a displacement amount correcting unit 54 are provided.

  That is, as shown in FIG. 8, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a condensing means 2, a detection cantilever 3A, a correction cantilever 3B, a light receiving element 4, and a displacement. An amount measurement unit 51, a corrected displacement amount measurement unit 53, a displacement amount correction unit 54, a displacement amount straight line approximation unit 55, and an inclination output unit 56 are provided. The displacement measuring unit 51, the corrected displacement measuring unit 53, the displacement correcting unit 54, the displacement straight line approximating unit 55, and the tilt output unit 56 are the same in hardware as the computer 5, and the computer 5 is replaced with the displacement measuring unit. 51, a program for functioning as a corrected displacement amount measuring unit 53, a displacement amount correcting unit 54, a displacement straight line approximating unit 55, and an inclination output unit 56 are read. Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A and the correction cantilever 3B are mounted on a transparent container 6 as a specimen contact portion.

[6-1. light source]
In the present embodiment, the light source 1 is the same as in the second embodiment.

[6-2. Condensing means]
In this embodiment, the condensing means 2 is the same as that of 2nd Embodiment.

[6-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first to third embodiments.

[6-4. Correction cantilever]
In the present embodiment, the correction cantilever 3B is the same as in the second embodiment.

[6-5. Transparent container]
In the present embodiment, the transparent container 6 is the same as in the second embodiment.
In FIG. 8, the transparent container 6 is indicated by a two-dot chain line.

[6-6. Light receiving element]
In the present embodiment, the light receiving element 4 is the same as in the second embodiment.

[6-7. Displacement measurement unit]
The displacement amount measurement unit 51 according to the present embodiment is the same as the third embodiment except that the measured displacement amount of the detection cantilever 3A is sent to the displacement amount correction unit 54. Accordingly, because it measures the displacement amount of the displacement measuring unit 51 constantly detects cantilever 3A, measuring the displacement amount of the detection cantilever 3A in a predetermined time range from at least the first time point t ₁ to the second time point t ₂ It is supposed to be.

In the present embodiment, as in the third embodiment, the first time point t ₁ and the second time point t ₂ are determined by an operator instructing the computer 5 through an interface (not shown) such as a keyboard. It is assumed that the instruction content is set by reading the displacement amount measuring unit 51, the corrected displacement amount measuring unit 53, the displacement amount correcting unit 54, the displacement amount straight line approximating unit 55, and the inclination output unit 56.

[6-8. Corrected displacement measurement unit]
In the present embodiment, the correction displacement amount measuring unit 53 measures the displacement amount of the correction cantilever 3B at least within a predetermined time range from the first time point t ₁ to the second time point t _2. It is configured in the same way.

Therefore, in the present embodiment, the correction displacement amount measurement unit 53 always measures the displacement amount of the correction cantilever 3B. Therefore, from the time T ₁ before the specimen is brought into contact with the detection cantilever 3A, It is assumed that the displacement amount of the correction cantilever 3B is measured from one time point t ₁ to the second time point t ₂ .
Further, the measured displacement amount of the correction cantilever 3 </ b> B is sent to the displacement amount correction unit 54.

[6-9. Displacement correction unit]
In the present embodiment, the displacement amount correction section 54, at least a point from the first time point t ₁ to correct the displacement amount of the detection cantilever 3A within a predetermined time range to the second time point t _2, and the detection of the corrected The second embodiment is the same as the second embodiment except that the displacement amount of the cantilever 3A for use is sent to the displacement amount linear approximation unit 55.

That is, in this embodiment, the displacement amount correction section 54, the displacement amount of the first in a predetermined time range from time t ₁ to a second time point t _2, the detection cantilever 3A measured displacement amount measuring unit 51 for each time point Then, the displacement amount of the correction cantilever 3B measured by the correction displacement amount measurement unit 53 is subtracted, and the corrected displacement amount of the detection cantilever 3A is sent to the displacement amount linear approximation unit 55. Thereby, the influence of the deflection other than the interaction can be eliminated, and the displacement generated by the interaction generated in the detection cantilever 3A can be obtained more accurately.

[6-10. Displacement straight line approximation part]
In this embodiment, the displacement amount straight line approximation unit 55 uses the displacement amount of the detection cantilever 3A after correction sent from the displacement amount correction unit 54 to perform a predetermined time from the first time point t ₁ to the second time point t _2. The amount of displacement of the detection cantilever 3A up to the range is linearly approximated with respect to time. The third embodiment is the same as the third embodiment except that the displacement amount of the detection cantilever 3A corrected by the displacement amount correction unit 54 is used instead of the displacement amount measured by the displacement amount measurement unit 51.

[6-11. Tilt output section]
In the present embodiment, the inclination output unit 56 outputs the inclination of a straight line obtained by linear approximation, and is the same as that in the third embodiment.
Therefore, as in the third embodiment, the inclination value captured by the inclination output unit 56 is output to an output device (not shown), and the operator can detect the substance to be detected in the sample based on this inclination. It is assumed that information such as presence / absence and concentration is recognized.

[6-12. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, in a state where the detection cantilever 3A and the correction cantilever 3B are attached to the support 61, The specimen is brought into contact with the detection cantilever 3A and the correction cantilever 3B while irradiating light from the light source 1 to the detection cantilever 3A and the correction cantilever 3B. Then, the displacement amounts of the detection cantilever 3A and the correction cantilever 3B are measured at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ . Next, at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ , the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B. Thereafter, the corrected displacement amount of the detection cantilever 3A is linearly approximated with respect to time, and the detection target substance is detected by the inclination of the straight line obtained by the linear approximation.
This will be described in detail below.

  First, the detection tool cantilever 3A and the correction cantilever 3B are mounted on the support tool 61 so that the support member 31A and the support member 31B are sandwiched between the support tool 61 and the ceiling surface 64 of the transparent container 6. At this time, as in the second embodiment, in order to perform correction more accurately, the detection cantilever 3A and the correction cantilever 3B are installed as close as possible. Further, in order to uniformly irradiate the light used for measuring the amount of displacement, the detection cantilever 3A and the correction cantilever 3B are arranged in a line in the predetermined direction along the light linearly collected by the light collecting means 7. Furthermore, they are juxtaposed so as to be parallel to each other and extend in the same direction.

Further, as conditions used for detection, information on the first time point t ₁ and the second time point t ₂ is preliminarily converted into a displacement amount measuring unit 51, a corrected displacement amount measuring unit 53, a displacement amount correcting unit 54, a displacement amount linear approximation unit 55, and Input to the tilt output unit 56 in advance.
Then, after filling the transparent container 6 with the standard solution not containing the detection target substance, the light source 1 irradiates the detection cantilever 3A and the correction cantilever 3B with light. The irradiated light is reflected by the reflection surface 32A of the detection cantilever 3A and the reflection surface 32B of the correction cantilever 3B, and is irradiated toward the light receiving element 4 as in the second embodiment. Light is received at the portion 41A. At this time, if the light reflected by the detection cantilever 3A and the correction cantilever 3B is not received by the light receiving element 4, the positions and inclinations of the detection cantilever 3A, the correction cantilever 3B, the light receiving element 4 and the like are adjusted. The initial adjustment is performed so that the light is reliably received as described above. Then, based on the information on the light receiving position, the displacement measuring unit 51 and the corrected displacement measuring unit 53 measure the displacement amounts of the detection cantilever 3A and the correction cantilever 3B.

In this embodiment, after the standard solution in the transparent container 6 is discharged in this state, the specimen is injected into the transparent container 6 and the detection cantilever 3A and the correction cantilever 3B are brought into contact with the specimen. This time is time T ₁ .
When the detection cantilever 3A and the specimen come into contact with each other, the detection target substance that can interact with the specific substance immobilized on the detection cantilever 3A is contained in the specimen as described in the first embodiment. Similarly, deflection occurs in the detection cantilever 3 </ b> A, and the displacement amount is measured by the displacement amount measurement unit 51 using the light receiving element 4.

  On the other hand, when the correction cantilever 3B comes into contact with the specimen, a deflection having the same magnitude as the deflection generated in the detection cantilever 3A due to factors other than the interaction also occurs in the correction cantilever 3B. The displacement of the deflection is measured by the correction displacement measuring unit 53 using the light receiving element 4 in the same manner as the detection cantilever 3A.

Here, in the present embodiment, since the displacement amount measuring unit 51 and the corrected displacement amount measuring unit 53 always measure the displacement amount, the displacement amount from the first time point t ₁ to the second time point t ₂ is also measured. Will be measured. Accordingly, the measured displacement amounts of the detection cantilever 3A and the correction cantilever 3B including the measurement results from the first time point t ₁ to the second time point t ₂ are sent to the displacement amount correction unit 54.

  As in the second embodiment, the displacement amount correction unit 54 subtracts the displacement amount of the correction cantilever 3B from the displacement amount of the detection cantilever 3A, thereby detecting the displacement amount due to factors other than the interaction. Correction is performed to remove from the amount of displacement. Further, the corrected correction amount of the detection cantilever 3A is sent to the displacement amount linear approximation unit 55.

The displacement amount linear approximation unit 55 uses the displacement amount after correction of the detection cantilever 3A sent from the displacement amount correction unit 54 in the same manner as in the third embodiment, but the displacement amount of the detection cantilever 3A. Is approximated by a straight line, and an approximate straight line representing the change with time of the displacement is obtained.
Then, the information on the approximate straight line is sent to the tilt output unit 56, and the information on the tilt of the approximate straight line is captured by the tilt output unit 56 as in the third embodiment. The inclination value captured by the inclination output unit 56 is output to an output device (not shown), and based on the output value, the operator detects the presence / absence and concentration of the detection target substance in the sample.

[6-13. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.
Further, according to the detection method of the present embodiment, the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B, and therefore, due to factors other than the interaction between the specific substance and the detection target substance. It is possible to eliminate the influence of deflection and perform more accurate detection.
Furthermore, the same advantages as those of the third embodiment can be obtained.

[7. Fifth Embodiment]
Hereinafter, a fifth embodiment of the present invention will be described with reference to the drawings.
FIG. 9 is a perspective view schematically showing an outline of a cantilever sensor system according to a fifth embodiment of the present invention. FIG. 10 is a graph schematically showing an example of the relationship between time and displacement when the detection cantilever 3A is bent. 9 and 10, the same parts as those in FIGS. 1 to 8 are denoted by the same reference numerals as those in FIGS.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the third embodiment. However, in the present embodiment, the displacement amount of the detection cantilever 3A is approximated by a polynomial with respect to time, and the detection target substance is detected by the coefficient of the polynomial obtained by the above approximation (polynomial approximation). Yes. Accordingly, a displacement amount polynomial approximation unit (displacement amount approximation unit) 57 and a coefficient output unit 58 are provided instead of the displacement amount straight line approximation unit 55 and the inclination output unit 56.

  That is, as shown in FIG. 9, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a condensing means 2, a detection cantilever 3A, a light receiving element 4, a displacement amount measuring unit 51, A displacement polynomial approximation unit 57 and a coefficient output unit 58 are provided. The displacement measuring unit 51, the displacement polynomial approximating unit 57, and the coefficient output unit 58 are the same in hardware as the computer 5, and the computer 5 is replaced with the displacement measuring unit 51, the displacement polynomial approximating unit 57, and the coefficient output unit 58. It is configured by loading a program for functioning as Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A is mounted on the transparent container 6 as the specimen contact portion.

[7-1. light source]
In the present embodiment, the light source 1 is the same as in the first and third embodiments.

[7-2. Condensing means]
In the present embodiment, the light collecting means 2 is the same as that in the first and third embodiments.

[7-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first to fourth embodiments.

[7-4. Transparent container]
In the present embodiment, the transparent container 6 is the same as in the first and third embodiments.
In FIG. 9, the transparent container 6 is indicated by a two-dot chain line.

[7-5. Light receiving element]
In the present embodiment, the light receiving element 4 is the same as in the first and third embodiments.

[7-6. Displacement measurement unit]
The displacement measuring unit 51 receives information on the light receiving position of the light receiving element 4 and measures the displacement of the detection cantilever 3A at least within a predetermined time range from the first time point t ₁ to the second time point t _2. Is.
In the present embodiment, the displacement amount measuring unit 51 is configured in the same manner as in the third embodiment except that the measured displacement amount of the detection cantilever 3A is sent to the displacement amount polynomial approximating unit 57. Yes.

Note that the first time point t ₁ and the second time point t ₂ are instructed by the operator to the computer 5 through an interface (not shown) such as a keyboard, so that the contents of the instruction are approximated by the displacement amount measuring unit 51 and the displacement amount polynomial approximation. It is assumed that the setting is made by reading the unit 57 and the coefficient output unit 58.

[7-7. Displacement polynomial approximation part]
The displacement amount polynomial approximation unit 57 according to the present embodiment approximates the displacement amount of the detection cantilever 3A by a polynomial with respect to time. Specifically, the displacement amount of the detection cantilever 3A in the predetermined time range from the first time point t ₁ to the second time point t ₂ sent from the displacement amount measurement unit 51 is received, approximated, and time A function representing the displacement is obtained as a polynomial with respect to.

For example, if the transition of the displacement amount as indicated by a two-dot chain line in FIG. 10 was measured by displacement measuring unit 51, the displacement of the polynomial approximation unit 57, predetermined from the first time point t ₁ to the second time point t ₂ By approximating the amount of displacement measured in the time range with a polynomial, an approximate curve X representing the change in the amount of displacement in the predetermined time range is obtained. Here, the degree of the polynomial is set in advance. As estimated by the present inventors, this approximate curve X also changes with time in the amount of displacement in a partial time range (that is, a predetermined time range) in the entire time range in which the deflection of the detection cantilever 3A is progressing. It represents. That is, the data measured over time of the displacement amount of the detection cantilever 3A in the cantilever sensor is accurate enough to obtain sufficiently high detection accuracy even if it is approximated by a polynomial with respect to time. It can represent the change over time in the amount of displacement.

At this time, the specific approximation method is not limited, and is arbitrary as long as the effects of the present invention are not significantly impaired. For example, the least square method described above can be used.
In the present embodiment, it is assumed that the displacement amount polynomial approximation unit 57 performs polynomial approximation using the least square method.
Information about the obtained polynomial (approximate polynomial) is sent to the coefficient output unit 58.

[7-8. Coefficient output section]
The coefficient output unit 58 according to the present embodiment outputs a polynomial coefficient obtained by the polynomial approximation of the displacement polynomial approximation unit 57. Specifically, the information of the approximate polynomial sent from the displacement amount polynomial approximation unit 57 is taken in and the respective coefficients are output.

  As described above, the approximate polynomial obtained by the displacement polynomial approximation unit 57 is in a partial time range (that is, a predetermined time range) in the entire time range in which the deflection of the detection cantilever 3A proceeds. This represents a change with time of the displacement amount. However, as estimated by the present inventors, each coefficient of the approximate polynomial includes information on the change in displacement over the entire time range in which the deflection of the detection cantilever 3A is proceeding. That is, each coefficient of the approximate polynomial is closely related to the interaction between the detection target substance and the detection cantilever 3A. When the interaction is small, for example, the absolute value of the highest order coefficient of the approximate polynomial is small. When the interaction is large, for example, the absolute value of the coefficient of the highest order of the approximate polynomial is large. When this is used, the displacement amount is measured in the entire time range in which the deflection of the detection cantilever 3A is progressing. Similarly to the above, it is possible to detect the detection target substance in the sample liquid. Furthermore, more detailed data analysis can be performed by taking into consideration coefficients of orders other than the highest order of the approximate polynomial.

  Therefore, the coefficient output unit 58 outputs each coefficient of the approximate polynomial. For example, when the absolute value of the coefficient of the highest order of the polynomial is 0, the displacement amount of the detection cantilever 3A does not change, and therefore the specimen It can be determined that the substance to be detected does not exist. On the other hand, when the absolute value of the coefficient is larger than 0, the displacement amount of the detection cantilever 3A is changed. When such a change appears, the detection target substance and the specific substance are identified. It is possible to determine that the detection target substance is present in the specimen because an interaction with the substance has occurred.

  In addition, a predetermined threshold value is set in advance, and if the absolute value of the coefficient is equal to or greater than the threshold value, it is determined that the detection target substance is present. If the absolute value of the coefficient is less than the threshold value, the detection target substance is not present. You may make it determine. This is to prevent erroneous detection due to noise during displacement measurement. Note that this threshold value is arbitrarily set according to the measurement accuracy of the measurement apparatus, the type of specimen, and the like.

  Further, the magnitude of the coefficient includes information on the amount and concentration of the detection target substance in the specimen. Therefore, it is possible to measure the above-mentioned amounts and concentrations by coefficients. Also in this case, as in the third embodiment, information such as a table indicating the correspondence between the coefficients of the approximate polynomial and the concentration of the detection target substance is recorded in advance in a recording unit (not shown) in the computer 5. The computer 5 may be provided with a calculation unit (not shown) that outputs information such as concentration from the above coefficients based on the information.

  In the present embodiment, the value of the coefficient output by the coefficient output unit 58 is output to an output device (not shown). Further, it is assumed that the operator recognizes information such as the presence / absence and concentration of the detection target substance in the sample based on the value of the coefficient.

[7-9. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, the detection cantilever 3A is mounted on the support 61 and the detection can be performed from the light source 1. The specimen is brought into contact with the detection cantilever 3A while irradiating the cantilever 3A with light. Then, at least from the time point t ₁ to the second time point t ₂ , the displacement amount of the detection cantilever 3A is measured. Thereafter, the displacement amount of the detection cantilever 3A is approximated by a polynomial with respect to time, and the detection target substance is detected by the polynomial coefficient obtained by the polynomial approximation.
This will be described in detail below.

Similar to the third embodiment, except that information on the first time point t ₁ and the second time point t ₂ is input to the displacement amount measurement unit 51 and the displacement amount polynomial approximation unit 57. The cantilever 3A is brought into contact, and the displacement amount of the detection cantilever 3A at that time is measured. The measured displacement amount of the detection cantilever 3A from the first time point t ₁ to the second time point t ₂ is sent to the displacement amount polynomial approximation unit 57.

The displacement amount polynomial approximating unit 57 measures the displacement amount sent from the displacement amount measuring unit 51 in a predetermined time range from the first time point t ₁ to the second time point t ₂ according to the condition given by the operator. The displacement amount of the detection cantilever 3A is approximated by a polynomial, and an approximate polynomial representing the change with time of the displacement amount is obtained.

  Information on the approximate polynomial is sent to the coefficient output unit 58, and the coefficient output unit 58 takes in the information on the coefficient of the approximate polynomial. The coefficient values taken in by the coefficient approximating unit 58 are output to an output device (not shown), and the operator detects the presence / absence and concentration of the detection target substance in the sample based on the values output to the output device. To do.

[7-10. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.
It is also possible to measure the amount and concentration of the detection target substance from the coefficients of the approximate polynomial.
Further, the same advantages as those of the first and third embodiments can be obtained.

[8. Sixth Embodiment]
Next, a sixth embodiment of the present invention will be described with reference to the drawings.
FIG. 11 is a perspective view schematically showing an outline of a cantilever sensor system according to a sixth embodiment of the present invention. In FIG. 11, the same parts as those in FIGS. 1 to 10 are denoted by the same reference numerals as those in FIGS.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the fifth embodiment. However, in the present embodiment, the displacement amount of the detection cantilever is corrected using the correction cantilever 3B as in the second and fourth embodiments. For this reason, the configuration of the fifth embodiment is used. In addition, a correction cantilever 3B, a correction displacement amount measurement unit 53, and a displacement amount correction unit 54 are provided.

  That is, as shown in FIG. 11, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a condensing means 2, a detection cantilever 3A, a correction cantilever 3B, a light receiving element 4, and a displacement. An amount measuring unit 51, a corrected displacement amount measuring unit 53, a displacement amount correcting unit 54, a displacement amount polynomial approximating unit 57, and a coefficient output unit 58 are provided. The displacement measuring unit 51, the corrected displacement measuring unit 53, the displacement correcting unit 54, the displacement polynomial approximating unit 57, and the coefficient output unit 58 are connected to the computer 5 in terms of hardware, and the computer 5 is connected to the displacement measuring unit. 51, a program for functioning as a corrected displacement measuring unit 53, a displacement correcting unit 54, a displacement polynomial approximating unit 57, and a coefficient output unit 58 are read. Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A and the correction cantilever 3B are mounted on a transparent container 6 as a specimen contact portion.

[8-1. light source]
In the present embodiment, the light source 1 is the same as in the second and fourth embodiments.

[8-2. Condensing means]
In the present embodiment, the light collecting means 2 is the same as in the second and fourth embodiments.

[8-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first to fifth embodiments.

[8-4. Correction cantilever]
In the present embodiment, the correction cantilever 3B is the same as in the second and fourth embodiments.

[8-5. Transparent container]
In the present embodiment, the transparent container 6 is the same as in the second and fourth embodiments.
In FIG. 11, the transparent container 6 is indicated by a one-dot chain line.

[8-6. Light receiving element]
In the present embodiment, the light receiving element 4 is the same as in the second and fourth embodiments.

[8-7. Displacement measurement unit]
The displacement measuring unit 51 according to the present embodiment is the same as the fifth embodiment, except that the measured displacement of the detection cantilever 3A is sent to the displacement correcting unit 54. Therefore, since the displacement amount measuring unit 51 measures the displacement amount of constantly detecting cantilever 3A, measuring the displacement amount of the detection cantilever 3A in a predetermined time range from the first time point t ₁ to the second time point t ₂ It is like that.

In the present embodiment, as in the fifth embodiment, the first time point t ₁ and the second time point t ₂ are determined by an operator instructing the computer 5 through an interface (not shown) such as a keyboard. It is assumed that the instruction content is set by reading the displacement amount measuring unit 51, the corrected displacement amount measuring unit 53, the displacement amount correcting unit 54, the displacement amount polynomial approximating unit 57, and the coefficient output unit 58.

[8-8. Corrected displacement measurement unit]
The correction displacement amount measurement unit 53 measures the displacement amount of the correction cantilever 3B within at least a predetermined time range from the first time point t ₁ to the second time point t ₂ .
In the present embodiment, the corrected displacement amount measuring unit 53 is configured in the same manner as in the fourth embodiment.

[8-9. Displacement correction unit]
The displacement amount correction unit 54 determines whether the correction displacement amount measurement unit 53 uses the displacement amount of the detection cantilever 3A measured by the displacement amount measurement unit 51 at least in a predetermined time range from the first time point t ₁ to the second time point t _2. By subtracting the measured displacement amount of the correction cantilever 3B, the displacement amount of the corrected detection cantilever 3A is calculated and sent to the displacement amount polynomial approximation unit 57. As a result, the amount of displacement caused by the interaction generated in the detection cantilever 3A can be obtained more accurately by eliminating the influence of deflection other than the interaction.
In the present embodiment, the displacement amount correction unit 54 is the same as the second and fourth embodiments, except that the displacement amount of the detection cantilever 3A after correction is sent to the displacement amount polynomial approximation unit 57. .

[8-10. Displacement polynomial approximation part]
The displacement amount polynomial approximation unit 57 uses the displacement amount of the corrected detection cantilever 3A sent from the displacement amount correction unit 54 for detection within a predetermined time range from the first time point t ₁ to the second time point t ₂ . The displacement amount of the cantilever 3A is approximated by a polynomial with respect to time. This embodiment is the same as the fifth embodiment except that the displacement amount of the detection cantilever 3A corrected by the displacement amount correction unit 54 is used instead of the displacement amount measured by the displacement amount measurement unit 51.

[8-11. Coefficient output section]
The coefficient output unit 58 outputs each coefficient of a polynomial obtained by polynomial approximation. In this embodiment, the coefficient output unit 58 is configured in the same manner as in the fifth embodiment.
Therefore, as in the fifth embodiment, the value of the coefficient output by the coefficient output unit 58 is output to an output device (not shown). Based on this coefficient, the operator can detect the substance to be detected in the sample. It is assumed that information such as presence / absence and concentration is recognized.

[8-12. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, in a state where the detection cantilever 3A and the correction cantilever 3B are attached to the support 61, The specimen is brought into contact with the detection cantilever 3A and the correction cantilever 3B while irradiating light from the light source 1 to the detection cantilever 3A and the correction cantilever 3B. Then, the displacement amounts of the detection cantilever 3A and the correction cantilever 3B are measured at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ . Next, at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ , the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B. Thereafter, the displacement amount of the detection cantilever 3A after correction is approximated by a polynomial with respect to time, and the detection target substance is detected by the coefficient of the polynomial obtained by the polynomial approximation.
This will be described in detail below.

Information on the first time point t ₁ and the second time point t ₂ is input to the displacement amount measurement unit 51, the corrected displacement amount measurement unit 53, the displacement amount correction unit 54, the displacement amount polynomial approximation unit 57, and the coefficient output unit 58. In the same manner as in the second and fourth embodiments, the specimen is brought into contact with the detection cantilever 3A and the correction cantilever 3B, and the displacement amount of the detection cantilever 3A and the correction cantilever 3B at that time is determined. taking measurement. The measured displacement amounts of the detection cantilever 3A and the correction cantilever 3B from the first time point t ₁ to the second time point t ₂ are sent to the displacement amount correction unit 54.

  In the displacement amount correction unit 54, as in the second and fourth embodiments, the displacement amount due to factors other than the interaction is detected by subtracting the displacement amount of the correction cantilever 3B from the displacement amount of the detection cantilever 3A. Correction for removal from the displacement amount of the cantilever 3A is performed. Further, the corrected correction amount of the detection cantilever 3A is sent to the displacement polynomial approximation unit 57.

The displacement amount polynomial approximation unit 57 uses the displacement amount after correction of the detection cantilever 3A sent from the displacement amount correction unit 54 in the same manner as in the fifth embodiment, but the displacement amount of the detection cantilever 3A. Is approximated by a polynomial, and an approximate polynomial representing the change with time of the displacement with respect to time is obtained.
Information on the approximate polynomial is sent to the coefficient output unit 58, and the coefficient output unit 58 takes in the information on the coefficient of the approximate polynomial. The coefficient values taken in by the coefficient approximating unit 58 are output to an output device (not shown), and the operator detects the presence / absence and concentration of the detection target substance in the sample based on the values output to the output device. To do.

[8-13. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.
Further, according to the detection method of the present embodiment, the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B, and therefore, due to factors other than the interaction between the specific substance and the detection target substance. It is possible to eliminate the influence of deflection and perform more accurate detection.
Furthermore, the same advantages as those of the fifth embodiment can be obtained.

[9. Seventh Embodiment]
The seventh embodiment of the present invention will be described below with reference to the drawings.
FIG. 12 is a perspective view schematically showing an outline of a cantilever sensor system according to a seventh embodiment of the present invention. FIG. 13 is a graph schematically showing an example of the relationship between the time and the displacement when the detection cantilever 3A is bent. 12 and 13, parts similar to those in FIGS. 1 to 11 are denoted by the same reference numerals as in FIGS. 1 to 11.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the third embodiment. However, in this embodiment, the displacement amount of the detection cantilever 3A is approximated by an exponential function with respect to time, and the detection target substance is detected by the coefficient of the exponential function obtained by the above approximation (exponential function approximation). It has become. Accordingly, a displacement amount exponent function approximation unit (displacement amount approximation unit) 59 and a coefficient output unit 58 are provided instead of the displacement amount straight line approximation unit 55 and the inclination output unit 56.

  That is, as shown in FIG. 12, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a condensing means 2, a detection cantilever 3A, a light receiving element 4, a displacement amount measuring unit 51, A displacement index function approximating unit 59 and a coefficient output unit 58 are provided. The displacement measuring unit 51, the displacement index function approximating unit 59, and the coefficient output unit 58 are hardware-related to the computer 5, and the computer 5 is replaced with the displacement measuring unit 51, the displacement index function approximating unit 59, and the coefficient output. This is configured by reading a program for functioning as the unit 58. Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A is mounted on the transparent container 6 as the specimen contact portion.

[9-1. light source]
In the present embodiment, the light source 1 is the same as in the first, third, and fifth embodiments.

[9-2. Condensing means]
In this embodiment, the condensing means 2 is the same as that of 1st, 3rd, 5th embodiment.

[9-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first to sixth embodiments.

[9-4. Transparent container]
In the present embodiment, the transparent container 6 is the same as in the first, third, and fifth embodiments.
In FIG. 12, the transparent container 6 is indicated by a one-dot chain line.

[9-5. Light receiving element]
In the present embodiment, the light receiving element 4 is the same as in the first, third, and fifth embodiments.

[9-6. Displacement measurement unit]
The displacement measuring unit 51 receives information on the light receiving position of the light receiving element 4 and measures the displacement of the detection cantilever 3A at least within a predetermined time range from the first time point t ₁ to the second time point t _2. Is.
In the present embodiment, the displacement measuring unit 51 is the same as the third and fifth embodiments except that the measured displacement of the detection cantilever 3A is sent to the displacement index function approximating unit 59. It is configured.

Note that the first time point t ₁ and the second time point t ₂ are instructed by the operator to the computer 5 through an interface (not shown) such as a keyboard, so that the contents of the instructions are indicated by the displacement amount measuring unit 51, the displacement amount index function It is assumed that the approximation unit 59 and the coefficient output unit 58 are set by reading.

[9-7. Displacement index function approximation part]
The displacement amount exponent function approximator 59 according to the present embodiment approximates the displacement amount of the detection cantilever 3A with an exponential function with respect to time. Specifically, it sent from the displacement measuring section 51 receives the displacement amount of the detection cantilever 3A in a predetermined time range from the first time point t ₁ to the second time point t _2, by approximating it, time An exponential function representing the amount of displacement is obtained as an exponential function for.

For example, when the transition of the displacement amount as shown by the two-dot chain line in FIG. 13 is measured by the displacement amount measuring unit 51, the displacement amount exponent function approximating unit 59 is from the first time point t ₁ to the second time point t ₂ . By approximating the displacement measured in the predetermined time range with an exponential function, an approximate curve XIII representing the change of the displacement in the predetermined time range is obtained. As estimated by the present inventors, this approximate curve XIII shows the change over time in the displacement amount in a partial time range (that is, a predetermined time range) in the entire time range in which the deflection of the detection cantilever 3A proceeds. It represents. That is, the data measured over time of the displacement amount of the detection cantilever 3A in the cantilever sensor is accurate enough to obtain sufficiently high detection accuracy even if it is approximated exponentially with respect to time. It can represent the change over time in the amount of displacement.

At this time, the specific approximation method is not limited, and is arbitrary as long as the effects of the present invention are not significantly impaired. For example, the least square method described above can be used.
In the present embodiment, it is assumed that the displacement amount exponent function approximating unit 59 performs exponential function approximation using the least square method.
Information about the obtained exponential function (approximate exponential function) is sent to the coefficient output unit 58.

[9-8. Coefficient output section]
The coefficient output unit 58 according to the present embodiment outputs the coefficient of the exponential function obtained by the exponential function approximation of the displacement amount exponential function approximating unit 59. Specifically, the information of the approximate exponential function sent from the displacement amount exponential function approximating unit 59 is taken in, and each coefficient is output.

  As described above, the approximate exponential function obtained by the displacement index function approximating unit 59 is a partial time range (that is, a predetermined time range) in the entire time range in which the deflection of the detection cantilever 3A proceeds. ) Represents the change with time of the displacement amount. However, as estimated by the present inventors, each coefficient of the approximate exponential function includes information on the change in displacement over the entire time range in which the deflection of the detection cantilever 3A is proceeding. That is, each coefficient of the approximate exponential function is closely related to the interaction between the detection target substance and the detection cantilever 3A.

なお、この式において、Ａ１及びＡ２はこの指数関数の係数を表わし、ｅは自然対数の底を表わし、ｔは時間を表わす。この場合、相互作用が小さい場合は係数Ａ２は小さくなり、相互作用が大きい場合は係数Ａ２は大きくなるため、これを利用すれば、検出用カンチレバー３Ａのたわみが進行している全時間範囲において変位量を測定した場合と同様に検体液中の検出対象物質を検出することが可能である。 For example, a case where approximation is performed using an exponential function of the following formula will be described as an example.

In this equation, A1 and A2 represent the coefficients of the exponential function, e represents the base of the natural logarithm, and t represents time. In this case, when the interaction is small, the coefficient A2 is small, and when the interaction is large, the coefficient A2 is large. Therefore, by using this, the displacement of the detection cantilever 3A is displaced over the entire time range. As in the case of measuring the amount, it is possible to detect the detection target substance in the sample liquid.

  Therefore, the coefficient output unit 58 outputs each coefficient of the approximate exponential function. For example, when the exponential function is the above equation and the absolute value of the coefficient A2 is 0, the displacement amount of the detection cantilever 3A changes. Therefore, it can be determined that the detection target substance does not exist in the specimen. On the other hand, when the absolute value of the coefficient A2 is larger than 0, a change in displacement occurs in the detection cantilever 3A. When such a change appears, the detection target substance and The interaction with the specific substance has occurred, and therefore, it can be determined that the detection target substance is present in the specimen.

  In addition, a predetermined threshold value is set in advance, and if the absolute value of the coefficient is equal to or greater than the threshold value, it is determined that the detection target substance is present. If the absolute value of the coefficient is less than the threshold value, the detection target substance is not present. You may make it determine. This is to prevent erroneous detection due to noise during displacement measurement. Note that this threshold value is arbitrarily set according to the measurement accuracy of the measurement apparatus, the type of specimen, and the like.

  Further, the magnitude of the coefficient includes information on the amount and concentration of the detection target substance in the specimen. Therefore, it is possible to measure the above-mentioned amounts and concentrations by coefficients. Also in this case, as in the third embodiment, information such as a table indicating the correspondence between the coefficient of the approximate exponential function and the concentration of the detection target substance is recorded in advance in a recording unit (not shown) in the computer 5. The computer 5 may be provided with a calculation unit (not shown) that outputs information such as concentration from the above coefficients based on the information.

  In the present embodiment, the value of the coefficient output by the coefficient output unit 58 is output to an output device (not shown). Further, it is assumed that the operator recognizes information such as the presence / absence and concentration of the detection target substance in the sample based on the value of the coefficient.

[9-9. Detection method]
When the detection target substance in the sample is detected by the detection method of the present embodiment using the above-described cantilever sensor system, first, detection is performed from the light source 1 with the detection cantilever 3A attached to the support 61. The specimen is brought into contact with the detection cantilever 3A while irradiating the cantilever 3A with light. Then, at least from the time point t ₁ to the second time point t ₂ , the displacement amount of the detection cantilever 3A is measured. Thereafter, the displacement amount of the detection cantilever 3A is approximated by an exponential function with respect to time, and the detection target substance is detected by the exponential function coefficient obtained by the exponential function approximation.
This will be described in detail below.

The sample and detection are performed in the same manner as in the third embodiment except that information on the first time point t ₁ and the second time point t ₂ is input to the displacement amount measurement unit 51 and the displacement amount index function approximation unit 59. The displacement amount of the detection cantilever 3A at that time is measured by bringing the cantilever 3A into contact. The measured displacement amount of the detection cantilever 3A from the first time point t ₁ to the second time point t ₂ is sent to the displacement amount exponent function approximation unit 59.

The displacement amount exponent function approximating unit 59 measures the displacement amount sent from the displacement amount measuring unit 51 in a predetermined time range from the first time point t ₁ to the second time point t ₂ according to the condition given by the operator. Further, the displacement amount of the detected cantilever 3A is approximated by an exponential function, and an approximate exponential function representing the change with time of the displacement amount is obtained.

  Information about the approximate exponential function is sent to the coefficient output unit 58, and the coefficient output unit 58 takes in the coefficient of the approximate exponential function. The coefficient values taken in by the coefficient approximating unit 58 are output to an output device (not shown), and the operator detects the presence / absence and concentration of the detection target substance in the sample based on the values output to the output device. To do.

[9-10. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.
It is also possible to measure the amount and concentration of the detection target substance from the coefficient of the approximate exponential function.
Furthermore, the same advantages as those of the first, third, and fifth embodiments can be obtained.

[10. Eighth Embodiment]
Next, an eighth embodiment of the present invention will be described with reference to the drawings.
FIG. 14 is a perspective view schematically showing an outline of a cantilever sensor system according to an eighth embodiment of the present invention. 14, the same parts as those in FIGS. 1 to 13 are denoted by the same reference numerals as those in FIGS. 1 to 13.

  The cantilever sensor system according to the present embodiment measures the displacement amount of the detection cantilever by an optical method as in the seventh embodiment. However, in the present embodiment, the displacement amount of the detection cantilever is corrected using the correction cantilever 3B as in the second, fourth, and sixth embodiments. For this reason, the seventh embodiment In addition to the above configuration, a correction cantilever 3 </ b> B, a correction displacement amount measurement unit 53, and a displacement amount correction unit 54 are provided.

  That is, as shown in FIG. 14, the cantilever sensor system used in the detection method of the present embodiment includes a light source 1, a condensing means 2, a detection cantilever 3A, a correction cantilever 3B, a light receiving element 4, and a displacement. An amount measuring unit 51, a corrected displacement measuring unit 53, a displacement correcting unit 54, a displacement index function approximating unit 59, and a coefficient output unit 58 are provided. The displacement measuring unit 51, the corrected displacement measuring unit 53, the displacement correcting unit 54, the displacement index function approximating unit 59, and the coefficient output unit 58 are connected to the computer 5 in hardware and the computer 5 is used to measure the displacement. And a program for causing the function to function as the unit 51, the corrected displacement measuring unit 53, the displacement correcting unit 54, the displacement index function approximating unit 59, and the coefficient output unit 58. Furthermore, also in the cantilever sensor system of the present embodiment, it is assumed that the detection cantilever 3A and the correction cantilever 3B are mounted on a transparent container 6 as a specimen contact portion.

[10-1. light source]
In the present embodiment, the light source 1 is the same as in the second, fourth, and sixth embodiments.

[10-2. Condensing means]
In this embodiment, the condensing means 2 is the same as that of 2nd, 4th, 6th embodiment.

[10-3. Cantilever for detection]
In the present embodiment, the detection cantilever 3A is the same as in the first to seventh embodiments.

[10-4. Correction cantilever]
In the present embodiment, the correction cantilever 3B is the same as in the second, fourth, and sixth embodiments.

[10-5. Transparent container]
In this embodiment, the transparent container 6 is the same as that of 2nd, 4th, 6th embodiment.
In FIG. 14, the transparent container 6 is indicated by a two-dot chain line.

[10-6. Light receiving element]
In the present embodiment, the light receiving element 4 is the same as in the second, fourth, and sixth embodiments.

[10-7. Displacement measurement unit]
The displacement amount measurement unit 51 according to the present embodiment is the same as that of the seventh embodiment, except that the measured displacement amount of the detection cantilever 3A is sent to the displacement amount correction unit 54. Therefore, since the displacement amount measuring unit 51 measures the displacement amount of constantly detecting cantilever 3A, measuring the displacement amount of the detection cantilever 3A in a predetermined time range from the first time point t ₁ to the second time point t ₂ It is like that.

In the present embodiment, as in the seventh embodiment, the first time point t ₁ and the second time point t ₂ are determined by the operator instructing the computer 5 through an interface (not shown) such as a keyboard. It is assumed that the instruction content is set by reading the displacement amount measuring unit 51, the corrected displacement amount measuring unit 53, the displacement amount correcting unit 54, the displacement amount exponent function approximating unit 59, and the coefficient output unit 58. .

[10-8. Corrected displacement measurement unit]
The correction displacement amount measurement unit 53 measures the displacement amount of the correction cantilever 3B within at least a predetermined time range from the first time point t ₁ to the second time point t ₂ .
In the present embodiment, the corrected displacement amount measuring unit 53 is configured in the same manner as in the fourth embodiment.

[10-9. Displacement correction unit]
The displacement amount correction unit 54 determines whether the correction displacement amount measurement unit 53 uses the displacement amount of the detection cantilever 3A measured by the displacement amount measurement unit 51 at least in a predetermined time range from the first time point t ₁ to the second time point t _2. By subtracting the measured displacement amount of the correction cantilever 3B, the displacement amount of the corrected detection cantilever 3A is calculated and sent to the displacement amount exponent function approximation unit 59. As a result, the amount of displacement caused by the interaction generated in the detection cantilever 3A can be obtained more accurately by eliminating the influence of deflection other than the interaction.
In the present embodiment, the displacement amount correction unit 54 sends the displacement amount of the corrected detection cantilever 3A to the displacement amount exponent function approximation unit 59, except for the second, fourth, and sixth embodiments. It is the same.

[10-10. Displacement index function approximation part]
The displacement index function approximating unit 59 uses the displacement amount of the detection cantilever 3A after correction sent from the displacement amount correcting unit 54 to detect a predetermined time range from the first time point t ₁ to the second time point t _2. The displacement amount of the cantilever 3A is approximated by an exponential function with respect to time. This embodiment is the same as the seventh embodiment except that the displacement amount of the detection cantilever 3A corrected by the displacement amount correction unit 54 is used instead of the displacement amount measured by the displacement amount measurement unit 51.

[10-11. Coefficient output section]
The coefficient output unit 58 outputs each coefficient of the exponential function obtained by exponential function approximation. In this embodiment, the coefficient output unit 58 is configured in the same manner as in the seventh embodiment.
Therefore, as in the seventh embodiment, the value of the coefficient output by the coefficient output unit 58 is output to an output device (not shown). Based on this coefficient, the operator can detect the substance to be detected in the sample. It is assumed that information such as presence / absence and concentration is recognized.

[10-12. Detection method]
When detecting the detection target substance in the sample by the detection method of the present embodiment using the above-described cantilever sensor system, first, in a state where the detection cantilever 3A and the correction cantilever 3B are attached to the support 61, The specimen is brought into contact with the detection cantilever 3A and the correction cantilever 3B while irradiating light from the light source 1 to the detection cantilever 3A and the correction cantilever 3B. Then, the displacement amounts of the detection cantilever 3A and the correction cantilever 3B are measured at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ . Next, at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ , the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B. Thereafter, the displacement amount of the detection cantilever 3A after correction is approximated with respect to time by an exponential function, and the detection target substance is detected by the coefficient of the exponential function obtained by the exponential function approximation.
This will be described in detail below.

Information on the first time point t ₁ and the second time point t ₂ is input to the displacement amount measuring unit 51, the corrected displacement amount measuring unit 53, the displacement amount correcting unit 54, the displacement amount exponent function approximating unit 59, and the coefficient output unit 58. Except for this, the specimen is brought into contact with the detection cantilever 3A and the correction cantilever 3B in the same manner as in the second embodiment, and the displacement amount of the detection cantilever 3A and the correction cantilever 3B at that time is measured. . The measured displacement amounts of the detection cantilever 3A and the correction cantilever 3B from the first time point t ₁ to the second time point t ₂ are sent to the displacement amount correction unit 54.

  As in the second, fourth, and sixth embodiments, the displacement amount correction unit 54 subtracts the displacement amount of the correction cantilever 3B from the displacement amount of the detection cantilever 3A, thereby causing displacement due to factors other than the interaction. Correction for removing the amount from the displacement amount of the detection cantilever 3A is performed. Further, the corrected correction amount of the detection cantilever 3 </ b> A is sent to the displacement index function approximation unit 59.

The displacement index function approximating unit 59 uses the displacement after correction of the detection cantilever 3A sent from the displacement correction unit 54 in the same manner as in the seventh embodiment, but the displacement of the detection cantilever 3A. The amount is approximated by an exponential function, and an approximate exponential function representing a change with time of the displacement amount is obtained.
Information about the approximate exponential function is sent to the coefficient output unit 58, and the coefficient output unit 58 takes in the coefficient of the approximate exponential function. The coefficient values taken in by the coefficient approximating unit 58 are output to an output device (not shown), and the operator detects the presence / absence and concentration of the detection target substance in the sample based on the values output to the output device. To do.

[10-13. effect]
When the detection method of the present embodiment is used, the detection target substance in the sample can be detected as described above. Further, at this time, it is possible to perform accurate detection in a shorter time than in the prior art.
Further, according to the detection method of the present embodiment, the displacement amount of the detection cantilever 3A is corrected using the displacement amount of the correction cantilever 3B, and therefore, due to factors other than the interaction between the specific substance and the detection target substance. It is possible to eliminate the influence of deflection and perform more accurate detection.
Furthermore, the same advantages as those of the seventh embodiment can be obtained.

[11. Others]
By the way, when the detection cantilever 3A and the correction cantilever 3B are detachably provided as in the above-described embodiment, the analyzer used in the above cantilever sensor system is usually other than the detection cantilever 3A and the correction cantilever 3B. It is comprised with the following structural member. Specifically, for example, a support portion (cantilever mounting portion) 61 for mounting the detection cantilever 3A and the correction cantilever 3B, and a transparent container (sample contact portion) for contacting the sample with the detection cantilever 3A and the correction cantilever 3B 6, a displacement amount measuring unit 51, a displacement amount comparing unit 52, a corrected displacement amount measuring unit 53, a displacement amount correcting unit 54, a displacement amount straight line approximating unit 55, an inclination output unit 56, a displacement amount polynomial approximating unit 57, and a coefficient output unit. 58, an analysis apparatus provided with a computer (function unit) 5 for realizing a function to be used as appropriate among the displacement index function approximation unit 59 and the like. Such an analyzer is also included in the scope of the present invention.

Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, and can be arbitrarily modified and implemented without departing from the gist of the present invention.
For example, in the first embodiment and the second embodiment, the displacement amount is compared by the computer, but the displacement amount is output as it is, and the operator compares the displacement amount to detect the detection target substance. May be performed.
In the third to eighth embodiments, the operator may perform approximation, calculation of inclination, and the like.

Further, for example, in the first and second embodiments, the displacement amount may be measured at least at the first time point t ₁ and the second time point t ₂ in addition to the constant measurement. The same applies to the correction in the second embodiment.
Further, for example, in the third to eighth embodiments, the displacement amount may be measured at least in a predetermined time range from the first time point t ₁ to the second time point t ₂ in addition to the constant measurement. The same applies to the correction in the fourth, sixth, and eighth embodiments.

Further, in each of the above embodiments, the description has been made by ignoring the presence of noise for the sake of easy understanding. However, in the case where there is noise in the measurement of the displacement amount, the detection target substance in the specimen is similarly processed. Can be detected.
Furthermore, for example, the configuration of the transparent container 6 that is the specimen contact portion may be formed in a flow path shape so that the specimen is brought into contact with the detection cantilever or the correction cantilever in the flow.

Further, for example, it is possible to compare a plurality of measurement results and compare analysis results of a plurality of types of specimens and detection target substances. However, in that case, it is preferable that the conditions of the first time point t ₁ and the second time point t ₂ are the same.

  Further, for example, when the spot light size of the light emitted from the light source 1 is large enough to irradiate the detection cantilever 3A and the correction cantilever 3B used for analysis, the rod lens 21 or the like is not used. It is also possible to irradiate the detection cantilever 3 </ b> A and the correction cantilever 3 </ b> B simply by condensing the light from the light source 2 with one cylindrical lens 23.

Further, for example, two or more cantilevers (including the detection cantilever 3A and the correction cantilever 3B) may be supported on one support member.
Further, for example, the detection cantilever 3A and the correction cantilever 3B may be arranged in two or more rows, or may be arranged irregularly, in addition to being juxtaposed in a row.

  Further, the difference value output by the displacement amount comparison unit 52, the inclination value output by the inclination output unit 56, the coefficient value output by the coefficient output unit 58, and the like are output to an output device or the like as in the above embodiment. Alternatively, it may be output to a calculation unit or the like, and the calculation unit or the like may take in the values of the difference, slope, coefficient, etc., and determine the presence / absence of the detection target substance or calculate the concentration.

Furthermore, for example, other members not described in the above embodiment can be used in combination with the cantilever sensor system as appropriate.
The configurations of the first to eighth embodiments described above can be implemented in any combination as long as the effects of the present invention are not significantly impaired.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples, and may be arbitrarily modified and implemented without departing from the gist of the present invention. be able to. In the following examples and comparative examples, “%” representing the concentration represents “% by weight” unless otherwise specified. Further, in the explanation section described with reference to the drawings, the reference numerals in parentheses “[]” correspond to the reference numerals used in the referenced drawings.

[Example 1]
Using influenza A (H3N2) / Fukuoka / C29 / 85, the virus (substance to be detected) was cultured according to the following procedure.
First, a canine kidney-derived cell line (MDCK cell) was cultured in a flask at 37 ° C. for 3 days, and then the cell growth medium was removed. Next, the virus was inoculated on MDCK cells and allowed to adsorb at room temperature for 1 hour, then the virus was removed, and an influenza medium containing bovine serum albumin (BSA) at a concentration of 0.3% was added at 37 ° C. for 3 hours. Cultured for days. Infected cells exhibiting cytopathic effect (CPE) 3-4 + and culture supernatant were collected and centrifuged at “4 ° C., 3000 rpm” for 10 minutes. The supernatant was dispensed in 2.5 ml portions as a virus solution. The virus titer was measured and found to be 4 × 10 ⁷ [TCID / ml].

  Next, the sugar compound (1), which is a specific substance, was synthesized by the procedure shown in the reaction formula of FIG. Ts represents a tosyl group, DMF represents N, N-dimethylformamide, Bn represents a benzyl group, Me represents a methyl group, Ac represents an acetyl group, TMS represents a trimethylsilyl group, r.p. t. Represents room temperature.

That is, first, commercially available compound (2) and NaN ₃ were reacted in DMF at 50 ° C. for 1.5 hours to obtain compound (3) after post-treatment and purification. This compound (3) and NaI were reacted in acetone for 1 hour under reflux, and after workup and purification, compound (4) was obtained.
Next, the sialic acid derivative (5) and the compound (4) are coupled by reacting in DMF in the presence of CsF at −10 ° C. to 0 ° C. for 15 hours, and after workup and purification, the compound (6) Got. Thereafter, this compound (6) was hydrolyzed in MeOH using water and LiOH at 0 ° C. to room temperature for 3 days to obtain compound (7) after post-treatment and purification. This compound (7) was first treated with 5% -Pd / carbon in a mixed solvent of MeOH and 1N hydrochloric acid under a hydrogen atmosphere, subjected to a reduction reaction, filtered, and further subjected to NaOAc at room temperature. The reaction was neutralized for 30 minutes, and the sugar compound (1) was obtained after purification. The reaction was carried out in a nitrogen atmosphere except for the reduction reaction with Pd / C. The compounds (3) to (7) were purified by silica gel chromatography, and the sugar compound (1) was purified by gel filtration. The total yield of compound (1) from compound (2) was 8.3%.

In addition, two cantilevers made of silicon nitride (manufactured by Olympus Corporation) having a thickness of 0.8 μm, a length of 200 μm, and a width of 40 μm were prepared as cantilevers used for measurement. The cantilever is coated with gold only on one side.
One of the two cantilevers was used as a detection cantilever, and the surface was modified by the following process.
First, it was cleaned for 5 minutes by an ozone cleaner (UV ozone cleaner manufactured by Laser Techno Co., Ltd.). Then, it was immersed in a 10 mM ethanol solution of 16-mercaptohexadecanoic acid for 12 hours at room temperature, washed with ethanol, and sufficiently dried.

Next, N-hydroxysuccinimide and 1-Ethyl-3- (3-dimethylaminopropyl) -carbohydrate hydrate are immersed in an aqueous solution adjusted to have a concentration of 5.0 mM and 20.0 mM, respectively, at room temperature for 20 minutes. Then, it was thoroughly dried. Then, the saccharide compound (1) was immersed in a 6.5 mM methanol solution at room temperature for 19 hours, washed with methanol, and sufficiently dried. As a result, the sugar compound (1) was immobilized on the detection cantilever as a sugar chain. Further, it was immersed in a 1.0 M ethanolamine aqueous solution for 30 minutes, washed with water, and sufficiently dried. Finally, it was immersed in a 0.3% BSA (bovine serum albumin) aqueous solution for 24 hours, washed with water, and sufficiently dried.
On the other hand, the remaining one cantilever was used as a correction cantilever, immersed in a 0.3% BSA aqueous solution for 24 hours, washed with water, and then sufficiently dried.

The detection cantilever and the correction cantilever were set in a measurement cell (specimen contact portion) so that both were parallel and in the same direction. At this time, the distance between the two cantilevers was set to 2 mm.
The measurement cell has a structure in which a Teflon (registered trademark) base part is covered with a glass substrate, and the detection cantilever and the correction cantilever are irradiated with laser light through the glass substrate to detect the detection cantilever. And the reflected light from the correction cantilever can be taken out. Further, the measurement cell is provided with a liquid inlet, from which the liquid in the measurement cell is replaced.

  Next, an apparatus as shown in FIG. 5 is constructed, and the output light from the He-Ne laser [1] is 50 μm wide by the rod lens [21] and the two cylindrical lenses [22, 23]. The light was condensed so as to form a straight line with a length of 1 cm, and simultaneously irradiated to the tip of each of the detection cantilever [3A] and the correction cantilever [3B] set in the measurement cell [6]. Two reflected lights from the detection cantilever [3A] and the correction cantilever [3B] were simultaneously observed by one CCD camera (light receiving element) [4]. The output image of the CCD camera [4] is taken into the personal computer [5] and subjected to image processing to obtain the center positions of the two reflected lights, and the deflection amounts of the detection cantilever [3A] and the correction cantilever [3B] are calculated. The time change was measured. Here, as the deflection amount of the detection cantilever [3A] and the correction cantilever [3B], the change in the angle of the tip of each of the detection cantilever [3A] and the correction cantilever [3B] was measured.

FIG. 16 shows the result of measuring the amount of displacement while the measurement cell is filled with the virus solution. Here, the displacement amount output shown in FIG. 16 is a value obtained by subtracting the displacement amount of the correction cantilever from the displacement amount of the detection cantilever. The measurement started 5 minutes after the virus solution was filled (first time point), and ended 30 minutes after the start of measurement (second time point).
From FIG. 16, it can be seen from the measurement results that the amount of deflection of the detection cantilever has changed due to the interaction between the influenza virus and the sugar chain.
Moreover, about this displacement amount after correction | amendment, when the change was linearly approximated by the least squares method and the inclination was calculated | required, the inclination was -0.3.

[Example 2]
The virus solution used in Example 1 was diluted to a concentration of 1/3 with an influenza medium containing no virus. Using this diluted virus solution, the displacement amount of the detection cantilever was measured in the same manner as in Example 1. The results are shown in FIG. In FIG. 17, the output of the displacement amount is a value obtained by subtracting the displacement amount of the correction cantilever from the displacement amount of the detection cantilever.

FIG. 17 shows that even when the concentration is diluted, the amount of deflection of the detection cantilever changes due to the interaction between the influenza virus and the sugar chain.
Further, with respect to the displacement after correction, the change was linearly approximated by the least square method, and the inclination thereof was obtained. As a result, the inclination was −0.1.

  As described above, the slope of the approximate line obtained in Example 1 is −0.3, whereas the slope of the approximate line obtained in Example 2 in which the concentration of the same specimen is diluted to 1/3. Was -0.1. That is, the magnitude of the slope of the approximate line changed in proportion to the concentration of the specimen. From this, it can be seen that the slope of the approximate line obtained by the above-described linear approximation is dependent on the virus concentration.

[Comparative Example 1]
Measurement was carried out in the same manner as in Example 1 except that an influenza medium containing BSA at a concentration of 0.3% was used as a sample after sterilization instead of the virus solution. The results are shown in FIG. In FIG. 18, the output of the displacement amount is a value obtained by subtracting the displacement amount of the correction cantilever from the displacement amount of the detection cantilever.

It can be seen from the measurement results that the specimen does not contain the influenza virus that is the detection target substance, and in this case, the deflection amount of the detection cantilever does not change.
Further, with respect to the displacement amount after the correction, the change was linearly approximated by the least square method, and the inclination was found to be 0.

  The detection method and cantilever sensor system using the cantilever of the present invention can be used in any industrial field, and are suitable for use in fields such as medical treatment, food analysis, and biological analysis. is there.

It is a perspective view showing typically the outline of the cantilever sensor system concerning a 1st embodiment of the present invention. FIG. 2A is a diagram schematically illustrating a state of a detection cantilever before a specific substance and a detection target substance interact, and FIG. 2B illustrates an embodiment of the present invention. FIG. 5 is a diagram schematically showing a state of a detection cantilever when a deflection is generated by the interaction between a specific substance and a detection target substance. It is sectional drawing which shows typically the principal part of the cantilever sensor system concerning 1st Embodiment of this invention. FIG. 2 is a graph for explaining the first embodiment of the present invention and schematically showing an example of a relationship between time and a displacement amount when the detection cantilever causes a deflection. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 2nd Embodiment of this invention. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 3rd Embodiment of this invention. FIG. 10 is a graph illustrating a third embodiment of the present invention and schematically illustrating an example of a relationship between time and a displacement amount when a detection cantilever causes deflection. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 4th Embodiment of this invention. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 5th Embodiment of this invention. FIG. 10 is a graph illustrating a fifth embodiment of the present invention and schematically illustrating an example of a relationship between time and a displacement amount when a detection cantilever causes a deflection. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 6th Embodiment of this invention. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 7th Embodiment of this invention. FIG. 10 is a graph illustrating a seventh embodiment of the present invention and schematically illustrating an example of a relationship between time and a displacement amount when a detection cantilever causes deflection. It is a perspective view which shows typically the outline | summary of the cantilever sensor system concerning 8th Embodiment of this invention. It is reaction formula which shows the procedure for synthesize | combining the sugar_chain | carbohydrate used in Example 1 of this invention. It is a graph which shows the result of Example 1 of this invention. It is a graph which shows the result of Example 2 of this invention. 6 is a graph showing the results of Comparative Example 1. It is a typical perspective view showing the principal part about an example of the cantilever for a detection. It is sectional drawing which expands the surface vicinity about an example of a cantilever for a detection, and shows it typically.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Light source 2 Condensing means 3A Detection cantilever (cantilever)
3B Correction cantilever 4 Light receiving element 5 Computer 6 Transparent container 21 Rod lens 22, 23 Cylindrical lens 31A, 31B Indicating member 32A, 32B Reflecting surface 33A, 33B Irradiated part 41A, 41B Light receiving part 51 Displacement measuring unit 52 Displacement comparison 53 Corrected displacement measuring unit 54 Displacement correcting unit 55 Displacement straight line approximating unit (displacement approximating unit)
56 slope output unit 57 displacement polynomial approximation unit (displacement approximation unit)
58 Coefficient output unit 59 Displacement index function approximating unit (displacement approximating unit)
61 Supporting tool 62, 63 Hole 64 Ceiling surface 100 Cantilever 101 for detection Cantilever main body 102 Specific substance 103 Metal film 104 Organic molecule 105 Interaction part 106 Support member 107 Concavity and convexity pattern S Detection target substance T Specific substance

Claims (15)

A method for detecting a detection target substance using a cantilever that causes deflection when the detection target substance is present in the specimen when brought into contact with the specimen,
Contact the specimen with the cantilever,
The first time point and the second time point before the time point required for the cantilever to deflect when the sample contains a detection target substance after the time point when the sample is brought into contact with the cantilever. Measure the amount of displacement of the cantilever at the time,
A detection target substance is detected by comparing a displacement amount of the cantilever measured at the first time point with a displacement amount of the cantilever measured at the second time point. Detection method. Detection using a cantilever that causes deflection when a detection target substance is present in the specimen and a correction cantilever that causes deflection regardless of the presence or absence of the detection target substance in the specimen when contacted with the specimen A method for detecting a target substance,
The specimen is brought into contact with the cantilever and the correction cantilever,
The first time point and the second time point before the time point required for the cantilever to deflect when the sample contains a detection target substance after the time point when the sample is brought into contact with the cantilever. At each point in time, the amount of displacement of each of the cantilever and the correction cantilever is measured,
The displacement amount of the cantilever is corrected with the displacement amount of the correction cantilever,
Using the cantilever, wherein the detection target substance is detected by comparing the displacement amount of the cantilever measured at the first time point after the correction with the displacement amount of the cantilever measured at the second time point. A method for detecting a substance to be detected. A method for detecting a detection target substance using a cantilever that causes deflection when the detection target substance is present in the specimen when brought into contact with the specimen,
Contact the specimen with the cantilever,
After the time point when the sample is brought into contact with the cantilever, if the sample contains a substance to be detected, the time from the first time point to the second time point before the time required for the cantilever to bend passes. Until the time, measure the amount of displacement of the cantilever,
The amount of displacement of the cantilever is linearly approximated with respect to time,
A method for detecting a substance to be detected using a cantilever, wherein the substance to be detected is detected based on a slope of a straight line obtained by the above linear approximation. A detection target using a cantilever that generates a deflection when a detection target substance is present in the sample when brought into contact with the sample, and a correction cantilever that generates a deflection independent of the presence or absence of the detection target substance in the sample A method for detecting a substance,
The specimen is brought into contact with the cantilever and the correction cantilever,
After the time point when the sample is brought into contact with the cantilever, if the sample contains a substance to be detected, the time from the first time point to the second time point before the time required for the cantilever to bend passes. Until the time point, measure the amount of displacement of each of the cantilever and the correction cantilever,
The displacement amount of the cantilever is corrected with the displacement amount of the correction cantilever,
After the correction, the displacement amount of the cantilever is linearly approximated with respect to time,
A method for detecting a substance to be detected using a cantilever, wherein the substance to be detected is detected based on a slope of a straight line obtained by the above linear approximation. A method for detecting a detection target substance using a cantilever that causes deflection when the detection target substance is present in the specimen when brought into contact with the specimen,
Contact the specimen with the cantilever,
After the time point when the sample is brought into contact with the cantilever, if the sample contains a substance to be detected, the time from the first time point to the second time point before the time required for the cantilever to bend passes. Until the time, measure the amount of displacement of the cantilever,
Approximate the displacement of the cantilever with a polynomial with respect to time,
A detection target substance detection method using a cantilever, wherein the detection target substance is detected by a coefficient of a polynomial obtained by the approximation. A detection target using a cantilever that generates a deflection when a detection target substance is present in the sample when brought into contact with the sample, and a correction cantilever that generates a deflection independent of the presence or absence of the detection target substance in the sample A method for detecting a substance,
The specimen is brought into contact with the cantilever and the correction cantilever,
After the time point when the sample is brought into contact with the cantilever, if the sample contains a substance to be detected, the time from the first time point to the second time point before the time required for the cantilever to bend passes. Until the time point, measure the amount of displacement of each of the cantilever and the correction cantilever,
The displacement amount of the cantilever is corrected with the displacement amount of the correction cantilever,
Approximate the displacement of the cantilever after correction with a polynomial with respect to time,
A detection target substance detection method using a cantilever, wherein the detection target substance is detected by a coefficient of a polynomial obtained by the approximation. A method for detecting a detection target substance using a cantilever that causes deflection when the detection target substance is present in the specimen when brought into contact with the specimen,
Contact the specimen with the cantilever,
After the time point when the sample is brought into contact with the cantilever, if the sample contains a substance to be detected, the time from the first time point to the second time point before the time required for the cantilever to bend passes. Until the time, measure the amount of displacement of the cantilever,
Approximate the amount of cantilever displacement with an exponential function over time,
A detection target substance detection method using a cantilever, wherein the detection target substance is detected by a coefficient of an exponential function obtained by the approximation. A detection target using a cantilever that generates a deflection when a detection target substance is present in the sample when brought into contact with the sample, and a correction cantilever that generates a deflection independent of the presence or absence of the detection target substance in the sample A method for detecting a substance,
The specimen is brought into contact with the cantilever and the correction cantilever,
After the time point when the sample is brought into contact with the cantilever, if the sample contains a substance to be detected, the time from the first time point to the second time point before the time required for the cantilever to bend passes. Until the time point, measure the amount of displacement of each of the cantilever and the correction cantilever,
The displacement amount of the cantilever is corrected with the displacement amount of the correction cantilever,
Approximate the displacement of the cantilever after correction with an exponential function with respect to time,
A detection target substance detection method using a cantilever, wherein the detection target substance is detected by a coefficient of an exponential function obtained by the approximation. The detection target substance using the cantilever according to any one of claims 1 to 8, wherein a specific substance capable of interacting with the detection target substance is immobilized on a surface of the cantilever. Detection method. The method for detecting a detection target substance using a cantilever according to claim 9, wherein the specific substance is a sugar chain. The method for detecting a detection target substance using a cantilever according to any one of claims 1 to 10, wherein the detection target substance is at least one of a virus and a bacterium. A cantilever that causes deflection if a detection target substance is present in the sample when contacted with the sample; and
A specimen contact portion for bringing the specimen into contact with the cantilever;
The amount of displacement of the cantilever deflection is determined from the time when the time required for the cantilever to deflect when the sample contains the detection target substance after the sample is brought into contact with the cantilever. A displacement amount measuring unit for measuring the displacement amount of the cantilever at the first time point and the second time point,
A cantilever sensor system, comprising: a displacement amount comparison unit that compares the displacement amount of the cantilever measured at the first time point with the displacement amount of the cantilever measured at the second time point. A cantilever that causes deflection if a detection target substance is present in the sample when contacted with the sample; and
A specimen contact portion for bringing the specimen into contact with the cantilever;
After the time point when the sample is brought into contact with the cantilever, the time point from the first time point before the time point required for the cantilever to bend when the sample contains the detection target substance is from the first time point. A displacement measuring unit for measuring the displacement of the cantilever between two time points;
A displacement amount approximating unit for linearly approximating the displacement amount of the cantilever with respect to time;
A cantilever sensor system comprising: an inclination output unit that outputs an inclination of a straight line obtained by the linear approximation. A cantilever that causes deflection if a detection target substance is present in the sample when contacted with the sample; and
A specimen contact portion for bringing the specimen into contact with the cantilever;
After the time point when the sample is brought into contact with the cantilever, the time point from the first time point before the time point required for the cantilever to bend when the sample contains the detection target substance is from the first time point. A displacement measuring unit for measuring the displacement of the cantilever between two time points;
A displacement amount approximating unit for approximating the displacement amount of the cantilever with a polynomial with respect to time;
A cantilever sensor system comprising: a coefficient output unit that outputs a coefficient of a polynomial obtained by the approximation. A cantilever that causes deflection if a detection target substance is present in the sample when contacted with the sample; and
A specimen contact portion for bringing the specimen into contact with the cantilever;
After the time point when the sample is brought into contact with the cantilever, the time point from the first time point before the time point required for the cantilever to bend when the sample contains the detection target substance is from the first time point. A displacement measuring unit for measuring the displacement of the cantilever between two time points;
A displacement amount approximating section for approximating the displacement amount of the cantilever with an exponential function with respect to time;
A cantilever sensor system comprising: a coefficient output unit that outputs a coefficient of an exponential function obtained by the approximation.

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