JP2008241619A - Cantilever, biosensor and probe microscope - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find out a shape of a cantilever for enhancing weight detecting sensitivity and to detect the physical quantitird related to a detection target. <P>SOLUTION: A cantilever type biosensor is attached to the leading end of a pedestal 12 so as to support one end of the cantilever 10, and a plurality of through-holes 10A opened to the surface of the cantilever 10 and pierce the cantilever 10 in its thickness direction, are provided to the cantilever 10 by drilling. The openings of the through-holes 10A, respectively have rectangular shapes, and a plurality of the through-holes 10A are provided by drilling so as to enlarge the opening areas of the through-holes 10A to the utmost. According to this constitution, since the movement of molecules becomes smooth, when the cantilever 10 is vibrated, the occurrence of large viscosity resistance is prevented and viscosity resistance is reduced. Accordingly, the change quantity of a change in frequency with respect to a mass change becomes large. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a cantilever, a biosensor, and a probe microscope that can detect an antigen-antibody reaction and a protein with high sensitivity, and more particularly, a substance dissolved in a liquid using a cantilever (cantilever), The present invention relates to a cantilever capable of detecting a substance suspended in the atmosphere with high sensitivity, a biosensor, and a probe microscope capable of detecting a sample surface shape with high resolution.

  A cantilever used in an atomic force electron microscope has a resonance point, and a sensor capable of measuring a force in units of pN (piconewton), which is a minute force, by utilizing the fact that the resonance point is shifted by the force received from the outside. It is used as.

  As a paper using a cantilever as a biosensor, a sensor (Non-Patent Document 1) published by Lang et al. Is known.

  This sensor is a sensor that detects a physical quantity, chemical quantity, temperature, stress, or the like by detecting a change in the resonance frequency of a small cantilever using an optical lever.

Further, in the cantilever resonance type biosensor, a plate-like one is used in order to adsorb a large number of molecules and the like on the cantilever surface.
"Artificial Nose" (Analytica Chemica Acta Analyca Chemical Acta 393 (1999) p. 59)

  However, the above-described cantilever resonance type biosensor has a problem that since the liquid is moved when the cantilever is resonated in the liquid, a large viscous resistance is generated, the Q value is lowered, and the detection sensitivity is lowered. In order to improve detection sensitivity, it is necessary to increase the resonance frequency and reduce the weight of the cantilever.

  The present invention has been made to solve the above problem, and provides a cantilever, a biosensor, and a probe microscope that can detect a physical quantity related to a detection object with high sensitivity by improving detection sensitivity. Objective.

  In order to achieve the above object, a cantilever according to the present invention is a plate-like cantilever supported by a substrate via a support portion, and is a plurality of cantilevers that open on the surface and penetrate in the thickness direction of the cantilever. This is characterized in that a through hole is formed.

  According to the cantilever according to the present invention, when the cantilever is vibrated, the movement of molecules is smoothed by the plurality of through-holes of the cantilever, so that it is possible to prevent a large viscous resistance from being generated. Moreover, since the weight of the cantilever can be reduced without significantly reducing the resonance frequency, the detection sensitivity can be improved. Further, the cantilever having two support portions and a large opening has a lot of twist components, but in the present invention, an increase in the twist components can be prevented.

  Therefore, by making a plurality of through holes on the surface of the cantilever, it is possible to prevent the occurrence of a large viscous resistance, thereby improving the detection sensitivity and detecting the physical quantity related to the detection object with high sensitivity. Can do.

  The opening part of the through-hole which concerns on this invention can be made into the rectangular shape of a magnitude | size whose side is 3 micrometers-6 micrometers.

  The probe can be formed in an unopened portion where the through hole of the cantilever is not drilled. Thereby, the detection sensitivity can be improved, and the shape of the surface of the detection target can be detected with high sensitivity and high resolution.

  Further, at least a part of the unopened portion where the through hole of the cantilever according to the present invention is not drilled can be used as the reflecting surface.

  Moreover, a strain resistance element can be provided in the support part of the cantilever according to the present invention. Thereby, based on the output of the strain resistance element, it is possible to detect the physical quantity related to the detection target without degrading the detection sensitivity.

  Further, an unopened portion where the through-hole of the cantilever is not drilled can be made a part of the capacitance element.

  The above cantilevers can be immersed in the liquid or placed in the atmosphere. As a result, even when the cantilever is vibrated in the liquid or the atmosphere, the physical quantity related to the detection target can be detected without deteriorating the detection sensitivity.

  In addition, a biosensor according to the present invention includes the above-described cantilever and detection means for detecting the amount of substance attached to the cantilever.

  According to the biosensor of the present invention, when the cantilever is vibrated, the movement of the molecules is smoothed by the plurality of through holes of the cantilever, so that the detection means adheres to the cantilever without generating a large viscous resistance. The amount of adhered substance can be detected. This improves the weight detection sensitivity. Further, since the weight of the cantilever is reduced and the resonance frequency hardly changes, the weight detection sensitivity is improved.

  Therefore, by forming a plurality of through-holes on the surface of the cantilever, it is possible to prevent the occurrence of a large viscous resistance and to detect the amount of substance adhering to the cantilever with high sensitivity in order to reduce the weight. Can do.

  The probe microscope according to the present invention includes a cantilever in which a probe is formed in the above-described unopened portion, and the cantilever is arranged so that an atomic force acts between the probe and the surface of the sample. It is configured.

  According to the probe microscope of the present invention, when the cantilever is vibrated, the movement of the molecules is smoothed by the plurality of through-holes of the cantilever, so that the probe and the sample are highly sensitive without generating a large viscous resistance. It is possible to detect an interatomic force acting between the surface and the surface.

  Therefore, by making a plurality of through-holes on the surface of the cantilever, it is possible to prevent the occurrence of a large viscous resistance, so that the atomic force acting between the probe and the sample surface can be generated with high sensitivity. Can be detected.

  As described above, according to the cantilever, biosensor, and probe microscope of the present invention, it is possible to prevent a large viscous resistance from being generated by drilling a plurality of through holes on the surface of the cantilever. By improving the weight detection sensitivity, it is possible to detect the physical quantity related to the object to be detected and the amount of substance attached to the cantilever with high sensitivity, or increase the atomic force acting between the probe and the sample surface. The effect that it can detect with a sensitivity is acquired.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. As shown in FIG. 1, the cantilever-type biosensor according to the first embodiment of the present invention includes a thin plate-like cantilever 10 supported by a base 12 as a substrate.

  An actuator 14 composed of a piezoelectric element that vibrates the cantilever 10 by vibrating the pedestal 12 is attached to the pedestal 12. The actuator 14 is attached so as to be integrated with the pedestal 12 by being bonded or mechanically bonded to the pedestal 12. Further, the position where the actuator 14 is attached may be a position where the cantilever 10 can be vibrated in the thickness direction of the cantilever 10, and as shown in the figure, the side where the cantilever is not formed or the cantilever is formed. It is attached to the side.

  In addition, a strain resistance element, which is a self-detecting sensor, is embedded in the joint portion 16 as a support portion of the cantilever 10 with the base 12. When the cantilever 10 is vibrated in the thickness direction by the actuator 14, tensile and compressive stress is generated in the joint 16 with the base 12 of the cantilever 10, and the resistance value of the strain resistance element changes. Ten vibration states can be detected.

The cantilever 10 can be formed integrally with the pedestal 12 by etching a semiconductor substrate formed of silicon, SiN, SiO ₂ or the like into a thin plate shape with a portion corresponding to the pedestal 12 remaining. As for the strain resistance element, a pair of electrodes is formed by a semiconductor technology at the junction 16 with the pedestal 12 of the cantilever 10, and a strain resistance pattern is formed by ion implantation of impurity atoms such as boron between the electrodes. Formed and created. The resistance value of the strain resistance is desirably 2 kΩ or less. The cantilever 10 and the pedestal 12 are preferably formed of a silicon substrate, but an electrode may be formed and a strain resistance element may be attached without ion implantation.

  A detection circuit 18 for detecting a change in the resistance value of the strain resistance element is connected to the electrode of the strain resistance element. The detection circuit 18 includes a bridge circuit that configures a Wheatstone bridge to which electrodes of the strain resistance element are connected, and a power source that applies a voltage to the bridge circuit, detects a resistance change of the strain resistance element as a voltage change, Output the detected signal. The detection circuit 18 is connected to a positive feedback circuit 20 for driving the actuator 14 to resonate the cantilever 10 and an FV conversion circuit (FM demodulation circuit) 22 for converting a frequency into a voltage. A personal computer 26 that performs data processing and display is connected to the FV conversion circuit 22.

  The personal computer 26 has a general personal computer configuration and includes a CPU, a ROM, a RAM, a hard disk, a display, and the like. The personal computer 26 stores data input from the FV conversion circuit 22 in the hard disk, and also stores the data. Predetermined data processing is performed based on the processed data.

  Next, the principle for detecting the mass of the substance attached to the cantilever of this embodiment will be described. The cantilever bends when an external force is applied, and the resonance frequency changes when the mass changes in a resonating state. Considering the cantilever as a vibrator, the operation of the cantilever can be expressed by the following equation of motion (1).

  Here, m is the effective mass of the cantilever, a is the viscosity coefficient of the liquid in which the cantilever is immersed, k is the spring constant of the cantilever, Asinωt is the excitation force of the actuator, F (x) is the excitation force of the actuator, x Is the displacement of the cantilever. Further, since F (x) is represented by the product of the force gradient F ′ and the displacement x, it can be represented by the following equation (2).

  Further, the general formula can be expressed by the following formula (3).

  If a and F ′ are almost negligible from the above equation (1), the resonance frequency f0 of the cantilever is expressed by the following equation (4) using the effective mass m of the cantilever and the spring constant k.

  Here, when the cantilever resonates at the frequency f0 and the mass of the cantilever increases by Δm, the frequency change Δf is expressed by the following equation (5) from the above equation (4).

  Therefore, by detecting the change in the resonance frequency of the cantilever from the above equation (5), the change in the mass of the cantilever, that is, the mass of the substance attached to the cantilever can be detected. Since the change in frequency can be measured with an accuracy of 1 Hz or less, the above equation (5) means that the change in the mass of the cantilever can be measured with a picogram or a femtogram. For example, if the resonance frequency f0 is 100 kHz and the effective mass m of the cantilever is 10 ng, the mass of the substance attached to the cantilever can be detected with a sensitivity of about 0.2 pg / Hz.

  Here, it is necessary to consider that the viscosity coefficient a changes between the atmospheric measurement and the underwater measurement. Hereinafter, the analysis of the frequency change Δf when viscosity is considered (underwater) will be described.

  When the viscosity coefficient a is considered, it is expressed by the following equation (6) from the above equation (3), assuming that a is not 0.

  When the above equation (6) is fully differentiated with respect to m and k, the following equation (7) is obtained.

  If the change Δk of the spring constant is ignored, Δk = 0, and the above expression (7) is expressed by the following expression (8).

Here, in the above equation (8), when the mass m of the piezoresistive cantilever used in the experiment is 45.6 × 10 ⁻⁹ and the spring constant k is 40, Δm and Δf1 with a as a parameter The relationship is as shown in FIG.

As shown in FIG. 2, Δf1 decreases as Δm increases. The change Δf1 / Δm when a = 0.0005 is −0.022 [Hz · ng ⁻¹ ], and the change Δf1 / Δm when a = 0.00075 is −0.0185. [Hz · ng ⁻¹ ] and the change amount Δf1 / Δm when a = 0.001 is −0.01185 [Hz · ng ⁻¹ ].

  From the result of FIG. 2, it can be seen that when the viscous resistance a is increased, the change amount of the frequency change with respect to the mass change is reduced, so that the mass detection sensitivity is lowered. Thus, in order not to lower the detection sensitivity, it is necessary to reduce the viscous resistance a. That is, when the cantilever is vibrated, the detection sensitivity is improved as the movement of the molecule is smoother.

  Hereinafter, the configuration of the cantilever 10 of the present embodiment will be described with reference to FIG. As shown in FIG. 3A, one end of the cantilever 10 is supported and attached to the tip of the pedestal 12, and two electrodes 12 </ b> A and 12 </ b> B are formed in the pedestal 12. Further, as shown in FIG. 3B, the two electrodes 12 </ b> A and 12 </ b> B are connected by a joint portion 16. The surface of the cantilever 10 is provided with a plurality of through holes 10 </ b> A that open to the surface and penetrate in the thickness direction of the cantilever 10. The openings of the through holes 10A each have a rectangular frame structure, and each side has a size of 3 μm to 6 μm. From the result shown in FIG. 2, since it is preferable to move the molecules smoothly in order to reduce the viscous resistance, a plurality of through holes 10A are formed in order to enlarge the opening area as much as possible. Moreover, in order to increase the area of the part to which the substance adheres, the cantilever 10 may be configured so that the surface area becomes as large as possible.

  Further, as shown in FIG. 3C, a wiring 16A for connecting the two electrodes 12A and 12B is provided in the joint portion 16, and a connection portion between the wiring 16A and the electrodes 12A and 12B. Each is provided with a strain resistance element (piezoresistive element) 16B.

  Hereinafter, a measurement method using the cantilever biosensor of the present embodiment will be described. When a vibration signal is input to the actuator 14 from the positive feedback circuit 20, the pedestal 12 is vibrated, and thereby the cantilever 10 is vibrated in the thickness direction of the cantilever. When the cantilever 10 is immersed in the reaction solution in the container 24, the reaction solution adheres to the cantilever 10, and the frequency of the cantilever 10 slightly decreases due to the influence of the viscosity of the reaction solution. However, since various vibration modes are generated at this time, the cantilever 10 resonates at a frequency different from the original resonance frequency. Since the movement of the cantilever 10 and the pedestal 12 at this time is not integrated, tensile and compressive stress is generated in the strain resistance element 16B, and the resistance of the strain resistance element 16B changes, so that a constant voltage is applied to the strain resistance element 16B. The current changes according to the vibration of the cantilever 10. By detecting this current change as a voltage change by the bridge circuit of the detection circuit 18, the vibration frequency of the cantilever 10 can be detected, and thereby the vibration state of the cantilever 10 can be detected.

  Here, when the cantilever 10 is vibrated, the plurality of through-holes 10A of the cantilever 10 can smoothly move the molecules, so that a large viscous resistance is prevented and the viscous resistance is reduced. Therefore, the amount of change in frequency with respect to mass change is large.

  In addition, the voltage change detected by the detection circuit 18 is amplified by the positive feedback circuit 20, the phase is aligned, and is input to the actuator 14. As a result, the cantilever 10 is vibrated at the resonance frequency. The voltage change detected by the detection circuit 18 is converted to an analog signal (output V) by the FV conversion circuit 22 and input to the personal computer 26.

  Next, calculation processing by a computer will be described with reference to FIG. In step 100, the analog signal output from the FV conversion circuit is converted into a digital signal, and in step 102, the output V is stored in the memory of the computer.

  In the next step 104, the output captured last time is compared with the output captured this time, the output change ΔV is calculated, and in step 106, the mass of the substance attached to the cantilever is calculated based on the above equation (5). To do. Thereby, the time change of the mass of the substance adhering to the cantilever can be detected. Further, by integrating the time change of the mass over a predetermined time, the total amount of the substance attached to the cantilever within the predetermined time can be detected. The mass of the substance attached to the cantilever detected in this way is displayed on a display device such as an LCD connected to the computer.

  In step 108, it is determined whether or not the output V has changed within a predetermined time. If it is determined that the output V has changed, the process returns to step 100, but the output V has not changed within the predetermined time. Is determined that the mass change of the substance adhering to the cantilever has ceased, and the calculation process is terminated. In addition, the computer can process and calculate noise removal, reaction speed, and the like.

  In order to use the biosensor of this embodiment for detection of an antigen-antibody reaction, the antibody is first attached to the surface of the cantilever and the cantilever is immersed in the reaction solution, and then the measurement sample having the antigen is reacted in the reaction vessel 24. Put into the solution. This makes it clear whether or not the constitution has factors such as allergies. Contrary to this case, it can be seen that allergens are produced in the human body when the antibody is first placed in the reaction container and then the antigen is introduced.

  Next, the examination result regarding the magnitude | size of the opening part of 10 A of through-holes of the cantilever 10 is demonstrated. As shown in FIG. 5, the rectangular size of the opening of the through hole of the cantilever is 3 μm × 3 μm (see FIG. 5A), 4 μm × 4 μm (see FIG. 5B), 5 μm × 5 μm ( (See FIG. 5 (C)) and 6 μm × 6 μm (see FIG. 5 (D)) are shown below. The above-described cantilever has a length of 100 μm, a width of 49 to 51 μm, and a thickness of 4 μm.

  Examining the change in detection sensitivity with respect to the change in the size of the opening of the through hole shows that the detection sensitivity improves as the size of the opening of the through hole increases, as shown in FIG. Further, when the change in the resonance frequency with respect to the change in the size of the opening of the through hole is examined, as shown in FIG. 7, the resonance frequency increases as the size of the opening of the through hole increases. It turns out that it is a resonance frequency. Further, when the change in the surface area with respect to the change in the size of the opening of the through hole is examined, it can be seen that the surface area decreases as the size of the opening of the through hole increases, as shown in FIG.

  From the above examination results, it is sufficient that the opening of the through hole has a rectangular shape with a side of 3 μm to 6 μm, and in order to increase detection sensitivity, a rectangular shape with a side of 6 μm is used. Is preferred.

  Further, in order to increase the surface area, a rectangular shape with one side having a small size may be used. For example, a rectangular shape with one side having a size of 3 μm may be used.

  Next, the examination result regarding the entire length of the cantilever 10 will be described. As shown in FIG. 9, the cantilever has a total length of 100 μm (see FIG. 9A), 80 μm (see FIG. 9B), and 60 μm (see FIG. 9C). The results of the examination will be described below. The above-described cantilever has a through hole having a size of 6 μm × 6 μm, a width of 50 μm, and a thickness of 4 μm.

  Examining the change in detection sensitivity with respect to the change in the overall length of the cantilever, it can be seen that the detection sensitivity decreases as the overall length of the cantilever increases, as shown in FIG. Further, when the change in the resonance frequency with respect to the change in the overall length of the cantilever is examined, it can be seen that as shown in FIG. 11, the resonance frequency decreases as the overall length of the cantilever increases. Further, when the change in the surface area with respect to the change in the overall length of the cantilever is examined, it can be seen that the surface area increases as the overall length of the cantilever increases as shown in FIG.

  FIG. 10 and FIG. 12 may be taken into consideration for the weight detection, and it can be understood that the overall length of the cantilever may be shortened comprehensively. Further, in order to reduce the frequency, the thickness of the cantilever may be reduced.

  From the above examination results, in order to increase the detection sensitivity, the entire length of the cantilever may be shortened. In order to increase the resonance frequency, the entire length of the cantilever may be shortened, and in order to decrease the resonance frequency, the entire length of the cantilever may be increased. In order to increase the surface area, the entire length of the cantilever may be increased.

  As described above, according to the cantilever-type biosensor according to the first embodiment of the present invention, a plurality of through holes are formed in the surface of the cantilever so as to facilitate the passage of molecules. Since it is possible to prevent the occurrence of a large viscous resistance, the detection sensitivity can be improved and the mass of the substance attached to the cantilever can be detected without reducing the Q value even in the liquid.

  Also, by making multiple through-holes on the surface of the cantilever, the movement of molecules becomes smooth, the viscosity resistance is reduced, and the amount of change in frequency with respect to mass change is increased. The mass of the substance attached to the cantilever can be detected with sensitivity.

  In addition, since a strain resistance element is embedded in the cantilever as a sensor, the optical lever method is not used, so that it is not necessary to adjust the optical axis when using a cantilever biosensor in a solution or the like, and can be used easily. .

  Further, by converting a signal indicating the voltage change detected by the detection circuit into digital data and measuring a physical quantity related to the measurement object based on the digital data, there is no limit to the frequency region of the voltage change that can be detected, and Since the voltage change can be detected with high accuracy even when the voltage change is large, the physical quantity relating to the measurement object can be measured with high accuracy and in a wide range.

  In the present embodiment, an example in which the actuator 14 is configured by a piezoelectric element has been described. However, in the present embodiment, as shown in FIG. 13, each electrode portion of the piezoelectric element is covered with an insulating film 28 to electrically It may be insulated. Also in this case, similarly to the above, one of the insulating films of the actuator 14 is bonded or mechanically bonded to the base 12 to integrate the actuator 14 with the base 12. Since the electrode of the actuator 14 is covered with the insulating film 28, the measurement can be started immediately by immersing the cantilever 10 in the reaction solution.

  In the above description, the case where the cantilever is immersed in the solution has been described as an example. However, the cantilever may be disposed in the atmosphere in which the measurement target is floating.

  Further, as shown in FIG. 14, the cantilever 10 and the base 12 may be covered with an insulating film 28. In this case, the actuator 14 may be covered with an insulating film as shown in FIG. 13, or may not be covered. Thereby, when the cantilever 10 is immersed in the reaction solution, a leak current is prevented from flowing on the surface of the cantilever 10, and the current can be accurately measured by the detection circuit 18.

  Next, a second embodiment of the present invention will be described. In the second embodiment, instead of the strain resistance element of the first embodiment, a capacitance element whose capacitance changes according to the vibration of the cantilever is used as a sensor for detecting a change in the vibration state of the cantilever. It is what you use. In the present embodiment, as shown in FIG. 15, the strain resistance element is not provided at the joint portion 16 between the cantilever 10 and the base 12.

  Further, as shown in FIG. 16, the counter electrode 30 is fixed to the pedestal 12 so as to face and parallel to the cantilever 10, and the through-hole 10 </ b> A of the cantilever 10 is not opened by the counter electrode 30. Is a part of the capacitance element, and the capacitance element is configured between the counter electrode 30 and the unopened portion of the cantilever 10. And the cantilever 10 and the counter electrode 30 are connected to the detection circuit 18 provided with the bridge circuit which comprises a Wheatstone bridge with an electrostatic capacitance element similarly to the above. As a result, when the cantilever vibrates, the capacitance of the capacitive element periodically changes. Therefore, the bridge circuit of the detection circuit can detect the vibration of the cantilever and output a vibration signal.

  Here, when the cantilever 10 is vibrated, the plurality of through-holes 10A of the cantilever 10 can smoothly move the molecules, so that a large viscous resistance is prevented and the viscous resistance is reduced. Therefore, the amount of change in frequency with respect to mass change is large.

  According to the present embodiment, the change in the resonance frequency is detected from the vibration signal output from the detection circuit, and the change in the mass of the substance adhering to the cantilever is detected from the change in the resonance frequency as described above. Can do.

  In addition, since the viscous resistance is reduced by the plurality of through holes of the cantilever and the change amount of the frequency change with respect to the mass change is increased, the time change of the mass of the substance attached to the cantilever can be detected with high detection sensitivity. .

  Next, a third embodiment of the present invention will be described with reference to FIG. In the present embodiment, the counter electrode of the second embodiment is used as an actuator. As a sensor for detecting the vibration of the cantilever, the strain resistance element 16B similar to that of the first embodiment is used.

  The strain resistance element 16B is connected to the bridge circuit of the detection circuit 18 as in the first embodiment. Further, the proximal end side of the cantilever 10 is grounded, and the counter electrode 30 constituting the capacitance element is connected to the positive feedback circuit 20.

  According to the present embodiment, the voltage change of the strain resistance element 16B is detected by the bridge circuit of the detection circuit 18, and the detected signal is input to the positive feedback circuit 20 and input to the counter electrode 30 as an excitation signal. The cantilever 10 is controlled to resonate. The signal detected by the bridge circuit of the detection circuit 18 is input to the personal computer 26 via the FV conversion circuit 22, and the substance attached to the cantilever 10 in the personal computer 26 due to the change in the resonance frequency in the same manner as described above. Changes in the mass of the time are detected.

  Next, a fourth embodiment of the present invention will be described with reference to FIG. In this embodiment, an electromagnetic induction actuator is used instead of the electrostatic induction actuator of the third embodiment. In the present embodiment, the electromagnetic induction coil 32 is fixed to the pedestal 12 so as to face the cantilever 10 and be substantially parallel thereto, and the magnetic thin film 34 made of a magnetic material is coated on the surface side of the cantilever 10. . As a sensor for detecting the vibration of the cantilever, the strain resistance element 16B similar to that of the first embodiment is used.

  According to the present embodiment, the signal from the strain resistance element 16B is detected by the bridge circuit of the detection circuit 18 in the same manner as described above, and the detected signal is input to the positive feedback circuit 20 and applied to the electromagnetic induction coil 32 as an excitation signal. Therefore, the cantilever 10 is resonantly oscillated. Further, the signal detected by the bridge circuit of the detection circuit 18 is inputted to the personal computer 26 through the FV conversion circuit 22 in the same manner as described above, and the substance attached to the cantilever 10 from the change of the resonance frequency in the personal computer 26. Changes in the mass of the time are detected. Although only one side is coated in FIG. 18, it may be coated on both sides, or may be coated on the opposite side to FIG.

  FIG. 19 shows a fifth embodiment of the present invention, for attaching a special chemically reactive group to the insulating film of the cantilever shown in FIG. 14 in order to attach a substance to be detected. The thin film 36 made of gold or the like is covered. The kind of thin film is appropriately selected according to the substance to be deposited. Thereby, it is possible to detect a temporal change in a physical quantity relating to a measurement target such as a protein, DNA, antibody, or antigen that is artificially selected via a thiol group or the like.

  Next, a sixth embodiment will be described. As shown in FIG. 20, the cantilever biosensor according to the sixth embodiment includes a semiconductor laser 212 that irradiates laser light, laser light emitted from the semiconductor laser 212, and a lens (not shown). The position detector 214 is configured by a cantilever 210 having a reflecting surface for reflecting the light collected by (2) and a photodiode or the like provided so that the laser light reflected by the reflecting surface of the cantilever 210 is incident. A change in the resonance frequency of the small cantilever 210 is detected using an optical lever, and a physical quantity, chemical quantity, temperature, stress, or the like is detected.

  Further, the cantilever type biosensor includes an actuator 216 composed of a piezoelectric element that vibrates the cantilever 210 by vibrating the pedestal 215, a detection circuit 218 for detecting a change in the resonance frequency of the cantilever 210, and an actuator 216. Are provided, a positive feedback circuit 220 for causing the cantilever 210 to resonate, an FV conversion circuit (FM demodulation circuit) 222 for converting the frequency into a voltage, and a personal computer 226 for performing data processing and display.

  Further, as shown in FIG. 21, the cantilever 210 has an unopened portion where the through-hole 10A is not formed as a reflecting surface. The reflective surface of the cantilever 210 is flat.

  According to the present embodiment, the laser beam from the semiconductor laser is irradiated onto the reflecting surface of the cantilever, the reflected light from the cantilever is incident on the position detector, and the change in the resonance frequency is detected from the vibration signal output from the position detector. It is possible to detect a change in the mass of the substance attached to the cantilever over time and the like from the change in the resonance frequency.

  Also, when the cantilever is vibrated, the plurality of through-holes of the cantilever smooth the movement of the molecule, the viscosity resistance is reduced, and the amount of change in the frequency change with respect to the mass change is increased. Changes in the mass of the substance attached to the cantilever over time can be detected.

  Next, a seventh embodiment will be described. In the seventh embodiment, a case where the present invention is applied to a scanning probe microscope will be described.

  In the scanning probe microscope according to the seventh embodiment, as shown in FIG. 22, a probe 310A is formed in an unopened portion where a through hole of the cantilever 310 is not formed. Further, the strain resistance element 16B is provided at the joint 16 between the cantilever 310 and the pedestal, as in the first embodiment.

  The cantilever 310 is fixed to the optical lever detector or cantilevered by the scanning mechanism, and the cantilever 310 is arranged so that an atomic force acts between the probe 310A of the cantilever 310 and the surface of the sample. Has been.

  The laser beam is incident on the back side of the probe 310A and reflected to form an optical lever optical system. The back surface is coated with gold or Al.

  In the scanning probe microscope according to the seventh embodiment, the actuator is controlled by the scanning mechanism so that the cantilever 310 is moved in each of the X direction, the Y direction, and the Z direction, and the cantilever 310 is resonantly oscillated. . Then, similarly to the first embodiment, the signal output from the strain resistance element 16B is detected by the bridge circuit of the detection circuit and input to the computer via the FV conversion circuit. Then, the change in the atomic force between the probe 310A of the cantilever 310 and the surface of the sample is detected from the change in the resonance frequency in the computer, and the three-dimensional surface shape of the sample is measured.

  According to the scanning probe microscope according to the present embodiment, when the cantilever is vibrated, the plurality of through-holes of the cantilever smooth the movement of molecules, the viscosity resistance is reduced, and the Q value is improved. Since the amount of change in frequency relative to the change in atomic force is large, the change in atomic force between the probe and the sample surface can be detected with high detection sensitivity, and the three-dimensional surface of the sample. The shape can be measured with high accuracy.

  In the above-described embodiment, an example in which a strain resistance element or a capacitance element is used as the self-sensing element has been described, but a piezoelectric element, an electromagnetic induction element, a temperature sensing element, or the like may be used. . Further, as an actuator, a temperature-driven actuator, a light-driven actuator, or the like may be used instead of the piezoelectric element or the electrostatic-drive capacitance element. Furthermore, although the example which coat | covered the cantilever with the insulating film was demonstrated, you may make it cover with a natural oxide film.

It is the schematic which shows the structure of the cantilever type | mold biosensor which concerns on the 1st Embodiment of this invention. It is a graph which shows the relationship of the change of the frequency with respect to the change of the mass at the time of considering a viscosity coefficient. (A) The figure which shows the structure of the cantilever and pedestal which concerns on the 1st Embodiment of this invention, (B) The figure which shows the structure of a cantilever, and (C) The figure which shows the structure of the junction part of a cantilever and a pedestal. is there. It is a flowchart which shows the process routine which detects the substance adhering to the cantilever of the 1st Embodiment of this invention. It is the schematic which shows the structural example of the several cantilever from which the magnitude | size of the opening part of a through-hole differs. It is a graph which shows the relationship of the change of the detection sensitivity with respect to the change of the magnitude | size of the opening part of a through-hole. It is a graph which shows the relationship of the change of the resonant frequency with respect to the change of the magnitude | size of the opening part of a through-hole. It is a graph which shows the relationship of the change of a surface area with respect to the change of the magnitude | size of the opening part of a through-hole. It is the schematic which shows the structural example of the several cantilever from which the whole length differs. It is a graph which shows the relationship of the change of the detection sensitivity with respect to the change of the whole length of a cantilever. It is a graph which shows the relationship of the change of the resonant frequency with respect to the change of the whole length of a cantilever. It is a graph which shows the relationship of the change of a surface area with respect to the change of the whole length of a cantilever. It is the schematic which shows the modification of the 1st Embodiment of this invention. It is the schematic which shows the other modification of the 1st Embodiment of this invention. It is a figure which shows the structure of the cantilever which concerns on the 2nd Embodiment of this invention. It is the schematic which shows the structure of the cantilever type | mold biosensor which concerns on the 2nd Embodiment of this invention. It is the schematic which shows the structure of the cantilever type | mold biosensor which concerns on the 3rd Embodiment of this invention. It is the schematic which shows the structure of the cantilever type | mold biosensor which concerns on the 4th Embodiment of this invention. It is the schematic which shows the structure of the cantilever type | mold biosensor which concerns on the 5th Embodiment of this invention. It is the schematic which shows the structure of the cantilever type | mold biosensor which concerns on the 6th Embodiment of this invention. It is a figure which shows the structure of the cantilever which concerns on the 6th Embodiment of this invention. It is a figure which shows the structure of the cantilever which concerns on the 7th Embodiment of this invention.

Explanation of symbols

10, 210, 310 Cantilever 10A Through hole 12, 215 Base 12A Electrode 14, 216 Actuator 16 Joint 16B Strain resistance element 18, 218 Detection circuit 20, 220 Positive feedback circuit 22 Conversion circuit 26, 226 Personal computer 30 Counter electrode 212 Semiconductor Laser 214 Position detector 310A Probe

Claims (11)

  A plate-shaped cantilever supported by a substrate via a support part, the cantilever having a plurality of through holes that open in the surface and penetrate in the thickness direction of the cantilever.   The cantilever according to claim 1, wherein the opening of the through hole has a rectangular shape with a side of 3 μm to 6 μm.   The cantilever according to claim 1 or 2, wherein a probe is formed in an unopened portion where the through hole of the cantilever is not drilled.   The cantilever according to claim 1 or 2, wherein at least a part of an unopened portion where the through hole of the cantilever is not drilled is a reflective surface.   The cantilever according to any one of claims 1 to 3, wherein a strain resistance element is provided on a support portion of the cantilever.   The cantilever according to claim 1 or 2, wherein an unopened portion of the cantilever where the through hole is not formed is a part of the capacitance element.   The cantilever according to any one of claims 1 to 6, wherein the cantilever is immersed in a liquid or disposed in the atmosphere. The base material of the cantilever, silicon, SiN, and any one cantilever according to claim 1 to claim 7 which is formed of at least one of SiO _2. Surface, gold, platinum, SiO _2, insulator, organic, and any one cantilever according to claim 1 to claim 8 which is coated with at least one magnetic material. A cantilever according to any one of claims 1 to 9,
Detection means for detecting the amount of the substance attached to the cantilever;
Including biosensors. A cantilever according to claim 3,
A probe microscope in which the cantilever is arranged so that an atomic force acts between the probe and the surface of a sample.

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