JP2004301704A - Three-dimensional structure measuring device and three-dimensional structure measuring system - Google Patents

Abstract

An object of the present invention is to provide a three-dimensional structure measuring apparatus and a three-dimensional structure measuring system capable of specifying a physical structure of a three-dimensional minute object on a microchip.
A three-dimensional structure measuring apparatus includes a microchip 1 serving as a substrate, a rotor 4 provided on the microchip 1 and rotating a sample disposed thereon, and a rotor 4 provided on the microchip 1 to provide a sample. A radiation source 2 for irradiating an energy beam, a sensor array 3 disposed around the rotor 4 for detecting the energy beam passing through the sample, a mechanism for moving the rotor 4 in the direction of the rotation axis, a sample introduction hole 6, And a sample suction hole 7. As a mechanism for moving the rotor 4 in the rotation axis direction, an electrostatic motor, a deformation element, or the like can be used.
[Selection diagram] Fig. 1

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an apparatus for measuring a three-dimensional structure of a micro sample.
[0002]
[Prior art]
Recent advances in micromachine technology have made it possible to create minute three-dimensional structures in chips. As a result, microchips capable of performing various analyzes such as μ-TAS (Micro Total Analysis System) capable of performing chemical and biochemical analyzes are being realized. μ-TAS refers to an integrated chemical / biochemical analysis system in which functional units for liquid feeding, mixing, reaction, analysis, etc. are integrated on a chip of about several cm square, such as glass or silicon. 1).
[0003]
By the way, to measure and observe a minute three-dimensional structure, a microscope, a laser microscope, an electron microscope and the like have been used, but in order to measure the internal structure, in particular, X-ray CT, MRI, etc. Was used.
[0004]
[Non-patent document 1]
"Production Research," Vol. 52, No. 7, July 2000, P304-311
[0005]
[Problems to be solved by the invention]
These devices themselves are very large for minute samples, and it has been difficult to make the devices compact in accordance with the microchip. For this reason, in an analysis microchip such as μ-TAS, it is possible to specify the kind of chemical species and the like and measure the concentration in the chip, but to specify the physical structure of the minute substance contained therein. I couldn't do that. Also, a microchip for analyzing viruses and the like is preferably disposable, but it was difficult to reduce the cost as disposable.
[0006]
In view of the above problems, an object of the present invention is to provide a three-dimensional structure measuring apparatus and a three-dimensional structure measuring system capable of specifying the physical structure of a three-dimensional minute object on a microchip.
[0007]
[Means for Solving the Problems]
In order to achieve the above object, a first feature of the present invention is (a) a microchip serving as a substrate, (b) a rotor provided on the microchip and configured to rotate a sample placed thereon, (c) ) A radiation source provided on the microchip and irradiating the sample with energy rays, (d) a sensor array arranged around the rotor and detecting the energy rays passing through the sample, and (e) rotating the rotor. The gist is to provide a three-dimensional structure measuring apparatus including a mechanism for moving in the axial direction. Here, “energy rays” correspond to light rays, X-rays, radiation, infrared rays, isotopes, and the like.
[0008]
According to the three-dimensional structure measuring apparatus according to the first aspect of the present invention, the radiation source, the sensor array, and the like are arranged on the microchip, and the physical structure of the three-dimensional minute object can be specified by the microchip alone. .
[0009]
Further, the mechanism for moving the three-dimensional structure measuring apparatus according to the first feature in the rotation axis direction may be any one of an electrostatic motor, a deformation element, and a molecular motor. In particular, the use of a molecular motor makes it possible to rotate and move a nano-order sample.
[0010]
Further, the three-dimensional structure measuring apparatus according to the first feature may further include a sample inflow channel. The “sample inflow channel” includes, for example, a cover plate in which a sample introduction hole for introducing a sample, a sample channel, and a sample suction hole are formed. By disposing the cover plate on the microchip, a sample inflow channel is obtained.
[0011]
Further, the radiation source of the three-dimensional structure measuring apparatus according to the first feature may be provided in a part of the sensor array or may be fixed on the sample. When fixed on a sample, the three-dimensional structure measuring apparatus according to the first feature may further include a mechanism for fixing the radiation source on the sample. Fixing the radiation source on the sample is particularly preferable for improving the accuracy when measuring the three-dimensional structure of the sample on the order of nanometers. Micro tweezers or cantilevers may be used as a mechanism for fixing the radiation source.
[0012]
A second feature of the present invention is that (a) a microchip serving as a substrate, a rotor provided on the microchip and rotating a sample disposed thereon, and a rotor provided on the microchip to apply energy rays to the sample. (B) a three-dimensional structure measuring apparatus having a radiation source to be irradiated, a sensor array arranged to surround the rotor and detecting an energy ray passing through the sample, and a mechanism for moving the rotor in the direction of the rotation axis; An amplifier for amplifying the electric signal supplied from the sensor array, and (c) an electric circuit obtained from the amplifier is operated by an operation circuit. The gist of the present invention is to provide a three-dimensional structure measurement system including an information processing unit for obtaining a three-dimensional image.
[0013]
According to the three-dimensional structure measurement system according to the second feature, the three-dimensional structure of the sample can be specified from the two-dimensional cross-sectional image of the sample obtained on the microchip and the position information of the sample.
[0014]
BEST MODE FOR CARRYING OUT THE INVENTION
Next, first and second embodiments of the present invention will be described with reference to the drawings. In the following description of the drawings, the same or similar parts are denoted by the same or similar reference numerals. However, it should be noted that the drawings are schematic.
[0015]
(First Embodiment)
In the first embodiment, an apparatus for measuring a three-dimensional structure of a micro sample will be described. The sample to be measured here is a minute sample of the order of several to several hundred μm such as dust, red blood cells, white blood cells, bacteria, pollen and the like.
[0016]
The three-dimensional structure measuring apparatus according to the first embodiment, as shown in FIG. 1A, rotates a microchip 1 serving as a substrate and a sample provided on the microchip 1 and disposed on the top. A rotor 4, a radiation source 2 provided on the microchip 1 for irradiating the sample with energy rays, a sensor array 3 disposed around the rotor 4 and detecting energy rays passing through the sample, and a rotor 4. A mechanism for moving in the direction of the rotation axis, a sample introduction hole 6 and a sample suction hole 7 are provided.
[0017]
The microchip 1 has a size of about several cm square, and is made of a glass material such as quartz, silicon rubber such as polydimethylsiloxane (PDMS), or an acrylic resin such as polymethyl methacrylate (PMMA). Conceivable. Further, a glass epoxy resin, a fluorine resin such as polypropylene (PP) or polytetrafluoroethylene (PTFE), a semiconductor material such as silicon, a metal, or the like may be used.
[0018]
The rotor 4 includes a cylindrical rotating body and a rotating motor for rotating the rotating body, and the rotating motor rotates the sample placed on the rotating body. By using a mechanism such as an electrostatic motor as the rotating motor, it is possible to make the rotating body perform a rotating motion even if the rotating body itself is minute.
[0019]
As a mechanism for moving the rotor 4 in the direction of the rotation axis, for example, as shown in FIG. 1B, a stator 11 of an electrostatic motor having a thread 13 and a rotor 4 having a thread groove 12 are used. In addition, rotation and axial movement can be imposed on the rotor 4. With the recent micro-cutting technology, it is possible to cut a thread groove 12 of about 10 μm (refer to http://www.micro.ne.jp/materials/sokeizaila.html ). Accordingly, the rotor itself can be moved in the axial direction at the same time as the rotation of the rotor, and the three-dimensional structure of the sample can be measured.
[0020]
As a mechanism for moving the rotor 4 in the rotation axis direction, as shown in FIG. 2, a deformation element 14 such as a piezoelectric element, a bimorph, or a shape memory alloy is arranged below the rotor 4 to push up the rotor 4 in the axial direction. May be. In the medical CT, the sample is fixed and the radiation source and the sensor are rotated. However, in the three-dimensional structure measuring apparatus according to the first embodiment, since the radiation source and the sensor array are fixed, the deformation element Wiring of a sensor, a rotary motor, and the like when 14 is incorporated in a minute chip becomes easy.
[0021]
As the radiation source 2, various radiation sources such as light rays, X-rays, radiation, infrared rays, and isotopes can be used. Considering the scattering effect, it is desirable to use radiation (α rays or β rays). Although the radiation source 2 is provided in a part of the sensor array 3 in FIG. 1, the radiation source 2 may be provided at any position on the microchip 1.
[0022]
As shown in FIG. 3A, the sensor arrays 3 are arranged in a ring shape so as to surround the rotor 4. Each element is formed of a semiconductor PN junction including a P region 3a and an N ⁺ region 3b, for example, as shown in FIG. With this element, light rays and radiation can be detected in analog quantities. In the first embodiment, the sensor array 3 detects light rays and radiation emitted from the radiation source 2 and passing through the sample on the rotor 4. By analyzing this detection signal, a two-dimensional cross-sectional image of the sample can be obtained. Further, since the rotor 4 moves in the rotation axis direction, a three-dimensional image can be obtained by analyzing a two-dimensional cross-sectional image of the sample. Since the sensor element can be formed in a size of about 50 to 100 nm, for example, if the diameter of the rotor 4 is 1 mm, a sensor array 3 having about 30,000 to 60,000 elements is theoretically formed. And excellent resolution can be obtained.
[0023]
When the sample 5 is introduced onto the rotor 4, the sample 5 may be directly arranged by a mechanism such as a manipulator. However, as shown in FIG. 1 may be arranged. In the cover plate 10, a sample introduction hole 6, a sample flow path 8, and a sample suction hole 7 for introducing a sample are formed. After disposing the cover plate 10 on the microchip 1, the sample channel 8 is filled with fluid. When the sample 5 is placed in the sample introduction hole 6 and the fluid is sucked from the sample suction hole 7, the sample 5 is guided to the central rotor 4 according to the flow of the fluid. At this time, when the sample 5 is detected on the rotor 4, a configuration may be provided in which a mechanism for stopping the flow of the fluid is provided. The fluid may be liquid or air. For example, when the sample 5 is red blood cells, a liquid may be used, and when the sample 5 is dusty, air may be used. By providing the sample inflow channel on the microchip 1 as described above, the sample can be easily moved to a target location.
[0024]
According to the three-dimensional structure measuring apparatus according to the first embodiment, the radiation source 2, the sensor array 3, and the like are arranged on the microchip 1, and the three-dimensional structure measurement conventionally performed by X-ray CT or MRI is performed. , Within the microchip 1. Further, since the three-dimensional structure measuring mechanism such as the radiation source 2 and the sensor array 3 is arranged in the microchip 1, the microchip 1 can be disposable. Furthermore, since the three-dimensional structure measuring apparatus according to the first embodiment rotates on the rotor 4 side and does not rotate on the detection side such as the sensor array 3, it is easy to wire the sensor array 3. There is also.
[0025]
Next, a three-dimensional structure measuring system including a mechanism for processing information obtained by the above-described three-dimensional structure measuring apparatus will be described.
[0026]
As shown in FIG. 4, the three-dimensional structure measurement system according to the first embodiment includes a radiation source 2, a sensor array 3, a rotor 4, sample introduction units 6, 7, an amplifier 15, and an information processing unit 16. . The sample 5 is introduced from a sample introduction part including a sample introduction hole 6 and a sample suction hole 7 and arranged on the rotor 4. Energy rays such as light rays, radiation, and infrared rays emitted from the radiation source 2 are detected by the sensor array 3 after passing through the sample 5. The amplifier 15 amplifies the electric signal supplied from the sensor array 3 and detects a small electric signal. The elements of the sensor array 3 are connected to an amplifier 15 respectively. The information processing section 16 calculates an electric signal obtained from the amplifier 15 by an arithmetic circuit, and forms a two-dimensional cross-sectional image of the sample using a three-dimensional image reconstruction algorithm. The information processing unit 16 controls the rotation of the rotor 4 and obtains position information of the sample 5 from the rotor 4. Then, processing data 17 of a three-dimensional image of the sample is obtained from the obtained two-dimensional sectional image calculation result and the position information of the sample 5.
[0027]
In FIG. 4, the radiation source 2, the sensor array 3, the rotor 4, and the sample introduction units 6 and 7 are arranged on the microchip 1, and the amplifier 15 and the information processing unit 16 are arranged outside the microchip 1. The source 2, the sensor array 3, the rotor 4, the sample introduction units 6 and 7, the amplifier 15, and the information processing unit 16 may all be formed on the microchip 1.
[0028]
According to the three-dimensional structure measurement system according to the first embodiment, the three-dimensional structure of the sample can be specified from the two-dimensional cross-sectional image of the sample obtained on the microchip 1 and the position information of the sample 5.
[0029]
(Second embodiment)
As described in the first embodiment, an apparatus for measuring the three-dimensional structure of a micro-order micro sample can be manufactured by using a semiconductor forming technique such as MEMS. In order to measure the structure of a nano-order minute sample, further measures are required. In the second embodiment, an apparatus capable of measuring a three-dimensional structure of such a nano-order sample will be described.
[0030]
In order to handle a minute structure on the order of nanometers, it is effective to use a molecular motor 30 instead of the electrostatic motor described with reference to FIG. As shown in FIG. 5, the molecular motor 30 is a motor for rotating the flagella of bacteria, and has a diameter of about 1 to 10 nm and rotates with a difference in ion concentration ( http://bunshi3.bio.nagoya-u.ac. jp / bunshi4 / fla.html or,, see http://www.kyoto-np.co.jp/kp/sp ecial / yume / yume14.html). A helical filament 20 having a length several times as long as the body length is connected to the molecular motor 30 via a hook 21 as a screw to supply a driving force for rotation. The molecular motor 30 is formed in the periplasm 23 in a lipid bilayer or the like (outer membrane 22, inner membrane 24), and contains therein a motor protein complex (Mot complex) that converts the inflow energy of ions into energy, There is a switch complex that controls the direction of rotation of the motor.
[0031]
As shown in FIG. 6, the molecular motor 30 is connected to a shaft so as to face each other, and the sample 5 is fixed on the shaft. Then, the sample 5 can be rotated by rotating the molecular motor 30.
[0032]
On the other hand, the sample 5 is arranged on the rotor 4 as shown in FIG. In the second embodiment, an electron beam source 27 is arranged on a sample 5 such as a protein immersed in a liquid scintillator 26. The electron beam emitted from the electron beam source 27 passes through the sample 5 and is detected by the electron beam detecting optical sensor array 25. Here, a method for acquiring three-dimensional information of the sample 5 using an electron beam (β-ray) obtained by radiolabeling DNA as the electron beam source 27 will be described below. For example, assuming that a spherical protein molecule composed of 300 amino acids is used as the sample 5, the molecular weight is about 30,000 Da, the diameter is about 4.3 nm, and the density is about 1.49 g / cm ³ . When the range parameter of 10 KeV electrons is calculated as 2.819E-4 g / cm ^{2 with} carbon as a main component, the range is 1.9 μm (“Radiation” written by Fumio Yamazaki, Kyoritsu Shuppan Co., Ltd., 1977). When the energy of the electrons is further reduced, information can be collected from the material layer in the nano region as shown in FIG. The average inelastic collision distance of electrons in a solid is less than 5 nm near 50 eV ("Thin Film Handbook" Ohm Co., and "Elucidation of surface structure and surface coupling by photoelectron spectroscopy", Surface Science, CRL Brandle (see "Elucidation of surface structure and bonding by photoelectron spectroscopy", Surface Science 48, 99, 1975). However, considering that the protein is in the aqueous solution, it is important to arrange the electron beam detecting optical sensor array 25 as close to the protein as possible. Further, it is desirable that the position of the electron beam source 27 is also arranged in the sample 5. The size of the electron beam detecting optical sensor array 25 is on the order of μm in order to detect the electron beam source 27.
[0033]
Further, as shown in FIG. 9, it is possible to form a nano-order cantilever 31 on the microchip 1 by the development of the MEMS technology. The cantilever 31 fixes the electron beam source 27 on the sample 5. As a mechanism for fixing the electron beam source 27 on the sample 5, micro tweezers or the like may be used instead of the cantilever 31. By providing a mechanism for fixing the radiation source on the microchip 1, the radiation source can be easily fixed.
[0034]
Further, also in the second embodiment, it is possible to provide a three-dimensional structure measuring system as shown in FIG. 4, as in the first embodiment.
[0035]
According to the three-dimensional structure measuring apparatus according to the second embodiment, the electron beam source 27, the sensor array 25 for detecting an electron beam, and the like are arranged on the microchip 1 and conventionally performed by X-ray CT or MRI. The three-dimensional structure measurement can be performed in the microchip 1. Furthermore, since a mechanism such as the molecular motor 30 and the electron beam source 27 is provided, a three-dimensional structure of a nano-order minute sample can be specified.
[0036]
(Other embodiments)
Although the present invention has been described with the above embodiments, it should not be understood that the description and drawings forming part of this disclosure limit the present invention. From this disclosure, various alternative embodiments, examples, and operation techniques will be apparent to those skilled in the art.
[0037]
For example, in the embodiment of the present invention, dust, erythrocytes, leukocytes, proteins, and the like have been described as examples of the minute sample, but it is needless to say that the present invention is not limited thereto.
[0038]
In FIG. 3, the elements of the sensor array 3 are indicated by circles, and in FIG. 7, the elements of the electron beam detecting optical sensor array 25 are indicated by squares. Is not limited to this.
[0039]
In the first embodiment, the sensor array 3 has been described as being configured with a semiconductor PN junction, but is not limited thereto, and may be configured with a PIN junction photodiode or the like.
[0040]
As described above, the present invention naturally includes various embodiments and the like not described herein. Therefore, the technical scope of the present invention is determined only by the invention specifying matters according to the claims that are appropriate from the above description.
[0041]
【The invention's effect】
According to the present invention, it is possible to provide a three-dimensional structure measuring apparatus and a three-dimensional structure measuring system capable of specifying the physical structure of a three-dimensional minute object on a microchip.
[Brief description of the drawings]
FIG. 1A is a top view of a three-dimensional structure measuring apparatus according to a first embodiment.
FIG. 2B is a cross-sectional view of the three-dimensional structure measuring apparatus according to the first embodiment.
FIG. 2 is another cross-sectional view of the three-dimensional structure measuring apparatus according to the first embodiment.
FIG. 3A is a diagram illustrating a sensor array of the three-dimensional structure measuring apparatus according to the first embodiment as viewed from above. (B) is a sectional view of a sensor array of the three-dimensional structure measuring apparatus according to the first embodiment.
FIG. 4 is a configuration block diagram of a three-dimensional structure measurement system according to the first embodiment.
FIG. 5 is a schematic view of a molecular motor of the three-dimensional structure measuring apparatus according to the second embodiment.
FIG. 6 is a schematic diagram of a three-dimensional structure measuring apparatus provided with a molecular motor according to a second embodiment.
FIG. 7 is a top view of a rotor unit of the three-dimensional structure measuring apparatus according to the second embodiment.
FIG. 8 is a graph showing an average inelastic collision distance of electrons in a solid.
FIG. 9 is a schematic diagram in which an electron beam source is fixed to a sample by a cantilever.
[Explanation of symbols]
Reference Signs List 1 Chip 2 Source 3 Sensor array 3a P region 3b N ⁺ region 3c Oxide film 3d Wiring 3e N-type silicon substrate 4 Rotor 5 Sample 6 Sample introduction hole 7 Sample suction hole 8 Sample flow path 11 Stator 12 Thread groove 13 Thread 14 Deformation element 15 Amplifier 16 Information processing unit 17 Processing data such as image and position information 20 Fiber 21 Hook 22 Outer membrane 23 Periplasm 24 Inner membrane 25 Electron beam detecting optical sensor array 26 Liquid scintillator 27 Electron beam source 30 Molecular motor 31 Cantilever

Claims (7)

A microchip serving as a substrate,
A rotor that is provided on the microchip and rotates a sample disposed on the top,
A source provided on the microchip and irradiating the sample with energy rays,
A sensor array that is arranged around the rotor and detects energy rays that have passed through the sample,
A mechanism for moving the rotor in the direction of the rotation axis. The three-dimensional structure measuring apparatus according to claim 1, wherein the moving mechanism is any one of an electrostatic motor, a deformation element, and a molecular motor. The three-dimensional structure measuring apparatus according to claim 1, further comprising an inflow channel of the sample. The three-dimensional structure measuring apparatus according to claim 1, wherein the radiation source is provided in a part of the sensor array. The three-dimensional structure measuring apparatus according to any one of claims 1 to 3, wherein the radiation source is fixed on the sample, and further includes a mechanism for fixing the radiation source on the sample. The three-dimensional structure measuring apparatus according to claim 5, wherein the mechanism for fixing the radiation source is a micro-tweezer or a cantilever. A microchip serving as a substrate, a rotor provided on the microchip and rotating a sample disposed thereon, a source provided on the microchip and irradiating the sample with energy rays, and A sensor array that is arranged around the periphery and detects an energy ray that has passed through the sample, and a three-dimensional structure measuring apparatus that has a mechanism that moves the rotor in a rotation axis direction;
An amplifier for amplifying the electric signal supplied from the sensor array,
An information processing unit that calculates an electrical signal obtained from the amplifier by a calculation circuit, and obtains a three-dimensional image of the sample from the calculation result and positional information of the sample obtained from the rotor. Three-dimensional structure measurement system.

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