WO2010122829A1

WO2010122829A1 - Nmr probe

Info

Publication number: WO2010122829A1
Application number: PCT/JP2010/051710
Authority: WO
Inventors: 泰昭寺尾; 孝史三木
Original assignee: 株式会社神戸製鋼所
Priority date: 2009-04-20
Filing date: 2010-02-05
Publication date: 2010-10-28
Also published as: JP2010249761A

Abstract

Disclosed is an NMR probe which enables saving of the labor and time to fabricate an RF coil for each sample chip and improvement of the uniformity of the high-frequency magnetic field. The NMR probe (1) is provided with a first substrate (2) having a first RF coil (7) fabricated by microfabrication, a second substrate (3) fixedly disposed in parallel to the first coil substrate (2) and having a second RF coil (8) fabricated by microfabrication, and a sample substrate (4) disposed between the first substrate (2) and the second substrate (3) and having a sample space (4a) fabricated by microfabrication. A deuterated solvent is applied to the surface of the sample substrate (4) or the inner side surfaces of the coil substrate (9) (the surfaces defining a plug-in space (9a)).

Description

NMR probe

The present invention relates to an NMR probe having an RF coil and a sample space, and more particularly to an NMR probe suitable for measuring a small amount of sample.

FIG. 4 is a schematic diagram of an NMR apparatus for explaining an analysis method for a small amount of sample by nuclear magnetic resonance (NMR). As shown in FIG. 4, the sample 102 to be measured is placed in a strong static magnetic field B0 in the Z-axis direction created by the superconducting electromagnet 101 of the NMR apparatus 100, and the high-frequency magnetic field B1 is applied to the RF coil with respect to this sample 102. 103 is applied in the X-axis direction. The nuclear magnetization in the sample 102 is excited by the high-frequency magnetic field B1, and a signal emitted in the process of relaxation after excitation is measured. By analyzing the measured signal with hardware and a PC, information such as the three-dimensional structure and function of the sample is acquired.
The present invention relates to a probe used in this NMR analysis, that is, a probe having an RF coil and a sample space. This probe is used particularly for analyzing a small amount of a biological tissue sample whose spatial dimension is on the order of mm.

As this type of technology, for example, there is a technology described in Patent Document 1. The NMR probe constituent member described in Patent Literature 1 includes a sample chip in which an RF coil and a sample well are integrated, and a gradient magnetic field chip into which the sample chip is inserted.

Japanese Unexamined Patent Publication No. 2008-58315

In the NMR probe component described in Patent Document 1, since the RF coil and the sample well are integrated, it is necessary to prepare a sample chip in which an RF coil is formed for each sample, which is very troublesome. Take it. The RF coil of the NMR probe component is a planar coil that irradiates the sample with electromagnetic waves only from one direction on the X axis. However, in this embodiment, sufficient uniformity of the high-frequency magnetic field cannot be ensured. When the uniformity of the high frequency magnetic field is low, the nuclear magnetic resonance phenomenon in the sample varies, and the NMR signal is adversely affected.

The present invention has been made in view of such problems, and provides an NMR probe that can save the trouble of producing an RF coil for each sample chip and can improve the uniformity of a high-frequency magnetic field as compared with the conventional technique. The purpose is to do.

In order to achieve the above object, the present invention includes a first substrate including a first RF coil formed by a microfabrication technique, a second RF coil formed by a microfabrication technique, and parallel to the first substrate. A second substrate fixedly disposed on the substrate, a sample substrate disposed between the first substrate and the second substrate and having a sample space formed by a microfabrication technique, the first substrate, and the sample A magnetic susceptibility that is disposed in at least one of the gap between the substrate and the gap between the second substrate and the sample substrate, and is approximately equal to the magnetic susceptibility of the first substrate, the second substrate, and the sample substrate. An NMR probe comprising: a gap filling material having:

According to this configuration, the RF coil and the sample space are separated. As a result, when the sample is replaced, it is only necessary to replace the sample substrate on which the RF coil is not formed, and it is possible to omit the trouble of manufacturing the RF coil for each sample chip (substrate).

In addition, since RF coils are arranged on both sides of the sample space, the sample can be irradiated with electromagnetic waves from both directions on the X-axis, and the uniformity of the high-frequency magnetic field can be improved as compared with the conventional case. it can. Furthermore, by arranging a gap filling material having a magnetic susceptibility comparable to that of the substrate, the continuity of the high-frequency magnetic field is increased, and as a result, the uniformity of the high-frequency magnetic field can be further improved.

In the present invention, it is preferable that the first RF coil is formed on an inner surface and an outer surface of the first substrate, and the second RF coil is formed on an inner surface and an outer surface of the second substrate.

According to this configuration, each of the first RF coil and the second RF coil is a coil wound at least twice with a predetermined interval, and the strength of the high-frequency magnetic field in the sample space is increased and the uniformity is improved.

Furthermore, in the present invention, the coil inner diameter of the first RF coil formed on the inner surface of the first substrate is larger than the coil inner diameter of the first RF coil formed on the outer surface of the first substrate, and the second The coil inner diameter of the second RF coil formed on the inner surface of the substrate is preferably larger than the coil inner diameter of the second RF coil formed on the outer surface of the second substrate.

According to this configuration, the arrangement of the RF coil becomes a three-dimensional arrangement centering on the sample space, and the uniformity of the high-frequency magnetic field in the sample space can be further improved.

Furthermore, in the present invention, the gap filling material is preferably the same solvent as the sample solvent put in the sample space.

According to this configuration, the magnetic susceptibility of the sample solvent and the magnetic susceptibility of the gap filling material are the same, and as a result, the uniformity of the high-frequency magnetic field can be improved.

Furthermore, in the present invention, the gap filling material is preferably a deuterated solvent solution.

According to this configuration, the magnetic susceptibility of the gap filling material is approximately the same as that of the substrate. Thereby, the uniformity of a high frequency magnetic field can be improved.

Furthermore, in the present invention, a spacer substrate that is fixedly disposed between the first substrate and the second substrate and forms a space for inserting the sample substrate is provided, and the sample substrate has a corner that is continuous in the insertion / removal direction. Preferably, the portion is smoothly chamfered, and the inner surface of the spacer substrate is formed into a smooth curved surface that matches the corner of the sample substrate. According to this configuration, the sample substrate can be replaced (inserted / removed) more easily.

Furthermore, in the present invention, it is preferable that the magnetic susceptibility of the first RF coil and the second RF coil is approximately the same as the magnetic susceptibility of the first substrate, the second substrate, the spacer substrate, and the sample substrate. According to this configuration, the continuity of the high frequency magnetic field is increased, and the uniformity of the high frequency magnetic field can be further improved.

Furthermore, in the present invention, the magnetic susceptibility of the first substrate, the second substrate, the spacer substrate, and the sample substrate is approximately the same as the magnetic susceptibility of a solvent (sample solvent) put in the sample space of the sample substrate. It is preferable. According to this configuration, the continuity of the high frequency magnetic field is increased, and the uniformity of the high frequency magnetic field can be further improved.

It is a perspective view which shows the probe for NMR which concerns on one Embodiment of this invention. It is a figure of the coil board | substrate shown in FIG. 1, (a) is a top view, (b) is the B section enlarged view of (a), (c) is a front view, (d) is a side view. It is a figure of the sample board | substrate shown in FIG. 1, (a) is a top view, (b) is a front view, (c) is a side view. (A) is a schematic diagram of the NMR apparatus for demonstrating the analysis method of a small sample by a nuclear magnetic resonance method (NMR), (b) is the A section enlarged view of (a).

Hereinafter, modes for carrying out the present invention will be described with reference to the drawings.

(Configuration of NMR probe)
FIG. 1 is a perspective view showing an NMR probe 1 according to an embodiment of the present invention. As shown in FIG. 1, the NMR probe 1 includes a coil substrate 9 and a sample substrate 4 disposed so as to be inserted into the coil substrate 9. The shape of the NMR probe 1 is a rectangular parallelepiped. Here, as shown in the NMR apparatus 100 in which the sample 102 is set in FIG. 4, the NMR probe 1 is, for example, installed in the bore portion of the NMR apparatus 100 shown in FIG. 4. The NMR probe 1 is installed in a strong static magnetic field in the Z-axis direction created by the superconducting electromagnet 101 of the NMR apparatus 100, and a high-frequency magnetic field is applied in the X-axis direction by an RF coil. A high frequency oscillator (not shown) is connected to the RF coil. The shape of the NMR probe 1 is not limited to a rectangular parallelepiped, and may be, for example, a cube.

(Coil substrate)
FIG. 2 is a diagram of the coil substrate 9 constituting the NMR probe 1 shown in FIG. 2A is a top view, FIG. 2B is an enlarged view of a portion B of FIG. 2A, FIG. 2C is a front view, and FIG. 2D is a side view.

As shown in FIG. 2, the coil substrate 9 is a spacer substrate that is disposed between the first substrate 2, the second substrate 3, and both the

substrates

2 and 3 and forms a space 9 a for inserting the sample substrate 4. 5 and 6. The coil substrate 9 is formed in a rectangular parallelepiped shape and has an insertion space 9a. The insertion space 9a is substantially oval when viewed from above. The material of the first substrate 2, the second substrate 3, and the

spacer substrates

5 and 6 constituting the coil substrate 9 is glass. Examples of materials other than glass include quartz and silica. The shape of the coil substrate 9 is not limited to a rectangular parallelepiped, and may be a cube, for example.

(First substrate and second substrate)
The first substrate 2 is a rectangular plate having the first RF coil 7 (when the thickness is larger than the width and length, it is more appropriate to call the rectangular parallelepiped rather than the rectangular plate). The first RF coil 7 includes a coil portion 7 b formed on the inner surface of the first substrate 2 and a coil portion 7 a formed on the outer surface of the first substrate 2. That is, the 1st RF coil 7 is a coil of the form wound twice. Here, the inner diameter D1 of the coil portion 7b is larger than the inner diameter D2 of the coil portion 7a. The distance H2 from the center line CL of the coil substrate 9 to the coil part 7a is longer than the distance H1 from the center line CL to the coil part 7b. Moreover, the coil part 7a and the coil part 7b are formed so that it may become concentric. In addition, the shape of the 1st board | substrate 2 is not restricted to a rectangle (or rectangular parallelepiped), For example, a square (or cube) etc. may be sufficient. The same applies to the second substrate 3 described later.

The coil part 7a and the coil part 7b are formed in a groove formed by etching on the surface of the first substrate 2 by sputtering or plating. Examples of the material of the first RF coil 7 include copper, gold, silver, aluminum, titanium, and chromium. It is possible to adjust the magnetic susceptibility of the substrate and the solvent (sample solvent) by adjusting the type and thickness of these materials. In this embodiment, the coil portion 7b is not in contact with the insertion space 9a, but the coil portion 7b may be in contact with the insertion space 9a. In this case, when the sample substrate 4 is inserted into the coil substrate 9, the coil portion 7b is not damaged by the microfabrication technique (etching, sputtering, plating, etc.) as described above so as not to damage the surface of the sample substrate 4 or the coil portion 7b. Is preferably formed.

The inner diameter D2 of the coil portion 7a and the inner diameter D1 of the coil portion 7b are preferably about 10 μm to 10 mm (where D1> D2). The distance H2 and the distance H1 are preferably about 20 μm to 5 mm (where H2> H1). Further, the line width W2 of the coil part 7a and the coil part 7b is preferably about 50 μm to 150 μm. The thickness W1 of the coil portion 7a and the coil portion 7b is preferably about 5 μm to 50 μm.

In addition, although the cross-sectional shape of the coil part 7a and the coil part 7b is a quadrangle in the example shown by (a) of FIG. 2, etc., a semicircular shape etc. may be sufficient.

In the through hole (not shown) formed in the thickness direction of the first substrate 2, the same type of metal as that of the coil portion 7a and the coil portion 7b is embedded by sputtering or plating. Thereby, the coil part 7a and the coil part 7b are mutually connected.

The second substrate 3 is a rectangular plate having the second RF coil 8 and is configured in the same manner as the first substrate 2. Similarly, the second RF coil 8 is a coil having the same material and shape as the first RF coil 7. Here, the coil part 8a and the coil part 8b of the second RF coil 8 correspond to the coil part 7a and the coil part 7b of the first RF coil 7, respectively, and the diameter of the coil part 8a and the diameter of the coil part 7a are Are equal, and the diameter of the coil portion 8b is equal to the diameter of the coil portion 7b. The second RF coil 8 and the first RF coil 7 are formed so as to be concentric. That is, the first RF coil 7 and the second RF coil 8 are disposed symmetrically with respect to the center of the coil substrate 9.

In addition, the 1st RF coil 7 and the 2nd RF coil 8 are not restricted to the coil of the form wound twice, Other forms may be sufficient. For example, the 1st RF coil 7 and the 2nd RF coil 8 may be a coil of the form wound 1 time, and it is only a coil part (

coil part

7b, 8b) on each inner surface of the 1st board | substrate 2 and the 2nd board | substrate 3. ) May be formed. Further, three windings are performed so that the coil portion is formed inside each of the first substrate 2 and the second substrate 3 (between the coil portion 7a and the coil portion 7b and between the coil portion 8a and the coil portion 8b). The coil of the form described above may be used.

(Spacer substrate)
The

spacer substrates

5 and 6 are substrates for forming the insertion space 9 a for the sample substrate 4. The

inner side surfaces

5a, 6a of the

spacer substrates

5, 6 are smooth curved surfaces so as to be in surface contact with the smoothly chamfered (R-formed)

corner portions

4b, 4c (see FIG. 3) of the sample substrate 4. (R is formed). The

spacer substrates

5 and 6 are long members having a predetermined thickness.

The spacer substrate 5 and the spacer substrate 6 are sandwiched between the first substrate 2 and the second substrate 3 arranged in parallel with a predetermined interval. The coil substrate 9 is formed by bonding these substrates to each other using a chemical solution or heat.

(Sample substrate)
FIG. 3 is a diagram of the sample substrate 4 constituting the NMR probe 1 shown in FIG. 3A, 3B, and 3C are a top view, a front view, and a side view of the sample substrate 4, respectively.

As shown in FIG. 3, the sample substrate 4 has a rectangular parallelepiped shape as a whole, and has a sample space 4a in which a biological tissue sample to be analyzed is placed. The shape of the sample substrate 4 in a top view is substantially elliptical. The sample space 4a is a circular hole space in a top view and is formed by a fine processing technique. This fine processing technology includes electron lithography, nano-lithography technology such as short wavelength exposure and polymer processing, etching technology such as wet etching, dry etching, lift-off, thermal NIL, optical NIL, soft NIL, Examples thereof include nanoimprint lithography (NIL) techniques such as direct NIL, and flow path processing is performed by these techniques.

Further, the

corners

4b and 4c continuous in the direction of inserting and removing the sample substrate 4 are smoothly chamfered (R-formed). Further, the thickness of the sample substrate 4 is substantially equal to the thickness of the

spacer substrates

5 and 6. The sample substrate 4 is manufactured so as to fit in the insertion space 9 a formed in the central portion of the coil substrate 9. The diameter of the bottomed cylindrical sample space 4a is preferably about 10 μm to 1 mm, and the length is preferably about 1 mm to 20 mm. The shape of the sample substrate 4 is not limited to a rectangular parallelepiped shape, and may be a cubic shape, for example.

(Gap filling)
As described above, the

corners

4b and 4c continuous in the direction of inserting and removing the sample substrate 4 and the inner side surfaces 5a and 6a of the

spacer substrates

5 and 6 are chamfered, so that the replacement (insertion and removal) of the sample substrate 4 can be performed. It becomes easy. In the present embodiment, the dehydrated solvent liquid is applied to the surface of the sample substrate 4 or the inner side surface of the coil substrate 9 (the surface that defines the insertion space 9a). This dehydrated solvent liquid enters a slight gap (space) between the sample substrate 4 and the coil substrate 9 to fill the gap. The dehydrated solvent solution is compatible with the magnetic susceptibility of the coil substrate 9 (the first substrate 2, the second substrate 3, and the spacer substrates 5 and 6) and the sample substrate 4 (having the same magnetic susceptibility). By using this dehydrated solvent solution, the sample substrate can be easily replaced (inserted / removed), the continuity of the high-frequency magnetic field between the coil substrate 9 and the sample substrate 4 is increased, and the uniformity of the high-frequency magnetic field is improved. improves.

The deuterated solvent liquid is a gap filling material arranged in at least one of the slight gap between the first substrate 2 and the sample substrate 4 and the slight gap between the second substrate 3 and the sample substrate 4. It is.

Note that the gap filling material may be a thin sheet material, a thin film, or the like disposed in a slight gap between at least one of the first substrate 2 and the second substrate 3 and the sample substrate 4.

As described above, the gap filling material has a magnetic susceptibility similar to that of the coil substrate 9 (the first substrate 2, the second substrate 3, and the spacer substrates 5 and 6) and the sample substrate 4. This means that the difference between the two magnetic susceptibilities at the flat interface is less than 30% of the sample susceptibility, more preferably less than 10% of the sample susceptibility. This allows the inhomogeneity of the magnetic field that occurs with respect to the range of magnetic susceptibility between these substrates and the sample solvent and the range of magnetic susceptibility between these substrates and the RF coils (7, 8) to It can be compensated by a magnetic field correction coil.

The gap filling material is also used to reduce the jump of magnetic susceptibility between the substrates (between the coil substrate 9 and the sample substrate 4). Therefore, it is desirable that the difference in magnetic susceptibility between the substrates (9, 4), the RF coils (7, 8), the sample solvent, and the gap filling material is as small as possible. That is, as described above, the difference between the two magnetic susceptibilities at the flat boundary surface is preferably less than 30% of the sample susceptibility, and more preferably less than 10% of the sample susceptibility.

The deuterated solvent solution is a solvent usually used in solution NMR or the like, and is a solvent in which the proton (H1) portion is substituted with heavy water (D). Deuterated solvent solutions include deuterated chloroform (CDCl ₃ ), deuterated DMSO ((D ₃ C) ₂ S═O), deuterated methanol (CD ₃ OD), deuterated water (D ₂ O), tetrahydrofuran, acetonitrile, dichloromethane, benzene, and toluene. -N, N-dimethylformamide and the like can be mentioned. The dehydrated solvent solution is compatible with the magnetic susceptibility of the coil substrate 9 (the first substrate 2, the second substrate 3, and the spacer substrates 5 and 6) and the sample substrate 4 (having a similar magnetic susceptibility), It is desirable that the deuterated solvent be the same as the solvent (sample solvent) put in the sample space 4a of the sample substrate 4. In such a case, the uniformity of the high frequency magnetic field is further improved.

As a sample solvent to be placed in the sample space 4a, in addition to the above deuterated solvent liquid, cyclohexane, CCl ₄ , CS ₂ , dioxane, tetrahydrofuran, HMPA, 1,2,4-trichlorobenzene, vinyl chloride, nitrobenzene, CF ₂ BrCl, CFCl ₃ or the like can be used.

Also, the first RF coil 7 and the second RF coil 8 are magnetized so as to match the magnetic susceptibility of the coil substrate 9 (first substrate 2, second substrate 3, and spacer substrates 5 and 6) and the sample substrate 4. It is preferable to have a magnetic susceptibility comparable to that of the magnetic field. Furthermore, it is preferable that the magnetic susceptibility of the coil substrate 9 and the sample substrate 4 is compatible (similar to that of the solvent) contained in the sample space 4 a of the sample substrate 4. According to such a form, the continuity of the high frequency magnetic field is further increased, and the uniformity of the high frequency magnetic field can be further improved.

Specifically, the magnetic susceptibility of the solvent used as the gap filling material, the sample solvent put in the sample space 4a, and the substrate material (the material of the coil substrate 9 and the sample substrate 4) is as follows.
Water: Magnetic susceptibility -9.05 × 10-6 (used as gap filler and sample solvent)
Acetone: magnetic susceptibility -5.8 × 10-6 (used as gap filler, sample solvent)
Borosilicate glass: Magnetic susceptibility -11.0 × 10-6 (substrate material)
Quartz glass: Magnetic susceptibility -15.0 × 10-6 (substrate material)

(Use of NMR probe)
The sample to be analyzed is enclosed in the sample space 4a of the sample substrate 4, and the sample substrate 4 is inserted into the insertion space 9a of the coil substrate 9 and attached, whereby the NMR probe 1 in which the sample is enclosed is completed. . The NMR probe 1 is installed, for example, in a bore portion of the NMR apparatus 100 shown in FIG. A strong static magnetic field generated by the superconducting electromagnet 101 of the NMR apparatus 100 is applied to the NMR probe 1 in the Z-axis direction, and a high-frequency magnetic field is applied in the X-axis direction by the first RF coil 7 and the second RF coil 8. .

Here, in the NMR probe 1, since the RF coil is formed on the coil substrate 9 different from the sample substrate 4 having the sample space 4a, when replacing the sample, the sample substrate on which the RF coil is not formed. Only 4 needs to be replaced. That is, the labor for producing the RF coil for each sample chip (substrate) is saved. Moreover, since the first RF coil 7 and the second RF coil 8 are arranged so as to sandwich the sample space 4a, it is possible to irradiate the sample with electromagnetic waves from both directions on the X axis. As a result, the uniformity of the high-frequency magnetic field can be improved as compared with the conventional case, and the resolution of the NMR spectrum is improved.

In addition, the first RF coil 7 and the second RF coil 8 are coils (coiled by two turns) having coil portions formed on the inner and outer surfaces of the first substrate 2 and the second substrate 3, respectively. The strength of the high frequency magnetic field can be increased and the uniformity can be further improved.

Furthermore, by optimizing the shape and arrangement of the first RF coil 7 and the second RF coil 8 as D1> D2 and H2> H1, the uniformity of the high-frequency magnetic field in the sample space 4a is further improved.

Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, and various modifications can be made as long as they are described in the claims. This application is based on a Japanese patent application filed on April 20, 2009 (Japanese Patent Application No. 2009-101611), the contents of which are incorporated herein by reference.

1: NMR probe 2: first substrate 3: second substrate 4: sample substrate 4a: sample space 5, 6: spacer substrate 7: first RF coil 8: second RF coil

Claims

A first substrate comprising a first RF coil formed by microfabrication technology;
A second substrate having a second RF coil formed by a microfabrication technique and fixedly disposed in parallel to the first substrate;
A sample substrate disposed between the first substrate and the second substrate and having a sample space formed by a microfabrication technique;
Magnetization of the first substrate, the second substrate, and the sample substrate is disposed in at least one of the gap between the first substrate and the sample substrate and the gap between the second substrate and the sample substrate. An NMR probe comprising: a gap filling material having a magnetic susceptibility equivalent to a magnetic rate.
The NMR probe according to claim 1, wherein
The first RF coil is formed on an inner surface and an outer surface of the first substrate,
The NMR probe according to claim 1, wherein the second RF coil is formed on an inner surface and an outer surface of the second substrate.
The NMR probe according to claim 2, wherein
The coil inner diameter of the first RF coil formed on the inner surface of the first substrate is larger than the coil inner diameter of the first RF coil formed on the outer surface of the first substrate,
The NMR probe characterized in that the inner diameter of the second RF coil formed on the inner surface of the second substrate is larger than the inner diameter of the second RF coil formed on the outer surface of the second substrate. .
The NMR probe according to claim 1, wherein
The NMR probe according to claim 1, wherein the gap filling material is the same solvent as the sample solvent put in the sample space.
The NMR probe according to claim 2, wherein
The NMR probe according to claim 1, wherein the gap filling material is the same solvent as the sample solvent put in the sample space.
The NMR probe according to claim 3, wherein
The NMR probe according to claim 1, wherein the gap filling material is the same solvent as the sample solvent put in the sample space.
The NMR probe according to claim 1, wherein
The NMR probe, wherein the gap filling material is a deuterated solvent liquid.
The NMR probe according to claim 2, wherein
The NMR probe, wherein the gap filling material is a deuterated solvent liquid.
The NMR probe according to claim 3, wherein
The NMR probe, wherein the gap filling material is a deuterated solvent liquid.
The NMR probe according to claim 4 or 5, wherein
A spacer substrate that is fixedly disposed between the first substrate and the second substrate and that forms a space for inserting the sample substrate;
The sample substrate is smoothly chamfered at the corners continuous in the insertion / extraction direction,
The NMR probe according to claim 1, wherein an inner side surface of the spacer substrate is formed into a smooth curved surface matching the corner of the sample substrate.