Tool for generating shear flow

Abstract

To provide a tool for generating a share flow in a sample, in which a sample tube and an agitation bar are accurately positioned.SOLUTION: A shear flow generation tool 10 is a tool for generating a shear flow in a sample S while being inserted in a sample introduction hole 91 of a magnetic resonance device 90, and includes: a sample tube 1 for storing the sample S; an agitation bar 2 inserted in the sample tube 1 at a top end 2a, the agitation bar applying a shear force on the sample S by rotating around a longer axis; and a holding unit 3 for holding the sample tube 1 and the agitation bar 2.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to an apparatus for generating shear flow in a sample in a sample tube located within a magnetic resonance instrument. [Background technology]

[0002] Rheo-NMR (hereinafter referred to as Rheo-NMR) is a measurement technique that performs nuclear magnetic resonance while generating a shear flow in a sample containing the object to be measured.

[0003] Rheo-NMR measurements allow the investigation of samples under shear flow, and allow the identification and analysis of dynamic phenomena such as the shear rate, shear viscosity, and shear-thinning of the sample. In most previous Rheo-NMR measurements, samples such as polymers and foods were used as the measurement target. In recent years, Rheo-NMR measurements have been used to analyze the fluidity of blood in blood vessels, for example, in the field of biorheology, which is the academic field that studies the function and shape of living organisms from the mechanical aspects such as deformation and fluidity.

[0004] A rheology unit used in rheo-NMR measurement is described in the following Patent Document 1. The following Non-Patent Documents 1 and 2 describe a rheometer or Couette cell used in rheo-NMR measurement.

[0005] Also, as shown in Non-Patent Document 3, the re-NMR measurement can be performed using an existing NMR device. The sample to be measured is placed in a sample tube called an NMR tube. The sample tube is attached to a rotating member called a spinner and placed at a predetermined measurement position of the NMR device. A stirring rod thinner than the sample tube is inserted into the sample introduction hole from the upper open end of the sample introduction hole provided vertically in the NMR device, and the tip of the stirring rod is inserted into the sample in the sample tube. Many existing NMR devices are provided with a spinner and a driving mechanism that rotates the spinner. By using this driving mechanism provided on the NMR device side to rotate the spinner and the sample tube relative to the stirring rod, a shear flow is generated in the sample. By performing NMR measurement under such an environment, the re-NMR measurement of the sample is performed. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2016-529517 [Non-patent literature]

[0007] [Non-Patent Document 1] Paul T. Callaghan and Elmar Fischer, “Rheo-NMR: a New Application for NMR Microscopy and NMR Spectroscopy”, [online], 2001, Bruker Corporation, [Retrieved March 29, 2019], Internet <URL:https: / / www.bruker.com / fileadmin / user_upload / 8-PDF-Docs / MagneticResonance / NMR / Rheo-NMR_Report2001.pdf> [Non-Patent Document 2] Patrick JB Edwards, Motoko Kakubayashi, Robin Dykstra, Steven M. Pascal, and Martin AK Williams, “Rheo-NMR Studies of an Enzymatic Reaction: Evidence of a Shear-Stable Macromolecular System”, Biophysical Journal, Volume 98, Issue 9, 5 May 2010, Pages 1986-1994. [Non-Patent Document 3] Daichi Morimoto, Erik Walinda, Naoto Iwakawa, Mayu Nishizawa, Yasushi Kawata, Akihiko Yamamoto, Masahiro Shirakawa, Ulrich Scheler, and Kenji Sugase, “High-Sensitivity Rheo-NMR Spectroscopy for Protein Studies”, Analytical Chemistry, Volume 89, Issue 14, June 30, 2017, Pages 7286-7290. Summary of the Invention [Problem to be solved by the invention]

[0008] High-resolution NMR instruments for sample analysis use superconducting magnets to improve measurement sensitivity. In order to generate high magnetic fields of several tens of teslas or more, a coolant such as liquid helium or liquid nitrogen is placed around the superconducting magnet. As a result, NMR instruments using superconducting magnets are large instruments with a total height of over 2 meters. The position of the sample tube cannot be seen from outside the NMR instrument.

[0009] On the other hand, the sample tube in which the sample is placed and rotated together with the spinner is cylindrical with an outer diameter of about 5 mm, and the inner diameter into which the tip of the stirring rod is inserted is also about 4 mm. The stirring rod is even thinner than the sample tube, with an outer diameter of about 3 mm.

[0010] Thus, the gap between the inner diameter of the sample tube and the outer diameter of the stirring rod is very narrow, about 0.5 mm. The vertical position in the NMR device where the sample tube is placed is also several meters away from the open end of the sample introduction hole extending in the vertical direction. It was difficult to insert the tip of the stirring rod from outside the NMR device through the open end of the sample introduction hole into the sample tube placed at the measurement position in the NMR device with an error of within about 0.5 mm from a position several meters away. In this case, it is necessary not only to insert the tip of the stirring rod into the sample tube, but also to accurately align the center of the diameter of the sample tube with the center of the diameter of the stirring rod, which makes it even more difficult. In Rheo-NMR measurements, it is required to reliably perform accurate alignment of the sample tube and the stirring rod.

[0011] In addition, in some NMR instrument models, the sample introduction hole has a reverse taper shape, where the diameter increases slightly from the upper open end to the lower end. When the sample introduction hole has such a reverse taper shape, it becomes even more difficult to accurately align the center of the diameter of the sample tube with the center of the diameter of the stirring rod at the position where the sample tube is placed.

[0012] It is an object of the present invention to provide an apparatus for generating shear flow in a sample, the apparatus having precisely aligned sample tubes and stir bars. [Means for solving the problem]

[0013] In order to achieve the above object, the present invention includes, for example, the following aspects. (Section 1) An apparatus for generating a shear flow in a sample when inserted into a sample introduction hole of a magnetic resonance apparatus, comprising: A sample tube for storing a sample; a stirring rod whose tip is inserted into the sample tube and which rotates about its longitudinal axis to apply a shear force to the sample; a holder for holding both the sample tube and the stirring rod; An apparatus comprising: (Section 2) Item 2. The apparatus described in item 1, wherein the holding portion holds the sample tube and the stirring rod coaxially. (Section 3) The holding portion is A cylindrical stirring rod holder that holds the rear end side of the stirring rod; a cylindrical sample tube holder for holding the sample tube; a cylindrical housing for holding the stirring rod holder and the sample tube holder; The device according to item 1 or 2, comprising: (Section 4) The housing has a first cavity and a second cavity communicating with the first cavity along a longitudinal direction, the stirring rod holder fits into the second cavity in the housing; Item 4. The device described in item 3, wherein the sample tube holder has a rear end that fits into the first cavity in the housing. (Section 5) the stirring rod holder rotatably holds the rear end side of the stirring rod in a state where the rear end side of the stirring rod is inserted therein; Item 5. The device according to item 3 or 4, wherein the sample tube holder holds the sample tube inserted therein. (Section 6) The stirring rod holder has a third cavity at the front end side that accommodates the rear end side of the sample tube, and a fourth cavity at the rear end side that accommodates a bearing that rotatably holds the stirring rod. (Section 7) A main shaft connected to the stirring rod and transmitting rotational power around a long axis to the stirring rod; a cylindrical spindle housing portion that houses the spindle; Further equipped with 7. The device according to any one of items 1 to 6, wherein the spindle housing portion has a circumferential groove on its side, and a ring-shaped elastic member is disposed in the groove and protrudes from the groove and elastically deforms to fit the opening end of the sample introduction hole. (Section 8) Item 8. The device according to item 7, wherein the main shaft housing has a hole extending along the longitudinal axis on a side surface thereof. Effect of the Invention

[0014] SUMMARY OF THE PRESENT DISCLOSURE According to the present invention, it is possible to provide an apparatus for generating shear flow in a sample, in which the sample tube and the stirring rod are precisely aligned. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram of a shear flow generating device according to one embodiment. [Diagram 2] 1 is a schematic cross-sectional view for explaining a state in which a shear flow generating device according to one embodiment is used. FIG. [Diagram 3] FIG. 3 is a partial enlarged view of the lower area of ​​the two areas enclosed by dashed lines in FIG. 2. [Figure 4] FIG. 3 is a partial enlarged view of the upper region of the two regions surrounded by dashed lines in FIG. 2, and is a schematic view for explaining a state in which a spindle housing part according to one embodiment is inserted into a sample introduction hole of a magnetic resonance apparatus. [Diagram 5] FIG. 4 is a cross-sectional view of a retainer according to one embodiment. [Figure 6] FIG. 2 is a cross-sectional view of a stirring rod holder according to one embodiment. [Figure 7] FIG. 2 is a cross-sectional view of a sample tube holder according to an embodiment. [Figure 8] FIG. 2 is a cross-sectional view of a spindle, a spindle housing, and a tip position adjustment mechanism according to one embodiment in an assembled state. [Figure 9] FIG. 2 is a cross-sectional view of a spindle housing according to one embodiment. [Figure 10] FIG. 13 is a cross-sectional view of a tip position adjustment mechanism according to one embodiment. [Figure 11] 13A and 13B are diagrams illustrating a cylindrical portion that configures the tip position adjustment mechanism. [Figure 12] 13 is a diagram showing a handle used to adjust the position of a cylindrical portion. FIG. [Figure 13] FIG. 2 is a diagram illustrating an electric motor mounting portion and an electric motor according to an embodiment. [Figure 14] 5 is a schematic cross-sectional view for explaining a state in which the electric motor mounting portion and the electric motor are used. FIG. [Figure 15] 4 shows test results regarding performance evaluation of Example 1. [Figure 16] 4 shows test results regarding performance evaluation of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Hereinafter, an embodiment of the present invention will be described in detail with reference to the accompanying drawings. In the following description and drawings, the same reference numerals denote the same or similar components, and therefore, redundant description of the same or similar components will be omitted.

[0017] Fig. 1 is a schematic diagram showing a shear flow generating instrument according to an embodiment. Fig. 2 is a schematic cross-sectional view for explaining a state in which the shear flow generating instrument according to an embodiment is used. Fig. 3 is a partial enlarged view of a lower region of two regions enclosed by a dashed line in Fig. 2. Fig. 4 is a partial enlarged view of an upper region of two regions enclosed by a dashed line in Fig. 2, and is a schematic diagram for explaining a state in which a spindle housing part according to an embodiment is inserted into a sample introduction hole of a magnetic resonance apparatus.

[0018] As shown in Figs. 1 to 3, an instrument 10 for generating a shear flow in a sample according to one embodiment of the present invention (hereinafter, referred to as the shear flow generating instrument 10 or simply the instrument 10) is an instrument for generating a shear flow in a sample S while being inserted into a sample introduction hole 91 of a magnetic resonance apparatus 90. As shown in a partially enlarged view of Fig. 3, the shear flow generating instrument 10 includes a sample tube 1 for storing the sample S, a stirring rod 2 whose tip is inserted into the sample tube 1 and rotates around its long axis to apply a shear force to the sample S, and a holder 3 for holding both the sample tube 1 and the stirring rod 2. In the following description, the long axis direction of the instrument 10 is the Z axis direction shown in the figure. For each part constituting the instrument 10, the tip side is the Z1 direction side shown in the figure, and the rear end side is the Z2 direction side.

[0019] For each part constituting the shear flow generating device 10 described below, it is preferable to use a material that is not paramagnetic, and it is even more preferable to use a non-magnetic material (e.g., a material with a relative permeability approximately close to 1) that does not adversely affect the inhomogeneity of the magnetic field B0 generated by the superconducting magnet.

[0020] The sample tube 1 is a cylindrical member with a bottom that stores the sample S, and is also called an NMR tube. The stirring rod 2 is a rod-shaped member, and a tip 2a is inserted into the sample S in the sample tube 1, and the stirring rod 2 applies a shear flow to the sample S to be measured by rotating it about the long axis. The sample tube 1 and the stirring rod 2 are made of, for example, glass or resin. The sample tube 1 and the stirring rod 2 may be either hydrophilic or hydrophobic, but are preferably hydrophobic. In view of the relationship between magnetic permeability and hydrophobicity, the sample tube 1 and the stirring rod 2 are preferably made of glass, such as borosilicate glass, and more preferably made of PYREX GLASS (registered trademark).

[0021] The holding unit 3 holds both the sample tube 1 and the stirring rod 2. Preferably, the holding unit 3 holds the sample tube 1 and the stirring rod 2 coaxially. That is, the holding unit 3 holds the cylindrical sample tube 1 and the rod-shaped stirring rod 2 so that their long axes are roughly aligned. The detailed structure of the holding unit 3 will be described later with reference to FIG. 5. Each part constituting the holding unit 3 is formed from a resin such as polyoxymethylene (POM) or a metal such as aluminum.

[0022] In this embodiment, the shear flow generating instrument 10 further includes a spindle 4, a spindle housing 5, a tip position adjustment mechanism 6, and an electric motor 7 that applies rotational power to the spindle 4. The electric motor 7 is attached to an electric motor mounting part 8, which will be described later, and the electric motor mounting part 8 is attached to an open end flange 94 of the magnetic resonance apparatus 90.

[0023] The main shaft 4 is, for example, a rod-shaped or cylindrical member that is connected to the rear end 2b of the stirring rod 2 and transmits rotational power about the long axis to the stirring rod 2. The holding part 3 is connected to a main shaft housing part 5 that rotatably houses the main shaft 4, and is connected to a tip position adjustment mechanism 6 via the main shaft housing part 5.

[0024] Please refer to Figures 2 to 4. A superconducting magnet (not shown) for generating a magnetic field B0 and a probe (not shown) for signal measurement are provided around a predetermined measurement position of the magnetic resonance apparatus 90. In this embodiment, the direction of the long axis of the sample introduction hole 91 is the vertical direction, which is along the magnetic field B0. The magnetic field B0 is a magnetic field for defining the quantization axis of the magnetic moment of a substance contained in the sample S, and is a high magnetic field of, for example, several tens of tesla or more.

[0025] An open end flange 94 is provided at the upper end 91a of the sample introduction hole 91. The shear flow generating device 10 is inserted into the sample introduction hole 91 from the tip of the holder 3 that holds both the sample tube 1 and the stirring rod 2, through the open end flange 94. The tip position adjustment mechanism 6 is engaged with the upper end 91a of the open end flange 94, so that the tips 1a, 2a of the sample tube 1 and the stirring rod 2 are positioned at predetermined measurement positions in the magnetic resonance spectrometer 90.

[0026] Illustratively, the dimension of the shear flow generating device 10 from the tip of the sample tube 1 to the rear end of the tip position adjustment mechanism 6 is about 1 m to 2 m. The outer diameter of the stirring rod 2 is about 3 mm, and the inner diameter of the sample tube 1 is about 4 mm. The outer diameter of the sample tube 1 is about 5 mm. This creates a gap of about 1 mm in the radial direction (direction perpendicular to the Z axis) between the sample tube 1 and the stirring rod 2. The sample S is stored in the gap of about 1 mm, and shear force is applied to it. The rotation speed of the main shaft 4, which is rotated by the electric motor 7, is about 0.0167 Hz to about 66.7 Hz (about 1 rpm to about 4,000 rpm). In this embodiment, the sample tube 1 has a solid portion 1c filled with contents at the tip 1a of the hollow portion. Illustratively, the length of the solid portion 1c along the long axis (Z axis) direction of the sample tube 1 is about 8 mm, and the distance between the solid portion 1c of the sample tube 1 and the tip 2a of the stirring rod 2 is about 1 mm. In this embodiment, the sample S can also enter a gap of about 1 mm occurring in the axial direction between the sample tube 1 and the stirring rod 2.

[0027] The accurate positional relationship between the sample tube 1 and the stirring rod 2 is held by the holder 3 before they are inserted into the sample introduction hole 91 of the magnetic resonance instrument 90. The rotational power of the stirring rod 2 for applying a shear force to the sample S is transmitted to the stirring rod 2 from an electric motor 7 arranged outside the magnetic resonance instrument 90 via the main shaft 4. This makes it possible to place the sample tube 1 and the stirring rod 2 in a precisely aligned state at a predetermined measurement position of the magnetic resonance instrument 90, and makes it possible to apply a shear force to the sample S stored in the sample tube 1 in such a precisely aligned state within the magnetic resonance instrument 90.

[0028] Furthermore, as will be described later, a circumferential groove can be provided on the side surface of the spindle housing part 5. In the groove, a ring-shaped elastic member 56 can be placed, which protrudes from the groove and elastically deforms to have an outer diameter that fits the open end 91a of the sample introduction hole 91. The ring-shaped elastic member 56 can further reduce radial positional deviation of the spindle housing part 5 within the sample introduction hole 91 when the shear flow generating instrument 10 is inserted into the sample introduction hole 91.

[0029] In addition, a magnetic resonance apparatus 90 for performing rheo-NMR measurements is normally equipped with a rotating member called a spinner and a drive mechanism for rotating the spinner. However, when performing rheo-NMR measurements using a shear flow generating device 10, these spinners and drive mechanisms are not used.

[0030] 5 is a cross-sectional view of the holding part according to one embodiment. (A) is an exploded cross-sectional view showing the engagement between the stirring rod holder 31 and the housing 33, and (B) is an exploded view showing the engagement between the sample tube holder 32 and the housing 33. (C) is a cross-sectional view of each part constituting the holding part 3.

[0031] The holding unit 3 according to one embodiment includes a stirring rod holder 31, a sample tube holder 32, and a housing 33 as structures for holding both the sample tube 1 and the stirring rod 2.

[0032] The stirring rod holder 31 is a cylindrical member that holds the rear end 2b of the stirring rod 2. The sample tube holder 32 is a cylindrical member that holds the sample tube 1. The housing 33 is a cylindrical member that holds the stirring rod holder 31 and the sample tube holder 32. The housing 33 has a first cavity 331 and a second cavity 332 that communicates with the first cavity 331 along the longitudinal direction. The stirring rod holder 31 fits into the second cavity 332 located on the rear end side of the first cavity 331, and the rear end 32b side of the sample tube holder 32 fits into the first cavity 331 located on the tip side of the second cavity 332. In this way, the stirring rod holder 31 is fixed to the housing 33. The stirring rod holder 31 and the housing 33 may be fixed with a screw (not shown). The rear end 1b side of the sample tube 1 is housed in the third cavity 311 of the stirring rod holder 31. Note that "fitted" also includes a state in which they are fitted together using a male screw and a female screw (screwed engagement).

[0033] More specifically, the first cavity 331 of the housing 33 is a cavity with a circular cross section having a diameter larger than the diameter of the stirring rod holder 31 and slightly larger than the diameter of the rear end 32b of the sample tube holder 32. The second cavity 332 of the housing 33 is a cavity with a circular cross section having a diameter slightly larger than the diameter of the stirring rod holder 31 and smaller than the diameter of the rear end 32b of the sample tube holder 32. Therefore, when the male thread of the rear end 32b of the sample tube holder 32 is fitted (screwed) into the female thread of the first cavity 331 with the cylindrical stirring rod holder 31 placed in the second cavity 332, the tip 31a of the stirring rod holder 31 comes into contact with the rear end 32b of the sample tube holder 32, thereby restricting the movement of the stirring rod holder 31 toward the tip side. Furthermore, rear end 31b of the stirring rod holder 31 abuts against a step at the rear end of the second cavity 332, restricting movement of the stirring rod holder 31 toward the rear end. Thus, the stirring rod holder 31 is fixed to the housing 33. Furthermore, the sample tube holder 32 is fixed to the housing 33 by screwing. As a result, with the sample tube 1 and the stirring rod 2 aligned, the stirring rod holder 31, the sample tube holder 32 and the housing 33 are fixed together.

[0034] The housing 33 has an outer peripheral surface 333 at the rear end side which is male threaded and is screwed into the inner peripheral surface 51 of the hollow portion at the tip end side of the spindle housing 5. Preferably, the housing 33 has a hole 334 extending along the long axis direction on the side surface at the rear end side. The hole 334 is connected to the hollow portion of the cylindrical housing 33. In this embodiment, the rear end of the protective tube 21 described later and the spindle 4 are connected, for example, by a cylindrical coupler 48 (see FIG. 3, made of rubber, for example). When the rear end of the protective tube 21 and the spindle 4 are connected by the coupler 48, it is possible to visually check the inside of the housing 33 through the hole 334. The coupler 48 can be brought into the hollow portion of the housing 33 and connected to the spindle 4 when the stirring rod holder 31 is attached to the housing 33 in advance.

[0035] 6 is a cross-sectional view of a stirring bar holder according to one embodiment, in which (A) to (C) are exploded views or exploded cross-sectional views sequentially showing the assembly of each part constituting the stirring bar holder, and (D) is a cross-sectional view of the state in which each part constituting the stirring bar holder is assembled.

[0036] The stirring rod holder 31 rotatably holds the stirring rod 2 with the rear end 2b of the stirring rod 2 inserted therein. The stirring rod holder 31 is a cylindrical member, and has a third cavity 311 on the front end 31a side for accommodating the rear end 1b of the sample tube 1, and a fourth cavity 312 on the rear end 31b side for accommodating the rotation holder 22 that rotatably holds the stirring rod 2.

[0037] As shown in (A) to (D), the stirring rod 2 is connected such that the rear end 2b fits into the hollow part of, for example, a cylindrical protective tube 21 (made of, for example, aluminum). The stirring rod 2 and the protective tube 21 can be connected in various connection modes, for example, by bonding with an adhesive, by adhesion with a sticky substance, or by crimping the protective tube 21 through plastic deformation. The stirring rod 2 is further inserted into a plurality of bearings 221 arranged via a cylindrical spacer 222. The plurality of bearings 221 and the spacer 222 constitute the rotation holder 22, which holds the stirring rod 2 rotatably. The rotation holder 22 is housed in the fourth cavity 312 of the stirring rod holder 31.

[0038] An annular lid 313 and a bearing 314 are attached to the rear end 31b of the stirring rod holder 31. The rear end 2b of the stirring rod 2, i.e., the rear end of the protective tube 21, is inserted through the lid 313 and the bearing 314. The bearings 221, 314 are formed using a non-magnetic material such as resin, glass, ceramic, etc. Preferably, the bearings 221, 314 are radial deep groove ball bearings made of a resin housing and glass or ceramic balls.

[0039] 7 is a cross-sectional view of a sample tube holder according to one embodiment, where (A) is an exploded view of the components constituting the sample tube holder, and (B) is a half-sectional view of the components assembled together.

[0040] The sample tube holder 32 holds the sample tube 1 inserted therein. As shown in (A) and (B), the sample tube holder 32 is a generally cylindrical member, and the sample tube 1 is inserted into the hollow portion of the sample tube holder 32. The sample tube 1 is further inserted into the hollow portion of the annular elastic member 321 and the cylindrical fixing screw 322. In this embodiment, the inner peripheral surface of the hollow portion at the rear end 32b of the sample tube holder 32 is a female thread, and the outer peripheral surface 322a at the tip side of the fixing screw 322 is a male thread. When the tip side of the fixing screw 322 is screwed into the hollow portion at the rear end 32b of the sample tube holder 32, the annular elastic member 321 is crushed and deformed, and the elastic member 321 holds the sample tube 1. The annular elastic member 321 is, for example, an O-ring made of Viton (registered trademark).

[0041] The process of assembling the sample tube 1 and the stirring rod 2 to the housing 33 will be described. As described below, both the sample tube 1 and the stirring rod 2 are fixed to the housing 33. As a result, the positional relationship between the sample tube 1 and the stirring rod 2 is determined with reference to the housing 33 before the holder 3 is inserted into the sample introduction hole 91 of the magnetic resonance spectrometer 90.

[0042] First, the assembly of the stirring rod 2 and the housing 33 will be described. As shown in order in FIG. 6 (A) to (D), the stirring rod holder 31 that supports the stirring rod 2 rotatably around its long axis is assembled. The rotation holder 22 that rotatably holds the stirring rod 2 is assembled, and the positional relationship between the stirring rod 2 and the rotation holder 22 is fixed. The assembled rotation holder 22 is housed in the fourth cavity 312 of the stirring rod holder 31, and the positional relationship between the rotation holder 22 and the stirring rod holder 31 is fixed. Then, as shown in FIG. 5 (A) and (C), the stirring rod holder 31 with the assembled rotation holder 22 is inserted and fitted into the second cavity 332 in the housing 33, and the positional relationship between the stirring rod holder 31 and the housing 33 is fixed. By fixing the stirring rod holder 31 inside the housing 33 in this way, the stirring rod 2 is fixed to the housing 33, and the positional relationship between the stirring rod 2 and the housing 33 is fixed.

[0043] Next, the assembly of the sample tube 1 to the housing 33 will be described. As shown in Fig. 7(A) and (B) in order, the sample tube holder 32, which fixes the sample tube 1 in an inserted state, is assembled to fix the positional relationship between the sample tube 1 and the sample tube holder 32. Then, as shown in Fig. 5(A) to (C), with the stirring rod holder 31 first fixed inside the housing 33, the rear end 32b of the sample tube holder 32 is inserted and fitted into the first cavity 331 in the housing 33, thereby fixing the positional relationship between the sample tube holder 32 and the housing 33. By attaching the sample tube holder 32 to the housing 33 in this way, the sample tube 1 is fixed to the housing 33, and the positional relationship between the sample tube 1 and the housing 33 is fixed.

[0044] As described above, both the sample tube 1 and the stirring rod 2 are fixed to the housing 33, and the positional relationship between the sample tube 1 and the stirring rod 2 is defined with the housing 33 as a reference. In this manner, according to the holder 3 of the shear flow generating instrument 10 according to one embodiment, the positional relationship between the sample tube 1 and the stirring rod 2 can be defined with the housing 33 as a reference, and the accurate positional relationship between the sample tube 1 and the stirring rod 2 can be defined and fixed before the instrument 10 is inserted into the sample introduction hole 91 of the magnetic resonance instrument 90.

[0045] Fig. 8 is a cross-sectional view of the spindle, the spindle receiving section, and the tip position adjustment mechanism according to one embodiment in an assembled state. Fig. 9 is a half-sectional view of the spindle receiving section according to one embodiment.

[0046] The spindle receiving portion 5 is a cylindrical member that rotatably receives the spindle 4. An inner peripheral surface 51 of the hollow portion on the front end side is a female thread, and an outer peripheral surface 52 on the rear end side is a male thread. The inner peripheral surface 51 of the hollow portion screws into an outer peripheral surface 333 on the rear end side of the housing 33 or an outer peripheral surface 52 on the rear end side of another spindle receiving portion 5, both of which are male threads.

[0047] Preferably, the spindle housing 5 has a hole 53 extending along the long axis direction provided on its side. The hole 53 is connected to the hollow portion of the cylindrical spindle housing 5. In general, high-precision machining can be performed using a machine tool for precision small-scale machining. In this embodiment, by providing the hole 53 on the side of the spindle housing 5, the length of the hollow portion (through hole) of the spindle housing 5 cut out in one machining operation is shortened and divided into small portions. This allows the hollow portion of the spindle housing 5 to be machined with high precision using a machine tool for precision small-scale machining.

[0048] Preferably, a bearing 54 is disposed in the hollow portion of the spindle accommodating portion 5. The spindle 4 is inserted through the bearing 54. The bearing 54 is formed using a non-magnetic material similar to the bearings 221 and 314. Preferably, the bearing 54 is a radial deep groove ball bearing similar to the bearings 221 and 314.

[0049] Preferably, a plurality of annular elastic members 56 are disposed in the spindle housing 5 via a plurality of annular spacers 55. Each annular spacer 55 has a circumferential groove on its side, and the annular elastic member 56 is disposed in the groove. The annular elastic member 56 is, for example, an O-ring made of Viton (registered trademark). The annular elastic member 56 has an outer diameter that fits the opening end 91a of the sample introduction hole 91 by protruding from the groove of the annular spacer 55 and elastically deforming. More preferably, the annular elastic member 56 has an outer diameter that fits both the diameter of the upper opening end 91a and the diameter of the lower end 91b side of the sample introduction hole 91 that has a reverse tapered shape in which the diameter increases slightly from the upper opening end 91a toward the lower end 91b.

[0050] Fig. 10 is a half-sectional view of a tip position adjustment mechanism according to one embodiment. Fig. 11 is a diagram showing a cylindrical part constituting the tip position adjustment mechanism. (A) is a half-sectional side view, and (B) is a top view.

[0051] The tip position adjustment mechanism 6 adjusts the position of the holder 3 within the sample introduction hole 91, at a position along the longitudinal direction of the sample introduction hole 91. Preferably, the holder 3 is disposed so that the tapered portion 32c of the sample tube holder 32 included in the holder 3 fits into a predetermined position within the sample introduction hole 91 (for example, a tapered cavity provided in a spinner, not shown). The tip position adjustment mechanism 6 includes an annular base 61, a cylindrical portion 62, and a fixing ring 63.

[0052] The annular base 61 and the fixing ring 63 are both annular members, and in this embodiment, the inner peripheral surfaces of both are female-threaded. The fixing ring 63 functions as a so-called double nut, and prevents the tubular portion 62 from loosening.

[0053] The cylindrical portion 62 is a cylindrical member. An inner peripheral surface 621 of the hollow portion on the tip side is a female thread, and an outer peripheral surface 622 on the rear end side is a male thread. The inner peripheral surface 621 of the hollow portion screws into the outer peripheral surface 52 on the rear end side of the spindle accommodating portion 5, connecting the spindle accommodating portion 5 and the cylindrical portion 62. The outer peripheral surface 622 screws into the inner peripheral surfaces of the annular base portion 61 and the fixing ring 63. This screw-on connection makes it possible to change (adjust) the position of the cylindrical portion 62 along the longitudinal direction with the annular base portion 61 as a reference.

[0054] 12A and 12B are diagrams showing a handle used to adjust the position of the cylindrical portion, in which (A) is a top view and (B) is a side view.

[0055] Preferably, a hole 623 is provided in the surface of the solid portion on the rear end 62b side of the cylindrical portion 62. A pin 691 and a hole 692 are provided in the handle 69. When the handle 69 is rotated around the longitudinal axis of the cylindrical portion 62 with the pin 691 of the handle 69 engaged with the hole 623 of the cylindrical portion 62, the position of the cylindrical portion 62 relative to the annular base portion 61 can be changed.

[0056] The diameter of hole 692 provided in handle 69 is made larger than the diameter of main shaft 4. As a result, when handle 69 is disposed on the rear end 62b side of cylindrical portion 62, main shaft 4 passes through hole 692. As a result, it is possible to rotate handle 69 around the long axis of cylindrical portion 62 without main shaft 4 interfering with handle 69.

[0057] Fig. 13 is a diagram illustrating an electric motor mounting portion and an electric motor according to one embodiment, and Fig. 14 is a schematic cross-sectional view for explaining a usage state of the electric motor mounting portion and the electric motor.

[0058] In the shear flow generating instrument 10, the tip position adjustment mechanism 6 is fixed to an upper end 91a of an open end flange 94 of a magnetic resonance apparatus 90. An electric motor mounting part 8 to which an electric motor 7 is attached is also fixed to the upper end 91a of the open end flange 94. In this embodiment, the electric motor mounting part 8 is disposed on the upper part of the open end flange 94 provided at the upper end of the open end 91a so as to cover the tip position adjustment mechanism 6. The electric motor 7 is disposed on a top plate 81 above the electric motor mounting part 8, and the rotational power of the electric motor 7 is applied to the main shaft 4 which penetrates a hollow part of a cylindrical part 62 of the tip position adjustment mechanism 6. In this embodiment, the rotating shaft 71 of the electric motor 7 and the rear end 4b of the main shaft 4 are connected by, for example, a cylindrical coupler 49 (made of, for example, rubber).

[0059] As described above, according to the shear flow generating device of one embodiment of the present invention, it is possible to provide a device that generates a shear flow in a sample, in which the sample tube and the stirring rod are accurately aligned.

[0060] The accurate positional relationship between the sample tube 1 and the stirring rod 2 is held by the holder 3 before they are inserted into the sample introduction hole 91 of the magnetic resonance instrument 90. The rotational power of the stirring rod 2 for applying a shear force to the sample S is transmitted to the stirring rod 2 from an electric motor 7 arranged outside the magnetic resonance instrument 90 via the main shaft 4. This makes it possible to place the sample tube 1 and the stirring rod 2 in a precisely aligned state at a predetermined measurement position of the magnetic resonance instrument 90, and makes it possible to apply a shear force to the sample S stored in the sample tube 1 in such a precisely aligned state within the magnetic resonance instrument 90.

[0061] When the motor 7 is used to transmit the rotational power to the stirring rod 2, the rotation speed of the main shaft 4 and the stirring rod 2 driven to rotate by the motor 7 is about 0.0167 Hz to about 66.7 Hz (about 1 rpm to about 4,000 rpm). According to the shear flow generating device 10 according to one embodiment, the sample tube 1 and the stirring rod 2 are accurately aligned, and even if the stirring rod 2 is rotated at a relatively high rotation speed of about 30 Hz or more, a good NMR signal can be measured in the rheo-NMR measurement. Furthermore, when the motor 7 is used to drive the stirring rod 2, a relatively high rotational torque by the motor 7 can be transmitted to the stirring rod 2. This makes it possible to repeatedly measure a good NMR signal in the rheo-NMR measurement, even for a sample S with a relatively high viscosity.

[0062] In Rheo-NMR measurements, if it becomes possible to repeatedly measure good NMR signals with high reproducibility, it will be possible to quantitatively evaluate the physical properties of proteins as samples, for example. This will enable the quantitative evaluation of the stability of antibody drugs, for example. In addition, if it becomes possible to measure samples with higher viscosity in Rheo-NMR measurements, it will be possible to measure the process of making butter from milk at the atomic level in real time, for example.

[0063] The following examples of the present invention will make the features of the present invention clearer. EXAMPLES

[0064] In Example 1, a shear flow generating device was manufactured and its performance was evaluated. For the performance evaluation, the same shear flow generating device as that described in the above embodiment was used, except that water was used as a sample and a stub without the adjustment mechanism was used instead of the tip position adjustment mechanism. The test results for the performance evaluation are shown in Figures 15 and 16.

[0065] The test results shown in Figure 15 correspond to a vertical cross-sectional view of the sample tube and the stirring rod when the shear flow generating device is inserted into the sample introduction hole of the magnetic resonance apparatus and in use. As shown in Figure 15, it was confirmed that the sample was uniformly distributed in the sample tube even when the rotation speed of the stirring rod was increased from 0 rpm to 300 rpm to apply shear force to the sample.

[0066] The results of NMR measurements (proton NMR measurements) on the sample are shown in Figure 16. Even when the rotation speed of the stirrer was increased from 0 rpm to 1200 rpm and shear force was applied to the sample, the NMR signal of the sample showed signal peaks at the same positions as when no shear force was applied to the sample. These signal peaks were located at approximately 4.7 ppm, confirming that the signals originated from the water in the sample. Regarding the signal peaks of impurities, indicated by an "*" mark in the graph, it was confirmed that the signal intensity was reduced when shear force was applied to the sample.

[0067] From the test results shown in Figures 15 and 16, it was confirmed that the performance of the fabricated shear flow generating device was good. [Explanation of symbols]

[0068] 1 sample tube 2 Stirring rods 3 Holding part 4 spindle 5 Spindle housing 6 Tip position adjustment mechanism 7 Electric motor 8 Motor mounting section 10. Shear flow generating device 21 Protection tube 22 Rotational support part 31 Stirring rod holder 32 Sample tube holder 33 Case 48,49 Cylindrical coupling 51 Inner surface 52 Outer surface 53 holes 54 Bearing 55 Spacer 56 Annular elastic member (O-ring) 61 Circular base 62 Cylindrical part 63 Fixing ring 69 Handle 71 (Electric motor) rotating shaft 81 Tabletop 90 Magnetic Resonance Apparatus 91 Sample introduction hole 91a Open end 94 Open end flange 221 Bearing 222 Spacer 311 The Third Cavity 312 The Fourth Cavity 313 Circular Lid 314 Bearing 321 Annular elastic member (O-ring) 322a outer surface 331 First Cavity 332 Second Cavity 333 Outer surface 334 holes 621 Inner surface 622 Outer surface 623 holes 691 Pins 692 holes B0 static magnetic field S sample

Claims

1. An apparatus for generating a shear flow in a sample when inserted into a sample introduction hole of a magnetic resonance apparatus, comprising: A sample tube for storing a sample; a stirring rod whose tip is inserted into the sample tube and which rotates about its longitudinal axis to apply a shear force to the sample; a holder for holding both the sample tube and the stirring rod; An apparatus comprising:

2. The apparatus of claim 1 , wherein the holder holds the sample tube and the stir bar coaxially.

3. The holding portion is A cylindrical stirring rod holder that holds the rear end side of the stirring rod; a cylindrical sample tube holder for holding the sample tube; a cylindrical housing for holding the stirring rod holder and the sample tube holder; The apparatus of claim 1 , comprising:

4. The housing has a first cavity and a second cavity communicating with the first cavity along a longitudinal axis direction, the stirring rod holder fits into the second cavity in the housing; The instrument of claim 3 , wherein the sample tube holder has a rear end that fits into the first cavity in the housing.

5. the stirring rod holder rotatably holds the rear end side of the stirring rod in a state where the rear end side of the stirring rod is inserted therein; 4. The device according to claim 3, wherein the sample tube holder holds the sample tube inserted therethrough.

6. 4. The apparatus of claim 3, wherein the stirring rod holder has a third cavity at a front end side for accommodating a rear end side of the sample tube, and a fourth cavity at a rear end side for accommodating a bearing that rotatably holds the stirring rod.

7. A main shaft connected to the stirring rod and transmitting rotational power around a long axis to the stirring rod; a cylindrical spindle housing portion that houses the spindle; Further equipped with 7. The device according to claim 1, wherein a circumferential groove is provided on a side surface of the spindle accommodating portion, and a ring-shaped elastic member is disposed in the groove and protrudes from the groove and elastically deforms to fit the opening end of the sample introduction hole.

8. The instrument of claim 7 , wherein the mandrel housing has a hole in a side thereof extending along a longitudinal axis.

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