Ultrasonic wave irradiation apparatus

Abstract

This ultrasonic wave irradiation apparatus comprises an ultrasonic wave generation device having a vibration element for generating ultrasonic waves by vibrating. The ultrasonic wave generation device has a container installation part capable of installing an irradiation object accommodation container in which an object to be irradiated with ultrasonic waves is accommodated, and the ultrasonic wave generation device propagates ultrasonic waves generated by the vibration element to the irradiation object accommodation container.

Description

Ultrasonic irradiation device

[0001] The present invention relates to an ultrasonic irradiation device.

[0002] The usefulness of ultrasound has been confirmed in various fields. Ultrasound is used, for example, for pulverization, suspension, atomization, dissolution, stirring, heating, aggregation, and reaction promotion. It is also known that ultrasound can be used to promote the formation of amyloid fibers and to fragment and refine amyloid fibers. In recent years, technology that applies the properties of ultrasound has attracted attention, and ultrasound irradiation devices that can irradiate ultrasound to a target object have been developed.

[0003] In this regard, an ultrasonic irradiation device is known that generates amyloid by irradiating ultrasonic waves to a supersaturated solution of an amyloid-causing protein contained in a well (for example, Patent Document 1). The ultrasonic irradiation device described in Patent Document 1 includes a treatment tank (container) containing a fluid medium (water), an ultrasonic generator provided outside the treatment tank, and a sample plate having multiple wells immersed in the medium in the treatment tank, and ultrasonic waves generated by the ultrasonic generator are propagated through the medium, thereby irradiating ultrasonic waves to the solution in each well.

[0004] Japanese Patent Application Laid-Open No. 2023-060987

[0005] Conventional ultrasonic irradiation devices transmit ultrasonic waves through a fluid to irradiate the target object, but they have the problem of requiring a container to contain the fluid, which leads to the device being large. In addition, there are issues such as low energy efficiency due to the greater attenuation of ultrasonic waves when propagating through a fluid compared to when propagating through a solid, and the necessity of a fluid degassing device to suppress the generation of bubbles, which makes the device structure complicated as a whole.

[0006] The technology disclosed herein has been made to solve these problems, and aims to achieve a smaller ultrasonic irradiation device, a simpler structure, and improved energy efficiency.

[0007] In order to solve the above problems, the ultrasonic irradiation device according to the present disclosure employs the following configuration. That is, the gist of the technology according to the present disclosure is as follows. [1] An ultrasonic irradiation device including an ultrasonic generator having a vibration element that generates ultrasonic waves by vibrating, the ultrasonic generator having a container installation section capable of installing an irradiation target container that houses an object to be irradiated with the ultrasonic waves, and the ultrasonic irradiation device propagates the ultrasonic waves generated by the vibration element to the irradiation target container through a solid. [2] The ultrasonic irradiation device according to [1], wherein the ultrasonic generator further has a first propagation section that propagates the ultrasonic waves through a solid, the first propagation section having the container installation section and propagating the ultrasonic waves to the irradiation target container. [3] The ultrasonic irradiation device according to [1] or [2], wherein the container installation section is formed with a holding section that holds an acoustic coupling agent that can propagate ultrasonic waves between the ultrasonic generator and the irradiation target container. [4] The ultrasonic irradiation device according to any one of [1] to [3], further comprising a rotation mechanism that rotates the irradiation object container placed in the container installation section relative to the ultrasonic generator around a rotation axis that is arranged along the alignment direction of the vibration element and the container installation section. [5] The ultrasonic irradiation device according to [4], wherein the rotation mechanism has: a bearing hole that passes through the ultrasonic generator along the rotation axis, a shaft that is inserted into the bearing hole and connected to the irradiation object container so as to rotate integrally with the irradiation object container, and a rotation device that is arranged on the opposite side of the container installation section with respect to the vibration element in the alignment direction, to which the shaft is connected, and that rotates the shaft around the rotation axis. [6] The ultrasonic irradiation device described in [4] or [5], wherein the irradiation object container has one or more container sections arranged circumferentially around the rotation axis and in which the objects are contained, and the container installation section is formed with a holding section that holds an acoustic coupling agent capable of propagating ultrasonic waves between the ultrasonic generator and the container section, and the holding section is formed as an annular groove extending circumferentially around the rotation axis.[7] The ultrasonic irradiation device according to any one of [1] to [6], wherein the container installation section is formed as a recessed section capable of accommodating the irradiation object container and having an open opening on one side, and the ultrasonic irradiation device further includes a lid member capable of opening and closing the open opening of the recessed section. [8] The ultrasonic irradiation device according to [7], wherein at least one of the container installation section and the lid member has a window section formed therein for performing fluorescence measurement of the object from outside the recessed section. [9] The ultrasonic irradiation device according to any one of [1] to [8], further including a temperature control device capable of adjusting the temperature of the object.

[10] The ultrasonic irradiation device according to [2], wherein the ultrasonic generator has a second propagation section arranged on the opposite side of the vibration element to the first propagation section, and which propagates ultrasonic waves generated by the vibration element through a solid.

[11] The ultrasonic irradiation device according to [1], wherein the container installation section is formed on the vibration element.

[12] The ultrasonic irradiation device according to

[11] , wherein the irradiation object container has one or more container sections arranged circumferentially and containing the objects, and the vibration element extends in an annular shape along the one or more wells.

[13] The ultrasonic irradiation device according to any one of [1] to

[12] , further comprising the irradiation object container.

[0008] According to the present disclosure, the ultrasonic irradiation device can be made smaller.

[0009] Fig. 1 is a longitudinal sectional view of an ultrasonic irradiation device according to an embodiment. Fig. 2 is a perspective view of a sample plate according to an embodiment. Fig. 3 is a perspective view of an ultrasonic generator according to an embodiment. Fig. 4 is a diagram showing an example of a connection mode between a shaft part of a rotation mechanism and a sample plate. Fig. 5 is a longitudinal sectional view of an ultrasonic irradiation device according to a first modified example of the embodiment. Fig. 6 is a longitudinal sectional view of an ultrasonic irradiation device according to a second modified example of the embodiment.

[0010] Hereinafter, embodiments of the present disclosure will be described. Note that each configuration and their combinations in the embodiments are merely examples, and additions, omissions, substitutions, and other modifications of configurations are possible as appropriate within the scope of the gist of the present disclosure. The present disclosure is not limited by the embodiments, but only by the claims. Furthermore, a numerical range expressed using "to" means a range that includes the numerical values ​​written before and after "to" as the lower and upper limits, and "A to B" means greater than or equal to A and less than or equal to B.

[0011] [Overall Configuration] FIG. 1 is a longitudinal cross-sectional view of an ultrasonic irradiation device 100 according to an embodiment. FIG. 1 illustrates a cross section (referred to as a longitudinal cross section) along the rotation axis indicated by reference symbol A1. FIG. 1 also illustrates the vertical direction of the ultrasonic irradiation device 100. In this embodiment, the vertical direction is defined as the arrangement direction of the piezoelectric elements indicated by reference symbols 21a and 21b and the container installation section indicated by reference symbol 22b. In the arrangement direction of the piezoelectric elements 21a and 21b (vibration elements) and the container installation section 22b, the piezoelectric elements 21a and 21b are the lower side, and the container installation section 22b is the upper side. Although two piezoelectric elements are used in this example, a single piezoelectric element may be used. The number of piezoelectric elements is not particularly limited, but is typically one to four, preferably one, two, or four, more preferably one or two, and particularly preferably two. The rotation axis A1 is arranged along the vertical direction. The ultrasonic irradiation device 100 is used in a state where the up-down direction of the ultrasonic irradiation device 100 coincides with the vertical direction (the direction of gravity) and the upper side (the container installation section 22b side) of the ultrasonic irradiation device 100 coincides with the upper side in the vertical direction. However, the technology of the present disclosure is not limited to this.

[0012] The ultrasound irradiation device 100 according to this embodiment irradiates an object (hereinafter referred to as the ultrasound irradiation target) with ultrasound, thereby causing changes in the object, such as pulverization, suspension, microparticulation, dissolution, stirring, heating, aggregation, and reaction promotion. As an example, the ultrasound irradiation target of the ultrasound irradiation device 100 is a solution (hereinafter referred to as the target solution L1) containing a protein and a fluorescent molecule that adsorbs to protein aggregates and emits light. In this embodiment, the protein is, for example, amyloid beta, which causes Alzheimer's disease, beta-2 microglobulin, which causes dialysis amyloidosis, or alpha-synuclein, which causes Parkinson's disease. When the protein is amyloid beta, beta-2 microglobulin, or alpha-synuclein, the fluorescent molecule is thioflavin T, which adsorbs to amyloid beta, beta-2 microglobulin, or alpha-synuclein aggregates and emits fluorescence. The ultrasound irradiation device 100 according to this embodiment irradiates the target solution L1 with ultrasound, thereby generating protein aggregates through an aggregation reaction. The ultrasound irradiation device 100 irradiates the target solution L1 with excitation light and detects the fluorescence emitted by the fluorescent molecules. However, the target to be irradiated with ultrasound according to the present disclosure is not limited to the above.

[0013] 1, the ultrasonic irradiation device 100 includes a sample plate 1, an ultrasonic generator 2, a cover member 3, a rotation mechanism 4, a temperature control device 5, a light irradiation device 6, a light detection device 7, and a housing 8. Each component of the ultrasonic irradiation device 100 will be described below.

[0014] [Sample Plate] FIG. 2 is a perspective view of a sample plate 1. The sample plate 1 is a container that contains a target solution L1 (ultrasound irradiation target). The sample plate 1 is an example of an "irradiation target container" according to the present disclosure. The sample plate 1 has a main body 11, a bearing hole 12, multiple wells 13, multiple through-holes 14, and multiple wall portions 15. The sample plate 1 is formed as a transparent body from a resin material such as polypropylene. The material of the irradiation target container according to the present disclosure is not particularly limited, but polypropylene, which has excellent ultrasonic transparency, is preferably used. Alternatively, an amorphous cyclic olefin resin, which has excellent ultrasonic and optical transparency, may be used as the material of the irradiation target container. Amorphous cyclic olefin resin is more preferable as the material of the irradiation target container from the viewpoint of excellent optical transparency.

[0015] The main body 11 is formed in a disk shape perpendicular to the vertical direction. The bearing hole 12 is disposed at the center of the main body 11 and is a through-hole that passes through the main body 11 in the vertical direction. A shaft 42 (described below) having the rotation axis A1 as its central axis is inserted into the bearing hole 12.

[0016] The multiple wells 13 constitute the multiple channels of the sample plate 1. Each well 13 has a bottomed cylindrical shape extending in the vertical direction. The upper end of each well 13 is connected to the main body 11 and opens to the upper surface of the main body 11. The lower end of each well 13 protrudes (hangs) downward from the lower surface of the main body 11 and is closed. The multiple wells 13 are disposed at equal distances from the bearing hole 12 and are arranged circumferentially around the bearing hole 12 (i.e., the rotation axis A1). More specifically, the multiple wells 13 are arranged at predetermined intervals (equal intervals) along the circumference of a circle C1 centered on the bearing hole 12. The sample plate 1 according to this embodiment has, as an example, 18 wells 13. The target solution L1 is contained in these multiple wells 13. The openings of the multiple wells 13 are closed by transparent sealing members (not shown). The multiple wells 13 are an example of "multiple storage sections" according to the present disclosure. In the present disclosure, the number of storage units is not particularly limited, and the number of storage units does not have to be multiple. Furthermore, the shape and number of storage units are not particularly limited. For example, the wells 13 may be turned upside down so that the openings closed with transparent sealing members face downward (i.e., toward the ultrasonic generator), and ultrasonic waves may be irradiated onto the target object through the sealing members. In this case, the main body 11 is configured to be located at the center of each well 13 in the vertical direction.

[0017] The plurality of through holes 14 penetrate the main body 11 in the vertical direction and are arranged radially around the bearing hole 12. More specifically, the plurality of through holes 14 are arranged axially symmetrically around the bearing hole 12 between the bearing hole 12 and the plurality of wells 13.

[0018] The multiple wall portions 15 are arranged between adjacent wells 13 in the circumferential direction, hang down from the lower surface of the main body portion 11, and connect the wells 13 to each other.

[0019] [Ultrasonic Generator] As shown in FIG. 1 , the ultrasonic generator 2 includes a drive unit 21, a front mass 22 (an example of a "first propagation unit" according to the present disclosure), a rear mass 23 (an example of a "second propagation unit" according to the present disclosure), a flange 24, a bolt 25, and a nut 26. The ultrasonic generator 2 is configured as a bolt-tightened Langevin-type transducer in which the drive unit 21, the front mass 22, the rear mass 23, and the flange 24 are stacked vertically and fastened together with the bolt 25 and the nut 26. However, the ultrasonic generator according to the present disclosure is not limited to a Langevin-type transducer. In the ultrasonic generator 2 according to this embodiment, the front mass 22 and the rear mass 23 are disposed on opposite sides of the drive unit 21, and the flange 24, which is disposed at a vibration node position, is held by the housing 8. The resonant frequency of the ultrasonic generator 2 is not particularly limited, but is set to, for example, 20 to 300 kHz. The resonant frequency of the ultrasonic generator 2 can be adjusted by changing the size, weight, material, etc. of the front mass 22, rear mass 23, etc.

[0020] The drive unit 21 includes piezoelectric elements 21a and 21b (an example of a "vibration element" according to the present disclosure) and electrode plates 21c and 21d, which are stacked vertically. The piezoelectric elements 21a and 21b are polarized piezoelectric ceramics (PZT piezoelectric elements). An external oscillator (not shown) is electrically connected to the electrode plates 21c and 21d. The electrode plates 21c and 21d are terminals for applying a voltage of a predetermined frequency supplied from the oscillator to the piezoelectric elements 21a and 21b. The piezoelectric elements 21a and 21b vibrate when a voltage is applied, thereby generating ultrasonic waves. The piezoelectric elements 21a and 21b and the electrode plates 21c and 21d are formed in an annular shape, and a bolt 25 is inserted through them. Note that, although two piezoelectric elements are used in this example, the number of piezoelectric elements is not particularly limited and may be one. Furthermore, the vibration element according to the present disclosure is not limited to a piezoelectric element. The vibration element according to the present disclosure may be a piezoelectric element (electrostrictive element) that excites (generates) ultrasonic waves by vibrating when a voltage is applied, or may be a magnetostrictive element that excites (generates) ultrasonic waves by vibrating when exposed to an oscillating magnetic field.

[0021] The front mass 22 and the rear mass 23 are metal blocks that propagate the ultrasonic waves generated by the piezoelectric elements 21 a and 21 b through solid propagation (propagation through a solid medium). The front mass 22 and the rear mass 23 resonate with the ultrasonic vibrations transmitted from the piezoelectric elements 21 a and 21 b, expanding and contracting, and vibrating in the vertical direction and in a direction perpendicular to the vertical direction, thereby amplifying and propagating the ultrasonic vibrations. Examples of materials for the front mass 22 and the rear mass 23 include metal materials such as aluminum alloy, titanium, steel (S45C), and stainless steel. Among these, stainless steel, which is resistant to rust (corrosion), is preferred. However, the materials for the first propagation portion and the second propagation portion according to the present disclosure are not limited to metal materials. The first propagation portion and the second propagation portion may be solid members capable of propagating ultrasonic waves.

[0022] 1, the front mass 22 is disposed above the drive unit 21 and is fixed to the piezoelectric elements 21a and 21b via a flange 24. The front mass 22 has a block main body 221, a peripheral wall 222, and an upright wall 223.

[0023] The block main body 221 is a component that propagates ultrasonic waves generated by the piezoelectric elements 21a and 21b in a solid state. It is formed in a generally truncated cone shape with a diameter that increases upward. The central axis of the block main body 221 coincides with the rotation axis A1. The block main body 221 is formed with a blind threaded hole 22a that opens at the lower end surface of the block main body 221 and extends in the up-down direction. The central axis of the threaded hole 22a coincides with the rotation axis A1. A bolt 25 is inserted into the threaded hole 22a, and a male thread formed on the outer periphery of the bolt 25 threadably engages with a female thread formed on the inner periphery of the threaded hole 22a. In this embodiment, the cross section of the block main body 221 that is perpendicular to the rotation axis A1 is circular, but this is not limiting. For example, the cross section of the front mass 22 may be polygonal.

[0024] The peripheral wall portion 222 is formed in a cylindrical shape extending in the vertical direction and extends upward from the periphery of the upper end surface of the block main body portion 221. The central axis of the peripheral wall portion 222 coincides with the rotation axis A1. The block main body portion 221 and the peripheral wall portion 222 form a container mounting portion 22b, a recessed portion in which the sample plate 1 can be mounted, at the upper end of the front mass 22. More specifically, the container mounting portion 22b is a space surrounded by the upper end surface of the block main body portion 221 and the inner peripheral surface of the peripheral wall portion 222. The height dimension (length in the vertical direction) of the peripheral wall portion 222 is greater than the height dimension of the sample plate 1. Therefore, the container mounting portion 22b is deeper than the height of the sample plate 1. Furthermore, the peripheral wall portion 222 is formed with a window portion 22d that enables fluorescence detection by the photodetector 7 from outside the container mounting portion 22b. The window portion 22d is formed as a through-hole that penetrates the peripheral wall portion 222 in the radial direction. The opening at the upper end of the peripheral wall portion 222 forms an opening 22e of the container installation portion 22b.

[0025] The upright wall portion 223 is formed in a cylindrical shape that extends vertically and has a smaller diameter than the peripheral wall portion 222, and extends upward from the upper end surface of the block main body portion 221. The central axis of the upright wall portion 223 coincides with the rotation axis A1. The height dimension of the upright wall portion 223 is smaller than the height dimension of the peripheral wall portion 222. The block main body portion 221, the peripheral wall portion 222, and the upright wall portion 223 form a holding portion 22c in the container installation portion 22b that can hold the acoustic coupling agent B1. The upright wall portion 223 prevents the acoustic coupling agent contained in the holding portion 22c from being sprayed by ultrasonic waves and leaking toward the bearing hole 41.

[0026] 3 is a top view of the ultrasonic generator 2 according to the embodiment. As shown in FIG. 3, the holding portion 22c is formed as an annular groove extending circumferentially around the rotation axis A1. This holding portion 22c can hold an acoustic coupling agent B1 capable of propagating ultrasonic waves. The front mass 22 contacts the sample plate 1 via the acoustic coupling agent B1. Note that the acoustic coupling agent B1 does not necessarily have to be interposed between the front mass 22 and the sample plate 1, and the front mass 22 and the sample plate 1 may be in direct contact with each other.

[0027] Furthermore, the holder 22c is capable of receiving the plurality of wells 13 of the sample plate 1. The sample plate 1 is placed on the container setting section 22b with the bottoms (lower ends) of the plurality of wells 13 received in the holder 22c.

[0028] As shown in FIG. 1 , the acoustic coupling agent B1 is filled into the holder 22c and interposed between the front mass 22 of the ultrasonic generator 2 and the well 13 of the sample plate 1. The acoustic coupling agent B1 may be any material capable of removing air from between the front mass 22 and the well 13, and a gel-like material with low vibration attenuation is preferred. However, the acoustic coupling agent according to the present disclosure is not particularly limited, and examples include gel-like and cream-like materials. Water may also be used as the acoustic coupling agent. When air is present between the ultrasonic generator 2 and the sample plate 1 without using the acoustic coupling agent B1, a so-called dry contact state is achieved, and ultrasonic waves propagate through space. By interposing the acoustic coupling agent B1 between the ultrasonic generator 2 and the sample plate 1, ultrasonic attenuation can be suppressed compared to air propagation, thereby improving energy efficiency. However, the acoustic coupling agent is not a required component in the present disclosure, and the ultrasonic irradiation device does not necessarily require the use of an acoustic coupling agent. In this embodiment, if the acoustic coupling agent B1 is not used, the sample plate 1 can be given a heating effect due to friction at the contact point between the ultrasonic generator 2 and the sample plate 1 when the sample plate 1 is rotated relative to the ultrasonic generator 2 by the rotation mechanism 4 described below, making it suitable for use in heating the target solution L1.

[0029] As shown in FIG. 1 , the rear mass 23 is disposed below the drive unit 21 and is fixed to the piezoelectric elements 21a and 21b. That is, the rear mass 23 is disposed on the opposite side of the front mass 22 with the piezoelectric elements 21a and 21b interposed therebetween. The rear mass 23 is formed in a cylindrical shape extending in the vertical direction. The central axis of the rear mass 23 coincides with the rotation axis A1. That is, the rear mass 23 is disposed coaxially with the front mass 22. The rear mass 23 has a through-hole 23a extending in the vertical direction. A bolt 25 is inserted through the through-hole 23a. The rear mass 23 functions as a counterweight to maintain a weight balance with the front mass 22. Note that in this embodiment, the cross section of the rear mass 23 perpendicular to the rotation axis A1 is circular, but this is not limiting. For example, the cross section of the rear mass 23 may be polygonal.

[0030] The flange 24 is a member for supporting the ultrasonic generator 2 on an arbitrary structure. The flange 24 is formed in an annular shape, and a bolt 25 is inserted through the flange 24. The flange 24 is interposed between the drive unit 21 and the front mass 22 and protrudes radially outward. The flange 24 is disposed at a node of the ultrasonic vibration generated by the ultrasonic generator 2 (i.e., a position where the wavelength amplitude is zero and no vibration occurs). As shown in FIG. 1 , in this embodiment, the flange 24 is fixed to the housing 8 as a structure, thereby supporting the ultrasonic generator 2 on the housing 8. The material of the flange 24 is not particularly limited, but may be a metal material. In this embodiment, the flange 24 is formed as a separate member from the front mass 22. However, the flange 24 may be formed as a part of the front mass 22. In other words, the front mass 22 and the flange 24 may be formed integrally.

[0031] The bolt 25 and nut 26 are fastening members for fastening the drive unit 21, the front mass 22, the rear mass 23, and the flange 24 together. As shown in FIG. 1 , the bolt 25 is formed as a stud bolt without a head, for example. The bolt 25 is inserted vertically through the through-hole 23a of the rear mass 23, and its upper end reaches the front mass 22 via the drive unit 21 and the flange 24 and is threaded into the threaded hole 22a. The lower end of the bolt 25 protrudes downward from the rear mass 23 and is threadedly engaged with a nut 26. By tightening the nut 26, the front mass 22, the drive unit 21, and the rear mass 23 are fixed to each other and integrated. As a result, the ultrasonic generator 2 is configured as a bolt-tightened Langevin-type transducer.

[0032] [Cover Member] The cover member 3 is a member that can open and close the opening 22e of the container mounting portion 22b, which is formed as a recess. As shown in FIG. 1 , the cover member 3 is formed, for example, in a plate shape (disk-shaped in this example) and is disposed at the upper end of the peripheral wall portion 222, oriented perpendicular to the vertical direction. The opening 22e formed at the upper end of the peripheral wall portion 222 is closed by the cover member 3, thereby forming the container mounting portion 22b as a shielded space that is shielded from external light. The cover member 3 is formed with a shaft support hole 3a that supports the shaft portion 42 of the rotation mechanism 4 and an irradiation hole 3b that allows the light irradiation device 6 to irradiate the target solution L1 in the container mounting portion 22b with light. The shaft support hole 3a and the irradiation hole 3b are formed as through-holes that penetrate the cover member 3 in the vertical direction. A temperature control device 5 (described below), such as a heater, can be installed inside the cover member 3 to control the temperature of the target solution L1 in the well 13.

[0033] [Rotation Mechanism] The rotation mechanism 4 rotates the sample plate 1 placed on the container placement section 22b relative to the ultrasonic generator 2. As shown in FIG. 1 , the rotation mechanism 4 includes a bearing hole 41, a shaft 42, and a rotation device 43.

[0034] The bearing hole 41 is a through-hole that passes through the ultrasonic generator 2 along the rotation axis A1. Specifically, the bearing hole 41 passes through the front mass 22 and the bolt 25 in the vertical direction.

[0035] The shaft 42 is a shaft member extending in the vertical direction. The shaft 42 is inserted into the bearing hole 41 and connected to the sample plate 1 so as to rotate integrally with the sample plate 1. The central axis of the shaft 42 coincides with the rotation axis A1. The upper end of the shaft 42 passes through the sample plate 1, the temperature control device 5, and the cover member 3, and protrudes above the cover member 3. The lower end of the shaft 42 passes through the bolt 25, protrudes below the bolt 25, and is connected to the rotation device 43.

[0036] The rotation device 43 rotates the shaft portion 42 around the rotation axis A1. The rotation device 43 is disposed below the ultrasonic generator 2. In other words, the rotation device 43 is disposed on the opposite side of the container installation portion 22b in the vertical direction with respect to the piezoelectric elements 21a and 21b. The shaft portion 42 protruding downward from the ultrasonic generator 2 is connected to the rotation device 43. The rotation device 43 has, for example, a motor as a drive source and a gear that transmits the rotational driving force of the motor to the shaft portion 42, and rotates the shaft portion 42 at an appropriate rotation speed. Note that the configuration of the rotation device according to the present disclosure is not limited to this, and any means can be adopted.

[0037] 4 is a diagram showing an example of a connection between the shaft 42 of the rotation mechanism 4 and the sample plate 1. As shown in FIG. 4, the rotation mechanism 4 may have a connecting member 44 that connects the shaft 42 and the sample plate 1. The connecting member 44 has a fixing portion 441 and an engaging portion 442. The fixing portion 441 is formed in a cylindrical shape, and is fitted onto and fixed to the shaft 42. The engaging portion 442 is inserted into the through-hole 14 of the sample plate 1 to engage with the sample plate 1. As a result, when the shaft 42 rotates around the rotation axis A1, the sample plate 1 rotates integrally with the shaft 42.

[0038] [Temperature Control Device] The temperature control device 5 is disposed in the container mounting section 22b and adjusts (controls) the temperature of the target solution L1 contained in the sample plate 1. As shown in FIG. 1 , the temperature control device 5 is formed, for example, in a disk (plate) shape and is mounted so as to overlap the sample plate 1 from above. The temperature control device 5 measures the temperature in the wells 13 of the sample plate 1 and controls the target solution L1 contained in the wells 13 to a predetermined temperature based on the measured temperature. The temperature control device 5 is formed with an irradiation hole 5a that enables the light irradiation device 6 to irradiate the target solution L1 in the container mounting section 22b with light. The irradiation hole 5a is formed as a through-hole that penetrates the temperature control device 5 in the vertical direction. Note that the configuration of the temperature control device according to the present disclosure is not limited to this, and any means can be employed. The temperature control device may be configured to include, for example, a heating device such as an electric heater or a heat pump, or a cooling device such as a heat exchanger or a Peltier element cooler.

[0039] [Light Irradiation Device] The light irradiation device 6 irradiates the target solution L1 with excitation light having a predetermined wavelength. The light irradiation device 6 has, for example, a light-emitting diode as a light-emitting element (light source) that emits excitation light. However, the configuration of the light irradiation device 6 is not limited thereto. The light irradiation device 6 is inserted into the irradiation hole 3b of the lid member 3 and the irradiation hole 5a of the temperature control device 5, and irradiates the wells 13 with excitation light from above. When viewed along the rotation axis A1, the light irradiation device 6 is arranged on an orbit around the multiple wells 13. Note that the light irradiation device 6 may be provided corresponding to each well 13. The light irradiation device 6 may also irradiate the excitation light through a window 22d formed in the front mass 22.

[0040] [Photodetector] The photodetector 7 detects fluorescence emitted by fluorescent molecules when irradiated with excitation light by the light irradiation device 6. The photodetector 7 has, for example, a phototransistor as a fluorescence receiving element that receives the fluorescence. The photodetector 7 may also have, for example, a photomultiplier tube as a fluorescence receiving element that receives the fluorescence. However, the configuration of the photodetector 7 is not limited to this. The photodetector 7 receives fluorescence in the well 13 from the side of the well 13 through the window 22d of the front mass 22.

[0041] The housing 8 accommodates the ultrasonic generator 2. The material of the housing 8 is not particularly limited, but may be, for example, a metal material. The housing 8 supports the flange 24 of the ultrasonic generator 2.

[0042] [Operation] The operation of the ultrasound irradiation device 100 will be described below using the detection of protein aggregates using the ultrasound irradiation device 100 according to this embodiment as an example. In the following description, as an example, the ultrasound irradiation device 100 is used to generate protein (β2 microglobulin) aggregates (amyloid fibers) in a target solution L1 containing β2 microglobulin as an amyloidogenic protein, thioflavin T as a fluorescent molecule, sodium chloride (NaCl), and hydrochloric acid (HCl), and the aggregates are detected using ThT fluorescence (thioflavin T fluorescence). The solution concentrations of the target solution L1 are, for example, β2 microglobulin at 0.3 mg / mL, NaCl at 150 mM, HCl at 30 mM, and thioflavin T at 5 μM. The resonant frequency of the ultrasound generator 2 configured as a Langevin transducer is 23 kHz. However, the present disclosure is not limited thereto.

[0043] First, the holder 22c formed in the container mounting section 22b of the front mass 22 is filled with acoustic coupling agent B1, and the sample plate 1 containing the target solution L1 in the multiple wells 13 is mounted on the container mounting section 22b. At this time, the multiple wells 13 are received in the holder 22c, so that a portion of the wells 13, including their bottoms, is immersed in the acoustic coupling agent B1. This results in the acoustic coupling agent B1 being interposed between the front mass 22 and the wells 13 of the sample plate 1. The temperature control device 5 sets the measurement temperature to, for example, 37°C.

[0044] In this state, the ultrasonic generator 2 is activated, generating ultrasonic waves due to the vibration of the piezoelectric elements 21a and 21b. The ultrasonic generator 2 generates ultrasonic waves having a frequency of, for example, 23 to 25 kHz. Here, the frequency of the ultrasonic waves may be fixed or may be swept within a specified range. The ultrasonic waves may be generated continuously or may be generated and stopped repeatedly at a specified cycle. The ultrasonic waves generated by the piezoelectric elements 21a and 21b are propagated through a solid medium by the front mass 22 and irradiated via the acoustic coupling agent B1 to the multiple wells 13 of the sample plate 1 placed in the container placement section 22b. As a result, the target solution L1 contained in the multiple wells 13 is irradiated with ultrasonic waves. The target solution L1 is irradiated with ultrasonic waves through the bottom of the wells 13. Irradiating the target solution L1 with ultrasonic waves accelerates protein aggregation, resulting in the generation of aggregates (amyloid fibers).

[0045] At this time, the rotation mechanism 4 rotates the sample plate 1 around the rotation axis A1. In other words, ultrasonic irradiation of the target solution L1 is performed while the sample plate 1 is being rotated around the rotation axis A1 by the rotation mechanism 4, or while the sample plate 1 is repeatedly rotated and stopped. When the rotation device 43 rotates the shaft 42 around the rotation axis A1, the sample plate 1 connected to the shaft 42 rotates around the rotation axis A1. Note that the shaft 42 is supported by the shaft support hole 3a of the cover member 3, suppressing whirling (axial wobble) of the shaft 42. The rotation mechanism 4 rotates the sample plate 1 at a rotation speed of, for example, 0.1 Hz. Because the holder 22c is formed as an annular groove extending circumferentially around the rotation axis A1, the multiple wells 13 rotate (circumnavigate) around the rotation axis A1 along the holder 22c. This allows ultrasonic irradiation to be uniformly performed on the target solution L1 contained in each of the multiple wells 13. Furthermore, the sample plate 1 is rotated, and the target solution L1 contained in each well 13 is stirred.

[0046] While the multiple wells 13 are rotating, the light irradiation device 6 irradiates the solution in each well 13 with excitation light through a transparent sealing member. The light irradiation device 6 irradiates, for example, light that has passed through a short-pass filter with a cutoff wavelength of 450 [nm] as excitation light.

[0047] When the light irradiating device 6 irradiates the target solution L1 in the wells 13 with excitation light, fluorescent molecules bind (adsorb) to aggregates formed in the target solution L1, thereby emitting fluorescence. The light detecting device 7 detects the fluorescence emitted by the fluorescent molecules. As described above, because the sample plate 1 is transparent, the fluorescence from the target solution L1 in each well 13 passes through the sidewall of each well 13. Therefore, the light detecting device 7 receives the fluorescence in the wells 13 through the window 22d of the front mass 22. Because the peak fluorescent wavelength of ThT fluorescence is approximately 482 nm, the light detecting device 7 detects light that has passed through a long-pass filter with a cutoff wavelength of 475 nm, for example.

[0048] Protein aggregates can be detected by detecting fluorescence from the target solution L1.

[0049] [Operations and Effects] As described above, the ultrasonic irradiation device 100 according to this embodiment includes the ultrasonic generator 2 having the piezoelectric elements 21 a, 21 b (vibration elements) that generate ultrasonic waves by vibrating. The ultrasonic generator 2 has a container installation section 22 b on which the sample plate 1 containing the target solution L1 as the object to be irradiated with ultrasonic waves can be installed, and the ultrasonic waves generated by the piezoelectric elements 21 a, 21 b are propagated to the sample plate 1.

[0050] That is, the ultrasonic irradiation device 100 according to the present embodiment is configured to irradiate ultrasonic waves to the target solution L1 by solid propagation. On the other hand, conventional devices that irradiate ultrasonic waves to a target object by fluid propagation require a large-scale processing tank for immersing the target container in a fluid such as water, resulting in an increase in the overall size of the device. Furthermore, the generation of bubbles can reduce the ultrasonic intensity, and a fluid degassing device for suppressing this can contribute to the increase in the overall size of the device. In contrast, the ultrasonic irradiation device 100 according to the present embodiment irradiates ultrasonic waves to the target solution L1 by solid propagation, eliminating the need for a large-scale processing tank or fluid degassing device for immersing the sample plate 1 in a fluid. As a result, according to the present embodiment, the ultrasonic irradiation device 100 can be made smaller and its structure simplified. Furthermore, since ultrasonic waves are attenuated less in solid propagation than in fluid propagation, the ultrasonic irradiation device 100 according to the present embodiment can improve the energy efficiency of ultrasonic wave introduction into the target object and achieve lower output power compared to the conventional devices described above. Furthermore, the ultrasonic irradiation device 100 according to this embodiment employs a configuration in which ultrasonic waves are irradiated to an object by solid propagation, and therefore can reduce ultrasonic unevenness and has excellent reproducibility compared to the conventional devices described above.

[0051] In addition, the ultrasonic generator 2 according to this embodiment has a front mass 22 that propagates the ultrasonic waves generated by the piezoelectric elements 21a and 21b through a solid, and the front mass 22 has a container mounting portion 22b that propagates the ultrasonic waves generated by the piezoelectric elements 21a and 21b to the sample plate 1.

[0052] That is, in the ultrasonic irradiation device 100 according to this embodiment, a container mounting section 22b for mounting the sample plate 1 is formed on the front mass 22, which propagates ultrasonic waves through solids. Ultrasound is irradiated onto the target solution L1 via solid propagation through the front mass 22. Because the container mounting section 22b is formed on the front mass 22, a container for mounting the sample plate 1 does not need to be provided separately from the ultrasonic generator 2. This allows the ultrasonic irradiation device 100 to be further miniaturized. Furthermore, by providing a highly temperature-resistant front mass 22, ultrasonic irradiation is possible at high and low temperatures, facilitating temperature control. As a result, stable ultrasonic irradiation is possible, even at temperatures higher than room temperature (e.g., above 40°C). Furthermore, by enlarging the diameter of the front mass 22, the ultrasonic irradiation area can be increased. As a result, ultrasonic irradiation over a large area is possible. However, the first propagation section is not a required component in the present disclosure.

[0053] Furthermore, the container installation section 22b according to this embodiment is formed with a holding section 22c that holds an acoustic coupling agent B1 capable of propagating ultrasonic waves between itself and the sample plate 1.

[0054] According to this, by using the acoustic coupling agent B1, it is possible to suppress the attenuation of ultrasonic waves generated by the ultrasonic generator 2 when they are transmitted from the front mass 22 to the sample plate 1. As a result, ultrasonic waves can be efficiently irradiated onto the target solution L1 contained in the sample plate 1. Note that in the present disclosure, the acoustic coupling agent is not an essential component.

[0055] The ultrasonic irradiation device 100 according to this embodiment further includes a rotation mechanism 4. The rotation mechanism 4 rotates the sample plate 1 placed on the container installation part 22b relative to the ultrasonic generator 2 around a rotation axis A1 arranged along the vertical direction (the direction in which the piezoelectric elements 21a, 21b and the container installation part 22b are aligned).

[0056] According to this, by rotating the sample plate 1, it is possible to uniformly irradiate the target solution L1 contained in the sample plate 1 with ultrasonic waves, thereby suppressing variations in the effect of ultrasonic waves (aggregation in this example) on the sample plate 1. Furthermore, by rotating the sample plate 1, it is possible to stir the target solution L1 without providing a stirrer for stirring the target solution L1.

[0057] The rotation mechanism 4 according to this embodiment includes a bearing hole 41 that passes through the ultrasonic generator 2 along the rotation axis A1, a shaft 42 that is inserted into the bearing hole 41 and connected to the sample plate 1 so as to rotate integrally with the sample plate 1, and a rotation device 43 that is connected to the shaft 42 and rotates the shaft 42 about the rotation axis A1. The rotation device 43 is disposed on the opposite side (lower side in this example) from the container installation part 22b in the vertical direction with respect to the piezoelectric elements 21a and 21b.

[0058] That is, the rotation mechanism 4 has a configuration in which the shaft 42 is inserted into the bearing hole 41 that penetrates the ultrasonic generator 2, and thereby the rotation device 43 is installed on the opposite side of the container installation section 22b. This eliminates the need for a structure for installing the rotation device 43 on the container installation section 22b side, i.e., above the container installation section 22b, and therefore the ultrasonic irradiation device 100 can be made smaller than when the rotation device 43 is installed above the container installation section 22b.

[0059] The sample plate 1 according to this embodiment has one or more wells 13 arranged circumferentially around the rotation axis A1, each well 13 containing a target object. The container installation section 22b is formed with a holding section 22c that holds an acoustic coupling agent B1 capable of propagating ultrasonic waves between the well 13 and the front mass 22. The holding section 22c is formed as an annular groove that extends circumferentially around the rotation axis A1.

[0060] According to this, by forming the holding portion 22c as an annular groove, one or more wells 13 can rotate (revolve) around the rotation axis A1 along the holding portion 22c while maintaining contact with the acoustic coupling agent B1. This allows ultrasonic waves to be efficiently applied to the target solution L1 while rotating the sample plate 1. Furthermore, by forming the holding portion 22c as an annular groove, the amount of acoustic coupling agent B1 used can be kept small.

[0061] The container installation section 22b according to this embodiment is formed as a recessed section having an opening 22e on one side (the upper side in this example) that can accommodate the sample plate 1. The ultrasonic irradiation device 100 further includes a lid member 3 that can open and close the opening 22e of the recessed section.

[0062] According to this, by closing the opening 22e with the lid member 3, the container installation section 22b can be formed as a shielded space that is shielded from external light. This reduces the influence of external light. Note that the orientation in which the opening of the container installation section according to the present disclosure is formed is not particularly limited, and it does not have to be upward.

[0063] Furthermore, the container setting section 22b according to this embodiment is formed with a window section 22d for measuring the fluorescence of the target solution L1 from outside the container setting section 22b.

[0064] This allows fluorescence measurement of the target solution L1 from outside the container installation section 22b. The window section 22d may be formed in the lid member 3. The window section according to the present disclosure may be formed in at least one of the container installation section and the lid member.

[0065] The ultrasonic irradiation device 100 according to this embodiment further includes a temperature control device 5 capable of adjusting the temperature of the target solution L1.

[0066] This allows the temperature of the target solution L1 contained in the sample plate 1 to be controlled to an appropriate temperature.

[0067] The ultrasonic generator 2 according to this embodiment also has a rear mass 23 that is disposed on the opposite side of the front mass 22 across the piezoelectric elements 21a and 21b, and that propagates the ultrasonic waves generated by the piezoelectric elements 21a and 21b through a solid.

[0068] By disposing the rear mass 23 on the opposite side of the front mass 22 with the piezoelectric elements 21a and 21b (vibration elements) in between, it is possible to maintain a weight balance with the front mass 22. Furthermore, the ultrasonic generator 2 having the rear mass 23 is suitable for generating ultrasonic waves having a low frequency of, for example, less than 100 kHz. However, the ultrasonic generator according to the present disclosure does not necessarily have to have a rear mass.

[0069] [Modification] The following describes an ultrasonic irradiation device according to a modification of the embodiment. In the following description, differences from the ultrasonic irradiation device 100 described using Figures 1 to 4 will be mainly described, and similar components will be denoted by the same reference numerals and detailed description will be omitted.

[0070] [Modification 1] Fig. 5 is a longitudinal sectional view of an ultrasonic irradiation device 100A according to Modification 1 of the embodiment. As shown in Fig. 5, the ultrasonic irradiation device 100A according to Modification 1 differs from the ultrasonic irradiation device 100 described above in that the ultrasonic generator 2 does not have a front mass 22 and a rear mass 23, and a container installation portion 22b is formed in the drive unit 21 (piezoelectric elements 21a, 21b).

[0071] In the first modification, a container installation section 22b is formed on the upper surfaces (axial end surfaces) of the annular piezoelectric elements 21a and 21b (vibration elements) to provide a space in which the sample plate 1 can be installed. That is, the sample plate 1 is placed on the piezoelectric elements 21a and 21b. Furthermore, an annular holding section 22c is formed on the upper surfaces of the piezoelectric elements 21a and 21b to hold the acoustic coupling agent B1 between the piezoelectric elements 21a and 21b and the sample plate 1. The piezoelectric elements 21a and 21b contact the sample plate 1 via the acoustic coupling agent B1. The acoustic coupling agent B1 does not necessarily need to be interposed between the piezoelectric elements 21a and 21b and the sample plate 1; the piezoelectric elements 21a and 21b may be in direct contact with the sample plate 1. The holes in the piezoelectric elements 21a and 21b form bearing holes 41 that penetrate the ultrasonic generator 2, and the shaft 42 of the rotation mechanism 4 is inserted through them. The number of piezoelectric elements is not particularly limited, but may be, for example, one to four.

[0072] In the ultrasonic irradiation device 100A according to Modification 1, ultrasonic waves generated by the piezoelectric elements 21a and 21b are irradiated onto the target solution L1 via solid propagation through the piezoelectric elements 21a and 21b and the sample plate 1. According to Modification 1, ultrasonic waves generated by the piezoelectric elements 21a and 21b are irradiated onto the target object without a propagation element such as the front mass 22, thereby suppressing ultrasonic attenuation. As a result, energy efficiency can be improved. Furthermore, since the ultrasonic irradiation device 100A according to Modification 1 does not include a propagation element such as the front mass 22, the entire device can be made more compact. Furthermore, from a temperature perspective, for example, at temperatures below room temperature (e.g., below 40°C), stable ultrasonic irradiation can be achieved even when the piezoelectric elements 21a and 21b are in contact with the sample plate 1 without using a propagation element such as the front mass 22. Therefore, the ultrasonic irradiation device 100A according to Modification 1 can be suitably used for biological reactions typically performed at temperatures below 40°C or polymer polymerization reactions performed using only ultrasonic waves at around 25°C.

[0073] [Modification 2] Fig. 6 is a longitudinal sectional view of an ultrasonic irradiation device 100B according to Modification 2 of the embodiment. As shown in Fig. 6, the ultrasonic irradiation device 100B according to Modification 2 differs from the ultrasonic irradiation device 100 described above in that, similar to Modification 1, the piezoelectric elements 21a and 21b (vibration elements) have container installation portions 22b formed thereon.

[0074] The driving unit 21 (piezoelectric elements 21a, 21b) according to Modification 2 extends annularly along the circumferentially arranged multiple wells 13. In other words, the piezoelectric elements 21a, 21b are present only on the circumference where the wells 13 are arranged. In Modification 2, a container installation portion 22b is formed on the upper surface (axial end surface) of the piezoelectric elements 21a, 21b to provide a space in which the sample plate 1 can be installed. Similar to Modification 1, a holding portion 22c is formed annularly on the upper surface of the piezoelectric elements 21a, 21b to hold the acoustic coupling agent B1 between the piezoelectric elements 21a, 21b and the sample plate 1. The piezoelectric elements 21a, 21b contact the sample plate 1 via the acoustic coupling agent B1. The acoustic coupling agent B1 does not necessarily need to be interposed between the piezoelectric elements 21a, 21b and the sample plate 1; the piezoelectric elements 21a, 21b may be in direct contact with the sample plate 1. The number of piezoelectric elements is not particularly limited, but may be, for example, one to four. 6, the regions of the piezoelectric elements 21a and 21b inside the holding portion 22c are hollow. The ultrasonic generator 2 according to the second modification also has a support member 27 inside the drive unit 21 that supports the drive unit 21. A bearing hole 41 that passes through the ultrasonic generator 2 is formed in the support member 27, and a shaft 42 of the rotation mechanism 4 is inserted through the bearing hole 41.

[0075] The ultrasonic irradiation device 100B according to the second modification can achieve the same effects as those of the first modification. That is, the ultrasonic irradiation device 100B according to the second modification does not include a propagation member such as the front mass 22, and therefore, the energy efficiency can be improved and the entire device can be made smaller. Furthermore, in the second modification, the piezoelectric elements 21a and 21b are present only on the circumference where the well 13 is located, and therefore, ultrasonic waves can be irradiated to the well 13 more efficiently. As a result, the energy efficiency can be further improved.

[0076] The embodiments of the ultrasound irradiation device according to the present disclosure have been described above, but each aspect disclosed in this specification can be combined with any other feature disclosed in this specification.

[0077] 1: Sample plate (an example of an "irradiation target container") 2: Ultrasonic wave generator 3: Lid member 4: Rotation mechanism 5: Temperature control device 6: Light irradiation device 7: Light detection device 8: Housing 13: Well 21a, 21b: Piezoelectric element 22: Front mass (an example of a "first propagation part") 22b: Container installation part 22c: Holding part 23: Rear mass (an example of a "second propagation part") 41: Bearing hole 42: Shaft part 43: Rotation device 100, 100A, 100B: Ultrasonic wave irradiation device

Claims

1. An ultrasonic irradiation device comprising an ultrasonic generator having a vibration element that generates ultrasonic waves by vibrating, the ultrasonic generator having a container installation section capable of installing an irradiation target container in which an object to be irradiated with the ultrasonic waves is contained, and the ultrasonic waves generated by the vibration element are propagated through a solid to the irradiation target container.

2. The ultrasonic irradiation device of claim 1, wherein the ultrasonic generating device further has a first propagation section that propagates the ultrasonic waves through a solid, the first propagation section having the container installation section and propagating the ultrasonic waves to the container to be irradiated.

3. An ultrasonic irradiation device as described in claim 1 or 2, wherein the container installation section is formed with a holding section that holds an acoustic coupling agent capable of propagating ultrasonic waves between the ultrasonic generator and the irradiation target container.

4. An ultrasonic irradiation device as described in claim 1 or 2, further comprising a rotation mechanism that rotates the irradiation target container installed in the container installation section relative to the ultrasonic generator around a rotation axis arranged along the alignment direction of the vibration element and the container installation section.

5. The ultrasonic irradiation device described in claim 4, wherein the rotation mechanism comprises: a bearing hole penetrating the ultrasonic generator along the rotation axis; a shaft portion inserted into the bearing hole and connected to the irradiation object container so as to rotate integrally with the irradiation object container; and a rotation device arranged on the opposite side of the container installation portion with respect to the vibration element in the arrangement direction, to which the shaft portion is connected and which rotates the shaft portion around the rotation axis.

6. The ultrasonic irradiation device of claim 4, wherein the irradiation object container has one or more container sections arranged circumferentially around the rotation axis and in which the objects are contained, and the container installation section is formed with a holding section that holds an acoustic coupling agent capable of propagating ultrasonic waves between the ultrasonic generator and the container section, and the holding section is formed as an annular groove extending circumferentially around the rotation axis.

7. The ultrasonic irradiation device according to claim 1 or 2, wherein the container installation section is formed as a recessed section capable of accommodating the irradiation target container and having an opening on one side, and the ultrasonic irradiation device further comprises a lid member capable of opening and closing the opening of the recessed section.

8. The ultrasonic irradiation device according to claim 7, wherein at least one of the container mounting portion and the lid member is formed with a window portion for performing fluorescence measurement of the object from outside the recess portion.

9. The ultrasonic irradiation device according to claim 1 or 2, further comprising a temperature control device capable of adjusting the temperature of the object.

10. The ultrasonic irradiation device according to claim 2, wherein the ultrasonic generator has a second propagation section arranged on the opposite side of the vibration element to the first propagation section, and which propagates the ultrasonic waves generated by the vibration element through a solid.

11. The ultrasonic irradiation device according to claim 1, wherein the container mounting portion is formed on the vibration element.

12. The ultrasonic irradiation device of claim 11, wherein the irradiation object container has one or more container sections arranged in a circular shape in which the objects are contained, and the vibration element extends in a circular shape along the one or more wells.

13. The ultrasonic irradiation device according to claim 1 or 2, further comprising a container for accommodating the irradiation object.