WO2004054704A1 - Particles handling method and device - Google Patents

Abstract

An Si substrate (1) is thinned by plasma-etching or chemical etching. A region (2) of this thin Si substrate is provided, and an ultrasonic wave generator (3) for generating an ultrasonic wave is provided on the bottom of the region (2). The ultrasonic wave generator (3) comprises a piezoelectric element (7) such as of PZT having upper and lower electrodes (4, 5). The piezoelectric element (7) is attached to a predetermined position on the back of the substrate (1). It is desirable that the lower limit of the thickness of the piezoelectric element (7) is 1 μm or greater in view of the power of the generated ultrasonic wave necessary to handle particles or 50 μm or less to lower the drive voltage in view of its practical use as a small device. Further it is desirable that the thickness of the substrate (1) made of Si is 500 μm or less in view of local or efficient application of ultrasonic wave like the thickness of the PZT piezoelectric element (7). When an ultrasonic wave of a frequency of 1 kHz or greater is emitted from the bottom of the substrate (1) where the ultrasonic generator (3) is provided toward the top surface of the substrate (1), particles (8) dispersed in a solution over the substrate (1) gather in the central part at which the piezoelectric element is placed and which is the antinode of the sound vibration, and the particles are aggregated and condensed.

Description

 Description Method and apparatus for handling fine particles

 According to the present invention, fine particles having a size of 100 / m or less, drug powder, DNA, and the like developed on the substrate (in the present specification, these are collectively referred to simply as “fine particles”) are used on the substrate. The present invention relates to a method and an apparatus for conveying, mixing, concentrating, and separating. Background art

 In the fields of biology, medicine, and pharmacy, techniques for analyzing and diagnosing very small amounts of samples dispersed in liquids in a non-contact manner are required for various reasons, such as high-speed processing and portability of equipment. .

 Conventionally, there has been proposed a method using a laser to emit light or a liquid flow by heating to handle fine particles dispersed in a liquid (conventional example 1).

 Also, in microchemical analyzers and medical analyzers that apply micromachining, etc., in order to enhance their portability, minute flow for guiding an analyte or a chemical solution on a substrate on which an analysis element is arranged is proposed. A card-shaped analyzer provided with a road-to-cavity has been proposed (conventional example 2).

 However, when the thermal effect is used, as in Conventional Example 1, there is a problem in the response speed and stability of the fine particles, and it is maintained at a high surface tension in the thin liquid film spread on the substrate. It was difficult to handle a large amount of fine particles in a lump, and the amount of particles that could be handled was small and lacked practicality.

 In addition, in the case of Conventional Example 2, it was difficult to clean a solid analytical sample such as a drug solution or DNA adhered to the minute flow path cavity, and it had to be used as a disposable device. Therefore, there is a problem that an advanced and complicated analysis becomes expensive and its use is limited.

The present invention has been made based on new knowledge to solve the problems of the prior art, and has described the aggregation phenomenon of fine particles by ultrasonic radiation and the development of liquid on a flat substrate. It is an object of the present invention to provide a technique for handling fine particles by using ultrasonic waves on a substrate without using a guide such as a flow path and a cavity by utilizing the surface tension of a film. Disclosure of the invention

 First, the principle of the present invention will be described.

 When ultrasonic waves are applied to the fine particles dispersed in the liquid placed in the container, the pressure of the ultrasonic standing node formed in the container is lower than that of the antinode, and as a result, the particles are dispersed in the liquid. Fine particles collect in the nodes and are concentrated. This is known as the “aggregation phenomenon of fine particles due to ultrasonic radiation pressure” and is described in the literature (Applied Physics Vol. 67, No. 3, p. 323-326).

 On the other hand, in the case of irradiating the fine particles in the thin liquid film with a wavelength less than the wavelength of the applied ultrasonic wave spread or applied on the substrate, the motion of the fine particles is quasi-two-dimensionally constrained by the thickness of the liquid film, Further, since the distance from the ultrasonic source is equal to or shorter than the wavelength, the fine particles dispersed in the liquid gather at the antinode of the vibration unlike the case where the ultrasonic radiation pressure is used, as described later. This difference is thought to be due to the pronounced effects of the near-field effect of ultrasonic waves and the effect of surface tension acting between the liquid film particles and the substrate.

 The present invention utilizes the new phenomenon of agglomeration of fine particles due to ultrasonic radiation and the surface tension of a liquid film spread on a flat substrate, and uses ultrasonic waves on the substrate without a guide such as a channel or cavity. The purpose is to provide a technology for handling fine particles.

 In the present specification, “ultrasonic waves” generally refers to various kinds of elastic waves having a high frequency as ultrasonic waves, and refers to sound waves having a frequency of about 1 kHz or more.

 In order to achieve the above object, the method for handling fine particles according to the present invention comprises the steps of: developing fine particles mixed with a solution, applying ultrasonic waves thereto, and transporting, mixing, aggregating, concentrating, or It is characterized by being separated.

 The method for handling fine particles of the present invention is characterized in that the thickness of the liquid film formed by mixing the solution and the fine particles is equal to or less than the wavelength of the applied ultrasonic wave.

Further, the method for handling fine particles of the present invention is characterized in that a solution and fine particles are mixed and formed. It is characterized in that the thickness of the formed liquid film is in the range of 3 to 10 times the particle diameter of the fine particles. Further, in the fine particle handling apparatus of the present invention, an ultrasonic wave generating source is provided on a back surface of a substrate that spreads the fine particles mixed with the solution on the front surface, and ultrasonic waves are applied to the fine particles mixed with the liquid from the back surface side of the substrate. It is characterized by applying.

 Further, the fine particle handling apparatus of the present invention is characterized in that a piezoelectric element composed of a PZT film formed on the back surface of a substrate by an aerosol deposition method is used as an ultrasonic wave generating source.

 Further, the particle handling apparatus of the present invention is characterized in that at least two or more ultrasonic sources are provided on the back surface of the substrate, and these ultrasonic sources are sequentially operated.

 Further, the fine particle handling apparatus of the present invention is characterized in that the fine particles are 1 or more and 100 µm or less.

 Further, the fine particle handling apparatus of the present invention is characterized in that the ultrasonic wave applied to the fine particles mixed with the solution is 1 kHz or more.

 Further, the fine particle handling apparatus of the present invention is characterized in that a liquid film formed by mixing the solution and the fine particles has a thickness of 1 Omm or less.

 Further, the fine particle handling apparatus of the present invention is characterized in that the thickness of the substrate is in the range of 0.5 to 500 zm.

 Further, the fine particle handling apparatus of the present invention is characterized in that the voltage amplitude applied to the ultrasonic generator is 30 V or less.

According to the present invention, it is possible to collectively handle a large amount of fine particles maintained at a high surface tension in a thin liquid film spread on a substrate, and the amount that can be handled is practically required. It is enough. It also has excellent transport response speed and stability of fine particles. In addition, in the present invention, fine particles can be handled (conveyed, aggregated, mixed, dispersed, separated, etc.) in a non-contact manner without forming a microchannel (cavity) on the substrate surface, so that the liquid film and the fine particles come into contact with each other. The surface is flat, making it easy to clean the device.In addition, since there is no fixed guide such as a flow path on the surface of the substrate where the liquid film and fine particles come in contact, the same device can be used in any direction. Transport, aggregation, and dispersion of fine particles and liquid can be performed. Further, according to the present invention, the operation is easier than conventional ones, It is possible to provide a dring device. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a front sectional view schematically showing a fine particle handling apparatus according to Embodiment 1 of the present invention.

 FIG. 2 shows an experimental example 1 according to the first embodiment of the present invention, and is an image viewed from the upper surface of the fine particle handling apparatus.

 FIG. 3 shows Experimental Example 2 according to Embodiment 1 of the present invention, and is an image viewed from the upper surface of a fine particle handling apparatus.

 FIG. 4 shows Experimental Example 3 according to Embodiment 1 of the present invention, and is an image viewed from the upper surface of the fine particle handling apparatus.

 FIG. 5 shows Experimental Example 4 according to Embodiment 1 of the present invention, and is an image viewed from the upper surface of a fine particle handling apparatus.

 FIG. 6 is a diagram showing a result of measuring a vibration state of the substrate when applying ultrasonic waves according to Embodiment 1 of the present invention with a laser displacement meter.

 FIG. 7 is a front view showing an example in which the back surface of the substrate is etched, and a piezoelectric element as an ultrasonic generation source is provided in the etched portion.

 FIG. 8 shows that a plurality of piezoelectric elements, which are ultrasonic wave generating sources, are arranged on a flat back surface of a substrate according to Embodiment 2 of the present invention, and are sequentially driven to be applied on the substrate surface. FIG. 4 is a front view showing a state of transporting fine particles in a liquid film.

 FIG. 9 is an explanatory diagram showing an example in which fine ultrasonic sources are arranged in a matrix according to Embodiment 2 of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings. [Embodiment 1]

 1 to 7 show the first embodiment.

Fig. 1 is a front sectional view showing the outline of the particle handling apparatus. The figure on the left shows when the power is off, and the figure on the right shows when the power is on. The particle handling device is manufactured according to the following procedure.

 First, the silicon is processed by plasma etching (ICP-RIE: Inductive Plasma Coupling Reactive Etching) or chemical etching (anisotropic etching) to provide a thin Si substrate region 2 as shown in Fig. 1. (As a result, a very small container (cavity) is formed.) On the bottom surface of this region 2, an ultrasonic wave generating source 3 for generating ultrasonic waves is provided.

 In the ultrasonic generator 3, a piezoelectric element 7 such as PZT provided with the upper electrode 4 and the lower electrode 5 is attached to a predetermined position on the back surface of the substrate 1. At this time, the piezoelectric element 7 as the ultrasonic wave generation source 3 is applied to the lower electrode 5 such as Pt by applying PZT fine particles to the lower electrode 5 by an aerosol deposition method (for example, a fine particle deposition method disclosed in Patent Publication 2002-20878). When formed directly by spraying on the provided Si substrate 1, the absorption of generated ultrasonic waves is minimized because no adhesive is used, so that the liquid film applied on the Si substrate 1 Sound waves can be efficiently propagated over a wide frequency range.

 Further, the lower limit of the thickness of the PZT piezoelectric element 7 to be formed is 1 zm or more in view of the generation power of the ultrasonic waves necessary for handling the fine particles, and is 50 to reduce the driving voltage from the viewpoint of practical use as a small device. It is desirable to set it to m or less. Also, the thickness of the 反 | anti-one formed by Si or the like is 500 // m or less in consideration of local or efficient application of ultrasonic waves, similarly to the thickness of the PZT piezoelectric element 7. desirable. Next, a mixture of glass particles 8 having a particle diameter of 500 μm or less and a solution 9 is applied or dropped onto the substrate 1 provided with the ultrasonic generator 3 thus formed, and a thin liquid film 10 is formed. When ultrasonic waves are generated at a frequency of 1 kHz or more from the bottom surface of the substrate 1 on which the ultrasonic wave source 3 is disposed toward the surface of the substrate 1, fine particles dispersed in the solution on the surface of the substrate 1 are formed. As shown in FIGS. 2 to 5, the piezoelectric elements 8 are arranged at the center of the ultrasonic source, which is the antinode of acoustic vibration, and are aggregated and concentrated. One

In Experimental Examples I to II shown in FIGS. 2 to 5, the particle diameter of the fine particles 8 is 5 μm, 20 μm, and 124 zm, the thickness of the liquid film 10 is 1 to 6 mm, and the thickness of the Si substrate 1 Is 65 zm, 100 μm, piezoelectric element (PZT layer) 7 Thickness is 10 to 15 μm, driving ultrasonic frequency is 10 kHz, 13 kHz, 96 kHz, 144 kHz, 214 kHz, driving voltage is 10 V earth 9 kinds of solution, water, ethylene glycol, paraffin, silicone oil It is. At this time, the surface of the liquid film 10 is dragged by the surface tension acting between the fine particles 8 and swells with the aggregation of the fine particles 8 .When the applied ultrasonic vibration is cut off, the thermal vibration of the solution 9 and the substrate 1 Due to the surface tension, the fine particles 8 concentrated and collected just below the ultrasonic source are dispersed again. That is, the aggregation operation of the fine particles 8 can be performed reversibly by turning on and off the ultrasonic irradiation.

 Also, the fine particles that aggregated during the ultrasonic irradiation are not collected statically, but create a flow between them and the liquid, and are collected while moving dynamically. Therefore, it is possible to mix different kinds of fine particles, and it is also possible to mix and react fine particles with a solution.

 The speed of aggregation of the microparticles 8 can be controlled by the drive voltage applied to the piezoelectric element 7, and it has been confirmed that the moving speed of the microparticles 8 increases as the power of the ultrasonic source (element amplitude) increases. . In addition, as shown in Experiments 1 to 3 in FIGS. 2 to 4, the aggregating operation can be realized by ultrasonic waves regardless of the particle diameter of the fine particles 8 and the type of the solution 9. The frequency of the irradiation ultrasonic wave at this time is not the resonance frequency of 1 (5 kHz with solution, 20 kHz without solution: 20 kHz).

 In addition, the aggregation speed of the fine particles 8 changes according to the viscosity of the solution or the particle size of the fine particles, in addition to the above-described driving voltage applied to the piezoelectric element 7. By utilizing this property, it is possible to separate fine particles or separate fine particles from a solution.

Further, Experimental Example I in FIG. 5 is a result of examining the change in the aggregation operation when the frequency of the ultrasonic wave was changed. The coagulation operation could be realized over 10 kHz to 200 kHz. At this time, in all the experiments (1) to (6) above, the sound wave wavelength in the solution was 7 mm to 150 mm, and the thickness of the liquid film 10 and the size of the cavity formed on the substrate 1 used in the experiment From the above, it is considered from the wavelength of the ultrasonic wave that the trapping phenomenon of the fine particles in the liquid of the present invention is considered to be due to the effect of near-field ultrasonic waves. The mechanism of the aggregation phenomenon of the fine particles in the liquid due to the ultrasonic radiation pressure described above is as follows. It was confirmed that they were different. In addition, the amplitude (d) of the vibration part of the substrate is very small, from 1 Onm (at 10 kHz) to 2 nm (at 214 kHz). Became. For confirmation, the vibration state of the substrate 1 when ultrasonic waves were applied was measured with a laser displacement meter (manufactured by Ono Sokki Co., Ltd .: LV-16010 & Fringe Count Yuichi LV-0 201). As a result, as shown in Fig. 6, it was a primary vibration mode in which the maximum displacement occurred at the center of the ultrasonic source where particles were aggregated by applying ultrasonic waves. Also, when only the fine particles 8 were placed on a substrate provided with the same ultrasonic source with the liquid removed, and the ultrasonic waves were irradiated, the fine particles 8 on the S-anti-vibrator only vibrated on the spot, and these fine particles 8 No aggregation phenomenon of 8 was observed. In other words, the method of handling fine particles of the present invention is essentially different from the principle of using vibration and gravity, such as a power feeder used to convey minute parts such as screws. confirmed.

 In this example, water, ethylene glycol, paraffin, and silicon oil were used as the solution 9 to be applied to prevent spontaneous evaporation and drying, but the same operation can be performed with other liquids such as alcohols. Select appropriately according to the application. Also, the force acting on the microparticles 8 by the ultrasonic wave becomes small depending on the particle size, and eventually becomes disturbed due to Brownian motion and cannot be handled. Experimentally, it was confirmed that operation was possible up to a particle diameter of about 0.5 µm. In the present invention, the thickness of the liquid film 10 is affected by the particle size of the fine particles 8 used, but is preferably about 3 to 10 times the diameter of the fine particles used experimentally.

 If a liquid 9 having a high viscosity or a large surface tension is used as the liquid 9 forming the liquid film 10, the influence of gravity can be ignored, and the liquid 9 is developed on the substrate 1 without applying a special cover to the surface of the substrate 1. The liquid 9 and the fine particles 8 can be used without spilling, which has an advantage that the apparatus is simplified.

 Further, in the experiment of the above embodiment, a minute cavity is provided on the substrate 1 by etching, but this is not for guiding the solution 9 but for the local and efficient ultrasonic wave in the solution 9 and the fine particles 8. This is because the thickness of the Si substrate 1 is reduced to apply the voltage, and the reflection of the sound wave from the side wall is used. This is not essential from the operating principle of the present apparatus. Therefore,

Etching is performed on the Si substrate 1 in order to efficiently apply ultrasonic waves, and the portion where the thickness is reduced does not need to be provided on the surface of the substrate 1 on which the liquid film 10 is applied, as shown in FIG. In this manner, the back surface of the substrate 1 may be etched, and the piezoelectric element 7 serving as the ultrasonic wave generating source 3 may be provided. That is, if ultrasonic waves are applied to the substrate 1, the fine particles 8 in the liquid film 10 generate ultrasonic waves. It is confined in the vicinity of the source 3 and does not require a guide for minute cavities or minute channels, and enables stable handling and analysis of fine particles on one flat (flat) substrate. In addition, this eliminates the need for providing a complicated flow path (cavity) and facilitates cleaning of the analyzer.

 In the case of the configuration shown in Fig. 7, it is difficult to form a piezoelectric film using conventional thin-film technology.If PZT fine particles are sprayed from a nozzle by an air port sol deposition method and local patterning is performed. It can be easily manufactured.

 [Embodiment 2]

 FIG. 8 and FIG. 9 show the second embodiment.

 Based on the basic operation of the first embodiment, as shown in FIG. 8, a plurality of piezoelectric elements で, which are the ultrasonic wave generation sources 3, are arranged on the back surface of the flat Si substrate 1 and sequentially driven, and The fine particles 8 in the liquid film 10 applied on the surface can be transported. Next, the operation will be described. First, when one of the plurality of arranged piezoelectric elements 7 is operated, particles 8 existing around the piezoelectric element 7 are located near the piezoelectric element 7 based on the principle of the first embodiment. Agglomerates. Next, when the driving of the piezoelectric element 7 is stopped or gradually weakened, and the adjacent piezoelectric element 7 is gradually driven, the fine particles 8 gathered in the vicinity of the piezoelectric element 7 are separated by the same principle. It is attracted to the vicinity and aggregates near the piezoelectric element 7. By sequentially driving such an operation over a plurality of adjacent piezoelectric elements 7, as a result, the microparticles 8 can move according to the arrangement of the piezoelectric elements arranged on the substrate 1.

Such an arrangement of the piezoelectric elements 7 corresponds to the pattern of the conventional microchannel, and the arrangement and size thereof are selected as required for operations such as transport, mixing, and aggregation. Fine ultrasonic sources are arranged in a matrix as shown in Fig. 9 and driven sequentially in a single-stroke form.By combining the ultrasonic sources to be driven, the same element can be used to remove the fine particles 8 on the substrate 1. Handling in any vector direction is possible, and the device can be provided at low cost for various purposes. The arrangement interval of the ultrasonic sources and the switching time of each ultrasonic source are appropriately adjusted according to the viscosity of the liquid, the thickness of the liquid film, the size of the particles, the frequency and the intensity of the ultrasonic wave. Industrial applicability As described above, the method and the apparatus for handling fine particles according to the present invention are capable of transporting, mixing, concentrating, transferring fine particles having a size of 100 / m or less, drug powder, DNA and the like spread on the substrate. It is useful for separation, and especially suitable for non-contact handling, analysis and diagnosis of extremely small amounts of samples dispersed in liquids in the fields of biology, medicine and pharmacy.

Claims

The scope of the claims  I. A method for handling fine particles, comprising developing fine particles mixed with a solution on a substrate, applying ultrasonic waves to the fine particles, and conveying, mixing, aggregating, concentrating, or separating the fine particles and the solution.  2. The method of claim 1, wherein the thickness of the liquid film formed by mixing the solution and the particles is equal to or less than the wavelength of the applied ultrasonic wave. .  3. The method for handling fine particles according to claim 1, wherein the thickness of the liquid film formed by mixing the solution and the fine particles is in the range of 3 to 10 times the particle diameter of the fine particles. 4. An ultrasonic wave generating source is provided on the back surface of a substrate for developing fine particles mixed with a solution on the surface, and ultrasonic waves are applied to the fine particles mixed with the liquid from the back surface side of the substrate. Handling equipment.  5. The apparatus for handling fine particles according to claim 4, wherein a piezoelectric element composed of a PZT film formed on the back surface of the substrate by an aerosol deposition method is used as an ultrasonic generation source.  6. The fine particle handling apparatus according to claim 4, wherein at least two or more ultrasonic sources are provided on the reverse side of the S, and these ultrasonic sources are sequentially operated. .  7. The device for handling fine particles according to any one of claims 4 to 6, wherein the fine particles have a size of l〃m or more and 100〃m or less.  8. The handle for fine particles according to any one of claims 4 to 7, wherein the ultrasonic wave applied to the fine particles mixed with the solution is 1 kHz or more. Device.  9. The fine particles according to any one of claims 4 to 8, wherein the thickness of the liquid film formed by mixing the 'solution' and the fine particles is 1 mm or less. Handling equipment.  10. The apparatus for handling fine particles according to any one of claims 4 to 9, wherein the thickness of the substrate is in a range of 0.5 to 500 / zm. II. The voltage amplitude applied to the ultrasonic source is 30 V or less. The device for handling fine particles according to any one of paragraphs 4 to 10 ₍