Patent Application
20190293599
This application is based upon and claims the benefit of priority from Japanese Patent Application No. 2018-053019, filed Mar. 20, 2018, the entire contents of which are incorporated herein by reference.
Embodiments described herein relate generally to an analyzing apparatus for analyzing a particle in a liquid.
As an analyzing apparatus for analyzing particles in a specimen liquid, there is the one including an image sensor. The particles include, for example, a cell labeled with a labeling substance and another type of cell not labeled with the labeling substance. The specimen liquid is supplied onto a sensor surface of the image sensor. Although it is necessary to detect whether desired particles are contained in the specimen liquid and to quickly determine the number of particles, a time (settling time) until the particles naturally arrive at the sensor surface is long and it takes time to complete measurement of the particles with the image sensor.
In general, according to one embodiment, an analyzing apparatus is disclosed. The analyzing apparatus includes a generation device to generate an electromagnetic force for drawing a particle in a first liquid that is to be supplied onto a substrate, wherein the electromagnetic force draws the particle to the substrate side, and a measurement device to measure an image of the first liquid on the substrate. The analyzing apparatus further includes a control device to control the generation device, and a liquid channel structure that includes a first supply channel for supplying a liquid onto the substrate and a first drain channel for draining a liquid on the substrate.
Embodiments will be described hereinafter with reference to the accompanying drawings. The drawings are schematic or conceptual drawings, and dimensions and ratios are not necessarily the same as those in reality. Further, in the drawings, the same reference symbols (including those having different subscripts) denote the same or corresponding parts, and overlapping explanations thereof will be made as necessary. In addition, as used in the description and the appended claims, what is expressed by a singular form shall include the meaning of “more than one”.
The fine particle analyzing apparatus 1 includes a substrate 2. A specimen liquid (liquid) containing fine particles (hereinafter, referred to as a “target particles”), such as cells labeled with a magnetic bead or beads, is supplied onto the substrate 2.
The fine particle analyzing apparatus 1 further includes a magnetic force generation device 3 that generates a magnetic force for drawing the target particle in the specimen liquid on the substrate 2 to the substrate 2 side. The magnetic force generation device 3 is, for example as shown in
The fine particle analyzing apparatus 1 further includes a measurement device 4 that measures an image of the specimen liquid on the substrate 2. In the present embodiment, the measurement device 4 includes an image sensor. The image sensor is, for example, an array sensor, such as a CMOS (complementary metal-oxide semiconductor) image sensor or a CCD (charge coupled device) image sensor. The CMOS image sensor includes photodiodes as photoelectric conversion elements for each pixel and a plurality of MOS transistors that select and drive the photodiodes. In the present embodiment, the measurement device 4 is a lensless image sensor the sensor surface (a plurality of pixels) of which directly contacts the specimen liquid. More specifically, directly contacting the specimen liquid means that an objective lens for magnifying an image to be analyzed is not included between the photodiode and the specimen liquid. The distance between the photodiode and the specimen liquid is less than 1 mm, less than 10 μm, or less than 1 μm. The target particle is drawn and held onto the sensor surface (to the substrate 2 side) by a magnetic force.
The fine particle analyzing apparatus 1 further includes a control device 5 that controls the magnetic force generation device 3. The control device 5 controls the magnetic force generation device 3 so that a magnetic force is generated or the generated magnetic force vanishes. In a case where the magnetic force generation device 3 is an electromagnet shown in
The fine particle analyzing apparatus 1 further includes a liquid channel structure 6 (6a, 6b) provided on the substrate 2. The liquid channel structure 6 includes a first supply channel 11 for supplying a liquid onto the substrate 2 and a first drain channel 12 for draining a liquid on the substrate 2. The liquid channel structure 6 is configured from a first member 6a and a second member 6b, and the second member 6b is provided outside the first member 6a. The material of the first member 6a and the second member 6b is, for example, a resin, such as polydimethylsiloxane (PDMS).
The first supply channel 11 includes a portion vertical to a surface of the substrate 2 and a portion parallel to the surface. The portion vertical to the surface of the substrate 2 of the first supply channel 11 is formed of the second member 6b, and the portion parallel to the surface of the substrate 2 of the first supply channel 11 is formed of the first member 6a. The same applies to the first drain channel 12. The first member 6a has an opening 7 and the specimen liquid is supplied onto the substrate 2 through the opening 7. The opening 7 functions as a liquid reservoir part of the specimen liquid.
Next, with reference to
First, as shown in
Next, the control device 5 controls the magnetic force generation device 3 to generate a magnetic force. Since the target particle 8 is labeled with the magnetic beads, the target particle 8 is drawn to the sensor surface by the magnetic force, as shown in
Since, as described above, the target particle 8 is drawn to the sensor surface by the magnetic force, the time until the target particle 8 in the specimen liquid 20 arrives at the sensor surface (settling time) is shortened. Consequently, the time required to complete measurement of the target particle in the specimen liquid 20 supplied onto the substrate 2 is shortened.
Next, the measurement device 4 measures an image of the specimen liquid 20 on the substrate. In the present embodiment, the measurement device 4 measures an image of the specimen liquid 20 on the sensor surface on the substrate. On this occasion, to be more effective, not an ambient light but an illumination light for obtaining a bright-field image may be irradiated into the specimen liquid 20 from a light source not illustrated. In the present application, the fine particle analyzing apparatus 1 encompasses a fine particle analyzing apparatus that does not include a light source.
Next, the control device 5, based on the image measured by the measurement device 4, determines whether or not the target particle 8 in the specimen liquid 20 is held on the sensor surface. In the present embodiment, if the target particle 8 has been measured, the control device 5 determines that the target particle 8 is held. In a case where the target particle 8 is determined to be held on the sensor surface, the control device 5 controls the magnetic force generation device 3 to keep generating the magnetic force.
After that, a cleaning is performed as shown in
After completion of cleaning, the number of target particles or the like is measured and analyzed in a condition without the foreign substance 9.
Note that, when the target particle 8 is labeled with a fluorescent bead or a fluorescent staining in addition to the magnetic bead, and the specimen liquid 20 is irradiated with light having a predetermined wavelength, then the target particle 8 emits fluorescence having a predetermined wavelength, and an image formed by the fluorescence is measured with the measurement device 4 that further includes a filter not transmitting the irradiated light. The measurement of fluorescence facilitates identifying a type of the target particle. In addition, in a case where the target particle has a subcategory, the subcategory can be discriminated by the fluorescence. The light having the predetermined wavelength is irradiated from a light source (not shown) into the specimen liquid 20. In the present application, the fine particle analyzing apparatus 1 encompasses a fine particle analyzing apparatus that does not include a light source.
After that, the control device 5 controls the magnetic force generation device 3 to vanish the generated magnetic force.
Next, as shown in
Further, returning to the first step of supplying a specimen liquid, the same process may be repeated. Thus, a small amount of target particles contained in a large quantity of specimen liquid can be analyzed.
The fine particle analyzing apparatus 1 of the present embodiment differs from the fine particle analyzing apparatus 1 of the first embodiment in a point that a liquid channel structure 6 further includes a second drain channel 13.
In the present embodiment, for example, in a state where a target particle is held on a sensor surface by a magnetic force, a first cleaning liquid is supplied from a first supply channel 11 onto a substrate 2, and a foreign substance, a specimen liquid, and a first cleaning liquid are drained from a first drain channel 12.
After that, in a state where a magnetic field has vanished, a second cleaning liquid is supplied from the first supply channel 11 onto the substrate 2, and the second cleaning liquid containing the target particle is drained from the second drain channel 13. Thus, mixing of the foreign substance into the second cleaning liquid containing the target particle can be prevented, and thereafter another further analysis, such as genomic analysis or protein analysis, can be performed on the target particle 8 in the drained cleaning liquid 22.
The fine particle analyzing apparatus 1 of the present embodiment differs from the fine particle analyzing apparatus 1 of the second embodiment in a first point that a liquid channel structure 6 forms a cavity region 10 (
The fine particle analyzing apparatus 1 of the present embodiment differs from the fine particle analyzing apparatus 1 of the second embodiment in a second point that the liquid channel structure 6 further includes a second supply channel 14 (
The first supply channel 11, the first drain channel 12, and the second drain channel 13 of the present embodiment correspond to the first supply channel 11, the first drain channel 12, and the second drain channel 13 of the second embodiment, respectively. Therefore, the target particle can be drained as in the second embodiment, and the same effect as that of the second embodiment can be obtained.
In addition, in the case of the present embodiment, for example, as shown in
The fine particle analyzing apparatus 1 of the present embodiment differs from the fine particle analyzing apparatus 1 of the first to third embodiments in a point that an electrophoretic force generation device is used instead of the magnetic force generation device 3. The electrophoretic force generation device includes a first electrode 31 provided on a sensor surface in a cavity region 10, a second electrode 32 provided on an upper surface of the cavity region 10 and facing the first electrode 31, and a direct voltage source 33 for applying a direct voltage between the first electrode 31 and the second electrode 32. The first electrode 31 and the second electrode 32 are, for example, formed of a conductive transparent material, such as ITO (indium tin oxide) or conductive glass.
Note that, although
The fine particle analyzing apparatus 1 of the present embodiment differs from the fine particle analyzing apparatus 1 of the first to third embodiments in a point that a dielectrophoretic force generation device is used instead of the magnetic force generation device 3. The dielectrophoretic force generation device includes a first electrode 51 provided on an upper surface in a cavity region 10, a second electrode 52 provided on an upper surface of the cavity region 10 and disposed apart from the first electrode 51, and an alternating voltage source 53 for applying an alternating voltage between the first electrode 51 and the second electrode 52. The first electrode 51 and the second electrode 52 are, for example, formed of a conductive transparent material, such as ITO or conductive glass.
Note that, the target particle is not limited to a bio-based fine particle, such as a cell, and, for example, may be a floating fine particle, such as PM10 or PM2.5. In this case, instead of the specimen liquid, for example, a solvent in which the floating fine particle is dissolved is used.
Although in the above-described embodiments, the liquid channel structure including a portion vertical to the substrate 2 and a portion parallel to the substrate 2 is used for the supply channel and the drain channel, as shown in
Although in the above-described embodiments, the number of types of the target particle is one, two or more types of the target particle may be used. In this case, the numbers of the supply channels and drain channels may be appropriately changed according to the number of types of the target particle. For example, the number of the supply channels is the same as the number of types of the target particle, and the number of the drain channels is the same as the number of types of the target particle.
The target particle may be drawn to and held on the substrate side by use of an electromagnetic force other than an electrophoretic force and a dielectrophoretic force, for example, a force based on an electroosmotic flow. In addition, a labeling substance that labels a target particle according to an electromagnetic force to be used can be appropriately used. For example, usable is a labeling substance that includes at least one of a magnetic bead, a chargeable bead, and a bead having a predetermined complex dielectric constant and a predetermined size, which work according to the electromagnetic force to be used. As labeling principle, an antigen antibody, an aptamer, and the like are usable.
In addition, although in the above-described embodiments, the substrate 2 and the structure 6 are members separated from each other, a member formed by integrating the substrate 2 and the structure 6 may be used.
While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Indeed, the novel embodiments described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions and changes in the form of the embodiments described herein may be made without departing from the spirit of the inventions. The accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the inventions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2018-053019 | Mar 2018 | JP | national |
