ABSTRACT
Abstract
A microchip is provided, which includes a substrate including a fluid channel structure. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid introduction channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid so as to suppress a spiral flow field generated after the merging.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. application No. U.S. Ser. No. 14/879,639, filed on Oct. 9, 2015, which is a continuation of U.S. application Ser. No. 13/580,912, filed on Aug. 23, 2012, which is a national stage of International Application No. PCT/JP2011/000902 filed on Feb. 18, 2011, which claims priority to Japanese Patent Application No. 2010-043968 filed on Mar. 1, 2010, the disclosures of each of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to a microchip and a particulate analyzing device. More particularly, the present invention relates to a microchip or the like for optically, electrically or magnetically analyzing the characteristics of particulates such as cells or microbeads in channels.
BACKGROUND
In recent years, microchips have been developed in which an area and/or a channel or channels for performing chemical and biological analyses are provided by application of micro-machining techniques used in the semiconductor industry. These microchips have begun to be utilized for electrochemical detectors in liquid chromatography, small electrochemical sensors in medical service sites, and the like.
Analytical systems using such microchips are called micro-TAS (micro-Total-Analysis System), lab-on-a-chip, bio chip or the like, and is paid attention to as a technology by which chemical and biological analyses can be enhanced in speed, efficiency and level of integration or by which analyzing devices can be reduced in size.
The micro-TAS, which enables analysis with a small amount of sample and enables disposable use of microchips, is expected to be applied particularly to biological analyses where precious trace amounts of samples or a multiplicity of specimens are treated.
An application example of the micro-TAS is a particulate analyzing technology in which characteristics of particulates such as cells and microbeads are analyzed optically, electrically or magnetically in channels arranged on microchips. In the particulate analyzing technology, fractional collection of a population satisfying a predetermined condition or conditions from among particulates on the basis of analytical results of the particulates is also conducted.
Patent Literature 1, Japanese Patent Laid-open No. 2003-107099, for example, discloses âa particulate fractionation microchip having a channel for introducing particulate-containing solution, and a sheath flow forming channel arranged on at least one lateral side of the introducing channel.â The particulate fractionation microchip further has âa particulate measuring section for measuring the particulates introduced, at least two particulate fractionating channels disposed on the downstream side of the particulate measuring section so as to perform fractional collection of the particulates, and at least two electrodes disposed in the vicinity of channel ports opening from the particulate measuring section into the particulate fractionating channels so as to control the moving direction of the particulates.â
The particulate fractionation microchip disclosed in Patent Literature 1 , typically, is so designed that fluid laminar flows are formed by a âtrifurcated channelâ having a channel for introducing a particulate-containing solution and two sheath flow forming channels (see â FIG. 1 â of the literature).
FIGS. 17A and 17B show a trifurcated channel structure according to related art ( FIG. 17A ), and sample liquid laminar flows formed by the channel structure ( FIG. 17B ). In the trifurcated channel, a sample liquid laminar flow passing through a channel 101 in the direction of solid-line arrow in FIG. 17A can be sandwiched, from the left and right sides, by sheath liquid laminar flows introduced through channels
102 , 102 in the directions of dotted-line arrows in the figure. By this, as shown in FIG. 17B , the sample liquid laminar flow can be fed through the center of the channel. Incidentally, in FIG. 17B , the sample liquid laminar flow is depicted in solid lines, and the channel structure in dotted lines.
According to the trifurcated channel shown in FIGS. 17A and 17B , the sample liquid laminar flow is sandwiched by the sheath liquid laminar flows from the left and right sides, whereby with respect to the sandwiching direction (the Y-axis direction in FIGS. 17A and 17B ), the sample liquid laminar flow can be fed in the state of being deflected to an arbitrary position in the channel. With respect to the vertical direction (the Z-axis direction in FIGS. 17A and 17B ) of the channel, however, it has been very difficult to control the sample liquid feeding position. In other words, in the trifurcated channel according to related art, it has only been possible to form the sample laminar flow that is oblong in the Z-axis direction.
Therefore, the microchip having the trifurcated channel according to related art has the problem that in the case where, for example, a particulate-containing solution as a sample liquid is made to flow through a channel and subjected to optical analysis, there would be a dispersion of the feeding position of the particulates in the vertical direction (depth direction) of the channel. Therefore, there has been the problem that the flowing speed of particulates differs depending on the feeding position of the particulates, variation of detection signals increases, and the accuracy of analysis is degraded.
Patent Literature 2, Japanese Examined Patent Publication No. 7-119686, discloses a channel structure that introduces a sample liquid into the center of a sheath liquid laminar flow from an opening at the center of the channel through which the sheath liquid laminar flow is fed to thereby feed the sample liquid laminar flow being surrounded by the sheath liquid laminar flow (see FIGS. 2 and 3 of the literature). The channel structure enables the sample liquid to be introduced into the center of the sheath liquid laminar flow, thereby eliminating the dispersion of the feeding position of the particulates in the depth direction of the channel, so that the high accuracy of analysis can be obtained.
FIGS. 18A and 18B show a channel structure according to related art applied for introducing a sample liquid to the center of a sheath liquid laminar flow ( FIG. 18A ), and a sample liquid laminar flow formed by the channel structure ( FIG. 18B ). In this channel structure, the sheath liquid laminar flow is introduced into each of channels
102 and 102 in the direction of arrow T in FIG. 18A and fed to a channel 103 . Then, the sample liquid fed to a channel 101 in the direction of arrow S can be introduced from an opening 104 to the center of the sheath liquid laminar flow fed through the channel 103 . The sample liquid laminar flow can be thereby fed, being converged to the center of the channel 103 , as shown in FIG. 18B . In FIG. 18B , the sample liquid laminar flow is depicted in solid lines, and the channel structure in dotted lines.
On the other hand, in Patent Literature 2, it is pointed out that, when introducing the sample liquid laminar flow into the sheath liquid laminar flow in such a channel structure, turbulence occurs in the sample liquid laminar flow, which raises the case where the sample liquid laminar flow is not a flat and stable laminar flow (see the rows 12 to 46 in the right column on page 4 of the literature). Note that âflat laminar flowâ indicates a laminar flow converted in the depth direction (the Z-axis direction) of the channel in FIGS. 18A and 18B , and ânon-flat laminar flowâ indicates a laminar flow dispersed and spread in the depth direction of the channel.
In the above Patent Literature, it is proposed to provide the opening of the channel through which the sample liquid laminar flow is introduced with a pair of plate projections (see the reference numeral 18 in FIG. 10 of the literature) or the like in order to suppress the turbulence (wake) of the laminar flow at the merging portion of the sample liquid laminar flow and the sheath liquid laminar flows. The plate projections 18 extend from the opening wall of the channel through which the sample liquid laminar flow is introduced in the flowing direction of the sample liquid laminar flow and guides the sample liquid flowing out from the opening.
SUMMARY
With the plate projections 18 disclosed in the above Patent Literature 2, it is possible to guide the sample liquid flowing out from the opening and let the sample liquid flow through the channel as a stable laminar flow converged in the depth direction of the channel.
However, the channel structure is complicated when such a guide structure is provided at the opening of the channel through which the sample liquid laminar flow is introduced. Further, it is necessary to laminate three or more substrate onto one another in order to form such a channel structure on a microchip. Therefore, high accuracy is needed for the formation of the channel structure on each substrate and the lamination of the substrates, which increases the manufacturing cost of the microchip.
In light of the foregoing, it is desirable to provide a microchip capable of feeding a sample liquid laminar flow converged to the center of a channel and easily manufacturable.
According to an embodiment of the present invention, there is provided a microchip, which includes a substrate including a fluid channel structure. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid introduction channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid so as to suppress a spiral flow field generated after the merging.
According to another embodiment of the present invention, there is provided a particulate analyzing device, which includes a microchip including a substrate that includes a fluid channel structure. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid introduction channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid so as to suppress a spiral flow field generated after the merging.
According to yet another embodiment of the present invention, there is provided a method of manufacturing a microchip. A substrate including a fluid channel structure is provided. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid from the first and second fluid introduction channels to suppress a spiral flow field generated after the merging.
It should be noted that the âparticulatesâ in the present embodiment widely include microscopic bioparticles such as cells, microorganisms, liposome, etc. as well as synthetic particles such as latex particles, gel particles, industrial particles, etc. The microscopic bioparticles include chromosome, liposome, mitochondria, organelle, etc. which constitute various cells. The cells here include animal cells (blood corpuscle cells, etc.) and plant cells. The microorganisms includes bacteria such as colibacillus, etc., viruses such as tobacco mosaic virus, etc., and fungi such as yeast, etc. Further, the microscopic bioparticles may include also microscopic biopolymers such as nucleic acid, proteins, and complexes thereof. The industrial particles may be, for example, organic or inorganic polymer materials, metals or the like. The organic polymer materials include polystyrene, stylene-vinylbenzene, and polymethyl methacrylate. The inorganic polymer materials include glass, silica, and magnetic materials. The metals include gold colloid and aluminum. The shape of these particulates is usually spherical, but may be non-spherical. Besides, the particulates are not particularly limited as to size, mass or the like.
According to the embodiments of the present invention described above, a microchip capable of feeding a sample liquid laminar flow converged to the center of a channel and easy manufacturability is provided.
BRIEF DESCRIPTION OF DRAWINGS
FIGS. 1A and 1B are schematic diagrams illustrating a channel structure on a microchip according to a first embodiment of the present invention, in which FIG. 1A shows a top view and
FIG. 1B shows a sectional view;
FIGS. 2A, 2B and 2C are schematic diagrams illustrating sections of a merge channel 12 of the microchip according to the first embodiment of the present invention, in which FIG. 2A shows section P-P, FIG. 2B shows section Q-Q, and FIG. 2C shows section R-R, respectively in FIGS. 1A and 1B ;
FIG. 3 is a schematic diagram illustrating a structure of a communicating port 111 of the microchip according to the first embodiment of the present invention;
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. application No. U.S. Ser. No. 14/879,639, filed on Oct. 9, 2015, which is a continuation of U.S. application Ser. No. 13/580,912, filed on Aug. 23, 2012, which is a national stage of International Application No. PCT/JP2011/000902 filed on Feb. 18, 2011, which claims priority to Japanese Patent Application No. 2010-043968 filed on Mar. 1, 2010, the disclosures of each of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to a microchip and a particulate analyzing device. More particularly, the present invention relates to a microchip or the like for optically, electrically or magnetically analyzing the characteristics of particulates such as cells or microbeads in channels.
BACKGROUND
In recent years, microchips have been developed in which an area and/or a channel or channels for performing chemical and biological analyses are provided by application of micro-machining techniques used in the semiconductor industry. These microchips have begun to be utilized for electrochemical detectors in liquid chromatography, small electrochemical sensors in medical service sites, and the like.
Analytical systems using such microchips are called micro-TAS (micro-Total-Analysis System), lab-on-a-chip, bio chip or the like, and is paid attention to as a technology by which chemical and biological analyses can be enhanced in speed, efficiency and level of integration or by which analyzing devices can be reduced in size.
The micro-TAS, which enables analysis with a small amount of sample and enables disposable use of microchips, is expected to be applied particularly to biological analyses where precious trace amounts of samples or a multiplicity of specimens are treated.
An application example of the micro-TAS is a particulate analyzing technology in which characteristics of particulates such as cells and microbeads are analyzed optically, electrically or magnetically in channels arranged on microchips. In the particulate analyzing technology, fractional collection of a population satisfying a predetermined condition or conditions from among particulates on the basis of analytical results of the particulates is also conducted.
Patent Literature 1, Japanese Patent Laid-open No. 2003-107099, for example, discloses âa particulate fractionation microchip having a channel for introducing particulate-containing solution, and a sheath flow forming channel arranged on at least one lateral side of the introducing channel.â The particulate fractionation microchip further has âa particulate measuring section for measuring the particulates introduced, at least two particulate fractionating channels disposed on the downstream side of the particulate measuring section so as to perform fractional collection of the particulates, and at least two electrodes disposed in the vicinity of channel ports opening from the particulate measuring section into the particulate fractionating channels so as to control the moving direction of the particulates.â
The particulate fractionation microchip disclosed in Patent Literature 1 , typically, is so designed that fluid laminar flows are formed by a âtrifurcated channelâ having a channel for introducing a particulate-containing solution and two sheath flow forming channels (see â FIG. 1 â of the literature).
FIGS. 17A and 17B show a trifurcated channel structure according to related art ( FIG. 17A ), and sample liquid laminar flows formed by the channel structure ( FIG. 17B ). In the trifurcated channel, a sample liquid laminar flow passing through a channel 101 in the direction of solid-line arrow in FIG. 17A can be sandwiched, from the left and right sides, by sheath liquid laminar flows introduced through channels
102 , 102 in the directions of dotted-line arrows in the figure. By this, as shown in FIG. 17B , the sample liquid laminar flow can be fed through the center of the channel. Incidentally, in FIG. 17B , the sample liquid laminar flow is depicted in solid lines, and the channel structure in dotted lines.
According to the trifurcated channel shown in FIGS. 17A and 17B , the sample liquid laminar flow is sandwiched by the sheath liquid laminar flows from the left and right sides, whereby with respect to the sandwiching direction (the Y-axis direction in FIGS. 17A and 17B ), the sample liquid laminar flow can be fed in the state of being deflected to an arbitrary position in the channel. With respect to the vertical direction (the Z-axis direction in FIGS. 17A and 17B ) of the channel, however, it has been very difficult to control the sample liquid feeding position. In other words, in the trifurcated channel according to related art, it has only been possible to form the sample laminar flow that is oblong in the Z-axis direction.
Therefore, the microchip having the trifurcated channel according to related art has the problem that in the case where, for example, a particulate-containing solution as a sample liquid is made to flow through a channel and subjected to optical analysis, there would be a dispersion of the feeding position of the particulates in the vertical direction (depth direction) of the channel. Therefore, there has been the problem that the flowing speed of particulates differs depending on the feeding position of the particulates, variation of detection signals increases, and the accuracy of analysis is degraded.
Patent Literature 2, Japanese Examined Patent Publication No. 7-119686, discloses a channel structure that introduces a sample liquid into the center of a sheath liquid laminar flow from an opening at the center of the channel through which the sheath liquid laminar flow is fed to thereby feed the sample liquid laminar flow being surrounded by the sheath liquid laminar flow (see FIGS. 2 and 3 of the literature). The channel structure enables the sample liquid to be introduced into the center of the sheath liquid laminar flow, thereby eliminating the dispersion of the feeding position of the particulates in the depth direction of the channel, so that the high accuracy of analysis can be obtained.
FIGS. 18A and 18B show a channel structure according to related art applied for introducing a sample liquid to the center of a sheath liquid laminar flow ( FIG. 18A ), and a sample liquid laminar flow formed by the channel structure ( FIG. 18B ). In this channel structure, the sheath liquid laminar flow is introduced into each of channels
102 and 102 in the direction of arrow T in FIG. 18A and fed to a channel 103 . Then, the sample liquid fed to a channel 101 in the direction of arrow S can be introduced from an opening 104 to the center of the sheath liquid laminar flow fed through the channel 103 . The sample liquid laminar flow can be thereby fed, being converged to the center of the channel 103 , as shown in FIG. 18B . In FIG. 18B , the sample liquid laminar flow is depicted in solid lines, and the channel structure in dotted lines.
On the other hand, in Patent Literature 2, it is pointed out that, when introducing the sample liquid laminar flow into the sheath liquid laminar flow in such a channel structure, turbulence occurs in the sample liquid laminar flow, which raises the case where the sample liquid laminar flow is not a flat and stable laminar flow (see the rows 12 to 46 in the right column on page 4 of the literature). Note that âflat laminar flowâ indicates a laminar flow converted in the depth direction (the Z-axis direction) of the channel in FIGS. 18A and 18B , and ânon-flat laminar flowâ indicates a laminar flow dispersed and spread in the depth direction of the channel.
In the above Patent Literature, it is proposed to provide the opening of the channel through which the sample liquid laminar flow is introduced with a pair of plate projections (see the reference numeral 18 in FIG. 10 of the literature) or the like in order to suppress the turbulence (wake) of the laminar flow at the merging portion of the sample liquid laminar flow and the sheath liquid laminar flows. The plate projections 18 extend from the opening wall of the channel through which the sample liquid laminar flow is introduced in the flowing direction of the sample liquid laminar flow and guides the sample liquid flowing out from the opening.
SUMMARY
With the plate projections 18 disclosed in the above Patent Literature 2, it is possible to guide the sample liquid flowing out from the opening and let the sample liquid flow through the channel as a stable laminar flow converged in the depth direction of the channel.
However, the channel structure is complicated when such a guide structure is provided at the opening of the channel through which the sample liquid laminar flow is introduced. Further, it is necessary to laminate three or more substrate onto one another in order to form such a channel structure on a microchip. Therefore, high accuracy is needed for the formation of the channel structure on each substrate and the lamination of the substrates, which increases the manufacturing cost of the microchip.
In light of the foregoing, it is desirable to provide a microchip capable of feeding a sample liquid laminar flow converged to the center of a channel and easily manufacturable.
According to an embodiment of the present invention, there is provided a microchip, which includes a substrate including a fluid channel structure. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid introduction channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid so as to suppress a spiral flow field generated after the merging.
According to another embodiment of the present invention, there is provided a particulate analyzing device, which includes a microchip including a substrate that includes a fluid channel structure. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid introduction channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid so as to suppress a spiral flow field generated after the merging.
According to yet another embodiment of the present invention, there is provided a method of manufacturing a microchip. A substrate including a fluid channel structure is provided. The fluid channel structure includes a first fluid introduction channel and a second fluid introduction channel configured to meet so as to allow merging of a first fluid introduced from the first fluid channel and a second fluid introduced from the second fluid introduction channel. A tapered portion is configured to be positioned after merging the first fluid and the second fluid from the first and second fluid introduction channels to suppress a spiral flow field generated after the merging.
It should be noted that the âparticulatesâ in the present embodiment widely include microscopic bioparticles such as cells, microorganisms, liposome, etc. as well as synthetic particles such as latex particles, gel particles, industrial particles, etc. The microscopic bioparticles include chromosome, liposome, mitochondria, organelle, etc. which constitute various cells. The cells here include animal cells (blood corpuscle cells, etc.) and plant cells. The microorganisms includes bacteria such as colibacillus, etc., viruses such as tobacco mosaic virus, etc., and fungi such as yeast, etc. Further, the microscopic bioparticles may include also microscopic biopolymers such as nucleic acid, proteins, and complexes thereof. The industrial particles may be, for example, organic or inorganic polymer materials, metals or the like. The organic polymer materials include polystyrene, stylene-vinylbenzene, and polymethyl methacrylate. The inorganic polymer materials include glass, silica, and magnetic materials. The metals include gold colloid and aluminum. The shape of these particulates is usually spherical, but may be non-spherical. Besides, the particulates are not particularly limited as to size, mass or the like.
According to the embodiments of the present invention described above, a microchip capable of feeding a sample liquid laminar flow converged to the center of a channel and easy manufacturability is provided.
BRIEF DESCRIPTION OF DRAWINGS
FIGS. 1A and 1B are schematic diagrams illustrating a channel structure on a microchip according to a first embodiment of the present invention, in which FIG. 1A shows a top view and
FIG. 1B shows a sectional view;
FIGS. 2A, 2B and 2C are schematic diagrams illustrating sections of a merge channel 12 of the microchip according to the first embodiment of the present invention, in which FIG. 2A shows section P-P, FIG. 2B shows section Q-Q, and FIG. 2C shows section R-R, respectively in FIGS. 1A and 1B ;
FIG. 3 is a schematic diagram illustrating a structure of a communicating port 111 of the microchip according to the first embodiment of the present invention;
FIGS. 4A and 4B are schematic diagrams illustrating a structure of the communicating port 111 of the microchip according to the first embodiment of the present invention ( FIG. 4A ) and an opening 104 of a channel structure according to related art shown in FIGS. 18A and 18B ( FIG. 4B );
FIGS. 5A, 5B and 5C are schematic diagrams illustrating alternative examples of a tapered portion 122 of the microchip according to the first embodiment of the present invention, in which the upper part shows a top view and the lower part shows a sectional view;
FIGS. 6A and 6B are schematic diagrams illustrating a channel structure on a microchip according to a second embodiment of the present invention, in which FIG. 6A shows a top view and FIG. 6B shows a sectional view;
FIGS. 7A, 7B and 7C are schematic diagrams illustrating sections of a merge channel 12 of the microchip according to the second embodiment of the present invention, in which FIG. 7A shows section P-P, FIG. 7B shows section Q-Q, and FIG. 7C shows section R-R, respectively in FIGS. 6A and 6B ;
FIGS. 8A, 8B, and 8C are schematic diagrams illustrating alternative examples of a tapered portion 123 of the microchip according to the second embodiment of the present invention, in which the upper part shows a top view and the lower part shows a sectional view;
FIGS. 9A and 9B are schematic diagrams illustrating taper angles in a depth direction of a channel of the tapered portion 123 of the microchip according to the second embodiment of the present invention, in which the upper part shows a top view and the lower part shows a sectional view;
FIGS. 10A and 10B are schematic diagrams illustrating an alternative example of a tapered portion 123 and a contracted portion 121 of the microchip according to the second embodiment of the present invention, in which FIG. 10A shows a top view and FIG. 10B shows a sectional view;
FIGS. 11A and 11B are schematic diagrams illustrating a channel structure on a microchip according to a third embodiment of the present invention, in which FIG. 11A shows a top view and FIG. 11B shows a sectional view;
FIGS. 12A, 12B and 12C are schematic diagrams illustrating sections of a merge channel 12 of the microchip according to the third embodiment of the present invention, in which FIG. 12A shows section P-P, FIG. 12B shows section Q-Q, and FIG. 12C shows section R-R, respectively in FIGS. 11A and 11B ;
FIG. 13 is a schematic diagram illustrating an alternative example of tapered portions
122 and 123 of the microchip according to the third embodiment of the present invention, in which the upper part shows a top view and the lower part shows a sectional view;
FIGS. 14A and 14B are schematic diagrams illustrating an alternative example of a tapered portion 123 and a contracted portion 121 of the microchip according to the third embodiment of the present invention, in which FIG. 14A shows a top view and FIG. 14B shows a sectional view;
FIGS. 15A and 15B are diagrams illustrating a manufacturing method of a microchip according to an embodiment of the present invention, which show top schematic diagrams of substrates constituting a chip;
FIGS. 16A and 16B are schematic diagrams illustrating a manufacturing method of a microchip according to an embodiment of the present invention, in which FIG. 16B shows a section along P-P in FIG. 16A ;
FIGS. 17A and 17B are schematic diagrams illustrating a trifurcated channel structure according to related art ( FIG. 17A ), and sample liquid laminar flows formed by the channel structure ( FIG. 17B );
FIGS. 18A and 18B are schematic diagrams illustrating a channel structure according to related art applied for introducing a sample liquid to the center of sheath liquid laminar flows ( FIG. 18A ), and sample liquid laminar flows formed by the channel structure ( FIG. 18B ).
FIGS. 19A and 19B are schematic diagrams illustrating the channel structure according to related art shown in FIGS. 18A and 18B , in which FIG. 19A shows a top view and FIG. 19B shows a sectional view;
FIGS. 20A, 20B and 20C are schematic diagrams illustrating a fluid velocity vector field in the channel structure according to related art shown in FIGS. 18A and 18B , in which FIG. 20A shows section P-P, FIG. 20B shows section Q-Q, and FIG. 20C shows section R-R, respectively in FIGS. 19A and 19B ; and
FIG. 21 is a schematic diagram illustrating a fluid velocity vector field in the channel structure according to related art shown in FIGS. 18A and 18B .
DETAILED DESCRIPTION
Preferred embodiments for carrying out the present invention will be described hereinafter with reference to the drawings. Note that the embodiments described below are typical exemplary embodiments of the present invention, and the invention is not to be narrowly construed due to the embodiments.
1. Fluid Velocity Vector Field in Channel Structure According to Related Art
The channel structure according to related art which is applied for introducing a sample liquid to the center of a sheath liquid laminar flow, shown in FIGS. 18A and 18B , has the problem that, when introducing the sample liquid laminar flow into the sheath liquid laminar flow, turbulence occurs in the sample liquid laminar flow, and the sample liquid laminar flow is not converted to the center of the channel.
Specifically, referring to FIGS. 19A and 19B , in the case where a sample liquid laminar flow S is introduced from an opening 104 to the center of sheath liquid laminar flows T respectively introduced to channels
102 and 102 and flowing through a channel 103 , the sample liquid laminar flow S is dispersed in the depth direction of the channel (the Z-axis direction) in some cases. If the sample liquid laminar flow S is not converted to the center of the channel, the feeding position of the particulates contained in the sample liquid laminar flow S is dispersed in the depth direction of the channel, and therefore, the detection signal of the particulates also varies, which causes degradation of the accuracy of analysis.
The inventors of the present invention have conducted numerical calculation of the fluid velocity vector field (flow field) in the channel structure in order to find a factor of the turbulence of the sample liquid laminar flow occurring in the channel structure according to related art. As a result, they have found that the spiral flow field generated after the merging of the sample liquid laminar flow and the sheath liquid laminar flows causes the turbulence of the sample liquid laminar flow.
The fluid velocity vector field in the channel structure according to related art is described with reference to FIGS. 19A and 19B and FIGS. 20A to 20C . FIGS. 20A to 20C are schematic sectional diagrams of the channel structure according to related art, in which FIG. 20A shows section P-P, FIG. 20B shows section Q-Q, and FIG. 20C shows section R-R, respectively in FIGS. 19A and 19B .
When the sample liquid laminar flow S is introduced from the opening 104 into the center of the sheath liquid laminar flow T fed through the channel 103 , a high velocity vector appears at the center in the depth direction of the channel immediately after the introduction (see the arrows in FIG. 20A ). It is considered that the high velocity vector occurs because the merged sample liquid laminar flow S and sheath liquid laminar flows T are concentrated on the center of the depth direction of the channel for flowing faster.
Further, in the process that the flow fields from the channel 101 and the channels
102 and 102 are merged into one flow field, a high velocity vector occurring at the center in the depth direction of the channel grows into the flow field that rotates in the Z-axis positive or negative direction as shown in FIG. 20B , and further grows into the spiral flow field as shown in FIG. 20C . Then, it has been founded that the sample liquid laminar flow S is stretched out in the Z-axis positive and negative direction and dispersed in the depth direction of the channel. It has been also found that the deformation of the sample liquid laminar flow S due to the spiral flow field becomes more significant depending on the flow rate of the sheath liquids fed from the channels
102 and 102 .
Furthermore, the inventors of the present invention have found, as a result of the numerical calculation of the fluid velocity vector field (flow field), that a slow flow field occurring near the opening for introducing the sample liquid laminar flow into the center of the sheath liquid laminar flow causes the turbulence of the sample liquid laminar flow.
FIG. 21 schematically illustrates a slow flow field occurring in the vicinity of an opening 104 of the channel structure according to related art, shown in FIGS. 18A and 18B , which is applied for introducing the sample liquid to the center of the sheath liquid laminar flow.
In the vicinity of the opening 104 , a shear force occurs between the sheath liquid laminar flows T and the sample liquid laminar flow S due to the merging of the sheath liquids fed from the channels
102 and 102 and the sample liquid flowing out from the opening 104 . It has been found that, by the shear force, a slow velocity vector occurs in the vicinity of the opening 104 , and an unstable flow field with a stagnant flow is generated. Due to the stagnant flow field, the sample liquid laminar flow S becomes unstable and dispersed in the depth direction of the channel. It has been also found that the deformation of the sample liquid laminar flow S due to the stagnant flow field becomes more significant as the flow rate of the sample liquid flowing out of the opening 104 is lower.
2. Microchip According to First Embodiment of Invention
A first feature of a microchip according to an embodiment of the present invention is to provide a channel structure that suppresses the above-described spiral flow field generated after merging of the sample liquid laminar flow and the sheath liquid laminar flows and thereby avoids the turbulence of the sample liquid laminar flow. A second feature of a microchip according to an embodiment of the present invention is to provide a channel structure that suppresses the above-described stagnant flow field generated in the vicinity of an opening for introducing the sample liquid laminar flow to the center of the sheath liquid laminar flow and thereby avoids the turbulence of the sample liquid laminar flow.
FIGS. 1A and 1B are schematic diagrams illustrating a channel structure formed on a microchip according to a first embodiment of the present invention, in which FIG. 1A shows a top view and FIG. 1B shows a sectional view.
In the figures, the reference numeral 11 indicates a first introduction channel (which is referred to hereinafter as a sample liquid introduction channel 11 ) through which a first fluid (referred to hereinafter as a sample liquid) is introduced. The reference numerals 21 and 22 indicate second introduction channels (referred to hereinafter as sheath liquid introduction channels 21 and 22 ) which are arranged to sandwich the sample liquid introduction channel 11 and merged with the sample liquid introduction channel 11 from the both sides thereof, and through which a second fluid (referred to hereinafter as a sheath liquid) is introduced. Further, the reference numeral 12 indicates a merge channel which is connected to the sample liquid introduction channel 11 and the sheath liquid introduction channels
21 and 22 and through which the sample liquid and the sheath liquids fed from the respective channels are merged and flow.
The sample liquid introduction channel 11 has, at the merging portion with the sheath liquid introduction channels
21 and 22 , a communicating port 111 for introducing the sample liquid into the center of the merge channel 12 through which the sheath liquid laminar flow T flows. The channel depth of the sample liquid introduction channel 11 in the Z-axis direction is designed to be smaller than the channel depth of the sheath liquid introduction channels
21 and 22 , and the communicating port 111 is disposed at substantially the center position in the channel depth direction of the sheath liquid introduction channels
21 and 22 . Further, the communicating port 111 is also disposed at substantially the center position in the channel width direction (the Y-axis direction) of the merge channel 12 .
By introducing the sample liquid laminar flow S to the center of the sheath liquid laminar flow T from the communicating port 111 , the sample liquid laminar flow S can be fed in the state of being surrounded by the sheath liquid laminar flow T (see also FIGS. 2A, 2B and 2C described next). Note that the position where the communicating port 111 is placed is not limited to the center position of the channel depth direction of the sheath liquid introduction channels
21 and 22 and may be in its vicinity, as long as it allows the sample liquid laminar flow S to be fed into the merge channel 12 in the state of being surrounded by the sheath liquid laminar flow T. Likewise, the position of the communicating port 111 in the channel width direction of the merge channel 12 is not limited to the center position and may be in its vicinity.
In the figures, the reference numeral 122 indicates a tapered portion that functions to suppress the spiral flow field generated after the merging of the sample liquid laminar flow and the sheath liquid laminar flows illustrated in FIG. 20 . The tapered portion 122 is disposed in the merge channel 12 in close proximity to the merging portion of the sample liquid introduction channel 11 with the sheath liquid introduction channels
21 and 22 . The tapered portion 122 is formed so that the channel width in the sandwiching direction (the Y-axis direction) along which the sample liquid introduction channel 11 is sandwiched by sheath liquid introduction channels
21 and 22 is enlarged gradually along the feeding direction.
The fluid velocity vector field in the merge channel 12 and the function of the tapered portion 122 are described with reference to FIGS. 1A and 1B and FIGS. 2A to 2C . FIGS. 2A, 2B and 2C are schematic sectional diagrams of the merge channel 12 , in which FIG. 2A shows section P-P, FIG. 2B shows section Q-Q, and FIG. 2C shows section R-R, respectively in FIGS. 1A and 1B .
When the sample liquid laminar flow S is introduced from an opening 111 into the center of the sheath liquid laminar flow T flowing through the merge channel 12 , a high velocity vector appears at the center in the depth direction of the channel immediately after the introduction (see the dotted-line arrows in FIG. 2A ). The high velocity vector occurs because the merged sample liquid laminar flow S and sheath liquid laminar flows T are concentrated on the center of the depth direction of the channel for flowing faster as described earlier.
At the tapered portion 122 , when the laminar flow width of the merged sample liquid laminar flow S and sheath liquid laminar flow T is enlarged in the Y-axis direction, a flow field (see the solid-line arrows in FIG. 2B ), which is in reverse direction to the high velocity vector generated at the center in the depth direction of the channel, is generated. By generating the reverse flow field, the tapered portion 122 cancels out the flow field generated at the center in the depth direction of the channel and thereby prevents the flow field from growing into the spiral flow field. As a result, the sample liquid laminar flow S is maintained in the state of being converted to the center of the channel without being stretched out in the Z-axis direction by the spiral flow field (see FIGS. 2B and 2C ).
In the figures, the reference numeral 121 indicates a contracted portion that functions to narrow down the laminar flow width of the merged sample liquid laminar flow S and sheath liquid laminar flow T in the Y-axis direction and the Z-axis direction. The contracted portion 121 is disposed on the downstream side of the tapered portion 122 . The contracted portion 121 is formed so that the channel width is reduced gradually along the feeding direction. Further, the contracted portion 121 is formed so that the channel depth is also reduced gradually along the feeding direction. Specifically, the channel wall of the contracted portion 121 is formed to be narrowed along the feeding direction in the Y-axis and the Z-axis directions, and the contracted portion 121 is formed so that the area of the vertical section with respect to the feeding direction (the X-axis positive direction) decreases gradually. With such a shape, the contracted portion 121 feeds the liquids by narrowing down the laminar flow width of the merged sample liquid laminar flow S and sheath liquid laminar flow T in the Y-axis direction and the Z-axis direction.
FIG. 3 and FIGS. 4A and 4B are schematic diagrams illustrating a structure of the communicating port 111 . The channel depth of the sample liquid introduction channel 11 in the Z-axis direction is designed to be smaller than the channel depth of the sheath liquid introduction channels
21 and 22 , and the communicating port 111 is placed at substantially the center position of the channel depth direction of the sheath liquid introduction channels 21 and 22 (see FIG. 3 ). Further, in order to suppress the stagnant flow field generated in the vicinity, the communicating port 111 opens in an area including channel walls
211 and 221 of the sheath liquid introduction channel 21 and the sheath liquid introduction channel 22 .
This is described specifically with reference to FIGS. 4A and 4B . First, a structure of the opening 104 in the channel structure according to related art (see FIGS. 18A and 18B ) is described with reference to FIG. 4B . In the channel structure according to related art, by a shear force which occurs between the sheath liquid laminar flows T and the sample liquid laminar flow S due to the merging of the sheath liquids fed from the channels
102 and 102 and the sample liquid flowing out from the opening 104 , an unstable flow field with a stagnant flow (the diagonally shaded area in FIG. 4B ) is generated in the vicinity of the opening 104 (see also FIG. 21 ).
In this case, the sample liquid flows out to the stagnant, unstable flow field from the opening 104 . Consequently, the sample liquid laminar flow S becomes unstable before coming into contact with the fast-flowing sheath liquids fed f
CLAIMS
Claims ( 23 )
The invention claimed is:
1. A microfluidic chip for use with a particulate analyzing device, the microfluidic chip comprising:
a substrate; and
a fluid channel formed in the substrate, the fluid channel including:
a supply port configured to receive a sample liquid flow; and
a merge channel configured to convert the sample liquid flow into a sheath liquid laminar flow, the merge channel having a first fluid converting structure, a second fluid converting structure, and a third fluid converting structure, to convert the sample liquid flow into the sheath liquid laminar flow by introducing sheath liquid into the fluid channel or changing a cross section area, wherein
the first, second, and third fluid converting structures are provided at different longitudinal locations along the fluid channel,
a first surface portion of the fluid channel lies in a first plane upstream of the second and third fluid converting structures,
a second surface portion of the fluid channel lies in a second plane vertically above the first plane downstream of the second and third fluid converting structures, and
the first fluid converting structure is a first tapered portion narrowing the sample liquid flow in a first direction, the second fluid converting structure is a second tapered portion narrowing the sample liquid flow in a second direction, and the third fluid converting structure is a contracted portion narrowing the sample liquid flow in the second direction, and the first direction is orthogonal to the second direction.
2. The microfluidic chip of claim 1 , further comprising a detection portion downstream of the first, second, and third fluid converting structures.
3. The microfluidic chip of claim 1 , wherein the first fluid converting structure is configured to introduce sheath liquid into the fluid channel symmetrically with respect to a centerline of the sample liquid flow.
4. The microfluidic chip of claim 1 , wherein the first fluid converting structure is configured to convert the sample liquid flow in at least a lateral direction.
5. The microfluidic chip of claim 1 , wherein the second fluid converting structure is configured to convert the sample liquid flow in at least a vertical direction.
6. The microfluidic chip of claim 1 , wherein the third fluid converting structure is configured to convert the sample liquid flow in at least a vertical direction.
7. The microfluidic chip of claim 1 , wherein the sample liquid flow and the sheath liquid associated with the first fluid converting structure enter the merge channel in a center line.
8. The microfluidic chip of claim 1 , wherein the merge channel has a varying width upstream of the second and third fluid converting structures; and
wherein the fluid channel has a constant width between the second fluid converting structure and third fluid converting structure.
9. The microfluidic chip of claim 8 , wherein the fluid channel has a constant width between a detection portion and the second and third fluid converting structures.
10. The microfluidic chip of claim 1 , wherein within the merge channel the fluid channel transitions from a first cross section shape to a second cross section shape different from the first cross section shape.
11. The microfluidic chip of claim 1 , wherein
a first upper surface of the fluid channel lies in a third plane upstream of the first and second fluid converting structures, and
a second upper surface of the fluid channel lies in a fourth plane vertically below the third plane downstream of the first and second fluid converting structures.
12. A particulate analyzing device comprising:
a microfluidic chip, wherein the microfluidic chip comprises:
a substrate;
a fluid channel formed in the substrate; and
a detector configured to detect particulates in a sample liquid flow, the fluid channel including:
a supply port configured to receive the sample liquid flow; and
a merge channel configured to convert the sample liquid flow into a sheath liquid laminar flow, the merge channel having a first fluid converting structure, a second fluid converting structure, and a third fluid converting structure, to convert the sample liquid flow into the sheath liquid laminar flow by introducing sheath liquid into the fluid channel or changing a cross section area, wherein
the first, second, and third fluid converting structures are provided at different longitudinal locations along the fluid channel,
a first surface portion of the fluid channel lies in a first plane upstream of the second and third fluid converting structures,
a second surface portion of the fluid channel lies in a second plane vertically above the first plane downstream of the second and third fluid converting structures, and
the first fluid converting structure is a first tapered portion narrowing the sample liquid flow in a first direction, the second fluid converting structure is a second tapered portion narrowing the sample liquid flow in a second direction, and the third fluid converting structure is a contracted portion narrowing the sample liquid flow in the second direction, and the first direction is orthogonal to the second direction.
13. The particulate analyzing device of claim 12 , further comprising:
a detection portion in the microfluidic chip downstream of the first, second, and third fluid converting structures.
14. The particulate analyzing device of claim 12 , wherein the first fluid converting structure is configured to introduce sheath liquid into the fluid channel symmetrically with respect to a centerline of the sample liquid flow.
15. The particulate analyzing device of claim 12 , wherein the first fluid converting structure is configured to convert the sample liquid flow in at least a lateral direction.
16. The particulate analyzing device of claim 12 , wherein the second fluid converting structure is configured to convert the sample liquid flow in at least a vertical direction.
17. The particulate analyzing device of claim 12 , wherein the third fluid converting structure is configured to convert the sample liquid flow in at least a vertical direction.
18. The particulate analyzing device of claim 12 , wherein the sample liquid flow and the sheath liquid associated with the first fluid converting structure enter the merge channel in a center line.
19. The particulate analyzing device of claim 12 , wherein the merge channel has a varying width upstream of the second and third fluid converting structures; and
wherein the fluid channel has a constant width between the second fluid converting structure and third fluid converting structure.
20. The particulate analyzing device of claim 19 , wherein the fluid channel has a constant width between a detection portion and the second and third fluid converting structures.
21. The particulate analyzing device of claim 12 , wherein within the merge channel the fluid channel transitions from a first cross section shape to a second cross section shape different from the first cross section shape.
22. The particulate analyzing device of claim 12 , wherein
a first upper surface of the fluid channel lies in a third plane upstream of the first and second fluid converting structures, and
a second upper surface of the fluid channel lies in a fourth plane vertically below the third plane downstream of the first and second fluid converting structures.
23. A system comprising:
a particulate analyzing device; and
a microfluidic chip, wherein the microfluidic chip comprises:
a substrate; and
a fluid channel formed in the substrate, the fluid channel including:
a supply port configured to receive a sample liquid flow; and
a merge channel configured to convert the sample liquid flow into a sheath liquid laminar flow, the merge channel having a first fluid converting structure, a second fluid converting structure, and a third fluid converting structure, to convert the sample liquid flow into the sheath liquid laminar flow by introducing sheath liquid into the fluid channel or changing a cross section area, wherein
the first, second, and third fluid converting structures are provided at different longitudinal locations along the fluid channel,
a first surface portion of the fluid channel lies in a first plane upstream of the second and third fluid converting structures,
a second surface portion of the fluid channel lies in a second plane vertically above the first plane downstream of the second and third fluid converting structures, and
the first fluid converting structure is a first tapered portion narrowing the sample liquid flow in a first direction, the second fluid converting structure is a second tapered portion narrowing the sample liquid flow in a second direction, and the third fluid converting structure is a contracted portion narrowing the sample liquid flow in the second direction, and the first direction is orthogonal to the second direction.
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patent/CN105203786B/en
active
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2011-02-18
EP
EP11750320.1A
patent/EP2542901B1/en
active
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2011-02-18
WO
PCT/JP2011/000902
patent/WO2011108206A1/en
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Ceased
2011-02-18
KR
KR1020127022176A
patent/KR101776974B1/en
active
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2011-02-18
SG
SG2012059069A
patent/SG183247A1/en
unknown
2011-02-18
EP
EP22161298.9A
patent/EP4033252B1/en
active
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2011-02-18
CN
CN201180011184.6A
patent/CN102782502B/en
active
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2015
2015-10-09
US
US14/879,639
patent/US10744501B2/en
active
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2020
2020-07-13
US
US16/927,305
patent/US11229907B2/en
active
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2021
2021-12-28
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US17/563,680
patent/US20220118444A1/en
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Abandoned
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