ABSTRACT
Abstract
A microchip is provided that includes a flow path through which a liquid containing a micro particle flows, an orifice through which the liquid flowing through the flow path is discharged into a space outside the microchip, and a light-irradiated portion provided at a predetermined location of the flow path and configured to be irradiated with light. A width of the flow path and a depth of the flow path at the orifice are set to be smaller than a width of the flow path and a depth of the flow path at the light-irradiated portion, and the flow path is configured to gradually decrease from upstream of the orifice in a cross-section area perpendicular to a liquid-delivering direction between the light-irradiated portion and the orifice. A cartridge including the microchip is also provided.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
The present application is a continuation reissue application of Reissue application Ser. No. 16/293,189, filed on Mar. 5, 2019, now U.S. Patent Reissue Pat. No. RE48,827, which is an application for reissue of U.S. Pat. No. 9,588,036, filed as U.S. patent application Ser. No. 14/957,072 on Dec. 2, 2015, which is a continuation of U.S. patent application Ser. No. 14/322,084, filed on Jul. 2, 2014, now U.S. Pat. No. 9,207,160, issued on Dec. 8, 2015, which is a continuation of U.S. patent application Ser. No. 13/147,517, filed on Aug. 2, 2011, now U.S. Pat. No. 8,795,500, issued on Aug. 5, 2014, which is a National Stage of International Application No. PCT/JP2010/000775 filed on Feb. 9, 2010, and which claims priority to Japanese Patent Application No. 2009-034337, filed on Feb. 17, 2009, the entire contents of which are incorporated herein by reference.
BACKGROUND
The present invention relates to an apparatus and a microchip for sorting micro particles. More specifically, the present invention relates to a micro-particle sorting apparatus and the like, that detects properties of micro particles, which flow through a flow path formed in a microchip, within the chip, discharges liquid drops containing the micro particles to the outside of the chip, and controls the movement directions of the liquid drops on the basis of the detected properties of the micro particles for sorting.
Conventionally, in order to identify properties of micro particles such as biologically-relevant micro particles such as cells, microorganisms, liposomes or synthetic particles such as latex particles, gel particles, or industrial particles, there has been utilized an apparatus that introduces dispersion liquid of the micro particles into the flow path, and optically measures the properties of the micro particles that have been introduced into the flow path.
In particular, regarding the biologically-relevant micro particles, there has been widely used an apparatus called a flow cytometry (flow cytometer) (see Non-Patent Document 1). As flow cytometries, there are those that are designed only for measurement of the properties of the micro particles, or those that are configured to be capable of sorting only the micro particles each having a predetermined property on the basis of the measurement result. Regarding the latter, particularly an apparatus for a cell being as a sorting target is called âcell sorter.â The cell sorter currently available in the market is capable of measuring and sorting properties of cells at high speed, for example, several thousands to several tens thousands of cells per second.
In the conventional flow cytometry, properties of the size, the structure, and the like of the micro particles such as cells or micro beads are measured in the following manner. First, in a flow cell, sample solution containing micro particles being as measurement target is caused to flow into the center of a laminar flow of sheath liquid, to thereby arrange the micro particles in line in the flow cell. Next, in an optical detection portion, the micro particles arranged and flowing in the flow cell are irradiated with measurement light, and scattering light or fluorescence generating from the micro particles is detected. In this manner, the properties of the micro particles are measured. Subsequently, in a case where the sorting of the micro particles is performed, the sample liquid is discharged into a space outside the flow cell as liquid drops containing the micro particles, and movement directions of the liquid drops are controlled, to thereby sort the micro particles each containing a predetermined property.
Patent Document 1 ( FIG. 7 ) discloses an apparatus, as the conventional cell sorter, which includes a fluid system for arranging cells stained with fluorescent labeling reagent or the like in line in the flow cell, and a sorting system for controlling the movement directions of the liquid drops discharged into the space outside the flow cell.
Each of those conventional flow cytometries (cell sorters) cannot be easily disposed of by a user because the flow cell part constituting the flow path system is made of expensive quartz and is constituted of the orifice part separate from the flow cell. Thus, even if the flow cell part and the orifice part are sufficiently washed in every measurement, there is a fear that cross contamination of samples between measurements occur. Further, the space constituting the sorting system is set as an open space or a space having low air tightness, and hence contamination materials such as micro liquid drops (aerosol) generating during formation of the liquid drops may be mixed into a sample at the time of measurement, or biohazard such as infection or exposure with respect to apparatus users due to the aerosol may occur. The cross contamination between the samples, the contamination of the sample, the biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive, as described above remain obstacles particularly in a case of using stem cells or the like, which have been sorted by the cell sorter, for regenerative medicine.
As a technique for addressing the cross contamination between the samples, the contamination of the sample, the biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive, there has been, in recent years, developed a microchip including a silicon or glass substrate on which an area for performing a chemical and biological analysis and a flow path are provided. The analysis system using such a microchip is called μ-TAS (micro-total-analysis system), lab-on-a-chip, biochip, or the like.
As an example of applying the μ-TAS to the micro-particle sorting technique, there is a micro-particle sorting technique of optically, electrically, or magnetically analyzing the properties of the micro particles in the flow path or the area provided on the microchip. For example, Patent Document 2 discloses a micro-particle classifying microchip including, on a substrate, a micro-particle-containing solution introducing flow path, a sheath flow forming flow path arranged in at least one side portion of that flow path, a micro-particle measuring location for measuring the introduced micro particles, and two or more micro-particle classifying flow paths for classifying and collecting the micro particles, which are placed downstream with respect to the micro-particle measuring location. This microchip includes electrodes near the opening of the flow path from the micro-particle measuring location to the micro-particle classifying flow paths. According to the micro-particle sorting apparatus including this microchip, it is possible to control the movement directions of the micro particles due to interaction with respect to the electric field of the electrodes, to thereby sort the micro particles.
In the flow cytometry (cell sorter) applying the μ-TAS, the microchip enabling a disposable use (which is disposable) can constitute the flow path system. Therefore, the cross contamination of the samples between measurements does not occur. Further, the sorting system can be arranged in the airtight flow path provided in the chip. Therefore, no contamination material such as the aerosol is mixed into the sample during measurement. However, it is necessary to deliver at high pressure the liquid containing the micro particles through the flow path provided in the chip. Further, it is necessary to perform the control of the movement directions of the micro particles in such a state that the micro particles are flowing in the liquid. Therefore, it is difficult to increase the flowing velocity of the micro particles and the sorting speed, and to measure and sort the properties of the cells at high speed, for example, several thousands to several tens thousands of cells per second as in the conventional flow cytometry (cell sorter).
CITED DOCUMENT
Patent Document
Patent Document 1: Japanese Patent Application Laid-open No. 2007-46947
Patent Document 2: Japanese Patent Application Laid-open No. 2003-107099
Non-Patent Document
Non-Patent Document 1: Hiromitsu Nakauchi: Supplementary Volume of Cell Technology, Experimental Protocol Series, Master of Flow Cytometry, Shujunsha, second edition, published at 31 Aug. 2006
SUMMARY
Problem to be Solved by the Invention
As described above, in the conventional flow cytometry (cell sorter), the flow cell constituting the flow path system is not configured to be disposable, and hence there is a fear that cross contamination between samples occurs. Further, the space constituting the sorting system is set as an open space or a space having low air tightness, and hence the sample may be contaminated by the aerosol or the like. Further, even in the flow cytometry (cell sorter) applying the μ-TAS, it is difficult to increase the flowing velocity of the micro particles and the sorting speed, and hence there is a problem that it is difficult to achieve a high-throughput analysis.
In view of this, it is a main object of the present invention to provide a micro-particle sorting apparatus capable of performing a high-speed analysis and a safe, high-speed, inexpensive sorting by eliminating the cross contamination between the samples, the contamination of the sample, biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive.
Means for Solving the Problem
In order to solve the above-mentioned problems, the present invention provides a micro-particle sorting apparatus including: a microchip in which a flow path through which liquid containing a micro particle flows and an orifice through which the liquid flowing through the flow path is discharged as a liquid drop into a space outside the chip are provided; an oscillating element for transforming the liquid into the liquid drop and discharging the liquid drop at the orifice; a charge means for adding an electric charge to the discharged liquid drop; an optical detection means that detects an optical property of the micro particle flowing through the flow path, upstream of a liquid-delivering direction with respect to the orifice; paired electrodes provided so as to be opposed to each other while sandwiching the moving liquid drop therebetween along a movement direction of the liquid drop discharged into the space outside the chip; and two or more containers that collect the liquid drop passing between the paired electrodes, in which a width of the flow path and a depth of the flow path at a location of the orifice are set to be smaller than a width of the flow path and a depth of the flow path at a location at which the optical property of the micro particle is detected by the optical detection means, or in which a cross-section area of the flow path at a location of the orifice is set to be smaller than a cross-section area of the flow path at a location at which the optical property of the micro particle is detected by the optical detection means.
This micro-particle sorting apparatus may include a micro tube that introduces, into a laminar flow of liquid T flowing through the flow path, a laminar flow of another liquid S containing the micro particle, upstream of the liquid-delivering direction with respect to the location at which the optical property of the micro particles is detected by the optical detection means.
Further, this micro tube can be configured as the charge means by forming the micro tube of a metal on which voltage can be applied.
In this micro-particle sorting apparatus, it is preferred that at least the orifice portion of the microchip and the space in which the liquid drop discharged outside through the orifice moves be arranged in a cavity of the cartridge having light transmittance for light from the optical detection means.
In addition, it is preferred that the cavity of this cartridge be configured to be hermetically sealed.
The present invention further provides a microchip, in which a flow path through which liquid containing a micro particle flows and an orifice through which the liquid flowing through the flow path is discharged into a space outside the chip are provided, a predetermined location of the flow path is configured as a light-irradiated portion to be irradiated with light from an optical detection means for detecting an optical property of the micro particle flowing therethrough, a micro tube that introduces, into a laminar flow of liquid T flowing through the flow path, a laminar flow of another liquid S containing micro particle, upstream of the liquid-delivering direction with respect to the light-irradiated portion is provided, and a width of the flow path and a depth of the flow path at a location of the orifice are set to be smaller than a width of the flow path and a depth of the flow path at the light-irradiated portion, or a cross-section area of the flow path at a location of the orifice is set to be smaller than a cross-section area of the flow path at the light-irradiated portion.
This microchip may include an oscillating element for transforming the liquid into a liquid drop and discharging the liquid drop at the orifice.
In the microchip, it is preferred that the micro tube be formed of a metal on which voltage can be applied.
The present invention further provides a cartridge which has a cavity in which at least the orifice portion of the microchip according to claim 10 and the space in which the liquid drop discharged outside through the orifice moves are configured, and has light transmittance with which light from the optical detection means is caused to transmit to the light-irradiated portion.
It is preferred that the cavity of this cartridge be configured to be hermetically sealed.
Effects of the Invention
According to the present invention, it is possible to provide the micro-particle sorting apparatus capable of performing the high-speed analysis and the safe, high-speed, inexpensive sorting by eliminating the cross contamination between the samples, the contamination of the sample, the biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive.
Additional features and advantages are described herein, and will be apparent from the following Detailed Description and the figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 A view showing a schematic configuration of a micro-particle sorting apparatus A according to the present invention.
FIG. 2 A view showing a schematic configuration of the micro-particle sorting apparatus A.
FIG. 3 A view showing schematic configurations of a microchip 1 and an oscillating element 2 .
FIG. 4 Sectional schematic views describing a micro fluidic structure of a flow path 11 in vicinity of a provision location of a micro tube 16 and a limiter portion 17 , and a state of a sample-liquid laminar flow and a sheath-liquid laminar flow, which pass therethrough.
CROSS REFERENCES TO RELATED APPLICATIONS
The present application is a continuation reissue application of Reissue application Ser. No. 16/293,189, filed on Mar. 5, 2019, now U.S. Patent Reissue Pat. No. RE48,827, which is an application for reissue of U.S. Pat. No. 9,588,036, filed as U.S. patent application Ser. No. 14/957,072 on Dec. 2, 2015, which is a continuation of U.S. patent application Ser. No. 14/322,084, filed on Jul. 2, 2014, now U.S. Pat. No. 9,207,160, issued on Dec. 8, 2015, which is a continuation of U.S. patent application Ser. No. 13/147,517, filed on Aug. 2, 2011, now U.S. Pat. No. 8,795,500, issued on Aug. 5, 2014, which is a National Stage of International Application No. PCT/JP2010/000775 filed on Feb. 9, 2010, and which claims priority to Japanese Patent Application No. 2009-034337, filed on Feb. 17, 2009, the entire contents of which are incorporated herein by reference.
BACKGROUND
The present invention relates to an apparatus and a microchip for sorting micro particles. More specifically, the present invention relates to a micro-particle sorting apparatus and the like, that detects properties of micro particles, which flow through a flow path formed in a microchip, within the chip, discharges liquid drops containing the micro particles to the outside of the chip, and controls the movement directions of the liquid drops on the basis of the detected properties of the micro particles for sorting.
Conventionally, in order to identify properties of micro particles such as biologically-relevant micro particles such as cells, microorganisms, liposomes or synthetic particles such as latex particles, gel particles, or industrial particles, there has been utilized an apparatus that introduces dispersion liquid of the micro particles into the flow path, and optically measures the properties of the micro particles that have been introduced into the flow path.
In particular, regarding the biologically-relevant micro particles, there has been widely used an apparatus called a flow cytometry (flow cytometer) (see Non-Patent Document 1). As flow cytometries, there are those that are designed only for measurement of the properties of the micro particles, or those that are configured to be capable of sorting only the micro particles each having a predetermined property on the basis of the measurement result. Regarding the latter, particularly an apparatus for a cell being as a sorting target is called âcell sorter.â The cell sorter currently available in the market is capable of measuring and sorting properties of cells at high speed, for example, several thousands to several tens thousands of cells per second.
In the conventional flow cytometry, properties of the size, the structure, and the like of the micro particles such as cells or micro beads are measured in the following manner. First, in a flow cell, sample solution containing micro particles being as measurement target is caused to flow into the center of a laminar flow of sheath liquid, to thereby arrange the micro particles in line in the flow cell. Next, in an optical detection portion, the micro particles arranged and flowing in the flow cell are irradiated with measurement light, and scattering light or fluorescence generating from the micro particles is detected. In this manner, the properties of the micro particles are measured. Subsequently, in a case where the sorting of the micro particles is performed, the sample liquid is discharged into a space outside the flow cell as liquid drops containing the micro particles, and movement directions of the liquid drops are controlled, to thereby sort the micro particles each containing a predetermined property.
Patent Document 1 ( FIG. 7 ) discloses an apparatus, as the conventional cell sorter, which includes a fluid system for arranging cells stained with fluorescent labeling reagent or the like in line in the flow cell, and a sorting system for controlling the movement directions of the liquid drops discharged into the space outside the flow cell.
Each of those conventional flow cytometries (cell sorters) cannot be easily disposed of by a user because the flow cell part constituting the flow path system is made of expensive quartz and is constituted of the orifice part separate from the flow cell. Thus, even if the flow cell part and the orifice part are sufficiently washed in every measurement, there is a fear that cross contamination of samples between measurements occur. Further, the space constituting the sorting system is set as an open space or a space having low air tightness, and hence contamination materials such as micro liquid drops (aerosol) generating during formation of the liquid drops may be mixed into a sample at the time of measurement, or biohazard such as infection or exposure with respect to apparatus users due to the aerosol may occur. The cross contamination between the samples, the contamination of the sample, the biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive, as described above remain obstacles particularly in a case of using stem cells or the like, which have been sorted by the cell sorter, for regenerative medicine.
As a technique for addressing the cross contamination between the samples, the contamination of the sample, the biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive, there has been, in recent years, developed a microchip including a silicon or glass substrate on which an area for performing a chemical and biological analysis and a flow path are provided. The analysis system using such a microchip is called μ-TAS (micro-total-analysis system), lab-on-a-chip, biochip, or the like.
As an example of applying the μ-TAS to the micro-particle sorting technique, there is a micro-particle sorting technique of optically, electrically, or magnetically analyzing the properties of the micro particles in the flow path or the area provided on the microchip. For example, Patent Document 2 discloses a micro-particle classifying microchip including, on a substrate, a micro-particle-containing solution introducing flow path, a sheath flow forming flow path arranged in at least one side portion of that flow path, a micro-particle measuring location for measuring the introduced micro particles, and two or more micro-particle classifying flow paths for classifying and collecting the micro particles, which are placed downstream with respect to the micro-particle measuring location. This microchip includes electrodes near the opening of the flow path from the micro-particle measuring location to the micro-particle classifying flow paths. According to the micro-particle sorting apparatus including this microchip, it is possible to control the movement directions of the micro particles due to interaction with respect to the electric field of the electrodes, to thereby sort the micro particles.
In the flow cytometry (cell sorter) applying the μ-TAS, the microchip enabling a disposable use (which is disposable) can constitute the flow path system. Therefore, the cross contamination of the samples between measurements does not occur. Further, the sorting system can be arranged in the airtight flow path provided in the chip. Therefore, no contamination material such as the aerosol is mixed into the sample during measurement. However, it is necessary to deliver at high pressure the liquid containing the micro particles through the flow path provided in the chip. Further, it is necessary to perform the control of the movement directions of the micro particles in such a state that the micro particles are flowing in the liquid. Therefore, it is difficult to increase the flowing velocity of the micro particles and the sorting speed, and to measure and sort the properties of the cells at high speed, for example, several thousands to several tens thousands of cells per second as in the conventional flow cytometry (cell sorter).
CITED DOCUMENT
Patent Document
Patent Document 1: Japanese Patent Application Laid-open No. 2007-46947
Patent Document 2: Japanese Patent Application Laid-open No. 2003-107099
Non-Patent Document
Non-Patent Document 1: Hiromitsu Nakauchi: Supplementary Volume of Cell Technology, Experimental Protocol Series, Master of Flow Cytometry, Shujunsha, second edition, published at 31 Aug. 2006
SUMMARY
Problem to be Solved by the Invention
As described above, in the conventional flow cytometry (cell sorter), the flow cell constituting the flow path system is not configured to be disposable, and hence there is a fear that cross contamination between samples occurs. Further, the space constituting the sorting system is set as an open space or a space having low air tightness, and hence the sample may be contaminated by the aerosol or the like. Further, even in the flow cytometry (cell sorter) applying the μ-TAS, it is difficult to increase the flowing velocity of the micro particles and the sorting speed, and hence there is a problem that it is difficult to achieve a high-throughput analysis.
In view of this, it is a main object of the present invention to provide a micro-particle sorting apparatus capable of performing a high-speed analysis and a safe, high-speed, inexpensive sorting by eliminating the cross contamination between the samples, the contamination of the sample, biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive.
Means for Solving the Problem
In order to solve the above-mentioned problems, the present invention provides a micro-particle sorting apparatus including: a microchip in which a flow path through which liquid containing a micro particle flows and an orifice through which the liquid flowing through the flow path is discharged as a liquid drop into a space outside the chip are provided; an oscillating element for transforming the liquid into the liquid drop and discharging the liquid drop at the orifice; a charge means for adding an electric charge to the discharged liquid drop; an optical detection means that detects an optical property of the micro particle flowing through the flow path, upstream of a liquid-delivering direction with respect to the orifice; paired electrodes provided so as to be opposed to each other while sandwiching the moving liquid drop therebetween along a movement direction of the liquid drop discharged into the space outside the chip; and two or more containers that collect the liquid drop passing between the paired electrodes, in which a width of the flow path and a depth of the flow path at a location of the orifice are set to be smaller than a width of the flow path and a depth of the flow path at a location at which the optical property of the micro particle is detected by the optical detection means, or in which a cross-section area of the flow path at a location of the orifice is set to be smaller than a cross-section area of the flow path at a location at which the optical property of the micro particle is detected by the optical detection means.
This micro-particle sorting apparatus may include a micro tube that introduces, into a laminar flow of liquid T flowing through the flow path, a laminar flow of another liquid S containing the micro particle, upstream of the liquid-delivering direction with respect to the location at which the optical property of the micro particles is detected by the optical detection means.
Further, this micro tube can be configured as the charge means by forming the micro tube of a metal on which voltage can be applied.
In this micro-particle sorting apparatus, it is preferred that at least the orifice portion of the microchip and the space in which the liquid drop discharged outside through the orifice moves be arranged in a cavity of the cartridge having light transmittance for light from the optical detection means.
In addition, it is preferred that the cavity of this cartridge be configured to be hermetically sealed.
The present invention further provides a microchip, in which a flow path through which liquid containing a micro particle flows and an orifice through which the liquid flowing through the flow path is discharged into a space outside the chip are provided, a predetermined location of the flow path is configured as a light-irradiated portion to be irradiated with light from an optical detection means for detecting an optical property of the micro particle flowing therethrough, a micro tube that introduces, into a laminar flow of liquid T flowing through the flow path, a laminar flow of another liquid S containing micro particle, upstream of the liquid-delivering direction with respect to the light-irradiated portion is provided, and a width of the flow path and a depth of the flow path at a location of the orifice are set to be smaller than a width of the flow path and a depth of the flow path at the light-irradiated portion, or a cross-section area of the flow path at a location of the orifice is set to be smaller than a cross-section area of the flow path at the light-irradiated portion.
This microchip may include an oscillating element for transforming the liquid into a liquid drop and discharging the liquid drop at the orifice.
In the microchip, it is preferred that the micro tube be formed of a metal on which voltage can be applied.
The present invention further provides a cartridge which has a cavity in which at least the orifice portion of the microchip according to claim 10 and the space in which the liquid drop discharged outside through the orifice moves are configured, and has light transmittance with which light from the optical detection means is caused to transmit to the light-irradiated portion.
It is preferred that the cavity of this cartridge be configured to be hermetically sealed.
Effects of the Invention
According to the present invention, it is possible to provide the micro-particle sorting apparatus capable of performing the high-speed analysis and the safe, high-speed, inexpensive sorting by eliminating the cross contamination between the samples, the contamination of the sample, the biohazard with respect to the users, and the use of the flow cell and the orifice part, which are expensive.
Additional features and advantages are described herein, and will be apparent from the following Detailed Description and the figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 A view showing a schematic configuration of a micro-particle sorting apparatus A according to the present invention.
FIG. 2 A view showing a schematic configuration of the micro-particle sorting apparatus A.
FIG. 3 A view showing schematic configurations of a microchip 1 and an oscillating element 2 .
FIG. 4 Sectional schematic views describing a micro fluidic structure of a flow path 11 in vicinity of a provision location of a micro tube 16 and a limiter portion 17 , and a state of a sample-liquid laminar flow and a sheath-liquid laminar flow, which pass therethrough.
FIG. 5 Sectional schematic views describing a micro fluidic structure of the flow path 11 in vicinity of a pressure-rising portion 13 and an orifice 12 , and the sample-liquid laminar flow and the sheath-liquid laminar flow, which pass therethrough.
FIG. 6 A view schematically showing the sample liquid and the sheath liquid, which are transformed into liquid drops and discharged through the orifice 12 .
FIGS. 7 A, 7 B, and 7 C Sectional schematic views describing the width and the depth of the flow path 11 . FIG. 7 A shows a cross-section of the flow path 11 at an opening position of the micro tube 16 , FIG. 7 B shows a cross-section of the flow path 11 at a light-irradiated portion 33 , FIG. 7 C shows a cross-section of the flow path 11 at a location of the orifice 12 .
FIG. 8 Views describing another preferred embodiment with respect to the width and the depth of the flow path 11 .
FIG. 9 A view schematically showing sorting of the micro particles by the micro-particle sorting apparatus A.
FIG. 10 A view describing a first embodiment of a cartridge according to the present invention.
FIG. 11 A view describing a second embodiment of the cartridge according to the present invention.
FIG. 12 A view describing a third embodiment of the cartridge according to the present invention.
FIG. 13 A view describing a fourth embodiment of the cartridge according to the present invention.
DETAILED DESCRIPTION
Hereinafter, a preferred mode for carrying out the invention will be described with reference to the drawings. It should be noted that an embodiment to be described below shows one example of a typical embodiment of the present invention, and shall not be construed to limit the scope of the present invention. It should be noted that the description will be made in the following order.
1. Micro-particle sorting apparatus
2. Microchip
(1) Flow path
(2) Micro tube and limiter portion
(3) Light-irradiated portion
(4) Pressure-rising portion and orifice
3. Oscillating element
4. Width and Depth of flow path at each location of microchip
5. Operation of micro-particle sorting apparatus
6. Cartridge
1. Micro-Particle Sorting Apparatus
FIG. 1 is a view showing a schematic configuration of a micro-particle sorting apparatus according to the present invention. In the drawing, the micro-particle sorting apparatus denoted by the symbol A is mainly constituted of a cartridge 7 including a microchip 1 or micro fluidic structure as a component and of an apparatus main body including an optical detection means 3 that radiates the light to a predetermined location of the microchip 1 or micro fluidic structure. The microchip 1 is in such a state that one part thereof is exposed to the outside of the cartridge and the other part is housed within the cartridge 7 . In the inside of the cartridge 7 , a pair of paired electrodes
4 , 4 are provided. Further, to a side in opposite to the microchip 1 , of the cartridge 7 , three containers ( numerals
51 , 52 , 53 ) are connected so that the inside of each container is in communication with the cavity of the cartridge. The cartridge 7 includes the microchip 1 , the paired electrodes
4 , 4 , and the containers 51 to 53 as components is detachably attached to the main body of the micro-particle sorting apparatus A. In the main body of the micro-particle sorting apparatus A, during attachment of the cartridge 7 , an oscillating element (not shown) is provided at a position at which it is brought into contact with a part of the microchip 1 or micro fluidic structure.
A configuration of the micro-particle sorting apparatus A will be described in detail with reference to FIG. 2 . FIG. 2 is a view showing the schematic configuration of the micro-particle sorting apparatus A. The drawing shows the microchip 1 and the optical detection means 3 , the paired electrodes
4 , 4 , and the containers 51 to 53 which are described above. In the drawing, the numeral 2 denotes the oscillating element provided so as to be brought into contact with the part of the microchip 1 during attachment of the cartridge 7 to the main body of the micro-particle sorting apparatus A. Further, the numerals
6 , 6 denote grounding paired electrodes that have been grounded. It should be noted that here, the illustration of the cartridge 7 is omitted.
In the microchip 1 , there is formed a flow path 11 through which liquid (sample liquid) containing micro particles being as sorting targets flows. The optical detection means 3 radiates light (measurement light) to a predetermined location of the flow path 11 , and detects light (measurement target light) generating from the micro particles flowing through the flow path 11 . Hereinafter, in the flow path 11 , the location to be irradiated with the measurement light from the optical detection means 3 is referred to as a âlight-irradiated portion.â
The microchip 1 can be formed of glass or various type of plastics (PP, PC, COP, PDMS, for example). The material of the microchip is desirably material having transmittance for the measurement light radiated from the optical detection means 3 and low autofluorescence and causing small optical error due to its small wavelength dispersion.
Formation of the flow path 11 in the microchip 1 or micro fluidic structure can be performed by wet etching or dry etching with respect to a glass substrate, or by nano-imprinting, injection molding, or machining with respect to a plastic substrate. The microchip 1 can be formed by sealing a substrate, on which the flow path 11 and the like have been formed, with a substrate made of the same material or a different material.
The optical detection means 3 can be configured similarly to the conventional flow cytometry. Specifically, the optical detection means 3 is constituted of a laser light source, an irradiation system, and a detection system. The irradiation system is composed of collecting lens, a dichroic mirror, a bandpass filter, and the like for collecting and radiating the laser light with respect to the micro particles. The detection system detects the measurement target light generating from the micro particles due to the irradiation of the laser light. The detection system is, for example, constituted of a PMT (photo multiplier tube) and an area-image pick-up element such as a CCD or CMOS element. It should be noted that although FIG. 2 shows the case where the irradiation system and the detection system are individually configured, the irradiation system and the detection system are configured through the same optical path (see FIG. 1 ).
The measurement target light to be detected by the detection system of the optical detection means 3 is light generating from the micro particles due to the irradiation of the measurement light. The measurement target light can be, for example, forward scatter or side scatter, scattering light including Rayleigh scattering or Mie scattering, or fluorescence. The measurement target light is converted into an electrical signal, and optical properties of the micro particles are detected according to this electrical signal.
The sample liquid passing through the light-irradiated portion is discharged through an orifice provided at one end of the flow path 11 into the space outside the chip. At this time, the oscillating element 2 oscillates the microchip 1 so that the sample liquid can be transformed into liquid drops, and the liquid drops are discharged into the space outside the chip. In FIG. 2 , the symbol D denotes the liquid drops discharged into the space outside the chip.
The liquid drops D can contain the micro particles being as the sorting targets. The paired electrodes
4 , 4 are provided along movement direction of the liquid drop discharged into the space outside the chip, and arranged so as to be opposed to each other while sandwiching each of the moving liquid drops therebetween. To the discharged liquid drop, an electric charge is added by a charge means (not shown). The paired electrodes
4 , 4 controls, with its electrical repelling force (or attracting force) with respect to the electric charge added to the liquid drop, the movement direction of the liquid drop. In this manner, the liquid drop is guided into any one of the containers 51 to 53 . It should be noted that the containers
52 and 53 that collect the liquid drops may be a commonly-used plastic test-tube container as shown in the drawing or the like, or may be a sorting plate container including a plastic substrate on which 96 wells and the like are formed or the like.
As described above, the micro-particle sorting apparatus A is characterized in that processes up to the property detection of the micro particles by the optical detection means 3 are performed in the microchip 1 , and then, the control of the movement directions of the micro particles is performed in the space outside the chip. In the micro-particle sorting apparatus A, on the basis of the optical properties of the micro particles, which are detected by the optical detection means 3 , the movement directions of the liquid drops each containing the micro particle are controlled by the paired electrodes
4 , 4 , and hence the micro particles each having a desired property can be collected by any one of the containers 51 to 53 for sorting.
It should be noted that in the micro-particle sorting apparatus A, the optical detection means 3 may be replaced, for example, by an electrical or magnetic detection means. In a case of electrically or magnetically detecting the properties of the micro particles, on both sides of the flow path 11 , micro electrodes are provided so as to be opposed to each other in order to measure resistance, capacitance, inductance, impedance, and value of change in electrical field between the electrodes, or magnetization, a change in magnetic field, and the like. In this case, the sorting of the micro particles is performed on the basis of electrical or magnetic properties of the micro particles.
Hereinafter, details of the respective components of the micro-particle sorting apparatus A and functions thereof will be described in order. First, with reference to FIGS. 3 to 8 , the microchip 1 and the oscillating element 2 will be described.
2. Microchip
(1) Flow Path
FIG. 3 is a view showing schematic configurations of the microchip 1 and the oscillating element 2 . In the microchip 1 , a sample inlet 15 through which the sample liquid is introduced, and a sheath liquid inlet 14 through which sheath liquid is introduced are formed. The sheath liquid introduced into the sheath liquid inlet 14 branches into two directions of the Y-axis positive and negative directions and is delivered through the flow path 11 , caused to turn at approximately 90 degrees twice before convergence, and then delivered to the downstream.
(2) Micro Tube and Limiter Portion
At the location of the flow path 11 , at which the sheath liquid is converged, a micro tube 16 for introducing the sample liquid, which has been introduced from the sample inlet 15 , into a sheath-liquid laminar flow is provided. A sample-liquid laminar flow passes through the micro tube 16 and is introduced into the sheath-liquid laminar flow that is introduced from the sheath liquid inlet 14 and passes through the flow path 11 . With this, the sample-liquid laminar flow can be delivered to the downstream of the flow path 11 while being surrounded with the sheath-liquid laminar flow.
The micro tube 16 is formed of a metal on which voltage can be applied, and is configured as the charge means that adds a positive or negative charge with respect to the sheath liquid and the sample liquid flowing through the flow path 11 . The sample liquid and the sheath liquid are transformed into liquid drops through the orifice 12 provided at one end of the flow path 11 , and the liquid drops are discharged into the space outside the chip. At this time, by applying on the micro tube 16 voltage, it is possible to add the positive or negative charge to the liquid drop to be discharged.
In FIG. 3 , the numeral 17 denotes a limiter portion provided to the flow path 11 . The limiter portion 17 is formed so as to have a cross-section perpendicular to a liquid-delivering direction, which gradually decreases in area from the upstream to the downstream of the flow path.
FIG. 4 are sectional schematic views describing a micro fluidic structure of the flow path 11 in vicinity of the provision location of the micro tube 16 and the limiter portion 17 and a state of the sample-liquid laminar flow and the sheath-liquid laminar flow, which pass therethrough. FIG. 4 A shows a horizontal sectional view (XY sectional view), and FIG. 4 B shows a vertical sectional view (ZX sectional view). In the drawing, the symbol S denotes the sample-liquid laminar flow, the symbol T denotes the sheath-liquid laminar flow, and the symbol P denotes the sorting-target micro particles contained in the sample liquid.
The sample-liquid laminar flow S is introduced through the micro tube 16 into the sheath-liquid laminar flow T passing through the flow path 11 , and then, delivered in such a state that the sample-liquid laminar flow S is surrounded with the sheath-liquid laminar flow T as shown in the drawing (as three-dimensional laminar flow).
Sidewalls of the flow path at the limiter portion 17 are formed so that the space therebetween narrows in the Y-axis direction in the drawing along the liquid-delivering direction. The limiter portion 17 has a counterbalance shape, which becomes gradually slimmer as viewed from above. With this shape, the limiter portion 17 limits the width of the laminar flow of the sheath liquid and the sample-liquid in the Y-axis direction in the drawing and delivers the laminar flow of the sheath liquid and the sample-liquid. Further, the limiter portion 17 is formed so that a bottom surface of the flow-path thereof is an inclined surface increasing in height in a depth direction (Z-axis positive direction) from the upstream to the downstream. The limiter portion 17 limits also the width of the laminar flow in that direction.
As described above, when the sample-liquid laminar flow S forms the three-dimensional laminar flow, surrounded with the sheath-liquid laminar flow T, and this three-dimensional laminar flow is delivered with the width of the laminar flow of the three-dimensional laminar flow being limited, the sheath-liquid laminar flow T can be delivered in such a state that the micro particles P are arranged in line in the limited sample-liquid laminar flow S. Further, it is possible to determine a flowing position of the micro particle P in the flow path 11 , and to accurately radiate the measurement light from the optical detection means 3 to the micro particles P.
In particular, the limiter portion 17 can limit the width of the laminar flow of the sample-liquid laminar flow S not only in the horizontal direction of the microchip 1 (Y-axis direction of FIG. 4 A ), but also the vertical direction (Z-axis direction of FIG. 4 B ). Thus, a focus position of the measurement light in the depth direction of the flow path 11 can be caused to precisely correspond to the flowing position of the micro particle P. Therefore, it is possible to accurately radiate the measurement light to the micro particles P and to obtain a high measurement sensitivity.
Here, it is conceivable that if the flow path 11 is formed as a sufficiently slim flow path, and a micro tube 16 having a small diameter is used to introduce the sample-liquid laminar flow S into the sheath-liquid laminar flow T passing through the flow path 11 , it is also possible to form the three-dimensional laminar flow having a previously limited laminar flow width. However, in this case, due to the small diameter of the micro tube 16 , the micro tube 16 may get blocked by the micro particles P.
In the microchip 1 , the limiter portion 17 is provided, and hence using the micro tube 16 having a diameter sufficiently larger than the diameter of each micro particle P contained in the sample liquid, the three-dimensional laminar flow is formed, the width of the laminar flow can be limited. Therefore, the problem of blocking of the micro tube 16 as described above does not occur.
FIG. 4 show a case where the micro tube 16 is provided so that its center is coaxially positioned with respect to the center of the flow path 11 . In this case, the sample-liquid laminar flow S is introduced into the center of the sheath-liquid laminar flow T passing through the flow path 11 . The position of the sample-liquid laminar flow S in the sheath-liquid laminar flow T can be arbitrarily set by adjusting an opening position of the micro tube 16 in the flow path 11 . Further, for limitation of the width of the laminar flow, it is sufficient that the limiter portion 17 be formed so as to have the cross-section perpendicular to the liquid-delivering direction, which gradually decreases in area from the upstream to the downstream of the flow path. The shape of the limiter portion 17 be not limited to the shape shown in FIG. 4 , and, for example, the limiter portion 17 may be formed so that both of the bottom surface of the flow-path and the top surface of the flow-path are as inclined surfaces in order to perform the limitation.
The inner diameter of the micro tube 16 can be appropriately set depending on the diameter of each micro particle P b
CLAIMS
Claims ( 29 )
The invention is claimed as follows:
1. A microchip for analyzing a micro particle comprising:
a flow path through which a liquid containing a micro particle flows; an orifice through which the liquid flowing through the flow path is configured to be discharged into a space outside the microchip; and a light-irradiated portion provided at a predetermined location of the flow path and configured to be irradiated with light, wherein a width of the flow path and a depth of the flow path within the microchip at the orifice are set to be smaller than a width of the flow path and a depth of the flow path within the microchip at the light-irradiated portion, and wherein the flow path is configured to gradually decrease within the microchip, from upstream of the orifice in a cross-section area perpendicular to a liquid-delivering direction between the light-irradiated portion and the orifice.
2. The microchip of claim 1 , comprising an oscillating element for transforming the liquid into a liquid drop and discharging the liquid drop at the orifice.
3. The microchip of claim 1 , comprising a micro tube that introduces, into a laminar flow of a liquid T flowing through the flow path, a laminar flow of a liquid S containing the micro particle, upstream of the liquid-delivering direction with respect to the light-irradiated portion.
4. The microchip of claim 3 , wherein the micro tube includes a metal on which voltage can be applied.
5. The microchip of claim 1 , wherein the microchip comprises a substrate and the flow path is provided within the substrate.
6. The microchip of claim 1 , further comprising: a sheath liquid inlet, and wherein the sheath liquid inlet branches into a first direction and a second direction, and wherein the first direction is opposite to the second direction.
7. A cartridge comprising:
a microchip for analyzing a micro particle comprising:
a flow path through which a liquid containing a micro particle flows;
an orifice through which the liquid flowing through the flow path is configured to be discharged into a space outside the microchip flow path; and
a light-irradiated portion provided at a predetermined location of the flow path and configured to be irradiated with light; and
a cavity in which at least the orifice and the space in which the liquid drop discharged outside through the orifice moves are configured,
wherein a width of the flow path and a depth of the flow path at the orifice are set to be smaller than a width of the flow path and a depth of the flow path at the light-irradiated portion,
wherein the flow path is configured to gradually decrease from upstream of the orifice in a cross-section area perpendicular to a liquid-delivering direction between the light-irradiated portion and the orifice, and
wherein the cavity has an optical window having light transmittance for light transmitted to the light-irradiated portion.
8. The cartridge of claim 7 , wherein the cavity is configured to be hermetically sealed.
9. The cartridge of claim 7 , wherein the microchip comprises further comprising an oscillating element for transforming the liquid into a liquid drop and discharging the liquid drop at the orifice.
10. The cartridge of claim 7 , wherein the microchip comprises further comprising a micro tube that introduces, into a laminar flow of a liquid T flowing through the flow path, a laminar flow of a liquid S containing the micro particle, upstream of the liquid-delivering direction with respect to the light-irradiated portion.
11. The cartridge of claim 10 , wherein the micro tube includes further comprising a metal on which voltage is configured to be applied.
12. The cartridge of claim 7 13 , wherein the microchip micro fluidic structure comprises a substrate and the flow path is provided within the substrate.
13. The cartridge of claim 7 , further comprising a micro fluidic structure comprising the flow path, the orifice, and the light irradiated portion.
14. The cartridge of claim 13 , wherein the micro fluidic structure is a microchip.
15. The cartridge of claim 7 , wherein the cartridge is detachably attached to a micro-particle sorting apparatus.
16. The cartridge of claim 7 , wherein the cavity furtherly house a pair of electrodes opposed to each other while sandwiching the moving liquid drop along a movement direction of the liquid drop discharged into the space.
17. The cartridge of claim 7 , wherein the space is an airtight space.
18. The cartridge of claim 7 , wherein further comprising a container for receiving discharged liquid drop.
19. The cartridge of claim 18 , wherein the container communicates with the cavity of the cartridge in an airtight manner.
20. The cartridge of claim 18 , wherein the container is a plastic tube.
21. The cartridge of claim 18 , wherein the container is detachably attached to the cartridge.
22. The cartridge of claim 7 , wherein the optical window is a cut out part of the cartridge.
23. The cartridge of claim 7 , wherein the optical window comprises plastic or glass or quartz.
24. The cartridge of claim 7 , wherein the cartridge is connected to a sample supplying path.
25. The cartridge of claim 24 , wherein the sample supplying path is disposable.
26. The cartridge of claim 7 , wherein the cartridge comprises plastic or glass.
27. A micro-particle sorting apparatus comprising:
a light source configured to irradiate light to micro particles, a flow path through which a liquid containing a micro particle flows; an orifice through which the liquid flowing through the flow path is configured to be discharged into a space outside the flow path; a light-irradiated portion provided at a predetermined location of the flow path and configured to be irradiated with light; paired electrodes provided so as to be opposed to each other while sandwiching the moving liquid drop there between along a movement direction of the liquid drop discharged into the space outside the flow path; and a cavity in which at least the orifice and the space in which the liquid drop discharged outside through the orifice moves are configured, wherein a width of the flow path and a depth of the flow path at the orifice are set to be smaller than a width of the flow path and a depth of the flow path at the light-irradiated portion, wherein the flow path is configured to gradually decrease from upstream of the orifice in a cross-section area perpendicular to a liquid-delivering direction between the light-irradiated portion and the orifice, and wherein the cavity has an optical window having light transmittance for light transmitted to the light-irradiated portion.
28. A micro particle sorting svstem of claim 27 , comprising:
an optical detection means that detects an optical property of the micro particle flowing through the flow path, upstream of a liquid-delivering direction with respect to the orifice.
29. A micro particle sorting system of claim 27 , wherein the light source is provided on a main body of a micro particle sorting apparatus.
US17/514,186
2009-02-17
2021-11-12
Microchip for sorting micro particles and cartridge including same
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