WO2014122873A1 - 微小粒子分析装置及び微小粒子分析システム - Google Patents
微小粒子分析装置及び微小粒子分析システム Download PDFInfo
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- WO2014122873A1 WO2014122873A1 PCT/JP2013/084878 JP2013084878W WO2014122873A1 WO 2014122873 A1 WO2014122873 A1 WO 2014122873A1 JP 2013084878 W JP2013084878 W JP 2013084878W WO 2014122873 A1 WO2014122873 A1 WO 2014122873A1
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Definitions
- This technology relates to a microparticle analysis apparatus and a microparticle analysis system. More specifically, the present invention relates to a microparticle analysis apparatus and a microparticle analysis system that identify individual microparticles using a difference in electrical characteristics.
- microparticles such as cells have different physical property values indicating electrical characteristics such as conductivity, dielectric constant, and conductivity depending on the type and state thereof. For example, the conductivity of extracellular fluid and intracellular fluid is higher in muscle cells and nerve cells than in skin cells with less water. Further, when the dielectric constant of a cell is measured by sweeping the frequency, the dielectric relaxation characteristics change according to the cell morphology.
- the dielectric cytometry described above can analyze and sort microparticles without labeling substances, and is therefore an extremely effective method in the life science research field such as regenerative medicine and immunology, or in the medical field such as clinical examination. is there.
- a sample liquid containing a plurality of microparticles is passed through the microchannel, and the complex dielectric constant is measured when each microparticle passes between the electrode pairs.
- the measurement accuracy tends to decrease.
- dielectric cytometry apparatuses are required to further improve measurement accuracy.
- the main object of the present disclosure is to provide a microparticle analysis apparatus and a microparticle analysis system that can accurately identify and sort individual microparticles without using a labeling substance.
- a microparticle analysis apparatus includes a sample channel into which a liquid containing a plurality of microparticles is introduced, a first electrode pair for forming an alternating electric field in at least a part of the sample channel, A measurement unit that measures the impedance between the first electrode pair, an analysis unit that calculates a characteristic value of the microparticles from the impedance measured by the measurement unit, and impedance data measured by the measurement unit include: And a determination unit that determines whether the particle is derived from fine particles. The determination unit may detect from the impedance data that the microparticles have passed the AC electric field, and perform determination based on the detection result. In that case, the determination unit obtains from the impedance.
- the passage of the fine particles can be detected from the peak position and peak height of the conductance.
- the determination unit starts detecting the passage of the microparticles when the value of the capacitance and / or conductance obtained from the impedance exceeds a threshold value, and determines whether the microparticles pass when the value is equal to or less than the threshold value. Detection can be terminated.
- the determination unit can determine that the impedance data is derived from the fine particles only when the capacitance and / or conductance value exceeds a threshold value for a predetermined time.
- the characteristic value may be calculated by the analysis unit for data determined by the determination unit to be derived from the fine particles.
- the analysis unit may calculate the characteristic value by comparing or fitting the data measured by the measurement unit with a specific model.
- a specific model for example, a dielectric relaxation phenomenon model based on a complex dielectric spectrum can be used.
- the microparticle analyzer may have a sorting unit that sorts the microparticles based on the characteristic values calculated by the analyzing unit.
- a dielectric having a second electrode pair for forming an electric field downstream of a region where the alternating electric field is formed in the sample flow path and generated by the electric field formed by the second electrode pair. The flow direction of the fine particles may be changed by the migration force.
- the sample channel may be provided with a narrowed portion, and the first electrode pair may be arranged so as to sandwich the narrowed portion.
- the microparticles may be cells.
- the characteristic value may be at least one value selected from the group consisting of membrane capacitance, cytoplasmic conductivity and particle size.
- the measurement unit may measure the complex impedance at multiple points in a frequency range of 0.1 to 50 MHz.
- a microparticle analysis system includes a sample channel into which a liquid containing a plurality of microparticles is introduced, a first electrode pair for forming an alternating electric field in at least a part of the sample channel, A measurement unit that measures the impedance between the first electrode pair, a microparticle analysis device, an analysis unit that calculates a characteristic value of the microparticles from the impedance measured by the measurement unit, and a measurement by the measurement unit And an information processing device including a determination unit that determines whether the impedance data is derived from the fine particles.
- the fine particle analysis system may further include a display device that displays characteristic values of the fine particles calculated by the analysis unit of the information processing device.
- FIGS. 2A and 2B are diagrams schematically showing a configuration example of the sample channel 2 shown in FIG. A and B are diagrams schematically showing another configuration example of the sample channel 2 shown in FIG. 2, wherein A is a perspective view, and B is a sectional view taken along the line bb.
- A is a perspective view
- B is a sectional view taken along the line bb.
- FIG. 1 is a diagram showing a schematic configuration of a fine particle analyzer of this embodiment.
- the fine particle analyzer 1 of the present embodiment includes a measurement system unit 100, a water flow formation system unit 200, a control system unit 300 that controls these, and the like.
- FIG. 2 is a diagram showing an outline of the configuration of the measurement system unit 100 shown in FIG.
- the measurement system unit 100 includes a sample channel 2, an electrode pair composed of an electrode 3 a and an electrode 3 b, a measurement unit 4, a determination unit 5, and an analysis unit 6.
- the information storage unit 7 and the imaging unit 8 are provided as necessary.
- a sample liquid including a plurality of microparticles 10 is introduced into the sample channel 2, and the impedance of each microparticle 10 is measured by the measurement unit 4.
- the microparticles 10 analyzed by the microparticle analyzer 1 of the present embodiment widely include living body-related microparticles such as cells, microorganisms, and ribosomes, or synthetic particles such as latex particles, gel particles, and industrial particles. .
- Biologically relevant microparticles include chromosomes, ribosomes, mitochondria, organelles (cell organelles), etc. that make up various cells.
- the cells include plant cells, animal cells, blood cells, and the like.
- microorganisms include bacteria such as Escherichia coli, viruses such as tobacco mosaic virus, and fungi such as yeast.
- the biologically relevant microparticles may include biologically relevant polymers such as nucleic acids, proteins, and complexes thereof.
- examples of the industrial particles include those formed of an organic polymer material, an inorganic material, or a metal material.
- organic polymer material polystyrene, styrene / divinylbenzene, polymethyl methacrylate, or the like can be used.
- inorganic material glass, silica, a magnetic material, etc. can be used.
- metal material for example, gold colloid and aluminum can be used.
- shape of these fine particles is generally spherical, it may be non-spherical, and the size and mass are not particularly limited.
- sample flow path 2 The sample channel 2 is formed in, for example, a microchip.
- the material constituting the sample flow path 2 is not particularly limited as long as it is insulative and does not affect the electrical characteristics of the microparticle 10 to be measured.
- Specific examples include polycarbonate, cycloolefin polymer, plastic materials such as polypropylene and polyimide, PDMS (polydimethylsiloxane), and glass.
- PDMS polydimethylsiloxane
- glass glass.
- insulating plastic material such as polyimide.
- FIGS. 3 and 4 are diagrams schematically showing a configuration example of the sample flow path 2.
- FIG. As shown in FIGS. 3 and 4, the sample channel 2 is provided with a constricted portion 21 through which the microparticles 10 can pass, and the impedance of the microparticles 10 is measured in the constricted portion 21.
- the narrowed portion 21 may be of a size that allows the microparticles 10 to be analyzed to pass one by one, and can be appropriately set according to the particle size of the microparticles 10 and the like.
- the constriction part 21 in the impedance measurement region 24 the contribution of the electric double layer capacitance can be greatly reduced, so that the influence of electrode polarization that causes noise is suppressed and the measurement sensitivity is increased. be able to.
- the sample channel 2 may have a constricted portion 21, an upstream inflow channel portion 22 and a downstream outflow channel portion 23 arranged coaxially, As shown in FIG. 4, these can also be arranged shifted in the thickness direction.
- the substrate thickness of the channel portion is increased, so that the pressure resistance is improved.
- the portion where the flow path is formed is mainly bonded to the portion where the flow path is not formed. Therefore, compared with the configuration shown in FIG. Becomes easy and can be manufactured at low cost.
- the sample channel 2 may be provided with an injection hole for injecting the microparticle 10 to be analyzed separately from the solvent constituting the sample liquid.
- a liquid containing the microparticles 10 to be analyzed from the injection hole for example, a sample whose cell concentration is adjusted by dilution with a medium or Blood sample etc.
- Electrodes 3a, 3b are for forming an alternating electric field in at least a part of the sample flow path 2, and are disposed so as to sandwich the constricted portion 21 as shown in FIGS. 3 and 4, for example.
- the material of the electrodes 3a and 3b is not particularly limited as long as it has little influence on the fine particles 10.
- a configuration in which a pair of electrodes is provided in the impedance measurement region 24 is shown, but the present disclosure is not limited to this, and a plurality of electrode pairs are provided in the impedance measurement region 24. Also good.
- a plurality of electrode pairs in the impedance measurement region 24 for example, detection by a four-terminal method or the like is possible, so that impedance measurement can be performed more precisely.
- the measuring unit 4 applies an AC voltage between the electrode 3a and the electrode 3b described above, and measures the impedance of each microparticle 10 passing through the AC electric field formed thereby.
- the configuration of the measurement unit 4 is not particularly limited as long as the impedance of each microparticle 10 can be measured.
- the measurement unit 4 may be configured to include one or two or more impedance analyzers and network analyzers.
- the complex dielectric spectrum of each microparticle 10 is obtained by changing the frequency of the AC voltage applied between the electrode 3a and the electrode 3b or by superimposing a plurality of frequencies and performing impedance measurement at the plurality of frequencies.
- Specific methods include a method of arranging a plurality of single frequency analyzers, a method of sweeping frequencies, a method of superimposing frequencies and extracting information on each frequency with a filter, and a method of measuring by response to an impulse. .
- the determination unit 5 determines whether the impedance data measured by the measurement unit 4 described above is derived from the fine particles 10.
- the impedance data measured by the measurement unit 4 includes a noise component in addition to the information derived from the microparticles 10 to be analyzed. Therefore, in the microparticle analysis apparatus of the present embodiment, the analysis result finally obtained by determining whether or not the impedance data measured by the measurement unit 4 is derived from the microparticles 10 in the determination unit 5. Improves accuracy.
- the determination unit 5 for example, it is detected from the impedance data measured by the measurement unit 4 that the microparticles 10 have passed the AC electric field, and determination is performed based on the detection result.
- the method for detecting that the microparticle 10 has passed the AC electric field is not particularly limited. For example, it is detected from the conductance obtained from the impedance, the peak position of the capacitance, the peak height, the peak width, and a combination thereof. A way to do this is conceivable.
- the determination unit 5 determines that the impedance data is derived from the microparticles 10 only when the capacitance and / or conductance value exceeds the threshold value for a predetermined time.
- the analysis unit 6 compares the impedance data determined to be derived from the microparticles 10 by the determination unit 5 and the dielectric spectrum calculated from the impedance data with a specific model formula such as a dielectric relaxation phenomenon model, and performs fitting. Then, the characteristic value of the microparticle 10 is obtained. For example, when the microparticle 10 to be analyzed is a cell, the characteristic values required by the analysis unit 6 include the microparticle 10 such as membrane capacitance, cytoplasmic conductivity, particle size, nucleus size, and nuclear membrane thickness. There are various structural parameters concerning.
- the information storage unit 7 stores characteristic values obtained by the analysis unit 6, impedance data measured by the measurement unit 4, and a complex dielectric spectrum.
- the information storage unit 7 does not need to be provided in the apparatus, and may be provided in an externally connected hard disk or server.
- the microparticle analysis apparatus may be provided with an imaging unit 8 that images the microparticles 10 that pass through the alternating electric field formed by the electrodes 3 a and 3 b or the narrowed portion 21 of the sample flow path 2.
- the configuration of the imaging unit 8 is not particularly limited, and an optical system including an imaging element such as a charge coupled device (CCD) or a complementary metal oxide semiconductor (CMOS) can be used. Data captured by the imaging unit 8 is used, for example, in the determination unit 5 or the analysis unit 6 to confirm the image of the passage of the fine particles 10.
- CCD charge coupled device
- CMOS complementary metal oxide semiconductor
- the water flow formation system unit 200 is for introducing a sample liquid containing a plurality of microparticles 10 into the sample flow path 2 of the measurement system unit 100, and includes a pump 201, a sample introduction unit 202, a valve 203, and the like. ing.
- a pressure is applied to the sample introduction unit 202 by the pump 201, the sample liquid injected into the sample introduction unit 202 is introduced into the sample flow path 2 of the measurement system unit 100 through the valve 203. It has come to be.
- valve 203 can be opened and closed, and its opening and closing is controlled by a control system unit 300 described later.
- the water flow forming system unit 200 may further include a flow meter, a temperature sensor, a pressure sensor, and the like.
- Control system unit 300 controls the measurement system unit 100 and the water flow forming system unit 200 described above. Then, for example, based on information input via the input interface, the pressure of the pump 201 of the water flow forming system unit 200 and the opening amount of the valve 203 are controlled, and the sample flows through the sample flow path 2 of the measurement system unit 100. Adjust the flow rate and flow rate of the liquid.
- the microparticle analysis apparatus 1 of the present embodiment includes impedance data measured by the measurement unit 4 of the measurement system unit 100, a determination result of the determination unit 5, a dielectric spectrum calculated by the analysis unit 6, and various characteristic values.
- a display unit for displaying, an output unit for outputting to various media, and the like can also be provided.
- an information input unit may be provided for the user to input display data selection information and information on the measurement sample.
- the operation of the microparticle analysis apparatus of this embodiment that is, a method for analyzing the microparticles 10 using the microparticle analysis apparatus 1 will be described.
- the sample liquid containing the microparticles 10 is allowed to flow through the sample flow path 2 or the microparticles are included in a state where a solvent such as physiological saline is allowed to flow. Liquid is injected and allowed to flow with the solvent.
- the flow rate (flow velocity) of the sample liquid is not particularly limited, and can be set as appropriate according to the diameter of the flow path and the constricted portion, the size of the microparticles 10, the number of data to be acquired, and the like.
- the flow rate of the sample liquid is set to a flow rate at which the microparticles 10 are present in the narrowed portion of the sample channel 2 for a time that is twice or more the impedance measurement interval in the measurement unit 4. It is preferable. Thereby, the influence of the flow rate of the sample liquid on the measurement result can be reduced.
- the flow rate of the sample liquid can be adjusted by a pressure adjusting unit of the liquid feeding unit.
- the measuring unit 4 applies an AC voltage between the electrodes 3a and 3b continuously or at a timing when the microparticles 10 pass, thereby forming an AC electric field in the sample flow path 2. And when passing through this alternating electric field, the impedance of the microparticle 10 is measured. For example, when the microparticle 10 is a cell and it is desired to confirm the dielectric relaxation phenomenon, the complex impedance may be measured at multiple points in the frequency range of 0.1 to 50 MHz.
- the fine particles 10 passing through the part 21 are imaged.
- the determination unit 5 detects from the impedance data measured by the measurement unit 4 that the microparticles 10 have passed the AC electric field, and based on the detection result, the measured impedance data is very small. It is determined whether or not it is derived from the particle 10. Specifically, it is determined that the data when the passage of the microparticle 10 is detected is derived from the microparticle 10, and the data when the passage of the microparticle 10 is not detected is determined to be derived from noise or the like. .
- the method for detecting the passage of the microparticles 10 is not particularly limited.
- the conductance value fluctuates with a noise width around an arbitrary average value.
- the conductance value decreases, and increases to the baseline again through an arbitrary minimum value.
- detection of the passage of the microparticle 10 is started when the capacitance and / or conductance value obtained from the impedance measured by the measuring unit 4 exceeds the threshold value, and when the value becomes equal to or less than the threshold value, the microparticle 10 is detected. It is preferable to end the detection of the passage of. That is, when the value of capacitance and / or conductance is less than or equal to the threshold value, the peak derived from the passage of the microparticle 10 is not recognized. Thereby, it can prevent detecting the change of the value by noise as a peak originating in passage of the microparticle 10.
- the detected peak is recognized as originating from the passage of the microparticle 10, and the impedance data is stored in the microparticle 10. It is preferable to determine that it is derived. Thereby, the passage detection accuracy of the fine particles 10 can be further improved.
- the passage confirmation of the microparticles 10 may be performed based on the image data captured by the imaging unit 8 together with the passage detection of the microparticles 10 by the determination unit 5. .
- the data determined to be derived from the microparticles 10 by the determination unit 5 is analyzed by the analysis unit 6 at the complex dielectric constant spectrum, dielectric relaxation, membrane capacitance, cytoplasmic conductivity, and particles. Calculate characteristic values such as size.
- the calculation method of these characteristic values is not particularly limited, and various calculation methods such as comparison with a specific model formula and fitting can be applied.
- the impedance data determined to be derived from the microparticles 10 by the determination unit 5 is corrected and then smoothed, and the complex dielectric constant at each frequency is obtained using the Debye equation.
- dielectric relaxation strength D e characteristics are determined regarding dielectric relaxation, such as dielectric relaxation time tau a and dielectric relaxation frequency f a.
- the particle size (diameter) d of the microparticle 10 can be calculated from the value of conductance G low at a frequency lower than the dielectric relaxation.
- membrane capacitance C m may be calculated from the particle size d and mitigation intensity D e
- cytoplasmic electric conductivity K can be calculated from the relaxation frequency f a and membrane capacitance C m and the particle size d.
- the microparticles 10 are identified based on the characteristic values calculated by the analysis unit 6, and sorting and state evaluation are performed. Further, the characteristic value calculated by the analysis unit 6 and the impedance data measured by the measurement unit 4 are stored in the information storage unit 7 and displayed on a display unit (not shown) in response to a user request. Can be output as data or printed.
- the microparticle analysis apparatus 1 obtains an electrical characteristic value from the impedance of the microparticle, and identifies each microparticle based on the value, so it is necessary to use a labeling substance. There is no.
- the determination unit that determines whether the impedance data is derived from fine particles is provided, the influence of noise and the like can be reduced. As a result, individual microparticles can be accurately identified without using a labeling substance.
- the fine particle analyzer 1 of this embodiment it is possible to perform analysis using a labeling substance as in the conventional apparatus.
- FIG. 5 is a diagram showing an outline of the configuration of the measurement system unit of the microparticle analyzer according to this modification.
- the same components as those of the measurement unit 100 shown in FIG. 2 are denoted by the same reference numerals, and detailed description thereof is omitted.
- the determination unit and the analysis unit are provided separately, but the present disclosure is not limited to this, and the determination may be performed in the analysis unit. Therefore, as shown in FIG. 5, in the microparticle analyzer according to this modification, the determination / analysis unit 9 is provided in the measurement system unit 110, and the impedance data measured by the measurement unit 4 in the determination / analysis unit 9. Whether or not it is derived from the fine particles 10 and the characteristic value is calculated.
- the method for determining whether or not the particle originates from the microparticle 10 is not particularly limited.
- the complex permittivity spectrum is calculated from the impedance data measured by the measurement unit 4, and the spectrum is calculated. Can be determined based on
- microparticle analysis apparatus of this modification as in the first embodiment described above, since the influence of noise and the like can be reduced, individual microparticles can be accurately identified without using a labeling substance. can do.
- the configuration, operation, and effects other than those described above in the microparticle analysis apparatus of this modification are the same as those in the first embodiment described above.
- FIG. 6 is a diagram showing a schematic configuration of the microparticle sorting apparatus of the present embodiment.
- the same components as those of the fine particle analyzer 1 shown in FIG. 1 are denoted by the same reference numerals, and detailed description thereof is omitted.
- the microparticle sorting device 30 of the present embodiment is provided with an electrode pair (electrodes 3 c and 3 d) and a sorting unit 31 on the downstream side of the impedance measuring unit of the sample channel 2. ing.
- Electrodes 3c, 3d are for forming an electric field downstream of the impedance measurement region of the sample flow path 2.
- the material of the electrodes 3c and 3d is not particularly limited as long as it has little influence on the fine particles 10.
- 6 shows a configuration in which a pair of electrodes is provided downstream of the impedance measurement region 24, the present disclosure is not limited to this, and a plurality of electrode pairs are provided in this region. May be provided.
- the sorting unit 31 controls the electric field formation based on the characteristic value calculated by the analyzing unit 6 and controls the flow direction of the microparticles 10. For example, as shown in FIG. 6, two or more branch flow paths 32 communicating with the sample flow path 2 are provided, and the voltage value applied between the electrodes 3 c and 3 d or the presence or absence of voltage application is controlled by the sorting unit 31. As a result, the flow direction of the microparticles 10 is changed and introduced into an arbitrary branch channel 32. By providing the sample channel 2 and the branch channel 32 in the microchip, analysis and sorting can be performed in the microchip.
- the operation of the microparticle sorting apparatus 30 of the present embodiment that is, a method for sorting the microparticles 10 using the microparticle sorting apparatus 30 will be described.
- the sample liquid containing the microparticles 10 to be sorted is caused to flow through the sample channel 2.
- an alternating voltage is applied between the electrodes 3a and 3b by the measurement unit 4 continuously or at the timing when the fine particles 10 pass, an alternating electric field is formed in the sample flow path 2, and the impedance of the fine particles 10 is reduced. taking measurement.
- the sorting unit 31 applies a predetermined voltage between the electrode 3c and the electrode 3d according to the characteristic value (identification result) calculated by the analysis unit 6 to form an electric field. Thereby, the dielectrophoretic force works, and the microparticles 10 can be guided to the arbitrary branch flow path 32.
- the determination unit that determines whether the impedance data is derived from microparticles is provided, the influence of noise and the like can be reduced. As a result, it is possible to accurately identify and sort individual microparticles without using a labeling substance.
- the conventional dielectric cytometry device has no algorithm and system that can detect and determine the peak in real time. For this reason, feature points cannot be extracted from measurement data in real time and can be sorted based on the measured dielectric constant value, but for example, sorting is performed based on the characteristics of the dielectric spectrum. I could't.
- the fine particle sorting apparatus of the present embodiment feature points can be extracted in real time, so those that could not be distinguished by the value of dielectric constant are also features such as dielectric relaxation characteristics and particle size. It becomes possible to distinguish based on the value.
- the fine particle sorting device of the present embodiment improves the sorting accuracy compared to the conventional device.
- the microparticles 10 in the case of cells, membrane capacitance C m, cytoplasmic electric conductivity K calculated by the analysis unit 6, and gating such particle size d it is possible to fractionation. Furthermore, since the microparticle sorting apparatus of this embodiment can sort a living cell without labeling, it is also possible to reuse the sorted cell.
- the configuration and effects other than those described above in the present embodiment are the same as those in the first embodiment described above.
- FIG. 7 is a diagram showing a schematic configuration of the microparticle analysis system of the present embodiment.
- the fine particle analyzer of the first embodiment described above calculation of characteristic values of fine particles and determination of measured impedance data are performed in the device, and these processes are connected to the analyzer. It can also be performed by one or more information processing apparatuses.
- the microparticle analysis system of this embodiment is provided with one or more information processing apparatuses 12 in addition to the microparticle analysis apparatus 11.
- the server 13 and the display device 14 may be connected to the microparticle analysis system of the present embodiment as necessary.
- the microparticle analyzer 11 is provided with a sample channel, an electrode pair for forming an alternating electric field in at least a part of the sample channel, and a measurement unit that measures the impedance between the electrode pair.
- the specific configuration and operation of the sample flow path, electrode pair, and measurement unit that constitute the microparticle analyzer 11 are the same as those in the first embodiment described above.
- the information processing apparatus 12 is connected to the microparticle analysis apparatus 11, and an analysis unit that calculates a characteristic value of the microparticle from the measured impedance, and whether the measured impedance data is derived from the microparticle.
- a determination unit for determining whether or not The specific configurations and operations of the analysis unit and the determination unit are the same as those in the first embodiment described above. Further, the analysis unit and the determination unit may be provided in one information processing apparatus, but may be provided in different information processing apparatuses.
- the server 13 is connected to the information processing device 12 and the image display device 14 via the network 15 and is provided with an information storage unit and the like. And the server 13 manages the various data uploaded from the information processing apparatus 12, and outputs it to the display apparatus 14 or the information processing apparatus 12 according to a request
- the display device 14 displays impedance data measured by the microparticle analyzer 11, characteristic values of the microparticles calculated by the information processing device 12, a determination result by the determination unit, and the like.
- the display device may be provided with an information input unit for selecting and inputting data to be displayed by the user. In this case, information input by the user is transmitted to the server 13 and the information processing apparatus 12 via the network 15.
- microparticle analysis system of the present embodiment since a determination unit that determines whether impedance data is derived from microparticles is provided, the influence of noise and the like can be reduced. As a result, individual microparticles can be accurately identified without using a labeling substance. Further, by storing and using information in the server 13, various data analysis can be performed without imposing a load on the fine particle analysis device 11 and the information processing device 12. This improves the data processing speed and facilitates data access, resulting in improved usability.
- the configuration of the present embodiment can be applied to the microparticle sorting apparatus of the second embodiment described above to form a microparticle sorting system.
- the configuration and effects other than those described above in the present embodiment are the same as those in the first embodiment described above.
- the present disclosure can take the following configurations.
- a sample flow channel into which a liquid containing a plurality of microparticles is introduced;
- a first electrode pair for forming an alternating electric field in at least a portion of the sample flow path;
- a measurement unit for measuring impedance between the first electrode pair;
- An analysis unit that calculates a characteristic value of the microparticle from the impedance measured by the measurement unit;
- a determination unit that determines whether the impedance data measured by the measurement unit is derived from the microparticles;
- a fine particle analyzer The said determination part is a microparticle analyzer as described in (1) which detects that the said microparticle passed the said alternating current electric field from the data of the said impedance, and performs determination based on the detection result.
- the determination unit is the microparticle analyzer according to (2), wherein the passage of the microparticle is detected from a peak position and a peak height of conductance obtained from the impedance.
- the determination unit starts detecting the passage of the microparticles when a capacitance and / or conductance value obtained from the impedance exceeds a threshold value, and detects the passage of the microparticles when the value is equal to or lower than the threshold value.
- the fine particle analyzer according to (2) or (3) which is finished.
- the determination unit according to (4) wherein the determination unit determines that the impedance data is derived from the fine particles only when the capacitance and / or conductance value exceeds a threshold value for a predetermined time.
- the microparticle analyzer according to any one of (1) to (5), wherein the analysis unit calculates the characteristic value for data determined to be derived from the microparticles by the determination unit. (7) The analysis unit according to (6), wherein the analysis unit calculates the characteristic value by comparing or fitting the data measured by the measurement unit with a specific model. (8) The fine particle analyzer according to (7), wherein the specific model is a dielectric relaxation phenomenon model based on a complex dielectric spectrum. (9) The microparticle analysis apparatus according to any one of (1) to (8), further including a sorting unit that sorts the microparticles based on the characteristic value calculated by the analysis unit.
- (11) Having two or more branch channels communicating with the sample channel;
- the characteristic value is at least one value selected from the group consisting of membrane capacitance, cytoplasmic conductivity, and particle size.
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Abstract
Description
前記判定部は、前記インピーダンスのデータから、前記微小粒子が前記交流電場を通過したことを検出し、その検出結果に基づいて判定を行ってもよい
その場合、前記判定部は、前記インピーダンスから求めたコンダクタンスのピーク位置及びピーク高さから、前記微小粒子の通過を検出することができる。
又は、前記判定部は、前記インピーダンスから求めたキャパシタンス及び/又はコンダクタンスの値が閾値を超えたときに前記微小粒子の通過の検出を開始し、閾値以下になったときに前記微小粒子の通過の検出を終了することができる。
そして、前記判定部は、前記キャパシタンス及び/又はコンダクタンスの値が所定時間閾値を超えていた場合のみ、前記インピーダンスのデータを前記微小粒子に由来するものと判定することもできる。
また、前記判定部で前記微小粒子に由来すると判定されたデータについて、前記解析部において前記特性値の算出を行ってもよい。
その場合、前記解析部は、前記測定部で測定されたデータについて、特定のモデルとの比較又はフィッティングを行うことにより、前記特性値を算出してもよい。
また、前記特定のモデルは、例えば複素誘電スペクトルに基づく誘電緩和現象モデルを使用することができる。
この微小粒子分析装置は、前記解析部で算出された特性値に基づいて、前記微小粒子を分取する分取部を有していてもよい。
その場合、前記サンプル流路の前記交流電場が形成される領域よりも下流側に電場を形成するための第2の電極対を有し、前記第2の電極対により形成される電場によって生じる誘電泳動力により、前記微小粒子の通流方向を変更してもよい。
また、前記サンプル流路と連通する2以上の分岐流路を有し、前記微小粒子は、前記分取部によってその通流方向が変更され、任意の分岐流路に導入される構成にすることもできる。
一方、前記サンプル流路には狭窄部が設けられており、前記第1の電極対は前記狭窄部を挟むように配置されていてもよい。
また、前記交流電場を通過する微小粒子を撮像する撮像部を有していてもよい。
更に、前記微小粒子は細胞であってもよい。
その場合、前記特性値は、膜キャパシタンス、細胞質の導電率及び粒子サイズからなる群から選択される少なくとも1種の値とすることができる。
また、前記測定部は、0.1~50MHzの周波数範囲で複素インピーダンスを多点測定してもよい。
この微小粒子分析システムは、更に、前記情報処理装置の前記解析部で算出された前記微小粒子の特性値を表示する表示装置を有していてもよい。
また、前記情報処理装置の前記解析部で算出された前記微小粒子の特性値を記憶する情報記憶部を備えるサーバを有していてもよい。
1.第1の実施の形態
(判定部を備える微小粒子分析装置の例)
2.第1の実施の形態の変形例
(解析部が判定部を兼ねている微小粒子分析装置の例)
3.第2の実施の形態
(判定部を備える微小粒子分取装置の例)
4.第3の実施の形態
(微小粒子分析システムの例)
先ず、本開示の第1の実施形態に係る微小粒子分析装置について説明する。図1は本実施形態の微小粒子分析装置の概略構成を示す図である。図1に示すように、本実施形態の微小粒子分析装置1は、測定系ユニット100、水流形成系ユニット200及びこれらを制御する制御系ユニット300などで構成されている。
図2は図1に示す測定系ユニット100の構成の概要を示す図である。図2に示すように、測定系ユニット100には、サンプル流路2と、電極3a及び電極3bで構成される電極対と、測定部4と、判定部5と、解析部6とを備えており、必要に応じて情報記憶部7や撮像部8が設けられる。そして、この微小粒子分析装置1では、サンプル流路2に複数の微小粒子10を含むサンプル液が導入され、測定部4において各微小粒子10のインピーダンスが測定される。
本実施形態の微小粒子分析装置1で分析される微小粒子10には、細胞、微生物及びリボゾームなどの生体関連微小粒子、又はラテックス粒子、ゲル粒子及び工業用粒子などの合成粒子などが広く含まれる。
サンプル流路2は、例えばマイクロチップ内に形成されている。サンプル流路2を構成する材料は、特に限定されるものではなく、絶縁性でかつ測定対象の微小粒子10の電気的特性に影響を与えないものであればよい。具体的には、ポリカーボネート、シクロオレフィンポリマー、ポリプロピレン及びポリイミドなどのプラスチック材料、PDMS(polydimethylsiloxane)及びガラスなどが挙げられる。その中でも、電極が形成しやすく、量産性にも優れることから、ポリイミドなどの絶縁性プラスチック材料で形成することが好ましい。
電極3a,3bは、サンプル流路2の少なくとも一部に交流電場を形成するためのものであり、例えば、図3及び図4に示すように、狭窄部21を挟むように配置されている。電極3a,3bの材質は、特に限定されるものではなく、微小粒子10への影響が少ないものであればよい。
測定部4は、前述した電極3aと電極3b間に交流電圧を印加し、それにより形成される交流電場を通過する各微小粒子10のインピーダンスを測定する。測定部4の構成は、各微小粒子10のインピーダンスを測定可能であれば、特に限定されるものではないが、例えば1又は2以上のインピーダンスアナライザーやネットワークアナライザーを備えた構成とすることができる。
判定部5は、前述した測定部4で測定されたインピーダンスのデータが、微小粒子10に由来するものか否かを判定する。測定部4で測定されたインピーダンスのデータには、分析対象の微小粒子10に由来する情報以外に、ノイズ成分が含まれている。そこで、本実施形態の微小粒子分析装置では、測定部4で測定されたインピーダンスデータについて、判定部5において微小粒子10に由来するものか否かを判定することで、最終的に得られる分析結果の精度を向上させている。
解析部6は、判定部5で微小粒子10に由来すると判定されたインピーダンスデータやインピーダンスデータから算出された誘電スペクトルなどについて、誘電緩和現象モデルなどの特定のモデル式との比較やフィッティングなどを行い、微小粒子10の特性値を求める。例えば、分析対象の微小粒子10が細胞である場合は、解析部6で求められる特性値としては、膜キャパシタンス、細胞質の導電率、粒子サイズ、核のサイズ、核膜の厚さなど微小粒子10に関する種々の構造パラメータが挙げられる。
情報記憶部7には、解析部6で求めた特性値や、測定部4で測定されたインピーダンスデータや複素誘電スペクトルが記憶される。なお、この情報記憶部7は装置内に設けられている必要はなく、外部接続されたハードディスクやサーバなどに設けられていてもよい。
本実施形態の微小粒子分析装置には、電極3a,3bにより形成された交流電場又はサンプル流路2の狭窄部21を通過する微小粒子10を撮像する撮像部8が設けられていてもよい。撮像部8の構成は特に限定されるものではなく、CCD(Charge Coupled Device)やCMOS(Complementary Metal Oxide Semiconductor)などの撮像素子を備えた光学システムを用いることができる。撮像部8で撮像されたデータは、例えば判定部5や解析部6において、微小粒子10の通過を画像確認するために利用される。
水流形成系ユニット200は、測定系ユニット100のサンプル流路2に、複数の微小粒子10を含むサンプル液を導入するためのものであり、ポンプ201、試料導入部202及びバルブ203などで構成されている。水流形成系ユニット200は、例えばポンプ201により試料導入部202に圧力を加えられると、試料導入部202に注入されたサンプル液が、バルブ203を介して測定系ユニット100のサンプル流路2に導入されるようになっている。
制御系ユニット300は、前述した測定系ユニット100や水流形成系ユニット200を制御するものである。そして、例えば入力インターフェースを介して入力された情報に基づいて、水流形成系ユニット200のポンプ201の圧力やバルブ203の開口量を制御し、測定系ユニット100のサンプル流路2を通流するサンプル液の流量や流速を調整する。
なお、本実施形態の微小粒子分析装置1には、測定系ユニット100の測定部4で測定されたインピーダンスデータ、判定部5の判定結果、解析部6で算出された誘電スペクトルや各種特性値を表示する表示部、各種媒体に出力する出力部などを設けることもできる。また、ユーザが、表示データの選択情報や測定試料に関する情報を入力するための情報入力部が設けられていてもよい。
次に、本実施形態の微小粒子分析装置の動作、即ち、微小粒子分析装置1を用いて、微小粒子10を分析する方法について説明する。本実施形態の微小粒子分析装置1では、サンプル流路2内に、微小粒子10を含むサンプル液を通流させるか、又は、生理食塩水などの溶媒を通流させた状態で微小粒子を含む液体を注入して溶媒と共に通流させる。
次に、本開示の第1の実施形態の変形例に係る微小粒子分析装置について説明する。図5は本変形例の微小粒子分析装置の測定系ユニットの構成の概要を示す図である。なお、図5においては、図2に示す測定ユニット100の構成要素と同じものには同じ符号を付し、詳細な説明は省略する。
次に、本開示の第2の実施形態に係る微小粒子分取装置について説明する。図6は本実施形態の微小粒子分取装置の概略構成を示す図である。なお、図6においては、図1に示す微小粒子分析装置1の構成要素と同じものには同じ符号を付し、詳細な説明は省略する。図6に示すように、本実施形態の微小粒子分取装置30には、サンプル流路2のインピーダンス測定部よりも下流側に電極対(電極3c,3d)と、分取部31が設けられている。
電極3c,3dは、サンプル流路2のインピーダンス測定領域よりも下流側に電場を形成するためのものである。電極3c,3dの材質は、特に限定されるものではなく、微小粒子10への影響が少ないものであればよい。また、図6には、インピーダンス測定領域24よりも下流側に、1対の電極を設けた構成を示しているが、本開示はこれに限定されるものではなく、この領域に複数の電極対を設けてもよい。インピーダンス測定領域24よりも下流側に複数の電極対を設けることにより、作用部に同時期に存在できる粒子の数が増えるため、単位時間当たりの処理能力を向上できると共に、微小粒子10の通流方向の微調整が可能となる。
分取部31は、解析部6で算出された特性値に基づいて、電場形成を制御し、微小粒子10の通流方向を制御する。例えば、図6に示すように、サンプル流路2と連通する2以上の分岐流路32を設け、分取部31により、電極3cと電極3d間に印加する電圧値又は電圧印加の有無を制御することで、微小粒子10の通流方向を変更し、任意の分岐流路32に導入する。そして、サンプル流路2及び分岐流路32をマイクロチップ内に設けることにより、マイクロチップ内で分析と分取を行うことが可能となる。
次に、本実施形態の微小粒子分取装置30の動作、即ち、微小粒子分取装置30を用いて、微小粒子10を分取する方法について説明する。本実施形態の微小粒子分取装置30では、サンプル流路2内に分取対象の微小粒子10を含むサンプル液を通流させる。そして、測定部4により、連続的に又は微小粒子10が通過するタイミングで、電極3a,3b間に交流電圧を印加し、サンプル流路2内に交流電場を形成し、微小粒子10のインピーダンスを測定する。
次に、本開示の第3の実施形態に係る微小粒子分析システムについて説明する。図7は本実施形態の微小粒子分析システムの概略構成を示す図である。前述した第1の実施形態の微小粒子分析装置では、装置内で、微小粒子の特性値の算出や、測定されたインピーダンスのデータの判定を行っているが、これらの処理を分析装置に接続された1又は2以上の情報処理装置で行うこともできる。
微小粒子分析装置11には、サンプル流路と、サンプル流路の少なくとも一部に交流電場を形成するための電極対と、この電極対間のインピーダンスを測定する測定部が設けられている。なお、微小粒子分析装置11を構成するサンプル流路、電極対、測定部の具体的構成及び動作は、前述した第1の実施形態と同様である。
情報処理装置12は、微小粒子分析装置11に接続されており、測定されたインピーダンスから微小粒子の特性値を算出する解析部と、測定されたインピーダンスのデータが微小粒子に由来するものか否かを判定する判定部が設けられている。なお、解析部及び判定部の具体的構成及び動作は、前述した第1の実施形態と同様である。また、解析部と判定部は、一の情報処理装置に設けられていてもよいが、それぞれ別の情報処理装置に設けられていてもよい。
サーバ13は、ネットワーク15を介して情報処理装置12や画像表示装置14と接続されており、情報記憶部などが設けられている。そして、サーバ13は、情報処理装置12からアップロードされた各種データを管理し、要求に応じて表示装置14や情報処理装置12に出力する。
表示装置14は、微小粒子分析装置11で測定されたインピーダンスのデータや情報処理装置12で算出された微小粒子の特性値、更には判定部での判定結果などを表示する。なお、表示装置には、ユーザが表示するデータを選択し入力するための情報入力部が設けられていてもよい。この場合、ユーザにより入力された情報は、ネットワーク15を介してサーバ13や情報処理装置12に送信される。
(1)
複数の微小粒子を含む液が導入されるサンプル流路と、
前記サンプル流路の少なくとも一部に交流電場を形成するための第1の電極対と、
前記第1の電極対間のインピーダンスを測定する測定部と、
前記測定部で測定されたインピーダンスから前記微小粒子の特性値を算出する解析部と、
前記測定部で測定されたインピーダンスのデータが、前記微小粒子に由来するものか否かを判定する判定部と、
を有する微小粒子分析装置。
(2)
前記判定部は、前記インピーダンスのデータから、前記微小粒子が前記交流電場を通過したことを検出し、その検出結果に基づいて判定を行う(1)に記載の微小粒子分析装置。
(3)
前記判定部は、前記インピーダンスから求めたコンダクタンスのピーク位置及びピーク高さから、前記微小粒子の通過を検出する(2)に記載の微小粒子分析装置。
(4)
前記判定部は、前記インピーダンスから求めたキャパシタンス及び/又はコンダクタンスの値が閾値を超えたときに前記微小粒子の通過の検出を開始し、閾値以下になったときに前記微小粒子の通過の検出を終了する(2)又は(3)に記載の微小粒子分析装置。
(5)
前記判定部は、前記キャパシタンス及び/又はコンダクタンスの値が所定時間閾値を超えていた場合のみ、前記インピーダンスのデータを前記微小粒子に由来するものと判定する(4)に記載の微小粒子分析装置。
(6)
前記判定部で前記微小粒子に由来すると判定されたデータについて、前記解析部において前記特性値の算出を行う(1)~(5)のいずれかに記載の微小粒子分析装置。
(7)
前記解析部は、前記測定部で測定されたデータについて、特定のモデルとの比較又はフィッティングを行うことにより、前記特性値を算出する(6)に記載の微小粒子分析装置。
(8)
前記特定のモデルは、複素誘電スペクトルに基づく誘電緩和現象モデルである(7)に記載の微小粒子分析装置。
(9)
前記解析部で算出された特性値に基づいて、前記微小粒子を分取する分取部を有する(1)~(8)のいずれかに記載の微小粒子分析装置。
(10)
前記サンプル流路の前記交流電場が形成される領域よりも下流側に電場を形成するための第2の電極対を有し、
前記第2の電極対により形成される電場によって生じる誘電泳動力により、前記微小粒子の通流方向を変更する(9)に記載の微小粒子分析装置。
(11)
前記サンプル流路と連通する2以上の分岐流路を有し、
前記微小粒子は、前記分取部によってその通流方向が変更され、任意の分岐流路に導入される(9)又は(10)に記載の微小粒子分析装置。
(12)
前記サンプル流路には狭窄部が設けられており、前記第1の電極対は前記狭窄部を挟むように配置されている(1)~(11)のいずれかに記載の微小粒子分析装置。
(13)
更に、前記交流電場を通過する微小粒子を撮像する撮像部を有する(1)~(12)のいずれかに記載の微小粒子分析装置。
(14)
前記微小粒子が細胞である(1)~(13)のいずれかに記載の微小粒子分析装置。
(15)
前記特性値が、膜キャパシタンス、細胞質の導電率及び粒子サイズからなる群から選択される少なくとも1種の値である(14)に記載の微小粒子分析装置。
(16)
前記測定部は、0.1~50MHzの周波数範囲で複素インピーダンスを多点測定する(14)又は(15)に記載の微小粒子分析装置。
(17)
複数の微小粒子を含む液が導入されるサンプル流路と、
前記サンプル流路の少なくとも一部に交流電場を形成するための第1の電極対と、
前記第1の電極対間のインピーダンスを測定する測定部と、
を備える微小粒子分析装置と、
前記測定部で測定されたインピーダンスから前記微小粒子の特性値を算出する解析部と、
前記測定部で測定されたインピーダンスのデータが、前記微小粒子に由来するものか否かを判定する判定部と、
を備える情報処理装置と、
を有する微小粒子分析システム。
(18)
更に、前記情報処理装置の前記解析部で算出された前記微小粒子の特性値を表示する表示装置を有する(17)に記載の微小粒子分析システム。
(19)
更に、前記情報処理装置の前記解析部で算出された前記微小粒子の特性値を記憶する情報記憶部を備えるサーバを有する(17)又は(18)に記載の微小粒子分析システム。
Claims (19)
- 複数の微小粒子を含む液が導入されるサンプル流路と、
前記サンプル流路の少なくとも一部に交流電場を形成するための第1の電極対と、
前記第1の電極対間のインピーダンスを測定する測定部と、
前記測定部で測定されたインピーダンスから前記微小粒子の特性値を算出する解析部と、
前記測定部で測定されたインピーダンスのデータが、前記微小粒子に由来するものか否かを判定する判定部と、
を有する微小粒子分析装置。 - 前記判定部は、前記インピーダンスのデータから、前記微小粒子が前記交流電場を通過したことを検出し、その検出結果に基づいて判定を行う請求項1に記載の微小粒子分析装置。
- 前記判定部は、前記インピーダンスから求めたコンダクタンスのピーク位置及びピーク高さから、前記微小粒子の通過を検出する請求項2に記載の微小粒子分析装置。
- 前記判定部は、前記インピーダンスから求めたキャパシタンス及び/又はコンダクタンスの値が閾値を超えたときに前記微小粒子の通過の検出を開始し、閾値以下になったときに前記微小粒子の通過の検出を終了する請求項2に記載の微小粒子分析装置。
- 前記判定部は、前記キャパシタンス及び/又はコンダクタンスの値が所定時間閾値を超えていた場合のみ、前記インピーダンスのデータを前記微小粒子に由来するものと判定する請求項4に記載の微小粒子分析装置。
- 前記判定部で前記微小粒子に由来すると判定されたデータについて、前記解析部において前記特性値の算出を行う請求項1に記載の微小粒子分析装置。
- 前記解析部は、前記測定部で測定されたデータについて、特定のモデルとの比較又はフィッティングを行うことにより、前記特性値を算出する請求項6に記載の微小粒子分析装置。
- 前記特定のモデルは、複素誘電スペクトルに基づく誘電緩和現象モデルである請求項7に記載の微小粒子分析装置。
- 前記解析部で算出された特性値に基づいて、前記微小粒子を分取する分取部を有する請求項1に記載の微小粒子分析装置。
- 前記サンプル流路の前記交流電場が形成される領域よりも下流側に電場を形成するための第2の電極対を有し、
前記第2の電極対により形成される電場によって生じる誘電泳動力により、前記微小粒子の通流方向を変更する請求項9に記載の微小粒子分析装置。 - 前記サンプル流路と連通する2以上の分岐流路を有し、
前記微小粒子は、前記分取部によってその通流方向が変更され、任意の分岐流路に導入される請求項9に記載の微小粒子分析装置。 - 前記サンプル流路には狭窄部が設けられており、前記第1の電極対は前記狭窄部を挟むように配置されている請求項1に記載の微小粒子分析装置。
- 更に、前記交流電場を通過する微小粒子を撮像する撮像部を有する請求項1に記載の微小粒子分析装置。
- 前記微小粒子が細胞である請求項1に記載の微小粒子分析装置。
- 前記特性値が、膜キャパシタンス、細胞質の導電率及び粒子サイズからなる群から選択される少なくとも1種の値である請求項14に記載の微小粒子分析装置。
- 前記測定部は、0.1~50MHzの周波数範囲で複素インピーダンスを多点測定する請求項14に記載の微小粒子分析装置。
- 複数の微小粒子を含む液が導入されるサンプル流路と、
前記サンプル流路の少なくとも一部に交流電場を形成するための第1の電極対と、
前記第1の電極対間のインピーダンスを測定する測定部と、
を備える微小粒子分析装置と、
前記測定部で測定されたインピーダンスから前記微小粒子の特性値を算出する解析部と、
前記測定部で測定されたインピーダンスのデータが、前記微小粒子に由来するものか否かを判定する判定部と、
を備える情報処理装置と、
を有する微小粒子分析システム。 - 更に、前記情報処理装置の前記解析部で算出された前記微小粒子の特性値を表示する表示装置を有する請求項17に記載の微小粒子分析システム。
- 更に、前記情報処理装置の前記解析部で算出された前記微小粒子の特性値を記憶する情報記憶部を備えるサーバを有する請求項17に記載の微小粒子分析システム。
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Also Published As
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JPWO2014122873A1 (ja) | 2017-01-26 |
JP6299609B2 (ja) | 2018-03-28 |
CN104969063A (zh) | 2015-10-07 |
EP2955512A4 (en) | 2016-10-05 |
US9915599B2 (en) | 2018-03-13 |
EP2955512A1 (en) | 2015-12-16 |
US20150377763A1 (en) | 2015-12-31 |
CN104969063B (zh) | 2018-05-22 |
EP2955512B1 (en) | 2018-10-24 |
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