Cell analysis apparatus and cell analysis method

Abstract

To acquire morphological information, protein information and genetic information of a cell by one cell analyzer in a short time and at a low cost.SOLUTION: A cell analysis device of the present disclosure includes a first detector that detects scattered light and fluorescence from a cell containing a fluorescently stained protein introduced into a first flow path, a solution mixing unit that encapsulates each cell in a minute compartment and mixes the cell with a reaction solution, a temperature adjustment unit that performs an amplification reaction of a gene in the cell in the minute compartment, a second detector that detects fluorescence from the minute compartment, and a processing device. The processing device analyzes the morphological information of the cell based on the scattered light, analyzes the first fluorescence pattern based on the fluorescence from the protein, analyzes the second fluorescence pattern based on the fluorescence from the protein in the minute compartment, acquires the genetic information based on the fluorescence from the gene, and links the morphological information of the cell, the information of the protein, and the genetic information for each cell based on the first fluorescence pattern and the second fluorescence pattern.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates to a cell analysis device and a cell analysis method. [Background technology]

[0002] In the diagnosis of blood cancer and monitoring tests for minimal residual disease, flow cytometry (FCM) is used to analyze proteins in blood or bone marrow fluid, while next-generation sequencing (NGS) and quantitative PCR are used for genetic analysis.

[0003] Flow cytometry is a device that fluorescein-labeled samples (cells or particles) are passed through a flow, laser light is shone on the flow, and the intensity of scattered or fluorescent light emitted from the sample is measured. The light intensity is then used to quantify the properties of the sample. Fluorescent labeling of samples is performed to quantify specific targets on the cell surface or inside the cell, or to identify cell types. Forward scattered light reveals cell size, and side scattered light reveals the complexity of the internal structure. This information can be used to identify cell type and morphology. Combining the protein information and morphological information obtained in this way to classify blood cell components and verify the reliability of the data is essential for testing.

[0004] Next-generation sequencers can comprehensively analyze genetic information from patient samples, making them applicable to a wide range of patients, but they have issues with high testing costs and long analysis times.Quantitative PCR has relatively low testing costs and short analysis times, but they have issues with a narrow range of patients (Non-Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Patent Application Publication No. 2018 / 0208978 [Non-patent literature]

[0006] [Non-Patent Document 1] H. Doehner et al., Blood Vol. 140, No. 12, pp. 1345-1377, 2022 [Non-patent document 2] F. Guolo et al., Hematologica, Vol. 102, No. 9, pp. 348-351, 2017 [Non-patent document 3] P. Maurizio et al., Genome Res. Vol. 28, pp. 1345-1352, 2018 Summary of the Invention [Problem to be solved by the invention]

[0007] In recent years, it has been reported that combining protein and genetic information is useful for predicting the prognosis of blood cancer patients (Non-Patent Document 2). However, protein information is obtained by flow cytometry, and genetic information is obtained by quantitative PCR, and obtaining both protein and genetic information using a single device is expected to improve testing efficiency.

[0008] Techniques have been developed to analyze information on cell morphology, proteins, and genes using flow cytometry, as described in Patent Document 1. However, Patent Document 1 requires that protein pretreatment procedures (reaction of cell surface proteins with antibodies, cell fixation, washing, and cell permeabilization) be performed sequentially for each target protein, followed by gene amplification, which poses a problem of the long time required for analysis.

[0009] Non-Patent Document 3 describes that to obtain protein and gene information using a next-generation sequencer, a base sequence (barcode) that serves as an identifier is added to an antibody that recognizes a protein on the cell surface, and then the antibody is encapsulated in a microcompartment for each cell, and the base sequence is analyzed to obtain protein and gene information. However, this technology has issues such as higher testing costs and longer analysis times than conventional next-generation sequencers. In addition, this method cannot obtain cell morphology information.

[0010] Therefore, the present disclosure provides a technology for obtaining morphological information, protein information, and genetic information of cells in a short time and at low cost using a single cell analysis device. [Means for solving the problem]

[0011] In order to solve the above problems, the cell analysis device of the present disclosure includes a first optical system including a first flow path into which cells containing a plurality of fluorescently stained proteins are introduced, a first light source that irradiates the cells with light, and a first detector that detects scattered light from the cells and fluorescence from the plurality of proteins in the cells, a solution mixing unit that encapsulates the cells that have passed through the first optical system in microcompartments one by one and mixes them with a reaction solution, a temperature adjustment unit that performs an amplification reaction of genes in the cells in the microcompartments, a second optical system including a second light source that irradiates the microcompartments with light, and a second detector that detects fluorescence from the plurality of proteins in the microcompartments and fluorescence from the amplified genes, and a second optical system that outputs a detection signal from the first detector and a detection signal from the second detector. and a processing device that processes the scattered light from the first detector and analyzes the cells, wherein the processing device performs the following processes: analyzing morphological information of the cells based on a detection signal of the scattered light from the first detector; analyzing a first fluorescence pattern based on fluorescence from the multiple proteins in the cells from the first detector; analyzing a second fluorescence pattern based on fluorescence from the multiple proteins in the microcompartment from the second detector; acquiring genetic information based on a detection signal of fluorescence from the amplified genes from the second detector; and linking the morphological information, protein information, and genetic information of the cells for each cell based on the first fluorescence pattern and the second fluorescence pattern.

[0012] Further features related to the present disclosure will become apparent from the description of this specification and the accompanying drawings. Also, aspects of the present disclosure are achieved and realized by the elements and combinations of various elements and the aspects of the following detailed description and the appended claims. The description of this specification is merely exemplary and does not limit the scope or application of the claims of the present disclosure in any way. [Effects of the Invention]

[0013] According to the technology of the present disclosure, morphological information, protein information, and genetic information of cells can be obtained in a short time and at low cost using a single cell analysis device. Problems, configurations, and effects other than those described above will become clear from the description of the following embodiments. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a schematic diagram showing an embodiment of a cell analysis device. [Figure 2] FIG. 2 is a schematic diagram showing an example of the configuration of a solution mixing section. [Figure 3] FIG. 2 is a schematic diagram illustrating a configuration example of a temperature adjusting unit. [Figure 4A] 1 is a graph showing an example of the change in the fluorescence pattern of a protein before and after lysis. [Figure 4B] 1 is a graph showing an example of the change in the fluorescence pattern of a protein before and after lysis. [Figure 5A] 1 is a graph showing an example of the change in the fluorescence pattern of a protein before and after lysis. [Figure 5B] 1 is a graph showing an example of the change in the fluorescence pattern of a protein before and after lysis. [Figure 6] 1 is a flowchart of a cell analysis method using a cell analysis device. DETAILED DESCRIPTION OF THE INVENTION

[0015] [First embodiment] <Cell analysis device> 1 is a schematic diagram of a cell analysis device 100 according to a first embodiment. The cell analysis device 100 is configured to be able to acquire morphological information, protein information, and genetic information of cells. The cell analysis device 100 includes a flow channel 1, a first optical system 10, a solution mixing unit 20, a temperature adjustment unit 30, a second optical system 40, and a control device 200.

[0016] A sample containing cells 101 containing fluorescently stained proteins is introduced into the flow channel 1. The cells 101 can be introduced into the flow channel 1 using, for example, a tube. The tube is connected to, for example, a pressure application mechanism or a liquid delivery mechanism (such as a pump) not shown, and the cells 101 can be caused to flow through the flow channel 1 by applying pressure.

[0017] Using capillaries in the flow channel 1 prevents the order of cell measurements from being changed and helps link the morphological, protein, and genetic information of each cell. Because the diameter of white blood cells in blood is 6 to 20 μm, the diameter of the capillaries can be, for example, 40 to 100 μm, but is not limited to this. The flow channel 1 may be entirely made of capillaries, or only a portion may be made of capillaries with the remaining portion made of any other material.

[0018] The first optical system 10 includes a light source 11 and a detection unit 12. The light source 11 includes one or more laser light sources. The light source 11 irradiates the cells 101 in the flow channel 1 with laser light. The detection unit 12 includes one or more detectors. For example, an optical sensor or an image sensor can be used as the detector. The detection unit 12 detects scattered light and fluorescence generated when the cells 101 are irradiated with laser light. The scattered light from the cells 101 can be used to detect cell morphology, and the fluorescence can be used to detect multiple proteins. The detection unit 12 is disposed on the opposite side of the flow channel 1 from the light source 11. The first optical system 10 may include optical components such as mirrors and filters as necessary. The positional relationship between the light source 11 and the detection unit 12 may be changed appropriately using such optical components.

[0019] The solution mixing section 20 has a flow path 2 for supplying a reaction solution and a flow path 3 for supplying a solvent. Flow paths 2 and 3 merge into flow path 1. Flow path 2 is connected to a container that contains the reaction solution. Flow path 3 is connected to a container that contains the solvent. The supply of the reaction solution from flow path 2 and the supply of the solvent from flow path 3 can be performed by driving a pressure application mechanism or a liquid delivery mechanism such as a pump (not shown). Alternatively, the reaction solution and solvent may be supplied manually by an operator.

[0020] Cells 101 flowing through channel 1 are mixed with the reaction solution introduced from channel 2 and the solvent introduced from channel 3 to form microcompartments for each cell. The reaction solution can be a known reaction solution containing enzymes, buffer solutions, and primers used in gene amplification reactions. The reaction solution may also contain alkaline solutions, surfactants, protease, and the like used to lyse cells. When droplets are used as microcompartments, known oils can be used as solvents. When water-soluble microcompartments such as agarose gel microcapsules or gel beads are used, known buffer solutions can be used as solvents.

[0021] The temperature control unit 30 has a heat source such as a heater or a Peltier element. The temperature control unit 30 adjusts the temperature of the liquid in the flow channel 1 to amplify the target gene contained in the cells 101 contained in the microcompartments 102 by isothermal amplification or PCR. When Loop-Mediated Isothermal Amplification (LAMP) is used as the isothermal amplification method, the temperature can be adjusted to, for example, 55°C to 70°C. When Rolling Circle Amplification (RCA) is used, the temperature is adjusted to, for example, 25°C to 45°C. When PCR is used, the temperature can be adjusted to, for example, between 55°C and 100°C, but is not limited thereto. Alternatively, cell lysis may be performed by heat treatment in the temperature control unit 30 without using a lysis solution for cell lysis.

[0022] The second optical system 40 includes a light source 41 and a detection unit 42. The flow path 1 of the second optical system 40 is connected to a waste liquid tank (not shown). The light source 41 includes one or more laser light sources. The light source 41 irradiates laser light onto the microcompartments 102 containing the cells 103 after gene amplification. The detection unit 42 includes one or more detectors. For example, an optical sensor or an image sensor can be used as the detector. The detection unit 42 detects the fluorescence of the protein in the microcompartment 102 and the fluorescence of the amplified gene. The detection unit 42 is disposed on the opposite side of the flow path 1 from the light source 41. The second optical system 40 may include optical components such as a mirror and a filter as necessary. The positional relationship between the light source 41 and the detection unit 42 may be changed appropriately using such optical components.

[0023] The control device 200 controls the overall operation of the cell analysis device 100. The control device 200 includes a processing device 201, a storage device 202, a display device 203, and an input device 204. The processing device 201 is composed of a processor such as a CPU or a GPU. The storage device 202 includes memory such as ROM and RAM, and storage. The storage device 202 stores programs executed by the processing device 201 and information necessary for analyzing the cells 101. The display device 203 is composed of, for example, a display or a touch panel. The input device 204 is composed of, for example, a mouse, a keyboard, a touch panel, a microphone, etc.

[0024] The processing device 201 is configured to receive detection signals from the first optical system 10 and the second optical system 40 of the cell analysis device 100, process them, and analyze the cells 101. At this time, the processing device 201 compares the protein fluorescence pattern obtained by the first optical system 10 with the protein fluorescence pattern obtained by the second optical system 40 for each cell, and links the cell morphology information, protein information, and genetic information for each cell. At this time, the measurement order of the cells can be used to assist in information linking.

[0025] FIG. 2 is a schematic diagram showing another example of the configuration of the solution mixing unit 20. In the example of FIG. 2, in addition to flow paths 2 and 3, the solution mixing unit 20 further includes flow path 4 for supplying a gene amplification reagent and flow path 5 for supplying a solvent. In this configuration, a cell lysis solution is supplied from flow path 2. A detection target cell 101 is mixed with the lysis solution introduced from flow path 2 and the solvent introduced from flow path 3 to form a microcompartment. After the cell 101 is lysed in this microcompartment, the gene amplification reagent introduced from flow path 4 and the mixed solvent from flow path 5 are mixed to form a microcompartment 102 again. In this way, the solution mixing unit 20 can perform cell lysis and mixing of the gene amplification reagent in two stages. By dividing the process into two stages, the concentration of the lysis solution can be maintained, thereby enhancing the cell lysis effect. Furthermore, the mixing of the gene amplification reagent dilutes the lysis solution, thereby suppressing the adverse effects of the lysis solution on the gene amplification reaction.

[0026] The flow channels 1, 2, 3, 4, and 5 can be formed, for example, by capillaries. Alternatively, the flow channels 1 to 5 may be formed, for example, by grooves formed in a resin substrate and a member covering the groove. The capillaries or substrates forming the flow channels 1 to 5 may be disposable.

[0027] FIG. 3 is a schematic diagram showing an example of the configuration of the temperature control unit 30. FIG. 3 shows a structure for using PCR for gene amplification, with a meandering flow path. The flow path within the temperature control unit 30 includes a high-temperature flow path 31, a medium-temperature flow path 32, and a flow path between them. Heat sources (not shown) are respectively located near the high-temperature flow path 31 and the medium-temperature flow path 32. In the high-temperature flow path 31, nucleic acids are dissociated at approximately 90°C to 100°C. Then, in the medium-temperature flow path 32, annealing and extension reactions are carried out at 55°C to 75°C. By repeating this reaction for several dozen cycles, the target gene can be amplified, and irradiation with laser light from a light source 41 generates fluorescence corresponding to the amount of gene present. The flow path of the temperature control unit 30 can be configured to meander as many times as the number of PCR cycles. When an isothermal amplification method is used for gene amplification, the temperature control unit 30 has, for example, a flow path adjusted to a constant temperature. In this case, the shape of the flow path is not particularly limited and may be linear or meandering as in FIG. 3.

[0028] <Linking information for each cell> In the cell analysis device 100 of this embodiment, the control device 200 links information for each cell using the fluorescence pattern detected by the first optical system 10 and the fluorescence pattern detected by the second optical system 40, i.e., the fluorescence patterns of proteins before and after cell lysis. The linking of information for each cell will be described in detail below.

[0029] 4A and 4B are graphs showing an example of changes in the fluorescence pattern of proteins before and after cell lysis by the cell analysis device 100. FIGS. 4A and 4B show an example in which the fluorescence intensity of proteins uniformly decreases before and after cell lysis. FIG. 4A shows the fluorescence patterns of eight types of proteins for cell a. FIG. 4B shows the fluorescence patterns of eight types of proteins for cell b. The solid line in the graph indicates the fluorescence pattern before cell lysis (first fluorescence pattern), and the dotted line indicates the fluorescence pattern after cell lysis (second fluorescence pattern). When the fluorescence intensity of proteins uniformly decreases due to the lysis process, results corresponding to the expression pattern of the proteins in the cells are confirmed, as shown in FIGS. 4A and 4B. In this way, the measurement information before and after cell lysis can be linked by the protein information pattern.

[0030] Furthermore, by preparing a reference fluorescently stained sample and measuring the fluorescence intensity before and after cell lysis using the cell analysis device 100, the fluorescence decrease rate for each protein can be calculated. The fluorescence decrease rate for each reference protein can be used to estimate the change in fluorescence intensity in the real sample before and after cell lysis. The fluorescence intensity signal of the real sample acquired by the second optical system 40 can be corrected by calculation using the fluorescence decrease rate for each reference protein. This improves the accuracy of linking the morphology, protein, and genetic information of each cell using the fluorescence pattern. The fluorescence measurement of the reference sample is performed in advance, for example, before measuring the real sample. Information about the reference fluorescence intensity and fluorescence pattern can be stored in the storage device 202 and used when linking information with the real sample.

[0031] 5A and 5B are graphs showing other examples of changes in the fluorescence pattern of proteins before and after lysis by the cell analysis device 100. FIGS. 5A and 5B show examples in which the rate of decrease in fluorescence intensity differs for each protein before and after cell lysis. FIG. 5A shows the fluorescence patterns of eight types of proteins for cell a. FIG. 5B shows the fluorescence patterns of eight types of proteins for cell b. The solid line in the graph indicates the fluorescence pattern before cell lysis (first fluorescence pattern), and the dotted line indicates the fluorescence pattern after cell lysis (second fluorescence pattern).

[0032] In cases such as those shown in Figures 5A and 5B, similar to the cases shown in Figures 4A and 4B, a reference fluorescently stained sample can be prepared and the fluorescence intensity measured before and after lysis using the cell analysis device 100 to calculate the fluorescence decrease rate for each protein. The fluorescence decrease rate for each reference protein can then be used to estimate the change in fluorescence intensity in the actual sample before and after cell lysis. Additionally, the fluorescence intensity signal of the actual sample acquired by the second optical system 40 can be corrected by matrix calculation using the fluorescence decrease rate for each reference protein. This improves the accuracy of linking morphology, protein, and genetic information for each cell. Alternatively, cells can be clustered into multiple types based on the protein fluorescence patterns obtained by the first optical system 10, and the fluorescence patterns obtained by the second optical system 40 can be assigned to each cluster, thereby linking morphology, protein, and genetic information for each cell.

[0033] <Cell analysis method> FIG. 6 is a flowchart of a cell analysis method using the cell analysis device 100.

[0034] (Steps S1 to S3) Steps S1 to S3 are similar to the pretreatment of conventional flow cytometry, and will be explained briefly. In step S1, the operator adds a fluorescently labeled antibody to a sample containing cells to stain the cells with the fluorescently labeled antibody. In step S2, the operator adds a hemolysis reagent to the sample to perform hemolysis. In step S3, the operator centrifuges and washes the sample.

[0035] (Step S4) In step S4, the operator introduces the sample that has been pretreated in steps S1 to S3 into the cell analysis device 100. For example, when the operator inputs an instruction to start operation into the control device 200, the control device 200 starts the operation of the cell analysis device 100.

[0036] (Step S5) The processing device 201 drives the light source 11 of the first optical system 10 to irradiate the cell 101 with laser light. The detection unit 12 transmits detection signals of scattered light and fluorescence from the cell 101 to the processing device 201. The processing device 201 acquires morphological information of the cell 101 based on the scattered light detection signal, and acquires protein information within the cell 101 based on the fluorescence detection signal. The protein information includes information on the fluorescence intensity and amount of each of a plurality of proteins. Note that the morphological information of the cell 101 may be acquired from an image rather than from scattered light.

[0037] (Step S6) The processing device 201 drives the liquid delivery mechanism to supply the reaction solution from the flow channel 2 and oil from the flow channel 3. This causes the cells 101 flowing through the flow channel 1 to mix with the reaction solution and oil.

[0038] (Step S7) The cells 101 mixed with the reaction solution and oil in the solution mixing section 20 are encapsulated in the microcompartments. The encapsulation of the cells into the microcompartments is carried out cell by cell.

[0039] (Step S8) Lysis of the cells 101 is carried out in the flow channel 1. If the reaction solution contains a lysis solution in step S6, the cells are lysed in the flow channel 1. If the reaction solution does not contain a lysis solution in step S6, the processing device 201 lyses the cells 101, for example, by driving a heat source to heat the flow channel 1.

[0040] (Step S9) The processing device 201 amplifies genes in cells by adjusting the temperature of the heat source of the temperature adjustment unit 30. The gene amplification method may be any method such as PCR or isothermal amplification.

[0041] (Step S10) The processing device 201 drives the light source 41 of the second optical system 40 to irradiate laser light onto the microcompartments 102 containing the gene-amplified cells 103. The detection unit 12 transmits a detection signal of fluorescence from the microcompartments 102 to the processing device 201. The processing device 201 acquires protein information and gene information based on the fluorescence detection signal. At this time, the processing device 201 links information for each cell using the protein information (protein fluorescence pattern) acquired in steps S5 and S10.

[0042] (Step S11) The processing device 201 displays the acquired morphological information, protein information, and gene information for each cell on the display device 203.

[0043] The above describes the use of protein information to link information for each cell. In addition, the cell measurement order, i.e., the order of data acquired by the first optical system 10 and the second optical system 40, can be used to assist in linking information for each cell. For example, even if the measurement order of a certain cell differs between the first optical system 10 and the second optical system 40 (for example, if the order of adjacent flowing cells is swapped), the information can be linked using the above-mentioned fluorescence pattern. Then, information on the measurement order in the first optical system 10 and the second optical system 40 can be stored in the storage device 202 as reference information.

[0044] <Summary of the First Embodiment> As described above, the cell analysis device 100 of the first embodiment comprises a flow path 1 (first flow path) into which cells 101 containing multiple fluorescently stained proteins are introduced, a first optical system 10 including a light source 11 (first light source) that irradiates light onto the cells 101, and a detection unit 12 (first detector) that detects scattered light from the cells 101 and fluorescence from multiple proteins in the cells 101, a solution mixing unit 20 that seals the cells 101 that have passed through the first optical system 10 in microcompartments 102 one by one and mixes them with a reaction solution, a temperature adjustment unit 30 that performs an amplification reaction of genes in the cells in the microcompartments 102, a second optical system 40 including a light source 41 (second light source) that irradiates light onto the microcompartments 102, and a detection unit 42 (second detector) that detects fluorescence from the multiple proteins in the microcompartments 102 and fluorescence from the amplified genes, and a control device 200 (processing device). The processing device performs the following processes: analyzing the morphological information of the cells based on the detection signal of the scattered light from the detection unit 12; analyzing a first fluorescence pattern based on the fluorescence from multiple proteins in the cells from the detection unit 12; analyzing a second fluorescence pattern based on the fluorescence from multiple proteins in the microcompartments from the detection unit 42; acquiring genetic information based on the detection signal of the fluorescence from the amplified genes from the detection unit 42; and linking the morphological information, protein information, and genetic information of the cells for each cell based on the first fluorescence pattern and the second fluorescence pattern.

[0045] In this way, information is linked using measurement data (fluorescence patterns) of proteins in cells. This eliminates the need to use identifiers such as barcodes to link information for each cell. The more types of proteins (fluorescence) to be measured, the more accurate the linking can be. Therefore, the technology of this embodiment is suitable for testing minimal residual disease (MRD) using fluorescence of eight or more colors. Furthermore, since a single cell analysis device 100 can acquire morphological information, protein information, and genetic information for each cell, cell analysis can be performed in a short time and at low cost. Therefore, the cell analysis device 100 according to the first embodiment is useful for improving the efficiency of blood cancer diagnosis and minimal residual disease monitoring tests.

[0046] [Variations] The present disclosure is not limited to the above-described embodiments and includes various modifications. For example, the above-described embodiments have been described in detail to clearly explain the present disclosure, and it is not necessary to include all of the described configurations. Furthermore, a part of one embodiment can be replaced with a configuration of another embodiment. Furthermore, a configuration of another embodiment can be added to a configuration of one embodiment. Furthermore, a part of the configuration of each embodiment can be added to, deleted from, or substituted for a part of the configuration of another embodiment. [Explanation of symbols]

[0047] 100: Cell analysis device 200: Control device 1 to 5: Flow path 10: First optical system 11: Light source (first light source) 12: Detector (first detector) 20: Solution mixing section 30: Temperature control section 31: High temperature flow path 32:Medium temperature flow path 40: Second optical system 41: Light source (second light source) 42: Detector (second detector) 101: Cell 102: Micro-compartment 103: Cells after gene amplification

Claims

1. a first flow path into which cells containing a plurality of fluorescently stained proteins are introduced; a first optical system including a first light source that irradiates the cells with light and a first detector that detects scattered light from the cells and fluorescence from the plurality of proteins in the cells; a solution mixing unit that encapsulates the cells that have passed through the first optical system into microcompartments one by one and mixes the cells with a reaction solution; a temperature control unit for performing an amplification reaction of genes in the cells in the microcompartments; a second optical system including a second light source that irradiates the microcompartment with light and a second detector that detects fluorescence from the plurality of proteins in the microcompartment and fluorescence from the amplified genes; a processing device that processes the detection signal of the first detector and the detection signal of the second detector to analyze the cells, The processing device includes: a process of analyzing morphological information of the cells based on the detection signal of the scattered light from the first detector; analyzing a first fluorescence pattern based on fluorescence from the plurality of proteins in the cell from the first detector; analyzing a second fluorescence pattern based on the fluorescence from the plurality of proteins in the microcompartment from the second detector; A process of acquiring genetic information based on a detection signal of the fluorescence from the amplified gene from the second detector; and performing a process of linking the morphological information, the protein information, and the genetic information of the cells for each cell based on the first fluorescent pattern and the second fluorescent pattern.

2. The processing device includes: The cell analysis device of claim 1, further comprising a process for assisting in linking the morphological information, protein information, and genetic information of the cells for each cell based on the order in which the cells were detected by the first optical system and the order in which the cells were detected by the second optical system.

3. The cell analysis device according to claim 1 , wherein the first channel includes a capillary.

4. The solution mixing unit or the temperature adjusting unit is further configured to lyse the cells, The processing device includes: A process of calculating the rate of decrease in fluorescence intensity for each protein before and after lysis of the reference cells; The cell analysis device according to claim 1 , further comprising a process of correcting the second fluorescence pattern based on the rate of decrease.

5. 2. The cell analysis device according to claim 1, wherein the reaction solution contains a lysis solution for lysing the cells and an amplification reagent for amplifying the genes in the cells.

6. the solution mixing unit has a second flow path for supplying the dissolution solution and a third flow path for supplying the amplification reagent; The cell analysis device according to claim 5 , wherein the third flow path is located downstream of the second flow path.

7. A cell analysis method using a cell analysis device, irradiating light onto cells containing a plurality of fluorescently stained proteins introduced into a first flow path using a first light source of the cell analysis device, and detecting scattered light from the cells and fluorescence from the plurality of proteins in the cells using a first detector; a solution mixing unit of the cell analysis device encapsulating the cells in microcompartments one by one and mixing the cells with a reaction solution; carrying out a gene amplification reaction in the cells in the microcompartments by a temperature control unit of the cell analysis device; irradiating the microcompartment with light using a second light source of the cell analysis device, and detecting fluorescence from the plurality of proteins in the microcompartment and fluorescence from the amplified gene using a second detector; analyzing morphological information of the cells based on the detection signal of the scattered light from the first detector by a processing device of the cell analysis device; analyzing, by the processing device, a first fluorescence pattern based on fluorescence from the plurality of proteins in the cell from the first detector; analyzing, by the processing device, a second fluorescence pattern based on the fluorescence from the plurality of proteins in the microcompartment from the second detector; acquiring genetic information based on a detection signal of the fluorescence from the amplified gene from the second detector by the processing device; linking, by the processing device, the morphological information, the protein information, and the genetic information of the cell for each cell based on the first fluorescent pattern and the second fluorescent pattern.

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