CN113188980A - Whole blood circulating tumor cell cascade sorting device and method based on fluorescence activated cell sorting technology - Google Patents

Whole blood circulating tumor cell cascade sorting device and method based on fluorescence activated cell sorting technology Download PDF

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CN113188980A
CN113188980A CN202110466035.4A CN202110466035A CN113188980A CN 113188980 A CN113188980 A CN 113188980A CN 202110466035 A CN202110466035 A CN 202110466035A CN 113188980 A CN113188980 A CN 113188980A
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sorting
cell
pipeline
whole blood
area
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CN113188980B (en
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秦玉岭
唐曲
丛辉
吴丽
陈欢欢
胡文琪
毛天智
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Nantong University
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N15/14Electro-optical investigation, e.g. flow cytometers
    • G01N15/1434Electro-optical investigation, e.g. flow cytometers using an analyser being characterised by its optical arrangement
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00Sampling; Preparing specimens for investigation
    • G01N1/28Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/38Diluting, dispersing or mixing samples
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00584Control arrangements for automatic analysers
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N2015/1006Investigating individual particles for cytology
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Abstract

The invention discloses a whole blood circulating tumor cell cascade sorting device based on a fluorescence activated cell sorting technology, which comprises a primary sorting pipeline and a plurality of secondary sorting pipelines; the primary sorting pipeline comprises a whole blood sample inlet, a cell sorting area and a waste liquid sample outlet; the secondary sorting pipeline comprises a diluent sample inlet, a cell sorting area, a cell diluting area, CTCs sample outlets and a waste liquid sample outlet; the cell sorting area comprises a fluorescence detection area and a pressure control system; the invention has simple operation, and can remove the nonspecific cells such as red blood cells, white blood cells, platelets and the like in a blood sample after a period of time by only injecting a certain volume of whole blood into the whole blood sample inlet and matching with the sample introduction of diluent, a fluorescence detection device, a sorting device, an injection pump and the like, thereby finally obtaining the high-purity circulating tumor cells.

Description

Whole blood circulating tumor cell cascade sorting device and method based on fluorescence activated cell sorting technology
Technical Field
The invention belongs to the technical field of medical examination, and particularly relates to a device and a method for whole blood circulating tumor cell cascade sorting based on a fluorescence activated cell sorting technology.
Background
Circulating Tumor Cells (CTCs) refer to Tumor Cells that are detached from a solid body in a primary Tumor body and are free in whole blood. CTCs carry a large amount of biological information of source tumor cells, and have important significance for monitoring gene mutation, drug resistance change, epigenetic variation and the like of primary tumors clinically. Moreover, the analysis of CTCs is also of great significance in the monitoring of patient prognosis and the judgment of tumor recurrence.
However, how to separate the CTCs with important biological information from the peripheral blood of human body with high efficiency is a difficult point. Various techniques have been reported so far, but most of these existing CTCs sorting systems have problems of low recovery rate and separation purity, and the like, and efficient CTCs sorting cannot be achieved. Moreover, the methods are only feasible in laboratory research, the difficulty of clinical large-scale use is still high, operators need to have quite high experimental skills, the repeatability is low, and the popularization difficulty is high.
The Fluorescence Activated Cell Sorting (FACS) system is based on flow method to perform Fluorescence Sorting to cells, and has wide application and high separation efficiency. Although a number of FACS-based CTCs sorting methods have emerged, there are mainly methods such as charge sorting, piezoelectric sorting, valve sorting, pump-driven sorting, bubble-driven sorting, and the like. These methods have great difficulty in commercial ease. At present, only flow cytometry has similar functions, but the equipment of the flow cytometer is expensive, the analysis cost is too high, and a large amount of blood samples are needed for single analysis. Therefore, sorting and analysis of CTCs still faces challenges.
Disclosure of Invention
The invention provides a whole blood circulating tumor cell cascade sorting device and method based on a fluorescence activated cell sorting technology, wherein a fluorescence activated cell sorting system is combined with a fluid flow direction control sorting system, so that automatic continuous multistage cell sorting can be realized, and the aim of efficiently sorting CTCs is fulfilled.
The invention adopts the following technical scheme:
a whole blood circulating tumor cell cascade sorting device based on fluorescence activated cell sorting technology comprises a primary sorting pipeline and a plurality of secondary sorting pipelines;
the primary sorting pipeline comprises a whole blood sample inlet, a cell sorting area and a waste liquid sample outlet; the secondary sorting pipeline comprises a diluent sample inlet, a cell sorting area, a cell diluting area, CTCs sample outlets and a waste liquid sample outlet; the cell sorting area comprises a fluorescence detection area and a pressure control system;
the inlet of the primary sorting pipeline is a whole blood sample inlet, the pipeline is divided into two branches after passing through a fluorescence detection area from the whole blood sample inlet, one branch is communicated with a waste liquid sample outlet, and the other branch is communicated with a next-stage cell diluent sample inlet pipeline;
the inlet of the secondary sorting pipeline is a diluent injection port, the cell diluent injection pipeline is divided into two branches after starting from the diluent injection port, and one branch is communicated with the upper-stage cell sorting area; the other branch is communicated with the cell dilution area, passes through the cell dilution area, reaches the cell sorting area, passes through the fluorescence detection area and is divided into two branches, one branch is communicated with the waste liquid outlet, and the other branch is communicated with the next-stage cell dilution liquid sample injection pipeline; the last stage secondary sorting pipeline is provided with a cell-free dilution area and a cell sorting area, the inlet of the last stage secondary sorting pipeline is a diluent injection port, the last stage secondary sorting pipeline is divided into two branches from the diluent injection port, and one branch is communicated with the last stage cell sorting area; the other branch is directly communicated with a CTCs sample outlet;
and a pressure control system is also arranged on a branch pipeline between the fluorescence detection area and the waste liquid sample outlet.
Further, the whole blood sample inlet is used for injecting blood or other liquid samples needing sorting; the diluent sample inlet is used for the inflow of cell diluent; the fluorescence detection area is provided with a laser detection system for detecting a fluorescence-labeled cell signal; the pressure control system is used for extruding the pipeline and preventing the cells from flowing continuously; the cell dilution zone is used for diluting the sorted target liquid by a diluent; the CTCs sample outlet is used for collecting liquid containing high-purity target products CTCs; the waste liquid outlet is used for collecting waste liquid.
Furthermore, the stage number N of the secondary separation pipeline is more than or equal to 2.
Furthermore, the whole blood sample inlet and the diluent sample inlet are both connected with an injection pump to provide power for liquid flowing in the device.
Furthermore, the cell dilution zone contains an upright column for fully and uniformly diluting the cell sap, thereby being beneficial to the subsequent cell sorting. Further increasing the target cell concentration.
Furthermore, the sorting pipeline is made of a high-performance polyolefin thermoplastic elastomer material with high transparency, high elasticity and good biocompatibility.
A method for sorting whole blood circulating tumor cells in a cascade manner based on a fluorescence activated cell sorting technology comprises the following steps:
1) injecting whole blood incubated by the fluorescent antibody into a whole blood sample injection port, and injecting diluent from a diluent sample injection port;
2) when the blood flows through the primary sorting pipeline, if no fluorescent signal is detected in the fluorescent detection area, the blood can continuously flow along the pipeline, finally flows out from the waste liquid outlet and is collected in a waste liquid bottle;
3) if a fluorescence signal is detected in the fluorescence detection area of the primary sorting, the computer system controls the pressure control system to extrude the pipeline to prevent the blood from flowing in the area of the pipeline, so that the blood with the signal flows to the other branch circuit and enters the secondary sorting pipeline, then the pressure control system is closed and is restored to a loose state from an extrusion state, and the subsequent non-signal blood continues to flow to a waste liquid outlet along the pipeline and enters a waste liquid bottle;
4) the blood entering the secondary sorting flows along with the diluent, is further diluted in the cell dilution zone and enters the cell sorting zone of the grade, the primary sorting logic is repeated, then the blood enters the next secondary sorting, and finally flows out from the sample outlet of the CTCs of the last grade, so that the high-purity target cell solution is obtained.
Furthermore, the cells flow from the last stage after being sorted from the previous stage to the last stage and then directly flow out from the sample outlets of the CTCs along with the diluent without being treated by a cell dilution zone.
Has the advantages that:
(1) compared with the traditional rare cell sorting method, the design is not limited by blood volume.
(2) After the whole blood is injected, all operations are performed inside the device, reducing the risk of contamination. Greatly shortening the analysis time.
(3) The whole set of equipment has low manufacturing cost, the pipeline is replaceable consumable, and the maintenance cost is low.
(4) The cell diluent can be replaced according to specific use conditions. For example, when the sorted cells are to be re-cultured, the buffer solution may be replaced with a cell culture solution.
Drawings
FIG. 1 is a plan view showing the layout of the apparatus of the present invention (four-stage sorting).
Fig. 2 is a three-dimensional structure diagram of the device of the invention.
FIG. 3 is a schematic view of a cell sorting section of the apparatus of the present invention.
FIG. 4 is a schematic diagram of a cell dilution zone of the device of the present invention.
The system comprises a whole blood sample inlet, a diluent sample inlet, a fluorescence detection zone, a cell sorting zone, a cell dilution zone, a cell selection.
Detailed Description
The invention will be further described with reference to the accompanying drawings.
A whole blood circulating tumor cell cascade sorting device based on fluorescence activated cell sorting technology comprises a primary sorting pipeline and a plurality of secondary sorting pipelines; the number N of stages of the secondary separation pipeline is more than or equal to 2, and efficient separation can be realized by increasing or reducing the number of stages according to actual requirements. The sorting pipeline is made of a transparent high-elasticity high-performance polyolefin thermoplastic elastomer with good biocompatibility, and the inner surface of the sorting pipeline has hydrophobic property.
The primary sorting pipeline comprises a whole blood sample inlet 1, a cell sorting area 4 and a waste liquid sample outlet 7; the secondary sorting pipeline comprises a diluent sample inlet 2, a cell sorting area 4, a cell diluting area 5, a CTCs sample outlet 6 and a waste liquid sample outlet 7; the cell separation zone 4 comprises a fluorescence detection zone 3 and a pressure control system 8;
the whole blood sample inlet 1 is used for injecting blood or other liquid samples needing sorting; the diluent sample inlet 2 is used for the inflow of cell diluent; the fluorescence detection area 3 is provided with a laser detection system for detecting a cell signal marked by fluorescence; the pressure control system 8 is used for extruding the pipeline to block the cells from flowing continuously; the cell dilution zone 5 is used for diluting the sorted target liquid by the diluent; the cell dilution zone 5 is internally provided with a stand column for fully and uniformly diluting cell sap, thereby being beneficial to subsequent cell sorting and further improving the concentration of target cells. The CTCs sample outlet 6 is used for collecting liquid containing high-purity target products CTCs; and the waste liquid outlet 7 is connected with a waste liquid collecting bottle for collecting waste liquid. The whole blood sample inlet 1 and the diluent sample inlet 2 are both connected with an injection pump to provide power for liquid flowing in the device.
The inlet of the primary sorting pipeline is a whole blood sample inlet 1, the pipeline is divided into two branches after the whole blood sample inlet 1 passes through a fluorescence detection zone 3, one branch is communicated with a waste liquid outlet 7, and the other branch is communicated with a sample inlet line of a next-stage cell diluent pipe;
the inlet of the secondary sorting pipeline is a diluent injection port 2, the diluent injection port 2 is connected with a cell dilution area 5 through a cell diluent injection pipeline, and the cell dilution injection pipeline is communicated with a primary cell sorting area 4 after starting from the diluent injection port 2; the cell dilution zone 5 is further communicated, the cell dilution zone 5 passes through the cell separation zone 4, and the cell separation zone passes through the fluorescence detection zone 3 and then is divided into two branches, one branch is communicated with a waste liquid outlet 7, and the other branch is communicated with a sample inlet line of a next-stage cell dilution liquid pipe; wherein, the last stage secondary sorting pipeline has no cell dilution area 5 and cell sorting area 4, the inlet of the last stage secondary sorting pipeline is a diluent injection port 2, and the last stage cell sorting area 4 is communicated from the diluent injection port 2; and is directly communicated with the CTCs sample outlet 6. And a pressure control system 8 is also arranged on a branch pipeline between the fluorescence detection zone 3 and the waste liquid sample outlet 7.
A method for sorting whole blood circulating tumor cells in a cascade manner based on a fluorescence activated cell sorting technology comprises the following steps:
1) injecting whole blood incubated by the fluorescent antibody into the whole blood sample injection port 1, and injecting diluent from the diluent sample injection port 2;
2) when blood flows through the primary sorting pipeline, if no fluorescent signal is detected in the fluorescent detection zone 3, the blood will continuously flow along the pipeline, finally flow out from the waste liquid outlet 7 and be collected in a waste liquid bottle;
3) if a fluorescence signal is detected in the fluorescence detection area 3 of the primary sorting, the computer system controls the pressure control system 8 to extrude the pipeline to prevent the blood from flowing in the area of the pipeline, the blood with the signal is forced to flow to the other branch and enter the secondary sorting pipeline, then the pressure control system 8 is closed and is restored to a loose state from an extrusion state, and the subsequent non-signal blood continues to flow to the waste liquid outlet 7 along the pipeline and enters a waste liquid bottle;
4) the blood entering the secondary sorting flows along with the diluent, is further diluted in the cell dilution zone 5 and enters the cell sorting zone 4 of the grade, the primary sorting logic is repeated, then enters the next secondary sorting, and finally flows out from the sample outlet 6 of the CTCs of the last grade, so that the target cell solution with high purity is obtained.
After the cells flow into the last stage from the previous stage, the cells directly flow out from the CTCs outlet 6 along with the diluent without being treated by the cell dilution zone 5.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.

Claims (8)

1. A whole blood circulating tumor cell cascade sorting device based on a fluorescence activated cell sorting technology is characterized by comprising a primary sorting pipeline and a plurality of secondary sorting pipelines;
the primary sorting pipeline comprises a whole blood sample inlet (1), a cell sorting area (4) and a waste liquid sample outlet (7); the secondary sorting pipeline comprises a diluent sample inlet (2), a cell sorting area (4), a cell diluting area (5), a CTCs sample outlet (6) and a waste liquid sample outlet (7); the cell sorting area (4) comprises a fluorescence detection area (3) and a pressure control system (8);
the inlet of the primary sorting pipeline is a whole blood sample inlet (1), the whole blood sample inlet (1) is divided into two branches after passing through a fluorescence detection zone (3), one branch is communicated with a waste liquid sample outlet (7), and the other branch is communicated with a next-stage cell diluent sample inlet pipeline;
the inlet of the secondary sorting pipeline is a diluent injection port (2), the cell diluent injection pipeline is divided into two branches after starting from the diluent injection port (2), and one branch is communicated with the upper-stage cell sorting area (4); the other branch is communicated with a cell dilution area (5), passes through the cell dilution area (5), reaches a cell sorting area (4), passes through a fluorescence detection area (3) and is divided into two branches, one branch is communicated with a waste liquid outlet (7), and the other branch is communicated with a next-stage cell dilution liquid sample injection pipeline; wherein, the last stage secondary sorting pipeline has no cell diluting area (5) and cell sorting area (4), the inlet of the last stage secondary sorting pipeline is a diluent injection port (2), the last stage secondary sorting pipeline is divided into two branches from the diluent injection port (2), and one branch is communicated with the last stage cell sorting area (4); the other branch is directly communicated with a CTCs sample outlet (6);
and a pressure control system (8) is also arranged on a branch pipeline between the fluorescence detection area (3) and the waste liquid sample outlet (7).
2. The device for the cascade sorting of the whole blood circulating tumor cells based on the fluorescence activated cell sorting technology is characterized in that the whole blood sample inlet (1) is used for injecting blood or other liquid samples needing sorting; the diluent injection port (2) is used for the inflow of cell diluent; the fluorescence detection area (3) is provided with a laser detection system for detecting a cell signal marked by fluorescence; the pressure control system (8) is used for extruding the pipeline and preventing the cell fluid from flowing continuously; the cell dilution zone (5) is used for diluting the sorted target liquid by a diluent; the CTCs sample outlet (6) is used for collecting liquid containing high-purity target products CTCs; and the waste liquid outlet (7) is used for collecting waste liquid.
3. The device for the cascade sorting of the whole blood circulating tumor cells based on the fluorescence activated cell sorting technology of claim 1, wherein the number of the secondary sorting lines N is greater than or equal to 2.
4. The device for the cascade sorting of the whole blood circulating tumor cells based on the fluorescence activated cell sorting technology is characterized in that the whole blood sample inlet (1) and the diluent sample inlet (2) are both connected with a syringe pump to provide the power for the liquid to flow in the device.
5. The device for the cascade sorting of the whole blood circulating tumor cells based on the fluorescence-activated cell sorting technology of claim 1, wherein the cell dilution zone (5) contains pillars for sufficiently and uniformly diluting the cell fluid to facilitate the subsequent cell sorting.
6. The device for the cascade sorting of the whole blood circulating tumor cells based on the fluorescence-activated cell sorting technology of claim 1, wherein the sorting pipeline is made of a high-performance polyolefin thermoplastic elastomer, and the inner surface of the sorting pipeline has hydrophobic properties.
7. A method for sorting whole blood circulating tumor cells in a cascade manner based on a fluorescence activated cell sorting technology is characterized by comprising the following steps:
1) injecting whole blood incubated by the fluorescent antibody into the whole blood sample injection port (1), and injecting diluent from the diluent sample injection port (2);
2) when blood flows through the primary sorting pipeline, if no fluorescence signal is detected in the fluorescence detection area (3), the blood can continuously flow along the pipeline and finally flows out of the waste liquid outlet (7) to be collected in a waste liquid bottle;
3) if a fluorescence signal is detected in the fluorescence detection area (3) of the primary sorting, the computer system controls the pressure control system (8) to extrude the pipeline to prevent the blood from flowing in the pipeline area of the stage, and forces the blood with the signal to flow to the other branch and enter the secondary sorting pipeline, then the pressure control system (8) is closed and is restored to a release state from an extrusion state, so that the subsequent blood without the signal continuously flows to a waste liquid outlet (7) along the pipeline of the stage and enters a waste liquid bottle;
4) the blood entering the secondary sorting flows along with the diluent, is further diluted in the cell dilution zone (5) and enters the cell sorting zone (4) of the stage, the primary sorting logic is repeated, then enters the next secondary sorting, and finally flows out from the CTCs outlet (6) of the last stage, so that the high-purity target cell solution is obtained.
8. The method for the cascade sorting of the circulating tumor cells in whole blood based on the fluorescence-activated cell sorting technique as claimed in claim 7, wherein the cells flowing from the previous sorting stage to the last sorting stage directly flow out from the CTCs outlets (6) with the diluent without being treated by the cell dilution zone (5).
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