CN107505249B - Microfluidic chip system for rare cell screening - Google Patents
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Abstract
The invention discloses a microfluidic chip system for rare cell screening, which comprises: the device comprises a micro-fluidic chip, an optical signal excitation and detection module, a data acquisition analysis and control module, a piezoelectric driving module and a pump control module. According to the invention, a piezoelectric element is adopted to excite a surface wave sound field, and the physical properties of cells are utilized to carry out coarse screening, so that part of non-target objects can be removed, and the purity and the capture rate of the fine screening can be improved; meanwhile, the method can also play roles in cleaning and three-dimensional focusing on the sample, so that the accuracy of subsequent detection and fine screening is improved; the piezoelectric element is adopted to excite the surface acoustic wave to push the target cells in the fluid to deviate from the original path in the fine screening area, so that the cell sorting can be rapidly realized, and meanwhile, the mechanical force acts on the cells, so that the activity of the cells is not influenced; the system provided by the invention has no damage to cells, can be used for conventional flow cell sorting and rare cell screening, and has great significance in promoting noninvasive prenatal screening and tumor prognosis detection.
Description
Technical Field
The invention relates to the technical field of microfluidic chips and biological particle detection and control, in particular to a microfluidic chip system for rare cell screening.
Background
The detection captures very little rare cells in blood, and is helpful for early diagnosis of diseases and monitoring of the conditions of patients. The existing flow cell sorter has the problems of huge volume, complex structure, repeated pipeline cleaning and time-consuming labor; and the sorting process is completed in the air, the system is open, aerosol pollution of samples containing cells, bacteria, viruses and the like can be generated, and the clinical application of the sample is limited. At present, the cell sorting systems of BD, beckman Coulter and other companies mostly adopt the electrostatic deflection separation mode of Jet-in-Air (U.S. Pat. No. 3710933 and No. 3826364), and although the cells can be separated at high speed, the cells can be damaged due to the high fluid shear force, and the activity and gene expression of the cells are influenced. In regenerative cell therapy and stem cell research, the cells sorted by the traditional electrostatic cell sorter have the problem of low survival rate. Meanwhile, in the research of cell regeneration, transgenic samples or samples infected by viruses/bacteria, the ensuring of the sealing and sterility of the environment is a very critical problem, and a cell sorting system based on a microfluidic chip has wide prospect.
The existing microfluidic cell sorting schemes, such as electroosmosis, electrophoresis, pneumatic control, mechanical valves, optical tweezers, photo-thermal gel and the like, have the problems of low sorting speed or complex and expensive structure; some high-throughput cell sorting methods such as membrane filtration, dielectrophoresis, ultrasound, surface acoustic wave separation methods and the like rely on the characteristics of the cells themselves, and are less versatile.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a microfluidic chip system for rare cell screening aiming at the defects in the prior art.
In order to solve the technical problems, the invention adopts the following technical scheme: a microfluidic chip system for rare cell screening, comprising: the device comprises a microfluidic chip, an optical signal excitation and detection module, a data acquisition analysis and control module, a piezoelectric driving module and a pump control module;
the micro-fluidic chip comprises a piezoelectric substrate and a cover plate which is sealed and attached to the piezoelectric substrate, wherein the piezoelectric substrate is coated with a coarse screening interdigital electrode and a fine screening interdigital electrode, and the coarse screening interdigital electrode and the fine screening interdigital electrode are used for generating a sound field for realizing cell sorting; forming a coarse screening area at the coarse screening interdigital electrode on the microfluidic chip, performing primary screening of target cells, forming a fine screening area at the fine screening interdigital electrode on the microfluidic chip, performing fine screening of target cells, and arranging a detection area between the coarse screening area and the fine screening area on the microfluidic chip;
the optical signal excitation and detection module comprises a light spot excitation modulation system and an optical signal detection system, and is used for generating laser to excite cells flowing through a detection area of the microfluidic chip to generate fluorescence and scattered light, collecting and detecting the generated fluorescence and scattered light to form optical signal information, converting the obtained optical signal information into an electric signal and transmitting the electric signal to the data acquisition analysis and control module;
the data acquisition analysis and control module is used for: generating a pump control trigger signal to control the pump control module; generating a coarse screen trigger signal to control the action of the coarse screen interdigital electrode; processing the electric signals received from the optical signal excitation and detection module to form a processing result, judging whether the processing result meets the fine screening conditions set by a user, and generating a fine screening trigger signal to control the action of the fine screening interdigital electrode when judging that the processing result meets the fine screening conditions set by the user;
the piezoelectric driving module is used for converting the received coarse screening trigger signal and the fine screening trigger signal into high-voltage signals so as to respectively drive the coarse screening interdigital electrode and the fine screening interdigital electrode to generate a required sound field;
the pump control module comprises a pump driving module, a sample pump, a sheath pump, a coarse screening waste liquid pump and a fine screening waste liquid pump.
Preferably, the bottom of the cover plate is provided with a pipeline groove and a plurality of openings which are communicated with the pipeline groove and penetrate through the cover plate, and the cover plate is attached to the piezoelectric substrate in a sealing way, so that the pipeline groove between the cover plate and the piezoelectric substrate forms a micro pipeline.
Preferably, the micro pipeline comprises a sample pipeline, a sheath liquid pipeline, a coarse sieve pipeline formed by converging the sample pipeline and the sheath liquid pipeline, a coarse sieve waste liquid pipeline formed by forking the coarse sieve pipeline after passing through the coarse sieve area, a detection pipeline, and a fine sieve waste liquid pipeline and a target pipeline formed by forking the detection pipeline after passing through the fine sieve area.
Preferably, the opening comprises a sample liquid inlet communicated with the sample inlet of the sample pipeline, a sheath liquid inlet communicated with the liquid inlet of the sheath liquid pipeline, a coarse screen waste liquid drain communicated with the tail end of the coarse screen waste liquid pipeline, a fine screen waste liquid drain communicated with the tail end of the fine screen waste liquid pipeline and a target liquid drain communicated with the tail end of the target pipeline.
Preferably, the cover plate is made of plastic or glass, and the piezoelectric substrate is made of piezoelectric ceramics, piezoelectric single crystals or piezoelectric composite materials.
Preferably, the electrode structures of the coarse screening interdigital electrode and the fine screening interdigital electrode are parallel, focusing or widening, the voltage waveform applied to the coarse screening interdigital electrode is a sine wave or a square wave, and the voltage waveform applied to the fine screening interdigital electrode is a sine wave or a square wave of the square wave envelope.
Preferably, when the fine screening area judges the target cells, a positive selection method or a negative selection method is adopted, and when the positive selection method is adopted, signals conforming to the characteristics of the target cells are used as judgment basis to control the actions of the fine screening interdigital electrodes; when the counter selection method is adopted, signals conforming to the characteristics of non-target cells are used as judgment basis to control the actions of the fine screening interdigital electrodes.
Preferably, the width of each pipeline in the micro pipeline is 10-500 mu m, the height of each pipeline is 20-200 mu m, and the single-finger widths of the coarse-sieve interdigital electrode and the fine-sieve interdigital electrode are 5-100 mu m.
Preferably, the spot excitation modulation system comprises a laser, a mirror, a first cylindrical lens and a second cylindrical lens, the spot excitation modulation system generating laser light and forming an elliptical spot for illuminating cells flowing through the detection zone.
Preferably, the optical signal detection system includes a fluorescence collection mirror, a first dichroic mirror, a second dichroic mirror, a first interference filter, a second interference filter, a third interference filter, a first lens, a second lens, a third lens, a first detector, a second detector, and a third detector.
The invention at least comprises the following beneficial effects:
1. the piezoelectric element is adopted to excite the surface wave sound field, the physical property of cells is utilized to carry out coarse screening, and partial non-target objects can be removed, so that the purity and the capture rate of the fine screening can be improved; meanwhile, the method can also play roles in cleaning and three-dimensional focusing on the sample, so that the accuracy of subsequent detection and fine screening is improved;
2. the piezoelectric element is adopted to excite the surface acoustic wave to push the target cells in the fluid to deviate from the original path in the fine screening area, so that the cell sorting can be rapidly realized, and meanwhile, the mechanical force acts on the cells, so that the activity of the cells is not influenced;
3. the microfluidic chip is formed by bonding and bonding a plurality of layers of plastic, metal or polymer materials containing micro-pipes, has an integral structure with sterile sealing, can be applicable to samples with biological hazards, can be used after being plugged and plugged, does not need to be cleaned, avoids cross contamination among the samples, and can be discarded after being used once; the system provided by the invention has no damage to cells, can be used for conventional flow cell sorting and rare cell screening, and has great significance in promoting noninvasive prenatal screening and tumor prognosis detection.
Drawings
FIG. 1 is a schematic block diagram of a system architecture of a microfluidic chip system for rare cell screening of the present invention;
fig. 2 is a schematic structural diagram of a microfluidic chip according to the present invention;
FIG. 3a is a schematic diagram of a parallel interdigitated electrode of the present invention;
FIG. 3b is a schematic view of a focusing interdigital electrode of the present invention;
FIG. 3c is a schematic view of a widening interdigital electrode of the present invention;
FIG. 4 is a schematic diagram of a micro-channel on a microfluidic chip according to the present invention;
FIG. 5a is a schematic diagram of a classification of the coarse screening process of the present invention;
FIG. 5b is a schematic diagram of the detection process of the present invention;
FIG. 5c is a schematic diagram of a sizing process of the present invention;
FIG. 6a is a schematic diagram of the traveling acoustic surface wave driving cell motion of the present invention;
FIG. 6b is a schematic diagram of the acoustic surface standing wave driven cell motion of the present invention;
FIG. 7 is a schematic diagram of a spot excitation modulation system according to the present invention;
FIG. 8 is a schematic diagram of an optical signal detection system according to the present invention;
fig. 9 is a functional block diagram of the present invention for system control.
Reference numerals illustrate:
30—sample tubing; 31-sheath fluid pipe; 32-coarse screen pipe; 33-a coarse screen waste liquid pipeline; 34-a detection conduit; 35-a fine screening waste liquid pipeline; 36-target conduit; 40-differential cells; 41-similar cells; 42-target cells; 43-standing wave node; 50-a coarse screening area; 51—a detection zone; 52-a fine screening area; 53-coarse screening interdigital electrodes; 54-fine screening interdigital electrodes; 60-piezoelectric substrate; 61-cover plate; 66—sample liquid inlet; 67-sheath fluid inlet hole; 68-a coarse screen waste liquid drain hole; 69-fine screening waste liquid drain holes; 70-a target liquid discharge hole; 71-a laser; 72-a mirror; 73—a first cylindrical lens; 74-a second cylindrical lens; 80-a fluorescent collection mirror; 81—a first dichroic mirror; 82-a second dichroic mirror; 83-a first interference filter; 84-a second interference filter; 85—a third interference filter; 86—a first lens; 87-a second lens; 88-a third lens; 89-a first detector; 90-a second detector; 91-third detector.
Detailed Description
The present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
It will be understood that terms, such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
As shown in fig. 1, a microfluidic chip system for rare cell screening according to the present embodiment is characterized by comprising: the device comprises a micro-fluidic chip, an optical signal excitation and detection module, a data acquisition analysis and control module, a piezoelectric driving module and a pump control module.
The micro-fluidic chip is provided with a coarse screening area 50, a detection area 51 and a fine screening area 52. The pump control module comprises a pump driving module, a sample pump, a sheath pump, a coarse screening waste liquid pump and a fine screening waste liquid pump. The piezoelectric driving module is used for converting the received coarse screening trigger signal and the fine screening trigger signal into high-voltage signals to respectively drive the coarse screening interdigital electrode 53 and the fine screening interdigital electrode 54 to generate required sound fields.
The data acquisition analysis and control module generates a pump control trigger signal and sends the pump control trigger signal to the pump driving module, and the pump driving module controls the operation and stop of each pump. The data acquisition analysis and control module generates a continuous coarse screen trigger signal and sends the continuous coarse screen trigger signal to the piezoelectric driving module, the piezoelectric driving module converts the coarse screen trigger signal into a high-voltage signal for driving the coarse screen interdigital electrodes 53 in the coarse screen area 50 to generate a continuous sound field to change the movement path of cells, so that the coarse screen function according to different physical properties of the cells is realized, the differential cells 40 with larger differences in physical properties are removed, samples are cleaned and focused, and the single cells are ensured to sequentially pass through the detection pipeline 34;
the optical signal excitation and detection module comprises a light spot excitation modulation system and an optical signal detection system; the light spot excitation modulation system generates laser and forms an elliptical light spot, irradiates the detection area 51, and irradiates each cell excited to flow through the detection area 51 of the microfluidic chip to generate fluorescence and scattered light; the optical signal detection system collects and detects the generated fluorescence and scattered light to form optical signal information, converts the obtained optical signal information into an electric signal and sends the electric signal to the data acquisition analysis and control module. The data acquisition analysis and control module carries out quantization and analysis processing on the received electric signals, carries out logic judgment on the processing results and the fine screening conditions set by the user, and sends a fine screening trigger signal to the piezoelectric driving module if the fine screening conditions set by the user are met; the piezoelectric driving module converts the fine screening trigger signal into a high-voltage signal for driving the fine screening interdigital electrode 54 in the fine screening area 52 to act, so that a sound field is generated to change the movement path of the target cells 42, and the target cells 42 and the non-target cells 41 are separated to different separation outlets, thereby realizing the fine screening separation of the cells. The user can set the starting and stopping of each pump, the starting and stopping of the coarse screen, the fine screen condition for starting the fine screen, the sorting parameters of the fine screen and the like through the computer, and the computer sends the parameters to the data acquisition analysis and control module for corresponding control. The data received by the data acquisition analysis and control module is processed and then sent to the computer and displayed on the user interface, so that the user can set corresponding parameters according to the pre-sampling result.
As shown in fig. 2, the microfluidic chip includes a piezoelectric substrate 60 and a cover sheet 61 sealingly attached to the piezoelectric substrate 60, and the piezoelectric substrate 60 is coated with coarse-screening interdigital electrodes 53 and fine-screening interdigital electrodes 54, and the coarse-screening interdigital electrodes 53 and the fine-screening interdigital electrodes 54 are used for generating a sound field for realizing cell sorting; a coarse screening area 50 is formed at a coarse screening interdigital electrode 53 on the microfluidic chip, primary screening of the target cells 42 is performed, a fine screening area 52 is formed at a fine screening interdigital electrode 54 on the microfluidic chip, fine screening of the target cells 42 is performed, and a detection area 51 is arranged between the coarse screening area 50 and the fine screening area 52 on the microfluidic chip, and whether the target cells 42 exist or not is detected. The bottom of the cover plate 61 is provided with a pipeline groove and a plurality of openings which are communicated with the pipeline groove and penetrate through the cover plate 61, the cover plate 61 is attached to the piezoelectric substrate 60 in a sealing way, and the pipeline groove between the cover plate 61 and the piezoelectric substrate 60 is made into a sealing space to form a micro pipeline. The cover 61 is made of plastic or glass, and the piezoelectric substrate 60 is made of piezoelectric ceramics, piezoelectric single crystals or piezoelectric composite materials. The width of each pipeline in the micro pipeline is 10-500 mu m, the height is 20-200 mu m,
the electrode structures of the coarse screening interdigital electrode 53 and the fine screening interdigital electrode 54 are parallel, focusing or widening, and the single-finger widths of the coarse screening interdigital electrode 53 and the fine screening interdigital electrode 54 are 5-100 mu m.
The coarse screening interdigital electrode 53 includes at least one pair, and the fine screening interdigital electrode 54 includes at least one pair; when a pair of coarse screening interdigital electrodes 53 or a pair of fine screening interdigital electrodes 54 are employed, the spacing between the two coarse screening interdigital electrodes 53 is an integer multiple of the half wavelength of the acoustic wave generated at the electrode, and the spacing between the two fine screening interdigital electrodes 54 is an integer multiple of the half wavelength of the acoustic wave generated at the electrode. When sorting is performed using an acoustic surface standing wave (i.e., using a pair of interdigital electrodes), the width of the coarse screen pipe 32 and the fine screen pipe contain at least one standing wave node 43 of the acoustic wave generated at this position, and the position of the standing wave node 43 is deviated from the cell flow to be selected.
The voltage waveform applied to the coarse screening interdigital electrode 53 is a sine wave or a square wave, and the voltage waveform applied to the fine screening interdigital electrode 54 is a sine wave of a square wave envelope or a square wave of a square wave envelope.
When in use, the focusing sound field can be formed by adopting a plurality of groups of interdigital electrode arrangement modes, such as symmetrical arrangement, annular arrangement and the like.
As shown in fig. 3a, 3b, and 3c, the interdigital electrode may have various forms, fig. 3a is a parallel interdigital, fig. 3b is a focusing interdigital, and fig. 3c is a widening interdigital. The parallel interdigital can generate parallel sound fields pointing in the length direction, and is relatively suitable for being used in coarse screening. The focusing interdigital can generate a high-intensity sound field in a smaller range, and is relatively suitable for fine screening. The widening interdigital transducer can generate a sound field in a certain frequency range (the frequency range is determined by the width range of the interdigital transducer), and is suitable for multiplexing.
As shown in fig. 4, the micro-pipeline includes a sample pipeline 30, a sheath liquid pipeline 31, a coarse screen pipeline 32 formed by converging the sample pipeline 30 and the sheath liquid pipeline 31, a coarse screen waste liquid pipeline 33 and a detection pipeline 34 formed by branching the coarse screen pipeline 32 after passing through a coarse screen area 50, and a fine screen waste liquid pipeline 35 and a target object pipeline 36 formed by branching the detection pipeline 34 after passing through a detection area 51 and a fine screen area 52 in sequence. The openings include a sample liquid inlet 66 in communication with the sample inlet end of the sample conduit 30, a sheath liquid inlet 67 in communication with the liquid inlet end of the sheath liquid conduit 31, a coarse screen waste liquid drain 68 in communication with the end of the coarse screen waste liquid conduit 33, a fine screen waste liquid drain 69 in communication with the end of the fine screen waste liquid conduit 35, and a target liquid drain 70 in communication with the end of the target conduit 36. The pump control module comprises a pump driving module, a sample pump, a sheath pump, a coarse screening waste liquid pump and a fine screening waste liquid pump. The pump driving module receives the pump control trigger signal sent by the data acquisition analysis and control module and controls the sample pump, the sheath pump, the coarse screen waste liquid pump and the fine screen waste liquid pump. The sample pump presses the sample to be measured into the sample pipeline 30 of the microfluidic chip through the sample liquid inlet hole 66, the sheath liquid pump presses the sheath liquid into the sheath liquid pipeline 31 of the microfluidic chip, and the coarse screening waste liquid pump and the fine screening waste liquid pump out the coarse screening waste liquid and the fine screening waste liquid and are also used for assisting the formation of a stable flow field in the flow channel. The target cells 42 are discharged from the target discharge hole 70.
Wherein, the waste liquid generated by the coarse screening of the coarse screening pipeline 32 is discharged through the coarse screening waste liquid pipeline 33, and the cells containing the target object enter the detection pipeline 34.. The waste liquid generated by the fine screen is discharged from the fine screen waste liquid pipeline 35, and the target objects are converged in the target pipeline. The branching positions of the waste liquid conduit, slightly wider than the detection conduit 34 and the target conduit 36, the coarse screen conduit 32 and the detection conduit 34 are between the original sample flow path and the offset particle flow path. In actual use, different cell sample flow rates and fluid distribution in the pipeline can be adjusted by setting different driving pressures of the pumps.
The fluid in the fluid channel always maintains a laminar flow state.
Each fluid branch pipe in the micro-pipeline on the micro-fluidic chip can have a multi-path branch form, such as a coarse screen waste liquid pipeline 33, a detection pipeline 34, a fine screen waste liquid pipeline 35 and a target pipeline 36, which can all comprise a plurality of branches, so as to realize multi-path separation; the micro-channels on a single micro-fluidic chip can be one or a plurality of micro-channels arranged in an array structure to improve the system flux.
As shown in fig. 5a, 5b, 5c, schematic diagrams of the coarse screening process, the detection process, and the fine screening process are shown, respectively. When the sample flows through the coarse screen area 50, according to the difference of physical properties (volume and density), a part of differential cells 40 (the difference of physical properties with the target cells 42 is larger) keep the original flow path unchanged, and other similar cells 41 (the physical properties similar to those of the target cells 42) and the target cells 42 deviate from the original orbit for a certain distance under the action of a sound field and keep stable flow. The cell can maintain the moving path unchanged even after passing through the sound field application region. The differential cells 40 flow into the coarse screen waste conduit 33, the similar cells 41, the target flow into the detection conduit 34. Due to the focusing effect of the sound field of the coarse screening area 50 on the cells, the cells to be tested pass through the laser detection area 51 one by one, and when the target cells 42 are detected, the pulse sound field of the fine screening area 52 is started, so that the target cells 42 deviate from the original flow channel, and the similar cells 41 enter the fine screening waste liquid pipeline 35, and the target cells 42 enter the target object pipeline 36. In the fine screening zone 52, it is necessary to ensure that only one cell is present in the sound field application zone as much as possible, otherwise the trapping purity is reduced.
The principle of the surface wave acoustic field driving the cell motion is shown in fig. 6a and 6 b. FIG. 6a shows the displacement of cells along the propagation direction of an acoustic field when travelling acoustic surface waves act on the cells, suitable for use in fine screening; figure 6b shows that when a standing acoustic surface wave is applied to a cell, the cell produces a displacement that tends to the node 43 of the standing wave. Meanwhile, when the acoustic surface standing wave is adopted, cells can generate a converging effect in the depth direction of the channel, and the method can be used in coarse screening and fine screening.
Because the fine screening sound field action zone is located below the detection zone 51, the trigger signal is generated after waiting for a certain cell flowing time, when the cell moves from the detection zone 51 to the downstream sound field action zone, the piezoelectric ceramic driving module generates a driving signal with a certain pulse width and a certain voltage, and the signal controls the sound field generation, so that the target cell 42 is pushed, and the purpose of separating the cell according to the difference of detected optical signals is achieved. Wherein, the amplitude of the driving voltage and the deformation of the piezoelectric ceramic become positive correlation, and the higher the voltage is, the larger the thrust is.
In the fine screening zone 52, the target cells 42 may be determined by either a positive selection method or a negative selection method. When the positive selection method is adopted, the action of the fine screening interdigital electrode 54 of the fine screening area 52 is controlled by taking the signal which accords with the characteristics of the target cells 42 as a judgment basis so as to control the sound field effect of the fine screening area 52; when the counter selection method is adopted, the action of the fine screening interdigital electrode 54 is controlled by taking the signal which accords with the characteristics of the non-target cells 42 as a judgment basis so as to control the sound field effect of the fine screening area 52. Taking the screening of fetal nucleated red blood cells in the peripheral blood of a pregnant woman as an example. In the coarse screen region 50, red blood cells and platelets may be removed from the sample, depending on the difference in cell physical properties. In the fine screening area 52, the arrival of the target cells 42 can be judged based on a positive signal of CD71 (fetal nucleated erythrocyte-specific antibody) by the positive selection method, thereby controlling the action of the fine screening interdigital electrode 54 to control the sound field effect of the fine screening portion. When the counter selection method is adopted, the arrival of the target cells 42 can be judged based on a positive signal of CD45 (leukocyte-specific antibody), so that the action of the fine screening interdigital electrode 54 is controlled and controlled, and the sound field of the fine screening part is not acted. When the antibody specificity of the target cell 42 is not good, the trapping rate can be improved by the counter selection method.
As shown in fig. 7, the optical signal excitation and detection module includes a light spot excitation modulation system and an optical signal detection system, and is used for generating laser to excite cells flowing through the detection region 51 of the microfluidic chip to generate fluorescence and scattered light, collecting and detecting the generated fluorescence and scattered light to form optical signal information, converting the obtained optical signal information into an electrical signal, and sending the electrical signal to the data acquisition analysis and control module.
The spot excitation modulation system includes a laser 71, a mirror 72, a first cylindrical lens 73 and a second cylindrical lens 74, and generates laser light and forms an elliptical spot for illuminating cells flowing through the detection zone 51.
As shown in fig. 8, the optical signal detection system includes a fluorescence collecting mirror 80, a first dichroic mirror 81, a second dichroic mirror 82, a first interference filter 83, a second interference filter 84, a third interference filter 85, a first lens 86, a second lens 87, a third lens 88, a first detector 89, a second detector 90, and a third detector 91.
The fluorescence collecting mirror 80, the first dichroic mirror 81, the first interference filter 83, the first lens 86, and the first detector 89 are sequentially arranged to form a first optical path; the fluorescence collecting mirror 80, the first dichroic mirror 81, the second dichroic mirror 82, the second interference filter 84, the second lens 87, and the second detector 90 are sequentially arranged to form a second optical path; the fluorescence collecting mirror 80, the first dichroic mirror 81, the second dichroic mirror 82, the third interference filter 85, the third lens 88, and the third detector 91 are disposed in this order, forming a third optical path. Therefore, three optical signal collecting and detecting light paths are formed, different lights are respectively collected and detected by different light paths, and a plurality of light paths can be set to collect and detect optical signals according to the judgment of a user on cells.
The sample cells are subjected to fluorescent staining treatment before entering the system for screening. The laser light emitted from the laser 71 is shaped into an elliptical spot by the beam and then perpendicularly irradiates on the cells in the detection area 51, the cells can cause different scattered light to the laser light due to the size, the content and the like of the cells, and fluorescent dyes on the cells can also be stimulated to emit fluorescent light in proportion to the number of the dyes. The scattered light and fluorescence are collected by the fluorescence collecting mirror 80, split by the dichroic mirror, processed by the interference filter and the lens in sequence, and finally received by the photodetector to be converted into an electric signal.
The data acquisition analysis and control module is used for: generating a pump control trigger signal to control the pump control module; generating a coarse screen trigger signal to control the action of the coarse screen interdigital electrode 53; the electrical signal received from the optical signal excitation and detection module is processed to form a processing result, whether the processing result meets the fine screening condition set by the user is judged, and when the processing result meets the fine screening condition set by the user, a fine screening trigger signal is generated to control the fine screening interdigital electrode 54 to act.
Fig. 9 is a schematic block diagram of the system control according to the present invention, where the data acquisition analysis and control module includes an FPGA, an analog-to-digital conversion module (ADC), a USB port, a digital-to-analog conversion module (DAC), and a single chip Microcomputer (MCU). An FPGA can be used as a core of the data acquisition analysis and control module. The signals are converted into digital signals through an analog-to-digital conversion module (ADC), then the digital signals are uploaded to the FPGA for preliminary digital signal processing, and then the digital signals are uploaded to a computer through a USB port to realize the functions of statistical analysis and the like. Meanwhile, the FPGA receives a control signal sent by a computer and transmits the control signal to a digital-to-analog conversion module (DAC) and a singlechip (MCU), so that parameters such as pump driving modules, piezoelectric driving modules and photoelectric detector bias voltages are controlled.
Although embodiments of the present invention have been disclosed above, it is not limited to the use of the description and embodiments, it is well suited to various fields of use for the invention, and further modifications may be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the particular details without departing from the general concepts defined in the claims and the equivalents thereof.
Claims (9)
1. A microfluidic chip system for rare cell screening, comprising: the device comprises a microfluidic chip, an optical signal excitation and detection module, a data acquisition analysis and control module, a piezoelectric driving module and a pump control module;
the micro-fluidic chip comprises a piezoelectric substrate and a cover plate which is sealed and attached to the piezoelectric substrate, wherein the piezoelectric substrate is coated with a coarse screening interdigital electrode and a fine screening interdigital electrode, and the coarse screening interdigital electrode and the fine screening interdigital electrode are used for generating a sound field for realizing cell sorting; forming a coarse screening area at the coarse screening interdigital electrode on the microfluidic chip, performing primary screening of target cells, forming a fine screening area at the fine screening interdigital electrode on the microfluidic chip, performing fine screening of target cells, and arranging a detection area between the coarse screening area and the fine screening area on the microfluidic chip;
the optical signal excitation and detection module comprises a light spot excitation modulation system and an optical signal detection system, and is used for generating laser to excite cells flowing through a detection area of the microfluidic chip to generate fluorescence and scattered light, collecting and detecting the generated fluorescence and scattered light to form optical signal information, converting the obtained optical signal information into an electric signal and transmitting the electric signal to the data acquisition analysis and control module;
the data acquisition analysis and control module is used for: generating a pump control trigger signal to control the pump control module; generating a coarse screen trigger signal to control the action of the coarse screen interdigital electrode; processing the electric signals received from the optical signal excitation and detection module to form a processing result, judging whether the processing result meets the fine screening conditions set by a user, and generating a fine screening trigger signal to control the action of the fine screening interdigital electrode when judging that the processing result meets the fine screening conditions set by the user;
the piezoelectric driving module is used for converting the received coarse screening trigger signal and the fine screening trigger signal into high-voltage signals so as to respectively drive the coarse screening interdigital electrode and the fine screening interdigital electrode to generate a required sound field;
the pump control module comprises a pump driving module, a sample pump, a sheath pump, a coarse screening waste liquid pump and a fine screening waste liquid pump;
the electrode structures of the coarse screening interdigital electrode and the fine screening interdigital electrode are parallel, focusing or widening, the voltage waveform applied to the coarse screening interdigital electrode is sine wave or square wave, and the voltage waveform applied to the fine screening interdigital electrode is sine wave or square wave of square wave envelope;
the coarse screening interdigital electrodes at least comprise a pair, and the fine screening interdigital electrodes at least comprise one; when a pair of coarse screening interdigital electrodes or a pair of fine screening interdigital electrodes are adopted, the distance between the two coarse screening interdigital electrodes is an integral multiple of half wavelength of sound waves generated at the electrodes, and the distance between the two fine screening interdigital electrodes is an integral multiple of half wavelength of sound waves generated at the electrodes.
2. The microfluidic chip system for rare cell screening according to claim 1, wherein a channel groove and a plurality of openings communicating with the channel groove and penetrating the cover sheet are formed in the bottom of the cover sheet, and the cover sheet is sealed and attached to the piezoelectric substrate such that the channel groove between the cover sheet and the piezoelectric substrate forms a microchannel.
3. The microfluidic chip system for rare cell screening according to claim 2, wherein the micro-channels comprise a sample channel, a sheath fluid channel, a coarse screen channel formed by converging the sample channel and the sheath fluid channel, a coarse screen waste channel formed by branching the coarse screen channel after passing through the coarse screen region, a detection channel, and a fine screen waste channel and a target channel formed by branching the detection channel after passing through the fine screen region.
4. The microfluidic chip system for rare cell screening according to claim 3, wherein the opening comprises a sample liquid inlet hole communicated with the sample inlet end of the sample tube, a sheath liquid inlet hole communicated with the liquid inlet end of the sheath liquid tube, a coarse screen liquid waste liquid drain hole communicated with the end of the coarse screen liquid waste tube, a fine screen liquid waste drain hole communicated with the end of the fine screen liquid waste tube, and a target liquid drain hole communicated with the end of the target tube.
5. The microfluidic chip system for rare cell screening according to claim 1, wherein the cover sheet is made of plastic or glass, and the piezoelectric substrate is made of piezoelectric ceramics or piezoelectric single crystals.
6. The microfluidic chip system for rare cell screening according to claim 1, wherein when the fine screening area judges the target cells, a positive selection method or a negative selection method is adopted, and when the positive selection method is adopted, signals conforming to the characteristics of the target cells are used as judgment basis to control the actions of the fine screening interdigital electrodes; when the counter selection method is adopted, signals conforming to the characteristics of non-target cells are used as judgment basis to control the actions of the fine screening interdigital electrodes.
7. The microfluidic chip system for rare cell screening according to claim 2, wherein each of the micro-channels has a width of 10 to 500 μm and a height of 20 to 200 μm, and the single finger widths of the coarse and fine screening interdigital electrodes are 5 to 100 μm.
8. The microfluidic chip system according to claim 1, wherein the spot excitation modulation system comprises a laser, a mirror, a first cylindrical lens and a second cylindrical lens, and wherein the spot excitation modulation system generates laser light and forms an elliptical spot for irradiating cells flowing through the detection zone.
9. The microfluidic chip system for rare cell screening according to claim 1, wherein the optical signal detection system comprises a fluorescence collection mirror, a first dichroic mirror, a second dichroic mirror, a first interference filter, a second interference filter, a third interference filter, a first lens, a second lens, a third lens, a first detector, a second detector, and a third detector.
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Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108681510A (en) * | 2018-05-21 | 2018-10-19 | 迈克医疗电子有限公司 | Data processing method and device |
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| CN112903793B (en) * | 2021-01-21 | 2022-04-19 | 中国科学技术大学 | Multi-parameter rapid detection device and method for water body |
| CN115656134B (en) * | 2022-12-23 | 2023-04-11 | 深圳市合川医疗科技有限公司 | Cell detection method, cell detection equipment, storage medium and cell detection device based on microfluidic chip |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330151A (en) * | 2001-06-20 | 2002-01-09 | 朱纪军 | Flow-type cell instrument based on microflow control technique |
| CN101726585A (en) * | 2009-11-30 | 2010-06-09 | 宁波普赛微流科技有限公司 | Flow cytometry based on microfluidic chip |
| CN104195028A (en) * | 2014-08-05 | 2014-12-10 | 深圳先进技术研究院 | Microfluidic chip and cell screening method for screening specific cells |
| CN104726331A (en) * | 2015-03-27 | 2015-06-24 | 西安交通大学 | Acoustic surface wave based microfluidic plasma separating chip and method |
| CN104830664A (en) * | 2015-05-07 | 2015-08-12 | 清华大学 | Microfluid cell sorting system driven by external piezoelectric ceramic |
| CN204874484U (en) * | 2015-04-20 | 2015-12-16 | 南京康芯微健康科技有限公司 | Rare cell automation equipment of catching |
| CN105950469A (en) * | 2016-06-08 | 2016-09-21 | 牛海涛 | Cell screening chip and microfluidic combined chip |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5382852B2 (en) * | 2009-02-06 | 2014-01-08 | 株式会社オンチップ・バイオテクノロジーズ | Disposable chip type flow cell and flow cytometer using the same |
| US8956536B2 (en) * | 2012-10-26 | 2015-02-17 | Becton, Dickinson And Company | Devices and methods for manipulating components in a fluid sample |
-
2017
- 2017-08-23 CN CN201710730952.2A patent/CN107505249B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330151A (en) * | 2001-06-20 | 2002-01-09 | 朱纪军 | Flow-type cell instrument based on microflow control technique |
| CN101726585A (en) * | 2009-11-30 | 2010-06-09 | 宁波普赛微流科技有限公司 | Flow cytometry based on microfluidic chip |
| CN104195028A (en) * | 2014-08-05 | 2014-12-10 | 深圳先进技术研究院 | Microfluidic chip and cell screening method for screening specific cells |
| CN104726331A (en) * | 2015-03-27 | 2015-06-24 | 西安交通大学 | Acoustic surface wave based microfluidic plasma separating chip and method |
| CN204874484U (en) * | 2015-04-20 | 2015-12-16 | 南京康芯微健康科技有限公司 | Rare cell automation equipment of catching |
| CN104830664A (en) * | 2015-05-07 | 2015-08-12 | 清华大学 | Microfluid cell sorting system driven by external piezoelectric ceramic |
| CN105950469A (en) * | 2016-06-08 | 2016-09-21 | 牛海涛 | Cell screening chip and microfluidic combined chip |
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