CN112226334A - Digital PCR cell separation chip and preparation method thereof - Google Patents
Digital PCR cell separation chip and preparation method thereof Download PDFInfo
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- CN112226334A CN112226334A CN202011125224.7A CN202011125224A CN112226334A CN 112226334 A CN112226334 A CN 112226334A CN 202011125224 A CN202011125224 A CN 202011125224A CN 112226334 A CN112226334 A CN 112226334A
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- 238000000926 separation method Methods 0.000 title claims abstract description 29
- 238000007847 digital PCR Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 29
- 239000010703 silicon Substances 0.000 claims abstract description 29
- 239000000758 substrate Substances 0.000 claims abstract description 29
- 238000004381 surface treatment Methods 0.000 claims abstract 2
- 239000012528 membrane Substances 0.000 claims description 11
- 230000002209 hydrophobic effect Effects 0.000 claims description 9
- 238000000576 coating method Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000011248 coating agent Substances 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 230000005660 hydrophilic surface Effects 0.000 claims description 2
- 238000000206 photolithography Methods 0.000 claims 2
- 238000000605 extraction Methods 0.000 abstract description 15
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 238000005530 etching Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 102
- 239000007788 liquid Substances 0.000 description 5
- 230000009471 action Effects 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 238000001259 photo etching Methods 0.000 description 3
- 238000003892 spreading Methods 0.000 description 3
- 230000007480 spreading Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005489 elastic deformation Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000003701 histiocyte Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000003698 laser cutting Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
- C12M23/04—Flat or tray type, drawers
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
- C12M33/04—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by injection or suction, e.g. using pipettes, syringes, needles
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Genetics & Genomics (AREA)
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Abstract
The invention discloses a digital PCR cell separation chip and a preparation method thereof, wherein the main body structure of the chip is a silicon substrate, a solution film forming area and an edge area are arranged on the silicon substrate, the edge area is positioned at the periphery of the solution film forming area, the solution film forming area is recessed in the silicon substrate, a cell groove is arranged in the solution film forming area, and the cell groove is composed of a plurality of cell anchor grooves which are closely distributed. The chip is prepared by etching and surface treatment of a silicon substrate, and the chip with the structure can accurately position the marked cells, thereby being beneficial to realizing accurate extraction of the marked cells and obtaining high-purity cell extracting solution.
Description
Technical Field
The invention relates to a biomedical detection device, in particular to a digital PCR cell separation chip and a preparation method thereof.
Background
At present, the extraction of the calibrated histiocyte is mostly carried out by adopting a laser cutting method, namely, the histiocyte is coated on a glass slide at first, then a cell membrane layer is dried, and finally, a required calibration target is cut by utilizing laser. The cell extract obtained by the method has a lot of impurities, and living cells are damaged in the process of roasting cell membranes, so that a cell separation device which can accurately display the calibrated target cells to facilitate the extraction of the target cells is required to be developed, thereby improving the purity of the cell extract.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a digital PCR cell separation chip and a preparation method thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is that the digital PCR cell separation chip is characterized in that the main body structure of the chip is a silicon substrate, a solution membrane forming area and an edge area are arranged on the silicon substrate, the edge area continuously surrounds the solution membrane forming area, the solution membrane forming area is inwards concave in the silicon substrate, a cell groove is arranged in the solution membrane forming area, and the cell groove is composed of a plurality of cell anchor grooves which are closely distributed.
In an embodiment of the present invention, the solution film forming region is subjected to a hydrophilic treatment, and the edge region is subjected to a hydrophobic treatment.
In one embodiment of the present invention, each surface of the cell anchor groove is coated with a hydrophilic coating. The solution film forming region is coated with a hydrophilic coating, and the edge region is coated with a hydrophobic coating.
In an embodiment of the present invention, the thickness of the silicon substrate in the solution film formation region is smaller than the thickness of the silicon substrate at the edge region.
In an embodiment of the invention, the silicon substrate is a flat-surfaced sheet, and the depth of the solution film forming region recessed in the silicon substrate is smaller than the thickness of a single cell membrane.
In one embodiment of the present invention, the cell anchor groove is hexagonal, pentagonal, quadrangular or circular.
In one embodiment of the present invention, the cell anchor grooves are arranged in a honeycomb structure.
In one embodiment of the present invention, the depth of the cell anchor groove is 2-15 μm.
In one embodiment of the present invention, the diameter of the inscribed circle of the cell anchor groove is 5-10 μm.
A method for preparing the digital PCR cell separation chip includes such steps as hydrophobic treating the surface of silicon substrate, photoetching to form an internal concave region, photoetching to form several closely arranged cell anchor slots, and hydrophilic surface treating.
The technical scheme has the following beneficial effects:
the cell anchor grooves which are closely arranged are etched in the solution film forming area of the silicon substrate, the hydrophilic treatment is carried out on the solution film forming area, and the hydrophobic treatment is carried out on the edge area outside the solution film forming area, so that the dropped cell solution can be automatically spread into a single cell liquid film in the solution film forming area, and the cells in the tiled cell solution film are spread into the single cell anchor groove, thereby realizing the fixation of the single cell, the specific position of the marked cell can be clearly displayed, further, the positioning of the marked cell can be accurately realized under the action of a fluorescence system, and the accurate extraction of the marked cell can be realized.
Drawings
FIG. 1 is a schematic structural view of a cell separation lance head according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of a cell separation chip according to an embodiment of the present invention;
FIG. 3 is an enlarged view of the invention at A in FIG. 2;
FIG. 4 is a schematic cross-sectional view of a cell separation chip according to an embodiment of the present invention;
fig. 5 is an enlarged view of the invention at B in fig. 4.
Description of reference numerals: the device comprises a fixed frame 1, a pressure pipe 2, a capillary 3, a pipe sleeve 4, a pressure elastic sheet 5, a convex pressure head 6, a screw 7, a silicon substrate 8, a solution film forming area 81, an edge area 82, a cell anchor groove 9 and a pressure cavity 10.
Detailed Description
The invention will now be further described with reference to the following examples and figures 1 to 5.
The cell extraction system comprises a hardware device, a digital PCR cell separation chip (hereinafter referred to as a cell separation chip or a chip), a digital PCR cell separation gun head (hereinafter referred to as a cell separation gun head or a gun head), and a control system, wherein the control system is used for controlling the gun head to be positioned to a target cell and extracting the target cell through the gun head. The specific method for extracting the single cell comprises the following steps: firstly, dripping a cell solution with labeled cells onto a cell separation chip, and automatically spreading the cell solution on the cell separation chip to form a solution film; and then positioning the target cells in a fluorescence system, and finally, operating the cell separation gun head to a specific position to suck the target cells under the control of the control system. The extraction method improves the purity of the cell extract, and is more beneficial to subsequent detection and analysis.
As shown in fig. 1, the cell separation gun head comprises a fixed frame 1, a pressure tube 2, a capillary tube 3, a tube sleeve 4 and a pressure mechanism, wherein the pressure tube 2, the capillary tube 3 and the tube sleeve 4 are connected together and fixed on the fixed frame 1, and the pressure mechanism is also installed on the fixed frame 1.
One end of the pressure pipe 2 is open, the other end is closed, and the open end of the pressure pipe 2 is sleeved with a sealing pipe sleeve 4, so that a pressure cavity 10 is formed between the sealing pipe sleeve 4 and the pressure pipe 2. The sleeve 4 is a deformable material having sealing performance, and thus the pressure chamber 10 is changed in volume by deformation of the sleeve. Under the action of external force, the pipe sleeve 4 deforms, the volume of the pressure chamber 10 becomes smaller, namely, air in the pressure chamber 10 is extruded out partially; when the external force disappears, the elastic deformation of the sleeve 4 disappears and the volume of the pressure chamber 10 returns to the original size. In this embodiment, the pipe sleeve 4 is a silica gel sealing ring.
The other end of pressure pipe 2 is sealed to be installed a capillary 3, capillary 3 is a superfine both ends open-ended pipe, capillary 3 with pressure pipe 2 inside hollow portion is linked together, promptly the one end of capillary 3 with pressure chamber 10 is linked together, and both constitute the linker. It can be further understood that when the pressure chamber 10 is squeezed, air in the pressure chamber 10 is discharged through the capillary tube 3, and when the external force disappears, the pressure chamber 10 returns to the initial state, and at this time, the air pressure in the pressure chamber 10 is lower than the atmospheric pressure, and the atmospheric pressure presses the cells at the tube opening of the capillary tube 3 into the capillary tube 3, in other words, when the external force disappears, the gun head sucks the target cells into the capillary tube 3, thereby realizing the extraction of the target labeled cells.
What deforms the sleeve 4 is the pressure means. The pressure mechanism comprises a pressure frame and a convex pressure head 6, the convex pressure head 6 is fixedly connected with the pressure frame, and one end of the pressure frame is fixedly arranged on the fixed frame 1 through a screw 7. The pressing frame is a pressure spring piece 55, and the pressure spring piece 5 can automatically rebound when the external force disappears. The convex pressure head 6 is arranged at the other end of the pressure spring piece 5. The convex pressure head 6 is arranged above the pipe sleeve 4, and the pipe sleeve 4 can be deformed by applying pressure to the pipe sleeve 4 through the convex pressure head 6, so that the pressure cavity 10 positioned below the pipe sleeve 4 is extruded. The control system controls external force to be applied to the pressure spring piece 5, the pressure spring piece 5 deforms to enable the convex pressure head 6 to abut against the pipe sleeve 4, the external force is transmitted to the pipe sleeve 4 through the convex pressure head 6, the pipe sleeve 4 is extruded to deform, and therefore air in the pressure cavity 10 is discharged.
The end of the male crimp 6 intended to contact the socket 4 is rounded so that the pinch damage to the socket 4 can be minimized. By controlling the degree of depression of the ram 6, the amount of deformation of the sleeve 4 can be controlled, and thus the amount of air discharged from the pressure chamber 10 can be controlled, as desired. The part of the pressure spring 5 close to the pipe sleeve 4 is positioned above the pipe sleeve 4 in parallel to form a cantilever, and the downward bending angle of the cantilever is different according to the external pressure, so that the deformation of the pipe sleeve 4 is different. In this implementation, the circular arc end of the protruding pressure head 6 with the mouth of pipe of pressure pipe 2 cooperatees, under the effect of outside pressure, pressure shell fragment 5 bends down, and protruding pressure head 6 just in time presses on the pipe box 4 of 2 openings of pressure pipe, thereby makes pipe box 4 realizes elastic deformation smoothly, and after outside pressure disappeared, pressure shell fragment 5 lifted, and pipe box 4 reverted original shape. In this embodiment, the pressure spring 5 is provided with the arc-shaped bend, and the arc-shaped bend improves the service performance of the pressure spring 5 in order to reduce the internal stress of the pressure spring 5 in the process of bending downwards and springing upwards.
The external force applied to the pipe sleeve 4 is controlled by a control system, and the air pressure in the pressure cavity 10 is changed through the cooperation between the pressure mechanism and the pipe sleeve 4, so that an air pressure difference is formed between the inside and the outside of the pressure cavity 10, and the cell liquid at the pipe orifice of the capillary 3 is sucked into the capillary 3 when the external force is eliminated. The specific implementation manner for changing the pressure inside and outside the pressure chamber 10 is as follows: the tube sleeve 4, the cavity wall of the pressure cavity 10, is extruded by external force, the cavity wall is deformed, part of air in the pressure cavity 10 is extruded, then the external force is released, when the external force disappears, the deformation of the cavity wall disappears, the pressure cavity 10 recovers to the original state, at the moment, the air pressure in the pressure cavity 10 becomes lower than the atmospheric pressure, the target cell fluid at the orifice of the capillary tube 3 is pressed into the capillary tube 3 by the atmospheric pressure, and the extraction of single target cell is realized.
The pressure tube 2 and the capillary tube 3 are made of stainless steel or quartz, and the inner diameter of the capillary tube 3 is 1-50 mu m. In order to avoid the phenomenon of siphoning when the target cell sap is sucked, the inner and outer surfaces of the capillary 3 need to be subjected to hydrophobic treatment, specifically, the inner and outer surfaces of the capillary 3 can be coated with hydrophobic coatings, so that the siphoning phenomenon is eliminated, and under the condition of pressure difference between the inside and the outside of the capillary 3, only cell substances pointed by the pipe orifice of the capillary 3 are allowed to be sucked into the capillary 3, namely, other substances except for the labeled cells are sucked as little as possible.
When the gun head is used for extracting the single marked cells paved on the chip, the adopted principle is as follows: the external pressure presses the tube sleeve 4, thereby squeezing out a part of the air in the pressure chamber 10; with the disappearance of the external pressure, the deformation of the tube sleeve 4 disappears, at this time, the air pressure in the pressure chamber 10 is smaller than the atmospheric pressure, and the target cell at the orifice of the capillary tube 3 is sucked into the capillary tube 3 by the difference between the internal air pressure and the external air pressure.
The way to achieve "as little as possible uptake of other substances than labeled cells" is by special design of the structure of the chip. The specific structure of the chip is shown in fig. 2-5, the main structure of the chip is a silicon substrate 8, a solution film forming region 81 and a margin region 82 are arranged on the silicon substrate 8, and the margin region 82 continuously surrounds the solution film forming region 81. The solution film forming region 81 is recessed in the silicon substrate 8, that is, the solution film forming region 81 is a recessed region formed by photo-etching on the silicon substrate 8 with a flat surface, and the recessed depth is smaller than the thickness of a single cell membrane. The solution film forming region 81 is photo-etched with a cell groove, and the cell groove is composed of a plurality of cell anchor grooves 9 which are closely arranged. The solution-film forming region 81 is subjected to hydrophilic treatment, i.e., each surface of the cell anchor groove 9 located in the solution-film forming region 81 is coated with a hydrophilic coating. The edge region 82 is coated with a hydrophobic coating to ensure that the cell solution dropped on the chip is spread only in the solution film forming region 81.
The cell anchor groove 9 is a hexagonal or pentagonal or quadrangular or circular groove. In this embodiment, the cell anchor grooves 9 are arranged in a honeycomb structure, and this arrangement can better spread the cell solution from the fluid mechanics angle, and can better fix the single cell after spreading, and the cell in the cell solution membrane after spreading is spread into the single cell anchor groove, thereby being more beneficial to the suction of the gun head. In this embodiment, the depth of the cell anchor groove 9 is 2-15 μm, preferably 2-5 μm, so as to avoid overlapping of multiple cells after the membrane in the unfolded cell liquid membrane is too thick, which is not beneficial to the extraction of single labeled cell. The diameter of the inscribed circle of the cell anchor groove 9 is 2-10 mu m, which is convenient for better realizing the fixation of each cell after being spread.
When the chip is prepared, the silicon substrate 8 with regular shape and smooth surface is selected to be firstly subjected to surface hydrophobic treatment, a shallow groove is etched on the silicon substrate 8 and is a solution film forming area 81, and annular steps are arranged around the shallow groove, so that the cell solution dropped into the shallow groove is prevented from overflowing the area; then, the cell anchor grooves 9 with a certain depth are photo-etched in the shallow grooves in a close arrangement, and finally, the solution film forming region 81 is subjected to hydrophilic treatment, so that each surface of the cell anchor grooves 9 is coated with a hydrophilic coating.
When single cell extraction is carried out by utilizing the cooperation of the gun head and the chip, the specific method comprises the following steps:
step 1: delivering a certain amount of cell solution after fluorescent labeling to the solution film forming area 81, wherein the cell solution can be diffused into a layer of cell liquid film under the action of surface tension and evenly and flatly paved on the solution film forming area 81, and cells contained in the cell liquid film can be respectively fixed in each cell anchor groove 9;
step 2: the marked cells in the fluorescence system emit fluorescence to realize the positioning of the marked cells;
and step 3: the control system controls the gun head to move to a target position on the chip, the orifice of the capillary 3 of the gun head is aligned with the marked cell, a certain external force is applied to the pressure spring 5 through the control system, the pressure spring 5 is pressed down onto the pipe sleeve 4, and the pipe sleeve 4 deforms, so that part of air in the pressure cavity 10 is extruded out through the orifice of the capillary 3; then, the external force is cancelled, and the marked cells at the opening of the capillary 3 are sucked into the capillary 3;
and 4, step 4: moving the gun head away from the chip under the control of the control system, and releasing the cells sucked into the capillary 3 into the collection container;
and 5: and (4) repeating the steps 1-4 until all target marker cells on the chip are extracted.
By adopting the extraction equipment and the extraction method, the activity of cells cannot be influenced in the whole extraction process, meanwhile, the precise extraction of the marked cells is realized through the specific design of the chip and the structure of the gun head, the automatic extraction of the single marked cell is realized under the action of a control system, and the obtained cell extracting solution has fewer impurities and higher purity.
The above-described embodiments are intended to illustrate rather than to limit the invention, and any changes and alterations made without inventive step within the spirit and scope of the claims are intended to fall within the scope of the invention.
Claims (10)
1. The utility model provides a digital PCR cell separation chip, its characterized in that, the major structure of chip is a silicon substrate, be equipped with solution membrane formation district and marginal zone on the silicon substrate, marginal zone centers on in succession around solution membrane formation district, solution membrane formation district indent in the silicon substrate, solution membrane formation district is equipped with the cell recess, the cell recess comprises the cell anchor groove that a plurality of closely arranged.
2. The digital PCR cell separation chip according to claim 1, wherein the solution film forming region is subjected to a hydrophilic treatment, and the edge region is subjected to a hydrophobic treatment.
3. The digital PCR cell separation chip of claim 2, wherein each surface of the cell anchor groove is coated with a hydrophilic coating.
4. The digital PCR cell separation chip according to claim 1, wherein the thickness of the silicon substrate of the solution film forming region is smaller than the thickness of the silicon substrate at the edge region.
5. The digital PCR cell separation chip of claim 1, wherein the silicon substrate is a flat-surfaced sheet, and the depth of the solution film forming region recessed into the silicon substrate is less than the thickness of a single cell film.
6. The digital PCR cell separation chip of claim 1, wherein the cell anchor groove is hexagonal, pentagonal, quadrangular or circular.
7. The digital PCR cell separation chip of claim 5, wherein the cell anchor grooves are arranged in a honeycomb structure.
8. The digital PCR cell separation chip according to any one of claims 1 to 6, wherein the depth of the cell anchor groove is 2 to 15 μm.
9. The digital PCR cell separation chip of claim 7, wherein the diameter of the inscribed circle of the cell anchor groove is 2-10 μm.
10. The method for preparing a digital PCR cell separation chip according to any one of claims 1 to 8, wherein the surface of the silicon substrate is cleaned, an inner concave region is formed on the silicon substrate by photolithography, a plurality of cell anchor grooves are formed in the inner concave region by photolithography, and the cell anchor grooves are subjected to hydrophilic surface treatment.
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| CN202011125224.7A CN112226334A (en) | 2020-10-20 | 2020-10-20 | Digital PCR cell separation chip and preparation method thereof |
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| CN202011125224.7A CN112226334A (en) | 2020-10-20 | 2020-10-20 | Digital PCR cell separation chip and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113073029A (en) * | 2021-03-17 | 2021-07-06 | 长春长光辰英生物科学仪器有限公司 | Infiltration modified cell sorting chip for laser induced transfer and sorting method |
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2020
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Application publication date: 20210115 |