CN105400679B - A kind of micro flow control chip device for cell separation - Google Patents
A kind of micro flow control chip device for cell separation Download PDFInfo
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- CN105400679B CN105400679B CN201410457958.3A CN201410457958A CN105400679B CN 105400679 B CN105400679 B CN 105400679B CN 201410457958 A CN201410457958 A CN 201410457958A CN 105400679 B CN105400679 B CN 105400679B
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- flow control
- microfluidic channel
- micro flow
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- 238000000926 separation method Methods 0.000 title claims abstract description 30
- 239000012530 fluid Substances 0.000 claims abstract description 38
- 239000007788 liquid Substances 0.000 claims abstract description 26
- 229920002120 photoresistant polymer Polymers 0.000 claims description 7
- 229920005439 Perspex® Polymers 0.000 claims description 4
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 11
- 238000005119 centrifugation Methods 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 31
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 230000001605 fetal effect Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 5
- 210000003754 fetus Anatomy 0.000 description 5
- 210000003924 normoblast Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000003793 prenatal diagnosis Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000013024 dilution buffer Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000010147 laser engraving Methods 0.000 description 2
- 230000008774 maternal effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 108010044495 Fetal Hemoglobin Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000001691 amnion Anatomy 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
Landscapes
- Centrifugal Separators (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
Abstract
The invention discloses a kind of micro flow control chip device for cell separation.It includes centrifugal rotor, chip structure and chip lid；Centrifugal rotor is provided with least one chip standing groove and at least two liquid storage tanks；Liquid storage tank is connected by passage with the through hole set on chip standing groove；Chip structure includes the filter screen for pasting incorporated two panels chip and being arranged in two panels chip, inner side chip is provided with the fluid intake being connected with microfluidic channel, outside chip is provided with fluid issuing A and fluid issuing B, fluid issuing A is connected with the microfluidic channel on the chip of inner side, and fluid issuing B is connected with the microfluidic channel on the chip of outside；Chip structure is fixed in chip standing groove by chip lid；Fluid intake is connected by through hole with liquid storage tank, and the outlet that fluid issuing A and fluid issuing B cover setting with chip respectively is connected.The method of centrifugation can be used for the micro flow control chip device of cell separation by the present invention, separates cell with the mode of double-layer chip plus filter screen, has the advantages that cheap and easy operation.
Description
Technical field
The present invention relates to a kind of micro flow control chip device for cell separation, belong to micro-fluidic field.
Background technology
Fetal nucleated red blood (fetal nucleated red blood cell, FNRBC) is among maternal blood
The red blood cell of the fetal origin of presence.Compared with the cell of other fetal origins present in maternal blood, FNRBC possesses
Complete Fetal genome, there are a variety of Specific markers to be easy to separate, easily recognized by form or fetal hemoglobin,
Gestation is persistently present, one month postpartum excluded last time pregnant influence from parent disappearance, so, FNRBC can be more preferably
Ground is used in pre-natal diagnosis, so that it is determined that the health status of fetus.With traditional methods for prenatal diagnosis such as fine hair biopsy, amnion
Chamber centesis, percutaneous Umbilical blood art etc. are compared, and using FNRBC diagnose only need to take a small amount of peripheral blood from pregnant woman, and this is
A kind of detection method of Noninvasive, can avoid the complication such as infection, the miscarriage of conventional method, can reduce to greatest extent pair
Pregnant woman and the harmful effect of fetus, so being a kind of methods for prenatal diagnosis for having very much an application value.But, FNRBC is in pregnant woman
Only more than ten in negligible amounts in blood, usual every milliliter of blood.So separation is very difficult.
At present, FNRBC detection will pass through density-gradient centrifugation method, Fluorescence-activated cell sorting, magnetic field active cell
Separating method, micromanipulation partition method or selecting cell cultivation etc. are first enriched with to be analyzed again.The operation of these methods is numerous
It is trivial, easily error, it is difficult in clinical application.Accordingly, it is desirable to provide a kind of cost is low, simple operation, reaction are fast, integrated level
High cell separation apparatus.
The content of the invention
It is an object of the invention to provide a kind of micro flow control chip device for cell separation, available for cell separation and after
Continuous immunoassay, its simple in construction, simple operation is high relative to traditional cell separation technology automaticity, good reliability.
Micro flow control chip device provided by the present invention for cell separation, including centrifugal rotor, chip structure and core
Piece lid；
The centrifugal rotor is provided with least one chip standing groove and at least two liquid storage tanks；The liquid storage tank passes through logical
Road is connected with the through hole set on the chip standing groove；
The chip structure includes the filter screen for pasting incorporated two panels chip and being arranged in two panels chip, a piece of described
Chip is designated as inner side chip, and another chip is designated as outside chip, miniflow is equipped with the binding face of chip described in two panels
Body passage；The inner side chip is provided with the fluid intake being connected with the microfluidic channel, and the outside chip is provided with
An one fluid issuing A and fluid issuing B, the fluid issuing A is connected with the microfluidic channel on the inner side chip, described
Fluid issuing B is connected with the microfluidic channel on the outside chip；
The chip structure is fixed in the chip standing groove by the chip lid；The fluid intake passes through institute
State through hole with the liquid storage tank to be connected, the fluid issuing A and the fluid issuing B cover setting with the chip respectively
Outlet is connected.
In above-mentioned micro flow control chip device, the centrifugal rotor is placed provided with several symmetrically arranged described chips
Groove；
Each chip standing groove side sets two liquid storage tanks.
In above-mentioned micro flow control chip device, the centrifugal rotor is placed provided with two symmetrically arranged chips
Groove.
In above-mentioned micro flow control chip device, the chip is perspex layer, and the microfluidic channel set thereon can lead to
The mode for crossing laser engraving is obtained；
The filter screen is photoresist dry film, and micropore thereon can be set according to specific needs；
The depth of the microfluidic channel is 100~1000 μm.
In above-mentioned micro flow control chip device, the shape of the microfluidic channel described in two panels on chip is identical, so that
The fluid passage of insertion is formed when two panels perspex layer mutually fits.
In above-mentioned micro flow control chip device, it is connected through a screw thread and the chip lid and the chip structure is fixed on institute
State in chip standing groove, i.e., through hole is set in the position corresponding position of the chip lid and the chip structure, and in the chip
Position corresponding position on standing groove is threaded hole, the chip lid and chip structure can be just fixed on by screw described
On centrifugal rotor.
In above-mentioned micro flow control chip device, the outlet that the chip covers setting is groove-like, and it can be connected accordingly
The centrifuge tube of capacity can receive the liquid of outflow, and rubber washer can be set on groove, to strengthen sealing.
When the present invention works for the micro flow control chip device of cell separation, the centrifugal rotor is fixed on centrifuge
On, liquid is injected in the liquid storage tank, flows through the chip structure, and the outlet for covering setting from the chip flows into centrifuge tube
In.During using the present invention, using centrifugal force as driving force, make filter screen described in the small cell permeable of diameter from the chip of outside
The fluid issuing B outflows, and the big cell of diameter can not then pass through the filter screen, from the fluid issuing on the chip of outside
A flows out, so as to realize the purpose of cell separation.
The invention provides a kind of new mode filtered using continuous flow centrifugation come isolating fetal erythroblast
Device.The core of the device is micro-fluidic chip.Microfluidic chip technology is to utilize micro-machined method, biological, chemistry, doctor
The basic operations such as sample preparation, reaction, separation, the detection of credit analysis process are integrated on the chip of one piece of micro-meter scale, are had
Cost is low, simple operation, the advantages of reaction is fast, integrated level is high.General micro-fluidic chip is in the plane by fluid
Manipulate to realize purpose.And sensu lato micro-fluidic chip there can be three-dimensional structure, different microchannels is used in different layers
Structure, for realizing that cell separation can provide broader thinking.
The present invention is used for the micro flow control chip device of cell separation, the method for centrifugation can be used, with double-layer chip plus filter screen
Mode separate cell, there is cheap and easy operation；Meanwhile, apparatus of the present invention eliminate many behaviour by hand
Make, it is easy to integrated with subsequent biochemical detection chip.The present invention is to promoting the facilitation of cell separation and detection, further genralrlization should
Apparatus is of great significance.
Brief description of the drawings
Side views of the Fig. 1 for the present invention for the micro flow control chip device of cell separation.
Schematic diagrames of the Fig. 2 for the present invention for the micro flow control chip device chips lid of cell separation.
Schematic diagrames of the Fig. 3 for the present invention for centrifugal rotor in the micro flow control chip device of cell separation.
Schematic diagrames of the Fig. 4 for the present invention for the micro flow control chip device SMIS chip architecture of cell separation.
Fig. 5 flows to schematic diagram for the present invention for the liquid in the micro flow control chip device of cell separation.
Microfluidic channel schematic diagrames of the Fig. 6 for the present invention in the micro flow control chip device chips of cell separation.
Profiles of the Fig. 7 for the present invention for the micro flow control chip device SMIS chip architecture of cell separation.
Each mark is as follows in figure：
1 centrifugal rotor, 2 chip structures, 3 chip lids, 4 chip standing grooves, 5 liquid storage tanks, 6 inner side chips, 7 outside chips, 8
Photoresist dry film, 9 fluid intakes, 10 fluid issuing A, 11 fluid issuing B, 12 through holes, 13 screwed holes, 14 outlets.
Embodiment
The present invention will be further described below in conjunction with the accompanying drawings, but the invention is not limited in following examples.
As shown in figure 1, being used for the micro flow control chip device of cell separation for the present invention, it includes centrifugal rotor 1, chip knot
Structure 2 and chip lid 3.In the present invention, as shown in figure 3, centrifugal rotor 1 is provided with 2 symmetrical chip standing grooves 4, each chip
The side of standing groove 4 sets 2 liquid storage tanks 5, and each liquid storage tank 5 is connected by passage with the through hole set on chip standing groove 4.
As shown in figs. 4 and 7, the chip structure 2 in the present invention includes pasting the He of inner side chip 6 of incorporated perspex layer material
Outside chip 7, and the photoresist dry film 8 being arranged between inner side chip 6 and outside 7, inner side chip 6 and outside chip 7
Thickness is to be carved on 2mm, inner side chip 6 and outside chip 7 by way of laser engraving as microfluidic channel, its shape phase
Together, as shown in fig. 6, depth is 100~1000 μm；The thickness of photoresist dry film 8 is 100 μm in the present invention, through overexposure and
It is about 10 microns that diameter is formed with after development operation, and spacing is 20 microns of microwell array.As shown in fig. 6, being set on inner side chip 6
There is the fluid intake 9 being connected with microfluidic channel, outside chip 7 is provided with and communicated with the microfluidic channel on inner side chip 6
Fluid issuing A10 and the fluid issuing B11 that is connected with the microfluidic channel on outside chip 7.The present invention passes through chip lid 3
Chip structure 2 is fixed in chip standing groove 4, connected particular by following manner：Chip lid 3 and chip structure 2
Position corresponding position sets through hole 12, as shown in Figure 2 and Figure 6, and the position corresponding position on chip standing groove 4 is threaded hole
13, chip lid 3 and chip structure 2 can be just fixed on by screw on centrifugal rotor 1.Chip structure 2 is connected to core
After on piece standing groove 4, the fluid intake 9 on the chip 6 of inner side is set to be connected with liquid storage tank 5, fluid issuing A10 and fluid issuing
B11 is connected with the outlet 14 set on chip lid 3 respectively, and outlet 14 is arranged into groove-like, and it can connect corresponding appearance
The centrifuge tube of amount can receive the liquid of outflow, and rubber washer can be set on groove, to strengthen sealing.
During using above-mentioned micro flow control chip device isolating fetal erythroblast, it is connected with a chip standing groove 4
2 liquid storage tanks 5 in be separately added into fetus whole blood dilution and phosphate buffer for centrifugation, symmetrical liquid storage tank 5
In be also separately added into fetus whole blood dilution and phosphate buffer, then chip structure is loaded on centrifugal rotor, and in chip
The exit of lid 3 connects centrifuge tube.Centrifugal rotor is fixed on after centrifuge rotating shaft, carried out under 1000 revs/min of rotating speed from
The heart, now the liquid in liquid storage tank 5 under the action of the centrifugal by interface channel enter chip structure 2 in.Wherein, fetus whole blood is dilute
Release liquid to enter close to centrifugal rotor passage, phosphate buffer enters outer passage.Originally, two strands of liquid are in photoresist dry film 8
It can not be contacted under separation, but under the influence of centrifugal force, cell flows close to photoresist dry film 8, when the ground for flowing to micropore
Fang Shi, the cell being relatively large in diameter (such as leucocyte, erythroblast) will be stopped continues on inner channel flowing, finally from
The left side outlet fluid issuing A10 outflows of outside chip 7.And the less cell of diameter can just enter the logical of outside by micropore
The last right-side outlet fluid issuing B11 outflows from the lower section of outside chip 7 in road.Finally by the fetal nucleated red blood of screening
And the larger cell of leucocyte equal diameter needs further to screen by modes such as fluorescence labelings and obtains erythroblast.
The present invention is simple in construction for the micro flow control chip device of cell separation, with cheap, easy to process and
The advantages of operation.Meanwhile, the present invention also can be used in circulating tumor cell initial stage for the micro flow control chip device of cell separation
Separation etc., to promoting micro-total analysis system to be of great significance in biologic medical context of detection tool.
Claims (4)
1. the micro flow control chip device for cell separation, it is characterised in that：It includes centrifugal rotor, chip structure and chip
Lid；
The centrifugal rotor is provided with least one chip standing groove and at least two liquid storage tanks；The liquid storage tank by passage with
The through hole set on the chip standing groove is connected；
The chip structure includes the filter screen for pasting incorporated two panels chip and being arranged in two panels chip, chip described in two panels
Binding face on be equipped with microfluidic channel；The a piece of chip is designated as inner side chip, and another chip is designated as outboard wick
Piece, the inner side chip is provided with the fluid intake being connected with the microfluidic channel, and the outside chip is provided with one stream
Body exports A and a fluid issuing B, and the fluid issuing A is connected with the microfluidic channel on the inner side chip, the fluid
Outlet B is connected with the microfluidic channel on the outside chip；
The chip structure is fixed in the chip standing groove by the chip lid；The fluid intake passes through described logical
Hole is connected with the liquid storage tank, and the fluid issuing A and the fluid issuing B cover the outlet of setting with the chip respectively
It is connected；
The chip is perspex layer；
The filter screen is photoresist dry film；
The depth of the microfluidic channel is 100 ~ 1000 μm；
The shape of microfluidic channel described in two panels on chip is identical；
It is connected through a screw thread and the chip lid and the chip structure is fixed in the chip standing groove.
2. micro flow control chip device according to claim 1, it is characterised in that：The centrifugal rotor is right provided with several
Claim the chip standing groove set；
Each chip standing groove side sets two liquid storage tanks.
3. micro flow control chip device according to claim 2, it is characterised in that：The centrifugal rotor is symmetrical provided with two
The chip standing groove set.
4. micro flow control chip device according to claim 3, it is characterised in that：The outlet that the chip covers setting is recessed
Channel-shaped.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410457958.3A CN105400679B (en) | 2014-09-10 | 2014-09-10 | A kind of micro flow control chip device for cell separation |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410457958.3A CN105400679B (en) | 2014-09-10 | 2014-09-10 | A kind of micro flow control chip device for cell separation |
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| CN105400679A CN105400679A (en) | 2016-03-16 |
| CN105400679B true CN105400679B (en) | 2017-10-31 |
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| CN113005186B (en) * | 2019-12-20 | 2023-07-21 | 苏州昊通仪器科技有限公司 | Micro total analysis chip, chip assembly and single cell sample preparation method |
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| JPH11290060A (en) * | 1998-04-06 | 1999-10-26 | Asahi Medical Co Ltd | Cell separation filter suitable for recovering cell, cell separation system and separation of cell |
| JP2006110491A (en) * | 2004-10-15 | 2006-04-27 | Ushio Inc | Centrifugal separator for microchip |
| CN102175840A (en) * | 2010-12-30 | 2011-09-07 | 北京大学 | Whole blood centrifugal separation chip and preparation method thereof |
| CN102773122A (en) * | 2012-08-06 | 2012-11-14 | 苏州汶颢芯片科技有限公司 | Centrifugal microfluidic serum separation chip and preparation method thereof |
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| CN103240187A (en) * | 2012-02-14 | 2013-08-14 | 胡文聪 | Centrifugal microfluidic disk and method for separating targets form samples |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101343034B1 (en) * | 2006-09-05 | 2013-12-18 | 삼성전자 주식회사 | Centrifugal microfluidic device for target protein detection and microfluidic system comprising the same |
| US9211512B2 (en) * | 2012-11-28 | 2015-12-15 | Samsung Electronics Co., Ltd. | Microfluidic apparatus and method of enriching target cells by using the same |
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2014
- 2014-09-10 CN CN201410457958.3A patent/CN105400679B/en active Active
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| JPH11290060A (en) * | 1998-04-06 | 1999-10-26 | Asahi Medical Co Ltd | Cell separation filter suitable for recovering cell, cell separation system and separation of cell |
| JP2006110491A (en) * | 2004-10-15 | 2006-04-27 | Ushio Inc | Centrifugal separator for microchip |
| CN102175840A (en) * | 2010-12-30 | 2011-09-07 | 北京大学 | Whole blood centrifugal separation chip and preparation method thereof |
| CN103240187A (en) * | 2012-02-14 | 2013-08-14 | 胡文聪 | Centrifugal microfluidic disk and method for separating targets form samples |
| CN102773122A (en) * | 2012-08-06 | 2012-11-14 | 苏州汶颢芯片科技有限公司 | Centrifugal microfluidic serum separation chip and preparation method thereof |
| CN103018224A (en) * | 2012-12-14 | 2013-04-03 | 中国科学院上海微系统与信息技术研究所 | Separate detection system and method of rare cells based on centrifugal micro-fluidic technology |
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| Title |
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| Centrifugal microfluidics for cell analysis;Robert Burger等;《Current Opinion in Chemical Biology》;20120709;第16卷;第409–414页 * |
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