CN108117968A - A kind of single celled method of high-throughput automatic capture based on drop micro-fluidic chip - Google Patents
A kind of single celled method of high-throughput automatic capture based on drop micro-fluidic chip Download PDFInfo
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Abstract
The present invention provides a kind of single celled methods of high-throughput automatic capture based on drop micro-fluidic chip.Chip described in the micro-fluidic chip is formed by two layers, and upper strata is flow path entrance layer；Lower floor is flow path key-course；The flow path entrance layer has liquid flow path feeder connection and liquid flow path channel outlet；The flow path key-course is made of unicellular capture flow path channel, gas channels, drop formation unit.This method introduces the controllable gas flow path passage of air pressure, can form negative pressure flow path channel and single cell suspension is sucked capture trap automatically, convenient for observing, detecting the behaviors such as single celled multiplication, differentiation and drug response.The present invention realizes single celled high-throughput automatic capture using drop microflow control technique and fluid mechanics principle, compared to traditional unicellular catching method, has many advantages, such as that easy to operate, flexible, high-throughput, pollution-free, applied widely and scalability is strong.
Description
Technical field
The invention belongs to microflow control techniques and the crossing domain of cell biology, and in particular to one kind is micro-fluidic based on drop
The single celled method of high-throughput automatic capture of chip.
Background technology
Microfluid based Lab on a chip early stage is directed to the research of chip electrophoresis, and proposes micro-total analysis system (μ-TAS)
Concept, research work is concentrated mainly on continuous flow microfluidic system.In recent years, micro-fluidic chip field occur one it is new
Branch-discontinuous flow microfluidic system, i.e. liquid drop microfluidic system.Liquid drop microfluidic system is existed using immiscible two-phase fluid
Microchannel interface forms drop, and the volume of this kind of drop is usually nanoliter to picoliters (10-9~10-12L) scope.Compared with even
Afterflow system, drop have the characteristics that small, low diffusion, no cross contamination, quick kinetics, and with high pass
Measure the potentiality of analysis.Through development in a few years, the technology of preparing of drop has reached its maturity；It is meanwhile the division of drop, fusion, mixed
The rich and varied manipulation technologies such as splitting or integrating choosing, storage and coding also have extensive report.
The biophysical properties characterization of individual cell level can effectively illustrate the function and state of cell, disclose the list of cell
Body otherness, the early clinical diagnosis of differentiation and pathological study and disease for cell and treatment have very important
Meaning has become one of hot spot of research at present.Since cell is minimum, diameter is generally 5~500 μm, and constituent content is few, species
It is various so that it is difficult to manipulate and analyze.The unicellular research of early stage, mainly using patch-clamp, cell puncture etc. technologies, together
When operated by microscope three-dimensional micromanipulator.Capillary electrophoresis separation method have sampling volume is small, separative efficiency is high,
The advantages that separating rate is fast has been used for unicellular multi-component detection, achieves some achievements.But capillary category one-dimentional structure,
Sample introduction and molten membrane operations are complicated.Though traditional flow cytometer has realized integrated and automation, equally there is equipment instrument
Greatly, the shortcomings of internal structure is complicated, fragile.
In recent years, with the rapid development of drop microflow control technique, the application in single cell analysis causes more next
More concerns.Drop can effectively control diffusion, improve detection sensitivity, successfully should as unicellular microreactor
For in a variety of single cell analysis.However, studying in microfluidic system unicellular, primarily solve the problems, such as to be how to list
Cell is captured, and to realize single celled movement, fixation etc., then just can be analyzed it and be detected.At present, developed
Go out a variety of unicellular capture techniques, driving force mainly includes Fluid pressure, electric power, magnetic force, optical trap and mechanical force
Deng.Wherein, since external electrical original paper, magnetic force control unit, optical sensor and mechanical control device are complicated, cost is inclined
Height, inconvenient extensive use.It is unicellular simple and of low cost using physical barriers capture, but it be easy to cause cellular damage and inconvenience
In loading dynamic biochemical signal stimulus.Therefore suspension can be captured for a long time there is an urgent need to one kind cultivate unicellular, reduction cell damage
Wound and the unicellular capture micro-fluidic chip convenient for adding in medicine irritation.
The present invention realizes single celled high-throughput automatic capture using drop microflow control technique and hydrodynamics, by core
Piece channel interior forms negative pressure, and single cell suspension is automatically drawn into unicellular capture flow path channel, after unicellular capture trap,
It is unicellular to be retained in the drop of generation, realize unicellular automatic capture；By adjusting single cell suspension flow velocity and unicellular outstanding
The unicellular capture rate of liquid density domination.Whole device is simple in structure, without any complicated and expensive equipment, it can be achieved that high pass
Amount, easy to operate automation.Therefore, the present invention provides a kind of flexibly controllable single celled method of high-throughput automatic capture,
And it is expected to be applied in fields such as cytology, drug toxicology researchs.
The content of the invention
The object of the present invention is to provide a kind of single celled method of high-throughput automatic capture based on drop micro-fluidic chip,
Preparation process of the present invention is stablized, easy to operate, it can be achieved that quick, efficient, high throughput, automatic capture are unicellular.
A kind of drop micro-fluidic chip, the chip are formed by two layers, and upper strata is flow path entrance layer；Lower floor is flow path control
Preparative layer；
The flow path entrance layer has liquid flow path feeder connection and liquid flow path channel outlet；
The flow path key-course is by unicellular capture flow path channel, gas channels, (the unicellular capture of drop formation unit
Trap) composition；
The unicellular capture flow path channel is a long-channel being made of the U-shaped passage of multiple interactive connection, long logical
Road both ends connect liquid flow path feeder connection and liquid flow path channel outlet respectively, and the straight channel of each U-shaped passage has therewith
Parallel gas flow path passage is each dispersed with the drop life of several cylindrical depression pitting structures in the straight channel of U-shaped passage
Into unit.
After the chip vacuumizes, gas channels are in negative pressure state, and due to the gas permeability of PDMS, gas circuit drives surrounding
Fluid path passage forms negative pressure, can automatically suck single cell suspension from fluid path feeder connection, for unicellular feed liquor and capture.
The unicellular capture flow path channel is 100~300 μm wide, a length of 40~50mm of straight channel of U-shaped passage, straight channel
Spacing is 0.5~1mm.
The gas channels width is 200~500 μm, a length of 40~50mm, and spacing is 0.5~1mm.
The unicellular capture flow path channel and gas channels spacing are 0.5~1.5mm.
The drop formation unit is cylindrical depression pitting structure, shares 6000~10000, pitting a diameter of 15~
It is 45 μm, 80~200 μm high, 80~150 μm of pitting spacing.
A kind of preparation method of drop micro-fluidic chip, the chip preparation process are as follows：
(1) the SU-8 templates of channel part protrusion are prepared using photoetching and caustic solution：The SU-8 templates are by bilayer
Structure composition, first layer are made of unicellular capture flow path channel and gas channels, and the second layer is made of drop formation unit；
The preparation of SU-8 templates by whirl coating twice, front baking, exposure, after dry after, once development, post bake obtains；
(2) the PDMS modules being made based on SU-8 templates：By PDMS and initiator with volume ratio 10：1 is uniformly mixed, and pours
It notes in SU-8 templates, 75~85 DEG C of 30~60min of curing oven, PDMS and SU-8 templates is removed, obtain on structured
Layer chip；By upper strata chip and lower layer chip sealing-in after 1~4min of corona treatment with flow path entrance.
A kind of single celled method of high-throughput automatic capture based on drop micro-fluidic chip, it is micro-fluidic using above-mentioned drop
Chip follows the steps below：
The micro-fluidic chip of above-mentioned preparation is impregnated through 60~90% ethyl alcohol, after ultraviolet irradiation 30~60min sterilization treatments,
Liquid flow path channel outlet is blocked, vacuum culture case is placed in and vacuumizes 5~10min, then, quickly by single cell suspension with 5
×103Cells/mL~5 × 106The cell density of cells/mL adds in chip entrance, and control single cell suspension flow velocity is in 0.01m/
Between s~0.05m/s, when whole drop formation units are filled with single cell suspension, liquid flow path channel outlet is opened, by liquid
Surplus liquid excludes in body flow path channel, treats that cell adherence in die bottom surface, adds fresh DMEM in high glucose culture medium, is placed in 37
DEG C incubator culture.
A kind of application of the single celled method of high-throughput automatic capture based on drop micro-fluidic chip, what is captured is slender
Born of the same parents can be in the droplet structure long term culture of chip, and can be applied to cell Proliferation, differentiation and drug screening etc..
The present invention realizes single celled high-throughput automatic capture using drop microflow control technique and fluid mechanics principle, compares
In traditional unicellular catching method, there is easy to operate, flexible, high-throughput, pollution-free, applied widely and scalability
The advantages that strong.Present invention contemplates that providing a kind of flexible controllable unicellular catching method, and ground in cytology, drug toxicology
Study carefully the fields of grade to be applied.
Description of the drawings：
Fig. 1：Chip structure schematic diagram；(a) overall structure figure, (b) are partial enlarged view；
Fig. 2：Micro-fluidic chip side partial enlarged view.
Wherein：1 be liquid flow path feeder connection, 2 be liquid flow path channel outlet, 3 be unicellular capture flow path channel, 4
It is drop formation unit (unicellular capture trap) for gas flow path passage, 5,6 be unicellular；
Fig. 3：Micro-fluidic chip pictorial diagram.
Fig. 4：Single cell suspension density is 5 × 104During cells/mL, the unicellular distribution map in chip.
Fig. 5：Single cell suspension density is 5 × 105During cells/mL, the unicellular distribution map in chip.
Specific embodiment
A kind of single celled micro-fluidic chip of high throughput automatic capture, as shown in Figure 1, Figure 2, Figure 3 shows；The chip is by two layers
Composition, upper strata are flow path entrance layer；Lower floor is flow path key-course；
The flow path entrance layer has liquid flow path feeder connection 1 and liquid flow path channel outlet 2；
The flow path key-course is by unicellular capture flow path channel 3, gas channels 4, (the unicellular capture of drop formation unit
Trap) 5 compositions；
The unicellular capture flow path channel 3 is a long-channel being made of the U-shaped passage of multiple interactive connection, long logical
Road both ends connect liquid flow path feeder connection 1 and liquid flow path channel outlet 2 respectively, the straight channel of each U-shaped passage have with
Parallel gas flow path passage 4, the drops of several cylindrical depression pitting structures is dispersed in the straight channel of each U-shaped passage
Generation unit 5.
The unicellular capture flow path channel is 100~300 μm wide, a length of 40~50mm of straight channel of U-shaped passage, straight channel
Spacing is 0.5~1mm.
The gas channels width is 200~500 μm, a length of 40~50mm, and spacing is 0.5~1mm.
The unicellular capture flow path channel and gas channels spacing are 0.5~1.5mm.
The drop formation unit is cylindrical depression pitting structure, shares 6000~10000, pitting a diameter of 15~
It is 45 μm, 80~200 μm high, 80~150 μm of pitting spacing.
After chip vacuumizes, gas flow path passage 4 is in negative pressure state, and due to the gas permeability of PDMS, gas circuit drives week
The liquid flow path passage 3 enclosed forms negative pressure, and MCF-7 single cell suspensions 6 are caught under suction function through feeder connection 1 into unicellular
Flow path channel 3 is obtained, after drop formation unit 5, unicellular 6 are retained in the drop of generation, and remaining single cell suspension is through logical
Road entrance 2 flows out, and realizes unicellular automatic capture.
Embodiment 1
A kind of preparation method of the single celled micro-fluidic chip of high throughput automatic capture is as follows：
(1) preparation of the single celled micro-fluidic chip SU-8 templates of high-throughput automatic capture
Micro-fluidic chip prepares the SU-8 templates of channel part protrusion using photoetching and caustic solution；First, first layer
SU-8 glue thickness is got rid of as 100 μm, 95 DEG C of front baking 20min, mask is placed in SU-8 glue washers, uv-exposure by Temperature fall
30s dries 20min, Temperature fall after 95 DEG C；Secondly, based on the basis of first layer SU-8 glue, the second layer gets rid of SU-8 glue thickness and is
150 μm, 95 DEG C of front baking 30min, mask is placed in SU-8 glue washers by Temperature fall, uv-exposure 40s, is dried after 95 DEG C
40min, Temperature fall；Finally, above-mentioned SU-8 glue is developed 10min, 180 DEG C of post bake 2h using ethyl lactate, Temperature fall is standby
With.
(2) preparation of the single celled PDMS chips of high-throughput automatic capture
By PDMS and initiator with volume ratio 10：1 is uniformly mixed, and is cast in the SU-8 templates of preparation early period, 80 DEG C of baking ovens
Cure 30min, PDMS and SU-8 templates are removed, obtained with structured micro-fluidic chip；By PDMS and initiator with volume
Than 10：1 is uniformly mixed, and is cast in blank glass plate, and PDMS and SU-8 templates are removed, obtain sky by 80 DEG C of curing oven 30min
White PDMS chips (2)；Two holes are made a call on chip (2) with card punch, flow path entrance is corresponded to respectively, chip 1 and chip 2 is passed through
Sealing-in is spare after crossing corona treatment 120s.
Embodiment 2：
Single cell suspension density is 5 × 104During cells/mL, the unicellular experiment of chip automatic capture
The micro-fluidic chip of above-mentioned preparation is impregnated through 75% ethyl alcohol, and after ultraviolet irradiation 1h sterilization treatments, liquid flow path is led to
Road outlet is blocked, and is placed in vacuum culture case and is vacuumized 10min, then, the breast that will quickly be marked through cell membrane red fluorescence probe
Adenocarcinoma cell (MCF-7) single cell suspension is with 5 × 104The cell density of cells/mL adds in chip entrance, unicellular at this time outstanding
The flow velocity of liquid is 0.027m/s, when whole drop formation units are filled with single cell suspension, opens liquid flow path channel outlet,
Surplus liquid in liquid flow path passage is excluded, treats that cell adherence in die bottom surface, is added fresh DMEM in high glucose culture medium, put
In 37 DEG C of incubator cultures.Unicellular distribution map in chip is as shown in Figure 4.Cell density is 5 × 104It is cells/mL, slender
When born of the same parents' suspension flow velocity is 0.027m/s, chip captures single celled light field and fluorescence picture；It can according to fluorescence picture statistics
Know, the unicellular capture rate of chip is 42%.
Embodiment 3：
Single cell suspension density is 5 × 105During cells/mL, the unicellular experiment of chip automatic capture
The micro-fluidic chip of above-mentioned preparation is impregnated through 75% ethyl alcohol, and after ultraviolet irradiation 1h sterilization treatments, liquid flow path is led to
Road outlet is blocked, and is placed in vacuum culture case and is vacuumized 10min, then, the breast that will quickly be marked through cell membrane red fluorescence probe
Adenocarcinoma cell (MCF-7) single cell suspension is with 5 × 105The cell density of cells/mL adds in chip entrance, unicellular at this time outstanding
The flow velocity of liquid is 0.027m/s, when whole drop formation units are filled with single cell suspension, opens liquid flow path channel outlet,
Surplus liquid in liquid flow path passage is excluded, treats that cell adherence in die bottom surface, is added fresh DMEM in high glucose culture medium, put
In 37 DEG C of incubator cultures.Unicellular distribution map in chip is as shown in Figure 5.Cell density is 5 × 105It is cells/mL, slender
When born of the same parents' suspension flow velocity is 0.027m/s, chip captures single celled light field and fluorescence picture；It can according to fluorescence picture statistics
Know, the unicellular capture rate of chip is 66%.
It follows that when single cell suspension flow velocity it is constant, cell density within the specific limits when, cell density is bigger, catches
It is higher to obtain single celled efficiency.This unicellular capture chip can realize the unicellular capture of high efficiency, while, it can be achieved that it is unicellular
Long-term cultivation in situ and the assay in later stage in chip.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar can understand present disclosure and implement according to this, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent change or modification that Spirit Essence is made, should be covered by the protection scope of the present invention.
Claims (7)
1. a kind of drop micro-fluidic chip, it is characterised in that the chip is formed by two layers, and upper strata is flow path entrance layer；Lower floor
For flow path key-course；
The flow path entrance layer has liquid flow path feeder connection (1) and liquid flow path channel outlet (2)；
The flow path key-course is made of unicellular capture flow path channel (3), gas channels (4), drop formation unit (5)；
The unicellular capture flow path channel (3) is a long-channel being made of the U-shaped passage of multiple interactive connection, long-channel
Both ends connect liquid flow path feeder connection (1) and liquid flow path channel outlet (2) respectively, and the straight channel of each U-shaped passage has
Gas flow path passage (4) parallel with it is each dispersed with several cylindrical depression pitting structures in the straight channel of U-shaped passage
Drop formation unit (5).
2. according to a kind of drop micro-fluidic chip described in claim 1, it is characterised in that：The unicellular capture flow path channel is wide
100~300 μm, a length of 40~50mm of straight channel of U-shaped passage, straight channel spacing is 0.5~1mm.
3. according to drop micro-fluidic chip described in claim 1, it is characterised in that：The gas channels width is 200~500 μm,
A length of 40~50mm, spacing are 0.5~1mm.
4. according to drop micro-fluidic chip described in claim 1, it is characterised in that：The unicellular capture flow path channel and gas circuit
Interchannel is away from for 0.5~1.5mm.
5. according to drop micro-fluidic chip described in claim 1, it is characterised in that：The drop formation unit is cylindrical depression
Pitting structure, shares 6000~10000, a diameter of 15~45 μm of pitting, 80~200 μm high, 80~150 μm of pitting spacing.
6. according to a kind of single celled method of high-throughput automatic capture based on drop micro-fluidic chip described in claim 1,
It is characterized in that, using above-mentioned drop micro-fluidic chip, following the steps below：
The micro-fluidic chip of above-mentioned preparation is impregnated through 60~90% ethyl alcohol, after ultraviolet irradiation 30~60min sterilization treatments, by liquid
The outlet of body flow path channel is blocked, and is placed in vacuum culture case and is vacuumized 5~10min, then, quickly by single cell suspension with 5 ×
103Cells/mL~5 × 106The cell density of cells/mL adds in chip entrance, and control single cell suspension flow velocity is in 0.01m/s
Between~0.05m/s, when whole drop formation units are filled with single cell suspension, liquid flow path channel outlet is opened, by liquid
Surplus liquid excludes in body flow path channel, treats that cell adherence in die bottom surface, adds fresh DMEM in high glucose culture medium, is placed in 37
DEG C incubator culture.
7. according to a kind of answering for single celled method of high-throughput automatic capture based on drop micro-fluidic chip described in claim 6
With, it is characterised in that：Captured it is unicellular can in the droplet structure long term culture of chip, and can be applied to cell Proliferation,
Differentiation and drug screening etc..
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| CN113101989A (en) * | 2021-03-30 | 2021-07-13 | 苏州大学 | Cell capturing and stretching integrated arrayed microfluidic chip |
| CN113462543A (en) * | 2021-06-22 | 2021-10-01 | 东南大学 | Micro-fluidic chip for quantitatively detecting cancer cells in blood |
| CN113755332A (en) * | 2021-10-08 | 2021-12-07 | 临沂大学 | Single drop replacement capture microchip system with high time resolution and applications thereof |
| CN114177955A (en) * | 2020-09-14 | 2022-03-15 | 中国科学院大连化学物理研究所 | Microfluidic chip, template and preparation method |
| CN114247485A (en) * | 2020-09-25 | 2022-03-29 | 中国科学院青岛生物能源与过程研究所 | Micro-fluidic chip for particle screening and separation |
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| CN113462543A (en) * | 2021-06-22 | 2021-10-01 | 东南大学 | Micro-fluidic chip for quantitatively detecting cancer cells in blood |
| CN113462543B (en) * | 2021-06-22 | 2024-02-02 | 东南大学 | Microfluidic chip for quantitatively detecting cancer cells in blood |
| CN113755332A (en) * | 2021-10-08 | 2021-12-07 | 临沂大学 | Single drop replacement capture microchip system with high time resolution and applications thereof |
| CN113755332B (en) * | 2021-10-08 | 2023-10-31 | 临沂大学 | Single drop replacement capture microchip system with high time resolution and application thereof |
| CN114426922A (en) * | 2022-01-24 | 2022-05-03 | 国科温州研究院(温州生物材料与工程研究所) | High-throughput microfluidic chip for measuring cell mechanical parameters in wide pressure range and application |
| CN114426922B (en) * | 2022-01-24 | 2023-12-22 | 国科温州研究院(温州生物材料与工程研究所) | High-flux micro-fluidic chip for measuring cell mechanical parameters in wide pressure range and application |
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Application publication date: 20180605 |