CN108148751A - A kind of integrated drug screening and dyeing micro-fluidic chip and preparation method thereof - Google Patents
A kind of integrated drug screening and dyeing micro-fluidic chip and preparation method thereof Download PDFInfo
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- CN108148751A CN108148751A CN201611106348.4A CN201611106348A CN108148751A CN 108148751 A CN108148751 A CN 108148751A CN 201611106348 A CN201611106348 A CN 201611106348A CN 108148751 A CN108148751 A CN 108148751A
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- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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Abstract
A kind of integrated drug screening and dyeing micro-fluidic chip, are formed as follows：Upper strata is fluid path key-course, and lower floor is gas circuit key-course, and bottom surface is blank glass bottom plate；Specifically it is provided with following structures：Cell fluorescence dyeing injection port, fluorescent staining sample intake passage area, cell injection port, cell sample intake passage area, cell culture chamber, drug sample intake passage area, drug injection port, liquid outflow channel area, liquid outlet.A kind of integrated drug screening as described above and the preparation method of dyeing micro-fluidic chip, it is characterised in that：The integrated drug screening and the preparation method of dyeing micro-fluidic chip：Prepare the photoetching glue pattern plate of channel part protrusion；Development, post bake；With silylating reagent processing template；It obtains with structured polydimethylsiloxanechip chip；Irreversible sealing-in.Structure of the present invention is simple in structure, and preparation manipulation is convenient, and speed is fast, efficient, has wide range of applications.
Description
Technical field
The present invention relates to the design of microflow control technique and polymer chip, processing, making and applied technical fields, especially carry
A kind of integrated drug screening and dyeing micro-fluidic chip and preparation method thereof are supplied.
Background technology
In the prior art, micro-fluidic chip is a kind of system of the fluid flowing of manipulation micro volume in the tiny channels,
The scale of middle channel is tens to hundreds of microns, and the amount for carrying fluid is 10-9~10-18L.Each operation list of micro-fluidic chip
Member is connected each other by the flowing of fluid in microchannel network.Microfluidic control is the operation core of Microfluid based Lab on a chip,
The processes such as involved sample introduction, mixing, reaction, separation are completed in the movement of controlled fluid.Either macroscopic view still
Microfluid, valve are all the core components of fluid control.Due to its importance, the development of miniature valve is born early in micro-fluidic chip
Cause the extensive concern of people before.Theoretically, every component that can control microchannel closure and opening can conduct
Micro-valve in micro-fluidic chip uses.One ideal micro-valve should have following characteristics：Low leakage, low-power consumption, response speed
Soon, linear operation ability and adaptation are wide.Microfluid and miniature valve constitute the micro-fluidic chip system of complete set.
The core of microfluidic analysis is to utilize micro-fluidic chip by sample pretreatment, biological and chemical reaction, separation detection
Basic operation units is waited to be integrated on the chip with micron or nanometer microchannel network, complicated point is completed by manipulating fluid
Analysis process has many advantages, such as that sample and reagent consumption are few, analysis time is short, extensive parallel determination high-throughput, easy to implement.
The minimizing of analysis system, integrated and portability can be easily realized using microfluidic analysis technology.At present, the system is wide
It is general to apply in fields such as life science, disease diagnosis and therapy, pharmaceutical synthesis and screenings.
Cellular level drug screening micro-fluidic chip system is intended to cultivate cell by being designed with the chip of different function,
Medicine irritation is applied, and coordinate the detection device of automation to cell, acquisition drug and the signal of cell interaction collect number
According to so as to analyze the effect of drug, being screened and obtain the selection result.The advantages of system, is by sample complete analysis
The functions such as the micro of process and integrated, realizes highly sensitive quick detection, and high throughput output and on-line automaticization operate,
More previous cell-based screening Technological expression goes out great advantage, is very suitable for the screening of drug ingedient.
Immunofluorescence dyeing technology is to be combined antibody molecule with some probe materials, and group is carried out using antigen-antibody reaction
Knit or intracellular antigen substance positioning technology, be for observe intracellular protein distribution and positioning common method.It is immune
The traditional method of fluorescent staining needs to consume a large amount of reagent, manpower and time, the consumption of particularly certain precious antibody, limitation
The use of conventional method.Microfluidic chip technology greatly reduces sample consumption with it, saves labor and time cost, can li
Meter Jian Fang's spatially realizes the advantages such as automation, high-throughput experiment, has received widespread attention.
People are highly desirable to obtain a kind of excellent integrated drug screening of technique effect and the system of dyeing micro-fluidic chip
Preparation Method.
Invention content
The object of the present invention is to provide a kind of excellent integrated drug screenings of technique effect and dyeing micro-fluidic chip
Preparation method.To solve previous cell drug screening and complicated, a large amount of examinations of consumption complex for operation step present in dyeing course
The limitations such as agent.
The present invention provides a kind of integrated drug screenings and dyeing micro-fluidic chip, it is characterised in that：
The micro-fluidic chip is made of upper strata, lower floor, three layers of bottom surface sequential series fitting arrangement, wherein：Upper strata is liquid
Circuit control layer, lower floor are gas circuit key-course, and bottom surface is blank glass bottom plate；
The fluid path key-course is specifically provided with following structures：
--- cell fluorescence dyes injection port：Positioned in the most upstream of entire fluid path key-course；It is provided at least two
It is parallel with one another using its channel as entrance and finally converge into a shared channel；The common-use tunnel finally converged into is also respectively connected with
The cell culture chamber and liquid outflow channel in downstream；
--- fluorescent staining sample intake passage area (P1)：It is arranged in cell fluorescence dyeing injection port and cell sample intake passage area
(P2) for both communications between；
--- cell injection port：It is provided at least two, each cell injection port is all disposed within cell sample intake passage
On a wherein channel in area (P2), and each channel in aforementioned cells sample intake passage area (P2) all concatenates one carefully
Born of the same parents culturing room；
--- cell sample intake passage area (P2)：Fluorescent staining sample intake passage area (P1) is arranged between cell culture chamber；
--- cell culture chamber：At least two, it is arranged in cell sample intake passage area (P2) and drug sample intake passage area
(P3) between；
--- drug sample intake passage area (P3)：It is to include leading between all cell culture chambers of covering and drug injection port
The region in road；
--- drug injection port：Its quantity and cell culture chamber are equal, are respectively arranged in each cell culture chamber downstream
Channel on；
--- liquid outflow channel area (P4)：It is arranged in the downstream of cell culture chamber downstream passage and entire fluid path tail
Between the liquid outlet (13) at end；
--- liquid outlet (13)：It is arranged in the structured most downstream of entire fluid path key-course institute.
The integrated drug screening and dyeing micro-fluidic chip, it is characterised in that：The integrated drug screening and dye
Color micro-fluidic chip also meets following requirements：
Cell culture chamber setting there are four, the corresponding cell injection port in cell sample intake passage area (P2) upstream and
The drug injection port in downstream drug sample intake passage area (P3) also all there are four；Cloth is sequentially connected in series since upstream on each channel
It is equipped with 1 cell injection port, 1 cell culture chamber, 1 drug injection port.
The integrated drug screening and dyeing micro-fluidic chip, it is characterised in that：The integrated drug screening and dye
Color micro-fluidic chip also meets one or a combination set of following requirements：
First, there are four cell fluorescence dyeing injection port settings, the integrated drug screening and dyeing micro-fluidic chip
Middle setting there are four dyeing channel of the injection port as entrance using cell fluorescence, it is parallel with one another and finally converge into one it is shared logical
Road；The common-use tunnel finally converged into again one point be four, become four four channels for being each provided with a cell injection port,
It is logical that each cell injection port is also sequentially connected the cell culture chamber in downstream, drug injection port and liquid outflow followed by respectively
Road；
Second, liquid outflow channel area (P4)：It is to merge into at least two passes in cell culture chamber downstream finally
A shared liquid outlet (13) channel combined region；
Third, the lower floor of the micro-fluidic chip, that is, gas circuit key-course is specifically made of pump valve control zone, each fluorescence dye
Color liquid inlet has individual pump valve unit to control, so that sample introduction liquid does not influence mutually；Under gas circuit key-course specifically includes
State one or a combination set of structure：It is arranged on the valve of the control of each cell injection port upstream；It is arranged on each drug injection port
The valve of the control in downstream；It is arranged on the valve of the control on each cell fluorescence dyeing injection port downstream passage；Micro- core
The valve of all controls of piece is normally close valve, and when use opens.
The integrated drug screening and dyeing micro-fluidic chip, it is characterised in that：The integrated drug screening and dye
Color micro-fluidic chip also meets one or a combination set of following requirements：
First, each cell culture chamber by individual cell culture fluid entrance, medicine entrance, fluorescent staining liquid entrance, into
Sample channel forms；
Second, at least two cell culture chambers in parallel collectively constitute fluid path layer (in Fig. 1)；
Third, the upper strata chip and the material of lower layer chip are polydimethylsiloxane polymer, upper strata core
Piece 1~5mm of thickness, 100~500 μm of lower layer chip thickness；
Fourth, the size of the cell culture chamber is the spindle shape of 15mm × 2mm × 100 μm；
Fifth, the gas circuit of the chip is identical with fluid path channel height, it is 80~200 μm
Sixth, the gas circuit of the chip and fluid path channel width difference, gas channels width is 100~300 μm, and fluid path is led to
200~600 μm of road width.
The integrated drug screening and dyeing micro-fluidic chip, it is characterised in that：The integrated drug screening and dye
Color micro-fluidic chip also meets following requirements：
The fluid path layer is based on the PDMS modules obtained by SU-8 templates；Gas circuit layer is in the gas circuit SU-8 moulds being successful
A floor height is got rid of on plate in the polydimethylsiloxane film of 10~50 μm of template, the dimethyl silicone polymer of the fluid path layer
PDMS templates have structure side to be sealed to gas circuit layer polydimethylsiloxane film without structure side, gas circuit strata dimethyl-silicon
Oxygen alkane PDMS films have valve arrangement side plasma to be bonded on clean sheet glass.
A kind of integrated drug screening as described above and the preparation method of dyeing micro-fluidic chip is also claimed in the present invention,
It is characterized in that：The preparation method correlation step of the integrated drug screening and dyeing micro-fluidic chip requires as follows successively：
(1) the photoresist SU-8 templates of channel part protrusion are prepared using photoetching and caustic solution；
(2) developed with ethyl lactate to photoresist SU-8 templates, 165 DEG C~180 DEG C 1~3h of post bake；
(3) the photoresist SU-8 templates of chip lower floor silylating reagent is handled into 5~10min, is easily peeled off PDMS
Template bottom surface；
(4) by polydimethylsiloxane and initiator with volume ratio (5~20)：1 is uniformly mixed, and is cast in core respectively
On piece, understructure photoresist SU-8 templates, 80 DEG C of 20~40min of curing oven, by polydimethylsiloxane and chip
Upper strata photoresist SU-8 templates stripping, obtains with structured polydimethylsiloxane chip；
(5) chip lower floor structureless on the structured side of chip epipelagic zone and photoresist SU-8 templates is subjected to oxygen etc.
Gas ions handle 1~3min, and 70~90 DEG C of heat dry 30~60min, carry out irreversible sealing-in；
(6) the good polydimethylsiloxane chip of above-mentioned sealing-in and understructure photoresist SU-8 templates are removed,
With clean blank glass piece by 1~3min of oxygen plasma treatment, 70~90 DEG C of heat dry 30~60min and carry out irreversible envelope
Connect to get to integrated drug screening with dyeing micro-fluidic chip.
The integrated drug screening and the preparation method of dyeing micro-fluidic chip, it is characterised in that：The integrated chemical drug
Object is screened also meets following requirements with the preparation method of dyeing micro-fluidic chip：In the cell culture chamber of the micro-fluidic chip
After inoculating cell and cell confluent cultures region bottom surface, medicine irritation is added in drug sample introduction zone；Cell culture period terminates, Gu
Determine cell, carry out fluorescent staining.
The present invention is prepared for a kind of collection cell culture, drug screening and fluorescent staining using microfluid and microvalve technique
It is integrated, the micro-fluidic chip that three kinds of Testing index carry out in succession.Entire chip platform is simple in structure, easy to operate, integrated level
Height, analyze speed is fast, efficient, without any complicated and expensive equipment, is consumed without a large amount of cells and reagent.To sum up institute
It states, invents a kind of convenience, fast, integrated level is high, and the integrated drug screening having a wide range of application has with dyeing micro-fluidic chip
Particularly significant meaning.
The present invention solves previous cell drug screening and complexity complex for operation step present in dyeing course, consumption are big
Measure the technologies such as reagent limitation.Preparation process of the present invention is stablized, easy to operate, and integrated level is high.
Integrated drug screening of the present invention and the description of use of dyeing micro-fluidic chip：The chip can be used for applying not
Characteristics of cell biology is studied with acute drug stimulation, and fluorescent staining detection is carried out to cell state under this condition.Institute
Different types of cell culture can be carried out by stating integrated micro-flow control chip, can carry out the drug thorn of variety classes or various concentration
Swash, different types of antibody dyeing can be carried out.
The advantage of the invention is that：1st, it is easy to operate, quick；2nd, cell and reagent dosage are few, and experimental cost is cheap；3rd, no
Poisonous and harmful reagent is contacted, it is environmental-friendly；4th, Highgrade integration, have wide range of applications.
Description of the drawings
Below in conjunction with the accompanying drawings and embodiment the present invention is described in further detail：
Fig. 1 is integrated drug screening and dyeing microfluidic chip structure simplified schematic diagram；
Fig. 2 is integrated drug screening and dyeing micro-fluidic chip superstructure schematic diagram；
Fig. 3 is integrated drug screening and dyeing micro-fluidic chip understructure schematic diagram.
Specific embodiment
Reference numeral meaning is as follows：
In Fig. 1, reference numeral 1~4 is cell fluorescence dyeing injection port, specific to be respectively：Primary antibody entrance 1, secondary antibody
Entrance 2, nucleus dyestuff entrance 3, PBS buffer solution entrance 4；Fluorescent staining sample intake passage P1；5~8 be respectively cell injection port
One 5, cell injection port 26, cell injection port 37, cell injection port 48；Cell sample intake passage P1；R1~R4 is respectively：Carefully
One R1 of born of the same parents culturing room, two R2 of cell culture chamber, three R3 of cell culture chamber, four R4 of cell culture chamber, can cultivate simultaneously 4 kinds it is not of the same race
Class cell；9~12 are respectively：Drug injection port 1, drug injection port 2 10, drug injection port 3 11, drug injection port four
12；Drug sample intake passage P3 can add in variety classes drug or various concentration drug of the same race simultaneously；Liquid outflow channel P4, goes out
Liquid mouth 13；A~D is the valve of four cell fluorescences dyeing injection port that control reference numeral is 1~4 respectively, and four are respectively：Valve
One A, two B of valve, three C of valve, four D of valve；Separately have：Control five E of valve of dyestuff discharge, six J of valve of control drug discharge；Reference numeral F
~I is the valve of each cell injection port that control reference numeral is 5~8 respectively, is specifically respectively：Seven F of valve, eight G of valve, nine H of valve,
Ten I of valve；Reference numeral K~N is the valve of this four drug injection ports of control reference numeral 9~12 respectively, is specifically：Valve 11
K, 12 L of valve, 13 M of valve, 14 N of valve；
In Fig. 1, Fig. 2, the boundary line of basis material, which is omitted, to be not drawn into, and the boundary line of basis material is external square in Fig. 3
Shape frame is only to illustrate；Illustrate hereby.
Embodiment 1
A kind of integrated drug screening and dyeing micro-fluidic chip, the micro-fluidic chip is by upper strata, lower floor, three layers of bottom surface
Sequential series fitting arrangement composition, wherein：Upper strata is fluid path key-course, and lower floor is gas circuit key-course, and bottom surface is blank glass bottom
Plate；
The fluid path key-course is specifically provided with following structures：
--- cell fluorescence dyes injection port：Positioned in the most upstream of entire fluid path key-course；It is provided at least two
It is parallel with one another using its channel as entrance and finally converge into a shared channel；The common-use tunnel finally converged into is also respectively connected with
The cell culture chamber and liquid outflow channel in downstream；
--- fluorescent staining sample intake passage area (P1)：It is arranged in cell fluorescence dyeing injection port and cell sample intake passage area
(P2) for both communications between；
--- cell injection port：It is provided at least two, each cell injection port is all disposed within cell sample intake passage
On a wherein channel in area (P2), and each channel in aforementioned cells sample intake passage area (P2) all concatenates one carefully
Born of the same parents culturing room；
--- cell sample intake passage area (P2)：Fluorescent staining sample intake passage area (P1) is arranged between cell culture chamber；
--- cell culture chamber：At least two, it is arranged in cell sample intake passage area (P2) and drug sample intake passage area
(P3) between；
--- drug sample intake passage area (P3)：It is to include leading between all cell culture chambers of covering and drug injection port
The region in road；
--- drug injection port：Its quantity and cell culture chamber are equal, are respectively arranged in each cell culture chamber downstream
Channel on；
--- liquid outflow channel area (P4)：It is arranged in the downstream of cell culture chamber downstream passage and entire fluid path tail
Between the liquid outlet (13) at end；
--- liquid outlet (13)：It is arranged in the structured most downstream of entire fluid path key-course institute.
The integrated drug screening also meets following requirements with dyeing micro-fluidic chip：Cell culture chamber is provided with four
It is a, it is corresponding in the cell injection port of cell sample intake passage area (P2) upstream and the medicine in downstream drug sample intake passage area (P3)
Object injection port also all there are four；It is sequentially connected in series since upstream on each channel and is disposed with 1 cell injection port, 1 cell
Culturing room, 1 drug injection port.The integrated drug screening with dyeing micro-fluidic chip also meet it is following requirement one of or its
Combination：
First, there are four cell fluorescence dyeing injection port settings, the integrated drug screening and dyeing micro-fluidic chip
Middle setting there are four dyeing channel of the injection port as entrance using cell fluorescence, it is parallel with one another and finally converge into one it is shared logical
Road；The common-use tunnel finally converged into again one point be four, become four four channels for being each provided with a cell injection port,
It is logical that each cell injection port is also sequentially connected the cell culture chamber in downstream, drug injection port and liquid outflow followed by respectively
Road；
Second, liquid outflow channel area (P4)：It is to merge into at least two passes in cell culture chamber downstream finally
A shared liquid outlet (13) channel combined region；
Third, the lower floor of the micro-fluidic chip, that is, gas circuit key-course is specifically made of pump valve control zone, each fluorescence dye
Color liquid inlet has individual pump valve unit to control, so that sample introduction liquid does not influence mutually；Under gas circuit key-course specifically includes
State one or a combination set of structure：It is arranged on the valve of the control of each cell injection port upstream；It is arranged on each drug injection port
The valve of the control in downstream；It is arranged on the valve of the control on each cell fluorescence dyeing injection port downstream passage；Micro- core
The valve of all controls of piece is normally close valve, and when use opens.
The integrated drug screening also meets one or a combination set of following requirements with dyeing micro-fluidic chip：
First, each cell culture chamber is by individual cell culture fluid, medicine irritation, fluorescent staining liquid inlet, sample introduction
Channel forms；
Second, at least two cell culture chambers in parallel collectively constitute fluid path layer (in Fig. 1)；
Third, the upper strata chip and the material of lower layer chip are polydimethylsiloxane polymer, upper strata core
Piece 1~5mm of thickness, 100~500 μm of lower layer chip thickness；
Fourth, the size of the cell culture chamber is the spindle shape of 15mm × 2mm × 100 μm；
Fifth, the gas circuit of the chip is identical with fluid path channel height, it is 80~200 μm
Sixth, the gas circuit of the chip and fluid path channel width difference, gas channels width is 100~300 μm, and fluid path is led to
200~600 μm of road width.
The integrated drug screening also meets following requirements with dyeing micro-fluidic chip：
The fluid path layer is based on the PDMS modules obtained by SU-8 templates；Gas circuit layer is in the gas circuit SU-8 moulds being successful
A floor height is got rid of on plate in the polydimethylsiloxane film of 10~50 μm of template, the dimethyl silicone polymer of the fluid path layer
PDMS templates have structure side to be sealed to gas circuit layer polydimethylsiloxane film without structure side, gas circuit strata dimethyl-silicon
Oxygen alkane PDMS films have valve arrangement side plasma to be bonded on clean sheet glass.
A kind of integrated drug screening as described above and the preparation method of dyeing micro-fluidic chip, correlation step successively will
Ask as follows：
(1) the photoresist SU-8 templates of channel part protrusion are prepared using photoetching and caustic solution；
(2) developed with ethyl lactate to photoresist SU-8 templates, 165 DEG C~180 DEG C 1~3h of post bake；
(3) the photoresist SU-8 templates of chip lower floor silylating reagent is handled into 5~10min, is easily peeled off PDMS
Template bottom surface；
(4) by polydimethylsiloxane and initiator with volume ratio (5~20)：1 is uniformly mixed, and is cast in core respectively
On piece, understructure photoresist SU-8 templates, 80 DEG C of 20~40min of curing oven, by polydimethylsiloxane and chip
Upper strata photoresist SU-8 templates stripping, obtains with structured polydimethylsiloxane chip；
(5) chip lower floor structureless on the structured side of chip epipelagic zone and photoresist SU-8 templates is subjected to oxygen etc.
Gas ions handle 1~3min, and 70~90 DEG C of heat dry 30~60min, carry out irreversible sealing-in；
(6) the good polydimethylsiloxane chip of above-mentioned sealing-in and understructure photoresist SU-8 templates are removed,
With clean blank glass piece by 1~3min of oxygen plasma treatment, 70~90 DEG C of heat dry 30~60min and carry out irreversible envelope
Connect to get to integrated drug screening with dyeing micro-fluidic chip.
The integrated drug screening and the preparation method of dyeing micro-fluidic chip also meet following requirements：It is described micro-fluidic
In the cell culture chamber of chip after inoculating cell and cell confluent cultures region bottom surface, drug thorn is added in drug sample introduction zone
Swash；Cell culture period terminates, and fixed cell carries out fluorescent staining.
The present embodiment utilizes microfluid and microvalve technique, is prepared for a kind of collection cell culture, drug screening and fluorescence and contaminates
Color is integrated, the micro-fluidic chip that three kinds of Testing index carry out in succession.Entire chip platform is simple in structure, easy to operate, integrates
Degree is high, and analyze speed is fast, efficient, without any complicated and expensive equipment, is consumed without a large amount of cells and reagent.To sum up institute
It states, invents a kind of convenience, fast, integrated level is high, and the integrated drug screening having a wide range of application has with dyeing micro-fluidic chip
Particularly significant meaning.
The present embodiment solves previous cell drug screening and complicated, consumption complex for operation step present in dyeing course
The technologies limitation such as a large amount of reagents.The present embodiment preparation process is stablized, easy to operate, and integrated level is high.
Integrated drug screening described in the present embodiment and the description of use of dyeing micro-fluidic chip：The chip can be used for applying
Various concentration medicine irritation studies characteristics of cell biology, and carries out fluorescent staining detection to cell state under this condition.
The integrated micro-flow control chip can carry out different types of cell culture, can carry out the drug thorn of variety classes or various concentration
Swash, different types of antibody dyeing can be carried out.
Advantage of this embodiment is that：1st, it is easy to operate, quick；2nd, cell and reagent dosage are few, and experimental cost is cheap；3、
Poisonous and harmful reagent is not contacted, it is environmental-friendly；4th, Highgrade integration, have wide range of applications.
Embodiment 2
The SU-8 moulds of channel part protrusion are prepared in integrated drug screening with dyeing chip using photoetching and caustic solution
Plate, chip upper and lower structures are made of respectively two SU-8 template reverses PDMS；Two SU-8 templates make simultaneously, take two pieces it is clean
Net sheet glass, it is 100 μm, 95 DEG C of front baking 20min that SU-8 glue thickness is got rid of on photoresist spinner, Temperature fall, by chip levels
Two masks of structure are placed in SU-8 glue washers, uv-exposure 30s, dry 20min, Temperature fall after 95 DEG C；Finally, it uses
Above-mentioned SU-8 glue development 5min, 180 DEG C of post bake 2h, Temperature fall are obtained chip masterplate by ethyl lactate.
Embodiment 3
The SU-8 templates of chip understructure silylating reagent is handled into 10min, PDMS is made to be easily peeled off template bottom surface；
PDMS is with initiator with volume ratio 10：1 is uniformly mixed, and is cast in the upper and lower layer structure SU-8 templates of chip respectively, 80 DEG C of baking ovens are consolidated
Change 40min, PDMS and chip upper strata SU-8 templates are removed, obtained with structured PDMS chips；By chip upper strata with knot
The side of structure carries out oxygen plasma treatment 2min with chip lower floor structureless in SU-8 templates, and 80 DEG C of heat dry 1h, irreversible
Sealing-in；The good PDMS chips of above-mentioned sealing-in and understructure SU-8 templates are removed, with clean blank glass piece through peroxide etc.
Gas ions handle 2min, and 80 DEG C of heat dry 1h and carry out irreversible sealing-ins to get to integrated drug screening and dyeing micro-fluidic chip.
In Fig. 1, reference numeral 1~4 is cell fluorescence dyeing injection port, specific to be respectively：Primary antibody entrance 1, secondary antibody
Entrance 2, nucleus dyestuff entrance 3, PBS buffer solution entrance 4；Fluorescent staining sample intake passage P1；5~8 be respectively cell injection port
One 5, cell injection port 26, cell injection port 37, cell injection port 48；Cell sample intake passage P1；R1~R4 is respectively：Carefully
One R1 of born of the same parents culturing room, two R2 of cell culture chamber, three R3 of cell culture chamber, four R4 of cell culture chamber, can cultivate simultaneously 4 kinds it is not of the same race
Class cell；9~12 are respectively：Drug injection port 1, drug injection port 2 10, drug injection port 3 11, drug injection port four
12；Drug sample intake passage P3 can add in variety classes drug or various concentration drug of the same race simultaneously；Liquid outflow channel P4, goes out
Liquid mouth 13；Cell fluorescence dyes sample intake passage and connects cell fluorescence dyeing injection port with cell injection port, cell sample intake passage
Cell injection port is connected with cell culture chamber, drug sample intake passage connects drug injection port with cell culture chamber, liquid flow
Go out channel to connect drug injection port with liquid outlet；A~D is four cell fluorescences dyeing that control reference numeral is 1~4 respectively
The valve of injection port, four are respectively：One A of valve, two B of valve, three C of valve, four D of valve；Separately have：Control five E of valve, the control medicine of dyestuff discharge
Six J of valve of object discharge；Reference numeral F~I is the valve of each cell injection port that control reference numeral is 5~8 respectively, is had respectively
Body is：Seven F of valve, eight G of valve, nine H of valve, ten I of valve；Reference numeral K~N for respectively control this four drugs of reference numeral 9~12 into
The valve of sample mouth is specifically：11 K of valve, 12 L of valve, 13 M of valve, 14 N of valve.
All injection ports are controlled by individual valve, and different types of cell is divided by the structure that reference numeral is respectively 5~8
Not Jin Ru reference numeral be respectively R1~R4 four individual cell culture chambers, treat that cell growth is stablized, from reference numeral point
Different pharmaceutical Wei not be added at 9~12 structure stimulates cell, and the cells are fixed respectively liquid, cell confining liquid are from reference numeral point
Wei not add at 5~8 structure, be respectively by reference numeral then 1~4 structure at be separately added into primary antibody, secondary antibody, cell
After core dyestuff and PBS are rinsed, fluorescence microscope is carried out.
Claims (7)
1. a kind of integrated drug screening and dyeing micro-fluidic chip, it is characterised in that：
The micro-fluidic chip is made of upper strata, lower floor, three layers of bottom surface sequential series fitting arrangement, wherein：Upper strata is fluid path control
Preparative layer, lower floor are gas circuit key-course, and bottom surface is blank glass bottom plate, and the fluid path key-course is specifically provided with following structures：
--- cell fluorescence dyes injection port：Positioned in the most upstream of entire fluid path key-course；
--- fluorescent staining sample intake passage area (P1)：Be arranged in cell fluorescence dyeing injection port and cell sample intake passage area (P2) it
Between for link up both；
--- cell injection port：It is provided at least two, each cell injection port is all disposed within cell sample intake passage area
(P2) on the wherein channel in, and each channel in aforementioned cells sample intake passage area (P2) all concatenates a cell
Culturing room；
--- cell sample intake passage area (P2)：Fluorescent staining sample intake passage area (P1) is arranged between cell culture chamber；
--- cell culture chamber：At least two, be arranged in cell sample intake passage area (P2) and drug sample intake passage area (P3) it
Between；
--- drug sample intake passage area (P3)：It is to include covering the channel between all cell culture chambers and drug injection port
Region；
--- drug injection port：Its quantity and cell culture chamber are equal, are respectively arranged in the logical of each cell culture chamber downstream
On road；
--- liquid outflow channel area (P4)：It is arranged in the downstream of cell culture chamber downstream passage and entire fluid path caudal end
Between liquid outlet (13)；
--- liquid outlet (13)：It is arranged in the structured most downstream of entire fluid path key-course institute.
2. according to drug screening integrated described in claim 1 and dyeing micro-fluidic chip, it is characterised in that：The integrated chemical drug
Object is screened also meets following requirements with dyeing micro-fluidic chip：
There are four cell culture chamber settings, corresponding cell injection port and downstream in cell sample intake passage area (P2) upstream
The drug injection port in drug sample intake passage area (P3) also all there are four；It is sequentially connected in series and is disposed with since upstream on each channel
1 cell injection port, 1 cell culture chamber, 1 drug injection port.
3. according to drug screening integrated described in claims 1 or 2 and dyeing micro-fluidic chip, it is characterised in that：It is described integrated
Change drug screening and also meet one or a combination set of following requirements with dyeing micro-fluidic chip：
First, there are four cell fluorescence dyeing injection port settings, the integrated drug screening in dyeing micro-fluidic chip with setting
It puts there are four dyeing channel of the injection port as entrance using cell fluorescence, it is parallel with one another and finally converge into a shared channel；
The common-use tunnel finally converged into again one point be four, become four four channels for being each provided with a cell injection port, often
It is logical that a cell injection port is also sequentially connected the cell culture chamber in downstream, drug injection port and liquid outflow followed by respectively
Road；
Second, liquid outflow channel area (P4)：It is that at least two passes in cell culture chamber downstream are merged into final be total to
The channel combined region of one liquid outlet (13)；
Third, the lower floor of the micro-fluidic chip, that is, gas circuit key-course is specifically made of pump valve control zone, each fluorescent staining liquid
Body entrance has individual pump valve unit to control, so that sample introduction liquid does not influence mutually；Gas circuit key-course specifically includes following knots
One or a combination set of structure：It is arranged on the valve of the control of each cell injection port upstream；It is arranged on each drug injection port downstream
Control valve；It is arranged on the valve of the control on each cell fluorescence dyeing injection port downstream passage；The microchip
The valve of all controls is normally close valve.
4. according to drug screening integrated described in claim 3 and dyeing micro-fluidic chip, it is characterised in that：The integrated chemical drug
Object is screened also meets one or a combination set of following requirements with dyeing micro-fluidic chip：
First, each cell culture chamber is led to by individual cell culture fluid entrance, medicine entrance, fluorescent staining liquid entrance, sample introduction
Road forms；
Second, at least two cell culture chamber composition fluid path layers in parallel；
Third, the upper strata chip and the material of lower layer chip are polydimethylsiloxanepolymer polymer, upper strata chip thickness 1~
5mm, 100~500 μm of lower layer chip thickness；
Fourth, the size of the cell culture chamber is the spindle shape of 15mm × 2mm × 100 μm；
Fifth, the gas circuit of the chip is identical with fluid path channel height, it is 80~200 μm
Sixth, the gas circuit of the chip and fluid path channel width difference, gas channels width are 100~300 μm, fluid path channel width
200~600 μm.
5. according to drug screening integrated described in claim 4 and dyeing micro-fluidic chip, it is characterised in that：The integrated chemical drug
Object is screened also meets following requirements with dyeing micro-fluidic chip：
The fluid path layer is module；Gas circuit layer is that a floor height is got rid of in the gas circuit template being successful in the poly- of 10~50 μm of template
Dimethyl siloxane film, the dimethyl silicone polymer template of the fluid path layer have structure side to be sealed to gas circuit strata dimethyl-silicon
For siloxane film without structure side, gas circuit layer PDMS membrane has valve arrangement side plasma to be bonded to clean sheet glass
On.
6. integrated drug screening described in a kind of claim 1 and the preparation method of dyeing micro-fluidic chip, it is characterised in that：Institute
State integrated drug screening with dye micro-fluidic chip preparation method correlation step require successively it is as follows：
(1) the photoetching glue pattern plate of channel part protrusion is prepared using photoetching and caustic solution；
(2) developed with ethyl lactate to photoetching glue pattern plate, 165 DEG C~180 DEG C 1~3h of post bake；
(3) the photoetching glue pattern plate of chip lower floor silylating reagent is handled into 5~10min, PDMS is made to be easily peeled off template bottom surface；
(4) by dimethyl silicone polymer and initiator with volume ratio (5~15)：1 is uniformly mixed, and it is upper and lower to be cast in chip respectively
Layer structure photoresist template, 80 DEG C of 20~40min of curing oven shell dimethyl silicone polymer and chip upper strata photoetching glue pattern plate
From obtaining with structured polydimethylsiloxanechip chip；
(5) chip lower floor structureless on the structured side of chip epipelagic zone and photoetching glue pattern plate is carried out at oxygen plasma
1~3min is managed, 70~90 DEG C of heat dry 30~60min, carry out irreversible sealing-in；
(6) the good polydimethylsiloxanechip chip of above-mentioned sealing-in and understructure photoetching glue pattern plate are removed, with blank glass piece
By 1~3min of oxygen plasma treatment, 70~90 DEG C of heat dry 30~60min and carry out irreversible sealing-ins to get to integrated chemical drug
Object screens and dyeing micro-fluidic chip.
7. according to drug screening integrated described in claim 6 and the preparation method of dyeing micro-fluidic chip, it is characterised in that：Institute
It states integrated drug screening and also meets following requirements with dyeing the preparation method of micro-fluidic chip：The cell of the micro-fluidic chip
In culturing room after inoculating cell and cell confluent cultures region bottom surface, medicine irritation is added in drug sample introduction zone；Cell culture
End cycle, fixed cell, carries out fluorescent staining.
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