CN102174369A - Micro-slit-structure-based full PDMS (polydimethylsiloxane) micro-fluidic cell capturing chip and manufacturing method thereof - Google Patents
Micro-slit-structure-based full PDMS (polydimethylsiloxane) micro-fluidic cell capturing chip and manufacturing method thereof Download PDFInfo
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Abstract
The invention discloses a double-layer structure cell capturing chip, which is a micro-slit-structure-based full PDMS (polydimethylsiloxane) micro-fluidic cell capturing chip. The cell capturing chip consists of an upper solidified polydimethylsiloxane thin sheet and a lower solidified polydimethylsiloxane thin sheet, wherein micro-channels with different sizes and shapes are formed in the polydimethylsiloxane thin sheets respectively; the upper layer channel and the lower layer channel are staggered in parallel along edges; and 10+/-5 mu m slits are formed by the channels in an aligning and bonding method, and the length and the quantity of the slits can be adjusted and controlled according to different channel combination and alignment methods so that the amount of captured cells can be controlled. Based on a hydrodynamics principle, the chip blocks cells by using a slit structure so as to capture a limited quantity of cells, and simultaneously, the cell release can be controlled by adjusting the fluid pressure to realize repeated cell capturing. The chip is made by a conventional chip manufacturing method and can capture and release a single cell and a plurality of cells; moreover, the chip can be used for integrating a microelectrode for monitoring captured cells in real time. The invention also discloses a manufacturing method and process of the chip.
Description
Technical field
The present invention relates to that the PDMS micro-current controlled cell is caught chip and micro-current controlled cell is caught control.
Background technology
Cell is the very small elementary cell with unique vital movement, and traditional cell research is an object with a large amount of cell samples usually, and expectation obtains the general character of similar cell.Yet even also more or less there are differences between the cell of same type, therefore this analysis in fact only can provide the average response of whole cell sample, and has ignored the details between single cell and the cell.The heterogeneity of cell behavior for bacterium still be animal eukaryotic cell all be its inherent nature, in all complex biological incidents such as cell growth, differentiation and infection, also be ubiquitous.Therefore, in biology and chemical research, to controlledization of experiment condition, especially for single celled control, to help the understanding of basic vital process such as scientist's pair cell regulatory mechanism and molecular level interaction, also be to promote the constantly very strong driving force of development of science and technology always.At present, the most successful unicellular patch clamp and the laser optical tweezer technology of surely belonging to of catching and handle.The former unicellular is captured in single glass microelectrode suction pipe port by negative pressure with one, and is used to write down the single cell analysis technology of ion channel in cell membrane molecule activity.The laser optical tweezer technology is that the three-dimensional potential well that utilizes laser that a branch of height converges to form is captured and most of biological particles such as manipulation cell, organoid even biomacromolecule.But these two kinds of technology all need complex instrument, and efficient is too low.
Microflow control technique that grew up in recent years or lab-on-chip technology control and analyze the thinking of development that provides new for cell.Based on physical and chemical principles different under the microscale, scientist has been developed the micro-current controlled cell chip that to have various functions and different application.As the basic premise of cell subsequent analysis and research, the separation of cell and catching on the especially unicellular yardstick, almost all is an important ring in all micro-current controlled cell analytical equipments.At present, be used for cellular segregation on the chip and the means of catching relate to various fields such as light, electricity, sound, magnetic, hydromeehanics, mechanical workout and chemical process, mainly be divided into contact and contactless two kinds.Effect such as light, electricity, sound, magnetic all is contactless.Optical instrument is the laser optical tweezer technology and the combining of chip technology, and has utilized the transparent characteristic of most chips such as glass, PDMS and other macromolecular materials, and it can realize unicellularly catching and controlling, but it relates to the instrument complexity, controls singlely, limits more.Electrical method is and the most successful engagement means of micro-fluidic chip that it is integrated not only to help instrument, and the multiple mode of action is arranged, as electric osmose, electrophoresis, dielectrophoresis (nDEP, mode such as pDEP) not only can be carried out catching and separating of colony's cell, also can realize unicellular catching.But this mode often need be on chip integrated fine electrode, need complicated power supply control; In addition, voltage pair cell activity and solution system all have adverse influence.Acoustics and magnetics are emerging contactless cell control devices, but its control effect is limited, and very difficult realization is unicellular to be caught and control.Chemical process is strong as a kind of selectivity, and the application of method on micro-fluidic chip that bio-compatibility is good is increasingly extensive.It often realizes the cell adhesion and the combination of compartmentation by chemically modified in conjunction with the micromachined means, can reach unicellular selectivity and catch, be generally used for cell cultures, immunoassay etc., but its collection efficiency be relatively poor, control a little less than, and need complicated chemically modified to handle.Also having a kind of chemical process is to utilize hydrogel parcel cell to form to catch, this method action temperature and, but its operability is relatively poor.It is the most effective at present cell fixation mode that micromachining technology is used for catching of integral body and individual cells sample in conjunction with hydromeehanics control.Geometry traps such as little well that this technology often is complementary by finish size and cell, micropore, Wei Ba, little slit and microchannel or obstacle are caught cell, not only can form open array system, can also realize the control of pair cell in the microchannel.This method need not other control devices and instrument, the pair cell not damaged, can compatible other analyses or control method, can on unicellular yardstick, study physiological processs such as its stimuli responsive, interaction and migration, differentiation, apoptosis, be particularly useful for suspension cell is studied.Its shortcoming is that micro-processing technology is had relatively high expectations, and is difficult to realize in the Experiment of General Chemistry chamber.
Therefore, seek a kind of simple general-purpose, the chip manufacture method that adopts conventional processing means to realize, and high-level efficiency, the high-resolution cell capture method that can realize in common lab are significant.
Summary of the invention
The objective of the invention is to avoid the use of expensive device and meticulous undressed means, and a kind of micro-current controlled cell catching method simple, efficient general of making is provided, be used for expanding the effective means that the common lab pair cell is studied.
Purpose of the present invention reaches by following measure:
A kind of double-deck cell capture chip, it is based on full polydimethylsiloxane (PDMS) micro-current controlled cell of little narrow slit structure and catches chip, it is made of two solidified polydimethylsiloxane thin slices up and down, on the polydimethylsiloxane thin slice, be manufactured with the miniature recessed channel of different size and shape respectively, when upper and lower two polydimethylsiloxanes are superimposed, make upper and lower two-layer passage be parallel to each other staggered along the edge, form the single or multiple slits of 10 ± 5 μ m, this slit is used to stop that cell forms that the controlled of limited quantity cell caught.
Above-mentioned bilayer structure cell capture chip, described passage slit can make by the method for channel alignment bonding.
Above-mentioned bilayer structure cell capture chip, described passage slit length and quantity can be regulated and control by different combination of channels and alignment methods.
Above-mentioned bilayer structure cell capture chip can be controlled the quantity of catching cell by length and the size of adjusting slit, can form effectively catching from individual cells to tens cell.
Above-mentioned bilayer structure cell capture chip can utilize the principle of hydrodynamics pair cell to catch, and can catch the pressure-controlling release cell of back by the gangway, thereby can repeat the operation of catching of cell.
A kind of method of making above-mentioned bilayer structure cell capture chip, it comprises the following steps:
Step 3. slit is made and chip bonding: the two PDMS chips up and down that will make respective channel are simultaneously through Cement Composite Treated by Plasma, drip several deionized waters rapidly thereon, cover last slice then on following sheet, this moment is because the existence of water, two PDMS can slide mutually smoothly, with the microchannel parallel alignment on two-layer, make it form the slit of whole piece or partial-length, adjust slit width at microscopically and make it to be no more than 15 μ m (less than corresponding cell size), remove most of excessive moisture with the filter paper suction, keep up and down the layers of chips position and place infrared lamp under drying, firmly obtaining slit catches chip to get final product bonding behind about 30min, slit length can partly be adjusted according to align with tube, and the gangway of two-layer passage was to carry out sample introduction operation and pressure adjustment about last slice need were reserved.
The method of above-mentioned making bilayer structure cell capture chip, described step 3 can be carried out the regulation and control of combination of channels and slit: can adopt the microchannel of isomorphism type not to be combined to form the slit of different lengths, be used to regulate and control to catch the quantity of cell; Can adopt beeline channel to be combined to form longer slit, thereby form the linear arrangement of cell; Also can adopt point-like combination of channels or straight line and point-like combination of channels to form a plurality of slits of catching, realize catching small amounts of cells; Simultaneously, owing to can pass through the aligned position of the flexible control channel of slip of two PDMS up and down, can adopt suitable point-like combination of channels, the aligning that intersects forms small slit, and individual cells is caught.
Double-deck cell capture chip of the present invention can catch single and a plurality of cells and discharge easily, the steps include:
Inject cell suspension at upper strata feeder connection place, because the difference of hydrostatic pressure, cell are followed solution stream and are formed shunting to outlet and to lower floor's pipeline, stopped by slit, the cell streamwise constantly on slit ordered aggregation form and to catch, unnecessary cell is discharged from outlet with suspension; The effect of keep-uping pressure also can be to catching operations such as cell cleans.
Sample solution from the sucking-off that enters the mouth, is injected buffered soln in the lower floor entrance and exit of the passage, make liquid pressure reverse,, can discharge captured cell, and discharge, catch and discharge thereby can repeat pair cell from the upper strata channel outlet even the solution reverse direction flow is crossed slit.
Concrete effect of the present invention is as follows: the inventive method is utilized the microchannel to aim at bonding method and is made the narrow slit structure that can be used for catching small amounts of cells by simple chip manufacture method.Compare with cell capture technology on the traditional chip that utilizes hydrodynamic force principle and microstructure, this invention has the following advantages: 1, making method is simple, reliable, with low cost, adopts full PDMS material and water lubricating bonding method, does not need too much modification step; 2, need not clean room, need not accurate little processing instrument and means, only utilize traditional lithographic method can form the narrow slit structure that is applicable to cell size, can realize in the Experiment of General Chemistry chamber, be convenient to popularize; 3, this method makes structure and can conveniently adjust, and realizes catching and arranging from individual cells to the dozens of cell, and the capture rate height is controlled easy; 4, this chip is soft chip, and simultaneously the PDMS material makes follow-up modification and integrated operation is simple and feasible, also can make integrated microelectrode and be used for pair cell and monitor in real time and analyzing and testing.
Description of drawings
Fig. 1. PDMS microchannel chip manufacturing synoptic diagram;
Fig. 2 slit is made and the integrated synoptic diagram of chip.(a) PDMS of lower floor chip microchannel; (b) upper strata PDMS chip microchannel; (1) PBS buffered soln inlet; (2) PBS buffered soln outlet; (1 ') cell solution inlet; The outlet of (2 ') cell solution;
Fig. 3. cell capture and slit regulation and control.(a, e) beeline channel combination; (b, f) point-like passage, beeline channel combination; (c, g) beeline channel, point-like combination of channels; (d, h) point-like passage, point-like combination of channels;
Fig. 4. small amounts of cells is caught and unicellular catching.(a) the corresponding slit of point-like-a plurality of cell captures; (b) the staggered slit of point-like-a plurality of cell captures; (c) the staggered slit-individual cells of point-like is caught.
Embodiment
The invention will be further described below in conjunction with accompanying drawing and example.
The water that uses in the experimentation is redistilled water, and the experiment agents useful for same comprises Sodium phosphate dibasic, potassium primary phosphate, and Repone K, sodium-chlor, polyvinyl alcohol etc. are analytical pure.Used cell is human stomach cancer cell line (BGC-823).
The making of embodiment 1. bilayer structure cell capture chips:
1. adopt mode as shown in Figure 1 to prepare PDMS microchannel chip.
2. adopt as shown in Figure 2 mode to prepare slit and integrating cell is caught chip
Step 3. slit is made and chip bonding: the two PDMS chips up and down that will make respective channel are simultaneously through Cement Composite Treated by Plasma, drip several deionized waters rapidly thereon, cover last slice then on following sheet, this moment is because the existence of water, two PDMS can slide mutually smoothly, with the microchannel parallel alignment on two-layer, make it form the slit of whole piece or partial-length, adjust slit width at microscopically and make it to be no more than 15 μ m (less than corresponding cell size), remove most of excessive moisture with the filter paper suction, keep up and down the layers of chips position and place oven dry infrared lamp under, firmly obtaining slit catches chip to get final product bonding behind about 30min.Slit length can partly be adjusted according to align with tube, and the gangway of two-layer passage was to carry out sample introduction operation and pressure adjustment about last slice need were reserved.
Step 4. combination of channels and slit regulation and control: can adopt the microchannel of isomorphism type not to be combined to form the slit of different lengths, be used to regulate and control to catch the quantity of cell.Can adopt beeline channel to be combined to form longer slit, thereby form the linear arrangement of cell; Also can adopt point-like combination of channels or straight line and point-like combination of channels to form a plurality of slits of catching, realize catching small amounts of cells.Simultaneously, owing to can pass through the aligned position of the flexible control channel of slip of two PDMS up and down, can adopt suitable point-like combination of channels, the aligning that intersects forms small slit, and individual cells is caught.
In order to characterize the capture effect of this chip pair cell, we adopt different combination of channels to make little slit, and suspension BGC-823 cell sample is caught, and the result as shown in Figure 3.The steps include:
Embodiment 3. adopts bilayer structure cell capture chip, catches several cells or individual cells:
In order to characterize the acquisition performance of this chip to small amounts of cells, we adopt and reduce slit length and adopt the mode of staggered bonding that several and individual cells are caught, and the result as shown in Figure 4.
Claims (7)
1. double-deck cell capture chip, it is characterized in that: it is based on the full dimethyl silicone polymer micro flow control cell capture chip of little narrow slit structure, it is made of two solidified polydimethylsiloxane thin slices up and down, on the polydimethylsiloxane thin slice, be manufactured with the miniature recessed channel of different size and shape respectively, when upper and lower two polydimethylsiloxanes are superimposed, make upper and lower two-layer passage be parallel to each other staggered along the edge, form the single or multiple slits of 10 ± 5 μ m, this slit is used to stop that cell forms that the controlled of limited quantity cell caught.
2. bilayer structure cell capture chip according to claim 1, it is characterized in that: described passage slit makes by the method for channel alignment bonding.
3. bilayer structure cell capture chip according to claim 1 is characterized in that: described passage slit length and quantity are regulated and control by different combination of channels and alignment methods.
4. bilayer structure cell capture chip according to claim 1 is characterized in that: by length and the size of adjusting slit the quantity of catching cell is controlled, form effectively catching from individual cells to tens cell.
5. bilayer structure cell capture chip according to claim 1 is characterized in that: utilize the principle of hydrodynamics pair cell to catch, and catching the pressure-controlling release cell of back by the gangway, thereby can repeat the operation of catching of cell.
6. method of making above-mentioned bilayer structure cell capture chip, it comprises the following steps:
Step 1. glazing channel is made: the glass-chip passage adopts standard photoetching and the preparation of wet chemical lithographic technique;
Adopt the commercialization sol evenning chromium plate, carry out photoetching according to the channels designs pattern, etch depth is 30-50 μ m;
On step 2. is made, following two-layer polydimethylsiloxane (PDMS) microchannel thin slice: with the negative template of above-mentioned glass-chip, a certain amount of PDMS thereon casts, be heating and curing, promptly get PDMS chip after peeling off with respective male structure, with this PDMS formpiston after air plasma is handled, it in surperficial spin coating mass percentage concentration rapidly 0.1 ~ 0.5% polyvinyl alcohol water solution, and in infrared lamp oven dry down, with the positive template of this PDMS chip, the polydimethylsiloxane of casting thereon, can easily peel off after the curing, can obtain the PDMS chip consistent with the etching glass chip channel;
Step 3. slit is made and chip bonding: will make respective channel on, following two PDMS chips are simultaneously through Cement Composite Treated by Plasma, drip several deionized waters rapidly thereon, cover last slice then on following sheet, this moment is because the existence of water, two PDMS can slide mutually smoothly, with the microchannel parallel alignment on two-layer, make it form the slit of whole piece or partial-length, adjust slit width at microscopically and make it to be no more than 15 μ m, remove most of excessive moisture with the filter paper suction, in the maintenance, following layers of chips position also places oven dry under the infrared lamp, firmly obtaining slit catches chip to get final product bonding behind about 30min, slit length can partly be adjusted according to align with tube, and the gangway of two-layer passage was to carry out sample introduction operation and pressure adjustment about last slice need were reserved.
7. the method for making bilayer structure cell capture chip according to claim 6, described step 3 are carried out the regulation and control of combination of channels and slit: adopt the microchannel of isomorphism type not to be combined to form the slit of different lengths, be used to regulate and control to catch the quantity of cell; Adopt beeline channel to be combined to form longer slit, thereby form the linear arrangement of cell; Also can adopt point-like combination of channels or straight line and point-like combination of channels to form a plurality of slits of catching, realize catching small amounts of cells; Simultaneously,, intersect and aim at the small slit of formation, individual cells is caught because the aligned position of the flexible control channel of slip by upper and lower two PDMS adopts the point-like combination of channels.
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