CN1330154A - Cell microarray chip and its preparing process - Google Patents
Cell microarray chip and its preparing process Download PDFInfo
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Abstract
A cell micro-array chip for screening compounds, biologic moleculae, medicines, genom, or cDNA library, and finding new gene and its function is composed of bare chip with micro through holes in which cell strains are transplanted, cover plate with microfluid grooves or through holes for applying chemical liquid to said cell strains, and bottom plate with microelectrode array or sensor array for detecting said chip by optical, electrochemical, or sensor method.
Description
The present invention relates to biochip and preparation method thereof, especially is cell microarray chip and preparation method thereof.
Cell microarray chip is a kind of in the biochip, biochip mainly refers to the microarray that the biologically active substance (comprising nucleic acid, protein, cell and small tissue etc.) assembled constitutes on solid substrate, with realize to compound (comprising medicine), protein, nucleic acid, cell and other biological components accurately, fast, the screening or the detection of large information capacity.The principal feature of biochip comprises: (1) can assemble a large amount of (10 on a less solid substrate
2～10
6Kind) biologically active substance, that obtains contains much information, the efficient height, and the biological reagent of consumption is few, can save a large amount of reagent expenses, and cost is low; (2) adopted Micrometer-Nanometer Processing Technology, can reduce the preparation cost of single chip, realized producing in enormous quantities by improving integrated level; (3) in conjunction with micro mechanical technology (MEMS), can the pre-treatment of biological sample be extracted, amplification, reaction, and the information detection is mutually integrated, is prepared into miniature, full-automatic, pollution-free, as the to can be used for the microsample detection integrated intelligent biology chip of height.
Biochip has extremely important meaning on biological detection, medical test and medical diagnosis on disease, drug screening and gene sequencing.Traditional biological detects the method adopted and comprises a series of numerous and diverse steps, and especially time-consuming aspect extensive screening compound, effort, cost height can not satisfy the needs of extensive high-throughput drug examination.Traditional method is being carried out in the improved process, is that the biochip technology of representative arises at the historic moment with the cell chip.The strong means that provide are obtained and analyzed to the maturation of this technology and use and will bring a revolution for the exploitation and the life science association areas such as evaluation, food and environment of new drug for bioinformation.
Porous check-out console (as 96 orifice plates) is the existing a kind of conventional utensil that is used for medicine, biochemistry detection and screening that generally uses.Respectively the cell strain of different effect is placed or be fixed among the different holes in drug testing and when screening, by adding different chemicals, or the compound combination, or biochemical reagents, observe of the reaction of different effect cell, carry out the quick medicament screening for the chemical/biological material.96 reaction tanks on it are isolated from each other, and can select the number of reaction tank arbitrarily for use according to user's needs.This is existing a kind of method that is used for drug research and exploitation of generally using.In order to improve the efficient of drug screening, people are by micro-processing technology, at silicon, and glass, it is higher to make density on the substrates such as plastics, and the check-out console that the aperture is littler among the cavity, and prepares miniature detection probe such as electrode to different cell curings in detecting the cavity.But this method still needs one by one different individual cells strains are assigned among each cavity, can not mass and the stdn preparation, preparation process is still complicated, cost is higher, also be not easy to operate continuously fast simultaneously, more be not easy to simultaneously multi-component continuous rapid detection in the sample, and different cells are in different cycle statuss in the cavity, have caused many difficulties for the screening of medicine.Cell microarray chip proposed by the invention can prepare with a kind of cell microarray chip on mass ground, can make all cells on the chip be in the same cell cycle by the culture condition of control cell, and this is very important to drug screening; Simultaneously can carry out the detection of multiple data quantity and multiparameter; Miniaturization; Cost is low; Pollution-free.
Purpose of the present invention is exactly the weak point that exists at conventional utensil in present drug research and the exploitation, proposes a kind of new cell microarray chip and preparation method thereof.But this cell microarray chip stdn and mass production can be carried out the continuous real-time analysis of multinomial index of biological activity to a large amount of compound molecules, and sample and reagent consumption are little, the operation simple and feasible.
For achieving the above object, cell microarray chip proposed by the invention, it is made of cell chip nude film, encapsulation cover plate and base plate, the some micro-through-holes of dense arrangement on the cell chip nude film, the cell chip nude film is packaged between cover plate and the base plate.One of encapsulation cover plate form is that this encapsulation cover plate is furnished with the microfluid groove in the face of on the one side of chip nude film, and this microfluid groove just in time is communicated with the micro-holes on the chip nude film, and the input and output port of a pair of liquid is set; Two of encapsulation cover plate form is beaten some through holes on hard plate material (as glass, plastics etc.); the number of micro-holes equates on the number of through hole and the chip nude film; and the position of micro-holes can be corresponding one by one on the position of each through hole and the nude film, and on this cover plate covered with protective film.One of base plate form is to adopt mechanically resistant material to make, and its size is corresponding with chip nude film size; Two of base plate form is to adopt mechanically resistant material to make, and its size is corresponding with chip nude film size, and base plate is provided with microelectrode array, and microelectrode array is corresponding one by one with chip nude film array; Three of base plate form also is to adopt mechanically resistant material to make, and its size is corresponding with chip nude film size, and sensor array (sonic transducer or thermal sensor or chemical sensor array) is set on base plate, and makes sensor array corresponding one by one with chip nude film array.
In addition, be subjected to the environment detrimentally affect, at the single or double covered protection film of nude film in order to prevent the cell chip nude film.This protective film adopts macromolecular material or holey materials such as glass fibre or cloth to make, and this protective film can prevent that nude film is subjected to environmental influence on the one hand, and this protective film can make the nutritive medium porous enter on the other hand, and cell can not come out from nude film;
For achieving the above object, the preparation method of the cell microarray chip that the present invention provides comprises following content,
One, the preparation of chip nude film,
1. the preparation of chip nude film form one,
1) molding: preparation has the mould of fine columnar arrays;
2) injection moulding: macromolecular material (as silicon rubber, Mierocrystalline cellulose, plastics, conducting polymer albumen etc.) is injected mould, form the block macromolecular material that an inside is distributed with the small hollow pipe of massive parallel dense arrangement after the demoulding, small hollow pipe inside can be complete empty, also can be mesh structural porous weighting material;
3) introduce cell strain and cultivation: use micro-sampling method or other micro-apportioning method, different cell strains are introduced different pipelines, and cultivate under suitable condition, make it growth, in pipelines all in block materials, cover with required cell;
4) section: use rapid section machinery, with block materials along cutting perpendicular to the direction of microtubule or chipping;
5) covered protection film: at the single or double covered protection film of nude film, this protective film adopts macromolecular material or holey materials such as glass fibre or cloth to make, this protective film can prevent that nude film is subjected to environmental influence on the one hand, this protective film can make the nutritive medium porous enter on the other hand, and cell can not come out from nude film;
2. the preparation of chip nude film form two,
1) cell is introduced: introduce different cells in hollow microchannel (as the tubular fibre pipeline);
2) cell cultures: under different nutrient solutions and condition, make in each hollow microchannel and cover with required cell;
3) all conduit arrangements location, injection moulding: with an injection molding two-dimensional array is strained and be arranged into to different pipelines,, be prepared into the block materials that inside is distributed with a large amount of hollow pipe array with macromolecular material injection mould;
4) section: use rapid section machinery, with block materials along cutting perpendicular to the direction of microtubule or water is chipped;
5) covered protection film: at the one side or the two-sided covered protection film of nude film, this protective film or employing macromolecular material or holey films such as glass fibre or cloth, this protective film can prevent that nude film is subjected to the influence of poor environment on the one hand, this protective film does not influence the normal use of nude film on the other hand, be that the nutritive medium porous is entered, and cell can not come out from nude film;
Two, the preparation of encapsulation cover plate:
1. the preparation of cover plate form one is adopted complete processings such as machine drilling, laser boring, chemical corrosion to be processed into mobile microfluid groove for liquid in a side of hard plate material object chip nude film, and the input and output port of a pair of liquid is set.
2. the preparation of cover plate form two; adopt complete processings such as machine drilling, laser boring, chemical corrosion to go up and beat some through holes at hard plate material (as glass, plastics etc.); the number of micro-holes equates on the number of through hole and the chip nude film; and the position of micro-holes can be corresponding one by one on the position of each through hole and the nude film, and on this cover plate covered with protective film.
Three, the preparation of base plate:
1. the preparation of base plate form one adopts mechanically resistant material to make size and chip nude film size respective base.
2. the preparation of base plate form two adopts mechanically resistant material to make size and chip nude film size respective base, and base plate is provided with microelectrode array, and microelectrode array is corresponding one by one with chip nude film array.
3. the preparation of base plate form three, adopt mechanically resistant material to make size and chip nude film size respective base, and sensor array (sonic transducer or thermal sensor or chemical sensor array) is set on base plate, and make sensor array corresponding one by one with chip nude film array.
Four, encapsulation:
In any and the base plate form in any and the cover plate form in the said chip nude film form any carried out combination package become one, just can obtain the structure formation of certain cell chip, promptly obtain the cell chip of different structure form by the various combination package of three kinds of parts, to satisfy the needs that different detection methods (as optical means, electrochemical method, sensor, method) detect.
Advantage of the present invention is that the cell microarray chip that is proposed can carry out the qualitative or quantitative analysis of a kind of medicine for different cytosiies simultaneously on chip piece, and methods such as the gained result can use up, electricity, heat, sound or chemistry detect.For example available ordinary optical microscope, laser confocal microscope, CCD observe or surperficial excimer resonance (SPR), electroporations such as reflection optics such as (RIFS), electric current and current potential are interfered on the surface, perhaps method such as thermistor, quartz crystal oscillator is come the state of observation of cell or microorganism and is provided the result, also available other mark or cold method detection.Thereby increase work efficiency greatly, reduce reagent dosage, really accomplish fast, in good time, accurately, automatization and free of contamination drug screening and drug testing thereof.
In addition, little reaction of being carried out on each cell or the microbial reaction site can be quickened and regulates and control by physical methods such as electricity, light, sound or heat, for example, microelectrode can be set respectively in each micro channel, come little reaction on the control channel by the regulation and control electric field; By the size and Orientation of control current, required reactant is assembled or dispersion fast, or changed other physicochemical environment, thereby change the effect of cell or microorganism and medicine, improve detection sensitivity or shorten detection time.The given cell microarray chip of the present invention comprises zooblast, vegetable cell and microorganism micro-array chip.It can be used for the high flux screening of compound and combination, biomolecules or medicine, the Study on Modernization of conventional medicament, and genome or cDNA library screening, the discovery of new gene and the research of gene function, the research of proteomics etc.The present invention will accelerate the speed of new drug development greatly, reduce cost of development, raise the efficiency and accuracy, and the modernization of conventional medicament (comprising Chinese medicine) is had significant values.
Below in conjunction with accompanying drawing the specific embodiment of the present invention is described in further detail:
The cell chip nude film synoptic diagram that Fig. 1 the present invention proposes.
One of the cell chip encapsulation cover plate that Fig. 2 the present invention proposes synoptic diagram.
The miniflow build cell chip synoptic diagram that Fig. 3 the present invention proposes.
Two synoptic diagram of the cell chip encapsulation cover plate that Fig. 4 the present invention proposes.
The multi-hole type cell chip synoptic diagram that Fig. 5 the present invention proposes.
The block materials synoptic diagram that covers with the cell conduits is in a large number contained in the inside that Fig. 6 the present invention proposes.
The method synoptic diagram for preparing the cell chip nude film that Fig. 7 the present invention proposes.
The cell chip base plate synoptic diagram that Fig. 8 the present invention proposes.
In the above accompanying drawing, Fig. 1 is the nude film synoptic diagram of a kind of cell chip of the present invention's proposition: it is the cell chip nude film 2 by many small cell through hole 1 dense arrangement, fixes different cells in the small through hole on the chip nude film respectively.
A kind of cell chip encapsulation cover plate that Fig. 2 proposes for the present invention: can there be the cover plate 3 of microfluidic channel on its surface, this cover plate is provided with microfluid groove 4, when cover plate when having microfluid groove one cover on the cell chip nude film corresponding with Fig. 1, microfluid groove on the cover plate just in time joins the micro through hole on the cell chip nude film, makes the cell micro through hole site on the cell chip nude film connect to a cell chip with microfluid input port 5 and output port 6 that seals by the microfluid gutter channel.
Fig. 3 is the miniflow build cell chip corresponding with Fig. 2, and soup can directly join by the input aperture 5 of microfluid pipeline in the different cell strains, and wherein 7 is base plate.
Fig. 4 has the corresponding fluid injection through hole of micropore on the cell chip nude film corresponding with Fig. 1 for another cell chip encapsulation cover plate that the present invention proposes on the cover plate, wherein 8 is the cell chip through hole, and 9 are encapsulation multi-hole type cover plate.
Fig. 5 is the multi-hole type cell chip corresponding with Fig. 4, and soup can directly add in the different cell strains respectively by the fluid injection through hole, and wherein 7 is base plate, and 2 is the cell chip nude film, and 9 are encapsulation multi-hole type cover plate, and 10 is protective membrane.
The inside that Fig. 6 proposes for the present invention is distributed with the block materials 12 of the tiny hollow pipe 11 of massive parallel, growth and solidified different cells in each microtubule.
Fig. 7 is the method for preparing the cell chip nude film that the present invention proposes: by the rapid section machine will be corresponding with Fig. 6 block materials 12 along thinly slicing on the directions perpendicular to microtubule, promptly made the nude film of cell chip, wherein 13 is cutter.
The cell chip base plate that is provided with microelectrode array or sensor array 14 that Fig. 8 proposes for the present invention.
Further specify the present invention below in conjunction with several specific embodiments: embodiment one: the preparation of cell microarray chip.
1. the preparation of cell chip nude film ():
1) at first utilize machining process (as the line cutting processing, technologies such as machining) or LIGA technology, the body silicon process technology, injection moulding complete processing etc. or mould of application additive method preparation with fine columnar arrays, each column is of a size of 100um * 100um.
2) use the raw material injection metal die of Shooting Technique with a kind of silicon rubber, form the buik silicon elastomeric material that an inside is distributed with the small hollow pipe of massive parallel dense arrangement after the demoulding, small hollow pipe inside can be complete empty, also can be mesh structural porous weighting material.
3) can pour into the different nutritive mediums that this cell strain is cultivated that is fit in the wherein different pipelines, make pipe interior be suitable for the cell growth.
4) use micro-sampling method or other micro-apportioning method, different cell strains are introduced different ducts, (in pipeline, flow in suitable condition as nutritive medium, at certain proportion mixed gass such as carbonic acid gas, oxygen) cultivate, make it growth, in pipelines all in block materials, overgrow with required cell.
(as shown in Figure 6)
5) use rapid section machinery, along thinly slicing perpendicular to the direction of microtubule, (as shown in Figure 7) promptly makes required cell chip nude film (as shown in Figure 1) with block materials.
6) reticular membrane that adopts macromolecular material or porous materials such as glass fibre or cloth to make is attached in the one side of moulding nude film or two-sided, cover this protective film and can prevent that nude film is subjected to environmental influence on the one hand, this protective film can guarantee the normal use of nude film on the other hand, be that the nutritive medium porous is entered, and cell can not come out from nude film, and require this protective film and the surperficial contact of nude film (solid microchip substrate) good, certain elasticity is arranged, and the solution that is not easy to induce reaction on the contact substrate interface leaks.
2. the preparation of cell chip nude film (two):
1) at first utilizes some tubular fibre pipelines, in different tubular fibre pipelines, introduce different cells.
2) under different nutrient solutions and condition, make in each tubular fibre pipeline and cover with required cell.
3) with an injection molding two-dimensional array is strained and be arranged into to different pipelines, inject mould, be prepared into the block materials that inside is distributed with a large amount of hollow pipeline arrays with macromolecular material.
4) use rapid section machinery, block materials along thinly slicing perpendicular to the direction of microtubule, is promptly made required cell microarray chip nude film.
5) the netted protective film that adopts macromolecular material or porous materials such as glass fibre or cloth to make is attached to the single or double of moulding nude film, cover this protective film, can prevent that nude film is subjected to the detrimentally affect of environment on the one hand, this protective film can guarantee the normal use of nude film on the other hand, be that the nutritive medium porous is entered, and cell can not come out from nude film, and require this protective film and the surperficial contact of nude film (solid microchip substrate) good, certain elasticity is arranged, and the solution that is not easy to induce reaction on the contact substrate interface leaks.
3. the preparation of encapsulation cover plate ():
Adopt complete processings such as machine drilling, laser boring, chemical corrosion to be processed into mobile microfluid groove for liquid in a side of hard plate material object chip nude film, and the input and output port of a pair of liquid is set.(as shown in Figure 2)
4. the preparation of encapsulation cover plate (two):
Adopt complete processings such as machine drilling, laser boring, chemical corrosion to go up and beat some through holes at hard plate material (as glass, plastics etc.); the number of micro-holes equates on the number of through hole and the chip nude film; and the position of micro-holes can be corresponding one by one on the position of each through hole and the nude film, and on this cover plate covered with protective film.
5, the preparation of base plate ():
Adopt mechanically resistant material to make size and chip nude film size respective base.
6, the preparation of base plate (two):
Adopt mechanically resistant material to make size and chip nude film size respective base, and base plate is provided with microelectrode array, microelectrode array is corresponding one by one with chip nude film array.
7, the preparation of base plate (three):
Adopt mechanically resistant material to make size and chip nude film size respective base, and sensor array (sonic transducer or thermal sensor or chemical sensor array) is set on base plate, and make sensor array corresponding one by one with chip nude film array.
8, encapsulation:
In any and the base plate form in any and the cover plate form in the said chip nude film form any carried out combination package become one, just can obtain the structure formation of certain cell chip, be combined and packaged into the different structure form by three kinds of parts various, be of a size of the cell microarray chip of 2cm * 2cm, to satisfy the needs that different detection methods (as optical means, electrochemical method, sensor, method) detect.Embodiment two: genomic dna or the preparation of cDNA library chip
The preparation method of multitube road buik silicon elastomeric material is with embodiment one, perfusion is for the LB liquid culture agent of intestinal bacteria growth in pipeline, introduce different ducts with carrying the segmental intestinal bacteria of different size gene or cDNA, make it in incubator, to grow, in pipelines different in block materials, cover with and carry different size gene or the segmental intestinal bacteria of cDNA, this block materials edge is thinly sliced perpendicular to the direction of microtubule; With being furnished with microfluid such as gutter channel or the porous hard plate material encapsulates, constitute genomic dna or cDNA library chip at last.Embodiment three: the cell chip of different cell cycles
The preparation method of multitube road buik silicon elastomeric material is with embodiment one, in parallel microtubule, introduce with a kind of cell strain, but the different liquid culture agent of perfusion in different pipelines, chemical composition by the control nutrient solution, physical parameters such as gaseous constituent and temperature, pressure, control growth conditions, nutritional status, the cell cycle of cell in the different pipelines, and resistance, thereby can prepare the same cell strain array that on same chip, obtains different states.This chip can be used for studying the effect of pharmaceutical chemicals pair cell.
Claims (9)
1, cell microarray chip, it is made of cell chip nude film, encapsulation cover plate and base plate, the some micro-through-holes of dense arrangement on the cell chip nude film, the cell chip nude film is packaged between cover plate and the base plate.
2, cell microarray chip according to claim 1 is characterized in that: the single or double of cell chip nude film is coated with protective film.
3, cell microarray chip according to claim 2 is characterized in that: protective film adopts holey materials such as macromolecular material or glasscloth to make.
4, cell microarray chip according to claim 1, it is characterized in that: described encapsulation cover plate is furnished with the microfluid groove in the face of on the one side of chip nude film, this microfluid groove just in time is communicated with the micro-holes on the chip nude film, and the input and output port of a pair of liquid is set.
5, cell microarray chip according to claim 1; it is characterized in that: described encapsulation cover plate is provided with some through holes on hard plate material; the number of micro-holes equates on the number of through hole and the chip nude film; and the position of micro-holes can be corresponding one by one on the position of each through hole and the nude film, and on this cover plate covered with protective film.
6, cell microarray chip according to claim 1 is characterized in that: described base plate is to adopt mechanically resistant material to make, and its size is corresponding with chip nude film size.
7, cell microarray chip according to claim 1, it is characterized in that: described base plate is to adopt mechanically resistant material to make, its size is corresponding with chip nude film size, and base plate is provided with microelectrode array, and microelectrode array is corresponding one by one with chip nude film array.
8, cell microarray chip according to claim 1, it is characterized in that: described base plate is to adopt mechanically resistant material to make, its size is corresponding with chip nude film size, and sensor array (acoustic sensor array or thermal sensor array or chemical sensor array) is set on base plate, and makes sensor array corresponding one by one with chip nude film array.
9, cell microarray chip preparation method is characterized in that: this preparation method comprises following content:
(1) preparation of chip nude film,
The preparation of A, chip nude film form one,
A) molding: preparation has the mould of fine columnar arrays;
B) injection moulding: macromolecular material (as silicon rubber, Mierocrystalline cellulose, plastics, conducting polymer albumen etc.) is injected mould, form the block macromolecular material that an inside is distributed with the small hollow pipe of massive parallel dense arrangement after the demoulding, small hollow pipe inside can be complete empty, also can be mesh structural porous weighting material;
C) introduce cell strain and cultivation: use micro-sampling method or other micro-apportioning method, different cell strains are introduced different pipelines, and cultivate under suitable condition, make it growth, in pipelines all in block materials, cover with required cell;
D) section: use rapid section machinery, with block materials along cutting perpendicular to the direction of microtubule or chipping;
E) covered protection film: the single or double at nude film covers the holey protective film;
The preparation of B, chip nude film form two,
A) cell is introduced: introduce different cells in hollow microchannel (as the tubular fibre pipeline);
B) cell cultures: under different nutrient solutions and condition, make in each hollow microchannel and cover with required cell;
C) all conduit arrangements location, injection moulding: with an injection molding two-dimensional array is strained and be arranged into to different pipelines,, be prepared into the block materials that inside is distributed with a large amount of hollow micro tube array with macromolecular material injection mould;
D) section: use rapid section machinery, block materials along cutting perpendicular to the direction of microtubule or chipping, is promptly made required cell microarray chip nude film;
E) covered protection film: the single or double at nude film covers the holey protective film;
(2) preparation of encapsulation cover plate,
The preparation of A, cover plate form one:
Adopt complete processings such as machine drilling, laser boring, chemical corrosion to be processed into mobile microfluid groove for liquid in a side of hard plate material object chip nude film, and the input and output port of a pair of liquid is set;
The preparation of B, cover plate form two:
Adopt complete processings such as machine drilling, laser boring, chemical corrosion to go up and beat some through holes at hard plate material (as glass, plastics etc.), the number of micro-holes equates on the number of through hole and the chip nude film, and the position of micro-holes is corresponding one by one on the position of each through hole and the nude film, and on this cover plate covered with protective film;
(3) preparation of base plate,
A. the preparation of base plate form one adopts mechanically resistant material to make size and chip nude film size respective base;
B. the preparation of base plate form two is adopted mechanically resistant material to make size and chip nude film size respective base, and microelectrode array is set on base plate, and microelectrode array is corresponding one by one with chip nude film array;
C. the preparation of base plate form three is adopted mechanically resistant material to make size and chip nude film size respective base, and sensor array is set on base plate, and makes sensor array corresponding one by one with chip nude film array;
(4) encapsulation:
In any and the base plate form in any and the cover plate form in the said chip nude film form any carried out combination package become one, just can obtain the structure formation of certain cell chip, promptly obtain the cell chip of different structure form by the various combination package of three kinds of parts, to satisfy the needs that different detection methods (as optical means, electrochemical method, sensor, method) detect.
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