CN101693874A - Cell electrofusion chip device based on micro-chamber array structure - Google Patents
Cell electrofusion chip device based on micro-chamber array structure Download PDFInfo
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Abstract
The invention provides a cell electrofusion microelectrode array chip device based on a micro-chamber structure, which consists of a micro-chamber array chip, a periphery printed circuit board and a flow passage control module. The micro-chamber array chip consists of a quartz substrate layer, a metal microelectrode array, polymer side walls and a polymer water surrounding fender, wherein two opposite metal microelectrodes and two opposite polymer sidewalls form one micro-chamber which is arranged in an array shape; the micro-chamber array chip is bonded on the periphery printed circuit board to form electrical connection; the flow passage control module covers the micro-chamber array chip. In the invention, a certain electrical field is formed in the micro-chamber by outside electrical signals so as to control high-efficient queue and electrofusion of cells inside the micro-chamber, thus realizing that only one pair of cells inside the micro-chamber are subjected to fusion, and improving throughout and safety of cell fusion.
Description
Technical field
The present invention relates to the device that the biomass cells electricity merges.Particularly, the present invention relates to provide the cell chip that electricity merges, provide and produce the cell queuing, electricity causes perforation, the needed strength of electric field of fusion and electric-force gradient.The present invention relates to the accurate control of cell in the fusion of cell electricity, the efficient fusion of cell, be applicable to fields such as genetics, animals and plants distant hybridization breeding, developmental biology, drug screening, Monoclonal Antibody, cloning of mammalian animal.
Background technology
Cell electricity integration technology, was convenient to observe because its efficient is higher, easy and simple to handle, the pair cell toxicological harmless from the eighties in last century, was suitable for advantages such as instrument application and standard operation, had obtained fast development and widespread use.
The fusion of cell electricity can be divided into two main phase: cell queuing and cytogamy.
The principle of cell queuing is: when biomass cells is in the inhomogeneous field, formed dipole by electric field polarization, this dipole can be subjected to specific power on and moves at inhomogeneous field, i.e. dielectrophoresis (dielectrophoresis).Utilize dielectrophoresis can control the motion of cell, in cell electricity fusion process, utilize the dielectrophoresis phenomenon to make cell arrange bunchiness, compress the cell that is in contact with one another, finish the required queuing of cell electricity fusion process and merge after compress.
The principle of cytogamy is: highfield effect meeting causes membrane perforation, and this effect is called the cytolemma electricity and causes perforation effect (electroporation).In cell electricity fusion process, utilize electricity to cause the perforation effect, make the membrane perforation of two contacts, thereby make iuntercellular carry out exchange of substance in the film, tenuigenin, film are merged, electroporation under the electric field action of certain intensity is a kind of reversible perforation, cytolemma can reinstatement when reducing or cancel strength of electric field, and the film that produces cell electricity fusion process merges.
Traditional cell electricity emerging system all adopts large-scale integration slot usually, and its advantage is: (1) operation is comparatively easy, adopts large-scale integration slot to reduce and comprises sample feeding and the difficulty that goes out steps such as sample; (2) processing is easy, and the size of large-scale integration slot utilizes traditional mechanical processing tools can process needed integration slot structure comparatively easily generally all in a centimetre magnitude; (3) fusion amount is big, and traditional integration slot can hold several ml samples, and once experiment can obtain enough cells and carries out work such as later stage screening, cultivation.
But also there are some shortcomings in traditional cell electricity fusion device: (1) is because the interelectrode distance in the integration slot is bigger, signal is lined up, merges and compressed to the cell that reaches enough intensity, need very high extraneous driving voltage, often up on the hundreds of kilovolt, electrical security to system requires height, and the cost of system also so greatly improves; (2) interelectrode big spacing is unfavorable for the accurate control of pair cell etc.
For addressing this problem, the investigator combines cell electricity integration technology with the MEMS processing technology.The work range of MEMS technology is usually at 1～50 μ m, and the diameter range of this and cell is suitable, and the microstructure that is produced can effectively be controlled cell.There is how tame research institution to begin one's study and utilizes micro-fluidic chip technology or microelectrode array technique construction biochip to realize cell electricity mixing operation.
For example, the researchist of U.S. MIT has proposed to utilize the micro-fluidic chip technology to realize the accurate control of pair cell, reaches cell pairing efficiently and fusion; Domestic Zhao Zhi waits the researchist also to propose to utilize MEMS technique construction microelectrode array by force, and by making up the microelectrode array of micron dimension spacing, the cell electricity that is implemented under the low voltage condition merges.The Japanology person proposes utilizes a pair of microelectrode, by flowing of stream control cell, make cell movement arrive microelectrode to the band of position after, utilize electric field action to make two cells form pairing, relend and help electricimpulse and realize that electricity merges.
But still there is certain problem in said chip, though the micro-fluidic chip of being studied as U.S. MIT preferably resolves cell paired problem, these chip two interelectrode spacings are bigger, still needs higher external voltage can realize that electricity merges.And the chip that Zhao Zhiqiang proposes integrated microelectrode comparatively small amt, can not realize that high-throughput merges; Strength of electric field that microelectrode produced and electric-force gradient are also more weak, are difficult to realize the accurate control of cell; Selected work material anticorrosive, resistance of oxidation is also relatively poor; Simultaneously, because not integrated turnover sampling device, operation is comparatively inconvenience also.The method efficient that the Japanology person proposes is lower, merges flux and far can not satisfy the requirement of merging the back cell research.
Relevant patent is as follows both at home and abroad:
CN200810069511.3,2008, University Of Chongqing, Yang Jun
CN200810070158.0,2008, University Of Chongqing, Yang Jun
CN200810070159.5,2008, University Of Chongqing, Yang Jun
CN200710092892.2,2007, University Of Chongqing, Yang Jun
CN200610054121.x, 2006, University Of Chongqing, Zhao Zhiqiang etc.;
CN1482234,2003, Shanghai Inst. of Technical Physics, Chinese Academy of Sciences, Zhang Tao etc.;
CN86210174, nineteen ninety-five, institute of oncology, Liaoning, Liang Wei;
4326934，April?27，1982，Pohl；
441972，April?10，1982，Pohl；
4578168，March?25，1986，Hofman；
4695547，Sep?22，1987，Hillard；
4699881，Oct?13，1987，Matschke，et?al；
5007995，Apr?16，1991，Takahizuki。
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of chip apparatus that the cell electricity merges that is used for is proposed, the integrated small cell structure of array on the chip, make and only can hold two cells in each small chamber by regulating small chamber size structure, thereby realize line up the in twos fusion rate in twos in efficient and later stage of high cell.
Technical scheme of the present invention is as follows:
A kind of cell electrofusion chip device based on micro-chamber array structure is made of jointly small chamber array chip, peripheral printed circuit board and stream control device.Peripheral electrical signal loads on the array chip of small chamber by peripheral printed circuit board, forms certain electric field in each small cell structure, queuing and the fusion of control cell in small cell structure; The function of stream control device is to realize the sample introduction of cell suspending liquid in chip apparatus, go out sample and flow.
Wherein, described small chamber array chip is to be stratum basale with the quartz, described small chamber array chip is to be stratum basale with the quartz, on quartz substrate layer, adopt micro-processing technology to be formed with metal microelectrode array, polymer sidewall and polymer and enclose the water hurdle, the metal microelectrode array is integrated metal microelectrode in a large number, metal microelectrode and polymer sidewall are contour, and two relative metal microelectrodes have constituted a small chamber with two relative polymer sidewalls, and small chamber also is arranged in array; Polymer encloses the water hurdle and is centered around outside the small chamber of whole array, and the metal microelectrode array has two terminations to stretch out in polymer to enclose the water marge, be used for and peripheral printed circuit board bonding.
For realizing that only holding two cells in each small chamber carries out the individual layer queuing, the degree of depth of small chamber is 15 μ m, and width is 5～30 μ m, and length can be regulated between 10～60 μ m according to the size of target cell.The thickness of metal microelectrode that makes up small chamber is identical with the degree of depth of small chamber, and length is 10 μ m, and width is 20 μ m, and size is regulated between 10～60 μ m between metal microelectrode relatively, and spacing is 20～40 μ m between the adjacent metal microelectrode between the small cell structure.Polymer sidewall thickness and metal microelectrode consistency of thickness, the polymer sidewall places in the middle of the adjacent electrode, and width is identical with spacing between adjacent microelectrode, and length is consistent with small chamber, present position length, moves mutually with the cell between isolated two adjacent small chambers.The metal microelectrode material is selected good conductivity as far as possible, and is anticorrosive, resistance of oxidation is strong, and the material of good biocompatibility is as gold, platinum etc.The polymer material also should possess better biocompatibility, can select polyimide, polyphenylene ethyl etc.
Described small chamber array chip is bonded on the peripheral printed circuit board, forms with printed circuit board to be electrically connected.Peripheral printed circuit board adopts the standard printed circuit board process to design and make, mainly arranged on the printed circuit board and a plurality ofly can carry out the bonding point that bonding is connected, and be distributed with the pad that is connected with extraneous electrical signal with the array microelectrode on the array chip of small chamber.
Described stream control module covers on the array chip of described small chamber, is made up of PDMS stream control cover plate and conduit.On small chamber array chip one side, being formed with and the suitable sample storage pond of the small chamber region area of array of PDMS stream control cover plate, there are microchannel and injection port, outlet in both sides, sample storage pond, leave between the baseplane in described sample storage pond and the plane, top of the small chamber of array and hold the gap that cell flows through.The function of stream control module is control cell suspending liquid flowing in chip in cell electricity fusion process, cooperate the unique texture of small chamber to realize each small indoor two cell that only hold, and utilizing microfluid to blow out cell unnecessary in the sample storage pond, its path can be described as: conduit-injection port-microchannel-sample storage pond-microchannel-outlet-conduit.The degree of depth in microchannel and sample storage pond is 40 μ m; Injection port/outlet need run through PDMS stream control cover plate, and injection port and outlet place the both sides of groove, and the diameter of injection port and outlet is 2mm, can regulate according to practical situation.
The micro-chamber array structure that the present invention proposes has following advantage:
Special construction and stream control module in conjunction with small chamber that this device makes up can realize each small indoor two cell that only hold, the queuing rate in twos of cell and fusion rate height in twos;
Between specific conductivity that metal microelectrode is good and comparative electrode than short spacing, make device only need the very low intensive peripheral electrical signal can be at the electric field of small indoor generation sufficient intensity, realize cell queuing and electric fusion process, reduced device the requirement of peripheral signal generator and the cost of manufacture of system;
Low operating voltage has also improved the security of system;
Metal microelectrode selects for use materials such as gold, platinum to improve the biocompatibility and anti-oxidant, the corrosion resistance of chip, has also improved chip reliability;
When can realizing a large amount of cell, small chamber array merges the fusion efficiencies height;
Automatic sampling and automatic sample outlet reduce to improve its survival ability to merging the physical damnification of back cell.
Description of drawings
Fig. 1 is based on the structural representation of the cell electric amalgamation microelectrode array chip apparatus of small cell structure;
Fig. 2 is based on the STRUCTURE DECOMPOSITION synoptic diagram of the cell electric amalgamation microelectrode array chip apparatus of small cell structure;
The each several part exploded view of the small chamber of Fig. 3 array chip;
The synoptic diagram of the small cell structure of Fig. 4;
The assembling synoptic diagram of Fig. 5 stream control module;
The structural representation of the peripheral printed circuit board of Fig. 6.
Embodiment
Embodiment 1:
Referring to Fig. 1, Fig. 2, form by small chamber array chip 1, stream control module 2 and peripheral printed circuit board 3 based on the cell electric amalgamation microelectrode array chip apparatus of small cell structure.
Referring to Fig. 2, Fig. 3 and Fig. 4, small chamber array chip 1 has quartz substrate layer 8, adopts micro-processing technology to be formed with metal microelectrode array 4, polymer sidewall 7 and polymer on quartz substrate layer 8 and encloses water hurdle 6.Metal microelectrode array 4 is integrated metal microelectrode 5 in a large number, two relative metal microelectrodes 5 have constituted a small chamber 9 with two relative polymer sidewalls 7, and small chamber 9 also is arranged in array.Metal microelectrode array 4 materials can be selected materials such as gold, platinum, and the polymer material can be selected materials such as polyimide, polyphenylene ethyl; The degree of depth of small chamber 9 is 15 μ m, and width is 5～30 μ m, and length can be regulated between 10～60 μ m according to the size of target cell.The thickness of metal microelectrode 5 that makes up small chamber is identical with the degree of depth of small chamber 9, and length is 10 μ m, and width is 20 μ m, and size is regulated between 10～60 μ m between microelectrode relatively, and spacing is 20～40 μ m between adjacent microelectrode.The consistency of thickness of polymer sidewall 7 thickness and metal microelectrode array 4, polymer sidewall 7 places in the middle of the phase adjacent electrode, width is identical with spacing between adjacent microelectrode, and length is consistent with small chamber, present position 9 length, moves mutually with the cell between isolated two adjacent cells.The termination of metal microelectrode array 4 can be used for and peripheral printed circuit board 3 bondings.
Referring to Fig. 5,2 of stream control modules are made up of PDMS stream control cover plate 11 and conduit 10, and the PDMS stream is controlled cover plate 11 and covered on the small chamber array chip 1.PDMS stream control cover plate 11 towards small chamber array chip 1 one side integrated injection port 14, outlet 15, microchannel 13 and with the suitable sample storage pond 12 of the small chamber region area of array.Leave between the plane, top of the small chamber 9 of the baseplane in sample storage pond 12 and array and hold the gap that cell flows through.The degree of depth in microchannel 13 and sample storage pond 12 is 40 μ m; The needs of injection port 14/ outlet 15 run through PDMS stream control cover plate 11, and injection port 14 and outlet 15 place the both sides in sample storage pond 12, and injection port 14 is 2mm with the diameter of outlet 15, can regulate according to practical situation.
Small chamber array chip 1 places on the peripheral printed circuit board 3, forms by bonding and printed circuit board to be electrically connected.Referring to Fig. 6, peripheral printed circuit board 3 adopts the standard printed circuit board process to design and make, periphery printed circuit board 3 central authorities are square viewing window 16, for the observation of testing provides good sight clear line, arranged on the peripheral printed circuit board 3 and a plurality ofly can carry out the bonding point 18 that bonding is connected, and be distributed with the pad 17 that is connected with extraneous electrical signal with the termination of metal microelectrode array 4 on the small chamber array chip 1.
The packaged type of this chip apparatus is: small chamber array chip 1 is placed on the peripheral printed circuit board 3, utilize spun gold, adopt bonding technology to connect the termination of metal microelectrode array 4 on the small chamber array chip 1 and the bonding point 18 on the peripheral printed circuit board; Subsequently, with small chamber array chip 1 and 30 seconds of stream control module 2 usefulness oxygen plasma treatment, again with stream control module 2 left-hand threads on small chamber array chip 1, sample storage pond 12 coincide with metal microelectrode array 4 zones, the two will be closely linked under physical action.
Embodiment 2: the complete processing of part-structure in the said apparatus
1, small chamber array chip employing MEMS complete processing realizes procedure of processing following (metallic array electrode layer material described herein selects golden Au, and the polymer layer material is selected polyimide for use):
A. select quartzy substrate for use as the processing chip;
B. sputter one deck Ti/W on quartz substrate, wherein, the thickness of Ti/W layer is 50nm;
C. electroplate one deck gold by galvanized mode at the Ti/W laminar surface, thickness is 15 μ m;
D. on the Ti/W/Au layer, etch the shape of microelectrode array by the mode of photoetching;
E. spin-on polyimide glue forms the quite polyimide layer of (15 μ m) of thickness and Ti/W/Au layer thickness in the said structure surface;
F. the photoetching polyimide forms the side structure of small chamber.
2, the processing of PDMS stream control cover plate realizes that by reverse mould technology procedure of processing is as follows:
A. utilize print circuit plates making technology, processing thickness is the mould of 40 μ m, and mould structure is cell suspending liquid sample storage pond, injection port, outlet and microchannel;
B. mould is fixed on the culture dish;
C. pour the PDMS epoxy glue that mixes into, vacuumize after static;
D. place 75 ℃ of curing on the warm table;
E. take off and solidify back PDMS, cut out, and the glue of removing injection port, outlet gets final product according to small chamber array chip shape.
Embodiment 3: the application that the cell electricity merges
From the injection port 14 described in the embodiment 1, use micro pump to inject cell suspending liquid; After path that cell suspending liquid is formed through conduit 10, injection port 14 and microchannel 13 enters sample storage pond 12, cell will under action of gravity, will sink to sample storage pond 12 correspondences below small chamber 9; The special construction of small chamber 9 makes its individual layer only can hold 2 cells, and unnecessary cell will be piled up on it; At this moment, in conjunction with stream control device 2, utilize micro pump to inject the cell electricity and merge damping fluid; Because small chamber 9 is dimple structures, under the obstruction of polymer sidewall 7, two cells in the small chamber 9 can not gone out by miniflow; And pile up the unnecessary cell on it owing to lack little 7 obstruction, will be along the microchannel 13, outlet 15 and conduit 10 paths flow out; At this moment, in each the small chamber in the small chamber array chip 12 cells are only arranged; Apply sinusoidal wave electrical stimulation signal by peripheral printed circuit board 3 to metal microelectrode array 4 again, to form a non-homogeneous gradient electric field between the two relative microelectrodes 5 in the small chamber 9, two cells in the small chamber 9 will carry out the cell queuing under the dielectrophoresis force effect; After the completion queue, apply the square-wave pulse sequence signal, the cell of completion queue will be to finishing cell electroporation-processes such as cell electricity fusion under the high-intensity pulsed electrical field effect in small chamber 9.After finishing cell electricity fusion process,, leave standstill, utilize the cell self gravitation that the cell after the fusion is sunk in the sample storage pond 12 from small chamber 9 this device upset; At this moment,, utilize micro pump to inject cell culture fluid again in conjunction with stream control device 2, with the cell damping fluid in the sample storage pond 12 through the microchannel 13, outlet 15 and conduit 10 paths go out.Obtain the cell damping fluid and can utilize culture dish to collect, carry out the cultivation in later stage.
Claims (8)
1. cell electrofusion chip device based on micro-chamber array structure is characterized in that: it is by small chamber array chip, and peripheral printed circuit board and stream control module are formed;
Described small chamber array chip is to be stratum basale with the quartz, on quartz substrate layer, adopt micro-processing technology to be formed with metal microelectrode array, polymer sidewall and polymer and enclose the water hurdle, the metal microelectrode array is integrated metal microelectrode in a large number, metal microelectrode and polymer sidewall are contour, two relative metal microelectrodes constitute a small chamber with two relative polymer sidewalls, and small chamber also is arranged in array; Polymer encloses the water hurdle and is centered around outside the small chamber of whole array, and the metal microelectrode array has two terminations to stretch out in polymer to enclose the water marge, be used for and peripheral printed circuit board bonding;
Described small chamber array chip is bonded on the peripheral printed circuit board, forms with printed circuit board to be electrically connected;
Described stream control module covers on the array chip of described small chamber, it is made of PDMS stream control cover plate and conduit, on small chamber array chip one side, being formed with and the suitable sample storage pond of the small chamber region area of described array of PDMS stream control cover plate, there are microchannel and injection port, outlet in both sides, sample storage pond, leave between the baseplane in described sample storage pond and the plane, top of the small chamber of array and hold the gap that cell flows through.
2. the cell electrofusion chip device based on micro-chamber array structure according to claim 1 is characterized in that: the degree of depth of described small chamber be controlled at hold target cell within it individual layer arrange and exceed.
3. the cell electrofusion chip device based on micro-chamber array structure according to claim 2, it is characterized in that: the degree of depth of described small chamber is 15 μ m, width is 5～30 μ m, length is regulated between 10～60 μ m according to the size of target cell, guarantees that two cells of each small indoor only confession merge.
4. the cell electrofusion chip device based on micro-chamber array structure according to claim 2, it is characterized in that: the degree of depth of described small cell structure is 15 μ m, length is 10 μ m, width is 20 μ m, size is regulated between 10～60 μ m between comparative electrode, and spacing is 20～40 μ m between adjacent microelectrode.
5. the cell electrofusion chip device based on micro-chamber array structure according to claim 1 is characterized in that: the metal microelectrode material in the array chip of described small chamber is selected gold or platinum; The polymer material selection that makes up sidewall possesses the polyimide or the polyphenylene ethyl of insulativity and biocompatibility.
6. the cell electrofusion chip device based on micro-chamber array structure according to claim 1, it is characterized in that: arranged on the described peripheral printed circuit board that the small chamber of array on the array chip of a plurality of and small chamber carries out the bonding point that bonding is connected, and be distributed with the pad that is connected with extraneous electrical signal.
7. the cell electrofusion chip device based on micro-chamber array structure according to claim 1 is characterized in that: the degree of depth in described microchannel and sample storage pond is 40 μ m, and the diameter of injection port and outlet is 2mm.
8. the cell electrofusion chip device based on micro-chamber array structure according to claim 1 is characterized in that: the central authorities of the described peripheral printed circuit board position corresponding with the small chamber region of array is viewing window.
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| CN108330067A (en) * | 2018-05-14 | 2018-07-27 | 上海启文生物科技有限公司 | Integrated casket shape cell fusion electrode |
| CN108330067B (en) * | 2018-05-14 | 2023-08-25 | 上海启文生物科技有限公司 | Integrated casket-like cell fusion electrode |
| CN108993621A (en) * | 2018-07-09 | 2018-12-14 | 浙江大学 | A kind of small room array micro-fluidic chip and method for digital enzyme linked immunosorbent detection |
| CN115895876A (en) * | 2022-11-30 | 2023-04-04 | 重庆大学 | Cell electrofusion chip device based on bilateral flow field pairing structure array and preparation method |
| CN115895876B (en) * | 2022-11-30 | 2024-04-02 | 重庆大学 | Cell electrofusion chip device based on double-side flow field pairing structure array and preparation method |
| CN115926975A (en) * | 2022-12-02 | 2023-04-07 | 重庆大学 | Cell electrofusion chip device based on lateral double-hole structure |
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