CN102175840A - Whole blood centrifugal separation chip and preparation method thereof - Google Patents
Whole blood centrifugal separation chip and preparation method thereof Download PDFInfo
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- CN102175840A CN102175840A CN2010106144380A CN201010614438A CN102175840A CN 102175840 A CN102175840 A CN 102175840A CN 2010106144380 A CN2010106144380 A CN 2010106144380A CN 201010614438 A CN201010614438 A CN 201010614438A CN 102175840 A CN102175840 A CN 102175840A
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Abstract
The invention discloses a whole blood centrifugal separation chip and a preparation method thereof and belongs to the field of micro-electromechanical system. A vortex-type microfluid passage is arranged on the chip; a sample inlet is arranged in the passing center of the microfluid passage; at least one row of micro upright post rails are arranged in the microfluid passage; the microfluid passage is divided into two or more flow passages by the micro upright post rails; and the flow passages are connected with different sample outlets. By pouring the whole-blood sample into the centrifugal separation chip through a micro pump, cells and blood plasma are separated by gaps between the micro upright post rails; the structure of the chip is compact, so the total area of the chip is reduced; the separating efficiency is enhanced; and the separating process of the chip costs a short time.
Description
Technical field
The invention belongs to the MEMS (micro electro mechanical system) field, be specifically related to a kind of whole blood centrifuging chip and chip production method that biological sample separates, detects, analyzes that be used for.
Background technology
21st century is the development and the biochemistry detection technology in the epoch, particularly biochip of cross discipline development.Sensing technology is the important means that information is obtained, and the information of utilizing sensing technology to obtain biological sample is an important content of Measurement for Biotechnique development.
BioMEMS (biological MEMS (micro electro mechanical system)) technology in conjunction with biotechnology and MEMS (micro electro mechanical system) (MEMS) technology can realize serialization, integrated, microminiaturized with the discontinuous analytic process in the life science (as specimen preparation, chemical reaction and analyzing and testing), thereby obtains so-called micro-total analysis system.This system comprises sample introduction, separation, reaction and detection, and the system of broad sense also relates to and transports, and its final goal is to realize complete chemical analysis on microchip, with the breadboard all functions of replacement conventional analysis.Compare with traditional instrument, plurality of advantages such as micro-total analysis system has that volume is little, in light weight, cost is low, portable band, anti-pollution, analytic process robotization, fast, the required sample of analysis speed and reagent are few, association areas such as biology, analytical chemistry, medical science are produced revolutionary impact, become the key areas in the MEMS technical research.
In the early stage research of micro-total analysis system, it is more that detection technique is studied always, obtained development faster.Yet pretreatment technologies such as sample separation are as ingredient indispensable in this system, and but development is slow relatively, has become the bottleneck in the The whole analytical process, and it is restricting the development of biochemical analysis.Existing sample pre-treatments technology often realizes outside sheet, has shortcomings such as time-consuming, that labour intensity big, be difficult to realize robotization, precision is poor, sample and other biochemical reagents consumptions are big mostly, and often is the main cause of error at measurment.Traditional sample separation technology can not satisfy the needs of μ TAS (Micro total analysis system) development, is necessary to develop a kind of new differential from technology.The microminiaturized biological sample pretreater that utilizes micro-processing technology to make has many advantages such as analysis efficiency height, sample and reagent consumption few (micro updating), energy consumption are low, integrated level height.Micro-processing technology provides powerful technical support for the pre-treatment and the analyzing and testing of micro-biological sample.This sample processing chip all can obtain using very widely at aspects such as biological detection, the identification of poison, DNA analysis, cell separation and enrichment, medicine preparation and drug conveying, becomes the focus of micro-total analysis system research.
In sum, the differential centrifugation system is as the pith of the miniature biochemical analysis of development system, with chemical analysis field wide application prospect is arranged biomedical, design a kind of simple in structure, volume is little, be convenient to integrated tiny segregator, not only has higher precision, also have very high reliability, the processing technology of exploitation separating chips and each assembly of microfluid drive system, and system integration technology will be challenging, a significant job.
Summary of the invention
The object of the present invention is to provide a kind of whole blood centrifuging chip, can utilize the preparation of MEMS body silicon and surface micromachined technology.
Whole blood centrifuging chip provided by the invention as shown in Figure 1.Chip is provided with the vortex microfluidic channel, the center that this microfluidic channel detours is an injection port, be provided with little column fence of at least one row in microfluidic channel, described little column fence is divided into two or more runners with microfluidic channel, and above-mentioned runner connects different outlets.
Utilize micropump or syringe pump will be mixed with of the injection port injection of the complete blood cell of different sizes from the centrifuging chip:
1. arrange little column fence situation shown in Fig. 1 (a) for two: the little column fence of two rows is divided into inner flow passage, intermediate flow channel and outer flow passage from the inside to the outside successively with microfluidic channel.Described inner flow passage links to each other with the leucocyte outlet, and described intermediate flow channel links to each other with the red blood cell outlet, and described outer flow passage links to each other with the blood plasma outlet.The present invention utilizes the column spacing size (the little column of second row gap is less than the little column of first row gap) of centrifugal force and little column fence to separate.Specifically: red blood cell and blood plasma less than the first row little column gap are split into intermediate flow channel in the motion process in fluid channel, and greater than the leucocyte in the little column of first row gap in fluid channel motion process still at Nei Dao.Blood plasma less than the second row little column gap is split into outer flow passage in the motion process in fluid channel, and greater than the red blood cell in the little column of second row gap in fluid channel motion process still in intermediate flow channel.
2. arrange little column fence situation shown in Fig. 1 (b) for one: little column fence is divided into inner flow passage and outer flow passage from the inside to the outside successively with microfluidic channel.Described inner flow passage links to each other with the red blood cell outlet with leucocyte, and described outer flow passage links to each other with the blood plasma outlet.Utilize centrifugal force and little column array pitch size to carry out separation of whole blood, blood plasma less than little column gap is split into outer flow passage in the motion process in fluid channel, and greater than the red blood cell in little column gap and leucocyte in fluid channel motion process still at inner flow passage.
The microfluidic channel of centrifuging chip of the present invention, little column fence are that a plurality of little columns arrangements form, and it can be processed on silicon chip, and also the mode that can utilize mould to duplicate is processed on polymeric material.With chip bonding of the present invention together be polymeric material or glass material.
Described microfluidic channel is semicircle make-up form or spiral of Archimedes form, and the number of turns of the center of detouring is at least 3 circles, and the width of every circle is 50-500 μ m.The diameter of injection port is 500-800 μ m.
The column cross-section of described little column fence is circular, and its diameter is for being at least 6 μ m.
The column cross-section of described little column fence is a square, and its length of side is for being at least 6 μ m.
The present invention also provides a kind of whole blood centrifuging chip production method, comprises step:
(a) processing, cleaning silicon chip;
(b) get rid of photoresist, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) about positive deep erosion (ICP) silicon 30～200 μ m of silicon chip, form microfluidic channel, miniature column fence, injection port and outlet;
(d) PDMS is mixed in 10: 1 ratio with its hardening agent, and fully stir, with the bubble among the vacuum pump removal PDMS;
(e) handle, cleaning silicon chip, and coat remover on its surface;
(f) bubble-free PDMS is all watered in double dish, and leave standstill planarization, in 80 ℃ of baking ovens, toasted about 1 hour then;
(g) PDMS that solidifies is cut into the same with the silicon chip that fluid channel is arranged big, and punches at corresponding injection port and outlet position;
(h) surface of PDMS and wafer bonding is handled with oxonium ion;
(i) PDMS and silicon chip are carried out bonding by corresponding position, metal tube is installed at microfluidic channel injection port and outlet.
The present invention also provides a kind of whole blood centrifuging chip production method, comprises step:
(a) processing, cleaning silicon chip;
(b) get rid of photoresist, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) about positive deep erosion (ICP) silicon 30～200 μ m of silicon chip, form the mould of microfluidic channel, miniature column fence, injection port and outlet;
(d) PDMS is mixed in 10: 1 ratio with its hardening agent, and fully stir, with the bubble among the vacuum pump removal PDMS;
(e) handle, clean described mould, and coat release agent on its surface;
(f) bubble-free PDMS is all watered on mould, leave standstill planarization, in 80 degree baking ovens, toasted 1 hour then;
(g) will solidify PDMS and peel off from mould, and each unit of cutting;
(h) handle, clean double dish, and coat release agent on its surface;
(i) bubble-free PDMS is all watered in double dish, leave standstill planarization, in 80 degree baking ovens, toasted 1 hour then;
(j) PDMS that solidifies is cut into the silicon chip with microfluidic channel onesize, and in corresponding microfluidic channel injection port and the punching of outlet position;
(k) two bonding surfaces up and down of PDMS are handled with oxonium ion;
(i) two PDMS are carried out bonding by corresponding position, metal tube is installed at injection port and outlet.
The present invention also provides a kind of whole blood centrifuging chip production method, comprises step:
(a) processing, cleaning silicon chip;
(b) get rid of photoresist, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) at positive dark etch silicon 30～200 μ m of silicon chip, form microfluidic channel, little column fence;
(d) the positive and glass anode linkage with silicon chip forms the silex glass sheet;
(e) the silicon structure layer attenuate at the silex glass sheet back side of the method that adopts dry method, wet method or CMP after with bonding;
(f) photoresist, preceding baking, photoetching, development, back baking are got rid of in the silicon chip back side;
(g) deep erosion is into and out of the through hole of sample mouth;
(h) PDMS is mixed in 10: 1 ratio with its hardening agent, and fully stir, with the bubble among the vacuum pump removal PDMS; Handle, clean double dish, and coat release agent on its surface; Bubble-free PDMS is all watered in double dish, and leave standstill planarization, in 80 degree baking ovens, toasted 1 hour then;
(i) PDMS that solidifies is cut into the silicon chip with fluid channel onesize, and in corresponding microfluidic channel injection port and the punching of outlet position;
(j) surface of PDMS and silex glass sheet bonding is handled with oxonium ion, bonding is also installed the metal tube of import and export.
The present invention makes full use of red blood cell, the red blood cell yielding characteristics different with the leucocyte size in the whole blood, advantage and MEMS technology features in conjunction with centrifugal separation technology, a kind of novel whole blood centrifuging chip has been proposed, adopt the little raceway groove of vortex shape, double (or single) cross-flow filtration to combine, utilize Micropump that whole blood sample is injected the centrifuging chip, by the first 3 μ m left and right sides slit of row between little column leucocyte is separated, utilized between second row's column slit less than 1 μ m again red blood cell and separating plasma.If the fluid channel that will have a double column becomes row's column fluid channel, can be used for isolated cell and blood plasma.This separating chips separates when can be used for red blood cell, leucocyte with blood plasma, can also be used for the separation of other functional particles.Single-chip by microfluid system and micro-fluidic drive system is integrated, for formation comprises the microcomputer reason that the real chip of sampling, sample introduction, separation, reaction, measuring ability provides process technology, micro-packaging technology and micro biochemical chip to detect biochemical reaction, can bring new scientific breakthrough.
The invention has the advantages that:
(1) separating chips adopts the method that centrifuging combines with broach, has improved separation efficiency, has avoided the obstruction of detachment process;
(2) realized three kinds of structures of silicon-polymkeric substance, polymkeric substance-polymkeric substance, glass-silicon-polymkeric substance, realized the job operation of multiple material, can reduce cost;
(3) adopt transparent polymer or glass processing, can be in detachment process the Real Time Observation separating effect, reduce the error in the detachment process, improved work efficiency;
(4) by the design of microfluidic channel, the compact conformation of whole blood centrifuging chip of the present invention, the total area of chip reduces, and separation efficiency improves.The detachment process of this chip weak point consuming time.
Description of drawings
(a)-(b) of Fig. 1 is the structural representation according to the whole blood centrifuging chip of the embodiment of the invention;
(a)-(g) of Fig. 2 is the whole blood centrifuging chip preparing process process flow diagram according to one embodiment of the invention;
(a)-(i) of Fig. 3 is the whole blood centrifuging chip preparing process process flow diagram according to another embodiment of the present invention;
(a)-(h) of Fig. 4 is the whole blood centrifuging chip preparing process process flow diagram according to further embodiment of this invention;
Wherein, 1: chip; 2: injection port; 3: outlet; 4: microfluidic channel; 5: inboard little column fence; 6: the little column fence in the outside; 7: the through hole of cover plate; 8: silicon chip; 9: photoresist; 10: release agent; 11,14:PDMS; 12: metal tube; 13: mould; 15: glass; 41: inner flow passage; 42 intermediate flow channel; 43: outer flow passage.
Embodiment
Below in conjunction with accompanying drawing, by specific embodiment, the present invention is further elaborated.
The invention provides a kind of whole blood centrifuging chip, comprise chip 1, injection port 2, outlet 3.Described outlet 3 has three, is respectively leucocyte outlet 31, red blood cell outlet 32 and blood plasma outlet 33.Shown in Fig. 1 (a), chip 1 comprises the microfluidic channel 4 of semicircle make-up form or spiral of Archimedes form, and be arranged in each and every one little column fence of two in the described microfluidic channel 4 along the flow directions in the described microfluidic channel 4 (be microfluidic channel circumferentially), described little column fence is that a plurality of little columns arrangements form, and is respectively the little column fence 6 of the inboard little column fence 5 and the outside.Also can only be provided with the little column fence 5 of a row in the whole blood centrifuging chip microfluidic channel 4 of the present invention, shown in (b) among Fig. 1.The detour number of turns of center of microfluidic channel 4 is 4 circles, is spaced apart 200-400 μ m between each circle.The diameter of the injection port 2 of chip is 500-800 μ m.Inboard little column fence 5 and the little column fence 6 in the outside are divided into inner flow passage 41, intermediate flow channel 42 and outer flow passage 43 with microfluidic channel 4.Distance between little column of inboard little column fence 5 is 3-10 μ m, is preferably 3 μ m.Distance between little column of outer microtube column fence 6 is 1-3 μ m, is preferably 1 μ m.The cross section of little column fence 5 of internal layer and outer microtube column fence 6 is circular or square.Circular separating effect is best, so the cross section of little column 5 of internal layer and outer microtube column 6 is preferably circle.Round diameter can be taken as 6-30 μ m, the desirable 6-30 μ of square length of side m.Size in processing or separating experiment, is easily fitted into the column fracture during less than 6 μ m, if size during greater than 30 μ m, processing easily, but it is less to separate the slit that is used to separate in the raceway groove, separation efficiency is divided and is reduced.
Utilize micropump or syringe pump will be mixed with of injection port 2 injections of the haemocyte of different sizes from chip, utilize centrifugal force to separate with little column array pitch size, cell less than little column fence 5 gaps, inboard is split into intermediate flow channel 42 in the motion process in fluid channel, and greater than the cell in little column fence 5 gaps, inboard in fluid channel motion process still at inner flow passage 41, cell less than little column fence 6 gaps, the outside is split into outer flow passage 43 in the motion process in fluid channel, and greater than the cell in little column fence 6 gaps, the outside in fluid channel motion process still at inner flow passage 42.Inner flow passage 41, intermediate flow channel 42 and outer flow passage 43 be corresponding leucocyte outlet, red blood cell outlet and blood plasma outlet respectively.
Change the spacing of inboard little column fence 5 and the little column fence 6 in the outside on the chip 1, can be used for the separation of the haemocyte (for example turn round slowly micro beads that the bio-reactor cultured cell uses etc.) of different size.
Embodiment 1: process centrifugal separator on silicon chip
The structure of present embodiment is referring to Fig. 1, and technological process is referring to Fig. 2.
1) the silicon chip structural manufacturing process flow process of chip:
(a) processing, cleaning silicon chip 8;
(b) get rid of photoresist 9, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) about the positive deep erosion of silicon chip (ICP) silicon 100 μ m, form microfluidic channel 4, miniature column fence 5,6, injection port 2, three outlets 3;
2) the cover plate polymer process flow process of chip:
(d) handle, cleaning silicon chip 8, and coat release agent 10 on its surface;
(e) bubble-free silicon rubber photoresist (PDMS) 11 is all watered in double dish, and leave standstill planarization, in 80 ℃ of baking ovens, toasted about 1 hour then;
(f) PDMS11 that solidifies is cut into the same with the silicon chip that fluid channel is arranged big, and punches at corresponding injection port and outlet position.The surface of PDMS and silicon structure bonding is handled with oxonium ion, suitably increase bond strength, otherwise meeting leakage when sample introduction;
(g) PDMS and silicon chip structure are carried out bonding by corresponding position, install the metal tube 12 of import and export.
Embodiment 2: go out centrifugal separator with Polymer Processing
The structure of present embodiment is referring to Fig. 1, and technological process is referring to accompanying drawing 3.
1) the polymer architecture technological process of separation vessel:
(a) processing, cleaning silicon chip 8;
(b) get rid of photoresist 9, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) about positive deep erosion (ICP) silicon 100 μ m of silicon chip, form microfluidic channel 4, miniature column fence, injection port and outlet;
(d) handle, clean silicon structure mould 13, and coat release agent 10, bubble-free PDMS11 is all watered on the mould 13 of silicon structure, and leave standstill planarization, in 80 ℃ of baking ovens, toasted about 1 hour then on its surface;
(e) will solidify PDMS and peel off from silicon mould 13, and each unit of cutting;
2) cover plate polymer process flow process:
(f) handle, cleaning silicon chip 8, and coat release agent 10 on its surface;
(g) bubble-free PDMS14 is all watered in double dish, and leave standstill planarization, in 80 ℃ of baking ovens, toasted about 1 hour then;
(h) PDMS14 that solidifies is cut into the same with the silicon chip that fluid channel is arranged big, and punches at corresponding injection port and outlet position;
(i) two bonding surfaces are handled with oxonium ion up and down, suitably increase bond strength, otherwise meeting leakage when sample introduction is carried out bonding with two PDMS by corresponding position, installs the metal tube 12 of import and export.
Embodiment 3: the centrifugal separator of sandwich structure
The technological process of present embodiment is referring to Fig. 4.
(a) processing, cleaning silicon chip 8;
(b) get rid of photoresist 9, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) about positive deep erosion (ICP) silicon 50 μ m of silicon chip, form microfluidic channel 4, miniature column fence, injection port 2, outlet 3 (with method one similar);
(d) positive and glass 15 anode linkages of silicon chip;
(e), can adopt the method for dry method, wet method or CMP with the thinning back side silicon chip of the silex glass sheet behind the bonding;
(f) photoresist, preceding baking, photoetching, development, back baking are got rid of in the silicon chip back side;
(g) etch inlet and outlet deeply;
(h) PDMS11 that solidifies is cut into the same with silicon chip big, and gets through the hole at corresponding injection port and outlet position; The surface of PDMS and silicon structure bonding is handled with oxonium ion, suitably increase bond strength, install the metal tube 12 of import and export.
Shortcomings such as the present invention has overcome current separating chips complex structure, preparation technology's difficulty is big, separation efficiency is low, realize on a low cost, high-performance, the high efficiency micro chip integrated morphology microanalysis platform on the cell separation sheet, utilize MEMS body silicon and surface micromachined technology to come analytic system on the sheet of preparative centrifugation separation vessel.
It should be noted that at last the purpose of publicizing and implementing example is to help further to understand the present invention, but it will be appreciated by those skilled in the art that: without departing from the spirit and scope of the invention and the appended claims, various substitutions and modifications all are possible.Therefore, the present invention should not be limited to the disclosed content of embodiment, and the scope of protection of present invention is as the criterion with the scope that claims define.
Claims (8)
1. whole blood centrifuging chip, it is characterized in that, chip is provided with the vortex microfluidic channel, the center that this microfluidic channel detours is an injection port, in microfluidic channel, be provided with little column fence of at least one row, described little column fence is divided into two or more runners with microfluidic channel, and above-mentioned runner connects different outlets.
2. whole blood centrifuging chip as claimed in claim 1 is characterized in that described microfluidic channel is any deployable curve forms such as semicircle make-up form or spiral of Archimedes, and the number of turns that detours is at least 3 circles, and the width of every circle is 50-500 μ m.
3. whole blood centrifuging chip as claimed in claim 2, it is characterized in that, be provided with the little column fence of two rows in the described microfluidic channel, two little column fence are divided into three runners that width is identical with microfluidic channel, the column spacing that is positioned at little column fence of microfluidic channel inboard is 3-10 μ m, the column spacing of another little column fence is 1-3 μ m, and the column height of the identical or little column fence in the outside of the column height of two little column fence is a little less than the column height of the little column fence in inboard.
4. whole blood centrifuging chip as claimed in claim 3 is characterized in that, the xsect of each little column of described little column fence is a square or circular, and the diameter of circular little column is at least 6 μ m, and the length of side of foursquare little column is at least 6 μ m.
5. whole blood centrifuging chip as claimed in claim 1 is characterized in that, the diameter of described injection port is 500-800 μ m.
6. each described whole blood centrifuging chip production method of claim 1-5 is characterized in that, comprises step:
(1-1) chip preparation;
(a) processing, cleaning silicon chip;
(b) get rid of photoresist, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) at positive dark etch silicon 30～200 μ m of silicon chip, form microfluidic channel, little column fence, injection port and outlet;
(1-2) cover plate preparation;
(d) PDMS is mixed in 10: 1 ratio with its hardening agent, and fully stir, with the bubble among the vacuum pump removal PDMS;
(e) handle, clean double dish, and coat release agent on its surface;
(f) bubble-free PDMS is all watered in double dish, and leave standstill planarization, in 80 degree baking ovens, toasted 30 minutes to 1 hour then;
(g) PDMS that solidifies is cut into the silicon chip with microfluidic channel onesize, and beats several through holes at corresponding microfluidic channel injection port and outlet position;
(1-3) cover plate and chip bonding;
(h) surface of PDMS and wafer bonding is handled with oxonium ion;
(i) PDMS and silicon chip are carried out bonding by corresponding position, metal tube is installed at microfluidic channel injection port and outlet.
7. the preparation method of each described whole blood centrifuging chip slapper of claim 1-5 is characterized in that, comprises step:
(1-1) chip preparation;
(a) processing, cleaning silicon chip;
(b) get rid of photoresist, preceding baking, photoetching, development, back baking in the silicon chip front;
(c), form the mould of microfluidic channel, little column fence, injection port and outlet at positive dark etch silicon 30～200 μ m of silicon chip;
(d) PDMS is mixed in 10: 1 ratio with its hardening agent, and fully stir, with the bubble among the vacuum pump removal PDMS;
(e) handle, clean described mould, and coat release agent on its surface;
(f) bubble-free PDMS is all watered on mould, leave standstill planarization, in 80 degree baking ovens, toasted 30 minutes to 1 hour then;
(g) will solidify PDMS and peel off from mould, and each unit of cutting;
(1-2) cover plate preparation;
(h) handle, clean double dish, and coat release agent on its surface;
(i) bubble-free PDMS is all watered in double dish, leave standstill planarization, in 80 degree baking ovens, toasted 1 hour then;
(j) PDMS that solidifies is cut into the silicon chip with microfluidic channel onesize, and beats several through holes at corresponding microfluidic channel injection port and outlet position;
(1-3) cover plate and chip bonding;
(k) two bonding surfaces up and down of PDMS are handled with oxonium ion;
(l) two PDMS are carried out bonding by corresponding position, metal tube is installed at injection port and outlet.
8. each described whole blood centrifuging chip production method of claim 1-5 is characterized in that, comprises step:
(1-1) chip preparation;
(a) processing, cleaning silicon chip;
(b) get rid of photoresist, preceding baking, photoetching, development, back baking in the silicon chip front;
(c) at positive dark etch silicon 30～200 μ m of silicon chip, form microfluidic channel, little column fence;
(d) the positive and glass anode linkage with silicon chip forms the silex glass sheet;
(e) the silicon structure layer attenuate at the silex glass sheet back side of the method that adopts dry method, wet method or CMP after with bonding;
(f) photoresist, preceding baking, photoetching, development, back baking are got rid of in the silicon chip back side;
(g) lose deeply into and out of the sample mouth;
(1-2) cover plate preparation;
(h) PDMS is mixed in 10: 1 ratio with its hardening agent, and fully stir, with the bubble among the vacuum pump removal PDMS; Handle, clean double dish, and coat release agent on its surface; Bubble-free PDMS is all watered in double dish, and leave standstill planarization, in 80 degree baking ovens, toasted 30 minutes to 1 hour then;
(i) PDMS that solidifies is cut into the silicon chip with fluid channel onesize, and beats several through holes at corresponding microfluidic channel injection port and outlet position;
(1-3) cover plate and chip bonding;
(j) handle with oxonium ion on the surface of PDMS and silex glass sheet bonding, and bonding is also installed the metal tube of import and export.
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