CN1275040C - Micro flow control chip of silicon rubber and method for face finish - Google Patents
Micro flow control chip of silicon rubber and method for face finish Download PDFInfo
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- CN1275040C CN1275040C CN 200310119036 CN200310119036A CN1275040C CN 1275040 C CN1275040 C CN 1275040C CN 200310119036 CN200310119036 CN 200310119036 CN 200310119036 A CN200310119036 A CN 200310119036A CN 1275040 C CN1275040 C CN 1275040C
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Abstract
The present invention relates to a micro-fluid control chip of silicone rubber, which is obtained by using isocyanate function reagent as coupling agent by the silicone rubber chip so as to couple compounds of various hydroxy group classes, amino group classes and carboxyl classes to the surface of the silicone rubber. Various needed polymers can be modified by the surface of the chip, and the polymers can be longtime reserved on the surface of the chip. The performance of the surface is stable and persistent. The hydrophilicity, the electric charge density and the kinds of electric charge of the surface of the chip can be optionally adjusted by selecting different polymers so as to obtain different micro-fluid control chips of silicone rubber.
Description
Technical field:
The present invention relates to the micro-total analysis technology, silicon rubber (PDMS) micro-fluidic chip that provides surperficial sequencing to modify especially.
Background technology:
Micro-fluidic chip is that the sampling of sample, pre-treatment, sample introduction, separation, detection are integrated in several square centimeters big or small technology on the chip.Therefore amalyzing substances directed migration, course of reaction in microchannel just must strictly control the character on microchannel surface, reduces the absorption loss of analyte in transition process, and the condition of analyte response is provided.Silicon chip, glass, quartz are early stage chip materials, because their material price height, manufacturing process is loaded down with trivial details, have therefore limited popularizing and using of micro-fluidic chip.Silicon rubber (PDMS) since can utilize the template massive duplication, cheap, make simple, technical maturity, thereby receive increasing attention.Compare with the surface chemical modification of silicon chip, quartz, glass maturation, the surface chemical modification of silicon rubber still is at the initial stage.
The research that silastic surface is modified is the focus of surface chemistry research always, particularly aspect medical material.The uv induction grafting is a kind of important method, generally is with pending material organic solvent extraction, and finish-drying is immersed in the mixed solution of a certain amount of high polymer monomer and photosensitizer then, reacts several hrs under the irradiation of ultraviolet light.This method is more loaded down with trivial details, and the roughness on surface is uncontrollable.Because the transmittance of micro flow chip is lower, the microchannel size is little, and this method is used some difficulties in microchannel.
Cement Composite Treated by Plasma also is a kind of method relatively more commonly used.Plasma treatment is quick, simple, but the surface nature after this method is handled is lost easily, and the surface nature that can obtain by this method is more limited.
Chemical vapor deposition also has some application.But this method needs relatively more expensive instrument and equipment, and needs long-term experiment condition to grope, and similar to the uv induction grafting, this method also is difficult to be applied in the microchannel.
The technology contents of invention:
The objective of the invention is to a kind of silicon rubber micro-fluidic chip and surface modification method thereof, can make the various required polymkeric substance of finishing of chip by this method, and polymkeric substance can keep for a long time on the surface of chip, the stable in properties on surface is lasting.The kind of the water wettability by selecting the adjusting chip surface that different polymkeric substance can be random for use, electric density, electric charge is to obtain different silicon rubber micro-fluidic chips.
The invention provides a kind of silicon rubber micro-fluidic chip, it is characterized in that: described chip be by with the silicon rubber chip with isocyanate function reagent as coupling agent, the surface that various hydroxy kinds, carboxyl class, amino compound is coupled to silicon rubber obtains.
In the silicon rubber micro-fluidic chip of the present invention, the microchannel of chip can be straight line, broken line; Can be single microchannel, also can be array channel.Width of channel is between 1 micron and 1 millimeter, and the degree of depth is between 5 microns and 500 microns.
The present invention also provides the surface modification method of above-mentioned silicon rubber micro-fluidic chip, it is characterized in that: as coupling agent, hydroxy kind, carboxyl class or amino compound are coupled to the surface of silicon rubber with isocyanate function reagent.
In the surface modification method of silicon rubber micro-fluidic chip of the present invention, described isocyanate function reagent is diisocyanate or polyisocyanates, be selected from 2, the 4-toluene diisocyanate, 2, the 6-toluene diisocyanate, diphenyl methane-4,4 '-diisocyanate, 1, hexamethylene-diisocyanate, many benzene of polymethylene polyisocyanates, isophorone diisocyanate, XDI, naphthalene-1,5 diisocyanate, dicyclohexyl methyl hydride diisocyanate, a kind of or their polymer and their potpourri of tetramethylxylylene diisocyanate.
Coupling process carries out in solvent, and the solvent characteristics of use is not contain amino, hydroxyl or carboxyl, to avoid solvent and isocyanate reaction.The concentration of coupling agent is at 0.01 to 10 mole every liter.
With can add 0.01% to 10% catalyzer in the hydroxyl compound reaction: tertiary amine catalyst (for example tetramethyl butane diamine, triethylenediamine), Organometal compound catalyst (for example stannous octoate, dibutyl tin laurate).
In the surface modification method of silicon rubber micro-fluidic chip of the present invention, described hydroxy kind compound can be cellulose, methylcellulose or their derivant; The derivant of glucosan or glucosan; The hydrolysate of polyvinyl alcohol (PVA) or polyvinyl alcohol (PVA) and polyvinyl acetate alcohol ester, polyglycol, poly-hydroxyethyl methyl acrylate.
In the surface modification method of silicon rubber micro-fluidic chip of the present invention, described carboxyl compounds can be polyacrylic acid or polyacrylic derivant.Can also be further with contain amino compound coupling.
In the surface modification method of silicon rubber micro-fluidic chip of the present invention, described amino compound can be the derivant of derivant, tygon imido or the tygon imido of polylysine or polylysine.Can also be further and the compound coupling that contains amino or carboxyl.
In the surface modification method of silicon rubber micro-fluidic chip of the present invention, the preferably poly-dimethoxy silane of described silicon rubber.
In the surface modification method of silicon rubber micro-fluidic chip of the present invention, before coupling, silastic surface can activate with plasma or acid earlier.The source of the gas of plasma can be oxygen, nitrogen, hydrogen, air and their combination gas, between 1 second to the 30 minutes time of activation; Acid concentration at 0.1 to 10 mole every liter, 1 minute to the 10 hours time of activation.Chip surface after the activation has hydroxyl, amino or carboxyl to produce.The surface of chip can not activate yet, diisocyanate can with the reaction of moisture of remained on surface.
In the preparation process of silicon rubber micro-fluidic chip of the present invention, the template of micro flow chip can come from following any one material: silicon chip, quartz, glass, light-sensitive compound (SU-8), silicon rubber (PDMS), polymethylmethacrylate (PMMA), polycarbonate (PC) wait other macromolecular compounds.The egative film of silicon rubber chip can be following any one material: silicon rubber, glass, quartz, silicon chip, PMMA, PC and other polymkeric substance.
In the silicon rubber chip of the present invention, the feature of macromolecular compound is that amino, carboxyl or hydroxyl are arranged on the compound.Compound can be neutral, also can be charged.Neutral compound can be: cellulose, methylcellulose and their derivant; The derivant of glucosan and glucosan; Polyvinyl alcohol (PVA) and it and polyvinyl acetate alcohol ester hydrolysate; Polyglycol; Poly-hydroxyethyl methyl acrylate and other polyols.The electropositivity compound can be: polylysine, tygon imido and other polyamino compound.The negative electricity compound can be: polyacrylic acid and derivant, dextran sulfate and other sulfonic compounds.Compound also can be to mix polymers or block polymer.
The silicon rubber chip that the surface sequencing is modified can coupling neutrality compound, be used for the electrophoretic analysis of protein, nucleic acid, cell, reduce the absorption of biomacromolecule at silastic surface.Also can coupling polyamino compounds, thus allow the surface of chip have positive charge, realize the Electrostatic Absorption of pair cell, protein, nucleic acid, thus surface immobilized at chip; These amino also can with amino or the carboxyl reaction on the biomacromolecule, realize pair cell, protein and nucleic acid, especially enzyme molecule covalent coupling, thereby be used for the out-phase immunoassay, immobilized enzyme reaction, solid-phase nucleic acid hybridization analysis.
The basic process of the surface modification method of silicon rubber micro-fluidic chip of the present invention is: pattern is printed after the machine Aided Design as calculated, makes baffle plate, directly corrosion moulding on glass or quartz then, and chip is made in sealing-in; Also can make template with silicon chip, glass, quartz, metal, copy daughter board on various plastics, sealing-in becomes chip then.
The surface modification method of silicon rubber micro-fluidic chip of the present invention has the following advantages:
(1) the various required polymkeric substance of modification that the surface of chip can sequencing.
(2) based on (1), polymkeric substance can keep for a long time on the surface of chip, and the stable in properties on surface is lasting.
(3), select water wettability, the electric density of the adjusting chip surface that different polymkeric substance can be random, the kind of electric charge for use based on (1).
In addition, through the silicon rubber chip that surface modification method of the present invention is modified, have the advantage of following aspect at least:
(1) surface hydrophilic reduces the generation of bubble.
General aqueous solution can not be soaked into hydrophobic chip surface, and the total surface of chip is residual one deck bubble that has, and these bubbles are totally unfavorable to the operation on the chip, if these bubbles enter solution when electrophoresis, then can reduce separation efficiency even blocking-up electric current.And in the silicon rubber chip that surperficial sequencing of the present invention is modified, the water wettability of chip surface strengthens, and the surface of chip can be soaked into fully with solution, has reduced the generation of above situation.
(2) with reduce biomacromolecule especially protein in the absorption on the surface of chip.
The transhipment of protein in the microfluidic channel of chip is the problem of often facing in the biochemical analysis with separating, protein is very serious in hydrophobic surface adsorption, can reduce the efficient that protein shifts like this, remain in the protein of chip surface even can cause pollution the other biological sample.The efficient that the serious reduction of the absorption meeting on surface separates is selected suitable neutral hydrophilic polymer, can reduce absorption greatly, improves the efficient of separating.
(3) the silicon rubber chip of finishing can reduce the cost of microfluidic system.
Now a large amount of micro-fluidic chips that use mainly are glass and quartz material, because the surface of PDMS hydrophobicity and to the absorption of biomolecule greatly, practical application is few.The silicon rubber chip that the surface sequencing is modified can increase water wettability, so reducing the absorption of analyte can use in practice, relatively the cost with glass and quartz chip PDMS chip is extremely low, and can massive duplication, so can reduce the cost of microfluidic analysis greatly.
(4) the silicon rubber chip of surperficial sequencing modification can be used for integrated nucleic acid hybridization and proteolysis on the micro flow chip.
The nucleic acid molecules that the PDMS chip surface that amino or carboxyl base polymer are modified can the coupling amination be modified, if will contain the solution of specific nucleic acid fragment flows into, just can realize the hybridization identification of nucleic acid molecules in the microchannel, thereby nucleic acid molecules be carried out qualitative and quantitative.If at the surperficial conjugate enzyme molecule of chip, just can if combine, just can realize the peptide analysis of spectrum of protein to protein digestion in microchannel with analysis.
Description of drawings:
Fig. 1 is protein electrophoresis analysis PDMS chip figure
Fig. 2 is that the basic protein lysozyme is at the electrophoretogram that does not have on the PDMS chip of modifying
Fig. 3 is the electrophoretogram of basic protein lysozyme on polyethyleneglycol modified PDMS chip
Embodiment:
(1) makes chip.Make chip as shown in Figure 1, CAD draws mask, and the high precision printer prints is on the PMMA film, to scribbling the silicon chip sensitization of positive glue, develop then, become template after the etching, the Sylgard of Dow Corning Corporation 184 glue mixed by 10: 1,80 ℃ on the silicon template polymerization got final product in two hours.By same step, make the PDMS flat board at dull and stereotyped silicon chip.
(2) plasma treatment.The base plate of PDMS chip and PDMS was handled in plasma 10 minutes, realized irreversible sealing-in, made the PDMS microchannel of sealing.
(3) reaction of toluene diisocyanate.Under protection of nitrogen gas, feed the solution of the dimethyl formamide of 10% toluene diisocyanate, (in add dibutyl tin laurate 0.1%), room temperature reaction 10 minutes is extracted residual solution out with vacuum pump,
(4) coupling of tygon imido.Feed the dimethyl formamide solution of 2% tygon imido, reaction is 10 minutes under the room temperature, extracts residual solution out with vacuum pump.
(5) mensuration of electroosmotic flow.The effect of handling is reflected by electroosmotic flow.Phosphate buffer with pH2 is measured.The electroosmotic flow of the chip before handling is 0.00005cm.cm/s, and the electroosmotic flow of the chip after the processing is reverse, and electroosmotic flow is 0.0005cm.cm/s, and the electroosmotic flow before and after handling has increased by 10 times.
(6) water wettability of chip.Chip before handling can not be by water infiltration, and solution can not be full of microfluidic channel automatically.The water wettability of the chip after the processing obviously strengthens, and solution can be full of microchannel automatically.
(7) stability on the surface after the processing.Compare with the chip surface of Cement Composite Treated by Plasma, the stability on surface increases greatly.The effect of Cement Composite Treated by Plasma approximately can be kept about 1 day, and coupling the surface of polypropylene imido can keep about half each month.
Embodiment 2 polyacrylic surperficial couplings
(1) making of chip, plasma treatment embodiment 1 are similar.
(2) 1, the reaction of 6 diisocyanate normal hexanes.Under protection of nitrogen gas, feed the solution of the dimethyl formamide of 10%1,6 diisocyanate normal hexanes, (in add triethylamine 0.1%), room temperature reaction 10 minutes is extracted residual solution out with vacuum pump.
(3) polyacrylic surperficial coupling.Feed 1% polyacrylic dimethyl formamide solution and reacted 10 minutes down for 50 ℃, extract residual solution out with vacuum pump.
(4) stability on the surface after the water wettability of chip, the processing is similar to embodiment 1.
The modification of embodiment 3 neutral polymer polyglycol
(1) reaction of the making of chip, plasma treatment, toluene diisocyanate is similar to embodiment 1.
(2) coupling of polyglycol.The dimethyl formamide solution of the polyglycol of feeding 20% adds 0.5% dibutyl tin laurate in the solution, reaction is 30 minutes under the room temperature, and residual solution is extracted out with vacuum pump.
(3) water wettability of chip.Compare with the chip before handling, the water wettability of the chip after the processing obviously increases, but the weak and chip polyethyleneimine: ammonia treatment.
(4) stability on the surface after the processing.Coupling the surface of polyglycol can keep about half each month.
(5) protein electrophorese analysis.Chip after the processing is used for the electrophoretic analysis of albumen.The serious (see figure 2) of chip protein adsorption before handling, and electrophoresis can obtain good effect in the microchannel of albumen after processing.(see figure 3).
The modification of embodiment 4 neutral polymer poly-hydroxyethyl methyl acrylates
(1) reaction of the making of chip, plasma treatment, toluene diisocyanate is similar to embodiment 1.
(2) coupling of poly-hydroxyethyl methyl acrylate.The dimethyl formamide solution of the poly-hydroxyethyl methyl acrylate of feeding 5% does not have catalyzer in the solution, 50 ℃ were reacted 10 minutes, and residual solution is extracted out with vacuum pump.
(3) stability, the protein electrophorese analysis on the water wettability of chip, the surface after handling obtain with
The effect that embodiment three is close.
(4) anti-albumen Static Adsorption.Pour into fluorescein-labeled protein solution in microchannel, place after 10 minutes, with damping fluid flushing 5 minutes, the chip channel after the modification, fluorescence signal obviously is weaker than not modified microchannel.
The surperficial coupling of embodiment 5 protein (affinity element)
(1) at chip surface elder generation coupling electropositivity polymer poly ethene imido.
(2) An Ji activation.5% glutaraldehyde pH7 BAS process chip 1 hour.
(3) the surperficial coupling of affinity element.The plain pH7 BAS of 0.1% affinity process chip 1 hour.
(4) Biao Mian aftertreatment.With containing 1% lysine and 1% sodium borohydride pH7 BAS process chip 1 hour.
(5) effect of the surperficial coupling of affinity element.With 0.01% fluorescein-labeled biotin flushing chip, can find that the surface selectivity of finishing keeps biotin, fluorescence signal is strong, and not modified channel surface fluorescence signal is very weak.
Claims (10)
1, a kind of silicon rubber micro-fluidic chip is characterized in that: described chip be by with the silicon rubber chip with isocyanate function reagent as coupling agent, the surface that various hydroxy kinds, amino class, carboxyl compounds is coupled to silicon rubber obtains.
2, a kind of surface modification method of silicon rubber micro-fluidic chip is characterized in that: as coupling agent, hydroxy kind, carboxyl class or amino compound are coupled to the surface of silicon rubber with isocyanate function reagent.
3, surface modification method according to the described silicon rubber micro-fluidic chip of claim 2, it is characterized in that: described isocyanate function reagent is selected from 2, the 4-toluene diisocyanate, 2, the 6-toluene diisocyanate, diphenyl methane-4,4 '-diisocyanate, 1, hexamethylene-diisocyanate, many benzene of polymethylene polyisocyanates, isophorone diisocyanate, XDI, naphthalene-1,5 diisocyanate, dicyclohexyl methyl hydride diisocyanate, a kind of or their polymer and their potpourri of tetramethylxylylene diisocyanate.
4, according to the surface modification method of the described silicon rubber micro-fluidic chip of claim 2, it is characterized in that: described hydroxy kind compound is cellulose, methylcellulose or their derivant; The derivant of glucosan or glucosan; The hydrolysate of polyvinyl alcohol (PVA) or polyvinyl alcohol (PVA) and polyvinyl acetate alcohol ester; Polyglycol; The poly-hydroxyethyl methyl acrylate.
5, according to the surface modification method of the described silicon rubber micro-fluidic chip of claim 2, it is characterized in that: described carboxyl compounds is polyacrylic acid or polyacrylic derivant.
6, according to the surface modification method of the described silicon rubber micro-fluidic chip of claim 2, it is characterized in that: described amino compound is the derivant of derivant, tygon imido or the tygon imido of polylysine or polylysine.
7, according to the surface modification method of the described silicon rubber micro-fluidic chip of claim 2, it is characterized in that: described silicon rubber is poly-dimethoxy silane.
8, according to the surface modification method of claim 2 or 5 described silicon rubber micro-fluidic chips, it is characterized in that: the carboxyl in the described carboxyl compounds further with contain amino compound coupling.
9, according to the surface modification method of claim 2 or 6 described silicon rubber micro-fluidic chips, it is characterized in that: the amino in the described amino compound further with the compound coupling that contains amino or carboxyl.
10, according to the surface modification method of the described silicon rubber micro-fluidic chip of claim 2, it is characterized in that: before coupling, silastic surface activates with plasma or acid earlier.
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| CN 200310119036 CN1275040C (en) | 2003-12-11 | 2003-12-11 | Micro flow control chip of silicon rubber and method for face finish |
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| CN 200310119036 CN1275040C (en) | 2003-12-11 | 2003-12-11 | Micro flow control chip of silicon rubber and method for face finish |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1952658B (en) * | 2005-10-19 | 2011-09-14 | 陕西北美基因股份有限公司 | Process of sugar bio-chip |
| CN101654654B (en) * | 2009-09-16 | 2012-07-04 | 华东师范大学 | Method for modifying DNA microfluidic chip micro-channel with mixed screening medium |
| CN103033608A (en) * | 2011-10-10 | 2013-04-10 | 中山大学 | Integration micro-fluidic chip for immune analysis research and applications thereof |
| CN105474018B (en) * | 2013-08-23 | 2018-01-23 | 株式会社朝日精细橡胶研究所 | Microchemistry chip and reaction unit |
| CN110655669A (en) * | 2018-06-28 | 2020-01-07 | 浙江清华柔性电子技术研究院 | Antistatic silicone rubber |
| CN110947439A (en) * | 2019-12-20 | 2020-04-03 | 凡知医疗科技(江苏)有限公司 | Surface modification method of micro-fluidic chip |
| WO2022022480A1 (en) * | 2020-07-27 | 2022-02-03 | 南京金斯瑞生物科技有限公司 | Surface linker of semiconductor chip, preparation method therefor and application thereof |
| CN114225561B (en) * | 2022-02-23 | 2022-04-29 | 北京清源华建环境科技有限公司 | Concave polyhedral streamlined suspended lightweight filter material, preparation method and application |
| CN116218002B (en) * | 2022-12-21 | 2024-10-01 | 厦门为正生物科技股份有限公司 | Dextran modified PDMS, preparation method and microfluidic chip |
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