CN101813695A - Microfludic chip for rapid detection of microcystins and preparation method thereof - Google Patents
Microfludic chip for rapid detection of microcystins and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of biological analysis and detection, in particular to a microfludic chip for rapid detection of microcystins and a preparation method thereof. The microfludic chip is made of optically transparent polydimethylsiloxane and the like by a molding method, and mainly comprises a sample reaction microchannel layer, a valve control layer and a substrate layer. The microfludic chip comprises a sample enriched and immunoassay module which consists of parallel immune chromatographic column microanalysis chambers in nanolitre volume. Microcystin antibody proteins or antigens are fixed in each analysis chamber, and rapid on-site detection of representative algal toxins, namely microcystins in samples with different sources is realized. Besides the advantages of high sensitivity and specificity, the microfludic chip has the characteristics of rapidness, high efficiency, portability, low cost and easily automatic control, can finish automatic signal acquisition, remote transmission and signal analysis, and is suitable for on-site rapid detection and remote control detection in a wide range for the microcystins in the water environment.
Description
Technical field
The invention belongs to bioanalysis detection technique field, be specifically related to a kind of micro-fluidic chip that is used for field quick detection inspection Microcystin (microcystins), and this chip production method is provided.
Background technology
" wawter bloom " phenomenon is a global problem in " red tide " and the fresh water.The main rivers in the whole world are gone into the sea area all " red tide " phenomenon.The occurrence frequency and the scope of " red tide " and " wawter bloom " are on the rise at present, and all there is the repeatedly report of outburst in main bay of China and landlocked main lake (Taihu Lake, Dian Hu, Chaohu), have a strong impact on ecologic environment, aquaculture and human beings'health.The intoxicating phenomenon that is caused by algae toxin also has repeatedly report, and Fla. population 8,000,000 only just had 500 correlations poisonings report in 1994 to 2005.According to record, with prehuman PSP poisoning (Prakash et al., 1971) were arranged approximately 1600 times in 1970, and just took place 900 times in 1970 to 1984.(WHO, 1984) spot covers areas such as the U.S., Europe, Japan, the Asian-Pacific area, South America and Australia.
At present the domestic water pollution condition is serious, and wherein the environmental pollution that causes of algae increases the weight of especially day by day: show as blue-green algae, outburst frequency and the scope of green alga are rapid ascendant trend.Under the suitable situation of temperature and nutritional labeling, algae breeds rapidly, piles up at the water surface to pollute; When algae was dead, oxygen caused aquatic fish kill in the consume water again, gives out a foul smell to cause polluting repeatedly.Even more serious is that algae can produce various toxin, influences safety and the human beings'health of aquatic animal.Algae toxin also can enrichment in the fish body, thereby enters human diet by food chain.In addition, the algae toxin chemical property is highly stable, and the cleaning system of thermophilic digestion and ordinary tap water all is difficult to its removing.Therefore annual alga eruption not only causes the mass mortality of freshwater fish, destroys nature and ecologic environment, and has a strong impact on human beings'health.Main algae toxin in the fresh water environment is Microcystin (microcystins), and its main harm liver also is a kind of strong carcinogen.China now issue execution Drinking Water hygienic quality standard (2001,0.001mg/L) and water environment quality standard (GB3838-2002.Microcapsule algae toxin 0.001mg/L) has all comprised the test item of Microcystin; The World Health Organization (WHO) instructs in the drinking water standard of its recommendation has also increased Microcystin (MC, index (WHO.1998) such as 1ug/L) in (second edition).
In order to protect human health; aquatic environment and protection aquaculture; the early warning system of green alga outburst is badly in need of being used in country; and the key member of this system is exactly can the various algae toxin concentration of telemonitoring, the microsensor system of nitrogen, phosphorus, organic content, pH value, water temperature, oxygen content and intensity of illumination and water body turbidity in the water.By this sensor that on water body in large, distributes, monitor various parameters and toxin concentration in the water body in real time, just can provide early warning to drinking water quality and green alga outburst.
The algae toxin detection technique of domestic and foreign current mainly comprises:
1) bioassay method.The main method that adopts toxin such as feeding mouse, housefly, shortcoming is that the cycle is long, the expense height, poor repeatability, and need the personnel of special training to operate.
2) physical-chemical process.Main by high performance liquid chromatography, Capillary Electrophoresis, the combined gas chromatography mass spectrometry method, favorable reproducibility, but functions of the equipments are single, and volume is big and cost an arm and a leg portable, poor selectivity.
3) cytotoxicity detection technique.After direct-vision method was observed and added toxin, the toxin kind is judged in the reaction of cell, and was highly sensitive, but can only do observational measurement, can not measure concentration and need the good cell culture technique.
4) radioactivity standardization.The instrument costliness, the testing expense height, and suitable toxin sensing range is narrow.
5) immunoassay technology.Immunological technique mainly utilizes antigen and antibody is single-minded, the characteristics contratoxin of specific bond carries out qualitatively, and detection by quantitative now mainly contains the direct competitive detection method, indirect method, " sandwich " method.This method selectivity is strong, highly sensitive, is very potential a kind of method, but operation is more loaded down with trivial details, and commercial kit costs an arm and a leg, and is mainly manual operations, and automaticity is low and need the professional.
At present, most of algae toxins use and cost an arm and a leg, bulky HPLC-MS or GC-MS detects, and specimen preparation process complexity, length consuming time need the professional and technical personnel to operate, and testing cost is very high.Therefore limited the conventional sense number of times.In recent years, the scientist of the U.S., Germany and China uses immunological technique in conjunction with computing machine, sensor technology, the original position immunologic detection method of algae toxin in the research water.But these methods exist sample pre-treatments loaded down with trivial details, need the quality that detecting instrument cooperates, detection time is long and reviewer's needs are higher and be subjected to good training, be not suitable for field operation, temporal resolution is low, shortcomings such as detection cost height.Be badly in need of wanting a kind of efficient now, fast, portable and detection technique at a low price.
Still there is not practical representative algae toxin rapid detection system up to now both at home and abroad.Following technical development mainly concentrates on the multifunction and microminiaturization of detecting instrument.External multifunction instrument concentrates on the self-reacting device that can measure the water body multiple nutritional components simultaneously that is used for the marine environment analysis.But equipment volume is bigger, not too is fit to the environment of freshwater lake.The development trend that current algae toxin detects is: (1) analyzes the purpose that reaches monitoring and early warning continuously; (2) express-analysis reaches online detection and early warning fast; (3) high flux reaches the detection to the multiple toxin of several samples; (4) increasingly automatedly finish popularizing at natural water area; (5) portability adapts to the needs of quick layout and military chemical defence.
The microminiaturization of instrument concentrates on the application facet of micro-fluid chip in environmental analysis.This technology especially has a wide range of applications aspect the bioanalysis in chemistry, biology, biomedical engineering.Microsensor or analytical instrument based on micro-fluid chip are the development trends that FUTURE ENVIRONMENT is analyzed.Except environmental protection department (EPA), US military is also at the chip technology of seeking to be used for express-analysis water body component (the conventional water sample parameter such as kind, content and turbidity, pH value etc. that comprises microorganism and all contaminations).
The microfluid subject that grow up the nineties in 20th century is meant the science and technology of fluid in the small network channel of operation (5-500 micron).It is the development and incorporation of various modern technology such as Protocols in Molecular Biology, micro-processing technology, Machine Manufacturing Technology, computer technology.Be based on the micro device of extensive parallel processing biological information molecule principle, have that the information flux is big, a robotization, systematized characteristics.Micro-fluid chip is used for operation, and transmission microlitre (10-6L) is to the fluid of millimicro microlitre (10-15L) magnitude.Some steps of biochemical reaction can be comprised that analysis, washing, detection etc. are integrated on one or a few micro-fluid chip, its aperture, microchannel has only the micron order size, have the effect that concentrates with enrichment, can accelerated reaction shorten the test duration, thereby greatly reduce testing cost.Compare with the experimental technique of routine, the waste liquid that this technology greatly reduced the consumption (at least 3 orders of magnitude) of reagent, analyze to produce simultaneously is few.NE BY ENERGY TRANSFER in small scope, material disperse faster more even, and thermal energy conduction is fast, various the controlling of also easier realization, so reaction is fast, yield is high, pollutes less, cost is low.The micro-fluid chip of a new generation is by macromolecular material, silicone polydimethylsiloxane (PDMS) for example, make (seeing accompanying drawing 1), material cheap (being less than 10 U.S. dollars/sheet), manufacturing cycle short (being less than 24 hours), equipment needed thereby is the minority conventional equipment, does not need large-scale secret instrument, be suitable for large-scale production, can be used for producing disposable product.The trend of the development of this technology is chip lab, whole Biochemical Lab function can be integrated on the chip piece to finish.
In addition, since the physics elasticity of PDMS material, multiple functional module, for example little valve, fluid pump and fluid mixer can be integrated in the micro-fluid chip.And this valve slightly, can the controlling of functional modules such as fluid pump by computer programming.Like this integrated, digital control type micro-fluid chip just can be finished some complicated operations.For example separate, sample introduction cleans, chemistry or bioanalysis operations such as chromatographic column isolation identification.Based on the instrument of micro-fluid chip PCR for example, albumen crystallization instrument, DNA tests instrument all have been designed to create.Compare with usual manner, its principal feature is:
1) at a low price, because the amount of the reagent that uses is extremely micro-, the expense of finishing the test needs is extremely low;
2) efficient, reaction velocity is fast in micro-fluid chip, heat and mass efficient height, and test speed is fast;
3) use the manufacturing of masterplate technology, be applicable to large-scale production;
4) integrated easily, the test module of different target can be integrated in the chip piece very easily, finishes the multiple goal parallel parsing;
5) automaticity height, it can be easily and the modern electronic technology combination, not only makes the chip analysis test automatically, and signal transmission and the automatic analysis of signal also can be finished automatically.
6) compatible good, other microanalysis technology, microelectrode technology for example, biosensor technology also can be incorporated in the micro-fluid chip technology.
Summary of the invention
The object of the present invention is to provide a kind of micro-fluidic chip and preparation method thereof that is used for representative algae toxin Microcystin (microcystins) field quick detection.This chip compare with existing detection technique have efficiently, at a low price, the characteristics of portable and robotization.
The micro-fluidic chip that microcystins in actual sample (water sample and foodstuff samples such as fish, the shellfish) solution is carried out fast detecting that comprises provided by the invention, this chip is base material with the optically transparent material, by the sample channel layer, valve key-course and substrate layer constitute successively; Wherein, example enrichment and immunoassay module are arranged in the sample channel layer, this example enrichment and the immunoassay module immune chromatograph post microanalysis chamber that rises volume of receiving in parallel by one or several or series connection is formed.Each microanalysis chamber is connected with a plurality of sample introduction skies and outlet, each analysis room is fixed with Microcystin antibody protein or antigen by the polymerization filling bonding, can specific immune response take place with the microcystins in the sample mixture, the immunoassay signal is realized by the reactant (antibody or antigen) of mark, after repeatedly washing, the variation of the generation of immune labeled signal such as the variation of fluorescence intensity can be by the signal acquisition module collection analysises.Signal acquisition module is made up of ultraviolet LED and fluorescence photosensor array, specificity between antibody/Microcystin all can be gathered and reach in the microprocessor (computing machine) by photosensor array in conjunction with the optical signalling that causes and database is compared, and comes the concentration of the contained toxin of analytic sample.The optically transparent material that the present invention is used for the micro-fluidic chip of fast detecting microcystins is selected from inorganic material: quartzy, glass, hard high molecular polymer: polycarbonate, polymethylmethacrylate, poly-to this dioctyl phthalate ethylene glycol fat, polystyrene, polypropylene, elastomeric polymer: dimethyl silicone polymer; Mold materials is a silicon chip.
Among the present invention, immune chromatograph post microanalysis chamber is arranged in the sample channel floor.The valve key-course contains the pneumatic control valve door, the switch in the relevant duct of may command sample channel layer.The valve of valve key-course is by air pressure or electronic component control, and the diameter of valve passage is 1～3 μ m.
The immune chromatograph post microanalysis chamber of micro-fluidic chip of the present invention is that integral post or polymerization filling are irritated post, and polymerization filling is silica filler or other organic polymer.
The number of immune chromatograph post microanalysis of the present invention chamber can be determined by actual conditions, reach the wherein nature difference of each composition as sample number, the micro-fluidic chip that has prepared a monocyte sample in concrete enforcement of the present invention can be according to actual conditions in parallel by different way or series connection with this single channel.
Whole test system control hardware part is mainly by control section (computing machine), operating system (integrated micro-fluid chip, numerical control interface) and data acquisition, data analysis part (computing machine).Software systems mainly comprise LABVIEW program (control) and ImagePro program (data analysis).
The invention provides preparation method's (is example with positive glue) specific as follows of above-mentioned micro-fluidic chip:
(1) substrate is prepared: dry up with nitrogen after silicon chip is put into the deoxidation of Piranha solution, get rid of through spin coater with SU-82050 series and be coated with soft baking on the heated at constant temperature plate;
(2) expose and cure: with the sample channel layer that designs, the silicon chip template of valve key-course is placed on respectively gets rid of on the substrate that coats, and uses the exposure of uv-exposure machine, cures on heating plate afterwards;
(3) develop: silicon chip is put into developer solution develop, use isopropyl alcohol and washed with de-ionized water clean afterwards respectively, and dry up with nitrogen;
(4) hard baking: on hot plate, slowly add heat fixation;
(5) cast: PDMS (dimethyl silicone polymer) monomer and hardening agent mixed by the quality proportioning in 5: 1 to 20: 1, were poured on respectively on the corresponding silicon chip mould, solidified in baking oven, peeled off;
(6) bonding: two-layer PDMS chip calibration bonding is formed the chamber, microchannel, again with the substrate layer bonding.
Description of drawings
A kind of design drawing that is used for the fast detecting micro-fluidic chip of Microcystin (microcystins) of Fig. 1.
Fig. 2 is used for the fast detecting micro-fluidic chip of Microcystin (microcystins) and specifically implements synoptic diagram.
Number in the figure: 1 air valve gas access, 2 sample inlets, 3 air valve gas passages, 4 sample channels, 5 filler import/exports, microanalysis chambers 6,7 sample exports.
Embodiment
Substrate is prepared.Silicon chip is put into Piranha solution (98% concentrated sulphuric acid: 30% hydrogen peroxide=7: 3) boil cleaning 15min.Dry up with nitrogen with behind the deionized water rinsing 5 times, and cure 30min. at 200 ℃
Get rid of and be coated with.The SU-8 glue (down together) of Microchem company is poured on silicon chip central authorities, grasps silicon chip edge and make it also slowly rotation, make SU-8 cover silicon chip major part zone.(Inc.) with 3000 commentaries on classics/min spin coating 60s, it is comparatively even that glue is distributed for Spin-Coater KW-4A, ChematTechnology, leaves standstill 10min and alleviate edge projection effect with spin coater.
Soft baking.The purpose of soft baking is the solvent evaporates that makes in the SU-8 photoresist, and the key of technology controlling and process is that solvent evaporates is carried out with controlled speed.Keep 3min, 6min and 3min respectively at 65 ℃, 95 ℃ and 65 ℃.Slowly reduce to room temperature with the speed of 0.5 ℃/min afterwards.
Exposure.Adopt contact exposure machine (wavelength 365nm).
Post exposure bake (PEB, post exposure bake).The speed with 5 ℃/min progressively is raised to 95 ℃ by room temperature on the hot plate again, during keep 1min and 5min respectively at 65 ℃ and 95 ℃.Slowly reduce to room temperature with the speed of 0.5 ℃/min afterwards.
Be developed in the fuming cupboard and carry out, the principal ingredient of developer solution is 1-Methoxy-2-propyl acetate (PGMEA).Mould is put into the developer solution 7min that develops, use isopropyl alcohol and washed with de-ionized water clean afterwards respectively, and dry up with nitrogen.
Hard baking.120 ℃ of heating 5min on hot plate, 180 ℃ of heating 5min, 200 ℃ of heating 20min slowly reduce to room temperature again.
Cast PDMS forming polymer.PDMS monomer and hardening agent are mixed the Ex-all bubble according to 5: 1 quality proportioning.Be poured on the SU-8 mould that trimethyl chlorosilane was handled, 80 ℃ keep 1h to solidify on the horizontal hot plate of adjusting.Form the substrate that the upper strata has the microchannel layer.
PDMS layer with control channel is made.On silicon chip, get rid of resist coating,, make silica-based smooth formpiston through uv-exposure, development, and in 115 ℃ of annealing 20min, make the softening silica-based optical cement formpiston of photoresist with trimethyl chlorosilane stifling 5min in gas phase, make its surface silicon alkanisation, to prevent the adhesion of PDMS in injection moulding process.And having the PDMS layer monomer of control channel and the ratio of hardening agent is 18: 1, softer relatively.2000 commentaries on classics/min get rid of and are coated with 35s on photoresist spinner.Form the substrate that lower floor has the by-pass valve control passage.
Bonding and interface are made.With the punching of upper strata substrate, lower floor's substrate punching is used for control channel.Up and down two careful involutory, 80 ℃ of curing of spending the night.
The volume of single immune microanalysis chamber is 180 μ m * 30 μ m * 2 μ m.
If immune microanalysis chamber chromatographic column is the polymeric material packed column, can in three sample intake passages of Fig. 1, any post be adorned in the perfusion of polymeric material filler, closed post bottom valve, by-pass valve control air pressure is no more than 20psi, post speed is adorned in control simultaneously, treat that filler fills laggard damping fluid balance chromatographic column, bag is anti-or antigen by two, actual sample (water sample and fish, foodstuff samples such as shellfish) solution, specific antibody and mark competition thing arbitrary sample holes in figure one enter chromatographic column, incubation 5-10 minute, advance excessive antibody of lavation buffer solution flush away and mark competition thing, add the colour developing of colour developing damping fluid, specificity between antibody/algae toxin all can and reach in the microprocessor (computing machine) by the photosensor array collection of signal acquisition module in conjunction with the optical signalling that causes and compare with database, comes the concentration of the contained toxin of analytic sample.Whole test system control hardware part is mainly by control section (computing machine), operating system (integrated micro-fluid chip, numerical control interface) and data acquisition, data analysis part (computing machine).Software systems mainly comprise LABVIEW program (control) and ImagePro program (data analysis) as shown in Figure 2.
Claims (6)
1. micro-fluidic chip that is applied to the fast detecting Microcystin; It is characterized in that this chip is base material with the optically transparent material, successively by the sample channel layer, valve key-course and substrate layer constitute; Wherein, example enrichment and immunoassay module are arranged in the sample channel layer, this example enrichment and immunoassay module several independent immune chromatograph post microanalysis chambers that rise volume of receiving in parallel by one or several or series connection are formed, the Microcystin antibody protein has been fixed by the polymerization filling bonding by each analysis room, so that immune response takes place; The valve key-course contains the pneumatic control valve door, the switch in the relevant duct of may command sample channel layer.
2. micro-fluidic chip according to claim 1, it is characterized in that institute's optical clear states material and be selected from inorganic material: quartzy, glass, hard high molecular polymer: polycarbonate, polymethylmethacrylate, poly-to this dioctyl phthalate ethylene glycol fat, polystyrene, polypropylene, elastomeric polymer: dimethyl silicone polymer; Mold materials is a silicon chip.
3. micro-fluidic chip according to claim 1 is characterized in that the immune chromatograph post is that integral post or polymerization filling are irritated post, and polymerization filling is silica filler or other organic polymer.
4. micro-fluidic chip according to claim 1, the key compound that it is characterized in that the immunoassay module are two anti-or antigens, and the immunoassay signal realizes that by the reactant of mark label is various dyestuffs or fluorescence.
5. the preparation method of a micro-fluidic chip as claimed in claim 1 is characterized in that using method of molding, and concrete steps are as follows:
(1) substrate is prepared: dry up with nitrogen after silicon chip is put into the deoxidation of Piranha solution, get rid of through spin coater with SU-82050 series and be coated with soft baking on the heated at constant temperature plate;
(2) expose and cure: with the sample channel layer that designs, the silicon chip template of valve key-course is placed on respectively gets rid of on the substrate that coats, and uses the exposure of uv-exposure machine, cures on heating plate afterwards;
(3) develop: silicon chip is put into developer solution develop, use isopropyl alcohol and washed with de-ionized water clean afterwards respectively, and dry up with nitrogen;
(4) hard baking: on hot plate, slowly add heat fixation;
(5) cast: dimethyl silicone polymer monomer and hardening agent mixed by the quality proportioning in 5: 1 to 20: 1, were poured on respectively on the corresponding silicon chip mould, solidified in baking oven, peeled off;
(6) bonding: two-layer polydimethylsiloxanechip chip calibration bonding is formed the chamber, microchannel, again with the substrate layer bonding.
6. the application in the analyzing and testing Microcystin of micro-fluidic chip according to claim 1 is characterized in that concrete steps are as follows:
Sample solution enters chip by the injection port of described micro-fluidic chip, Microcystin antibody protein in the chip microanalysis chamber or the Microcystin generation specific immune response in antigen and the sample, the immunoassay signal is realized by the antigen of mark, after repeatedly washing, the variation that immune labeled signal produces such as the variation of fluorescence intensity are by the signal acquisition module collection analysis; Signal acquisition module is made up of ultraviolet LED and fluorescence photosensor array, specificity between antibody/algae toxin all can be gathered and reach in the microprocessor by photosensor array in conjunction with the optical signalling that causes and database is compared, and comes the concentration of the contained Microcystin of analytic sample.
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| CN102784674A (en) * | 2012-08-13 | 2012-11-21 | 苏州汶颢芯片科技有限公司 | Centrifugal micro-fluidic chip for detecting chromium ion form in water body and preparation method of centrifugal micro-fluidic chip |
| CN102784671A (en) * | 2012-08-13 | 2012-11-21 | 苏州汶颢芯片科技有限公司 | Centrifugal micro-fluidic chip for detecting pesticide residue and preparation method thereof |
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| CN103760052A (en) * | 2013-12-21 | 2014-04-30 | 中国科学院苏州生物医学工程技术研究所 | Piezoelectric detection sensor for microcystic toxins based on molecular imprinting technology |
| CN108517284A (en) * | 2018-03-19 | 2018-09-11 | 复旦大学 | It is a kind of to be used to study algal grown and the micro-fluidic chip of reproduction |
| CN110227563A (en) * | 2019-05-13 | 2019-09-13 | 晶准生物医学（深圳）有限公司 | The encapsulating method and PDMS micro-fluidic chip of PDMS micro-fluidic chip vaporization prevention |
| CN110227563B (en) * | 2019-05-13 | 2020-08-14 | 晶准生物医学（深圳）有限公司 | Evaporation-proof sealing method for PDMS (polydimethylsiloxane) micro-fluidic chip and PDMS micro-fluidic chip |
| CN112924663A (en) * | 2021-01-22 | 2021-06-08 | 大连理工大学 | Paper chip device for rapidly and quantitatively detecting algal toxins in water on site and application thereof |
| CN113358612A (en) * | 2021-05-24 | 2021-09-07 | 宁波大学 | Micro-nano optical sensor for algae detection and manufacturing and detection method thereof |
| CN113358612B (en) * | 2021-05-24 | 2022-11-08 | 宁波大学 | Micro-nano optical sensor for algae detection and manufacturing and detection method thereof |
| CN114192125A (en) * | 2021-12-03 | 2022-03-18 | 晋江精纯科技有限公司 | Preparation method of hybrid silica gel chromatographic packing |
| CN114192125B (en) * | 2021-12-03 | 2024-01-30 | 晋江精纯科技有限公司 | Preparation method of hybrid silica gel chromatographic packing |
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