CN101498704A - Valveless micro-flow control gradient real-time reaction chip and reaction control method - Google Patents
Valveless micro-flow control gradient real-time reaction chip and reaction control method Download PDFInfo
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Abstract
The invention relates to a valveless micro-fluidic gradient real-time reaction chip and a reaction control method in the micro-fluidic technical field. Magnetic particles are marked on target molecules which need reacting with drugs, while non-retentive micro-column arrays are arranged in a concentration gradient field forming zone in the front of the tail end of an outlet of a traditional pyramid-type micro-fluidic gradient chip, by the structure, a high gradient magnetic field generated under an external magnetic field previously adsorbs drug molecules marked with the magnetic particles before the gradient field reaction, thereby the drug molecules are fixed in a pipeline at the front end of the outlet of the pyramid-type micro-fluidic gradient chip. When in gradient real-time reaction, after being continuously shunted and mixed and finally forming the gradient field at the tail end of the chip and flowing through the soft non-retentive micro-column arrays, drugs can simultaneously react with the drug molecules fixed hereof. The design of the chip is mainly used in various aspects such as the research of biological macromolecule reaction and action mechanism, the screen of drugs, and the like.
Description
Technical field
The present invention relates to the chip and the control method in a kind of microflow control technique field, specifically, what relate to is a kind of Valveless micro-flow control gradient real-time reaction chip and reaction control method.
Background technology
Along with biomedical and chemical continuous development, at present a lot of researchs all concentrate on the molecular level.In recent years, the appearance of microflow control technique makes biochemical analysis new direction occur.Microflow control technique is meant to be controlled in micron order yardstick (main finger widths and height) pipeline and the technology of analysing fluid.Compare with the method for routine, microflow control technique can effectively reduce reagent consumption, shortens the reaction time, makes automaticity higher, realizes high flux, large-scale detection, thus reducing cost, testing result is also more reliable.Therefore all obtained at aspects such as disease detection, environmental monitoring, chemosynthesis, gene sequencing using widely.And in the research of gradient micro-fluid chip, though still be in the starting conceptual phase at present both at home and abroad, the possibility of its high throughput testing, especially noticeable to the advantages such as minimizing of precious reagent consumption is subjected to the great attention of domestic and international research institution.
Find through literature search prior art, calendar year 2001 Dertinger etc. " form the method for different complicated gradients " at last the 1240th page to the 1246 pages articles of delivering of the 6th phase of calendar year 2001 " analytical chemistry " (Analytical Chemistry) in microfluidic networks (Generation of gradients havingcomplex shapes using microfluidic networks) proposes to utilize the laminar flow of microfluid and the different linear discrete concentration gradient that hybrid technology forms sample, a kind of structure of pyramid is adopted in this chip design, make and adopt polymer plastic PDMS (dimethyl silicone polymer), with low cost, process-cycle is short, can be by accurate design so that behind the single injected sampling to chip, gradient fields in the chip outlet forms the linear concentration gradient distribution that forms medicine in the district, and this micro-fluidic chip has caused people's very big concern.By changing design, the micro-fluidic gradient chip of this pyramid also can be used to produce the CONCENTRATION DISTRIBUTION of logarithm, linearity or parabolic shape on chip in recent years.
Microfluid gradient chip research at present is hotter, but most research is in the formation of drug concentration gradient fields, as the formation of logarithm concentration field, theoretical research etc.If can will be fixed on the gradient fields of chip in advance with the target molecule of drug response forms in the district, drug molecule enters in the chip, can not only form in the gradient fields of chip end and form gradient in the district, and just react simultaneously with the target molecule that is fixed in this district, so multiple function is all concentrated in the monolithic micro-fluidic chip, just can directly observe the different drug concentration gradients and the interaction of target molecule at sheet, once experiment on sheet just is equivalent to traditional a plurality of tests, will more save time, more convenient operation, also more meaningful, really bring into play the application advantage of microfluid gradient chip on biochemical analysis.But the terminal gradient fields that target molecule accurately must be fixed on the gradient chip like this forms in the district, and can not be fixed on other zone in the chip, this just relates to the positioning and fixing of biomacromolecule in micro-fluidic chip, and for now, this also is the difficult point of whole micro-fluidic technologies.
In order to address the above problem, Hsin-Chih Yeh etc. are at article that " nucleic acids research " (Nucleic Acids Res) of 2006 the 21st phase e411 pages or leaves delivers " on the micro-fluidic platform research SP1-DNA react to each other " (A microfluidic-FCS platform for investigation on the dissociationof Sp1-DNA complex by doxorubicin) proposed a kind of improved design to the micro-fluidic gradient chip of pyramid, its agent structure layer remains the gradient chip of pyramid, but in this design, chip integral body be designed to three layers, the substrate that is divided into bottom, the pipeline configuration layer of pyramid gradient chip and based on the key-course of PDMS (dimethyl silicone polymer) material, because the PDMS material has very little Young modulus, therefore can control the deformation of this one deck ad-hoc location by adding source of the gas, the deformation of this layer can cause the pipeline configuration layer of pyramid structure that deformation also takes place, thus the opening of controlling plumbing fixtures and closure.By the valve of this three-decker design, just can control target molecule in fixing of gradient fields ad-hoc location and reacting to each other of medicine gradient fields and target molecule.Though the design of Hsin-Chih Yeh can effectively form in conjunction with gradient fields and react with target molecule, but this class chip has adopted and has added that valve is controlled the biomolecule of the reaction in the chip or fixing, need sandwich construction, increased the difficulty of processing.And the opening and closing of valve all need an extra source of the gas to operate on it, and have increased the difficulty of control.Therefore press for a kind of novel method of research, can carry out real-time biochemical reaction in the gradient fields that micro-fluidic gradient chip forms, chip is easy to processing and operation again simultaneously.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of Valveless micro-flow control gradient real-time reaction chip and reaction control method be provided, make its can be in single chip the formation of integrated drug concentration gradient fields and multi-functional with target molecule reaction etc.This chip need not valve it is controlled, and does not therefore need above-mentioned document introduction external source of the gas is controlled, and because structure does not relate to multilayer technology, compares above-mentioned valvular chip design, and difficulty of processing is also lower.
The present invention is achieved by the following technical solutions:
Valveless micro-flow control gradient real-time reaction chip involved in the present invention, comprise the micro-fluidic gradient chip of pyramid, the micro-fluidic gradient chip of described pyramid upper outlet proterminal concentration gradient field is provided with the soft magnetism micro-pillar array in the formation district, is used to produce high-gradient magnetic field and fixes the target molecule that is marked with magnetic particle.
The micro-fluidic gradient chip of described pyramid is a double-decker, i.e. the pipeline configuration on substrate and upper strata thereof.Wherein substrate is provided with the soft magnetism micro-pillar array on the corresponding position in the formation district, concentration gradient field in itself and pipeline configuration.The micro-fluidic gradient chip of Xing Chenging just is distributed with the micro-pillar array of soft magnetism in its terminal formation district, concentration gradient field like this.Medicine and medicine damping fluid are in injection port imports chip, and through each flow dividing structure and mixed structure, shunting constantly mixes, and the end at chip forms gradient fields and flows through the soft magnetism micro-pillar array at last.
Described soft magnetism micro-pillar array, be by certain forming by the microtrabeculae that has soft magnetism apart from assembled arrangement with certain altitude, these magnetic micro-pillar array can produce accurate Distribution of Magnetic Field under the effect of outside magnetic field, so just can reach and accurately control the purpose that magnetic particle distributes in micro-fluidic chip, and then control location and the reaction of target molecule in chip that is marked with magnetic particle.
Valveless micro-flow control gradient real-time reaction control method involved in the present invention comprises the steps:
The first step is made the soft magnetism micro-pillar array in the pipeline in the formation district, terminal concentration gradient field that the micro-fluidic gradient chip of pyramid exports;
Second step, feed the target molecule that has magnetic particle by the target molecule injection port, when it flows through formation district, concentration gradient field, apply the soft magnetism micro-pillar array of permanent magnetism iron (or adding electromagnetic field) magnetization in this district, this structure will produce high-gradient magnetic field, adsorb the target molecule that is marked with magnetic particle, finish the accurate positioning and fixing of target molecule in the concentration gradient field of pyramid gradient chip.
The 3rd step, when carrying out gradient real-time reaction, medicine and medicine damping fluid still enter in the chip respectively by the injection port of traditional pyramid gradient chip, through constantly shunting and mixing, end at chip forms gradient fields and flows through the soft magnetism micro-pillar array at last, just can react with the target molecule that is fixed on herein.So just can when forming concentration gradient, just implement online real time reaction, finish the formation of medicine gradient fields and multi-functional simultaneously with the reaction of target molecule etc.
The 4th step, reaction finishes, remove external magnetic field, because the soft magnetism of soft magnetism array and the paramagnetism of magnetic particle, neither have magnetic hysteresis, therefore no longer interact, feed magnetic particle damping fluid (as phosphate buffer) and just the compound that is marked with the target molecule-reactant of magnetic particle can be washed away, chip can utilize once more.
Mark drug molecule such as antibody, DNA etc. are methods at present biologically commonly used on the magnetic particle, have a lot of merchants to sell and the product of research unit.And advantages such as specific surface area is big, paramagnetism that magnetic nanoparticle also has.According to the magnetostatics theory, the expression formula of the magnetic field force Fmag that magnetic particle is subjected in the magnetic field is:
Wherein V is the volume of magnetic particle, χ
mBe the coefficient of magnetization of magnetic particle, μ
0Be permeability of vacuum,
Be Hamiltonian, promptly the size of magnetic field force is relevant with external magnetic field intensity and gradient, is suspended in the trend that move in the zone of the oriented magnetic field gradient maximum of magnetic particle in the microchannel.
Distribute in the microchannel as directly applying externally-applied magnetic field control magnetic particle, magnetic particle forms gathering easily, blocking pipe, and be not easy accurate control position.And by the difform soft magnetism microcomponent of preparation in microfluidic channel, can under the inducing of externally-applied magnetic field (permanent magnetism iron or electromagnetic field), produce non-equal high-gradient magnetic field, these magnetic particles are fixed on around the microtrabeculae, thereby increase the capture rate of magnetic particle.Because magnetic particle mainly is the place motion toward the magnetic field gradient maximum, therefore this absorption is mainly around microtrabeculae, its magnetic field force is also with the increase of the distance of magnetic particle and microtrabeculae and sharply reduce, therefore the arrangement by microtrabeculae can reach bigger adsorption area, again the effect of blocking pipe not.
Different with place of matchmakers in the background technology document is in the present invention, to be to be marked with the target molecule predetermined fixed of magnetic particle in the formation district, concentration gradient field of chip end.And magnetic particle then is to realize by soft magnetism micro-pillar array that micro-processing technology is produced in this zone in the accurate location in this zone and fixing.Owing to can control absorption and the release of magnetic bead in chip by simple control external magnetic field, so the present invention avoided the use of valve fully, makes the controlling and process and all become simple of chip.
The Valveless micro-flow control gradient real-time reaction chip of the present invention's design, entire reaction need not valve control, only need apply external magnetic field, so easy operating, and because chip can reuse, greatly reduce cost, can be applied in many-sides such as pharmacy, biomacromolecule reaction mechanism.
Description of drawings
Fig. 1 is the structural representation of the embodiment of the invention:
Fig. 2 is the planimetric map of the embodiment of the invention;
The soft magnetism micro-pillar array operation chart of Fig. 3 for relating in the embodiment of the invention;
Wherein: A is the synoptic diagram that does not add magnetic particle, and B is the synoptic diagram behind the absorption magnetic bead.
1 is substrate among the figure, and 2 is the soft magnetism micro-pillar array, and 3 is pipeline configuration, 4,5 is injection port, 6 is the liquid mixing district, and 7 for dividing a prong, and 8 enter the inlet point of gradient chip for the magnetic particle sample, 9-16 is an outlet liquid storage tank, 17 is the injection port of magnetic particle, and 18-25 is the preceding pipeline that forms the concentration gradient field of outlet, and 26 for adding the permanent magnetism iron, 27 is the single microtrabeculae in the soft magnetism micro-pillar array, and 28 is the magnetic particle that adsorbs.
Embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Shown in Fig. 1-2, the micro-fluidic gradient reaction chip of the valveless that present embodiment relates to, its essential characteristic is to improve design on the micro-fluidic gradient chip of traditional pyramid, in the pipeline in the formation district, terminal concentration gradient field that exports, increases soft magnetism micro-pillar array 2.Present embodiment can form the drug concentration gradient of 8 linearities endways by the sample introduction of injection port 4,5, and can carry out the reaction of medicine and target molecule simultaneously.Its structure comprises sample feeding mouth 4,5, mixer 6, and split point 7, magnetic particle injection port 17,2,8 outlets of soft magnetism micro-pillar array 9-16, and the sample pipe 18-25 of front end etc.
As shown in Figure 1, the structure of the micro-fluidic gradient chip of pyramid is a double-decker, is made of the pipeline configuration 3 on substrate 1 and upper strata thereof.Wherein substrate 1 is electroplate with the micro-pillar array of soft magnetism on the 18 corresponding positions, position in itself and pipeline configuration 3; And the pipeline configuration 3 on upper strata contains the agent structure of pipeline, and two parts are in conjunction with forming structure as shown in Figure 2.The micro-fluidic gradient chip of Xing Chenging just is distributed with the micro-pillar array 2 of soft magnetism in the pipeline 18-25 at its end outlet place like this.
As shown in Figure 3, be marked with at first the entering in the chip of target molecule of magnetic particle 28, and the soft magnetism micro-pillar array 2 of flowing through and being positioned at pipeline, because this structure can produce high-gradient magnetic field around it in externally-applied magnetic field, therefore can adsorb the target molecule that is marked with magnetic particle.Carry out the time marquis of gradient reaction, medicine and medicine damping fluid are entered in the chip by injection port 4 and injection port 5 places respectively, in gradient fields forms the district, form the drug concentrations gradient, and carry out the online in real time reaction with the target molecule that is marked with magnetic particle that is fixed in this zone.Because soft magnetism micro-pillar array 2 soft magnetisms after removing external magnetic field, can not adsorbed magnetic particle, and Fan Ying magnetic particle can be flushed away like this, chip can reuse simultaneously.
Described soft magnetism micro-pillar array 2, can pass through micro-processing technology, as technologies such as whirl coating, photoetching, plating preparations the micro structure array with soft magnetism (as permalloy), microstructure can be cylinder or cube etc., Gao Jun is at micron order for its length and width, and by certain being spaced.
Described magnetic particle 28 has magnetic, can react under magnetic field, is of a size of nanometer or micron, but surface fixed drug molecule.Can be by commercially available purchase, the Dynal Myone magnetic bead of being sold as Introgen company (U.S.).
Described soft magnetism micro-pillar array 2, its magnetization are that the mode by external permanent magnet or electromagnet applies.
The micro-fluidic gradient reaction chip of the valveless that the foregoing description relates to, its preparation can realize as follows:
1, the making of substrate of glass electroforming ferronickel micro-pillar array
Utilize electroplating technology to carry out the permalloy micro-pillar array.For ease of follow-up optical detection, substrate 1 adopts glass in the present embodiment.Specific embodiment: glass wafer cleans back sputtered with Ti/Cu electroforming Seed Layer respectively.Spin coating positive photoresist on substrate, obtaining thickness is the glue-line of 25 μ m.Template after the development obtains the permalloy micro-pillar array of height greater than 20 μ m in the ferronickel electroforming solution.Microtrabeculae 2 structures are cylinder in this example, and diameter 50um is 50um also at interval, and the substrate after the electroforming is removed Seed Layer, dry for standby.
2, preparation PDMS microfluidic channel
(1) preparation of photoresist template
At first adopt SU-8-3050 type negative photoresist (U.S. Micro Chem company), at the silicon chip of single-sided polishing or whirl coating on the glass sheet of titanium dioxide substrate is arranged, obtaining thickness is the photoresist of 50 μ m.Preceding baking post-exposure, the bar development of baking back, back, the back of developing is cleaned with isopropyl alcohol, and nitrogen dries up, and promptly obtains required photoresist template.The photoresist template before casting with silicon fluoride (SiHF3) treatment surface, damage photoresist template during with the PDMS mold releasability avoiding solidifying.
(2) making of PDMS microchannel
This example adopts the material of main part of dimethyl silicone polymer (PDMS, Dow corning company, the trade mark: Sygard 184) as chip.PDMS is a kind of macromolecule silastic material, has lower Young modulus and encapsulates characteristic preferably, low price, good biocompatibility, translucidus height.It is material commonly used in the present microfluid research.PDMS (DOW CORNING sylgard 184) performed polymer is mixed with the mass ratio of hardening agent according to 10:1, after the vacuum outgas, be cast on the photoresist template.After the curing it is taken off from template,, can obtain required PDMS sheet in injection port and outlet punching.
3, encapsulation bonding
The characteristic of utilizing the PDMS material to be easy to encapsulate is handled the PDMS microchannel of making 3 and glass substrate 1 surface that has little ferronickel post, the encapsulation of fitting then with the plasma treatment machine.
As Fig. 2-3, present embodiment relates to a kind of Valveless micro-flow control gradient real-time reaction control method, operates according to following steps:
1) makes the soft magnetism micro-pillar array.
In the pipeline in the formation district, terminal concentration gradient field that the micro-fluidic gradient chip of pyramid exports, make the soft magnetism micro-pillar array by electroplating technology;
2) absorption magnetic particle.
In practical operation, as shown in Figure 2, the magnetic particle 28 that is marked with drug molecule at first enters in the chip from magnetic particle injection port 17, be divided into 8 pipelines uniformly, at minute prong 8 places, because the flow resistance at the past 9-16 place, exit of fluid is less than past injection port 4 and injection port 5, and in fluid, similar and the circuit of mobile meeting of liquid, flow toward the place that flow resistance is little, therefore magnetic particle solution can flow out from these 8 pipelines of outlet 9-16, when the chip end of flowing through is fixed with soft magnetism micro-pillar array 2, as Fig. 2, shown in 3, externally-applied magnetic field 26 magnetizes the soft magnetism micro-pillar array in each pipeline, can produce high-gradient magnetic field around the microtrabeculae, the magnetic particle 28 that flows through can be adsorbed in this magnetic field, and the magnetic bead that is not adsorbed and other solution then flow out chip.
3) reaction.
After the drug molecule of magnetic particle mark is adsorbed on end, just can pass through gradient chip sample introduction, as shown in Figure 2, medicine and medicine damping fluid are entered in the chip by injection port 4 and injection port 5 places respectively, 6 mix and constantly shunting in the mixed zone, and 18-25 place endways forms concentration gradient.Because at minute prong 8 places, the flow resistance that the past injection port 17 (magnetic particle injection port) of solution flows out is greater than the flow resistance that flows out from exit 9-16, so solution can flow out from outlet 9-16.When flowing through exit front-end pipelines 18-25, can react with the drug molecule of mark on the magnetic particle 28 that is fixed in the pipeline, carry out the online in real time reaction.
4) flushing and replacing magnetic particle.
Reaction finishes, and removes external magnetic field 26, feeds the magnetic particle damping fluid from injection port 17, because soft magnetism structure 2 forfeiture magnetic can not be adsorbed magnetic particle 28, therefore along with damping fluid, magnetic particle 28 can dash from going out chip from outlet 9-16.Repeat above-mentioned 1 step, adsorb magnetic particle again, just can carry out reaction next time.
Described magnetic particle 28 can be by commercially available purchase, the DynalMyone magnetic bead of being sold as Introgen company (U.S.).
Described property particle damping fluid is meant the damping fluid that is used for the diluted magnetic particle, by used all kinds of magnetic particle manufacturers' explanation configuration, as the Dynal Myone magnetic bead use phosphate buffer of dilution Introgen company.
Described medicine is to comprise chemical classes micromolecule or biomacromolecule such as antibody, nucleic acid etc.Described medicine damping fluid is meant the solution that can be used for diluting drug molecule, as water, phosphate buffer etc.
Claims (8)
1, a kind of Valveless micro-flow control gradient real-time reaction chip is characterized in that, comprises the micro-fluidic gradient chip of pyramid, and the micro-fluidic gradient chip of described pyramid upper outlet proterminal concentration gradient field is provided with the soft magnetism micro-pillar array in the formation district.
2, Valveless micro-flow control gradient real-time reaction chip according to claim 1, it is characterized in that, the double-decker that the micro-fluidic gradient chip of described pyramid is the pipeline configuration on substrate and upper strata thereof, wherein substrate is provided with the soft magnetism micro-pillar array on the corresponding position in the formation district, concentration gradient field in itself and pipeline configuration.
3, Valveless micro-flow control gradient real-time reaction chip according to claim 1 and 2 is characterized in that, described soft magnetism micro-pillar array is by the microtrabeculae that has soft magnetism forming apart from assembled arrangement by setting.
4, Valveless micro-flow control gradient real-time reaction chip according to claim 1 and 2 is characterized in that, described soft magnetism micro-pillar array, and Gao Jun is at micron order for its length and width.
5, a kind of Valveless micro-flow control gradient real-time reaction control method is characterized in that, comprises the steps:
The first step is made the soft magnetism micro-pillar array in the pipeline in the formation district, terminal concentration gradient field that the micro-fluidic gradient chip of pyramid exports;
Second step, feed the target molecule that has magnetic particle by the target molecule injection port, when it flows through formation district, concentration gradient field, apply the permanent magnetism iron or add the soft magnetism micro-pillar array of electromagnetic field magnetization in this district, this structure will produce high-gradient magnetic field, adsorb the target molecule that is marked with magnetic particle, finish the positioning and fixing of target molecule in the concentration gradient field of pyramid gradient chip;
The 3rd step, when carrying out gradient real-time reaction, medicine and medicine damping fluid enter in the chip respectively by the injection port of pyramid gradient chip, through shunting and mixing, end at chip forms gradient fields and flows through the soft magnetism micro-pillar array at last, react online in real time reaction when forming concentration gradient with the target molecule that is fixed on herein;
In the 4th step, reaction finishes, and removes external magnetic field, and the compound that feeding magnetic particle damping fluid will be marked with the target molecule-reactant of magnetic particle washes away, and chip can utilize once more.
6, Valveless micro-flow control gradient real-time reaction control method according to claim 5 is characterized in that, described soft magnetism micro-pillar array prepares by micro-processing technology, micro structure array with soft magnetism, microstructure is cylinder or cube, and Gao Jun is at micron order for its length and width, and by being spaced.
7, Valveless micro-flow control gradient real-time reaction control method according to claim 5 is characterized in that, described magnetic particle is of a size of nanometer or micron, but surface fixed drug molecule.
8, Valveless micro-flow control gradient real-time reaction control method according to claim 5, it is characterized in that, described medicine and medicine damping fluid, wherein medicine comprises chemical classes micromolecule or biopharmaceutical macromolecular drug, the medicine damping fluid is meant the solution that is used to dilute drug molecule, and the magnetic particle damping fluid is meant the damping fluid that is used for the diluted magnetic particle, by used all kinds of magnetic particle manufacturers' explanation configuration.
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| CN103386336A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Microfluidic chip for producing droplets with concentration gradients |
| CN103869060A (en) * | 2014-03-07 | 2014-06-18 | 复旦大学附属中山医院 | Circulating tumor stem cell detection kit based on magnetic beads and microfluidic chip |
| CN104084245A (en) * | 2014-06-13 | 2014-10-08 | 华中科技大学 | Apparatus and system used for forming concentration gradient |
| CN107271706A (en) * | 2017-07-05 | 2017-10-20 | 大连理工大学 | A kind of micro-fluidic chip of the dynamic Some Circulating Factors concentration of real-time and precise control observation point |
| CN107850582A (en) * | 2015-07-12 | 2018-03-27 | 制药流体股份有限公司 | Microfluidic device |
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| CN115445677A (en) * | 2022-08-23 | 2022-12-09 | 深圳市第二人民医院(深圳市转化医学研究院) | Micro-fluidic chip combined with MALDI-TOF-MS analysis |
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| CN103386336A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Microfluidic chip for producing droplets with concentration gradients |
| CN103869060A (en) * | 2014-03-07 | 2014-06-18 | 复旦大学附属中山医院 | Circulating tumor stem cell detection kit based on magnetic beads and microfluidic chip |
| CN104084245A (en) * | 2014-06-13 | 2014-10-08 | 华中科技大学 | Apparatus and system used for forming concentration gradient |
| CN107850582A (en) * | 2015-07-12 | 2018-03-27 | 制药流体股份有限公司 | Microfluidic device |
| CN107850582B (en) * | 2015-07-12 | 2021-03-02 | 制药流体股份有限公司 | Microfluidic device |
| CN107271706A (en) * | 2017-07-05 | 2017-10-20 | 大连理工大学 | A kind of micro-fluidic chip of the dynamic Some Circulating Factors concentration of real-time and precise control observation point |
| CN108287236A (en) * | 2017-11-24 | 2018-07-17 | 中国农业大学 | A kind of biological sensor and its application based on High-gradient Magnetic separation and quantum dot |
| CN112570050A (en) * | 2019-09-27 | 2021-03-30 | 厦门大学 | Fluid transportation control system and method |
| CN110668398A (en) * | 2019-10-16 | 2020-01-10 | 武汉大学 | Preparation method and application of extremely progressive rigid-flexible gradient micro-column structure of bionic gecko |
| CN111019827A (en) * | 2019-12-26 | 2020-04-17 | 武汉大学 | Hydrogel oocyte in-vitro three-dimensional culture micro-fluidic chip based on different cross-linking degrees and application thereof |
| CN115445677A (en) * | 2022-08-23 | 2022-12-09 | 深圳市第二人民医院(深圳市转化医学研究院) | Micro-fluidic chip combined with MALDI-TOF-MS analysis |
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