CN100432224C - Microflow chip and method for preparing polymer microsphere using same - Google Patents
Microflow chip and method for preparing polymer microsphere using same Download PDFInfo
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- CN100432224C CN100432224C CNB2006100193546A CN200610019354A CN100432224C CN 100432224 C CN100432224 C CN 100432224C CN B2006100193546 A CNB2006100193546 A CN B2006100193546A CN 200610019354 A CN200610019354 A CN 200610019354A CN 100432224 C CN100432224 C CN 100432224C
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Abstract
The present invention relates to a micro-flow chip which comprises a synthetic channel and two flow focusing balling channels, wherein outlets of the two flow focusing balling channels are crossed at an inlet of the synthetic channel; each of the flow focusing balling channels is composed of a prepolymer micro ball channel, a dispersed phase channel and two continuous phase channels, wherein the two continuous phase channels are distributed at both sides of the discontinuous phase channel; the prepolymer micro-ball channel, the continuous phase channels and the discontinuous phase channel are all provided with inlets and outlets; the outlets of the continuous phase channels and the discontinuous phase channel are crossed at the inlet of the prepolymer micro-ball channel. The present invention also provides a method for making a polymer micro ball by using the micro-flow chip, which comprises the steps: injecting two kinds of continuous phase from inlets of continuous phase channels of the two flow focusing channels; respectively injecting discontinuous phase from the discontinuous phase channels of the two flow focusing channels. In this way, the polymer micro ball is obtained from the outlet of the synthetic channel. The present invention can exactly make controllable polymer micro balls with consistent size.
Description
Technical field
The present invention relates to a kind of micro flow chip and utilize micro flow chip to prepare the method for polymer microballoon, specially refer to little processing design and constitute, require design to meet principle of hydrodynamics, belong to the micro flow chip field.It can be applied to and obtain polymer microballoon in the chemosynthesis, belongs to the field of chemical synthesis.Also can in the biocompatible polymeric microballoon, add the cell curing balling-up, can be used as the enabling environment of cell cultures, transfer, storage and analysis, belong to the biocytology field.Also can be used for the medicament slow release field and be used for packaging medicine, belong to field of biological pharmacy.
Background technology
The controllable polymer micro-ball of 10-100 micron diameter has noticeable biology, chemistry, medical applications potentiality.Traditional polymer microballoon preparation is based on gunite, phase separation method and emulsion process mostly.Prepare polymer microballoon by traditional way, or its diameter can't control accurately, or microballoon has bigger distribution of sizes, perhaps needs a large amount of reaction reagents.And these traditional preparation process modes make to the coating of organism the time, are difficult to keep organism not to be damaged.The monodisperse polymer micro-sphere diameter of preparation generally is distributed in more than 100 microns or below 10 microns, is difficult to prepare by traditional means between the 10-100 micron at present.
Summary of the invention
The purpose of this invention is to provide a kind of micro flow chip and utilize micro flow chip to prepare the method for polymer microballoon, it is controlled that the polymer microballoon that this method makes can form big or small homogeneous, is shaped better.
The technical solution adopted for the present invention to solve the technical problems is: a kind of micro flow chip, comprise external phase raceway groove and disperse phase raceway groove, be provided with a synthetic raceway groove and two streams are focused into ball track, the outlet that two stream is focused into ball track intersects in the import of synthetic raceway groove, each stream is focused into ball track by prepolymer microballoon raceway groove, disperse phase raceway groove and two external phase raceway grooves constitute, described two external phase raceway grooves are distributed in disperse phase raceway groove both sides, prepolymer microballoon raceway groove, external phase raceway groove and disperse phase raceway groove all have input aperture and outlet, the outlet of external phase raceway groove and disperse phase raceway groove intersects in the input aperture of prepolymer microballoon raceway groove, the diameter of disperse phase raceway groove is the 30-500 micron, the diameter of external phase raceway groove is the 30-500 micron, and the input aperture diameter of prepolymer microballoon raceway groove is the 30-200 micron.
The above-mentioned shared input aperture of two external phase raceway grooves that is distributed in disperse phase raceway groove both sides.
The diameter of above-mentioned prepolymer microballoon raceway groove is gradually wide distribution from the import to the outlet, exit diameter is the 50-200 micron.
Above-mentioned synthetic raceway groove is provided with several Buffer Pools.
The present invention also provides the method for utilizing said microflow chip to prepare polymer microballoon: with two kinds of external phases respectively by the 1-2000 microlitre/hour the flow velocity input aperture that is focused into the external phase raceway groove of ball track from two streams inject, with disperse phase respectively by the 1-100 microlitre/hour flow velocity inject from the disperse phase raceway groove that two streams are focused into ball track, and the flow velocity that keeps external phase is higher than the flow velocity of disperse phase, promptly obtains polymer microballoon from synthetic raceway groove outlet.
The present invention at first utilize two independently stream focus on raceway groove the prepolymer reaction soln pulled accurately controlled prepolymer microballoon of power and shearing force preparation size by oil phase, controlled diameter range is about the 10-100 micron, the size fluctuation rate is less than 1%.Can utilize again and independently flow the ratio that the ratio of microballoon in synthetic raceway groove that focuses on two kinds of prepolymers of raceway groove change changes the polymer microballoon reactant.Changing the oil phase flow velocity simultaneously can effectively prevent to collide mutually, merge before the identical prepolymer microballoon reaction.Prepolymer microballoon raceway groove is arranged in order two kinds of reactant prepolymer microballoons and collides.Synthetic raceway groove further merges two kinds of prepolymer microballoons and reaction environment is provided.By above design can reach polymer microballoon size homogeneous controlled, than narrow size distribution (CV% is less than 5%), be shaped better, stability is strong, good reproducibility.The present invention is particularly suitable for preparation of slow releasing pharmaceutical microcapsule or cell fixation.
Description of drawings
Accompanying drawing is a structural representation of the present invention.
Embodiment
Referring to accompanying drawing, micro flow chip of the present invention, comprise that a synthetic raceway groove 2 and two streams are focused into ball track 1, the outlet that two stream is focused into ball track 1 intersects in the import of synthetic raceway groove 2, each stream is focused into ball track 1 by prepolymer microballoon raceway groove 8, disperse phase raceway groove 4 and two external phase raceway grooves 3 constitute, described two external phase raceway grooves 3 are distributed in disperse phase raceway groove 4 both sides, external phase raceway groove 3, disperse phase raceway groove 4 and prepolymer microballoon raceway groove 8 all have input aperture 5,6,7 and the outlet 9,10,11, the outlet 9 of external phase raceway groove 3 and disperse phase raceway groove 4,10 intersect at 7 places, input aperture of prepolymer microballoon raceway groove 8, the diameter of disperse phase raceway groove 4 is the 30-500 micron, the diameter of external phase raceway groove 3 is the 30-200 micron, and the input aperture diameter of prepolymer microballoon raceway groove 8 is the 30-200 micron.
Above-mentioned two external phase raceway grooves 3 can each by an input aperture, a but best shared input aperture 5.
The diameter of above-mentioned prepolymer microballoon raceway groove is gradually wide distribution from the import to the outlet so that this of prepolymer microballoon raceway groove formation is long apart from spout, and exit diameter is the 50-200 micron.
Above-mentioned synthetic raceway groove is provided with several Buffer Pools 12.Utilize the variation of flow rate of liquid in different channel structures, realize that each microballoon collides and merge.Two kinds of reaction solns mix mutually, because prepolymer is swift in response, polymer microballoon forms in synthetic raceway groove.Thereby obtain polymer microballoon in synthetic raceway groove outlet 13.
Said microflow chip can be pressed method and make: press raceway groove graphic making photo etched mask; On silicon chip or sheet glass, apply the photoresist material of 10-100 micron, oven dry with spin coating method; Utilize standard photolithography process to carry out photoetching, develop, oven dry; Utilize the photoresist material of projection on the silicon chip to be formpiston; The perfusion high molecular polymer solidifies; Take the polymeric colloid that is printed on channel pattern off, carry out oxide treatment after the punching, polymkeric substance raceway groove face and new polymkeric substance or sheet glass bonding.Obtain polymkeric substance miniflow chip.Perhaps, press raceway groove graphic making photo etched mask; On silicon chip or sheet glass, apply the photoresist material of 0.1-10 micron, oven dry with spin coating method; Utilize standard photolithography process to carry out photoetching, develop, oven dry; Utilize that photoresist material is protective layer on silicon chip or the sheet glass, obtain having the silicon chip or the sheet glass of channel structure with traditional wet etching silicon chip or sheet glass; To silicon chip or sheet glass punching, raceway groove face and the silicon chip or the sheet glass bonding that do not have channel structure.Obtain silica-based or the glass micro chip.
The present invention adopts said structure, during the preparation polymer microballoon, with two kinds of external phases press respectively the 1-1000 microlitre/hour flow velocity inject from the input apertures that two streams focus on the external phase raceway groove of raceway grooves, with disperse phase press respectively the 1-200 microlitre/hour flow velocity inject from the disperse phase raceway grooves that two streams focus on raceway grooves, and the flow velocity that keeps external phase is higher than the flow velocity of disperse phase, external phase is by the symmetrical extrusion structure of above-mentioned external phase raceway groove, make disperse phase form one stable focused flow owing to squeezing action at 7 places, prepolymer microballoon raceway groove input aperture, and focused flow is because surface tension, pull the effect of power and shearing force, head periodically ruptures, and produces uniform prepolymer microballoon.This structure is used to realize oily encapsulation reaction solution in the polymer microballoon preparation, to realize reaction soln being formed big or small homogeneous, the prepolymer microballoon that speed is certain.The microballoon of two kinds of pre-polymer solutions enters synthetic raceway groove through the outlet (being the outlet of prepolymer microballoon raceway groove) that stream is focused into ball track, two kinds of microballoons are realized being arranged in order and colliding at synthetic raceway groove place, while two kinds of solution realization response proportioning in this raceway groove, ratio range is (volume ratio) from 1: 5 to 5: 1, to obtain reaction product-polymer microballoon of different nature.
Now, come concrete scheme of the present invention is specified with the object lesson of sodium alginate and calcium chloride reaction.Embodiment
1-3% (mass ratio) sodium alginate and 0.5-5% (mass ratio) calcium chloride are added into the disperse phase raceway groove, oil injects from the external phase raceway groove, disperse phase is located in prepolymer microballoon raceway groove input aperture, owing to be subjected to the squeezing action of external phase to form one stable focused flow, and focused flow is owing to surface tension, pull the effect of power and shearing force, head periodically ruptures, and produces uniform microballoon.For realizing different pre-polymer solution proportionings, can change oil speed and pre-polymer solution speed.The pre-polymer solution flow velocity be controlled at respectively the 1-2000 microlitre/hour, the flow velocity of oil is controlled at all the time than pre-polymer solution flow velocity is high and gets final product.
Prepare sodium alginate and calcium chloride microballoon earlier: set oil phase, sodium alginate soln flow velocity, utilize a stream to focus on raceway groove earlier and coat out sodium alginate micro ball, adjust the oil phase flow velocity, obtain the sodium alginate micro ball that stable uniform has the predetermined size size.Set the calcium chloride solution flow velocity again, the calcium chloride microballoon of preparation stable uniform.Then, make sodium alginate micro ball to be arranged in order, to collide at T type raceway groove place with the calcium chloride microballoon successively by adjusting calcium chloride flow velocity and oil phase flow velocity.Suitably adjust the calcium chloride solution flow velocity, make sodium alginate micro ball can not collide mutually, be gathered into big sodium alginate micro ball.Oil phase flow velocity by changing the calcium chloride raceway groove and the calcium chloride solution flow velocity generation frequency of controlling the calcium chloride microballoon simultaneously, adjusting calcium chloride microballoon and sodium alginate micro ball are focused into the arrangement ratio in the exit of ball track at stream, adjust the ratio of reactant thus.Last calcium chloride microballoon and sodium alginate micro ball merge in synthetic raceway groove, and reaction generates the calcium alginate microsphere of bio-compatible.
The calcium alginate microsphere of the micro flow chip preparation by special construction design has big or small homogeneous thus, and size can accurately be controlled at the 10-100 micron, and fluctuation ratio is in 5%.
Claims (5)
1. micro flow chip, comprise external phase raceway groove and disperse phase raceway groove, it is characterized in that: be provided with a synthetic raceway groove and two streams are focused into ball track, the outlet that two stream is focused into ball track intersects in the import of synthetic raceway groove, each stream is focused into ball track by prepolymer microballoon raceway groove, disperse phase raceway groove and two external phase raceway grooves constitute, described two external phase raceway grooves are distributed in disperse phase raceway groove both sides, prepolymer microballoon raceway groove, external phase raceway groove and disperse phase raceway groove all have input aperture and outlet, the outlet of external phase raceway groove and disperse phase raceway groove intersects in the input aperture of prepolymer microballoon raceway groove, the diameter of disperse phase raceway groove is the 30-500 micron, the diameter of external phase raceway groove is the 30-500 micron, and the input aperture diameter of prepolymer microballoon raceway groove is the 30-200 micron.
2. micro flow chip according to claim 1 is characterized in that: the shared input aperture of two external phase raceway grooves that is distributed in disperse phase raceway groove both sides.
3. micro flow chip according to claim 1 and 2 is characterized in that: the diameter of prepolymer microballoon raceway groove is gradually wide distribution from the import to the outlet, and exit diameter is the 50-200 micron.
4. micro flow chip according to claim 1 and 2 is characterized in that: synthetic raceway groove is provided with several Buffer Pools.
5. method of utilizing the described micro flow chip of claim 1 to prepare polymer microballoon, it is characterized in that: with two kinds of external phases respectively by the 1-2000 microlitre/hour the flow velocity input aperture that is focused into the external phase raceway groove of ball track from two streams inject, with disperse phase respectively by the 1-100 microlitre/hour flow velocity inject from the disperse phase raceway groove that two streams are focused into ball track, and the flow velocity that keeps external phase is higher than the flow velocity of disperse phase, promptly obtains polymer microballoon from synthetic raceway groove outlet.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2006100193546A CN100432224C (en) | 2006-06-14 | 2006-06-14 | Microflow chip and method for preparing polymer microsphere using same |
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| CNB2006100193546A CN100432224C (en) | 2006-06-14 | 2006-06-14 | Microflow chip and method for preparing polymer microsphere using same |
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| CN1884514A CN1884514A (en) | 2006-12-27 |
| CN100432224C true CN100432224C (en) | 2008-11-12 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102242053B (en) * | 2011-04-01 | 2014-06-04 | 沈越 | Biochip with polymer three-dimensional nanostructure |
| CN104689775A (en) * | 2015-03-16 | 2015-06-10 | 武汉大学 | Droplet type micro-fluidic chip and method of preparing PVDF (Polyvinylidene Fluoride)-Fe 3O4 magnetic-electric composite microspheres by using the same |
| CN105567547B (en) * | 2015-12-11 | 2017-09-22 | 武汉友芝友医疗科技股份有限公司 | A kind of preparation method of the high gradient cell capture chip such as non-homogeneous |
| CN105498871B (en) * | 2015-12-16 | 2017-04-12 | 清华大学深圳研究生院 | Three-dimensional focusing microfluid chip and manufacturing method thereof |
| CN106824313A (en) * | 2017-02-23 | 2017-06-13 | 中国科学院上海微系统与信息技术研究所 | A kind of digital pcr chip and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004071638A2 (en) * | 2003-02-11 | 2004-08-26 | Regents Of The University Of California, The | Microfluidic devices and method for controlled viscous shearing and formation of amphiphilic vesicles |
| US20050037471A1 (en) * | 2003-08-11 | 2005-02-17 | California Institute Of Technology | Microfluidic rotary flow reactor matrix |
| US6994826B1 (en) * | 2000-09-26 | 2006-02-07 | Sandia National Laboratories | Method and apparatus for controlling cross contamination of microfluid channels |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6994826B1 (en) * | 2000-09-26 | 2006-02-07 | Sandia National Laboratories | Method and apparatus for controlling cross contamination of microfluid channels |
| WO2004071638A2 (en) * | 2003-02-11 | 2004-08-26 | Regents Of The University Of California, The | Microfluidic devices and method for controlled viscous shearing and formation of amphiphilic vesicles |
| US20050037471A1 (en) * | 2003-08-11 | 2005-02-17 | California Institute Of Technology | Microfluidic rotary flow reactor matrix |
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Granted publication date: 20081112 Termination date: 20170614 |