CN104689860A - A micro-fluidic chip used for antitumor drug screening at the single-ball level and applications - Google Patents
A micro-fluidic chip used for antitumor drug screening at the single-ball level and applications Download PDFInfo
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Abstract
A micro-fluidic chip used for antitumor drug screening at the single-ball level and applications are disclosed. A method includes a step of manufacturing a PDMS channel chip template by utilizing a hot-melt SU-8 template. Sunken holes of a plurality of sizes can be manufactured by a one-step method and used for forming tumor microballs with different sizes. The micro-fluidic chip is a chip comprising two layers, comprises twelve parallel micro-fluidic units, and can be used for antitumor drug screening at the single-ball level for tumor cells. The method is free of expensive etching devices, and has advantages of simple operation, rapidness, low experiment cost, no organic solvents, and capability of being environmental friendly and being integrated with other techniques.
Description
Technical field
The invention belongs to the processing of polymer chip, making, modification and application thereof, be specifically related to a kind of screening anti-tumor medicine micro-fluidic chip for three-dimensional list ball level and application.
Background technology
Monolayer cell culture is the main method of Cell culture invitro, and it has the advantage that cultivation is simple, easy to operate, expense is low, can widely apply, and is widely used as the experimental model of external pharmacology toxicological study.But the cultured in monolayer in vitro method of routine can not provide the environmental condition organized needed for normal growth growth, and growing environment has important impact to cellular gene expression and behavior, in body, the genome of each cell is identical, but its phenotype is different with functional structure in different organ and tissue, as embryonic cell heterotopic transplantation can make cell deterioration develop into teratoma, and fetal tissues can be developed in uterus; Equally, teratocarcinoma cell can be converted into normal cell in embryo.In monolayer cell culture, cell is attached in substrate plane and grows, and because lacking three-dimensional bracket, can only develop to two dimension, can not cellulation epimatrix.Owing to lacking body internal specific growth factor and differentiation factor effect, solid shape when cell can not break up and lose in substance.Therefore, the biological character that monolayer cell culture reflects, differs greatly with in-vivo tissue cell.Therefore for cell provides the mounting system similar in body, create and growing environment similar in substance, impel cell proliferation, break up and present the development trend that analog inner tissue 26S Proteasome Structure and Function proterties is Cell culture invitro.Three-dimensional cell cultivation is exactly based on These characteristics, the external stereoscopic culture method set up by some special culture techniques.Dimensional culture system provides support or the matrix of growing environment in analog for cell, and cell sets up iuntercellular and contacting between cell and extracellular matrix by connected modes such as compact siro spinning technology and gap connections, forms certain three-dimensional structure.Dimensional culture cellular gene expression, matrix secretion and cell function are movable all has notable difference with single-layer culturing cell, and more similar to cells in vivo.Therefore Three-dimensional cell culture can the structure of matter basis of retention body inner cell microenvironment, can embody again intuitive and the condition controllability of cell chulture, and external acellular and monolayer cell culture system and histoorgan and holistic approach are connected.
Clinical cancer therapy there will be MDR (multidrug resistance, MDR) phenomenon usually, and namely tumour cell is to the raw cross resistance of Treated with Chemotherapeutic Drugs produce.Although carried out large quantity research to its mechanism in recent years, also there is no this multidrug resistance of feasible method inhibition tumor cell clinically.Usually monolayer cell culture model is adopted in vitro in Drug-resistant Journal of Sex Research, the elementary cell of this model is single oncocyte, have ignored tumour as its Growth of Cells microenvironment of a special heterogeneous population and intercellular interaction, the result therefore obtained on this basis and experiment in vivo result often have very big-difference.There are some researches show that the structure function of dimensional culture tumour cell is obviously different from monolayer cultivation tumour cell, and similar to solid tumor in body, and carrying out biomedical research with the tumour cell of dimensional culture can more truly reflect situation in tumour body.In the research of dimensional culture tumour cell screening anti-tumor medicine, the size of tumour cell many cells microballoon can direct vivid tumour cell to the resistance to the action of a drug of medicine.
Utilize in recent years make arc-shaped recess micro-structural formed three-dimensional cell structure study cell behavior and function more and more pay close attention to by people.Can be cultured cell in vitro provides similar even identical Growth of Cells microenvironment tissue-derived with it and cell communication to the micro-structural formation three-dimensional cell structure of present report on the one hand, thus be both conducive to the differentiation directional induction of various types of cells, be conducive to again maintenance and the propagation of Cell Differentiation phenotype; Be expected on the other hand to build in vitro the cell three-dimensional corresponding to various organization, organ and grow analog or equivalent.And its application also relates to Stem cell differentiation, the resistance to the action of a drug of islet cell function regeneration, tumour cell, all many-sides such as vitro in organ's reconstruction.Along with the demand of biomedical sector, make arc-shaped recess microstructuring method also in develop rapidly, main method has: ice etches, Soft lithograph, electron beam lithography, in-situ synthesis, pneumatics etc. (1, Park, J.Y.; Hwang, C.M.; Lee, S.-H., Ice-lithographic fabrication of concave microwells and a microfluidic network.Biomedical Microdevices2008,11 (1), 129-133; 2, Xu, Y.; Xie, F.; Qiu, T.; Xie, L.; Xing, W.; Cheng, J., Rapid fabrication of a microdevice with concavemicrowells and its application in embryoid body formation.Biomicrofluidics2012,6 (1), 016504).
Although it is comparatively ripe that said method has developed now, still have several factors to limit it and apply more widely: the precision that the technology such as Soft lithograph, electron beam lithography is modified is high, but it needs specialized expensive instrument and complicated operation; Although in-situ synthesis is simple to operate, its molecule for fabricated in situ is expensive and system that is synthesis uses a large amount of organic reagent sometimes; Pneumatic mode technology is simple, quick, with low cost, but required passage template requires the penetrating template with small structure, and preparation method is loaded down with trivial details, complicated operation.In said method, the aperture of the depression of unified size can only be formed, the depression aperture of multiple size can not be formed by one-step method, and in the drug screening of tumour cell, the size of tumour microballoon have direct impact for screening anti-tumor medicine.
In sum, invention is a kind of simple, and fast, the strong and cheap one-step method of controllability makes that the screening anti-tumor medicine micro-fluidic chip for three-dimensional list ball level of the making arc of multiple size is of great significance.
Summary of the invention
The object of the present invention is to provide the screening anti-tumor medicine micro-fluidic chip for single ball level and application, complicated, expensive to solve the complex operation step existed in manufacture craft in the past, form tumour microballoon and the high flux of antineoplastic thereof and the drug screening of high intension fast.
The invention provides a kind of screening anti-tumor medicine micro-fluidic chip for single ball level, this chip is 2 layers of integral chip, upper strata is fluid chamber, long 700 microns, wide 700 microns, high 80 microns, there are parallel 12 groups of parallel microfluidic cell, the depression aperture of each unit different-diameter size and fluid passage, carry out the screening anti-tumor medicine experiment of the single ball level of parallel three-dimensional;
The preparation method of this chip is as follows:
(1) optical lithography is utilized to make the SU-8 polymer template of the aperture containing multiple diameter dimension;
(2) hot melt was carried out in 5 minutes at 85 degrees Centigrade to SU-8 polymer template, make the shape of aperture become umbilicate type from square;
(3) overall uv-exposure is carried out 90 seconds to the SU-8 polymer template after hot melt;
(4) uncured PDMS polymer solution (monomer and silane coupler volume proportion are 10:1) is poured on SU-8 polymer template, 85 degrees Centigrade solidification PDMS polymer solutions 40 minutes, peel off solidification PDMS polymer chip, obtain PDMS polymer reverse chip;
(5) uncured PDMS polymer solution (monomer and silane coupler volume proportion are 10:1) is poured on above-mentioned PDMS polymer reverse chip, 85 degrees Centigrade solidification PDMS polymer solutions 40 minutes, peel off solidification PDMS polymer chip, obtain the PDMS polymer chip with the different depression aperture of diameter;
(6) Soft lithograph fabrication techniques is utilized to contain the PDM S polymer chip of flow path channel;
(7) the PDMS polymer chip of the PDMS polymer chip utilizing the irreversible sealing-in of plasma instrument to contain flow path channel and the depression aperture having diameter different;
(8) finishing is carried out to above-mentioned integral chip, obtain micro-fluidic chip of the present invention;
Wherein, finishing condition is: 0.2%PF-127 process 4 hours, and rear sterilized water and PBS solution respectively rinse 2 times.
Screening anti-tumor medicine micro-fluidic chip for single ball level provided by the invention, the shrinkage pool of the micron level formed in the method, the width of this micropore and structure are fixed for designing, and the diameter of micropore is set as successively: 200,300,400,500,600,700,800 microns; The degree of depth of depression shape aperture controls by regulating the time of ethyl lactate development SU-8 polymer template, and the time is 5 minutes, and the curvature shapes of depression shape aperture is by regulating the heat time of hot melt to control at heating plate, and the heat time is 5 minutes.
Present invention also offers the application of described micro-fluidic chip, this chip is for the formation of the different three-dimensional bead of U87 cell of diameter and the screening of antineoplastic thereof.
The application of micro-fluidic chip provided by the invention, first finishing is carried out to the PDMS polymer chip of arc-shaped recess aperture, to reach the effect of cell not wall-attached surface, the thin osteocyte suspension of inoculation U87, under the condition of gravity, the three-dimensional microballoon of the formation that U87 cell can be spontaneous, in the process forming microballoon, due to the difference of hole diameter, the quantity of cell settlement is different, can form the U87 cell microsphere varied in size.
The application of micro-fluidic chip provided by the invention, the screening technique of described antineoplastic is: in each functional unit of micro-fluidic chip, inoculate U87 cell suspension, cultivates after 20-24 hour, and U87 cell forms three-dimensional single microballoon; U87 cell microsphere was cultivated after 4-5 days, added antineoplastic process 24-30 hour.
The application of micro-fluidic chip provided by the invention, described antineoplastic is resveratrol and PI3K inhibitor PI-103, concentration be respectively 200 micro-ly to rub/liter and 1.5 receive rub/liter.
The invention has the advantages that:
1, one-step method the aperture of multiple size can be formed, for the formation of the tumour microballoon varied in size;
2, also have 12 functional units, can carry out fluid-operated;
3, without the need to the instrument of costliness, simple to operate, quick;
4, experimental cost is cheap;
5, organic reagent is not related to, environmental friendliness;
6, can with other Integration ofTechnology.
Accompanying drawing explanation
Fig. 1 is the screening anti-tumor medicine micro-fluidic chip design drawing for single ball level; (1) be upper strata chip, (2) are lower layer chip.
Fig. 2 is the screening anti-tumor medicine micro-fluidic chip Experimental equipment for single ball level; (1) be overall chip design, (2) are single microfluidic cell.
Fig. 3 is the deep statistical figure of the depression aperture that the screening anti-tumor medicine micro-fluidic chip of single ball level is formed; (1) the depression aperture pictorial diagram of screening anti-tumor medicine micro-fluidic chip, the statistical chart of the little hole depth of depression that (2) are screening anti-tumor medicine micro-fluidic chip.
Fig. 4 is the U87 microsphere diameter statistical chart of screening anti-tumor medicine micro-fluidic chip cultivation U87 cell diverse location after four days of single ball level; (1) this screening anti-tumor medicine micro-fluidic chip cultivates the pictorial diagram of U87 cell after four days, and (2) cultivate U87 after tetra-days, the statistical chart of cell ball diameter for this screening anti-tumor medicine micro-fluidic chip.
Fig. 5 be U87 cell after the screening anti-tumor medicine micro-fluidic chip of single ball level cultivates 4 days, add the design sketch of 200 μm of ol/L resveratrols effect after 24 hours; (1) this screening anti-tumor medicine micro-fluidic chip cultivates the pictorial diagram of U87 cell after four days before dosing, (2) to cultivate U87 cell after four days for this screening anti-tumor medicine micro-fluidic chip and add 200 micro-resveratrol medicament process pictorial diagram of 24 hours of rubbing/rise, what figure open arrow indicated is the cell ball that diameter diminishes, the cell ball of the diameter increase of white arrow instruction, not having markd is unconverted cell ball.
Fig. 6 be U87 cell after the screening anti-tumor medicine micro-fluidic chip of single ball level cultivates 4 days, add 1.5 μm of ol/L PI-103 and act on the design sketch after 24 hours.(1) this screening anti-tumor medicine micro-fluidic chip cultivates the pictorial diagram of U87 cell after four days before dosing, (2) cultivate U87 for this screening anti-tumor medicine micro-fluidic chip and add 1.5 micro-PI-103 drug-treated pictorial diagram of 24 hours of rubbing/rise after tetra-days, what figure open arrow indicated is the cell ball that diameter diminishes, the cell ball of the diameter increase of white arrow instruction, not having markd is unconverted cell ball.
Detailed description of the invention
The following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment 1
Utilize optical etching technology to make SU-8 polymer template, template is 12 groups of parallel micropores different containing 7 kinds of diameters, and diameter is respectively 200,300,400,500,600, and 700,800 microns.Same dimension parallel 6 groups.Adopt conventional optical etching technology to make SU-8 template: to be applied on clean sheet glass by SU-8 photoengraving glue, after 95 degrees Celsius of front bakings heat 1 hour, remove organic reagent, after the cooling of SU-8 photoresist; Put the mask designed to expose after 90 seconds under ultraviolet, dry heating after 95 degrees Celsius 15 minutes.Be different from conventional method, SU-8 template developing time of the present invention is 5 minutes, is incomplete development, and after drying up developer, hot melt 5 minutes at 85 DEG C, makes the structure of the micropore in SU-8 template become arc from right angle; After cooling, SU-8 template is exposed 90 seconds completely under uviol lamp, form the SU-8 template with multiple diameter dimension arc-shaped recess micropore.PDMS(volume ratio 10:1 by uncured) be poured on the SU-8 polymer template made, and be heating and curing at 85 DEG C 40 minutes simultaneously.After device cooling, peel off upper strata PDMS chip and form reverse.Uncured PDMS is poured on PDMS polymer reverse chip, and is heating and curing at 85 DEG C 40 minutes simultaneously, after device cooling, peel off the PDMS polymer chip that upper strata PDMS polymer can form arc-shaped recess aperture.Utilize conventional lithographic technique to make the PDMS polymeric layer containing stream on upper strata, utilize plasma technology, irreversible sealing-in contains the PDMS layer of arc-shaped recess aperture and has the PDMS layer chip (as illustrated in fig. 1 and 2) of stream.Meanwhile, the aperture height (as shown in Figure 3) of the PDMS layer containing arc-shaped recess aperture is investigated.This method one-step method can form the depression micropore of multiple size, and with different curvature.
Embodiment 2
The PDMS polymer chip of sealing-in carries out the cultivation of U87 cell microsphere as shown in Figure 4.First PDMS polymer chip carries out sterilization treatment, ultraviolet irradiation spends the night, then the PF-127 solution of 0.2% is used to carry out finishing 4 hours, after respectively rinsing 2 times by sterilized water and PBS solution, inoculation U87 cell suspending liquid, cell under gravity, bottom the aperture that can be deposited to chip surface, spontaneous formation three-dimensional cell ball.Owing to devising the micropore result of different size dimension, U87 cell defines the many cells microballoon of different size.
Embodiment 3
The screening anti-tumor medicine micro-fluidic chip of single ball level is used for the research of the screening of the cancer therapy drug of U87 cell.Fig. 5 shows U87 cell after the PDMS polymer chip of the large dolly dimple aperture of difference cultivates four days, 200 μm of ol/L resveratrol medicament are added again by the fluid passage layer on upper strata, to the effect of U87 cell microsphere, the diameter of part many cells microballoon diminishes, cytoactive reduces, but does not occur apoptotic situation.Fig. 6 shows U87 cell after the PDMS polymer chip of the large dolly dimple aperture of difference cultivates four days, 1.5 μm of ol/L PI-103 medicines are added again by the fluid passage layer on upper strata, the diameter of part many cells microballoon diminishes, and cytoactive reduces, and has apoptotic situation to occur.
Claims (11)
1. the screening anti-tumor medicine micro-fluidic chip for single ball level, it is characterized in that: this chip is 2 layers of integral chip, there are parallel 12 groups of parallel microfluidic cell, the depression aperture of each unit different-diameter size and fluid passage, carry out the screening anti-tumor medicine experiment of the single ball level of parallel three-dimensional;
The preparation method of this chip is as follows:
(1) optical lithography is utilized to make the SU-8 polymer template of the aperture containing multiple diameter dimension;
(2) hot melt is carried out to SU-8 polymer template, make the shape of aperture become umbilicate type from square;
(3) overall uv-exposure is carried out to the SU-8 polymer template after hot melt;
(4) poured on SU-8 polymer template by uncured PDMS polymer solution, be heating and curing PDMS polymer solution, peels off solidification PDMS polymer chip, obtain PDMS polymer reverse chip;
(5) poured into by uncured PDMS polymer solution on above-mentioned PDMS polymer reverse chip, be heating and curing PDMS polymer solution, peels off solidification PDMS polymer chip, obtain the PDMS polymer chip with the different depression aperture of diameter;
(6) Soft lithograph fabrication techniques is utilized to contain the PDM S polymer chip of flow path channel;
(7) the PDMS polymer chip of the PDMS polymer chip utilizing the irreversible sealing-in of plasma instrument to contain flow path channel and the depression aperture having diameter different;
(8) finishing is carried out to above-mentioned integral chip, obtain micro-fluidic chip of the present invention;
Wherein, finishing condition is: 0.2%PF-127 process 4 hours, and rear sterilized water and PBS solution respectively rinse 2 times.
2. according to described in claim 1 for the screening anti-tumor medicine micro-fluidic chip of three-dimensional list ball level, it is characterized in that: in described step (1), the diameter of aperture is set as successively: 200,300,400,500,600,700,800 microns.
3. according to described in claim 1 for the screening anti-tumor medicine micro-fluidic chip of three-dimensional list ball level, it is characterized in that: in described step (2), the condition of hot melt is: 85 degrees Centigrade 5 minutes.
4. according to described in claim 1 for the screening anti-tumor medicine micro-fluidic chip of three-dimensional list ball level, it is characterized in that: in described step (2), the curvature shapes of depression shape aperture is by regulating the heat time of hot melt to control at heating plate, and the heat time is 5 minutes; The degree of depth of depression shape aperture controls by regulating the time of ethyl lactate development SU-8 polymer template, and the time is 5 minutes.
5. according to described in claim 1 for the screening anti-tumor medicine micro-fluidic chip of three-dimensional list ball level, it is characterized in that: in described step (3), the uv-exposure time is 90 seconds.
6. according to described in claim 1 for the screening anti-tumor medicine micro-fluidic chip of three-dimensional list ball level, it is characterized in that: in described step (4) and (5), uncured PDMS polymer solution is PDMS monomer and silane coupler volume proportion is 10:1.
7. according to described in claim 1 for the screening anti-tumor medicine micro-fluidic chip of three-dimensional list ball level, it is characterized in that: in described step (4) and (5), the condition be heating and curing is: 85 degrees Centigrade solidify 40 minutes.
8. the application of micro-fluidic chip described in claim 1, is characterized in that: this chip is for the formation of the different three-dimensional bead of U87 cell of diameter and the screening of antineoplastic thereof.
9. according to the application of micro-fluidic chip described in claim 8, it is characterized in that: first finishing is carried out to the PDMS polymer chip of arc-shaped recess aperture, to reach the effect of cell not wall-attached surface, the thin osteocyte suspension of inoculation U87, under the condition of gravity, the three-dimensional microballoon of the formation that U87 cell can be spontaneous, in the process forming microballoon, due to the difference of hole diameter, the quantity of cell settlement is different, can form the U87 cell microsphere varied in size.
10. according to the application of micro-fluidic chip described in claim 8, it is characterized in that: the screening technique of described antineoplastic is: in each functional unit of micro-fluidic chip, inoculate U87 cell suspension, cultivate after 20-24 hour, U87 cell forms three-dimensional single microballoon; U87 cell microsphere was cultivated after 4-5 days, added antineoplastic process 24-30 hour.
11., according to the application of micro-fluidic chip described in claim 10, is characterized in that: described antineoplastic is 200 micro-rub/rise resveratrol and 1.5 micro-PI3K inhibitor PI-103 that rub/rise.
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| CN108148751A (en) * | 2016-12-06 | 2018-06-12 | 中国科学院大连化学物理研究所 | A kind of integrated drug screening and dyeing micro-fluidic chip and preparation method thereof |
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