CN104774748A - Polyacrylate adhesive binding based biochip and preparation method thereof - Google Patents
Polyacrylate adhesive binding based biochip and preparation method thereof Download PDFInfo
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- CN104774748A CN104774748A CN201510192108.XA CN201510192108A CN104774748A CN 104774748 A CN104774748 A CN 104774748A CN 201510192108 A CN201510192108 A CN 201510192108A CN 104774748 A CN104774748 A CN 104774748A
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Abstract
The invention discloses a polyacrylate adhesive binding based biochip and a preparation method thereof. The biochip has a three-layer structure including an upper layer which is a substrate with a liquid inlet, a middle layer which is polyacrylate adhesive tape with engraved microchannels and a lower layer which is a holeless substrate. The preparation method comprises the steps that the upper substrate and the lower substrate are washed with a mixed solution in which the volume ratio of hydrochloric acid to methanol (V hydrochloric acid to V methanol) is 1:1; the substrates are subjected to sample application or modification by using a biological product; thermocompression bonding is carried out by using polyacrylate adhesive at 70-200 DEG C under the pressure of 0.1-3MPa, and thus the closed biochip with a microchannel biochemical chamber is obtained. The polyacrylate adhesive is low in cost; the binding process is simple and easy to operate and has a low requirement on skills of operators and equipment; moreover, the material of the substrates can be common glass slide and the like; the efficiency of biochip manufacture is improved and the cost is lowered; thus, the large-scale and commercial production of the biochip can be facilitated.
Description
Technical field
The invention belongs to gene field, be specifically related to biochip of a kind of acrylate resin bonding and preparation method thereof.
Background technology
Biochip, as a kind of high-throughput, the technique means that extensive, high-level efficiency obtains bioinformation, has started to be widely used in the aspects such as genomics research, proteomics research, single nucleotide polymorphism analysis, clinical medical inspection.In general biochip selects glass, quartz, metal etc. through respective handling as carrier.Sheet glass, owing to having cheapness, low Poison background and steady performance, has been widely used in the making of DNA chip.
Since biochip comes out, chip bonding is just the committed step in chip design process always.It is legal etc. that the bonding pattern that current biochip is relatively conventional at home and abroad mainly comprises the legal and organic solvent collateral key of pressure sintering, involution method, surface active collateral key.Traditional involution method uses the adhesive emulsion different from substrate material to carry out simple gluing involution to chip, without intensification hot melt, easily causes chip poorly sealed close, reaction chamber leakage.Conventional pressure sintering utilizes high temperature to make base material self hot melt carry out bonding, easily causes the change of fluid channel shape and volume, and very easily cause fluid channel to be blocked.Face activation collateral key is legal and organic solvent collateral key is legal needs vacuum seal environment, relies on large-scale bonding apparatus, cost intensive, is not suitable for commercialization, large-scale production.In a word, there is various practical problems in the bonding method of above-mentioned biochip in actual application, limits the promotion and application of biochip technology in every field.
Polyacrylic ester take esters of acrylic acid as homopolymer or the multipolymer of monomer.Acrylate is very easy to polymerization under light, heat or initiator effect.Polyacrylic ester can form good luster and water-fast film, bonding firmly, incrust, at room temperature pliable and tough and have rigidity, not easily deformation, has excellent light stability and weathering resistance, good water-fast, alkaline-resisting, chemical resistance and adhesiveproperties, be the good tackiness agent of metal, glass, leather, timber etc., be widely used in biomedicine.
Summary of the invention
Goal of the invention: in order to overcome the deficiencies in the prior art, first technical problem to be solved by this invention there is provided the biochip of the gluing bonding of a kind of polyacrylic ester.
Second technical problem to be solved by this invention there is provided the preparation method of above-mentioned biochip.
Technical scheme: in order to solve above-mentioned purpose, the technical solution adopted in the present invention is: the biochip of the gluing bonding of a kind of polyacrylic ester, chip is divided into three-decker, upper strata is the substrate with inlet opening, middle level is the polyacrylic ester adhesive tape of engraving fluid channel, lower floor is substrate not with holes, and three-decker bonding forms the closed biochip with fluid channel biochemical reaction chamber.
Wherein, the material of above-mentioned substrate is one or more in transparent glass, quartz, silicon, metal, nylon membrane, pottery, plastics.
Wherein, the material of above-mentioned polyacrylic ester be polyethyl acrylate, α-cyanogen for acrylate, other take esters of acrylic acid as one or more in the homopolymer of monomer or multipolymer.
The preparation method of the biochip of the gluing bonding of above-mentioned polyacrylic ester, comprises the following steps:
(1) upper and lower two layers of substrate deionized water and a small amount of washing composition are cleaned up, putting into volume ratio is V
hydrochloric acid: V
methyl alcohol25 DEG C of washing by soaking 0.5 ~ 1h in 36 ~ 38% hydrochloric acid of=1:1 and methanol mixed solution are then clean with deionized water rinsing;
(2) substrate step (1) obtained adopts physical chemistry modifying method, and fixed over the substrate surface by active organism probe, adorned substrate is upper substrate or underlying basal, or two layers of substrate is all modified up and down;
(3) two layers of substrate up and down that step (2) obtains is carried out thermocompression bonding with the polyacrylacid ester adhesive engraving fluid channel, bonding temperature is 70 ~ 200 DEG C, and bonding time is 1 ~ 10min, and bonding pressure is 0.1 ~ 3MPa.
Wherein, above-mentioned physical chemistry modifying method is the one during amination, aldehyde radical, carboxylated, sulfhydrylation or epoxy ethylization are modified.
Wherein, above-mentioned active organism probe is the one in DNA, RNA, oligonucleotide, protein, polypeptide, polysaccharide, cell or micro-assembly robot.
Beneficial effect: compared with prior art, advantage of the present invention is: (1) chip is three-decker, upper subtegulum is by the thermocompression bonding of polyacrylic ester, every bar fluid channel sealing is formed the biochemical reaction chamber closed, biochemical reagents can be flow to by inlet opening or flow out reaction chamber, thus reduce external environment to the detrimentally affect of biochemical reaction, avoid the mutual pollution of sample between air flowing contaminated samples or adjacent channels, improve science and the accuracy of biochip test result.
(2) polyacrylacid ester adhesive cost is low; suitability is wide; to substrate material without particular requirement; can the Conventional substrate materials such as bonding transparent glass, quartz, silicon, metal, nylon membrane, pottery or plastics; and then reduce the cost of manufacture of biochip on the whole, be beneficial to commercialization and large-scale production.
(3) polyacrylacid ester adhesive stable chemical nature, bonding temperature meets biological regularity, and adhesive tape can designed, designed as required, easy and simple to handle.The bonding temperature scope of polypropylene-base tackiness agent is at 70 ~ 200 DEG C, can meet the requirement of routine biochemistry temperature of reaction, adhesive tape can not occur and dissolve, fluid channel distortion is blocked and causes reaction chamber volume to change, be conducive to the quantified controlling of biochemical reaction, improve biochip can be handling.Simple for process, reaction chamber shape, volume and number can be designed as required, easy and simple to handle, low to the requirement of personnel's technology and equipment, improve the efficiency of film-making.
Embodiment
Below in conjunction with concrete embodiment, explain the present invention further:
The preparation of the aldehyde group modified quartz chip of embodiment 1
1. adopt quartz slide as underlying basal, specification is 68mm*18mm*0.4mm, simultaneously using 16 hole slides of same size as upper substrate, by assembling fixture determination size before upper subtegulum uses;
2. upper subtegulum washing composition is cleaned, putting into volume ratio after clean with deionized water rinsing is again V hydrochloric acid: 36 ~ 38% hydrochloric acid of V methyl alcohol=1:1 and methanol mixed solution room temperature (25 DEG C) are soaked, put into shaking table washing 0.5 ~ 1h, rotating speed 60rpm is then clean with deionized water rinsing;
3. adopt aldehyde group modified substrate: by substrate sulfuric acid and hydrogen peroxide boiling water bath 30min, then 1000rpm centrifuge dripping after cleaning with deionized water, substrate is immersed low concentration ammonia base silane solution, under room temperature condition, fixed temperature and humidity modifies 30min, clean with ethanol, dry, 110 DEG C of oven dry; By PH=7.0,0.01mol/L phosphate buffered saline(PBS), 25% glutaraldehyde is diluted to 5%, then chip is soaked 2h, clean with ethanol, room temperature dries, and 4 DEG C of sealed vacuums are preserved;
4. point sample instrument point sample: be 1-(3-the dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride solution of 40 μMs by 1 μ l concentration, 5 μ l concentration are that 2-(N-morpholine) the ethyl sulfonic acid solution of 40 μMs adds the good ddH2O of 24 μ l sterilizings, then add single-stranded DNA templates (final concentration is 25 μMs) (synthesis of INVITROGEN company) and make sampling liquid:
5’-NH2-TTTTTTTTTTAACCACTACGCCTCCGCTTTCCTCTCTATGGGCAGTCGGTGATTGTATCGTACTAGAGAGAATGAGGAACCCGGGGCAG-3’
Point sample is at Smart Arrayer
tM48 auto sample applicator (Boao Biological Co., Ltd's purchase) complete, arrange according to lattice position and size determination point sample X and Y platform, program adjust pre-point sample normal after, humidity is set 50%, starts sampling liquid to add point sample instrument and carry out DNA sample probe and be fixed on aldehyde group modified underlying basal;
5. on Bechtop, the underlying basal modified is snapped in plastic clamp, polyacrylic ester adhesive tape protective membrane is torn off, be attached to gently on underlying basal along fixture, the edge of adhesive tape tightly will align with substrate, then upper substrate with holes is being pushed down adhesive tape, during operation, will ensure that substrate two ends inlet opening aligns with adhesive tape fluid channel;
6. the chip of above-mentioned green tack is utilized one side thermocompressor, carry out 200 DEG C, pressure is 0.1M Pa, and the time is the thermocompression bonding of 1min, forms three-decker biochip.
The biochip of the gluing bonding of this polyacrylic ester is divided into three-decker, upper strata is the substrate with inlet opening, middle level is the polyacrylic ester adhesive tape that 68mm*18mm*0.4mm engraves 8 fluid channel, lower floor is substrate not with holes, and three-decker bonding forms the closed biochip with fluid channel biochemical reaction chamber.The material of substrate is quartz.The material of polyacrylic ester is that α-cyanogen is for acrylate.
The experiment of the aldehyde group modified quartz chip of embodiment 2 detects
This example is implemented purport and the aldehyde group modified quartz chip of the embodiment 1 prepared is carried out experiment detection, does not add closed single layer of chips in contrast with aldehyde group modified simultaneously.Single layer of chips adopts specification to be that the quartz slide of 68mm*18mm*0.4mm is as substrate equally, aldehyde group modified method is consistent with the three-decker chip of polyacrylic acid ester linkage with spotting methods, but only have one deck substrate structure, do not carry out any bonding, there is no the biochemical reaction chamber closed.
To 5 complete single layer of chips and embodiment 1 be made prepare three-decker chip brilliant core LuxScan 10K micro-array chip scanner (Boao Biological Co., Ltd's purchase) of loading test respectively of 5 aldehyde group modified polyacrylic acid ester linkages, adopt 650nm wavelength detecting, be 700 at PMT, Power=10, laser intensity is scan chip under 100% condition, then from the software that scanner carries, reads fluorescence background value.
Then the three-decker chip of 5 single layer of chips and 5 polyacrylic acid ester linkages is taken out respectively, 20 μMs of Cy5-dNTP (synthesis of GE Healthcare company) are added and Taq archaeal dna polymerase (purchase of TAKARA company) carries out fluorescent mark to spotted area, 50 DEG C of waters bath with thermostatic control minute, 1 time is got express developed with deionized water, nitrogen dries up, masking foil lucifuge.Adopt 650nm wavelength detecting, be 700, Power=10 at PMT, laser intensity is scan chip under 100% condition, then from scanner, reads sample fluorescence signal value, comparative experiments result.
Experimental result:
Adopt the three-decker chip of polyacrylic acid ester linkage, the fluorescent signal of its sample is strong, and background signal is weak, less to the interference of sample fluorescence signal; Single layer of chips fluorescent signal is weak, and background signal is strong, larger to the interference of sample fluorescence signal.
Table 1 polyacrylic acid ester linkage three-decker chip
| Substrate is numbered | Substrate 1 | Substrate 2 | Substrate 3 | Substrate 4 | Substrate 5 |
| Sample fluorescence signal value | 10297 | 11443 | 10164 | 9773 | 10522 |
| Background signal value | 358 | 536 | 366 | 203 | 307 |
Table 2 single layer of chips
| Substrate is numbered | Substrate 1 | Substrate 2 | Substrate 3 | Substrate 4 | Substrate 5 |
| Sample fluorescence signal value | 6197 | 6894 | 8252 | 8203 | 8523 |
| Background signal value | 1066 | 944 | 1295 | 1304 | 1653 |
Embodiment 3: the preparation of amido modified glass-chip
1. adopt simple glass slide glass as underlying basal, specification is 82mm*36.6mm*0.4mm, simultaneously using 16 hole slides of same size as underlying basal, by assembling fixture determination size before upper subtegulum uses;
2. upper subtegulum washing composition is cleaned, putting into volume ratio after clean with deionized water rinsing is again V hydrochloric acid: 36 ~ 38% hydrochloric acid of V methyl alcohol=1:1 and methanol mixed solution room temperature (25 DEG C) are soaked, put into shaking table washing 0.5 ~ 1h, rotating speed 60rpm is then clean with deionized water rinsing;
3. adopt amido modified underlying basal.By substrate sulfuric acid and hydrogen peroxide boiling water bath 30min, then 1000rpm centrifuge dripping after cleaning with deionized water, underlying basal is immersed low concentration ammonia base silane solution, under room temperature condition, fixed temperature and humidity modifies 30min, finally clean with ethanol, dry, 4 DEG C of sealed vacuums are preserved;
4. on Bechtop, the underlying basal modified is snapped in plastic clamp, polyacrylic ester adhesive tape protective membrane is torn off, be attached to gently on underlying basal along fixture, the edge of adhesive tape tightly will align with substrate, then upper substrate with holes is being pushed down adhesive tape, during operation, will ensure that inlet opening and fluid hole align with adhesive tape fluid channel;
5. the chip of above-mentioned green tack is utilized one side thermocompressor, carrying out temperature is 70 DEG C, and pressure is 3MPa, and the time is the thermocompression bonding of 10min;
6.DNA probe magnetic bead grappling: it is on the magnetic bead of 1 μm that ssDNA probe (single-stranded DNA templates with in embodiment 1) is connected to diameter by Streptavidin and biotin reaction, be the ultrasonic mixing of DNA probe magnetic bead Ultrasonic Cell Disruptor of 0.1M/ μ L by 200 μ L concentration, add 200 μ L SOLID
tMbead Deposition Buffer (purchase of Life Technologies company), centrifugal mixing, with liquid-transfering gun, DNA probe magnetic bead is added in chip fluid channel reaction chamber by sample holes, every runner 30 ~ 50 μ L, then put into 37 DEG C, loft drier and hatch 90min, magnetic bead is made to be anchored on lower layer chip surface completely, obtained biochip.
The biochip of the gluing bonding of this polyacrylic ester is divided into three-decker, upper strata is with sample holes and the substrate going out sample sky, middle level is the polyacrylic ester adhesive tape that 82mm*36.6mm*0.4mm engraves 8 fluid channel, lower floor is substrate not with holes, and three-decker bonding forms the closed biochip with fluid channel biochemical reaction chamber.The material of substrate is transparent glass.The material of polyacrylic ester is polyethyl acrylate.
The experiment of the amido modified glass-chip of embodiment 4 detects
The amido modified glass-chip that this example is implemented to be intended to embodiment 3 to have been prepared is applied to gene sequencing experiment, adopt magnetic bead anchoring effect and the signal power of the PDX-100 gene sequencer detection chip of general Dongxing, Nanjing bio tech ltd, in contrast with silica gel bonded amido modified chip simultaneously.The amido modified method of silica gel bonded chip is consistent with the chip method of polyacrylic acid ester linkage with magnetic bead anchorage method, but during bonding, adopt silica gel as tackiness agent, do not carry out any intensification melting operation, operate without any mechanical pressure, gluing bonding under room temperature (25 DEG C).
Instrument supplementary material reagent mainly contains Cy3-dNTP (20 μMs), Cy5-dNTP (20 μMs) (synthesis of GE Healthcare company), Taq archaeal dna polymerase (purchase of TAKARA company), primer (20 μMs) (synthesis of INVITROGEN company);
The complete polyacrylic ester bonding chip of preparation and silica gel bonded chip are put into gene sequencer respectively, the image analysis software of sequenator is utilized to carry out image scanning to the magnetic bead book in specific region before order-checking, add up the magnetic bead quantity in this area unit area, then three DNA sequencing experiments are carried out continuously, machine is utilized to carry the rear magnetic bead quantity of software statistics order-checking, counting loss quantity and loss ratio respectively;
Wavelength is adopted to be that 550nm and 650nm scans chip, laser intensity 100%, yield value 32, exposure value 400, each magnetic bead in sharp statistical unit area and the strength of signal of chip background, computation of mean values in three DNA sequencing processes.
Experimental result:
1. adopt amido modified glass-chip non-stop run three circulation on sequenator of polyacrylic acid ester linkage, magnetic bead loss ratio is less than 3%, and magnetic bead anchoring effect is better;
2. adopt amido modified glass-chip non-stop run three circulation on sequenator of polyacrylic acid ester linkage, chip background signal intensities is less than 10, less to the interference of bead signal.
Table 3 polyacrylic ester bonding chip magnetic bead anchoring effect
The fluorescence signal intensity of table 4 polyacrylic ester bonding chip magnetic bead and background
| Experimental procedure | Order-checking 1 | Order-checking 2 | Order-checking 3 |
| Magnetic bead fluorescent signal mean value | 230.778 | 230.778 | 185.222 |
| Background signal mean value | 3.333 | 5.556 | 5.023 |
Table 5 silica gel bonded chip magnetic bead anchoring effect
The fluorescence signal intensity of the silica gel bonded chip magnetic bead of table 6 and background
| Experimental procedure | Order-checking 1 | Order-checking 2 | Order-checking 3 |
| Magnetic bead fluorescent signal mean value | 171.22 | 169.46 | 185.88 |
| Background signal mean value | 15.52 | 16.01 | 21.59 |
Claims (6)
1. the biochip of the gluing bonding of polyacrylic ester, it is characterized in that, chip is divided into three-decker, upper strata is the substrate with inlet opening, middle level is the polyacrylic ester adhesive tape of engraving fluid channel, lower floor is substrate not with holes, and three-decker bonding forms the closed biochip with fluid channel biochemical reaction chamber.
2. the biochip of the gluing bonding of polyacrylic ester according to claim 1, is characterized in that, the material of described substrate is one or more in transparent glass, quartz, silicon, metal, nylon membrane, pottery, plastics.
3. the biochip of the gluing bonding of polyacrylic ester according to claim 1, it is characterized in that, the material of described polyacrylic ester is polyethyl acrylate, α-cyanogen for acrylate, other take esters of acrylic acid as one or more in the homopolymer of monomer or multipolymer.
4. the preparation method of the biochip of the gluing bonding of the polyacrylic ester described in claim 1 ~ 3 any one, is characterized in that, comprise the following steps:
(1) upper and lower two layers of substrate deionized water and a small amount of washing composition are cleaned up, putting into volume ratio is V
hydrochloric acid: V
methyl alcohol25 DEG C of washing by soaking 0.5 ~ 1h in 36 ~ 38% hydrochloric acid of=1:1 and methanol mixed solution are then clean with deionized water rinsing;
(2) substrate step (1) obtained adopts physical chemistry modifying method, and fixed over the substrate surface by active organism probe, adorned substrate is upper substrate or underlying basal, or two layers of substrate is all modified up and down;
(3) two layers of substrate up and down that step (2) obtains is carried out thermocompression bonding with the polyacrylacid ester adhesive engraving fluid channel, bonding temperature is 70 ~ 200 DEG C, and bonding time is 1 ~ 10min, and bonding pressure is 0.1 ~ 3 M Pa.
5. the preparation method of the biochip of the gluing bonding of polyacrylic ester according to claim 4, is characterized in that, described physical chemistry modifying method is the one during amination, aldehyde radical, carboxylated, sulfhydrylation or epoxy ethylization are modified.
6. the preparation method of the biochip of the gluing bonding of polyacrylic ester according to claim 4, is characterized in that, described active organism probe is the one in DNA, RNA, oligonucleotide, protein, polypeptide, polysaccharide, cell or micro-assembly robot.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109370891A (en) * | 2018-10-26 | 2019-02-22 | 郑州大学 | A kind of biochip and preparation method thereof |
| CN114308161A (en) * | 2021-12-31 | 2022-04-12 | 上海中航光电子有限公司 | Microfluidic chip and manufacturing method thereof |
-
2015
- 2015-04-21 CN CN201510192108.XA patent/CN104774748A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109370891A (en) * | 2018-10-26 | 2019-02-22 | 郑州大学 | A kind of biochip and preparation method thereof |
| CN114308161A (en) * | 2021-12-31 | 2022-04-12 | 上海中航光电子有限公司 | Microfluidic chip and manufacturing method thereof |
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Application publication date: 20150715 |