CN1482456A - Micro-array protein chip and making method thereof - Google Patents
Micro-array protein chip and making method thereof Download PDFInfo
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- CN1482456A CN1482456A CNA031478824A CN03147882A CN1482456A CN 1482456 A CN1482456 A CN 1482456A CN A031478824 A CNA031478824 A CN A031478824A CN 03147882 A CN03147882 A CN 03147882A CN 1482456 A CN1482456 A CN 1482456A
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- 102000004169 proteins and genes Human genes 0.000 title abstract description 19
- 230000008878 coupling Effects 0.000 claims abstract description 23
- 238000010168 coupling process Methods 0.000 claims abstract description 23
- 238000005859 coupling reaction Methods 0.000 claims abstract description 23
- 239000005304 optical glass Substances 0.000 claims abstract description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 12
- 238000001259 photo etching Methods 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 238000001338 self-assembly Methods 0.000 claims description 15
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052804 chromium Inorganic materials 0.000 claims description 13
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- 229910052799 carbon Inorganic materials 0.000 claims description 5
- RNOJZAYWQCKGRK-UHFFFAOYSA-N diazene hydrochloride Chemical compound Cl.N=N RNOJZAYWQCKGRK-UHFFFAOYSA-N 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 229940098773 bovine serum albumin Drugs 0.000 claims description 4
- 238000013016 damping Methods 0.000 claims description 4
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- 239000012190 activator Substances 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 3
- 239000012498 ultrapure water Substances 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 claims description 2
- -1 carboxyl absolute alcohol Chemical compound 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 abstract description 5
- 239000010931 gold Substances 0.000 abstract description 5
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
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Abstract
The present invention provides a micro array protein chip, including optical glass base-plate, chromic film micro array, bare gold film micro array, coupling layer and acceptor, wherein the mercapto end connects with the bare gold film array, the carboxyl end connects with the acceptor. The method for making chips comprises, mask photo-etching of grating, making chromic film or gold film through deposition or sputtering, removing gridding and assembling coupling layer, mounting the acceptor on the coupling layer. The method by the invention can realize the protein chips of various amount units in an effective and low cost way.
Description
Technical field
The invention belongs to biological technical field, particularly a kind of microarray protein-chip and preparation method thereof.
Background technology
Protein is the minimum active unit that constitutes life entity, promptly the most basic life form.There is protein more than 100,000 kinds in the human body, bears different tasks separately, bring into play specific effect, keep and control vital movement.In the different phase that life is grown, the kind of protein and formation are different; In different tissues, the protein of cellular expression is widely different.Gene is hereditary functional unit, the instruction synthetic protein.Gene mutation, its expression product---protein must take place unusually thereupon, and the generation of any disease and development all can at first be expressed on protein level.Therefore, on the protein level, inquire into the vital movement rule, the mechanism that study of disease takes place, not only for the understanding biological phenomena, and to the early stage accurately diagnosis of disease, all significant.
Protein-chip is the core original paper of research and analysis protein.It is on very little surface area, and fixedly the range protein bioactive molecule can detect various protein or effector molecules molecule and intermolecular interaction thereof simultaneously, and the expression of gene function, obtains the change information of protein group under the various conditions.Different detection methods, the structure of protein-chip is different, wherein, based on surface plasma body resonant vibration (Surface Plasmon Resonance, abbreviation SPR) chip of detection method need not sign with it and is paid attention to, and has obtained exploitation and use, and chip structure as shown in Figure 1.It is made up of optical glass substrate 1, golden membranous layer 2, lotus root connection layer 3 and receptive layers 4, gold film 2 is that the method by evaporation or sputter prepares on glass substrate 1, lotus root connection layer 3 is by one deck organic membrane of chemical self assembly in golden film 2 surface preparation, its effect is similar to " glue ", makes acceptor 4 energy indirect securement on golden film 2 surfaces.At present, the preparation of lotus root connection layer 3 and the fixation procedure of acceptor are:
A. be reagent with 16 carbon glycol (16-Heladecanecanedual 98%), preparation HO (CH)
16SH solution.
B. the optical glass sheet of gold-plated film is immersed the HO (CH) of preparation
16In the SH solution, keep more than 12 hours under the room temperature after, with pure anhydrous alcohol and ethane rinsing.
C. immerse in the 0.6M chloropropylene oxide solution, keep 4 hours (activation hydroxyl) under the room temperature after, by the abundant rinsing of " distilled water-ethanol-distilled water " process.
D. immerse in the poly-solution of alkaline grape, keep under the room temperature after 20 hours, by the abundant rinsing of " distilled water-ethanol-distilled water " process.
E. immerse in the bromoacetic acid, kept 16 hours under the room temperature, form free hydroxyl group, by the abundant rinsing of " distilled water-ethanol-distilled water " process.
F. immerse in the aqueous solution of 0.2M 1-3-dimethylaminopropyl-3-ethyl carbon diimide hydrochloride (EDAC) and 0.05M hydroxyl amber imines (NHS), hydroxyl is activated and is N-hydroxy-succinamide fat, uses the abundant rinsing of " distilled water-ethanol-distilled water " process again.”
G. receive PH5.0, sessile receptor with 10mM acetic acid.
H. use the HCl salt (it is 8.5 that NaOH is transferred to PH) of excessive 1M monoethanolamine, unreacted N-hydroxy-succinamide fat is deactivated.
This preparation method's deficiency is: (1) used reagent 16 carbon glycol are very expensive; (2) preparation process trouble; (3) have only 4 unit at present at most, can not satisfy the demand.
Summary of the invention
In order to obtain a kind of detectable microarray protein-chip of different capabilities, it is complicated and have only problem such as minority detecting unit to overcome cost height, the preparation process of existing preparation chip technology, but the invention provides a kind of high throughput testing or identification multiple proteins or effector molecules and interactional microarray protein-chip thereof and preparation method thereof.
Microarray protein-chip provided by the invention comprises the optical glass substrate, chromium film microarray, naked golden film microarray, coupling connection layer and the acceptor that are fixed together from bottom to top successively, it is characterized in that: described coupling connection layer is one deck HS-(CH
2)
10-COOH organic molecular film, an end of described organic molecular film is a sulfydryl, is connected with described naked golden membrane array, the other end is a carboxyl, is connected with described acceptor.
The unit number of naked golden film microarray of the present invention is 4 * 4～100 * 100.
The thickness of naked golden film of the present invention is 30～50nm.
Optical glass substrate of the present invention is 8 * 8～12 * 12mm
2Square sheet or diameter be the disk of 4～6mm, its thickness is 0.8～1.2mm,
The thickness of chromium film of the present invention is 2～5nm.
The present invention also provides a kind of method of making described microarray protein-chip, it is characterized in that this method comprises the steps:
1) cleans optical glass substrate, get rid of positive glue,, process grid, be about to the optical glass substrate array with the photoetching on positive glue face of grid mask in the one side of optical glass substrate; On positive glue grid face, successively evaporation or sputter chromium film and golden film are removed positive glue grid again, just make naked golden film microarray.
2) utilize chemical self assembly, on naked golden film microarray, prepare HS-(CH
2)
10-COOH organic molecular film constitutes coupling connection layer.
3) acceptor molecule is connected with described organic molecule, be about to acceptor and be fixed on the coupling connection layer, constitute the microarray protein-chip.
The method of the chemical self assembly of coupling connection layer of the present invention is as follows: clean naked golden film microarray earlier, it is placed on concentrated H again
2SO
4With H
2O
2Oxidation is 15 minutes in the mixed solution, cleans with ultra-pure water after finishing; Then, the naked golden film of microarray was immersed in the absolute alcohol 15 minutes, 11-sulfydryl 11 carboxyls (MUA) the absolute alcohol solution of putting into 1mM after the taking-up carries out self assembly; After self assembly finishes, clean 3 times with absolute alcohol, dry under 120 ℃ again, promptly finish making.
The method that acceptor of the present invention is fixed on the coupling connection layer is as follows: at first, will activate in the mixed solution with chip immersion 1-3-dimethylaminopropyl-3-ethyl carbon diimide hydrochloride (DEC), hydroxyl amber imines (NHS) and the ethyl sulfonic acid (NES) on MUA self assembly surface; After the activation, take out to immerse in damping fluid (PBS) solution and remove unnecessary activator; Then, described chip transferred in 37 ℃ the 0.1mg/ml receptor solution, constant temperature keeps taking out in the PBS solution that is placed on 37 ℃ after at least 1 hour, shakes on shaking table twice; Use 1% bovine serum albumin (BSA) to stop the surface can adsorbable point then; And then, be put into again in 37 ℃ the PBS solution and on shaking table, shake twice, so far, finished the fixing of acceptor.
The method for making of microarray protein-chip of the present invention can be efficiently, the microarray protein-chip of low-cost production different numbers unit.Microarray protein-chip of the present invention can one time the interaction of sensing multiple proteins or effector molecules molecule, have in real time, need not advantages such as mark, sensitivity and not damaged, can be used for the discovery and the exploitation of proteome research, clinical diagnosis and medicine.
Description of drawings
Fig. 1 is existing protein-chip structural principle synoptic diagram.
Fig. 2 is the structural representation of microarray protein-chip of the present invention.
Fig. 3 is a naked golden membrane array flow process chart of the present invention.
Fig. 4 is a coupling connection layer structural representation of the present invention.
Fig. 5 is the process flow diagram of acceptor fixing step of the present invention.
Embodiment
Below in conjunction with accompanying drawing, microarray protein-chip of the present invention and preparation method thereof is elaborated.
As shown in Figure 2, the present invention comprises optical glass substrate 5, chromium film microarray 6, naked golden film microarray 7, coupling connection layer 8 and the receptor 9 that is fixed together from bottom to top successively.Optical glass substrate 5 is that to select refractive index for use be 1.5～1.8 optical glass material, and its thickness is 0.8～1.2mm, and size is 0.8 * 0.8～1.2 * 1.2mm
2Square sheet or the disk of Φ 0.4～0.6mm, two-sided smooth; Chromium film microarray 6 is evaporation or the one side that sputters at optical glass substrate 5, and the thickness of chromium film is 2～5nm; Naked golden film microarray 7 is evaporations or sputters at chromium film microarray 6 surfaces, and the thickness of naked golden film is 30～50nm, and the unit number of naked golden film microarray is 4 * 4～100 * 100; Coupling connection layer 8 is to cover one deck HS-(CH on the naked golden film microarray 7 by chemical self assembly
2)
10-COOH organic molecular film; Receptor 9 is a target molecule, is the object of being studied, and is fixed on the coupling connection layer 8.The function of each layer is: optical glass substrate 5 is substrates of protein-chip, and chromium film microarray 6 is transition beds, and naked golden film microarray 7 is not come off in manufacturing process; Naked golden film microarray 7 is key stratums, is excitating surface plasma resonance and the realization necessary condition based on surface plasma resonance sensing.The surface of naked golden film microarray 7 is hydrophobic, and receptor 9 can't directly be fixed on its surface, and coupling connection layer 8 has been " bonding " effects, makes the surface of receptor 9 energy indirect securement at naked golden film microarray 7.
Naked golden membrane array is made flow process as shown in Figure 3.At first clean optical glass substrate, then get rid of positive glue in the one side of optical glass substrate.According to actual needs, select the grid mask of suitable number unit, photoetching on positive glue face processes grid, is about to the optical glass substrate array.Then, evaporation or sputter chromium film on the optical glass substrate surface of array are again at chromium film surface evaporation or sputter gold film.Then, remove positive glue grid, just finished the making of the naked golden film of microarray.
Coupling connection layer structural representation as shown in Figure 4.Coupling connection layer is one deck HS-(CH
2)
10-COOH organic molecular film, an end are sulfydryl, and the other end is a carboxyl, and the sulfydryl end links to each other with naked golden film, and c-terminus links to each other with acceptor, is the stiff end of acceptor.
The flow process of coupling connection layer assembling is as follows, during making, cleans naked golden film microarray earlier, it is placed on 90 ℃ 7: 3 the H that concentrates again
2SO
4With H
2O
2Oxidation is 15 minutes in the solution, cleans with ultra-pure water after finishing; Then, the naked golden film of microarray was immersed in the absolute alcohol 15 minutes, put into the MUA absolute alcohol solution 72 hours of 1mM after the taking-up, carry out the self assembly of MUA, after self assembly finishes, clean 3 times, promptly finished making down in dry 15 minutes at 120 ℃ again with absolute alcohol.
Fixedly process flow diagram is as shown in Figure 5 for acceptor.At first, will immerse in the MES mixed solution of 4 ℃ the NHS of DEC, 1mM of 10mM and 25mM, activate with the chip on MUA self assembly surface.After the activation, take out and immerse a period of time in the PBS solution, remove unnecessary activator.Then, as quickly as possible chip is transferred in 37 ℃ the 0.1mg/ml receptor solution, constant temperature keeps taking out in the PBS solution that is placed on 37 ℃ after 1 hour, shakes twice on shaking table, each 10 minutes.After finishing, the BSA with 1% stops the surface can adsorbable point.And then, be put into again in 37 ℃ the PBS solution, on shaking table, shake twice, at least 10 minutes at every turn.So far, promptly finished the fixing of acceptor, it has been placed in the PBS solution, kept under the room temperature, can use at any time.
By microarray protein-chip of the present invention being used in the SPR microarray protein sensing device, utilize the surface plasma body resonant vibration principle can detect protein or effector molecules molecule and for information about interactional on each unit, promptly once can obtain the interaction information of multiple proteins or effector molecules, thereby realize real-time high throughput testing, become a kind of strong tool of proteomics research, medical diagnosis on disease and drug screening.
Claims (8)
1. the microarray protein-chip comprises the optical glass substrate, chromium film microarray, naked golden film microarray, coupling connection layer and the acceptor that are fixed together from bottom to top successively, it is characterized in that: described coupling connection layer is one deck HS-(CH
2)
10-COOH organic molecular film, an end of described organic molecular film is a sulfydryl, is connected with described naked golden membrane array, the other end is a carboxyl, is connected with described acceptor.
2. microarray protein-chip according to claim 1 is characterized in that: the unit number of described naked golden film microarray is 4 * 4～100 * 100.
3. microarray protein-chip according to claim 1 is characterized in that: the thickness of described naked golden film is 30～50nm.
4. microarray protein-chip according to claim 1 is characterized in that: described optical glass substrate is 8 * 8～12 * 12mm
2Square sheet or diameter be the disk of 4～6mm, its thickness is 0.8～1.2mm.
5. microarray protein-chip according to claim 1 is characterized in that: the thickness of described chromium film is 2～5nm.
6. a method of making the described microarray protein-chip of claim 1 is characterized in that this method comprises the steps:
1) cleans optical glass substrate, get rid of positive glue,, process grid, be about to the optical glass substrate array with the photoetching on positive glue face of grid mask in the one side of optical glass substrate; On positive glue grid face, successively evaporation or sputter chromium film and golden film are removed positive glue grid again, just make naked golden film microarray;
2) utilize chemical self assembly, on naked golden film microarray, prepare HS-(CH
2)
10-COOH organic molecular film constitutes coupling connection layer;
3) acceptor is fixed on the coupling connection layer, constitutes the microarray protein-chip.
7. method for making according to claim 6 is characterized in that the method for chemical self assembly of described coupling connection layer is as follows: clean naked golden film microarray earlier, it is placed on concentrated H again
2SO
4With H
2O
2Oxidation is 15 minutes in the mixed solution, cleans with ultra-pure water after finishing; Then, the naked golden film of microarray was immersed in the absolute alcohol 15 minutes, the 11-sulfydryl 11 carboxyl absolute alcohol solution of putting into 1mM after the taking-up carry out self assembly; After self assembly finishes, clean 3 times with absolute alcohol, dry under 120 ℃ again, promptly finish making.
8. method for making according to claim 6, it is characterized in that the method that acceptor is fixed on the coupling connection layer is as follows: at first, will immerse with the chip on 11-sulfydryl 11 carboxyl self assembly surfaces in the mixed solution of 1-3-dimethylaminopropyl-3-ethyl carbon diimide hydrochloride, hydroxyl amber imines and ethyl sulfonic acid and activate; After the activation, take out to immerse in the damping fluid and remove unnecessary activator; Then, described chip transferred in 37 ℃ the 0.1mg/ml receptor solution, constant temperature keeps taking out in the damping fluid that is placed on 37 ℃ after at least 1 hour, shakes on shaking table twice; Stop the surface can adsorbable point with 1% bovine serum albumin then; And then, be put into again in 37 ℃ the damping fluid and on shaking table, shake twice, so far finished the fixing of acceptor.
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|---|---|---|---|
| CNA031478824A CN1482456A (en) | 2003-06-27 | 2003-06-27 | Micro-array protein chip and making method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031478824A CN1482456A (en) | 2003-06-27 | 2003-06-27 | Micro-array protein chip and making method thereof |
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|---|---|
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ID=34156178
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370632B (en) * | 2006-01-18 | 2011-02-09 | 荷兰应用科学研究会(Tno) | Optical micro-array for e.g. micro sensors |
| CN101165486B (en) * | 2006-10-18 | 2011-07-27 | 中国科学院上海应用物理研究所 | Micro fluid control array protein chip and its usage method |
| CN102297967A (en) * | 2010-06-22 | 2011-12-28 | 河南农业大学 | Surface plasma resonance detecting method for PVY/CMV (Potato Virus Y/Cucumber Mosaic Virus) |
| CN106536710A (en) * | 2014-08-08 | 2017-03-22 | 应用材料公司 | Patterned deposition of liquid films for biomedical devices |
| CN110265334A (en) * | 2019-06-27 | 2019-09-20 | 伊犁师范大学 | A kind of manufacturing device and its manufacturing method of integrated circuit |
| CN110907643A (en) * | 2019-12-02 | 2020-03-24 | 中国科学院重庆绿色智能技术研究院 | Preparation method of escherichia coli detection chip and detection chip |
| CN111273031A (en) * | 2020-02-29 | 2020-06-12 | 武汉大学 | Kit for biomarker detection and preparation method and application thereof |
| CN117871873A (en) * | 2024-02-18 | 2024-04-12 | 河南省科学院物理研究所 | Microscopic dark field biological detection method based on polymer microspheres |
-
2003
- 2003-06-27 CN CNA031478824A patent/CN1482456A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370632B (en) * | 2006-01-18 | 2011-02-09 | 荷兰应用科学研究会(Tno) | Optical micro-array for e.g. micro sensors |
| CN101165486B (en) * | 2006-10-18 | 2011-07-27 | 中国科学院上海应用物理研究所 | Micro fluid control array protein chip and its usage method |
| CN102297967A (en) * | 2010-06-22 | 2011-12-28 | 河南农业大学 | Surface plasma resonance detecting method for PVY/CMV (Potato Virus Y/Cucumber Mosaic Virus) |
| CN102297967B (en) * | 2010-06-22 | 2014-01-01 | 河南农业大学 | Surface plasma resonance detecting method for PVY/CMV (Potato Virus Y/Cucumber Mosaic Virus) |
| CN106536710A (en) * | 2014-08-08 | 2017-03-22 | 应用材料公司 | Patterned deposition of liquid films for biomedical devices |
| CN106536710B (en) * | 2014-08-08 | 2018-07-06 | 应用材料公司 | For the patterned deposition of the liquid film of biology device |
| CN110265334A (en) * | 2019-06-27 | 2019-09-20 | 伊犁师范大学 | A kind of manufacturing device and its manufacturing method of integrated circuit |
| CN110907643A (en) * | 2019-12-02 | 2020-03-24 | 中国科学院重庆绿色智能技术研究院 | Preparation method of escherichia coli detection chip and detection chip |
| CN111273031A (en) * | 2020-02-29 | 2020-06-12 | 武汉大学 | Kit for biomarker detection and preparation method and application thereof |
| CN117871873A (en) * | 2024-02-18 | 2024-04-12 | 河南省科学院物理研究所 | Microscopic dark field biological detection method based on polymer microspheres |
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