Semiconductor device manufacturing: process – Having biomaterial component or integrated with living organism
Reexamination Certificate
2001-01-09
2002-07-23
Ghyka, Alexander G. (Department: 2812)
Semiconductor device manufacturing: process
Having biomaterial component or integrated with living organism
C438S780000, C438S781000
Reexamination Certificate
active
06423552
ABSTRACT:
FIELD OF THE INVENTION
The prespent invention relates to a new method of preparation of chemical or compound microarray chip, particularly a method of preparation in situ of chemical or compound microarray with multi-stamping, and a chemical or compound microarray chip produced by said method.
The invention provides a microarray chip of chemical molecules immobilized on a solid support and a novel method of preparing for these microarray chips by microstamps. The array comprises of a set of different chemical molecules which are mainly some biomacromolecules including nucleic acids such as DNA, RNA and oligonucleotide; polypeptides or protein such as enzyme, antibody and antigen; and other synthetic compounds with biological activities such as peptide nucleic acids (PNA) and so on. Those microarray chips can be called as gene chips while those immobilized molecules have properties of nucleic acid molecules.
BACKGROUND OF THE INVENTION
It is extremely significant that chemical microarray chips are applied in biological detection, medical detection, pharmaceutical screen, gene sequence analysis and synthesis of chemical compound library With the development of molecular biology and the coming actualization of human genome project (HGP), the knowledge on structure and sequence of those biomacromolecules including nucleic acid and protein is mushrooming. In the time of post HGP, the most challenging work is how to analyze a large amount of biological information and find out the rules so as to understand the life better and make an essential revolution of medical therapy Modern medicine is converting the second stage at the level of system, apparatus, tissue and cell to the third stage at the level of the molecular interactions during the process of DNA RNA protein, the interactions between protein and nucleic acid, and the interactions between these biomacromolecules and the environment. Gene diagnosis and gene therapy at the level of molecular interactions will probably open out the roots of many diseases including the cancer. All these transformations in biology and medicine depend on rapid determination and analysis of a mass of gene sequences, which will influence the actualization of HGP and further development of biology and medicine. Those traditional methods of gene sequencing with many heavy and complicated procedures including chemical reaction, gel electrophoresis and so on, have some drawbacks such as time-consuming, difficult to operate and schlep. Biochip technology centred on genechips, is emerging as the times require during the improvement of those traditional methods of gene sequencing. Biochip technology integrates many discontiguous analytic units in the study of life science such as sample preparation, chemical reaction and detection, into one chip by methods of microelectonics and micromechanics, and achieves the consecution, integration and micromation of analytical technologies.
Sequence analysis of protein or nucleic acid is based on the specific interactions between those chemical molecules immobilized on solid-phase supports and those molecules as sample. For instance, in sequence analysis of nucleic acid, oligonucleotides as probes are immobilized on solid supports and one microarray of chemical molecules is formed. Then, these immobilized oligonucleotide probes are hybridized with the gene or oligonucleotides as sample in solution. Finally, the information of sample gene sequence can be obtained by analyzing the hybridization result based on computer programs. During the whole process, the preparation of oligonucleotide probe arrays is pivotal.
An ideal probe array needs high spatial resolution, small workload, high speed, simple operation and low cost. Currently two methods of preparing for oligonucleotide probe arrays have been described. One method is to synthesize those different single probes, respectively, based on solid-phase synthesis technology, then bind those probes at different locations on the substrate by ink-jet or printing. This method has some shortcomings including unreachable high spatial resolution, large synthetic workload, low integrity, time-consuming, high cost and disadvantages in mass production. The other method is the light-directed synthesis in situ by masks, which is devised by the researchers of Affymetrix Company in United States. The spatial resolution of those microarrays prepared by this method can reach up to 40 ×40 &mgr;m
2
and the synthesis can be speeded greatly for parallel working. However, low efficiency of photochemical reaction due to serious side reactions has led to low correctness of the sequences of synthetic probes. Also, high cost is still needed for those expensive reagents for specific protecting groups. Therefore, it is very necessary for preparation of chemical microarray chips to develop a new method.
OBJECT OF THE INVENTION
The object of the present invention is to provide a new method of in-situ synthesis for chemical or compound microarray chips with high density including DNA microarray and PNA microarray by multi-stamping.
SUMMARY OF THE INVENTION
The inventors have made a intensive study for chemical microarray chips and have unexpectively discovered a new method of preparation of chemical microarray chips. The method of the present invention has many advantages such as simple and reliable operation, low cost, high spatial resolution and high correctness. This method includes the following steps: first, design and prepare for microstamps with concavo-convex pattern according to the needed chemical microarray, then cover the corresponding reagents on the so of microstamps and stamp onto the same substrate one by one. Those chemical reactions can be carried out in the specific region of the substrate surface controlled by the concavo-convex pattern of microstamps. Then the preparation of chemical microarray chips is completed. Different chemical microarray chips can be prepared by using different chemical reagents.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG.
1
: Sketch drawing of microstamps prepared by one template in the present invention.
FIG.
2
: Sketch drawing of chemical microarray prepared by multi-stamping, the surface of four microstamps (A, B, C and D) is covered by four kind of chemical reagents (A, B, C and D), respectively.
FIG.
3
: Sketch drawing of chemical microarray prepared by overstamping, the surface of four microstamps (A, B, C and D) is covered by four kind of chemical reagents (A, B, C and D), respectively.
FIG.
4
: Stamp
1
, which is used to prepare for the complete array with two nucleotides.
FIG.
5
: Stamp
2
, which is used to prepare for the complete array with two nucleotides.
FIG.
6
: Stamp
3
, which is used to prepare for the complete array with two nucleotides.
FIG.
7
: Stamp
4
, which is used to prepare for the complete array with two nucleotides.
FIG.
8
: Stamp
5
, which is used to prepare for the complete array with two nucleotides.
FIG.
9
: Stamp
6
, which is used to prepare for the complete array with two nucleotides.
FIG.
10
: Stamp
7
, which is used to prepare for the complete array with two nucleotides.
FIG.
11
: Stamp
8
, which is used to prepare for the complete array with two nucleotides.
FIG.
12
: Sketch drawing of the complete array with two nucleotides on the substrate.
FIG.
13
~
FIG. 19
reflects the flow chart of template preparation, microstamp preparation and chemical microarray preparation.
FIG.
13
: Photolith gel
3
is covered at the dimension of micrometer on the smooth surface of the substrate such as glass and silicon.
FIG.
14
: Transfer the designed concavo-convex pattern onto photolith gel
3
.
FIG.
15
: The silastic PDMS as material were poured onto the template with photolith gel, and then polymerize, solidify and form microstamp
1
.
FIG.
16
: Microstamp
1
separated from the template with photolith gel.
FIG.
17
: The surface of microstamp covered by a layer of chemical reactant
4
.
FIG.
18
: Microstamp covered by a layer of chemical reactant
4
is stamping on the substrate
6
modified by chemical gro
Chen Yali
Lu Zuhong
Ma Jianmin
Xu Chunxiang
Zhang Liapang
Ghyka Alexander G.
Harness & Dickey & Pierce P.L.C.
Zuhong Lu
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