Chemical apparatus and process disinfecting – deodorizing – preser – Analyzer – structured indicator – or manipulative laboratory... – Calorimeter
Reexamination Certificate
2000-10-27
2003-09-23
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Analyzer, structured indicator, or manipulative laboratory...
Calorimeter
C422S050000, C422S064000, C422S068100, C435S287200, C435S006120, C436S164000
Reexamination Certificate
active
06623696
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a biochip, and more particularly, to a biochip capable of detecting other biomaterials by immobilizing biomaterials, such as DNA or protein, on a substrate, apparatus for detecting biomaterials using the biochip, and method therefor.
2. Description of the Background Art
Generally, the strength of a non-covalent bond, such as an ion bond, hydrogen bond, and van der waals bond, in an aqueous solution is very small, which is {fraction (1/30)}~{fraction (1/300)} times smaller than the strength of a covalent bond, thus making it difficult to have a stable bond. However, since a macromolecule has a large number of binding sites, it can maintain a stable bond at an ambient temperature. Such a non-covalent bond helps a specific molecule to selectively recognize other molecules.
The above molecule recognizing other molecules is defined as a receptor in a broad sense, which includes, for example, a membrane protein transferring a signal from a cell surface into a cell membrane, oligonucleotides or peptide nucleic acids(PNA) recognizing a predetermined sequence of DNA, antibody relating to an immune reaction, enzyme conducting hydrolysis of metabolite, and the like. And, the material selectively binding to these receptors is referred to as a ligand.
The Southern blotting, a method for detecting DNA having a specific base sequence, was developed by Edwin Southern in 1975. The DNA fragments of a test sample are separated by size by means of electrophoresis, and the separated DNA fragments are moved onto a solid substrate made of nitrocellulose or nylon membrane, thereby maintaining the relative position of the DNA fragments. Afterwards, the probe DNA or RNA having a specific base sequence which is labeled with a radioisotope is put into the DNA fragment immobilized on the solid substrate. Since the DNA or RNA put therein for use as a probe is bonded to the DNA fragments which can be complementarily bonded, by hybridization, it is possible to know the position of the DNA having a specific base sequence.
By applying this method, the Northern blotting for analyzing RNA and the Western blotting for analyzing protein were developed, and their principle is similar to that of the Southern blotting.
Such a number of methods using a binding reaction between a receptor and a ligand are employed in many fields, such as biological researches, medical diagnosis, new drug screening, forensic medicine, etc., most of which relate to a limited number of receptors and ligands.
For example, in case of making a DNA having four kinds of bases and having a sequential sequence of 10 bases, the DNA has a wide variety of structures with about more than 1,000,000 molecular types.
Therefore, an experiment for the binding reaction between a receptor and a ligand requires a very repetitive experimental procedure, and accordingly requires much labor forces, time, and enormous resources.
To solve this problem, there has been developed a biochip technique for forming a two-dimensional array of a plurality of receptors and ligands at a known position on a substrate.
Biochips are classified into DNA chip formed by using a DNA probe, protein chip formed by using an enzyme, antigen/antibody, bacteriorhodopshin, etc., and cell chip formed by using a cell, according to the type of a used biomaterials.
In this biochip method, it is important to integrate many kinds of probes on a single chip. It is reported that a DNA chip with 400,000 probes can be arranged on the substrate according to the conventional art.
The DNA chip is a high-density array of DNA fragments having a wide variety of base sequences on a narrow surface of the substrate, which is used to find out information on the DNA in an unknown sample by hybridization of an immobilized DNA and the unknown DNA sample.
Here, the hybridization means that gene subsequences are linked each other to form double-stranded DNA by complementary base pairing of hydrogen bond between the DNA bases of adenine-thymine (A-T), guanine-cytosine (G-C).
Hence, the unknown DNA sample is hybridized with DNA probes immobilized on the substrate, it is possible to learn about the base sequence of the DNA in the test sample by appropriately labeling the double-stranded DNA, or DNA probe or DNA sample.
Meanwhile, the fabrication methods for a DNA chip are mainly classified into a synthesis method for making a probe by directly synthesizing oligonucleotides on a substrate and a method for placing pre-synthesized nucleic acids (oligonucleotides, cDNA; complementary DNA, PNA; peptide nucleic acids, etc.) on a substrate.
The first method is a method using a photolithography frequently used in a semiconductor process disclosed in the U.S. Pat. No. 5,143,854. In this method, a functional group capable of synthesizing a nucleotide protected by a photolabile chemical material is introduced in advance onto a substrate. And then, a light is emitted on the predetermined positions by using photomask so that photolabile chemical material is removed and only the functional group that can be reacted with the nucleotide is exposed. Since each nucleotide participating in the reaction is also protected with a photolabile material at its end, the nucleotide can be synthesized one by one only in the position activated by exposure to light. Thereafter, non-reacted nucleotides are removed, and the process for selectively synthesizing a nucleotide on the substrate using other photomask pattern is repeated, resulting in forming oligonucleotides having a desired nucleotide sequence on the substrate.
Another method is a method for forming oligonucleotides on the surface by electrically discharging any one of four bases by piezoelectric printing as in the case of an ink jet printer. This method is disclosed in the U.S. Pat. No. 5,474,796.
Still another method is a method for arraying a pre-synthesized DNA on a substrate by mechanical microspotting, which is disclosed in Science 270 (1995), 467-470p. This method is disadvantageous in that a high density DNA fabrication is impossible and mass production is impossible, so it is mainly applied to a DNA chip fabrication for use in research fields.
As described above, the conventional methods of DNA chip fabrication are somewhat different, but have a common characteristic that different DNA molecules are arranged on a rectangular substrate of a predetermined size in a checker figure. In addition, fluorescence is measured in order to know the result of hybridization reaction. Since the DNA chip is fabricated by using a rectangular substrate, a high-priced image scanner is required to scan the surface of a two-dimensional substrate. The information on the image scanner is disclosed in the U.S. Pat. No. 5,091,652.
The above biochip and apparatus for detecting biomaterials according to the conventional art have the following disadvantages.
Firstly, high-priced equipment is required, and much time is needed in order to analyze the biological reaction patterns of the biochip.
Secondly, it takes much time for analysis because DNA molecules in the sample move to the surface by simple diffusion until they are hybridized with probes on the surface.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a biochip which is fabricated at a low cost, conducts a rapid analysis using a small amount of samples, and stores much information on biomaterials, apparatus for detecting biomaterials, and method therefor.
To achieve the above object, there is provided a biochip according to the present invention which includes:
a substrate having a center hole at a central portion; a biomaterial region arranged at a circumferential portion of the substrate; and an information region formed on the substrate between the biomaterial region and the center hole.
In addition, there is a biochip according to the present invention which has a disk-type substrate, and is made of any one of glass, silicon, acryl group, polycarbonate, PET(polyethylene terephtalate), polystyrene, and polypropylene.
In addition, there
Kim Su-Hyeon
Kim Tae-Han
Park Jo-Kyun
LG. Electronics Inc.
Morgan & Lewis & Bockius, LLP
Sines Brian
Warden Jill
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