TWI254744B - Integrated microarray devices - Google Patents

Abstract

This invention relates generally to the field of microarray technology. In particular, the invention provides an integrated microarray device, which device comprises a substrate comprising a plurality of distinct microlocations and a plurality of microarray chips, wherein the number of said microlocations equals to or is more than the number of said microarray chips. In preferred embodiments, the devices also comprises a temperature controller at some or all of the microlocations. The use of the integrated microarray devices for detecting interactions among various moieties in various fields, such as clinical diagnostics, drug discovery, environmental monitoring and forensic analysis, etc., are further provided.

Description

1254744 A7 B7 V. INSTRUCTIONS (1 Technical Field The present invention relates generally to the field of microarray technology. In particular, the present invention provides an integrated microarray device having a plurality of individual microlocations and A substrate of a plurality of microarray wafers, wherein the number of micro-locations is equal to or greater than the number of micro-array wafers. In a preferred embodiment, the germanium device further includes temperature controllers at some or all of the micro-positions. Bulk microarray devices can be used to detect interactions between different parts of various fields, such as clinical diagnostics, drug development, environmental monitoring, and forensic analysis. Background technology since the 1990s (Fod〇r ) et al., sdence, 251: 767-77 j (1991)) Microarray technology has developed rapidly since its first appearance. Currently, in the biochip technology, microarray technology has been widely used. Clinical diagnosis, disease mechanism development, drug research and development, environmental monitoring, functional gene development, etc. (Hacia et al., Nature

Genetics, Η: 441-447 (1996); and Heller et al., Proc. Natl. Acad. Sci. USA, Cong: 2150-2155 (1997)). Bioprobes, for example, oligonucleotides, DNA, RNA, peptides, proteins, cells, tissues, are immobilized on the surface of various substrates such as glass 矽, nylon membranes, and the like. These probes represent special information. Samples are also added to the reaction where the microarray is added to interact with the immobilized probe. Samples are labeled with isotopes, fluorescers, and chemical luminescent agents to facilitate integration. Various detection methods can be used according to different marking methods, for example, confocal fluorescent scanner, low luminescence detector, isotope imaging -4- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 PCT) 1254744 A7 _____ B7 V. Description of invention (2) Apparatus, etc. In order to achieve high total flow parallel analysis, high density microarrays have been developed with thousands of probes attached thereto. However, in many instances, a high density and high cost microarray is not necessarily required. In addition, high-density microarrays do not necessarily perform accurate signal detection because the different probes on the microarray are inherently slightly different. For example, if the probe is a DN A molecule, it has a different number of bases or a different sequence, both of which affect the result after changing the optimal hybridization state. / In the case of better mixing, there is no match. The ratio can be lowered to produce an accurate mixed signal. In addition, because only one side can be detected at a time, this detection operation is quite inconvenient for most microarrays. Invention Fu Xia The present invention provides an integrated microarray device which can be applied to various chemical and/or biological sample reactions and detections with high efficiency, high precision and low cost. In one aspect, the present invention provides an integrated microarray device comprising a substrate having a plurality of individual micro-locations and a plurality of microarray wafers, wherein the number of micro-locations is equal to or greater than that of the microarray wafer Quantity. In a preferred embodiment, the apparatus also includes some or all of the temperature controllers in the micro position. In another aspect, the present invention provides a method for detecting interaction between various target components, the method comprising: a) providing an integrated microarray device comprising a plurality of individual micro-locations And a substrate of the plurality of microarray wafers, wherein the number of the micro-positions is equal to or greater than the micro-array---- 5 the paper size is applicable to the Chinese National Standard (CNS) A4 regulation ^^ 297 dongdong) 1254744 V. Description of the invention 3) the number of column wafers, and a plurality of target components attached to the microarray wafer, b) contacting the plurality of target components provided by step a) with a test component; and detecting the test component and the plurality of The interaction between the target components. In a preferred embodiment, the apparatus provided herein includes a base f upon which a reaction ♦ is made. A _microarray positive film is placed in each reaction well. The microarray wafer is high or low, preferably a low density wafer. In addition, the temperature controller is placed inside or outside each of the reaction wells mentioned above. Child temperature controllers can individually control the temperature of each reaction well. When fabricating microarray wafers of such microarray devices, the probes are divided into different populations according to their respective melting temperatures (Tm values). Melting temperature values Probes with phase f close to each other will be attached to the same microarray wafer; the wafer will then be placed in the reaction well. The reaction temperatures of the different reaction wells can be controlled using the temperature controller of each individual. The reaction temperature of each well can be precisely controlled based on the Tm value of the fixed probe to reduce the position error ratio or detection error caused by improper temperature control. The size of this microarray device conforms to the standard 96-well plate, 38' well plate or 153 well plate. That is, the number of reaction wells and the distance between different wells are standardized. This kind of sigh can promote simple, efficient and automated operations like sample handling and cleaning with a robot. BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, the same reference numerals indicate the same parts. Figure 1 is a top plan view of an exemplary integrated microarray device. Figure 3 is a three-dimensional diagram of an exemplary integrated microarray device. -6 This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 297 mm) 1254744 A7 B7 V. Invention description (4 Figure 3 shows the electronic connection diagram of the temperature controller, its example A part of the integrated microarray device. Figure 4 is a structural diagram of a semiconductor temperature controller used in the microarray device of the present invention. The main method of checking Ji is to make the disclosure clearer, but not Limitations, the detailed description of the invention will be divided into the following sub-sections. A. Definitions Unless otherwise defined, all technical terms and scientific terms used herein are used in connection with those skilled in the art to which the invention pertains. The generic terms that are generally understood have the same meaning. All of the patents referred to in the application, the published applications and other published applications, are hereby incorporated by reference in its entirety. In the case of a referenced application, if the definitions in the published application and other public applications are contrary or inconsistent, the definitions set forth in this section shall prevail. “A, Or "an" means "at least one, or, or, one or more". ^ When used herein, "microarray wafer" refers to a system that has multiple one-dimensional, one-dimensional, or A solid substrate of a two-dimensional microstructure or micr〇_Scale structure on which specific processing can be performed, such as physical, chemical, biological, biophysical, or biochemical processing. Microstructures or microstructures, for example, channels And wells, which are either fabricated or attached to the substrate to promote physical, biological, biochemical, chemical reactions or processing on the wafer. The wafer may be very thin in one dimension, but in others Dimensions -7- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public love:) 1254744 A7 B7 5. Invention description (5) has various shapes, for example, rectangular, round, oval Or other irregular shape. The size of the major surface of the wafer varies very much, for example, from about 1 mm 2 to about 0.25 m 2 . Preferably, the wafer has a size of from about 4 mm 2 to about 25 cm 2 , characterized by Dimensions from about 1 Mm to about 5 cm. The surface of the wafer may be flat 'or uneven. The wafer in the uneven surface includes channels or wells made on the surface. As used herein, "micro position" The reference is made internally, on the surface or attached to the substrate where the microarray and/or other structural features are placed. As used herein, the term "individual microlocation", if required, Micro-positions that are sufficiently micro-separated so that reagents can be added and/or removed and reactions can be performed independently in a certain micro-location. It is not necessary to have each micro-location be "different" from all other micro-locations, although In some embodiments, each micro position may be different from all other micro positions. When used herein, the 'micro position' is in the well format, referring to a depression having a suitable two-dimensional shape at the micro-position that allows for the built-in or placement of microarray wafers and/or other structures or A device, such as a temperature controller. As used herein, "micro-position is thermally insulated" means that the micro-position has some that can be used to adjust and maintain a certain micro-position at a desired temperature, Affected by other micro-locations or outside of any micro-locations. As used herein, "moiety" encompasses both test components and target components. Non-limiting examples of components include cells, cell organs, viruses, particles, Molecules, for example, proteins, DNA and RNA, or their aggregation

1254744 A7 -------- B7 V. INSTRUCTIONS (6) Collectives or complexes. As used herein, "plant" refers to any of a variety of photosynthesis, plant-derived eukaryotic multi-complexed cell organisms that are characterized by the production of germs, contain chloroplasts, have cellulosic cell walls and are incapable of shifting ^. When used herein, "animal" refers to the multicellular organisms of the animal kingdom's characteristics that have the ability to move, non-photosynthetic metabolism, response to stimuli, limited growth, and fixed shape Structures. Non-limiting examples of animals include birds such as chickens, vertebrates such as fish and mammals such as mice, rabbits, tracing, dogs, pigs, cows, bulls, horses, transposons, and other non-human primates. As used herein, "bacteria" refers to a small prokaryotic organism (linear dimension of approximately j microns) that does not partition circular DNA and approximately 70 S ribosomes. Bacterial protein complexes differ from eukaryotes There are many antibacterial vitamins that interfere with bacterial protein synthesis but do not affect the infected subject. When used here, the term "eubacteria" refers to The main part of bacteria other than archaea. Most Gram-positive bacteria, cyanobacteria, mycoplasma, intestinal bacteria, Bacteroides and chloroplasts are all eubacteria. The membrane contains ester-linked lipids; there are peptidoglycans in the cell wall (if present); but no introns are found in eubacteria. When used here, archaea, the system referred to In addition to the main sub-particulates of bacteria other than eubacteria, archaea has a total of three main subjects · Extreme halophilic bacteria's extremely thermophilic bacteria associated with mites and sulphur. The ancient bacterium is different from the ribosome structure. Bacteria, with (in some cases) introns, and -9-I paper scales for the standard of home (CNS) M specifications (x 297 dong) 1254744

Its redundancy includes the properties of the film composition. When used in this field, "virus," refers to the need to parasitize in biological cells to survive but has no cell traits, consisting of (10) eight or (four) sputum and the outer layer of protein. The diameter of the virus ranges from about 2 〇 To about 3. Grade! ^Poly (Baltimore classification) has double-stranded DN A as its genome; grade π diseased mother has single-stranded DNA as its genome; rank 丨〗 virus has double-stranded RN A as its genome; The virus has a positive single-stranded RNA as its genome, and the genome itself acts as an mRNA; the grade v disease has a negative single-stranded RN A as its genome for use as a template for mRNA synthesis; and the grade... virus has positive single-stranded RNA Genomics, but DNA intermediates are not only in replication but also in the synthesis of mRN a. Most viruses are thought to cause disease in plants, animals and prokaryotes. When used here, "fungus, The classification refers to the classification of eukaryotes that grow in irregular mass, without roots, stems, or leaves, and lacks chlorophyll or other pigments that are viable for photosynthesis. Each organism (foliate) is unicellular to filamentous and has a branched cell structure (hyphae) surrounded by cell walls containing dextran or chitin or both, and contains true nuclei . As used herein, "intracellular component" refers to any component that is resident or located inside a cell. In other words, if one of them is present, it is placed in the cytoplasm or mother of the organelle and attached to any On the cell membrane, resident or placed in the same quality, if one of them exists, or resident or placed on the cell surface, in other words, attached to the cytoplasm -10-

1254744 A7 B7 V. INSTRUCTIONS (8) On the outer surface of the membrane or cell wall. As used herein, a term "macromolecule" refers to a molecule that is not attached to another molecule and that produces an antibody that specifically binds to the macromolecule. As used herein, a ''small molecule'' refers to a line that does not form a homo-aggregate or is not attached to a large or small particle and is unable to produce an antibody that specifically binds to the small molecule. molecule. Preferably, the small molecule has a molecular weight of about or less than 1 〇, 〇〇〇 Dalton. More particularly, the small molecule has a molecular weight of about or less than 5,000 Daltons. As used herein, ''vitamin'' refers to the tracking of organic matter required in certain biological species. Most of the vitamins function as a component of a specific coenzyme. When used here," The lipids are not dissolved in water, and an organic substance containing oil or fat can be extracted from cells and tissues by using a non-polar solvent such as chloroform or diethyl ether. As used herein, "receptor" refers to a molecule having the affinity for a known ligand. The receptor may be a naturally occurring or synthetic molecule. The receptor is also referred to in the art. Anti-ligand. When used herein, the receptor and the anti-ligand are used interchangeably. The receptor can be used in non-altered states or aggregated with other species. The receptor can be attached to (in covalent or non-covalent manner) or in direct or indirect contact with a binding substance via a specified binding substance or linker. Examples of receptors include, but are not limited to, antibodies, cell membrane receptor surface receptors, and Intrinsic receptors, monoclonal antibodies and antiserums that react with specific epitopes [eg, on viruses, cells, or other substances], drugs, multi-nuclear acid, nucleic acids, peptides, and auxiliary factors-11 - This paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1254744 A7 B7 V. Description of Invention (9) Sub, agglutination acid, sugar, polysaccharide, cell, cell membrane, and organelle. When used herein, "antibody" "including antibody fragments, examples Fragment Fab 'which is a line light chain region and variable heavy chain composed. As used herein, "humanized antibody" refers to an antibody which, after modification, includes a "human" sequence such as an amino acid such that it does not cause an immune response when administered to a human. Methods for the preparation of such antibodies are well known. For example, a hybridoma expressing a monoclonal antibody can be modified by the DNa recombination technique to express an amino acid composition of the immutable region of the antibody from a human-based antibody. Computer programs have been designed to identify such areas. As used herein, "structural and/or functionally related protein groups" refers to a group of proteins in their natural state that are structurally linked and located at the same cellular location, for example, Organelles, located in phase (4) tissues or organs, that function and/or function as the same biological stage, for example, a particular cell cycle stage or developmental stage, or function and/or function as the same biological pathway, eg, special Metabolic pathways, signal transduction pathways, etc.., on the crusting and/or functionally related = protein group, only need to include at least two protein shells belonging to the same group. The preferred system is structurally / or functionally related protein group '' includes more than two proteins belonging to the same group, for example most or all of the proteins belong to the same group. As used herein, "nutrition or storage protein" refers to a protein that is used as a source of cultivating cells or a storage mode for such nutrients. Nutritional obesity Non-limiting examples of Tibetan proteins include gliadin, ovalbumin, casein', and ferritin. Mouth L _ - 12- This paper size applies to China National Standard (Cns) specifications (21 〇χ 7 public) 1254744 V. Description of invention (1) When used here, • Shrinkage or active protein and The organism has contraction, and the system that is added to it changes the fineness. The protein that shrinks, the tongue, the weight of the tongue, or the ability to move around, the 4 tongue protein (non-limiting example package W protein, tubulin and dynein When muscle coagulation is used here, "structural egg silk, cable, or sheet to provide biopterin: used as a fibrin. to construct a sputum W constructor I or protect the biological structure of the worm shell ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Non-limiting examples of organic sisters being & humans or eggs 2 proteins that protect them from attack include antibodies, cellulose precursors, thrombin botulinum toxin, diphtheria toxin venom and anesthetic proteins. When used, "regulate protein & Quoting refers to the regulation of proteins such as or physiological activities. Non-limiting examples of regulatory proteins include alizarin, growth hormone, corticotropin and repressor. When used here, ,, • Refers to any substance that is required to analyze the test object. The sample is a biological sample, such as a raw liquid or biological tissue. Examples of biological fluids include urine, blood, plasma, clear, saliva, semen, feces, sputum, brain Spinal fluid, tears, mucus, amniotic fluid, or the like. Biological tissue cell aggregates, which typically form a special species of intracellular material that is linked to one of the structural elements of a human, animal, plant, bacterial, fungal, or viral structure. , including connective tissue, epithelial tissue, muscle tissue and nerve tissue. Examples of biological tissues include the 'lumral mass' lymph nodes, arteries and individual cells.

J&L and ordering _ - 13- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1254744 A7 B7 V. Description of invention (I) This may also be a molecule containing in vitro preparation. Target protein. As used herein, a "structural and/or functionally related group of enzymes" refers to a group of enzymes in their natural state that are structurally linked and located at the same cellular location, eg, cells. , / in tissue or organ, and/or as the same biological order = 旎, for example, a special cell cycle stage or developmental stage, or a function and / or as a function of the same biological pathway, such as 'special metabolic pathways t Signal transduction path, or as a regulator of path activation or biological function. The "structural and/or functionally related enzyme group" need only include at least two enzymes belonging to the same group. Preferred lines, structures ^ and/or functionally related enzyme groups, , including two or more enzymes belonging to the same group, for example, most or even all of the enzymes are the same when used here, "expressing specific ways in tissues or organs" The pattern in which the gene is only (transient or constitutive: present in a particular tissue or organ, but not in other tissues or crying when used here, "organization" refers to the same cell as the whole And the intracellular material that produces them. There are four basic tissues in the human body: skin; 2) connective tissue 'including blood, bone, and cartilage; 3) muscle-directed tissue; and 4) nerve tissue. ~ When used herein, "organ," refers to a part of the body that produces a specific function, such as breathing, excretion, or digestion. And when used, determines the percentage of mismatch "hybrid rigor -14- 1254744 A7 B7 V. Description of invention (12) (stringency of hybridization), as follows; 1) South rigorous degree · 0_ 1 x SSPE, 〇. i〇/. SDS, 65 ° C; 2) Degree: 0·2 x SSPE, oi% SDS, 50 °C (also known as medium rigor), and J) Low stringency: l.OxSSPE, 〇.i% SDS, 50 ° C. It should be understood With alternating buffers, salts and temperatures can achieve equal stringency. When used herein, the term "gene" refers to the passage of a cell that is specific to the chromosome's existence and can utilize different dual genotypes. Appears to confirm. Assuming that a split gene is present, the gene will also contain a set of DNA sequences (exons) that need to produce a single polypeptide. When used here, "gene wafer, the indicated line is fixed on the surface available Oligonucleotides for screening RNA samples (after reverse transcription) Acid array thus also a fast Analyzing RN A from sources which expresses the gene in the cell or tissue method. As used herein, "RNA" refers to a ribose unit that is attached to the 3, and position, via a oxime or pyrimidinyl group attached to the oxime position by a diacid diester. When used herein, ' 'Protein' refers to an amino acid linear polymer in which a specific sequence is linked by a peptide chain. When used herein, 'protein, also includes polypeptides, oligopeptides and peptides. B. Integral microarray device is included therein In one aspect, the present invention provides an integrated microarray device comprising a substrate having a plurality of individual micro-locations and a plurality of microarray wafers. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1254744 A7 _______ B7 V. INSTRUCTION DESCRIPTION (13) Bottom 'where the number of micro-locations is equal to or greater than the number of micro-array wafers. Any suitable substrate can be used for the integrated microarray device. In a preferred embodiment, the substrate comprises tantalum, for example, cerium oxide or tantalum nitride, plastic, glass, ceramic, rubber, polymer or a combination thereof. The substrate comprises a hydrophobic or hydrophilic surface. In addition, the substrate comprises a porous or non-porous surface. The micro-location can be created inside, on or attached to the substrate by any suitable method. For example, the microlocation can be fabricated directly as part of the substrate. Alternatively, the substrate may be fabricated first and then placed inside, or attached to, the substrate to create the micro-location. In a preferred embodiment, the micro-location and/or the microarray wafer are fabricated on the substrate. The device includes any suitable number of micro locations. For example, the device includes (12)d® micro-positions, where n is an integer of at least one. Preferably, η is 8, 3 2 or 1 2 8 . The microlocations may be distributed evenly or unevenly in the substrate. Preferably, the number of micro-positions and the distance between the micro-positions are matched to a standard microtiter plate, for example, a 9 6 _, 3 8 4 -, or 15 ^ 6 - well plate. The microlocation can be in any suitable format. For example, the micro-location can be fabricated inside or on the surface or over the surface of the substrate. Preferably, the micro position is a well format or a thermally insulated flat surface format. The apparatus includes (12) n wells, wherein the η is at least an integer of one. Preferably, the device comprises 96,384 or 1,536 wells. The well has any suitable -16- paper size applicable to China National Standard (CNS) Α4 size (210 X 297 mm) 1254744 A7 B7

5. Description of the Invention (15) The air contained between the side walls of adjacent wells is thermally insulated. The number of micro-locations in the device must be greater than or equal to the number of microarray wafers. Preferably, each device is used. A micro-location includes a microarray wafer. Any suitable microarray wafer can be used in the integrator microarray device. For example, microarray wafers are suitable for microarray wafers for nucleic acid analysis 'eg, gene wafers, and/ Or protein wafers, antibody wafers, can be used in the device (see generally Current Protocols in Molecular Biblogy by Ausubel et al., § 22, John Wiley &

Sons, Inc. (2000); and Schena (Ed.), Microarray Biochip technology, Eaton Publishing Company/Bio Techniques Books Division (2000)). In a specific embodiment, the microarray wafer disclosed in the following U.S. Patent No. is used in the apparatus: 6,245,51 1,6,215,894, 6,142,681, 6,101,946,6,004,755, 5,930,117, 5,928,437 and 5,716,459 ° The microarray wafer can have any desired density. The microarray wafers can have the same or different densities. In a particular embodiment, the microarray wafer has a density of (100) n spots/cm2, wherein η is at least an integer of one. Preferably, at least one of the microarray wafers has a density of less than or equal to 400 spots/cm2. However, there may be any number or percentage of microarray wafers, e.g., 50% microarray wafers, having a density of less than or equal to 400 spots/cm2. More preferably, all of the microarray wafers have a density of less than or equal to 400 spots/cm2. In another specific embodiment, at least one of the microarray wafers -18- the paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297

Order

1254744

Among the multiple components. The microarray wafer can be attached to multiple components with a face up or face down. This component can be attached to the microarray wafer i by any suitable method. The < points can be shared, non-covalent, connected via finger or non-finger, and attached to the microarray wafer either directly or through a connector. The connector is very sensitive to certain processes such as physics, chemistry or hair. / Λ Any suitable composition can be attached to the microarray wafer. The ingredients may be pure or mixed materials, may be chemical or biological materials, or may be synthesized or isolated/purified from biological sources or samples. Exemplary components include cells, organelles, viruses, molecules and their aggregates or complexes. Non-limiting examples of cells include animals, plants, fungi, bacteria, recombinant or artificially cultured cells. Animals, plants, fungi, bacterial cells can be obtained from any animal 's genus or subgenus of the plant, fungus or bacterial community. Cells from any genus or subgenus of any ciliate, cell slime mold, flagellate and microspores can also be attached to the microarray wafer. Extracted from birds such as chickens, vertebrates such as fish and mammals such as mice, rabbits, cats, dogs, pigs, cows, bulls, sheep, horses, monkeys and other non-human primates, and human cells can be attached To the microarray wafer. In the case of animal cells, cells drawn from a particular tissue or organ can be attached to the microarray wafer. For example, connective, epithelial, myocutaneous, and neural tissue cells can be used. Similarly, from the eye's auxiliary organs, spiral organs, ear organs, Chievitz organs, ring chamber organs, Corti organs, vital organs, sputum organs, terminal organs, external female reproduction Organs, external male reproductive organs, floating organs' -19- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1254744 A7 B7 V. Inventions Description Ruffim's florets , genital organs, Golgi apparatus &, taste organs, auditory organs, internal female reproductive organs, internal male reproductive organs, inserted organs, Jac〇bs〇n organs, neuro-health organs, neural crest organs , olfactory organs, inner ear organs, sagging organs, Rosenmliller organs, sensory organs, olfactory organs, auger sputum, secondary joint preparations, underarm organs, excess organs, tactile organs, 2 standard zhai, taste detector Ear, tactile organ, urinary organ, terminal vascular organ, inner ear organ, vestibular cochlear implant, degenerative organ, visual organ, visual organ, Nasal, mental organs, Weber (Webe〇 organ and Zuckerkandal organ cells can be used. Preferred lines, extracted from internal animal organs such as, brain, lung, liver, spleen, bone marrow, chest Line ^ 祆 霄 霄, pancreatic heart, lymph, blood bladder 'stomach, intestine, ovary, uterus, rectum, nervous system, gland, inner, j tube, etc. cells can also be used. In addition, from any plant, Cells such as yeast, bacteria such as eubacteria or archaea may also be used. Recombinant cells derived from any eukaryotic or prokaryotic source such as animal, plant, bacterial or bacterial cells may also be used. Human fluids such as; , urine, saliva, bone marrow, semen or other ascites fluid, and its sub-segment, such as serum or plasma, can also be used. Attachable organelles include cells, mitochondria, chloroplasts, ribosomes, ER 'high , basal organ, lysosome, f white zymocyte "secretory vesicles, vacuoles or microsomes. Viruses that can be attached to the life cycle of a virus, whether it is a whole virus or any viral structure For example, viral particles, two Class I = = = = virus' Level II virus' level IU virus' drug or the like ^ level: -20

1254744 A7 B7 V. INSTRUCTIONS (18) VI virus is taken out. Attachable intracellular components include resident or located inside the cell, in other words, in the cytoplasm or mother of the organelle; attached to any intracellular membrane; resident or located within the same mass, if any; or resident or located on the cell surface, in other words Any component that attaches to the outer surface of the cytoplasmic membrane or cell wall, if any. Any desired intracellular component can be isolated from the target cell. For example, organelles, molecules or aggregates or complexes thereof can be isolated. Non-limiting examples of such organelles include cells, mitochondria, chloroplasts, ribosomes, proteasomes, secretory vesicles, vacuoles or microparticles, membranous receptors, antigens, enzymes, and proteins in the cytoplasm. The attachable molecules may be inorganic molecules such as ions, organic molecules or complexes thereof. Non-limiting examples of attachable ions include sodium, potassium, magnesium, calcium, gas, iron, copper, zinc, strontium, agar, exchange, bismuth, bismuth, nickel, indium, fluorine, antimony, tin, boron or arsenic ions. Non-limiting examples of attachable molecules include amino acids, peptides, proteins, nucleofen acids, oligonucleotides, nucleic acids, vitamins, monosaccharides, hypoxia polysaccharides, carbohydrates, lipids or complexes thereof. Any amino acid can be attached to the microarray wafer. For example, D- and L-amino acids can be attached. In addition, any naturally occurring building blocks of peptides and proteins, including Ala (A), Arg (R), Asn (N), Asp (D), Cys (C), Gin (Q), Glu (E), Gly (G), His (Η), lie (I), Leu (L), Lys (K), Met (M), Phe (F), Pro (P) Ser (S), Thr (T), Trp (W), Tyr (Y) and Val (V) can all be attached. Any protein or peptide can be attached to the microarray wafer. For example, -21 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1254744 A7 B7 V. Description of invention (19) Enzymes, transport proteins such as ion channels and pumps, nutrient or storage proteins , contractile or mobile proteins such as actin and myosin, structural proteins, protective proteins or regulatory proteins such as antibodies, hormones and growth factors can be attached. Protein or peptide antigens can also be attached. Any nucleic acid, including single-, double-, and triple-stranded nucleic acids, can be attached to the microarray wafer. Examples of such nucleic acids include D N A, such as A -, B - or Z - type D N A, and R N A such as mRNA, tRNA and rRNA. Any core can be attached to the microarray wafer. Examples of such nucleus include adenine nucleus, guanine nucleus, thymidine nucleus, thymidine nucleus and uracil nucleoside. Any nucleoside acid can be attached to the microarray wafer. Examples of such nucleotides include A Μ P, G Μ P, C Μ P, UMP, ADP, GDP, CDP, UDP, ATP, GTP, CTP, UTP, dAMP, dGMP, dCMP, dTMP, dADP, dGDP, dCDP, dTDP, dATP, dGTP, dCTP and dTTP. Any vitamin can be attached to the microarray. For example, water-soluble vitamins such as thiamine, riboflavin can be tested for acid, pantothenic acid, vitamin B 6, vitamins, folic acid, vitamin B 2 and ascorbic acid. Similarly, fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K may be attached. Any single vinegar, D- or L-mono-billed and sugar or sucrose, can be attached to the microarray wafer. Examples of monosaccharides include triose such as glyceraldehyde, butyrate such as erythrose and threose, pentose such as ribose, gum sugar, xylose, lyxose and ribulose, hexose For example, allose, altrose, glucose, mannose, gulose-22- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1254744

DESCRIPTION OF THE INVENTION 20 'idose s galactose, tal (5) 〇se) and fructose such as sedoheptulose Se (Sed〇heptul〇Se). Any lipid can be attached to the microarray wafer. Examples of genus include dimercaptoglycerols such as tristearyl sulphate, trisodium sulphate and triolein, stone walls, phosphoric acid: oils such as phospholipids, ethanolamine, phospholipid choline, phospholipid lysine, quercetin And cardiolipin, sphingolipids such as sphingomyelin, cerebral palsy and nerve sputum, sterols such as cholesterol and sterols and sterol fatty acid esters. Fatty acid Y is a saturated fatty acid such as lauric acid, stem acid, hexadecanoic acid, stearic acid, probiotic acid and perylenetetracarboxylic acid, or unsaturated fatty acid such as oleic acid, oil, linoleic acid, peanut acid. In a specific embodiment of the feature, at least two microarray wafers are attached to the island. However, any number or percentage of microarray wafers, for example, 50% microarray wafers, can be attached to multiple components. Preferably, each microarray wafer is attached to a plurality of components. The microarray wafer can be attached to the same type or different types of components. In another specific embodiment, at least one of the micro-locations includes a temperature controller. However, there may be any number or percentage of micro-positions, for example, 50% micro-positions, including temperature controllers. Preferably, each micro position includes a temperature controller. More preferably, each micro position includes a microarray wafer and a temperature controller. Some temperature controllers, such as 50% temperature controllers, can be individually controlled. Preferably, each temperature controller can be individually controlled. Any suitable temperature controller can be used in the device. For example, 'Resistive heaters can be used, bidirectional semiconductor temperature controller, Tao L__-23- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1254744 A7 ---- B7 V. DESCRIPTION OF THE INVENTION (21) Porcelain heater or infrared heater. The substrate in the device can be a single unit. Alternatively, the substrate can be a modular unit that can be disassembled into at least two portions. C. Detection Method In another aspect, the present invention provides a method for detecting an interaction between a test component and various target components, the method comprising: & providing an integrated microarray device, The device includes a substrate having a plurality of individual micro-locations and a plurality of microarray wafers, wherein the number of micro-locations is equal to or greater than the number of micro-array wafers, and a plurality of target components are attached to the micro-array wafer; b) utilizing The plurality of target components provided in step a) are in contact with a test component; and c) detecting an interaction between the test component and the plurality of target components. The method can be used in any suitable category including prognosis, diagnosis, drug screening, environmental monitoring, and the like. Any suitable integrated microarray device, including those discussed in Section B above, can be used in the method. In a particular embodiment, the integrated microarray device includes a substrate having a plurality of individual micro-locations, each of which includes a microarray wafer and a temperature controller. The method can be used to detect any interaction between components selected by a group of cells, organelles, viruses, molecules, and their polymers or complexes. For example, the method can be used to detect interactions between micromolecules, such as DNA-DNA' DNA-RNA, RNA-RNA, DNA-protein, RNA-protein and protein-protein. This method can also be used to detect the interaction of micromolecules - small molecules or small molecules - small molecules. This method can also be used to detect the interaction between two components and above. -24 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1254744 A7 _B7 _ V. Invention description (22) More complex interactions are used. When DNA-DNA, DNA-RNA, and RNA-RNA interactions are to be detected, the contacts, in other words, hybridization, steps can be carried out under appropriate conditions, for example, at low, medium or high stringency. The interaction between the test component and the plurality of target components can be detected using an appropriate method. For example, the test component and the target component can be labeled to facilitate detection. It can be labeled using any suitable method. Examples of indications include radioactivity, fluorescence, chemistry, enzymes, luminescence, and FRET (Fluorescence Resonance Energy Conversion) labeling. The luminescent indicator can be a chemiluminescent label or a bioluminescent label. The label may be attached or bound to the test component either directly or indirectly, attached or bound to the target component by itself, or attached or bonded to both. The result read can be a positive or negative signal. Any suitable assay can be used, including sandwich or competition. In a preferred embodiment, the method is used to detect interaction between a test component and a plurality of genes, gene segments or their encoded products. More preferably, a plurality of target genes, gene fragments or their encoded products are contained in the biological pathway, and belong to the same period of the cell cycle of the protein i group having the same or similar biological function. Type, performance of the same tissue type, performance of the same organ type, performance of the same development stage, protein performance and / or activity will change in an unhealthy or disorderly pattern or stage, or protein performance and / Or the activity can be changed with drugs or other treatments. -25- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1254744 A7 —_B7__ V. Description of invention (23) This method can be used to detect a single test component or substance and multiple target components. Interaction between the two. Preferably, the method is used in a high total flow mode, in other words, to detect interaction between a plurality of target components or substances and a plurality of target components. The interaction between the test component or substance and the plurality of target components can be detected simultaneously or continuously. D. Example Device Description A top view of a typical integrated microarray device shown in FIG. The device comprises a substrate 1. The substrate 1 is made of plastic, glass, pulverized, ceramic, etc. and is permeable or impermeable, rigid or bendable. A plurality of reaction wells 2 can be fabricated on the substrate 1 by a suitable method such as etching. Then, the number of microwell wafers in each reaction well and the distance between different wells can be corrected according to actual needs. It is recommended that the parameters of the well (such as the number of reaction wells or the distance between different wells) be the same as standard plates, such as standard 96-well plates, 384-well plates or 1536-well plates, to facilitate automated operation with robots (eg Sample processing or cleaning). In the example shown in Figure 1, the dimensional parameters of the microarray device are the same as for the standard 96-well plate. That is, there are 96 reaction wells 2 on the substrate 1 and a distance of 9 mm from a well to Zheng near well, the same distance from the adjacent wells of the standard 96-well plate. Fig. 2 is a three-dimensional diagram of a well unit of a microarray device in which a reaction well 2 and an attached microarray wafer 3 are shown. The shape of the top end of the reaction well is square. The size around it should be less than or equal to the standard 9 6 _ well jut The shape of the microarray wafer 3 placed in the reaction well 2 is also square. In this preferred embodiment, the reaction well 2 and the microarray wafer 3 • 26 - the paper size of the standard ® ® standard (CNS) A4 specification (21GX 297 mm) '·~·' - - 1254744 A7 B7 5. The square shape of the invention (24) will ensure that the orientation of the microarray wafer 3 is correctly positioned. A skilled artisan will appreciate that the shape is not necessarily limited to a square. Other shapes such as a circular shape may also be used to form the reaction well 2 and the microarray wafer 3. For the microarray wafer 3, the surface of the fixed probe is face up (Fig. 2A) or face down (Fig. 2B). The bottom of the reaction well 2 is sealed and reagents (eg, hybridization reagents or cleaning reagents) can be added or removed from the top (Fig. 2A). In addition, the bottom end of the device can be designed to be partially open, that is, at least one microfluidic channel can be fabricated at the bottom to add or remove reagents (hybridization reagents or cleaning reagents) from the bottom (Fig. 2B). except. The reaction well 2 is manufactured as a unitary device or it comprises at least two disassembled parts. For example, if necessary, the bottom of the reaction well can be pulled down for later detection. The depth of the reaction well 2 can be modified depending on the thickness of the microarray wafer 3, and the reaction volume can be changed from several hundred micrometers to several centimeters. When the present microarray device is used to detect biological or pharmaceutical samples, the probes can be divided into different groups based on their characteristics, such as the number or sequence of probes. Probes from the same group can then be immobilized on the same microarray wafer 3 of the reaction well 2. The probe may be a cDNA, oligocore: y: acid' antigen or antibody, sensory organ, polypeptide, cell or tissue. The substrate of the microarray wafer 3 may be a crucible, a glass or nylon film or the like. The method of immobilizing the probe may be absorption, covalent binding, retention, etc. (Beattie et al., Molecular Biotechnology, 4: 213-225, (1995);

Enzyme & (4) (10) by Subramanian et al. (10), 21:26-34, (1999)). In many cases, such as diagnosing a disease, screening a drug or _____ - 27 - this paper scale applies to the towel a g home standard (CNS) A4 specification (210 X 297 mm 1254744 A7

To study certain specific gene functions, it is not necessary to have a high-density micro-device microarray wafer 3 low-density microarray wafer with dozens or hundreds of fixed probes on its upper mouth. Low-density microarrays can reduce the cost of manufacturing; Further, the microarray device of the present invention has a plurality of units (for example, the number of units is 96, 3 8 4 or 1536). :炊 The number of probes per reaction (4) is Μ, but the number of probes in the whole (four) 妓 well should be thousands to tens of thousands to achieve high yield analysis to provide medium density. In order to control the temperature of each reaction well 2, as shown in Fig. 2, a temperature control = 6 is attached to each reaction well 2. The connection temperature between the different temperatures = controller 6 shown in Fig. 3 is a column. Each of the temperature control devices 6 has two wires 9 and 9' respectively connected to the anode and cathode of the power supply. The individual temperature control of the different reaction wells 2 is achieved by addressable start/stop of different temperature controllers 6. The temperature controller 6 can be a resistor to heat the reaction well 2. It can be attached to the bottom of the reaction well 2. If the substrate is made of tantalum, microfabrication techniques can be utilized to etch the opposite side of the reaction well 2, followed by depositing a layer of metal (e.g., copper) on the crucible to fabricate the temperature controller 6. The bottom of the reaction well 2 can be made thinner as possible to facilitate heat transfer between the temperature controller 6 and the microarray wafer 3 in the reaction well 2. Alternatively, the temperature controller 6 can be a bidirectional semiconductor temperature controller. In one aspect, the bi-directional semiconductor temperature controller heats the reaction well 2 • On the other hand, it cools the reaction well 2 when its temperature is above ambient temperature (e.g., 5 〇〇 c). This bidirectional semiconductor temperature controller can be attached to the bottom of the reaction well 2 α -28- This paper scale applies to the Chinese National Standard (CNS) Α 4 specification (210X297 mm)

1254744 A7 _______B7 V. DESCRIPTION OF THE INVENTION (26) The temperature controller 6 can also be placed in the reaction well 2 using the method of Figure 2B. The temperature controller 6 can be coupled to the microarray wafer 3 by mechanical inlay. Alternatively, the combination can be achieved by introducing a layer of liquid that does not participate in the reaction or evaporation during the reaction. The bonding force is between the surface tension of the liquid (the surface and the surface of the temperature controller 6. In addition, the introduced liquid contributes to heat conduction. Those skilled in the art will be aware of any type of temperature controller, not limited to A resistor or a bidirectional semiconductor temperature controller can be applied to the foot temperature controller 6 of the present invention. For example, the ceramic heater can be applied to the temperature controller 6 by attaching it directly to the bottom of the reaction well 2. In addition, the 'infrared heater can be applied by using non-contact infrared light waves. The connection method between the temperature controller 6 and the computer to achieve the address control of the temperature controller 6 is not limited to the above-mentioned method. Any suitable The temperature control method can be used. In the preferred embodiment of the apparatus of the present invention shown in Figs. 1 and 2, the hole formed by the insulation between the mother reaction wells can be thinned. The beams interconnect the different reaction wells to facilitate thermal insulation between the different reaction wells 2. If the strength of the system is sufficient, the holes are The larger the size, the better. For example, if the substrate is made of plastic, the size of each pore is 3 x 2 mm. Depending on the materials used, different manufacturing methods, such as electro-absorption, can be used. (Simpson et al., Proc. Natl. Acad. Sci. USA, 21: 2256-2261 (1998)), Casting Method (Becker et al., Sensors Update, 2: 208-238 (1998): and Delamarche J. Am. Chem. Soc., 120:500- ____-29- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1254744 A7 __ B7 V. Description of invention ( 27~) 508 (1998)), and embossing method (〇κρρ et al., Current Opinion in Chemical Biology, 丄: 410-419 (1997)). When applying the microarray device to biochemical reactions, After the solution is added to the microarray wafer 3 of the reaction well 2, a cover strip (cover_slip) is used to cover the sample solution. This will avoid evaporation of the sample. And depending on the size of the microarray wafer (less than the area of the microarray wafer 3) The size of the cover strip is scalable. In addition, as shown in Figure 2, the height is high. A boiling point hydrophobic organic reagent (such as mineral oil) can be used to limit the reaction system. The volume of the reagent is determined by the sample volume and the area of the microarray wafer. As shown in Figure 2B, when the microarray wafer 3 is facing When placed in the reaction well, a hydrophobic and biocompatible liquid can be added to fill the reaction well 2. The gravity and boiling point of the liquid should be higher than water to allow the sample to float above the liquid for attachment. Probe interactions on the microarray wafer 3. After the reaction, the liquid 10 can be withdrawn through the microchannel manufactured at the bottom of the reaction well 2, and the cleaning solution can be added. The result of the reaction detection can be accomplished using a power-distribution device (CCD) or an isotope imager. It should have been decided when applying the labeling method to the sample. The integrated microarray device can be placed on a microscope that can be stably moved at a preset distance. The detector can detect one microarray wafer 3 at a time and can then be moved to the position of the next reaction well to be scanned. Such detection devices are relatively inexpensive, efficient, simple and easy to use, so they can be used in small hospitals or laboratories. Quoted Springs literature:

Beattie WG· et al. "Hybirdization of DNA targets to -30- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 dong) "~ ---- 1254744 A7 B7 V. Invention Description (28) glass-tethered oligonucleotide probesM, Moleuclar Biotechnology 4: 213-225 , 1995

''Integrated capillary electrophoresis for chemical analysis1' by Becker H. et al., by Baltes H. et al., Sensors Update, Vol. 3, VCH Weiheim 208-238, 1998 by Delamarche E. ''Microfluidic networks for chemical patterning of substrate: Design and application to bioassays", J. Am. Chem. Soc. 120: 500_508, 1998 by Fodor SPA et al., 'Light-directed spatially addressable parallel chemical synthesis', Science 251: 767-773, 1991

"Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis" by Hacia J.G. et al., Nature Genetics 14: 441-447, 1996;

Heller RA et al. "Discovery and analysis of inflammatory disease-related genes using cDNA microarrays", Proc. Natl. Acad. Sci. USA 94: 2150-2155, 1997 Kopp MU et al. "Developments in Technology and applications of microsystems", Current Opinion in Chemical Biology 1: 410-419, 1997,

Simpson PC et al. ''High_throughput genetic analysis using microfabricated 96-sample capillary array electrophoresis microplates", Proc. Natl. Acad. Sci. USA 95: _____-31 -_ This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 x 297 mm) 1254744 A7 B7 V. Description of invention (29) 2256-2261, 1998

Subamanian A. et al. ''Comparison of techniques for enzyme immobilization on silicon supports', Enzyme & Microbial Technol. 24: 26-34, 1999. The above examples are for illustrative purposes only and are not intended to limit the invention. Various changes may be made to the above-mentioned parts. As those skilled in the art will understand the modifications and variations of the above examples, the present invention is limited only by the scope of the attached patent application. _-32- This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

I254f _〇〇〇23 Patent Application Chinese Application Specialized Fiber Replacing (94 October) ? (. Month:: Paste Repair (More 乂中中牟44^ Announcement 1. 2. 3. An integrated body) The microarray dream ~ J flat, the I set includes a substrate having a plurality of individual micro-bits 4 and a plurality of micro-arrays, and the number of the micro-positions is equal to ^ ^ ^ The number i of the J-day film, and wherein the micro-locations contain a number of wells and hold 4 1 h ^ s σ, /, the middle part of the well is connected by using thin and thin The definition of the wall, /, Zhiyun I and I /, τ / special rank beam and the formation of the inside and outside of the well = to contain inert gas and heat the adjacent wells: patent application scope 4 The device, wherein the substrate comprises ruthenium, plastic, glass, ceramic, rubber, polymer or a combination thereof. The device of claim 2, wherein the (four),: oxidized stone or nitriding > · The device of claim 2, wherein the substrate comprises a surface that is hydrophobic or hydrophilic. 5. If the device of the patent application range is 1IM Wherein the substrate comprises a porous or non-porous surface. 6. The device of claim 2, wherein the micro-location and/or microarray wafer is fabricated on the substrate. A device comprising: (12) 11 micro-positions, wherein η is at least an integer of 1. 8. The device of claim 3, wherein the micro-location is evenly or unevenly distributed 9. In the apparatus of claim 1, wherein the number of the micro-positions and the distance between the micro-positions conform to the standard microtiter plate. 1) The device of claim 1 of the patent scope includes ( 12) n wells, where η 1254744 6. The scope of application for patents is at least an integer of 1. 11. If the patent application is the i-th well. I, which includes 96, 384 or 1,536 12. For example, the elliptical, square, and arbitrage of the first item of the scope of the patent, wherein the well has a private shape from a group consisting of a circle' 'Triangles and other irregular shapes. 13. As claimed in the patent scope:: geometry. The same shape. And the apparatus wherein the well has the same or M. as in the scope of the patent application, fluidly and fluid=suited, wherein at least one micro-position 15 is in contact with the fluid passage of the fluid passage outside the apparatus or the external passage of the apparatus All of the micro-locations of the fluid source device are in contact with the fluid channel outside the patent application. A device that is in fluid contact with each other' wherein at least two of the micro-positions are in fluid contact with each other as in the first aspect of the patent application. 18) For example, the device gas of the scope of the patent application is applied. 19. A device as claimed in claim 1, microarray wafer. t 2〇. The same or different density as the device of claim 1 of the patent application. 21. The apparatus of claim 1, wherein the microarray wafer has a density of (100) n sp〇t/Cm2, wherein n is at least! The integer/, is not tied to all of the micro-positions, wherein the inert gas system is empty, wherein each micro-position includes one in which the micro-array wafer has a 2-paper scale suitable for home (CNS) Α 4 A device of the first aspect of the invention, wherein at least one of the microarray wafers has a density of less than or equal to 400 sp〇t/cm 2 . 23. The device of claim 1, wherein all of the microarray wafers have a density of less than or equal to 400 sp〇t/cm2. 24. The device of claim 1, wherein at least one of the microarray wafers has a plurality of components attached thereto. The device of claim 24, wherein the microarray wafer has a plurality of components attached in a face-up or face-down direction. 26. The device of claim 24, wherein each component is selected from the group consisting of a cell organelle, a virus, a molecule, and a polymer or complex thereof. 27. The device of claim 26, wherein the cell line is selected from the group consisting of animal cells, plant cells, bacterial cells, recombinant cells, and artificial culture cells. 28. The device of claim 26, wherein the organelle is derived from cells, mitochondria, chloroplasts, ribosomes, ER, Golgi, lysosomes, proteasomes, secretory vesicles, vacuoles and microsomes Selected from the group consisting of. 29. The device of claim 26, wherein the molecule is selected from the group consisting of inorganic molecules, organic molecules, and complexes thereof. 30. The device of claim 29, wherein the inorganic molecule is derived from sodium, potassium, magnesium, calcium, chlorine, iron, copper, zinc, manganese, cobalt, iodine, molybdenum, hunger 'nickel' 'Group of broken, tin, boron and Kun ion -3- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) Installed in the spring six, the scope of the patent application. 31. The device of claim 29, wherein the amino acid, the peptide, the I 6 is from the #巧风刀于系攸, 乜, 乜, 寡, 寡, oligonucleotide, nucleic acid, vitamin = early (four) 'olig Selected from the group of sugars, carbohydrates, lipids and their complexes. 32. = Device of claim 1, wherein at least two of the microarray day sheets are attached to a plurality of components. 33. For example, please refer to the device of Article 32 of the patent, in which each microarray wafer is attached to the same type or different types of components. 34. The device of claim 1, wherein each of the devices is attached to a plurality of components. 3 ^ wherein there is at least one micro-position, wherein each of the micro-positions includes each of the temperature controllers, wherein the temperature controller is from the apparatus of the first aspect of the invention, including a temperature controller. 36. As for the device of claim 35, a temperature controller. 37. The device of claim 35 can be controlled individually. 38. For example, the cracking of the third paragraph of the patent scope is determined by a private resistance heater, a bidirectional semiconductor temperature controller, a group consisting of a ceramic crying or an infrared heater. 39. The device of claim 1, wherein the substrate is a single unit. 40. If you apply for a patent scope! The device of the item, wherein the substrate unit is 'disassembled into at least two parts. -4 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1254744 , the scope of the patent application • Ge α曱 gas 42. - a method a) other micro-number of the inside, b) the scope of the device of the first item 'which contains a plurality of inert chambers, and the plural The space is evenly distributed. Using two to detect the interaction between the test component and the plurality of target components, the method comprises: extracting an integrated microarray device, the split comprising a substrate having a plurality of = and a plurality of microarray wafers, wherein the micro Position: the number of the microarray wafers, and a plurality of target components attached to the column 3' and wherein the micro-locations comprise a complex well format, wherein all wells are connected by using a thin cross-mark and The outer wall defines 'where the thin beam and the inner wall of the well and the wall form an empty δ b gas and the adjacent wells are insulated. The plurality of target components provided in step a) are contacted with a test; c) ❹ The interaction between the test component and the multiple (four) standard components. • The method of claim 42, wherein the integrated microarray is provided with a substrate having an individual micro-position and each micro-position includes a microarray wafer and a temperature controller. 44. The method of claim 42 wherein the interaction to be detected is between components selected from the group consisting of a cell organelle, a virus, a molecule, and a polymer or complex thereof. Interaction. The method of claim 42, wherein the plurality of target components are a plurality of genes, a gene fragment or an encoded product thereof. 46. The method of claim 45, wherein the plurality of genes, gene fragments or encoded products thereof are contained in a biological pathway and belong to the same or -5-1254744 A group of proteins with similar biological functions, which behave in the same cell cycle stage, exhibiting the same cell type, exhibiting the same tissue type, exhibiting the same g-type evil, showing the same developmental stage, protein expression and/or Activities may change in an unhealthy or disorderly manner or stage, or protein performance and/or activity may be altered using drugs or other treatments. 47. The method of claim 4, wherein the interaction between the plurality of targets and the plurality of target components is detected. 48. The method of claim 4, wherein the interaction between the plurality of target components and the plurality of target components is detected simultaneously or continuously. -6 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)