Integrated microarray devices

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid

Reexamination Certificate

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C435S007100, C435S174000, C435S283100, C435S287200, C435S288400, C435S288500, C422S068100

Reexamination Certificate

active

06703203

ABSTRACT:

RELATED APPLICATION
This application is related to a Chinese national patent application Ser. No. 00109792.X, filed Jul. 4, 2000, entitled “INTEGRATED MICROARRAY DEVICES.” The disclosure of the above referenced patent application is incorporated by reference in their entirety.
1. TECHNICAL FIELD
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 comprise 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.
2. BACKGROUND ART
Microarray technology has been developing quickly since it first appeared in the 1990's (Fodor et al.,
Science,
251: 767-773 (1991)). Now as a representative category of biochip technology, microarray technology has been widely utilized in clinical diagnostics, disease mechanism research, drug discovery, environmental monitoring, functional genomics research etc. (Hacia et al.,
Nature Genetics,
14: 441-447 (1996); and Heller et al.,
Proc. Natl. Acad. Sci. USA,
94: 2150-2155 (1997)). Biological probes, such as oligonucleotides, DNA, RNA, peptides, proteins, cells, tissues, are immobilized on the surface of various substrate such as glass, silicon, nylon membrane etc. These probes represent particular information respectively. Sample is added into the reaction well in which the microarray is put to interact with immobilized probes. Sample may be labeled by isotope, fluorescent reagents, chemiluminescent reagents to facilitate the detection. According to different labeling methods, various detection methods can be used, such as confocal fluorescent scanner, low luminescence detector, isotope imager, etc.
To achieve high-throughput parallel analysis, high density microarrays have been developed on which several hundred thousand probes are immobilized. But in many cases, high density and high cost microarrays are not absolutely necessary. Moreover, high density microarrays do not necessarily mean high fidelity of detection signal because different probes on the microarray have subtle distinctions by nature. For example, if probes are DNA molecules, they may have different number of bases or different sequences, both of which contribute to the consequence of varied optimal hybridization conditions. Only under optimal hybridization conditions, mismatch ratio can be reduced to low level to facilitate the generation of accurate hybridization signals. Furthermore, the detection operation is inconvenient for most microarrays as they must be detected one at a time.
DISCLOSURE OF THE INVENTION
This invention provides an integrated microarray device which can be applied to multiple chemical and/or biological sample reactions and detections with high efficiency, high fidelity and low cost.
In one aspect, 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 comprise a temperature controller at some or all of the microlocations.
In another aspect, the invention provides a method for detecting interaction between a test moiety and a plurality of target moieties, which method comprises: a) providing 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, and a plurality of target moieties attached to said microarray chips; b) contacting a test moiety with said plurality of target moieties provided in step a); and c) detecting interaction between said test moiety and said plurality of target moieties.
In a preferred embodiment, the device provided herein includes a substrate, on which reaction wells are fabricated. In every reaction well a microarray chip is placed in. This microarray chip may be of a high or low, preferably, a low density chip. In addition, a temperature controller is placed inside or outside every reaction well mentioned above. These temperature controllers can individually control the temperature in each reaction well. When fabricating microarray chips customarily made for such microarray device, probes are divided into different groups according to their respective melting temperatures (T
m
value). Probes with close enough melting temperature values are immobilized on one microarray chip; the chip is then put into one reaction well. Reaction temperature in different reaction well can be controlled individually by attached temperature controller. The reaction temperature in every well can be controlled exactly according to the T
m
value of probes immobilized so that false positive rate or detection error caused by the inappropriate temperature control can be reduced. The dimension of this microarray device corresponds to standard 96-well plate, 384-well plate or 1536-well plate. That is, the number of reaction wells and the distance between different wells are standardized. This design facilitates simple, high efficient and automatic manipulation such as sample handling and washing by robotics.


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