JP2007502435A - Apparatus and method for hybridization and SPR detection - Google Patents

Apparatus and method for hybridization and SPR detection Download PDF

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Publication number
JP2007502435A
JP2007502435A JP2006533492A JP2006533492A JP2007502435A JP 2007502435 A JP2007502435 A JP 2007502435A JP 2006533492 A JP2006533492 A JP 2006533492A JP 2006533492 A JP2006533492 A JP 2006533492A JP 2007502435 A JP2007502435 A JP 2007502435A
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Japan
Prior art keywords
hybridization
cover
substrate
apparatus
frame
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Pending
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JP2006533492A
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Japanese (ja)
Inventor
ヤヌス ウォイトウィックス,
マーク オールダム,
スティーブン コックス,
ガリー シュロス,
ドゥーウィー ハガ,
トレイシー フェレア,
マイケル レックナー,
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アプレラ コーポレイション
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Priority to US10/448,803 priority Critical patent/US20040241659A1/en
Priority to US10/448,856 priority patent/US20040241660A1/en
Application filed by アプレラ コーポレイション filed Critical アプレラ コーポレイション
Priority to PCT/US2004/016907 priority patent/WO2004108268A1/en
Publication of JP2007502435A publication Critical patent/JP2007502435A/en
Application status is Pending legal-status Critical

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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02Adapting objects or devices to another
    • B01L2200/026Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/04Closures and closing means
    • B01L2300/041Connecting closures to device or container
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0636Integrated biosensor, microarrays
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877Flow chambers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00Supporting devices; Holding devices
    • B01L9/52Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips

Abstract

An apparatus and method for hybridization, wherein a hybridization chamber is provided. The hybridization chamber has a hybridization frame and a detection frame. The hybridization chamber can be housed in a housing that is releasably assembled to enclose the hybridization chamber. According to various embodiments, an apparatus for hybridization can include a housing that includes a base and a cover, a substrate including a microarray is disposed within the base, and the hybridization chamber includes a frame. And a portion of the substrate, wherein a cover is releasably combined with the berth to seal the hybridization chamber, and the cover includes an inlet port for preventing the injection device from contacting the microarray. Yes.

Description

(Field)
This teaching can relate to devices and methods for performing reactions with biological samples on solid surfaces, such as assays by hybridization. This apparatus is involved in the hybridization and detection process.

(background)
In the biological field, reactions on solid surfaces can be used for assays by hybridization. A known member of the binding pair located on the solid surface can hybridize with a target member from the biological sample of the binding pair to form a duplex in the hybridization fluid. The pattern of double-stranded binding pairs on the solid surface provides information about the biological sample. A pattern on the solid surface can be detected and this information can be mapped with respect to known members of the binding pair on the solid surface. During hybridization, it is desirable to control the volume on the solid surface, and during detection it is desirable to provide access to the solid surface.

  Providing a sealed hybridization chamber to reduce leakage and evaporation of hybridization fluid during processing and maintain accurate control over reaction temperature, duration, mixing, and other hybridization parameters. May be desirable. Hybridization parameters may include, for example, 18-24 hours with stirring at 400 rpm at a high temperature such as 55 ° C. It may be desirable if the housing that seals the hybridization chamber can provide a transport container for the hybridization chamber that can be sealed from the environment.

(Summary)
According to various embodiments, an apparatus for hybridization can include a substrate and a hybridization chamber that includes a detection frame, a hybridization frame, and a portion of the substrate, wherein the detection frame is Located on the substrate, a hybridization frame is positioned proximate to the detection frame to form a hybridization chamber. According to various embodiments, an apparatus for hybridization can include a housing that includes a base and a cover, a substrate including a microarray is disposed within the base, and the hybridization chamber includes a frame. And a portion of the substrate, wherein a cover is releasably combined with the berth to seal the hybridization chamber, and the cover includes an inlet port for preventing the injection device from contacting the microarray. Yes.

  According to various embodiments, a method for hybridization provides a housing that includes a base and a cover, provides a substrate that includes a microarray, a hybridization that includes a frame and a portion of the substrate. Providing the chamber and releasably combining the cover to the base to seal the hybridization chamber and compress the frame.

  According to various embodiments, an apparatus for hybridization includes a base and a cover, includes a housing in which the base and cover are releasably combined, a microarray, and is configured to be received in the housing. A substrate, a detection frame positioned on the substrate and forming a detection volume with the substrate, and a hybridization frame forming a hybridization volume with the substrate and the cover, the hybridization volume and the detection volume being Contact the microarray with fluid. According to various embodiments, an apparatus for hybridization includes a binding layer and a support, includes a substrate including a microarray, and a frame and a portion of the substrate, the frame penetrating the binding layer. A hybridization chamber positioned on the support and the binding layer includes a blackening agent for absorption.

  According to various embodiments, an apparatus for hybridization can include a hybridization chamber that includes a substrate as well as a detection frame, a cover, and a portion of the substrate, the cover comprising the hybridization A cavity for dispersing fluid over a portion of the substrate is provided, a detection frame is positioned on the substrate, and the substrate is configured for SPR detection. According to various embodiments, an apparatus for hybridization can include a housing including a cover, a substrate including a microarray, and a hybridization chamber including a frame and a portion of the substrate, the cover comprising: A cavity for dispersing hybridization fluid across the microarray is provided, a cover is combined with the frame to seal the hybridization chamber, the cover is provided with an inlet port, and the substrate is configured for SPR detection. ing.

  According to various embodiments, a method of hybridization provides a housing that includes a cover, provides a substrate that includes a microarray, and provides a hybridization chamber that includes a frame and a portion of the substrate. , Dispersing hybridization fluid across the microarray, and detecting hybridization by SPR.

  It should be understood that both the foregoing comprehensive description and the following description of the various embodiments are various and are illustrative only and not limiting. is there.

(Description of various embodiments)
Reference will now be made to various embodiments, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or like parts.

  As used herein, the term “hybridization” refers to the process of duplex formation between two members of a particular binding pair. A particular binding pair is often a strand of polynucleotide that is complementary or partially complementary. Those skilled in the field of molecular biology know that the term “polynucleotide” as used herein includes analogs of naturally occurring polynucleotides and does not include any restrictions on the length of the polynucleotide. If you can understand it. One of the polynucleotide strands can be immobilized on a solid substrate.

  The polynucleotide strands used for hybridization can be labeled with a detectable marker to facilitate double-stranded detection. Examples of detectable markers include, but are not limited to, fluorescent dyes, radioactive elements, enzymes, or other markers. According to various embodiments, detection can be provided by a CCD camera that detects a detectable marker. The strands of the polynucleotide used for hybridization need not be labeled. Hybridization of unlabeled binding pairs can be detected by surface plasmon resonance (SPR).

  Hybridization can be used for a variety of purposes, such as understanding structure-activity relationships between various substances, detecting and screening single nucleotide polymorphisms (SNPs), and decoding unknown substances. The term “specific binding pair” refers to a pair of molecules that have a specificity that is detectable beyond the background level of non-specific molecular interaction and are bound to each other. Examples of specific binding pairs include, but are not limited to, antibody-antigen (or hapten) pairs, ligand-receptor pairs, biotin-avidin pairs, polynucleotides having complementary base pairs. , Nucleic acid binding proteins and cognate nucleic acid sequences, members of multiprotein complexes, and the like. Each specific binding pair can include two members, or additional compounds can specifically bind to any member of a given specific binding pair.

According to various embodiments, an apparatus for hybridization can provide a hybridization chamber having a polynucleotide in a liquid phase or constrained to a substrate. For illustrative purposes, the drawings describe polynucleotides that are constrained to a substrate to form a microarray. The density of the microarray may be 4 binding sites per square millimeter, or up to 10 4 binding sites per square millimeter. The binding sites can be placed on the substrate by pin spot formation, ink jet, photolithography, and other methods known in the art of high density deposition. The features described in the drawings can be readily applied to devices for hybridization with solution phase nucleotides.

  According to various embodiments, “SPR”, as used herein, refers to an optical detection method capable of detecting a surface that can be used to monitor hybridization and other protein-nucleic acid binding. ing. SPR can be sensitive to thickness and the refractive index of a material at the interface between a free electron metal (eg, gold, silver, copper, cadmium, aluminum) and a bulk medium such as air or water. The microarray can be deposited on a metal substrate. SPR can use evanescent waves generated by light sources such as laser beams and light emitting diodes (LEDs) that are substantially monochromatic and non-coherent near-infrared light sources. This wave can be linearly polarized parallel to the incident surface impinging on the metal. The metal can be applied onto a support comprising plastic, such as glass or polycarbonate, to form a thin film portion of the substrate. You may comprise the whole board | substrate with a metal.

  According to various embodiments, as shown in FIG. 19, the substrate can be combined with a prism (Kretschmann prism coupling) or the substrate can be combined with a grating (grating coupling). SPR is when photons from an incident light beam are absorbed in a surface plasmon mode in the metal at the proper combination of refractive index, wavelength of incident light, and angle of incidence indicated by θ in FIG. It can be observed as a decrease in the intensity of the light reflected from the prism-metal interface (Kretschmann-prism coupling) or the grating-metal interface (lattice coupling). According to various embodiments, it is possible to determine an incident angle at which photon absorption is maximized, that is, an incident angle at which the intensity of reflected light is minimized. Hybridization on the metal surface of the substrate can change the refractive index, thereby changing the incident angle at which the intensity of reflected light is minimized. This change in angle of incidence can be used to detect the attachment or reduction of material on the metal surface in contact with the hybridization fluid.

  According to various embodiments, bonding particular bond pairs can increase the thickness of the microarray, which results in a change in the incident angle to signal the presence of the bond. Can do. By monitoring either the position of the angle of incidence or the refractive index at a constant angle near the angle of incidence, the presence or absence of binding at the binding site can be detected. SPR is relatively fast and can be performed without labeling. Detection can be provided by a CCD camera at a defined angle. SPR images are generated from variations in reflected light intensity from various binding sites. A hybridization chamber with a transparent cover can be used for detection by SPR.

  According to various embodiments, a SPR combined with a grating can be observed from a microarray having a surface area of at least 1.0 cm × 1.0 cm by a CCD camera detector. A CCD camera can provide simultaneous detection of the entire matrix of binding sites on the microarray.

  According to various embodiments, FIGS. 1A-1C illustrate an apparatus for hybridization, showing the relative positions of a detection frame and a hybridization frame. These embodiments may relate to a housing or instrument. According to various embodiments, such an instrument can provide a lid and holder configured like a chin that can be held together to form a hybridization chamber. In FIGS. 1A-1C, the entire housing or instrument is not shown. The detection frame 14 can be disposed on the substrate 10 formed by restraining the microarray 12. The hybridization frame 16 can be placed in the vicinity of the detection frame so that a seal can be formed with a cover / lid 18 (the cover in the housing embodiment and the lid in the instrument embodiment). According to various embodiments, the hybridization frame 16 may be compressible to better form such a seal. Compressible materials are known in the technical field of material science. According to various embodiments, the hybridization frame and / or detection frame may be selected from silicone rubber, FDA approved silicone rubber, EPDM rubber, neoprene (CR) rubber, SBR rubber, nitrile (NBR) rubber, butyl rubber, hyperon. It can be composed of at least one elastic material selected from (CSM) rubber, polyurethane (PU) rubber, Viton rubber, and polydimethylsiloxane (Dow Corning Slygard ™ elastomer).

  As used herein, the term “frame” refers to gaskets, rings, or seals. The frame may be square or circular with respect to the overall shape and / or cross section. The frame can be made of a compressible elastic material. The frame has no internal means for directing the flow, such as ports, or no means for mixing such directed flow, such as a reaction recess in the frame. The frame does not allow entry of contaminants into the hybridization chamber. The frame is single and does not include a plurality of members. The frame is not divided into a plurality of frames such as a lattice plate. As used herein, the term “detection frame” refers to a frame that attaches to a substrate and forms a detection chamber. As used herein, the term “hybridization frame” forms a hybridization chamber with a detection frame by being located on the detection frame, and is positioned adjacent to or in close proximity to the detection frame. It refers to a frame that forms a hybridization frame on the outside or forms a hybridization frame without a detection frame.

  As used herein, the term “proximity” refers to the location of the detection and hybridization frames, each having the same width, or one being wider and one over the other. Overlapping each other, each having the same center, or one of them being out of the center and adjacent to each other so that they touch each other on the side, or one of them surrounding the other, It includes arrangements that are located close to each other so that they are not in contact but are in a short distance.

  According to various embodiments, FIG. 1A shows a hybridization frame 16 that can be positioned on the detection frame 14. According to various embodiments, the detection frame 14 may be harder than the hybridization frame 16 to provide additional stability upon detection. Hybridization frame 16 can be compressed between detection frame 14 and cover / lid 18 to form a sealed hybridization chamber. FIG. 1B shows a hybridization frame 16 that can be positioned adjacent to the detection frame 14. The hybridization frame 16 can be compressed between the substrate 10 and the cover / lid 18 to form a sealed hybridization chamber. FIG. 1C shows a hybridization frame 16 that can be located near the detection frame 14. The hybridization frame 16 can be compressed between the substrate 10 and the cover / lid 18 to form a sealed hybridization chamber. Although the detection and hybridization frames shown in FIGS. 1A-1C are linear, the detection and hybridization frames may be any shape including circular, elliptical, and combinations thereof. As will be described later, the hybridization chamber may be provided with an overlapping volume for hybridization and a volume for detection.

  According to various embodiments, the detection frame and hybridization frame can be replaced with a single frame that forms both the hybridization chamber and the detection chamber. In embodiments of SPR detection, the hybridization chamber may be the detection chamber at the same time. It will be apparent to those skilled in the art that the features described in the two-frame embodiment can provide benefits for the one-frame embodiment as well.

  According to various embodiments, an apparatus for hybridization can include a housing or instrument. As shown in FIGS. 1A-1C, an apparatus for hybridization can relate to either a housing or an instrument without a housing. In the cartridge, the housing cover and base can function in a manner similar to the instrument lid and holder. According to various embodiments, FIGS. 2-11 and FIGS. 14-16 can relate to a housing. According to various embodiments, the housing can be located within the instrument for processing (including injection, binding reactions, washing, drying, etc.) and is shown in FIGS. 2-11 and 14-16. Benefit from the features. The housing can be removed from the instrument for detection or the detection can be performed within the instrument.

  According to various embodiments, FIGS. 2A-2C illustrate a hybridization device that uses a housing with various covers. 2A to 2C show a detection frame 14 that can be disposed on the substrate 10 formed by constraining the microarray 12 and a hybridization frame 16 that can be disposed on the detection frame 14. Hybridization frame 16 may be compressible to form a seal with cover 18 to enclose the hybridization chamber. According to various embodiments, as already mentioned, the detection frame and the hybridization frame can be in close proximity to each other. 2A-2C illustrate that the cover 18 may have a raised portion 22 and an introduction port 20. As shown in FIG. 2A, the raised portion 22 can protrude from the top surface of the cover 18 such that the cover 18 is substantially parallel to the microarray 12 on the substrate 10. As shown in FIGS. 2B and 2C, the raised portion 22 may be part of the cover and may be dome-shaped or vaulted so that the cover 18 is in fact relative to the microarray 12 on the substrate 10. It does not have to be parallel up. FIG. 2B shows a raised portion 22 that can have a hemispherical dome. FIG. 2C shows a raised portion 22 that can have a straight or square vault. Any other variation or combination of dome or vault can be used to increase the hybridization volume of the hybridization chamber. As shown in FIG. 2C, the port 20 can move to the side of the lifted site 22. The port does not necessarily have to be in the center and can be anywhere on the lifted or other part of the cover. The raised portion may be another component other than the cover attached to the cover.

  According to various embodiments, the hybridization chamber provides a hybridization volume of less than 300 microliters. The amount of hybridization fluid may be 1.0-50 microliters.

  According to various embodiments, FIGS. 2-11 and FIGS. 14-16 illustrate an apparatus for hybridization that includes a housing with a cover and a base. According to various embodiments, the housing can be assembled into a locked position and disassembled into an open position. The housing can comprise a cover, and the cover itself can comprise an upper portion and a compression plate. The compression plate can include a lifted site, an introduction port, and an exhaust port to allow gas displaced by the hybridization liquid to escape to the atmosphere. The inlet and outlet ports can be capped so that hybridization fluid does not escape from the hybridization chamber. According to various embodiments, the cap may be a sealing tape on the top of the introduction port, may surround the raised site (eg, FIGS. 3 and 4), or may plug the introduction port. Good (eg, FIG. 5D). The cover and the base can form a window exposing a portion of the lower substrate in the locked position. A bar code can be placed on the substrate and accessed and / or read through this window. The top can provide an opening so that the raised portion of the compression plate can protrude. The top and base can be provided with a reasonable pairing mechanism. The compression plate can have a raised portion on the opposite side of the raised site to engage the hybridization frame. Dividing the cover into a top and compression plate provides a releasably paired mechanism that can be moved to the locked position by pushing down, sliding, rotating, and / or inverting the top. it can. By pressing down, the compression plate can be engaged with the hybridization frame. By sliding, rotating, and / or flipping, the top is placed into the locked position without moving the compression plate. The top can be released by sliding, rotating, and / or flipping in the opposite direction. According to various embodiments, a method for hybridization includes providing the apparatus and releasably combining a cover and a base according to these operations.

  According to various embodiments, a barcode can be placed on a substrate. The term “barcode” refers to any marking that can identify a substrate that includes a microarray and / or hybridization. A barcode may be one-dimensional (eg, a bar), two-dimensional (eg, a matrix of points), or three-dimensional (eg, a hologram). Placement of the barcode on the substrate can include placement of an adhesive label on which the barcode is printed, placement of a contrasting colored multilayer opaque coating, or direct marking on the substrate as described below. According to various embodiments, the barcode can be placed on the housing or frame.

According to various embodiments, the barcode can be placed directly on the metal substrate by marking. The barcode can be marked on a metal substrate with a light beam from a laser or LED. The barcode can be marked to a certain depth in the substrate so that it can be read by a reader that can read the laser light refracted from the substrate after the substrate is exposed to the light beam from the reader. . The barcode is marked onto the substrate to a certain depth into the substrate so that incident light refracted from the substrate can present the barcode as black on a white background or white on a black background. can do. According to various embodiments, the barcode can be arranged in one step or multiple steps. The surface of the substrate can be changed by removing metal residues on the surface. Removal provides a uniform surface for placing the barcode and can establish a constant refraction angle in the returned light pattern. The surface of the substrate can be marked with a barcode. The marked barcode can be read by exposing the barcode to a light beam from a reader. The reader can be arranged to determine whether the marked barcode provides sufficient contrast to the background so that it can be read by the reader. According to various embodiments, the barcode can be marked on the substrate to a depth of between 1.27 × 10 −5 meters and 2.54 × 10 −5 meters.

  According to various embodiments, the housing includes a cover and a base and can be made of injection molded plastic. Injection molding can reduce the manufacturing cost of the housing and can provide a disposable container that can be discarded after the hybridization process. The housing can be composed of acrylonitrile-butadiene-styrene plastic, polyurethane, polyvinyl chloride, polycarbonate, polyethylene, Teflon, polystyrene, Kalrez ™, or other materials known in the art of consumable manufacturing. .

  As used herein, the terms “releasably paired” or “releasably combined” are used when the cover and base are in a locked position during hybridization and then the substrate for detection. It refers to being combined so that it can be released to provide access to. The base and cover can be releasably combined by a releasable combination mechanism. Various embodiments of releasable combination mechanisms are described herein. According to various embodiments, the locking position can be exposed to several types of agitation, and even under such agitation, the cover and base remain combined. Such types of agitation include housing tilt, housing rotation, housing reciprocation, housing movement in a circular pattern, and housing rotation about an axis.

  FIG. 3 shows an embodiment of the housing assembled and in the locked position. FIG. 4 shows the housing of FIG. 3 disassembled. The housing includes a cover 18 and a base 32, which are held in a locked position by a releasable combination mechanism 40. The releasable combination mechanism 40 can be moved to the locking position by pressing down and pressing the cover 18. The cover 18 can be released by releasing the restraint of the releasable combination mechanism 40 and pulling it up. The window 38 can be formed by the recess of the cover 18. A bar code (not shown) placed on the substrate 10 can be read through the window 38. Cap 36 prevents hybridization fluid from escaping from the hybridization chamber. FIG. 6 shows the disassembled housing. The cap 36 can be connected to the hybridization frame 16 by a cord 60. Both cap 36 and hybridization frame 16 can be removed to provide access to substrate 10 for detection.

  According to various embodiments, FIG. 6 shows the housing assembled and in the locked position. FIG. 7A shows the housing of FIG. 6 exploded. The housing can include a base 32 and a cover 18. Cover 18 may include an upper portion 30 and a compression plate 34. Upper portion 30 and base 32 may include a releasable combination mechanism 40. The upper portion 30 may include a handle 80 for handling the upper portion 30 by hand, and a window 38 for accessing a barcode (not shown) located on the substrate 10. The upper portion 30 can have an opening so that the raised portion 22 of the compression plate 34 can protrude. The releasable combination mechanism 40 can be moved to the locked position by rotating the upper portion 30. Dividing the cover 18 into an upper portion 30 and a compression plate 34 can provide a releasable combination mechanism 40 that can be moved to a locked position without rotating the compression plate 34 by rotating the upper portion. . By rotating the upper portion 30, the compression plate 34 can be pushed down to engage the hybridization frame 16. The upper part 34 can be released by rotating it in the opposite direction and pulling it up. The bottom surface of the base 32 can be provided with a recess that allows the housings to be stacked and stacked. According to various embodiments, FIG. 7C shows that the handle 80, the raised portion 22, and the cap 36 can be received in the recess 90 to allow stacking of two or more housings. . FIG. 7B shows the housings stacked on top of each other. According to various embodiments, the compression plate 34 can have a non-uniform thickness to provide compression of the hybridization frame 16. FIG. 7D shows a compression plate 34 'having a non-uniform thickness.

  According to various embodiments, FIG. 8 shows the housing being assembled but not in the locked position. A compression plate 34 can be disposed on the base 32. The upper portion 30 can be hinged to the base 32. The upper portion 30 can be divided into two portions that are hinged on opposite sides of the base 32. According to various embodiments, the upper portion 30 may be hinged to one side of the base 32, or the upper portion may be divided into more than two portions. The upper portion 30 can include ribs 100 to compress the compression plate 34 when the cover is moved to the locked position. The two portions of the upper portion 30 can form openings so that the raised portion 22 of the compression plate 34 can protrude through the upper portion 30 when the cover is in the locked position. The upper portion 30 and the base 32 can include a releasable combination mechanism 40. The releasable combination mechanism 40 can constrain the top 30 to the base 32 when the top 30 is flipped to a locked position along the hinged site. By constraining the upper portion 30 to the base 32, the rib 100 can be pushed to push the compression plate 34 down to engage the hybridization frame (not shown). The upper portion 30 can be released by releasing the restraint of the releasable combination mechanism 40.

  According to various embodiments, FIGS. 9A and 9B show unassembled and assembled housings, respectively. FIG. 9A shows the housing in an unassembled state, with a cover 18 that includes an upper portion 30 and a compression plate 34. The compression plate 34 can include a raised portion 22 and an introduction port 20. The top 30 can have five sides similar to a “match box” that is closed at one end. The base 32 can include a handle 80 for pushing the base 32 into and out of the upper portion 30. The upper portion 30 can include a rib 100. The compression plate 34 can be provided with an inclined rib to place the compression plate 34 into the base 32 and compress the compression plate 34 when the base 32 is pushed into the upper portion 30 to the locked position. FIG. 9B shows a side view of the assembled housing. Dashed lines indicate the interior of the housing including the base 32, the compression plate 34, and the ribs 100. The top 30 can be provided with an opening so that the raised portion 22 can protrude above the top 30. The handle 80 can protrude from the open end of the upper portion 30. The rib 100 and the inclined ribs of the compression plate 34 can provide a releasable combination mechanism that allows the compression plate 34 to be compressed. By pushing the base 32 into the upper portion 30, the rib 100 can be pushed to push the compression plate 34 down to engage the hybridization frame (not shown). Base 34 can be released by pulling handle 80 horizontally away from top 30.

  According to various embodiments, FIG. 10 illustrates a housing that is disassembled and assembled. FIG. 10 shows the housing with the cover 18 removed, which can include an upper portion 30 and a compression plate 34. The upper portion 30 can include a handle 80 for rotating the upper portion 30 to a locked position. Cap 36 prevents hybridization fluid from escaping from the hybridization chamber through the inlet port 20 of the raised portion 22 of the compression plate 34. The upper portion 30 can include an opening so that the raised portion 22 of the compression plate 34 can protrude above the upper portion 30. Base 32 and upper portion 30 may include a releasable combination mechanism 40. The releasable combination mechanism 40 can include a protrusion that moves along the guide when the top 30 is rotated to move the top 30 to the locked position. Dividing the cover 18 into an upper portion 30 and a compression plate 34 provides a releasable combination mechanism 40 that allows the compression plate 34 to be moved to a locked position without rotating by rotating the upper portion 30. it can. By rotating the upper portion 30, the compression plate 34 can be pushed down to engage the hybridization frame 16. The upper part 34 can be released by rotating it in the opposite direction and pulling it up. The base 32 can include a window 120 that provides access to the lower surface of the substrate 10. A barcode can be placed on the lower surface of the substrate 10 and can be accessed through the window 120.

  According to various embodiments, FIG. 11 shows a bottom view of an assembled housing similar to the housing shown in FIG. 6, but with another releasable combination mechanism. Base 32 may include an opening that provides visual access to substrate 10. The releasable combination mechanism 40 can keep the upper portion 30 and the base 32 in the locked position. FIG. 10 shows a releasable combination mechanism 40, which can include a protrusion that can move along the guide when the top 30 is rotated to move the top 30 to the locked position. FIG. 11 shows a releasable combination mechanism 40 that can include a protrusion that can move along the guide when the upper 30 is rotated to move the upper 30 to the locked position, the guide being a protrusion. A flexible tab may be provided that provides some degree of flexibility between the top 30 and the base 32 during insertion and / or rotation.

  According to various embodiments, the housing can be involved in batch process hybridization or continuous process hybridization. One skilled in the art will appreciate that the features of batch processing hybridization can be applied to continuous processing hybridization by adding an exhaust port. In addition, those skilled in the art will also appreciate that the features of continuous processing hybridization can be applied to batch processing hybridization by removing the discharge port. Furthermore, those skilled in the art will appreciate that both features can be applied in a combination of batch processing hybridization and continuous processing hybridization.

  According to various embodiments, FIGS. 14-16 illustrate an apparatus for hybridization having a housing that is directly coupled to a base whose cover is a substrate. One skilled in the art will appreciate that the features of the housing in which the substrate is disposed within the base can be applied to the housing on which the substrate is based. Furthermore, those skilled in the art will appreciate that the features of the housing on which the substrate is based can be applied to the housing in which the substrate is disposed within the base.

  According to various embodiments, FIG. 14 shows a housing that includes a cover 18 and a substrate 10, wherein the substrate is the base. The cover 18 can include a window 150. The window 150 may be part of the cover 18 or may be a transparent material that forms the surface of the cover 18. The cover 18 can include an introduction port 20 and a discharge port 160. A detection frame 14 (also a hybridization frame) can be placed between the cover 18 and the substrate 10. The substrate 10 can be configured according to SPR. The substrate 10 can include a free electron metal. The substrate 10 can be composed of metal or can comprise a support coated with a thin metal film. According to various embodiments, the substrate 10 can be combined with a grating 190, as shown in FIG. 19 (a). According to various embodiments, the substrate 10 can be combined with a prism 192, as shown in FIG. FIG. 19 shows the incident angle θ, and the arrows in the grating or the prism indicate the propagation direction of the surface plasmon. According to various embodiments, as shown in FIG. 14, to provide access for light traveling from the light source to the detector, a microarray, grating or prism in the hybridization chamber can be attached to a window 150. Can be aligned.

  According to various embodiments, FIG. 16 shows the bottom of the cover 18. Each of the covers 18 can include a cavity 72 that allows the hybridization fluid to be dispersed from the inlet port 20 or collected into the outlet port 160. According to various embodiments, the cover 18 can include an introduction port 20 having a cavity 72. The cavity 72 can have a uniform spread or can have a progressively widening cross section. The cavity 72 can disperse the hybridization fluid over the site containing the microarray of the substrate. Dispersing the hybridization fluid can provide uniform contact between the hybridization fluid and the microarray. The cover 18 can be combined with the detection frame 14 with an adhesive that is compatible with both the detection frame 14 and the cover 18. The adhesive provides either a releasable combination or a permanent combination.

  According to various embodiments, FIG. 15 shows a housing that can be based on a substrate. According to various embodiments, any previously described base can be used with the cover shown in FIG. FIG. 15 shows that the cover 18 can include an upper portion 30 and a compression plate 34. The upper portion 30 can include two raised portions 22. One of the lifted sites 22 includes an introduction port 20 and the other lifted site includes a discharge port 160. When the top 30 contacts the substrate 10, the compression plate 34 compresses the hybridization frame 16 into a detection frame 14 that can be attached to the substrate 10. FIG. 16 shows a bottom view of the upper portion 30. The upper portion 30 can include a distribution cavity 72 adjacent to the introduction port 20. Dispersion cavity 72 can be placed inside hybridization frame 16 and can provide an incremental width to disperse the hybridization liquid over a site within the hybridization chamber of substrate 10. A similar structure can exist adjacent to the discharge port 160 to collect the hybridization liquid from the hybridization chamber.

  According to various embodiments, the releasable combination mechanism can include spring tabs, protrusions and guides, flexible tabs that move the cover to the locked position once the desired compression is achieved. In addition to these, any of various releasable fasteners known in the packaging art can be implemented as a releasable combination mechanism.

  Those skilled in the art will appreciate that the combination or selection of features of the various embodiments for the housing can be applied to the housing for a particular application and processing environment for hybridization. Thus, many permutations of the features already described can be envisaged in this document.

  According to various embodiments, FIGS. 5A-5D show the cover's introduction port and the raised portion. 5A-5D show a lifted portion similar to FIG. 2A, where the lifted portion may protrude from the top surface of the cover. The features described in connection with FIGS. 5A-5D are also applicable to the lifted site shown in FIGS. 2B and 2C, where the lifted site may be part of the cover. The features described in connection with FIGS. 5A-5D are also applicable to lifted sites that are separate components from the cover. The features described in connection with FIGS. 5A-5D are also applicable to an introduction port that is located directly on the cover without a lifted site. FIG. 5A shows a cross-section of the raised portion 22, which includes an introduction port 20, an injection cavity 70, and a dispersion cavity 72. The injection cavity 70 and the dispersion cavity 72 can communicate with each other with a vertical overlap and a slight horizontal overlap. A horizontal overlap can provide a stopper for the infusion device. The injection device can supply hybridization fluid to the hybridization chamber, but the stopper can prevent the injection device from contacting the substrate under the dispersion cavity 72 and the hybridization chamber. .

  The term “injection device” as used herein refers to any device that supplies a hybridization fluid to a hybridization chamber. Infusion devices may include, but are not limited to, pipettes, syringes, barrels, and any other device known in the laboratory or manufacturing fluid treatment arts. The infusion device may be automated or manually operated.

  FIG. 5B shows a cross-section of the infusion device 74 located in the introduction port 20 of the lifted site 22. The inlet port 20 can be configured to inhibit the injector 74 so that the injector 74 does not contact the underlying substrate. The introduction port 20 can be configured to provide an opening around the infusion device 74 so that gas displaced by the hybridization fluid can escape to the surrounding environment. With the injection device 74 inhibited, the hybridization fluid can be removed into the overhead cavity 76. The hybridization fluid leaves the overhead cavity 76 undisturbed and fills only a portion of the hybridization volume. FIG. 5C shows a cross-section of the infusion device 74 located in the introduction port 20 of the lifted site 22. The raised site 22 can be provided with an exhaust port 78 so that gas displaced by the hybridization fluid can escape to the surrounding environment. The outlet port 78 can be configured to have a sufficiently small width so that the hybridization fluid does not substantially escape during hybridization, or can be covered with the cap 36 along with the inlet port 20. FIG. 5D shows a cross-section of the infusion device 74 located in the introduction port 20 of the lifted site 22. The introduction port 20 can be blocked by a plug or can be blocked by a portion of the cap 36. The blocked introduction port 20 is configured to inhibit the injection device 74. The stopper and / or cap can be constructed of a gas permeable material so that gas displaced by the hybridization fluid can escape while suppressing evaporation of the hybridization fluid during the hybridization procedure. The raised portion 22 can provide depth for insertion of the infusion device 74 into the overhead cavity 76 so that the infusion device 74 does not contact the underlying substrate. The length and / or width of the introduction port 20 can be configured such that the implanter 74 does not contact the substrate. According to various embodiments, the other part of the cover is provided with an exhaust port for allowing gas displaced by the hybridization fluid to escape while the inlet port is occupied by the injection device Can do.

  According to various embodiments, the introduction port can be configured to be cylindrical or conical. The introduction port may be a tapered hole to accept an infusion device tip or a tapered tip of the infusion device from an automatic liquid supply device. The inlet port (or outlet port) may be threaded to accept fluid fittings such as valves, luers, barbs, o-rings for automatic injection. The introduction port may be sealed with a septum, a tapered plug, a threaded plug, or a similar device that may be part of the cap or may be separate from the cap.

  According to various embodiments, the addition of the hybridization fluid includes applying several washing and reagent addition steps to the substrate and agitation, as is known in the hybridization art. The substrate can then be removed from the housing manually or robotically. The detection chamber can be filled with an overlay fluid to facilitate detection and remove bubbles from the detection chamber that can interfere with detection. A cover slip or overlay is placed on the detection frame to provide a flat optical surface for detection.

  According to various embodiments, FIGS. 12 and 13 show a substrate and a detection chamber. FIG. 12 shows the substrate 10 on which the microarray 12 is constrained together with the detection frame 14. The microarray 12 may be single as shown in FIG. 12, or may be divided into a plurality of sections. The detection frame 14 can be made of a material that is harder than the material of the hybridization frame. The detection frame 14 is configured to hold the coverslip 130 substantially parallel to the microarray 12 and surrounds a detection volume of hybridization fluid in the detection chamber. Cover slip 130 may be transparent for detection and may be composed of glass or plastic. In one embodiment, the detection chamber can hold a detection volume of 2.0-3.0 milliliters. FIG. 13 shows the substrate 10 together with the detection frame 14 on which the array of microarrays 142 separated by the partition 140 is constrained. A partition 140 divides the detection chamber into an array of chambers such that placing a coverslip on the detection frame 14 results in an array of chambers that are isolated from flow and can be individually examined by the detector. .

  According to various embodiments, FIGS. 18A-18F show cross sections of a substrate and a detection frame. FIGS. 18A-18F illustrate that the substrate 10 can include a support 180, an adhesive layer 182, and a bonding layer 184. It is shown that. The microarray 12 is bonded to the bonding layer 184. The tie layer 184 may be nylon, cellulose, nitrocellulose, gel, polymer, or other porous membrane known in the polymer chemistry art. The bonding layer 184 can be sprayed, laminated, deposited by chemical vapor deposition, or deposited by electrostatic deposition onto the substrate support 180 and adhesive layer 182. be able to. The support 180 may not be absorbent. The support 180 may be glass, fused silica, silicon, plastic, metal, ceramic, or polymer. The adhesive layer 182 may be hydrophobic to seal the hybridization chamber, such as a pressure sensitive acrylic adhesive. The detection frame 14 can be affixed to the microarray, any one of the layers of the substrate 10, or the interface of those layers. The detection frame 14 can be affixed to each of these with its own adhesive, or can be affixed using the adhesive properties of these layers. FIG. 18A shows the detection frame 14 attached to the microarray 12. FIG. 18B shows the detection frame 14 attached to the interface between the coupling layer 184 and the microarray 12. FIG. 18C shows the detection frame 14 attached to the bonding layer 184. FIG. 18D shows the detection frame 14 attached to the interface between the bonding layer 184 and the adhesive layer 182. FIG. 18E shows the detection frame 14 attached to the adhesive layer 182. FIG. 18F shows the detection frame 14 attached to the interface between the adhesive layer 182 and the support 180. Each of these adhesive contacts provides a seal at the bottom of the hybridization chamber. According to various embodiments, the detection frame 14 can be affixed to the adhesive layer 182 through the bonding layer 184. Support 180 can be coated with adhesive layer 182 and tie layer 184. The contour of the detection frame 14 can be removed from the coupling layer 184. The detection frame 14 can be placed on the adhesive layer 182 from which the binding layer has been removed.

  According to various embodiments, the bonding layer 184 can be transparent or opaque. Since the coupling layer 184 is made opaque to increase light absorption during detection, it can be blackened. By increasing the absorption, less light is refracted by the coupling layer 184 and less light causes a noise signal at the detector. The bonding layer 184 can be blackened by adding carbon black to its composition. The bonding layer 184 may comprise multiple layers that are transparent or opaque in nature.

  According to various embodiments, a method for hybridization provides a housing with a cover, a substrate with a microarray, a hybridization chamber that includes a frame and a portion of the substrate. Dispersing the hybridization fluid across the microarray and detecting hybridization by SPR. Providing a substrate can include combining a lattice with the substrate. Providing the substrate can include combining a prism with the substrate.

  According to various embodiments, a method for hybridization includes providing a housing comprising a base and a cover, providing a substrate comprising a microarray, a hybridization chamber comprising a frame and a portion of the substrate. And releasably combining the cover to the base to seal the hybridization chamber and compress the frame. The releasable combination means that the cover is pushed down and slid to the locking position, the cover is pushed down and restrained to the locking position, the cover is rotated to the locking position, and the base is slid to the locking position. Can be included. The cover may comprise a hinged portion and releasable combination may include flipping the hinged portion and constraining it to the locked position.

  According to various embodiments, the hybridization method includes supplying a hybridization fluid to the hybridization volume, hybridizing the fluid with the microarray, releasing the cover and base, and a hybridization frame. Removing, placing a coverslip on the detection frame to seal the detection volume, and detecting the result of the hybridization on the microarray. The method can include placing the substrate in the base, placing the hybridization frame proximate to the detection frame, and releasably combining the cover and base.

  For the purposes of this specification and the appended claims, unless expressly stated otherwise, all numbers expressing amounts, proportions and other numerical values used in the specification and claims are: It should be understood that in all cases it is modified by the term “about”. Thus, unless otherwise specified, the numerical parameters set forth in the specification and appended claims are approximate values that may vary depending on the desired properties desired to be obtained by the present invention. Although not intended to limit the application of the doctrine of equivalents to the technical scope of the claims, at a minimum, each of the numerical parameters should be interpreted in light of at least the reported number of significant digits. Should be interpreted by applying normal rounding techniques.

  Although the numerical ranges and parameters representing the broad technical scope of the present invention are approximate, the numerical values set forth in the specific examples are reported as precisely as possible. However, every numerical value is accompanied by some degree of error that inevitably results from the standard deviations found in their respective test measurements. Moreover, all ranges disclosed herein are to be understood to include any and all sub-ranges subsumed therein. For example, a range of “1-10” includes any and all subranges between a minimum value of 1 and a maximum value of 10 (including 1 and 10), ie, 5.5-10, etc. Includes all subranges having a minimum value of 1 or more and a minimum value of 10 or less.

  As used herein and in the appended claims, the singular forms “a”, “an”, and “the” are intended to refer to a plurality of objects unless the object is clearly and clearly limited to one object. It should be noted that it contains things. That is, a reference to “a substrate” includes a case where there are two or more substrates. As used herein, “include” and grammatical variations thereof are not intended to limit anything, and references to articles in the list and others refer to articles listed. It does not exclude other similar items that can be substituted for or added to the listed items.

  It will be apparent to those skilled in the art that various modifications and variations can be made in the various embodiments described above without departing from the spirit and scope of the teachings of the invention. Accordingly, the various embodiments described herein are intended to embrace other modifications and variations that fall within the scope of the appended claims and their equivalents.

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various embodiments.
1A-1C show various embodiments of the proximity detection and hybridization frames. 2A-2C show various embodiments of the cover. FIG. 3 shows various embodiments of the assembled and disassembled device. FIG. 4 shows various embodiments of the assembled and disassembled device. 5A-5D show various embodiments for the introduction port and the lifted site. FIG. 6 shows various embodiments of the assembled and disassembled device. FIG. 7 shows various embodiments of the assembled and disassembled device. FIG. 9 shows various embodiments of the assembled and disassembled device. FIG. 9 shows various embodiments of the assembled and disassembled device. FIG. 10 shows various embodiments of the assembled and disassembled device. FIG. 11 shows various embodiments of the assembled and disassembled device. FIG. 12 shows various embodiments of the substrate and detection frame, with a cover slip for detection. FIG. 13 shows various embodiments of the substrate and detection frame, with multiple partitions forming an array of chambers and microarrays. FIG. 14 shows various embodiments of the substrate and the detection frame, with a cover for SPR detection. FIG. 15 shows various embodiments of a cover having an introduction port and a discharge port for the flow of hybridization fluid. FIG. 16 shows various embodiments of the cover including the introduction port and the discharge port. 17A-17F show various embodiments of the substrate, enlarged to show attachment of the detection frame to the support, adhesive layer, binding layer, and microarray. FIG. 18 shows various embodiments of the cap. FIG. 19 shows various embodiments of combinations for SPR.

Claims (35)

  1. An apparatus for hybridization comprising:
    A substrate, and a detection frame, a hybridization frame, and a hybridization chamber comprising a portion of the substrate;
    An apparatus in which the detection frame is positioned on the substrate and the hybridization frame is positioned proximate to the detection frame to form the hybridization chamber.
  2. The apparatus of claim 1, further comprising a housing for the substrate and hybridization chamber, the housing comprising a base and a cover.
  3. The apparatus of claim 2, wherein the base and the cover are releasably combined to seal the hybridization chamber.
  4. The apparatus of claim 2, wherein the hybridization frame is compressible and can form a seal with the cover.
  5. The apparatus of claim 4, wherein the cover comprises a compression plate.
  6. The apparatus of claim 2, wherein the cover has a raised portion.
  7. The apparatus of claim 6, wherein the raised portion has an introduction port.
  8. The apparatus of claim 7, wherein the introduction port prevents contact of the infusion device to the substrate.
  9. The apparatus according to claim 6, wherein the raised portion protrudes from an upper surface of the cover.
  10. The apparatus of claim 6, wherein the raised portion is a portion of the cover.
  11. The apparatus of claim 2, wherein the housing further includes a window, the window providing access to a barcode attached to the substrate.
  12. The apparatus according to claim 2, wherein the cover has an introduction port and an exhaust port for circulation of hybridization fluid.
  13. The apparatus of claim 1, further comprising an instrument, the instrument comprising a holder and a lid.
  14. The apparatus of claim 13, wherein the holder and lid are closed to seal the hybridization chamber.
  15. The apparatus of claim 1, wherein the portion of the substrate comprises a microarray.
  16. The apparatus of claim 1, wherein a hybridization frame is located on the detection frame.
  17. The apparatus according to claim 1, wherein the detection frame is made of an elastic material harder than the hybridization frame and forms a detection chamber.
  18. The apparatus of claim 17, wherein the detection chamber includes a plurality of partitions, the plurality of partitions forming an array of chambers, the array of chambers being in fluid contact with the array of microarrays.
  19. An apparatus for hybridization comprising:
    A housing having a base and a cover,
    A substrate disposed within the base and having a microarray, and a hybridization chamber comprising a frame and a portion of the substrate;
    The cover is releasably associated with the base to seal the hybridization chamber;
    A device wherein the cover has an introduction port to prevent the infusion device from contacting the microarray.
  20. 20. The apparatus of claim 19, wherein the cover has a raised portion positioned above the hybridization chamber.
  21. 21. The apparatus of claim 20, wherein the lifted portion has the introduction port.
  22. The raised portion has an injection cavity and a dispersion cavity, and the injection cavity and the dispersion cavity are arranged so that the implanter does not contact the portion of the substrate. The apparatus of claim 21.
  23. The apparatus of claim 19, wherein an introduction port is configured to inhibit the implanter so that the implanter does not contact the substrate.
  24. A method for hybridization comprising:
    Providing a housing having a base and a cover;
    Providing a substrate having a microarray;
    Providing a hybridization chamber including a frame and a portion of the substrate; and releasably combining the cover to the base to seal the hybridization chamber and compress the frame. Method.
  25. The releasable combination
    25. The method of claim 24, comprising depressing the cover and sliding it to a locked position.
  26. The releasable combination
    25. The method of claim 24, comprising depressing the cover and restraining it in the locked position.
  27. The releasable combination
    The method of claim 24 including rotating the cover to a locked position.
  28. The releasable combination
    The method of claim 24 including sliding the base to a locked position.
  29. The cover has a hinged portion;
    To be releasably locked,
    25. The method of claim 24, comprising flipping the hinged portion and constraining it to a locked position.
  30. An apparatus for hybridization comprising:
    A housing having a base and a cover, wherein the base and the cover are releasably combined;
    A substrate having a microarray and configured to be received in the housing;
    A detection frame located on the substrate and forming a detection volume with the substrate; and a hybridization frame forming a hybridization volume with the substrate and the cover;
    An apparatus in which the hybridization volume and the detection volume are in contact with the microarray with a fluid.
  31. A method of hybridization using the apparatus of claim 30 comprising:
    Supplying a hybridization fluid to the hybridization volume;
    Hybridizing the fluid with the microarray;
    Releasing the cover and the base;
    Removing the hybridization frame;
    Placing a coverslip on the detection frame to seal the detection volume and detecting the result of the hybridization on the microarray.
  32. A method for assembling the apparatus of claim 30 comprising:
    Placing the substrate in the base;
    Placing the hybridization frame proximate to the detection frame, and releasably combining the cover and the base.
  33. An apparatus for hybridization comprising:
    A substrate comprising a binding layer and a support, having a microarray, and a hybridization chamber comprising a frame and a portion of the substrate, the frame penetrating the binding layer and positioned on the support. Have
    The device wherein the tie layer contains a blackening agent for absorption.
  34. 34. The apparatus of claim 33, further comprising a housing for the substrate and hybridization chamber, the housing having a base and a cover.
  35. 35. The apparatus of claim 34, wherein the base and the cover are releasably combined to seal the hybridization chamber.
JP2006533492A 2003-05-30 2004-05-28 Apparatus and method for hybridization and SPR detection Pending JP2007502435A (en)

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US10/448,803 US20040241659A1 (en) 2003-05-30 2003-05-30 Apparatus and method for hybridization and SPR detection
US10/448,856 US20040241660A1 (en) 2003-05-30 2003-05-30 Apparatus and method for hybridization
PCT/US2004/016907 WO2004108268A1 (en) 2003-05-30 2004-05-28 Apparatus and method for hybridization and spr detection

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KR100706464B1 (en) 2007-04-10

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