WO2000069553A1 - Vorrichtung und verfahren zur photolithographischen belichtung von biologischen stoffen - Google Patents
Vorrichtung und verfahren zur photolithographischen belichtung von biologischen stoffen Download PDFInfo
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- WO2000069553A1 WO2000069553A1 PCT/DE2000/001540 DE0001540W WO0069553A1 WO 2000069553 A1 WO2000069553 A1 WO 2000069553A1 DE 0001540 W DE0001540 W DE 0001540W WO 0069553 A1 WO0069553 A1 WO 0069553A1
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- light
- solid phase
- dna
- light source
- exposed
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
- G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
- G03F7/20—Exposure; Apparatus therefor
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- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
- G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
- G03F7/70—Microphotolithographic exposure; Apparatus therefor
- G03F7/70216—Mask projection systems
- G03F7/70275—Multiple projection paths, e.g. array of projection systems, microlens projection systems or tandem projection systems
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- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
- G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
- G03F7/70—Microphotolithographic exposure; Apparatus therefor
- G03F7/70216—Mask projection systems
- G03F7/70283—Mask effects on the imaging process
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- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
- G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
- G03F7/70—Microphotolithographic exposure; Apparatus therefor
- G03F7/70383—Direct write, i.e. pattern is written directly without the use of a mask by one or multiple beams
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- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
- G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
- G03F7/70—Microphotolithographic exposure; Apparatus therefor
- G03F7/70383—Direct write, i.e. pattern is written directly without the use of a mask by one or multiple beams
- G03F7/70391—Addressable array sources specially adapted to produce patterns, e.g. addressable LED arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00436—Maskless processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00585—Parallel processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/0059—Sequential processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00596—Solid-phase processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00608—DNA chips
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00659—Two-dimensional arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00702—Processes involving means for analysing and characterising the products
- B01J2219/00707—Processes involving means for analysing and characterising the products separated from the reactor apparatus
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00709—Type of synthesis
- B01J2219/00711—Light-directed synthesis
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00722—Nucleotides
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00725—Peptides
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00729—Peptide nucleic acids [PNA]
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
Definitions
- the invention relates to a device and a method for the photolithographic exposure of biological substances.
- DNA chips are the smallest, mostly planar surfaces, on which a large number of different oligomers (short, single-stranded DNA molecules) are attached in a spatially ordered manner. Such chips are used, for example, for the parallel recognition of numerous DNA sequences in a prepared tissue sample.
- the chip surface is wetted with a solution of single-stranded DNA pieces from the tissue sample, whereupon complementary matching DNA pieces from the solution attach themselves to the corresponding oligomers attached to the chip surface (hybridization). Then you use a suitable method, such as fluorescent labeling, to determine at which locations on the chip hybridization has taken place. If you know where on the chip which oligomers are attached, you can draw conclusions about DNA sequences in the tissue sample.
- the oligomers are synthesized directly on the chip with the help of an automatic micro pipetting system.
- the oligomer chain provided there is built up block by block (nucleobases) on each grid point.
- the chemical process is basically the same as for conventional oligomer synthesis in a test tube.
- oligomers are produced at the same time, by a single automatic system directly at the intended destination.
- the separate steps of oligomer synthesis and micropipetting in method 1) are thus combined into a single step.
- This in situ synthesis normally proceeds as follows: on a prepared substrate, the automatic pipetting device sequentially drops the first nucleobase provided there on each grid point. This is not very mechanically complex since there are only 4 different nucleobases (C, T, G, A). For example, 4 micropipettes coupled together can be used. After the application of the first nucleoside building block on each grid point, the substrate is washed and after a "capping step" the protective groups on the 5 'OH functions are removed in order to react with the respective to enable subsequent nucleoside building block.
- the second nucleobase is then pipetted on at each grid point.
- the substrate is then washed again and deprotected.
- the necessary oligomer chains are built up step by step on each grid point.
- This method is not particularly fast, since new pipettes have to be pipetted on each grid point for each nucleobase.
- the screen density is limited by the inaccuracy of the micropipettes. The inaccuracy has an even worse effect here, since each grid point must be hit several times in succession in an identical manner.
- nucleobases at the correct raster points are done using a completely parallel, photolithographic technique instead of sequential, precise pipetting steps.
- the method is based on the fact that light of a certain wavelength can be used to remove the 5 'OH protective groups from oligonucleotides in a targeted manner. Appropriate local radiation patterns can thus make oligonucleotide ends reactive at precisely those grid points to which a new nucleoside is to be attached in the next step.
- a nucleotide building block is only attached to the previously exposed areas, all unexposed areas remain unchanged.
- the local exposure patterns are generated by positioning a microphotographic black and white mask between the substrate and the light source, which covers all grid points that are not to be made reactive.
- the extension of the oligomer chains on all halftone dots by one nucleobase takes place as follows: With the help of a first one
- a possible problem with this method is the limited optical contrast of the liquid crystal displays available today (maximum 1: 100). The light intensity ratio between exposed and covered points is thereby reduced, which can result in a reduction in yield in oligomer synthesis.
- the photolithographic method with dynamic liquid crystal masks is the only one that allows simple, cheap and reliable production of chips with high screen density.
- the poor contrast of the liquid crystal displays leads to a reduction in the quality of the oligomer dots, which ultimately reduces the detection sensitivity of the chip.
- the object of the present invention is therefore a
- Another object of the invention is to provide a further method for the photolithographic exposure of biological substances.
- a device for the photolithographic exposure of biological substances comprising at least one light source, an optical fiber bundle and a control unit, each of the optical fibers being independent of O 00/69553,
- each other can be controlled with light and / or light can be coupled into it.
- the light source emits monochromatic or continuous light in a wavelength range from 100 to 800 nm. It is particularly preferred that the light source is a laser, a light-emitting diode, a metal halide lamp, a gas discharge lamp, a gas excitation lamp, an incandescent lamp or an arc lamp.
- light-emitting diodes and / or optical switches are arranged to control the individual light guides.
- substances to be exposed are applied directly to the ends of the light guides.
- substances to be exposed are arranged on a separate support.
- substances to be exposed are arranged on a separate carrier, this carrier being a DNA chip, a PNA chip or a peptide chip.
- the device preferably additionally has at least one detector.
- At least one of the detectors is arranged such that it detects the light used for exposure and / or at least one detector is arranged such that it detects the light reflected by the exposed substances and / or generated by fluorescence and that for Light guide for the detectors, if necessary, light guides and / or light guide bundles O n
- the detectors are CCD detectors and / or CCD cameras.
- a dynamic mask is provided for controlling the individual light guides. It is also particularly preferred that a set of static masks is provided for controlling the individual light guides.
- an apparatus is extremely preferred, wherein the light source emits such a spectrum of wavelengths which effects the deprotection of nucleotides, nucleotide analogs and peptide-nucleic acid building blocks for chain extension and for the construction of oligomers and that a bundle of optical fibers is arranged between this light source and the substrate , into which light can be selectively coupled by targeted control and that the solid phase on which the oligomer synthesis takes place is positioned precisely and rigidly behind the light guide bundle and that the solid phase on which the oligomer synthesis takes place is arranged in a chamber in the solutions and / or reagents necessary for DNA or PNA synthesis can be brought up to this solid phase by further devices.
- a separate support is arranged as the solid phase on which the oligomer synthesis takes place. It is also preferred according to the invention that the ends of the optical fibers themselves are the solid phase for carrying out the oligomer synthesis.
- Another object of the present invention is a method for the photolithographic exposure of biological substances, wherein they are arranged on a surface or at the end of an optical fiber and by means of
- a light source originates, which is arranged at the other end of the light guide, whereby each point which lies opposite an end of the light guide is exposed independently of the other points, the exposure pattern being preselected by means of a control unit.
- light of wavelength is used, which deprotects nucleotides, nucleotide analogs and peptide nucleic acid building blocks for chain extension and for building oligomers, and that one between them Arrows the light source and the substrate a bundle of optical fibers, m each of which is selectively coupled by selective control and that the solid phase on which the oligomer synthesis takes place is positioned precisely and rigidly behind the optical fiber bundle and that the solid phase on which the oligomer synthesis takes place , arranged in a chamber into which the solutions and / or reagents necessary for DNA or PNA synthesis are introduced to this solid phase by further devices.
- the device according to the invention enables simple and inexpensive photolithographic production of DNA chips of high screen density with an exposure contrast of well over 1: 100. This makes the simple production of 00/695 ⁇
- the device according to the invention and the method solve the problem in a completely new way by combining commercially available components. It enables the cheap production of DNA chips in a quality that was not possible before.
- the basic concept of the device and the method according to the invention is that a specific exposure pattern is not generated on the substrate by specifically covering raster dots with the aid of a static or dynamic mask, but by individually directing the light to each raster dot to be exposed via an optical light guide feeds.
- the end of an optical fiber must therefore be attached above each grid point in such a way that when light is coupled into the fiber, the light emerging at the end illuminates the corresponding grid point. Consequently, exactly as many optical fibers are required as raster points are provided.
- Attach the right light source e.g. a laser diode of the correct wavelength.
- Another possibility is the use of commercially available, electrically controllable optical switches. It is a hardware component with 2 connections for 2 optical fibers and an electrical control input. An electrical signal at the control input can determine whether the two optical fibers should be optically connected or not. One optical switch and two are therefore required for each grid point
- Optical fibers Light is permanently coupled into the free end of the first fiber, the free end of the second fiber serves as light output and is fastened over the respective grid point. A single light source is sufficient for the light coupling if all input fibers are bundled accordingly.
- Another option for targeted light coupling into the individual fibers of the optical fiber bundle is the use of automatically positioned static masks (e.g. photo or perforated masks) or an electronically controllable dynamic mask (e.g. LCD), which is placed between the light source and the input side of the static masks (e.g. photo or perforated masks) or an electronically controllable dynamic mask (e.g. LCD), which is placed between the light source and the input side of the static masks (e.g. photo or perforated masks) or an electronically controllable dynamic mask (e.g. LCD), which is placed between the light source and the input side of the
- the masks can be used to specifically mask those fiber inputs into which no light is to be coupled during the respective exposure step.
- the masks can be arranged geometrically differently and in particular can be much larger than the surface of the array to be exposed, since the light guide on the coupling side 69553 1
- an unordered fiber bundle can also be attached over the substrate.
- the points on a chip made in this way are then no longer grid-like, but randomly and irregularly arranged. In spite of this, the positions of the points are identical for all chips which have been produced with the same light guide arrangement. In principle, one can know which type of oligomer was synthesized at which point on the chip. For a given synthesis arrangement with random bundling of optical fibers, it is sufficient to couple light to each individual light guide one after the other and with a high-resolution CCD detector, which is placed in the substrate plane, to determine the position of the emerging light cones. In this way you can create a complete table with the assignment of all control addresses to the corresponding x-y substrate positions.
- Chips that are manufactured with the appropriate arrangement are manufactured with the appropriate arrangement.
- a separate photodetector must be attached to each fiber end instead of the light source (s).
- Such an optical reading system with optical fibers can considerably simplify the C ip detection compared to the conventional detection method with CCD detectors.
- a very interesting and novel application variant of the DNA chip synthesis process described here is the synthesis of oligomers directly on the ends of the light guides instead of on a separate substrate. This can be achieved by chemically preparing the optical fiber end faces through which the light exits in a manner similar to that of conventional DNA chip carrier surfaces. As a result, each end of the light guide itself becomes a small, independent carrier on which exactly one type of oligomer can now be synthesized using conventional photolythographic chemistry. The photo-activating light is therefore no longer radiated onto the carrier surface from the outside, but emerges directly on the carrier surface from the transparent, light-conducting carrier material.
- tion can be used. As described above, this can be achieved by tightly bundling the fiber ends.
- the oligomer point group produced remains inseparably connected to the device used for the production.
- Hybridization and subsequent detection are then also carried out at the ends of the light guides, the light guides in the opposite direction being used again for fluorescence detection to read out the fluorescence signals.
- the optical fiber tips can be chemically cleaned and the device can thus be made ready for a new synthesis.
- FIG. 1 shows the schematic structure of a first embodiment of the device according to the invention, in which the activation of the fibers is represented by optical switches;
- FIG. 2 shows the schematic structure of a second embodiment of the device according to the invention, in which the activation of the fibers by individual light sources is shown;
- Fig. 3 shows the schematic structure during the exposure of a separate carrier (chip) and 00/69553 j_ 4
- Fig. 4 shows the schematic structure during exposure, the substrate being located directly on the fiber ends.
- FIG. 1 shows a first exemplary embodiment of a device according to the invention.
- the light is guided by means of the light guide F to the array carrier C via the electrically controlled optical switches B.
- the controller S preferably a computer, provides the appropriate control of the individual switches B in a predetermined manner in the form of a dynamic or static mask.
- FIG. 2 shows a second exemplary embodiment of a device according to the invention.
- the controller S preferably a computer, ensures the corresponding activation of the individual switches A in a predetermined manner.
- control can take the form of a dynamic or static mask.
- FIG. 3 shows in detail how the individual substrate points E on the array carrier C are exposed by the optical fibers F.
- FIG. 4 shows that the substrates are arranged directly at the ends of the optical fibers F.
- Light source B electrically controlled optical switch
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/980,194 US6819843B1 (en) | 1999-05-14 | 2000-05-12 | Device and method for photolithographically irradiating biological substances |
EP00943606A EP1185364A1 (de) | 1999-05-14 | 2000-05-12 | Vorrichtung und verfahren zur photolithographischen belichtung von biologischen stoffen |
AU58033/00A AU5803300A (en) | 1999-05-14 | 2000-05-12 | Device and method for photolithographically irradiating biological substances |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19922941.4 | 1999-05-14 | ||
DE19922941A DE19922941A1 (de) | 1999-05-14 | 1999-05-14 | Vorrichtung und Verfahren zur photolithographischen Belichtung von biologischen Stoffen |
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Publication Number | Publication Date |
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WO2000069553A1 true WO2000069553A1 (de) | 2000-11-23 |
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PCT/DE2000/001540 WO2000069553A1 (de) | 1999-05-14 | 2000-05-12 | Vorrichtung und verfahren zur photolithographischen belichtung von biologischen stoffen |
Country Status (5)
Country | Link |
---|---|
US (1) | US6819843B1 (de) |
EP (1) | EP1185364A1 (de) |
AU (1) | AU5803300A (de) |
DE (1) | DE19922941A1 (de) |
WO (1) | WO2000069553A1 (de) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US20020075490A1 (en) * | 2000-12-20 | 2002-06-20 | Affymetrix, Inc. | System and method for addressable light-directed microarray printing |
DE10230320A1 (de) * | 2002-07-05 | 2004-02-05 | Marcel Rogalla | Programmierbare Beleuchtungsvorrichtung zur hochauflösenden, massiv parallelen, räumlichen Systhese und Analyse von Microarrays |
US20070122842A1 (en) * | 2005-11-30 | 2007-05-31 | Rajasekaran John J | Massively parallel synthesis of proteinaceous biomolecules |
US20070154946A1 (en) * | 2005-12-29 | 2007-07-05 | Rajasekaran John J | Massively parallel synthesis of biopolymeric arrays |
US9096953B2 (en) * | 2006-09-29 | 2015-08-04 | Intel Corporation | Method for high throughput, high volume manufacturing of biomolecule micro arrays |
US20100240544A1 (en) * | 2006-09-29 | 2010-09-23 | Liu David J | Aptamer biochip for multiplexed detection of biomolecules |
US20080108149A1 (en) * | 2006-10-23 | 2008-05-08 | Narayan Sundararajan | Solid-phase mediated synthesis of molecular microarrays |
US7622295B2 (en) * | 2006-12-19 | 2009-11-24 | Edelmira Cabezas | Molecular microarrays and helical peptides |
US8614086B2 (en) * | 2006-12-28 | 2013-12-24 | Intel Corporation | Quality control methods for the manufacture of polymer arrays |
US7923237B2 (en) * | 2006-12-28 | 2011-04-12 | Intel Corporation | Method and apparatus for combined electrochemical synthesis and detection of analytes |
US20080161202A1 (en) * | 2006-12-29 | 2008-07-03 | Edelmira Cabezas | Novel strategy for selective regulation of background surface property in microarray fabrication and method to eliminated self quenching in micro arrays |
US20100248975A1 (en) * | 2006-12-29 | 2010-09-30 | Gunjan Tiwari | Fluorogenic peptide substrate arrays for highly multiplexed, real-time monitoring of kinase activities |
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GB2270189A (en) * | 1992-08-29 | 1994-03-02 | Thermotor Limited | A display or sign. |
US5293437A (en) * | 1992-06-03 | 1994-03-08 | Visual Optics, Inc. | Fiber optic display with direct driven optical fibers |
US5510270A (en) * | 1989-06-07 | 1996-04-23 | Affymax Technologies N.V. | Synthesis and screening of immobilized oligonucleotide arrays |
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DE19823454A1 (de) * | 1998-05-18 | 1999-11-25 | Epigenomics Gmbh | Verfahren zur photolithographischen Herstellung von DNA, PNA und Protein Chips |
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US3689932A (en) * | 1970-05-25 | 1972-09-05 | Gerber Scientific Instr Co | Scanning device for exposing a photosensitive surface |
US4407964A (en) * | 1980-10-07 | 1983-10-04 | The Regents Of The University Of California | Homogeneous fluoroimmunoassay involving sensing radiation for forward and back directions |
US5424186A (en) * | 1989-06-07 | 1995-06-13 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis |
US5501680A (en) * | 1992-01-15 | 1996-03-26 | The University Of Pittsburgh | Boundary and proximity sensor apparatus for a laser |
DE4301716C2 (de) * | 1992-02-04 | 1999-08-12 | Hitachi Ltd | Projektionsbelichtungsgerät und -verfahren |
CA2102884A1 (en) * | 1993-03-04 | 1994-09-05 | James J. Wynne | Dental procedures and apparatus using ultraviolet radiation |
US5729331A (en) * | 1993-06-30 | 1998-03-17 | Nikon Corporation | Exposure apparatus, optical projection apparatus and a method for adjusting the optical projection apparatus |
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DE19626176A1 (de) * | 1996-06-29 | 1998-01-08 | Deutsche Forsch Luft Raumfahrt | Lithographie-Belichtungseinrichtung und Lithographie-Verfahren |
US6156494A (en) * | 1997-10-28 | 2000-12-05 | Mosaic Technologies | Serially directed combinatorial synthesis on fiber optic arrays |
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1999
- 1999-05-14 DE DE19922941A patent/DE19922941A1/de not_active Ceased
-
2000
- 2000-05-12 EP EP00943606A patent/EP1185364A1/de not_active Withdrawn
- 2000-05-12 US US09/980,194 patent/US6819843B1/en not_active Expired - Lifetime
- 2000-05-12 WO PCT/DE2000/001540 patent/WO2000069553A1/de not_active Application Discontinuation
- 2000-05-12 AU AU58033/00A patent/AU5803300A/en not_active Abandoned
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GB2270189A (en) * | 1992-08-29 | 1994-03-02 | Thermotor Limited | A display or sign. |
US5571639A (en) * | 1994-05-24 | 1996-11-05 | Affymax Technologies N.V. | Computer-aided engineering system for design of sequence arrays and lithographic masks |
DE19823454A1 (de) * | 1998-05-18 | 1999-11-25 | Epigenomics Gmbh | Verfahren zur photolithographischen Herstellung von DNA, PNA und Protein Chips |
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Also Published As
Publication number | Publication date |
---|---|
AU5803300A (en) | 2000-12-05 |
EP1185364A1 (de) | 2002-03-13 |
US6819843B1 (en) | 2004-11-16 |
DE19922941A1 (de) | 2000-11-30 |
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