DE10127220A1 - Carrier for analyzing chemical and biological samples, e.g. for diagnosis, on which binding reaction produces structure that can be read by optical methods - Google Patents
Carrier for analyzing chemical and biological samples, e.g. for diagnosis, on which binding reaction produces structure that can be read by optical methodsInfo
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- DE10127220A1 DE10127220A1 DE10127220A DE10127220A DE10127220A1 DE 10127220 A1 DE10127220 A1 DE 10127220A1 DE 10127220 A DE10127220 A DE 10127220A DE 10127220 A DE10127220 A DE 10127220A DE 10127220 A1 DE10127220 A1 DE 10127220A1
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- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6816—Hybridisation assays characterised by the detection means
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
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Abstract
Description
Analysen von biologischen Proben können vorteilhaft mit sogenannten Biochips durchgeführt werden. Dabei werden chemische oder biologische Substanzen auf Metall-, Glas-, Membran- oder Kunststoff-Oberflächen, insbesondere Polycarbonatträger, aufgebracht. Diese Substanzen reagieren danach mit weiteren Stoffen aus einer applizierten Probe. Die ortsspezifische Bindung dieser Stoffe ermöglicht dann einen Nachweis der molekularen Interaktion und meist auch eine Aussage über die gebundene Menge oder die Substanz-Zusammensetzung und/oder über die Stärke der Interaktion. Nach Stand der Technik werden die Bindungen meist über die Erzeugung eines optischen Signals nachgewiesen. Dabei wird üblicherweise ein Mikroskop oder ein funktional analoges Gerät, beispielsweise ein CD-Lesekopf, eingesetzt. Die Information über eine erfolgte oder nicht erfolgte Bindung an einer bestimmten Stelle wird durch Bildauswertung erhalten, welche bei Biochips höherer Dichte typischerweise durch eine Computersoftware nach einer Analog-Digital-Wandlung erfolgt. In einer Ausführungsvariante wird die Information über eine erfolgte oder nicht erfolgte Bindung an einer bestimmten Stelle durch die Ablagerung von Körnchen ("Beads") am Ort der Reaktion eines Stoffes aus einer applizierten Probe mit der trägergebundenen Substanz markiert (vgl. z. B. Taton, Mirkin, Letsinger [2000] Science 289, S. 1757-1760). Nach Stand der Technik werden solcherart gebundene Beads aber entweder durch die oben beschriebene Bildanalyse identifiziert oder sie bewirken eine chemische Umsetzung, welche mit im wesentlichen photometrischen Methoden (Farbumschlag, Farbstoffpräzipitat) nachgeweisen wird. Ein erfolgter Farbumschlag oder ein Farbstoffpräzipitat erfordert danach wiederum eine Bildanalyse zur Erzeugung der Information, welche für die weitere Computeranalyse verwendet werden kann.Analyzes of biological samples can be advantageous using so-called biochips be performed. Chemical or biological substances are applied to metal, Glass, membrane or plastic surfaces, especially polycarbonate supports, applied. These substances then react with other substances from one applied sample. The site-specific binding of these substances then enables one Evidence of the molecular interaction and usually also a statement about the bound Amount or substance composition and / or strength of interaction. According to the state of the art, the bonds are mostly created by creating an optical one Signal detected. Usually a microscope or a functional one analog device, such as a CD read head, used. The information about a Successful or non-successful binding at a certain point is determined by image evaluation obtained, which in biochips of higher density typically by computer software after an analog-to-digital conversion. In one embodiment, the Information about a successful or non-successful binding at a certain point by the deposition of granules ("beads") at the point of reaction of a substance from a applied sample marked with the carrier-bound substance (see e.g. Taton, Mirkin, Letsinger [2000] Science 289, pp. 1757-1760). According to the state of the art bound beads but either identified by the image analysis described above or they bring about a chemical reaction which is essentially photometric Methods (color change, dye precipitate) is detected. A successful one Color change or a dye precipitate then again requires an image analysis Generation of the information which is used for further computer analysis can.
Die hier beschriebene Methode gewährleistet eine wesentliche Vereinfachung dieses Vorganges dadurch, daß die Information über eine erfolgte oder nicht erfolgte Bindung an einer bestimmten Stelle dadurch erzeugt wird, daß eine chemische Reaktion zur Erzeugung von detektierbaren Strukturen, insbesondere Körnchen ("Beads") oder Schichten von Präzipitaten, am Ort der Reaktion eines Stoffes aus einer applizierten Probe mit der trägergebundenen Substanz in einer Weise erfolgt, welche in einer geeigneten Ausleseeinheit direkt ein binäres Signal erzeugt. Dieses Signal erfordert zu seiner Verwendung keine Bildverarbeitung im obigen Sinne mehr. Erfindungsgemäß geschieht dies in einer vorteilhaften Ausführungsvariante durch die Erzeugung von Silberkörnchen am Ort der Bindung, welche sich an einem Initiator, insbesondere einem Elektronendonator wie einem Metallmolekül- oder -körnchen, bilden, welches seinerseits mit der nachzuweisenden Probe verbunden ist (Fig. 1). Die binäre Auslesung ist dabei dadurch gewährleistet, daß die Größe des entstehenden Präzipitats so gewählt wird, daß seine Eigenschaften den informationstragenden Strukturen eines aus der Informationstechnologie bekannten optischen, magnetooptischen oder elektromagnetischen Massenspeichers im wesentlichen ähnlich sind. Die entstehende detektierbare Struktur kann in einer anderen vorteilhaften Ausführung auch durch Initiation einer chemischen Reaktion von einer vorher nur an bestimmten Stellen des Trägers aufgetragenen Substanz erzeugt werden, insbesondere in Form von signalgebenden Oberflächenstrukturen mit für den Detektor definierten Eigenschaften, welche im weiteren als Pits bezeichnet werden. Dazu wird zusätzlich zu dem auf den Träger aufgebrachten Molekül, welches mit der zu analysierenden Probe wechselwirken soll, noch eine Vorstufe eines weiteren Stoffes oder ein dazu geeignetes Gemisch, welche in eine detektierbare Struktur umgesetzt werden kann, aufgetragen. Die aufgetragene Fläche entspricht dabei im wesentlichen einem Pit. Nach Bindung eines Sensormoleküls bewirkt dieses eine Reaktion in diesem Stoff oder dem Stoffgemisch, welche die optischen Eigenschaften der beschichteten Struktur ändert, insbesondere durch eine sich in einer im wesentlichen monomolekular auf der Oberfläche bis zu den Rändern des Pits ausbreitenden und dort abbrechenden Reaktion.The method described here considerably simplifies this process in that the information about a successful or non-successful binding at a certain point is generated by a chemical reaction for the production of detectable structures, in particular granules ("beads") or layers of Precipitates, at the site of the reaction of a substance from an applied sample with the carrier-bound substance in a manner which directly generates a binary signal in a suitable readout unit. This signal no longer requires image processing in the above sense to be used. According to the invention, this is done in an advantageous embodiment variant by producing silver grains at the site of the bond, which form on an initiator, in particular an electron donor such as a metal molecule or granule, which in turn is connected to the sample to be detected ( FIG. 1). The binary reading is ensured in that the size of the precipitate is chosen so that its properties are essentially similar to the information-carrying structures of an optical, magneto-optical or electromagnetic mass storage device known from information technology. In another advantageous embodiment, the resulting detectable structure can also be generated by initiating a chemical reaction from a substance previously applied only at certain points on the carrier, in particular in the form of signal-emitting surface structures with properties defined for the detector, which are referred to below as pits , For this purpose, in addition to the molecule applied to the carrier, which is to interact with the sample to be analyzed, a precursor of another substance or a mixture which is suitable for this and which can be converted into a detectable structure is applied. The applied area corresponds essentially to a pit. After binding of a sensor molecule, this causes a reaction in this substance or the mixture of substances, which changes the optical properties of the coated structure, in particular by a reaction which spreads and breaks off in an essentially monomolecular manner on the surface up to the edges of the pit.
Die binäre Information eines solchen Massenspeichers kann die Positionsinformation liefern, welche die Zuordnung des durch die chemische oder biochemische Bindung eines Sensormoleküls erhaltenen binären Signals zu einer definierten Substanz ermöglicht, welche nach Stand der Technik durch Aufdrucken, lithographische Synthese oder andere geeignete Methoden in definierter Anordnung zu dieser Positionsinformation aufgebracht wurde.The binary information of such a mass storage device can be the position information provide the assignment of the by chemical or biochemical binding of a Sensor signal obtained binary signal to a defined substance enables which according to the prior art by printing, lithographic synthesis or others Suitable methods are applied to this position information in a defined arrangement has been.
Als Träger können Polymerkunststoffe mit verschiedenen, der analytischen Aufgabenstellung angepaßten physiko-chemischen Eigenschaften, aber auch Glas, Halbleiter, Metalle, Metallegierungen, Keramiken, Hybridmaterialien oder Kombinationen aus diesen Werkstoffen eingesetzt werden. Eine vorteilhafte Anwendung verwendet Träger aus Polycarbonat optischer Qualität sowie Datenstrukturen, wie sie in CD- und DVD- Technologie Anwendung finden.As a carrier, polymer plastics with different, the analytical Task adapted physico-chemical properties, but also glass, Semiconductors, metals, metal alloys, ceramics, hybrid materials or combinations made of these materials. An advantageous application uses carriers made of polycarbonate of optical quality as well as data structures as they are in CD and DVD Find technology application.
Die Erfindung sieht vor, daß man mit Vorteil eine Vielzahl von verschiedenen Molekülen (Molekülbibliotheken oder Moleküle für mehrere verschiedene individuelle Tests) auf der Substratoberfläche aufbringen kann. Verschiedene Moleküle werden dafür räumlich begrenzt innerhalb geordneter Strukturen aufgebracht. Dabei können die Flächen, insbesondere kleiner als 10 × 10 µm, mit Vorteil kleiner als 2 × 2 µm und mit besonderem Vorteil kleiner als 1 × 1 µm Ausdehnung haben. The invention provides that a large number of different molecules is advantageous (Molecular libraries or molecules for several different individual tests) on the Can apply substrate surface. Different molecules become spatial for this limited applied within ordered structures. The surfaces, in particular less than 10 × 10 µm, advantageously less than 2 × 2 µm and with particular Advantage less than 1 × 1 µm expansion.
Die auf die Substratoberfläche aufgebrachten Moleküle können Substanzen sein, welche für einen chemischen, biochemischen oder medizinischen Nachweis von Nutzen sind. Dies sind unter anderem Zucker, Steroide, Hormone, Lipide, Proteine, insbesondere mono- oder polyklonale oder rekombinante Antikörper, Peptide, Antigene aller Art, Mikroorganismen oder Teile davon, Präparationen und Extrakte aus biologischen Materialien, Stoffwechselmetaboliten, DNA, RNA sowie natürliche und artifizielle Derivate hiervon, insbesondere Aptamere und PNA, aber auch organisch-chemische Wirkstoff-Bibliotheken, wie sie z. B. für pharmakologische Entwicklungen eingesetzt werden, oder Haptene.The molecules applied to the substrate surface can be substances which are useful for chemical, biochemical or medical evidence. This include sugar, steroids, hormones, lipids, proteins, especially mono- or polyclonal or recombinant antibodies, peptides, antigens of all kinds, microorganisms or parts thereof, preparations and extracts from biological materials, Metabolism metabolites, DNA, RNA as well as natural and artificial derivatives thereof, in particular aptamers and PNA, but also organic chemical libraries, as they e.g. B. used for pharmacological developments, or haptens.
Neben diesen Molekülen können entsprechend einer vordefinierten Anordnung weitere Moleküle oder signalgebende Elemente auf benachbarten Pits aufgebracht sein, welche zur Kalibrierung oder Standardisierung der Analysen dienen. Diese können auf Flächen gleicher oder ähnlicher Größenordnung aufgebracht und insbesondere räumlich von den eigentlichen analytisch eingesetzten Molekülen durch von Molekülen freie Flächen (Leerflächen) voneinander getrennt sein.In addition to these molecules, others can be used according to a predefined arrangement Molecules or signaling elements can be applied to neighboring pits, which are used for Calibration or standardization of the analyzes are used. These can be on surfaces the same or similar order of magnitude and in particular spatially from the actual molecules used analytically by surfaces free of molecules (Empty spaces).
Der Analysenträger enthält dadurch in seiner einfachsten Form ein Muster von Pits, die
solche Moleküle enthalten, und dazwischen, aber nicht notwendigerweise in regelmäßiger
Anordnung, leere Stellen, die die Pits voneinander trennen. Mehrere solcher Parallelspuren
sowie lineare, kurvenförmige, radiale, spiralförmige, kreisförmige oder sonstige
geometrischen Anordnungen von Pits sind möglich und Bestandteil der Erfindung. Zum
Aufbringen der Sensormoleküle auf geometrische Muster von Pits können mehrere
Methoden nach Stand der Technik genutzt werden, insbesondere:
In its simplest form, the analysis carrier thus contains a pattern of pits which contain such molecules, and in between, but not necessarily in a regular arrangement, empty spaces which separate the pits from one another. Several such parallel tracks as well as linear, curved, radial, spiral, circular or other geometrical arrangements of pits are possible and form part of the invention. Several methods according to the prior art can be used to apply the sensor molecules to geometric patterns of pits, in particular:
- 1. Ein Flüssigkeitsbad (einfaches Eintauchen des Trägers nach selektiver Aktivierung von Pits).1. A liquid bath (simple immersion of the carrier after selective activation of Pits).
- 2. Benetzen mittels Mikrokanälen oder Mikrofluidischer Netzwerke.2. Wetting using microchannels or microfluidic networks.
- 3. Stempelverfahren, insbesondere Lithographische Verfahren wie Softlithographie.3. Stamp processes, in particular lithographic processes such as soft lithography.
- 4. Spotting-Verfahren. 4. spotting techniques.
- 5. Ink-Jet Verfahren.5. Ink-jet process.
- 6. Mechanische Übertragung von Substanzen mittels rotierenden Walzen (z. B. Laserdrucker, Photokopierer).6. Mechanical transfer of substances using rotating rollers (e.g. Laser printer, photocopier).
- 7. Spin-Coating.7. spin coating.
Als Sensormoleküle können alle Substanzen dienen, die für einen chemischen, biochemischen oder medizinischen Nachweis von Nutzen sind. Dies sind unter anderem Zucker, Steroide, Hormone, Lipide, Proteine, insbesondere mono- oder polyklonale oder rekombinante Antikörper (Fig. 1), Peptide, Antigene aller Art, Mikroorganismen oder Teile davon, Präparationen und Extrakte aus biologischen Materialien, Stoffwechselmetaboliten, DNA (Fig. 3), RNA sowie natürliche und artifizielle Derivate hiervon, insbesondere Aptamere und PNA, aber auch organisch-chemische Wirkstoff- Bibliotheken, wie sie z. B. für pharmakologische Entwicklungen eingesetzt werden, oder Haptene.All substances that are useful for chemical, biochemical or medical detection can serve as sensor molecules. These include sugar, steroids, hormones, lipids, proteins, especially mono- or polyclonal or recombinant antibodies ( Fig. 1), peptides, all kinds of antigens, microorganisms or parts thereof, preparations and extracts from biological materials, metabolites, DNA ( Fig. 3), RNA and natural and artificial derivatives thereof, in particular aptamers and PNA, but also organic chemical drug libraries, such as those used for. B. used for pharmacological developments, or haptens.
Weiterhin umfaßt die Erfindung ein für den Träger optimiertes Lesegerät, welches in vorteilhafter Ausführung ein halbautomatisches bzw. automatisches Positionieren und Auslesen des Trägers gestatten. Ein nachgeschaltetes Rechnersystem benötigt zur Auswertung der auf dem Träger untergebrachten Analysen spezielle Software, welche auf den jeweiligen Analysenträger zugeschnitten ist. Diese Software kann in vorteilhafter Ausführung in den auf dem Träger vorhandenen Datenanteil aufgebracht sein. Hierfür können deshalb Datenleser wie CD-ROM oder DVD-Player oder vergleichbare Geräte und deren Nachfolger verwendet werden, mit denen der Träger prinzipiell kompatibel ist. Ebenso kann die Analysensoftware auf optional auf dem Träger vorhandene Datenbanken zugreifen, um Standardwerte, die im Kontext der spezifischen Analyse benötigt werden, im Zugriff zu halten.Furthermore, the invention comprises a reader optimized for the wearer, which in advantageous embodiment a semi-automatic or automatic positioning and Allow the carrier to be read out. A downstream computer system requires Evaluation of the analyzes housed on the carrier special software, which on the respective analysis medium is tailored. This software can be beneficial Execution in the data portion present on the carrier. Therefor can therefore data readers such as CD-ROM or DVD player or comparable devices and whose successors are used, with which the carrier is compatible in principle. The analysis software can also be run on databases optionally available on the carrier access the standard values required in the context of the specific analysis in the Keep access.
Die Erfindung kann besonders vorteilhaft bei biochemischen oder biomedizinischen Nachweisverfahren Anwendung finden. Aufgrund der praktischen Handhabung sind beispielhaft insbesondere Nachweise in biochemischen Labors, in Labors von Arztpraxen und Krankenhäusern sowie in allen Bereichen des Umweltschutzes, der Qualitätskontrolle, der Biotechnologie, Forensik, Agrar- und Pflanzenhybridanalytik, sowie der molekularbiologischen, pharmazeutischen und medizinischen Forschung und Entwicklung möglich. Weitere Möglichkeiten der Anwendung einer erfindungsgemäßen Analyseplattform sind ebenso möglich und damit Gegenstand der Erfindung. Die Erfindung umfaßt die dazu notwendigen Substanzzusammenstellungen ("Kits"), welche Mittel zur erfindungsgemäßen Herstellung der detektierbaren Strukturen enthalten.The invention can be particularly advantageous in biochemical or biomedical Detection methods apply. Because of the practical handling exemplary, in particular, evidence in biochemical laboratories, in laboratories of medical practices and hospitals as well as in all areas of environmental protection, quality control, of biotechnology, forensics, agricultural and plant hybrid analysis, and the molecular biological, pharmaceutical and medical research and development possible. Other ways of using an inventive Analysis platforms are also possible and thus the subject of the invention. The Invention comprises the necessary substance combinations ("kits"), which Contain agents for the inventive production of the detectable structures.
- 1. Ein Träger aus Polycarbonat mit bestimmten definiert aufgebrachten Positionsinformationen in Form von "Pits", im wesentlichen identisch zu einer CD, wird mit 100% Ethanol gereinigt. Danach wird ein Antigen eines pathogenen Mikroorganismus mithilfe eines Stempels aus PDMS auf bestimmte Bereiche des Trägers aufgedruckt. Stempel und Polycarbonatträger werden dabei mithilfe einer Halterung so zueinander angeordnet, dass eine genaue Positionierung zueinander mit mindestens 1 Mikrometer Genauigkeit gewährleistet ist. Der Träger wird nach dem Druckvorgang für 40 min in einer Lösung von 1% Rinder-Serum-Albumin (BSA) inkubiert. Danach wird der Träger mit destilliertem Wasser gewaschen und mit menschlichem Proben-Serum für 15 min bei 37°C inkubiert. Nach 2 × 5 min Waschen in PBS (20 mM Na-Phosphat, 140 mM NaCl) wird der Träger mit einer 1 : 350 Verdünnung in PBS eines anti-Human-IgG-Antikörpers aus der Ziege, gekoppelt an Snm-Kolloidgoldpartikel, für 20 min bei Raumtemperatur inkubiert. Nach erneutem zweimaligen Waschen mit PBS wird eine Silberlösung zugegeben. Diese besteht in einer vorteilhafter Ausführung aus 110 mg Silberlaktat, 850 mg Hydroquinon, 2,55 g Zitronensäuremonohydrat, 2,35 g Tri-Natriumcitrat ad 100 ml Wasser, welche direkt vor der Reaktion frisch angesetzt wird. Nach 2-4 min im Dunkeln wird die Reaktion durch Waschen mit destilliertem Wasser gestoppt und anschließend mit 2,5% (w/v) Natriumthiosulfat in Wasser fixiert. In einer weiteren vorteilhaften Ausführung kann stattdessen eine dem Fachmann aus der Immunhistologie bekannte kommerzielle "Silver-Enhancement"-Lösung (z. B. von Sigma-Chemie, München) verwendet werden.1. A carrier made of polycarbonate with certain defined applied Position information in the form of "pits", essentially identical to a CD, is cleaned with 100% ethanol. After that, an antigen becomes a pathogenic Microorganism using a stamp from PDMS on certain areas of the Printed carrier. Stamp and polycarbonate carrier are made using a Bracket arranged to each other so that an exact positioning with each other accuracy of at least 1 micron is guaranteed. The carrier will after Printing for 40 min in a solution of 1% bovine serum albumin (BSA) incubated. The carrier is then washed with distilled water and washed with human sample serum incubated for 15 min at 37 ° C. After washing 2 × 5 min in PBS (20 mM Na-phosphate, 140 mM NaCl) the carrier with a 1: 350 Dilution in PBS of a goat anti-human IgG antibody coupled to Snm colloidal gold particles, incubated for 20 min at room temperature. After again a silver solution is added twice with PBS. This consists of an advantageous embodiment of 110 mg silver lactate, 850 mg hydroquinone, 2.55 g Citric acid monohydrate, 2.35 g trisodium citrate ad 100 ml water, which immediately before the reaction is freshly prepared. After 2-4 minutes in the dark the reaction is complete Washing stopped with distilled water and then with 2.5% (w / v) Sodium thiosulfate fixed in water. In a further advantageous embodiment, instead, a commercial one known to those skilled in immunohistology "Silver enhancement" solution (eg from Sigma-Chemie, Munich) can be used.
Nach erneutem Waschen mit destilliertem Wasser wird der Träger in einem im wesentlichen handelsüblichen CD-Laufwerk ausgelesen.After washing again with distilled water, the carrier is in an im read the essential commercially available CD drive.
- 1. Biotinylierte Antikörper gegen ein gesuchtes Protein werden mit einer Patienten- Serumprobe, welche vorher 1 : 3 in PBS (s. o.) verdünnt wurde, gemischt. Die Mischung wird 10 min. bei 13 000 × g zentrifugiert und der Überstand auf einen Detektionsträger aufgebracht, welcher an bestimmten Stellen in einem Vorgang analog zu dem in Beispiel 1 beschriebenen mit einem weiteren Antikörper beschichtet ist, welcher ein anderes Epitop auf dem aus dem Serum nachzuweisenden Protein bindet. Nach dreißigminütiger Inkubation bei Raumtemperatur und dreifachem Waschen in PBS wird ein in auf 4°C gekühltem PBS frisch angesetztes Gemisch aus core-Streptavidin und biotinyliertem Ferritin auf den Detektionsträger aufgebracht. Das Ferritin wurde dabei mit einem Kit nach Stand der Technik solcherart biotinyliert, daß durchschnittlich 4-10 Biotin- Moleküle pro Ferritin-Tetramer gebunden sind. Innerhalb einer Inkubationszeit von typischerweise 30 Minuten bilden sich bei einem bestimmten Gehalt des gesuchten Proteins große kreuzvernetzte Komplexe an den Stellen, an denen der Träger mit dem entsprechenden Antikörper beschichtet ist (Fig. 4). Diese Komplexe sind optisch zu detektieren, ihre Anordnung wird im Weiteren analog zu Beispiel 1 ausgelesen und nachgewiesen.1. Biotinylated antibodies against a searched protein are mixed with a patient's serum sample, which was previously diluted 1: 3 in PBS (see above). The mixture is 10 min. Centrifuged at 13,000 × g and the supernatant applied to a detection support which is coated at certain points in a process analogous to that described in Example 1 with a further antibody which binds another epitope on the protein to be detected from the serum. After thirty minutes of incubation at room temperature and washing three times in PBS, a mixture of core streptavidin and biotinylated ferritin freshly prepared in PBS cooled to 4 ° C. is applied to the detection support. The ferritin was biotinylated using a prior art kit such that an average of 4-10 biotin molecules are bound per ferritin tetramer. Within an incubation period of typically 30 minutes, at a certain content of the protein sought, large cross-linked complexes form at the locations where the support is coated with the corresponding antibody ( FIG. 4). These complexes are to be optically detected, their arrangement is subsequently read out and verified analogously to Example 1.
Fig. 1 schematische Darstellung eines erfindungsgemäßen Nachweises einer Bindungsreaktion eines Sensormoleküls (1) (hier: eines Antikörpers) an sein Antigen (2), welches an einen Träger (3) gebunden ist. Ein am Sensormolekül (1) befestigtes Kolloidgoldpartikel von 1 nm mittlerem Durchmesser (4) führt zur Abscheidung eines Silberkörnchens (5). Fig. 1 shows a schematic representation of a document according to the invention a binding reaction of a sensor molecule (1) (in this case an antibody) to its antigen (2), which is bound to a support (3). A colloidal gold particle of 1 nm average diameter ( 4 ) attached to the sensor molecule ( 1 ) leads to the deposition of a silver grain ( 5 ).
Fig. 2 Bild von feinen Linien im Mikrometerbereich, denen eine Antikörper-Antigen Reaktion mit nachgeschalteter Silberabscheidung nach Fig. 1 zugrunde liegt. Als Antigen wurde dabei Kaninchen-Immunglobulin verwendet, als Nachweisagens wurde ein Ziegenantikörper gegen Kaninchen-Immunglobulin eingesetzt, welcher an kolloidale Goldpartikel gekoppelt ist. Die Abscheidung der detektierbaren Struktur erfolgte durch Silberpräzipitation. A: mit einem CD-Lesekopf aufgenommenes Analogbild; B: bereits im Lesekopf des Gerätes kann in vorteilhafter Ausführung ein Binärsignal generiert werden; C: analoge Bildzeile aus A, gekennzeichnet durch die waagerecht, gestrichelte Linie in A; D: binäres Signal derselben Bildzeile, gebildet vermittels eines Schwellenkriteriums im Analogsignal, gekennzeichnet durch die waagerechte Linie in C. Fig. 2 image of fine lines in the micrometer range, which is based on an antibody-antigen reaction with downstream silver deposition according to Fig. 1. Rabbit immunoglobulin was used as the antigen, and a goat antibody against rabbit immunoglobulin was used as the detection agent, which antibody is coupled to colloidal gold particles. The detectable structure was deposited by silver precipitation. A: Analog image taken with a CD reading head; B: In an advantageous embodiment, a binary signal can already be generated in the read head of the device; C: Analog image line from A, characterized by the horizontal, dashed line in A; D: binary signal of the same image line, formed by means of a threshold criterion in the analog signal, characterized by the horizontal line in C.
Fig. 3 Beispiel eines Nachweises einer DNA-Hybridisierung an einem DNA-Array mit Hilfe des erfindungsgemäßen Mittels. Dabei wird Streptavidin (6) an einen Träger (3) gebunden. Unspezifische Bindestellen werden durch eine Blocksubstanz (7) abgesättigt. An Biotin (8) gekoppelte Nukleinsäuremoleküle (9) werden gebunden. Danach wird eine Probe, enthaltend ein mit einem "Tag"(10) versehenes Sensor- Oligonukleotid (11), zugegeben. Dessen Bindung wird schließlich durch ein mit einem das Tag (10) bindenden Tag-Bindemolekül (12) beschichtetes Kolloidgoldpartikel (13) nachgewiesen, welches zu einer Ablagerung eines Metalles (14) führt. Fig. 3 example of a detection of a DNA hybridization to a DNA array using the agent of the invention. Streptavidin ( 6 ) is bound to a support ( 3 ). Non-specific binding sites are saturated by a block substance ( 7 ). Nucleic acid molecules ( 9 ) coupled to biotin ( 8 ) are bound. A sample containing a sensor oligonucleotide ( 11 ) provided with a "tag" ( 10 ) is then added. Its binding is finally detected by a colloidal gold particle ( 13 ) coated with a tag binding molecule ( 12 ) that binds the tag ( 10 ), which leads to a deposition of a metal ( 14 ).
Fig. 4 Komponenten einer detektierbaren Struktur nach Beispiel 2. Ein auf einen Träger (3) aufgebrachter Rezeptor (15) bindet einen Liganden (16), welcher an ein Hapten, hier: Biotin (17), gekoppelt ist. Nach Zugabe einer Mischung aus Streptavidin (18) und biotinyliertem Ferritin (19) bilden sich detektierbare Molekülkomplexe (20). Fig. 4 is a detectable component structure according to Example 2. A on a carrier (3) applied receptor (15) binds a ligand (16) attached to a hapten, in this case biotin (17) is coupled. After adding a mixture of streptavidin ( 18 ) and biotinylated ferritin ( 19 ), detectable molecular complexes ( 20 ) are formed.
Claims (19)
Priority Applications (6)
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DE10127220A DE10127220A1 (en) | 2001-05-23 | 2001-05-23 | Carrier for analyzing chemical and biological samples, e.g. for diagnosis, on which binding reaction produces structure that can be read by optical methods |
AU2002317672A AU2002317672A1 (en) | 2001-05-23 | 2002-05-23 | Method for the biochemical detection of analytes |
EP02747165A EP1415261A2 (en) | 2001-05-23 | 2002-05-23 | Method for the biochemical detection of analytes |
DE10292255T DE10292255D2 (en) | 2001-05-23 | 2002-05-23 | Method for biochemical detection of analytes |
PCT/DE2002/001875 WO2002095651A2 (en) | 2001-05-23 | 2002-05-23 | Method for the biochemical detection of analytes |
US10/478,412 US20050026148A1 (en) | 2001-05-23 | 2002-05-23 | Method for the biochemical detection of analytes |
Applications Claiming Priority (1)
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DE10127220A DE10127220A1 (en) | 2001-05-23 | 2001-05-23 | Carrier for analyzing chemical and biological samples, e.g. for diagnosis, on which binding reaction produces structure that can be read by optical methods |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998001533A1 (en) * | 1996-07-08 | 1998-01-15 | Burstein Laboratories, Inc. | Cleavable signal element device and method |
WO1999035499A1 (en) * | 1997-12-30 | 1999-07-15 | Remacle Jose | Method comprising capture molecule fixed on disc surface |
WO2000026677A1 (en) * | 1998-10-30 | 2000-05-11 | Burstein Laboratories, Inc. | Trackable optical discs with concurrently readable analyte material |
-
2001
- 2001-05-23 DE DE10127220A patent/DE10127220A1/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998001533A1 (en) * | 1996-07-08 | 1998-01-15 | Burstein Laboratories, Inc. | Cleavable signal element device and method |
WO1999035499A1 (en) * | 1997-12-30 | 1999-07-15 | Remacle Jose | Method comprising capture molecule fixed on disc surface |
WO2000026677A1 (en) * | 1998-10-30 | 2000-05-11 | Burstein Laboratories, Inc. | Trackable optical discs with concurrently readable analyte material |
Non-Patent Citations (1)
Title |
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KIDO,Horacio, et.al.: Disc-based immunoassay microarrays. In: Analytica Chimica Acta 411, 2000, S.1-11 * |
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