WO2003083905A2 - Novel integrated circuit chip for bioassays_____________________ - Google Patents
Novel integrated circuit chip for bioassays_____________________ Download PDFInfo
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- WO2003083905A2 WO2003083905A2 PCT/US2003/009223 US0309223W WO03083905A2 WO 2003083905 A2 WO2003083905 A2 WO 2003083905A2 US 0309223 W US0309223 W US 0309223W WO 03083905 A2 WO03083905 A2 WO 03083905A2
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- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06K—GRAPHICAL DATA READING; PRESENTATION OF DATA; RECORD CARRIERS; HANDLING RECORD CARRIERS
- G06K19/00—Record carriers for use with machines and with at least a part designed to carry digital markings
- G06K19/06—Record carriers for use with machines and with at least a part designed to carry digital markings characterised by the kind of the digital marking, e.g. shape, nature, code
- G06K19/067—Record carriers with conductive marks, printed circuits or semiconductor circuit elements, e.g. credit or identity cards also with resonating or responding marks without active components
- G06K19/07—Record carriers with conductive marks, printed circuits or semiconductor circuit elements, e.g. credit or identity cards also with resonating or responding marks without active components with integrated circuit chips
- G06K19/0716—Record carriers with conductive marks, printed circuits or semiconductor circuit elements, e.g. credit or identity cards also with resonating or responding marks without active components with integrated circuit chips at least one of the integrated circuit chips comprising a sensor or an interface to a sensor
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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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54386—Analytical elements
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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
- B01J2219/00497—Features relating to the solid phase supports
- B01J2219/005—Beads
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00277—Apparatus
- B01J2219/0054—Means for coding or tagging the apparatus or the reagents
- B01J2219/00565—Electromagnetic means
- B01J2219/00567—Transponder chips
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2219/00572—Chemical means
- B01J2219/00576—Chemical means fluorophore
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- 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
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- 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
- B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00623—Immobilisation or binding
- B01J2219/00626—Covalent
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- 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
- B01J2219/00623—Immobilisation or binding
- B01J2219/0063—Other, e.g. van der Waals forces, hydrogen bonding
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- B01J2219/00632—Introduction of reactive groups to the surface
- B01J2219/00637—Introduction of reactive groups to the surface by coating it with another layer
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- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00702—Processes involving means for analysing and characterising the products
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- B—PERFORMING OPERATIONS; TRANSPORTING
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
- Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
Definitions
- the invention is directed to novel IC chips containing substances used particularly in bioassays.
- the invention is directed to a novel use of an integrated circuit chip comprising a transponder encoded with information that is transmitted to a receiver in response to a radio signal in assaying a biological molecule.
- the invention is directed to assay methods and kits using these chips.
- Solid phase assays have been used to determine the presence and/or amount of substances such as proteins, peptides, carbohydrates, lipids and small molecules in a variety of biological samples (e.g., blood, serum, urine, saliva, tissue homogenates).
- the solid phase is used to separate molecules that bind to the solid phase from those that do not.
- Small beads are generally used as the solid phase to capture the analyte.
- multiplex assay it is difficult to perform a multiplicity of assays in a single sample at about the same time (multiplex assay).
- transponders associated with the solid phase beads to index the particles constituting the solid phase (see, for example, U.S. Patent No. 5,641,634, WO 97/20074).
- a diagrammatic representation of the system for use in detecting DNA sequences is disclosed is shown at http://www.pharmaseq.com/illustration.html.
- the transponder has a photovoltaic cell as its power resource through light or laser (column 5, line 50-65.; Fig 6). A laser is used to activate the light cell and supply the power. The transponder then emits a radio signal. This can be a weakness.
- Radiotags or transponders have also been used in combinatorial chemical approaches (reviewed in Service, 1995, Science 270:577).
- a radiofrequency (RF) encodable microchip is coupled with a polypropylene capsule of derivatized polystyrene resin so that a radioscanner registers the identity of a capsule and the contents of each beaker it enters (see, U.S. Patent Nos. 5,777,045 and
- the data obtained is actually stored on the microchip itself, using a transmitter that writes the information to the chip (see, for example, U.S. Patent Nos. 5,741,462, 5,751,629, 5,874,214, 5,925,562 and 6,025,129).
- the data is not uploaded to the computer until the run is complete. Therefore the system disclosed comprises a recording device and storage unit. It has been suggested that this system may also be used in immunoassays and hybridization reactions and to detect macromolecules, to identify receptor bound ligands, and cell sorting.
- a radio frequency identification system (RFID) carries information in suitable transponders that contain tags having information. The information on the tags is retrieved in response to a radio signal by machine-readable means (for a review of RFID, see www.aimglobal.org)
- a basic RFID system contains the following three components:
- the antenna which acts as a conduit between the transponder and receiver, emits radio signals to activate the tag on the transponder and read and write information to it.
- the transponder contains a tag, which responds to a signal for the information it generated. It should be noted that the terms “transponder” and “tag” are used interchangeably in the art.
- the transponder or tag logic may be read-only or random access.
- the receiver receives the information transmitted by the transponder and decodes it.
- the information may further be processed.
- RFID can be used in transportation and logistics, manufacturing and processing security, animal tagging, waste management, time and attendance, postal tracking airline baggage reconciliation and road toll management.
- the invention is directed to an integrated circuit chip for use in an assay of a substance comprising:
- transponder encoded with information which may include but is not limited to data or binary code which is transmitted to a receiver in response to a radio signal and (b) at least one substance attached to said transponder.
- the chip of the present invention further comprises at least one metal option.
- a metal option is a wire that links circuits together and in a specific embodiment, connects to highest or lowest power.
- the invention is also directed to a method for obtaining said integrated circuit chip.
- the invention is further directed to a system for assaying a substance comprising
- a radio frequency identification system comprising: (i) an antenna which emits a radio signal; (ii) a transponder having a read-only tag, wherein said tag contains unique information and said transponder activated by said antenna of (ii) and (iii) receiver which receives and decodes said information and
- the system comprises (a) a radio frequency identification system comprising: (i) an antenna which emits a radio signal; (ii) a transponder having a read-only tag, wherein said tag contains binary code and said transponder activated by said antenna of (i) and (iii) receiver which receives and decodes said information and (b) at least one substance attached to said transponder.
- a radio frequency identification system comprising: (i) an antenna which emits a radio signal; (ii) a transponder having a read-only tag, wherein said tag contains binary code and said transponder activated by said antenna of (i) and (iii) receiver which receives and decodes said information and (b) at least one substance attached to said transponder.
- the chip of the present invention further comprises an electrode.
- the substance is attached to the chip so that it is contacted with the electrode.
- the substance may contain an electrochemiluminescent moiety.
- the invention is further directed to methods for using said integrated circuit for detecting binding of a first substance to a second substance comprising
- step (b) analyzing the incubated mixture of step (a) to detect binding of said first substance and said second substance and
- the substance attached to said transponder may contain a detectable moiety; alternatively, the second substance may contain a detectable moiety. In yet another embodiment, a detectable moiety may be added to the incubated mixture of step (a). In an even further embodiment, the substance attached to the transponder is a biological substance.
- the invention is directed to a multiplex assay using the chips of the present invention comprising:
- step (c) analyzing the incubated mixture of step (b) to detect binding of said substance to said chips and
- a different substance is attached to each chip.
- the substance is a biological sample.
- the substance contains a detectable moiety.
- the method of the present invention may be used to detect a pathogen on a cell or diagnose a disease of disorder; create a patient profile, determine ingredients in herbs and/or for drug screening. The invention is further directed to a kit for assaying a biological molecule comprising
- a transponder comprising a tag with information which is transmitted to a receiver in response to a radio signal
- a detectable moiety and/or a substance library (e.g., phage display library, a DNA library, a natural products library).
- a substance library e.g., phage display library, a DNA library, a natural products library.
- the invention is further directed to a kit for assaying a biological molecule comprising
- radiofrequency identification system comprising: (i) an antenna which emits a radio signal; (ii) a transponder having a read-only tag, wherein said tag contains unique information and said transponder activated by said antenna of (i) and (iii) receiver which receives and decodes said information and
- FIGURES Figure 1 shows a diagram of an RF ID system with "metal option”.
- Figure 2 shows a close up of a specific embodiment of the "metal option" component. Each metal line has two metal options, 0 or 1. Therefore, 14 Bits means fourteen metal options (0 or 1). The combination of all 14 metal lines series is 2 14 ID.
- Figure 3 shows RFID (metal option) with electrode for ECL.
- Figure 4 depicts the procedure used with an ECL labeled substance 13 and
- Figure 5 shows RF system with electrode only and without metal option ID.
- Figure 6 depicts the procedure used with ECL labeled substance 13 with a chip only containing an electrode.
- Figure 7 shows use of fluorophore labeled substance with RFID chips.
- Figure 8 shows the procedure used to generate and analyze information using the IC chips of the present invention.
- Figure 9 shows the use of SPR technology with RFID chips.
- Figure 10 shows the use of fluorophore labeled antibody with cell on RFID chip without the electrode.
- Figure 11 shows a specific embodiment where the primary antibody is nonlabeled.
- Figure 12 shows RF ID probe system. DETAILED DESCRIPTION OF THE INVENTION
- the IC chip of the present invention contains a transponder and a substance attached to said transponder.
- the substance may be attached to the chip of the present invention using procedures known in the art.
- the substance is covalently attached to the chip using a conjugating agent known in the art.
- a conjugating agent includes but is not limited to amino-alkyl silanes [e.g. n-octadecyltrimethoxy-silane (OTMS); n- octadecyltrichlorosilane (OTCS)] [Kleinfeld et al (1988) Neurosci, 8, 4098-4120; Mooney et al, (1996) Proc. Natl. Acad. Sci.
- aldehyde silanes where aldehydes react with primary amines on the proteins to form a Schiff s base linkage
- Macbeath et al (2000) Science 289, 1760-1757
- albumin-alkyl absorption [Hart et al, (1994) Electroanalysis 6, 617; Newman et al, (1992) Anal. Chim. Acta, 262, 13]
- photoresist technology with methyl- and amino-terminated silanes [Britland et al (1992) Biotechnol. Progr, 8, 155-160; Britland et al, (1992) Exp. Cell Res.
- One agent that can be used for non-specific, non-covalent attachment is poly-L- lysine.
- the target substance will be added to the poly-L-lysine treated or coated chip surface first.
- the non-specific, non-covalent bond will be formed between target substance and poly-L-lysine. This non-covalent bond will hold the target substance on the chip.
- This method can be used with various target substances, e.g. D ⁇ A, protein, and cell.
- the substance may be coated onto the chip.
- the chip is directly incubated in a solution containing the substance.
- the chip is then transferred to the blocking solution (e.g. BSA or casein) [Vogt et al, (1987) J. Immunol. Methods 101, 43-50] to fill the uncovered space on the surface of chip. ⁇ on-covalent bonds will be formed between the substance and surface of the chips.
- the amount of the substance in the coating can be adjusted, depending on the request and the concentration of the substance in the solution.
- the substance attached to the transponder may be a biological sample.
- the biological sample is a cell, subcellular component, organelle or tissue.
- the biological sample could also be nucleic acid and/or protein isolated from cell, tissue, urine and saliva.
- the substance attached to the transponder is a substance containing a non-radioactive detectable moiety, such as a whole cell, subcellular particle, virus, prion, viroid, lipid, fatty acid, nucleic acid, polysaccharide, protein, lipoprotein, lipopolysaccharide, glycoprotein, peptide, cellular metabolite, hormone, pharmacological agent, tranquilizer, barbiturate, alkaloid, steroid, vitamin, amino acid, sugar, non-biological polymer, synthetic organic molecule, organometallic molecule, inorganic molecule, biotin, avidin or streptavidin.
- a non-radioactive detectable moiety such as a whole cell, subcellular particle, virus, prion, viroid, lipid, fatty acid, nucleic acid, polysaccharide, protein, lipoprotein, lipopolysaccharide, glycoprotein, peptide, cellular metabolite, hormone, pharmacological agent, tranquilizer, barbi
- members of a DNA or phage display library may be attached to a plurality of transponders.
- the substance may also be an antibody; in a specific embodiment, the antibody is a monoclonal antibody.
- the substance may also be a receptor or a ligand.
- a ligand is a substance that binds to a receptor.
- the substance may be labeled with a nonradioactive detectable moiety such as a chromophore, fluorophore or luminescent agent.
- a nonradioactive detectable moiety such as a chromophore, fluorophore or luminescent agent.
- a chromogenic substrate is 5-bromo-4-chloro-3-indoyl phosphate.
- Luminescence occurs when a molecule in an electronically excited state relaxes to a lower energy state by the emission of a photon.
- the luminescent agent in one embodiment may be a chemiluminescent agent.
- chemiluminescence the excited state is generated as a result of a chemical reaction, such as lumisol and isoluminol.
- photoluminescence such as fluorescence and phosphorescence
- an electronically excited state is generated by the illumination of a molecule with an external light source.
- An example of bioluminescence is the enzyme, luciferase.
- electrochemiluminescence (ECL) the electronically excited state is generated upon exposure of the molecule (or a precursor molecule) to electrochemical energy in an appropriate surrounding chemical environment.
- ECL electrochemiluminescent agents
- electrochemiluminescent agents include but are not limited to metal cation-liquid complexes, substituted or unsubstituted polyaromatic molecules, mixed systems such as aryl derivatives of isobenzofurans and indoles.
- the electrochemiluminescent chemical moiety may comprise, in a specific embodiment, a metal-containing organic compound wherein the metal is selected from the group consisting of ruthenium, osmium, rhenium, iridium, rhodium, platinum, palladium, molybdenum, technetium and tungsten.
- BIA technology may be used to detect the binding of a sample to the chip of the present invention. This technology uses surface plasmon resonance (SPR) technology [BIACORE AB, Sweden]. The principle of SPR has been described by Karlsson et al, (2000) 278, 1-13 and BIACORE AB [http://www.biacore.com/biomol/principle.shtml].
- the IC chip of the present invention is a component of an RFID system.
- Each transponder or tag is separately encoded with an index number to identify the substance attached to the IC chip.
- the chip may be a bead or rectangular in shape.
- the size may be in the range of about 200 ⁇ 1500 ( ⁇ m) and is preferably about 1500 ⁇ m.
- an antenna is attached to said transponder and the antenna may be linear or planar.
- the invention includes but is not limited to the following three IC chips:
- RF with "metal option” for ID without ECL application see Figures 1 and 2).
- a "metal option” is a metal wire that connects to highest power (VDD) or lowest power (GND: ground).
- VDD highest power
- GND ground
- ROM, RAM and Flash are not needed.
- the metal option ID logic 1 creates an index ID by a metal photo mask process.
- a photomask is a special film for a semiconductor process.
- Modulator 2 converts the ID binary number to an RF band. The signal will transmit out to the air through the Analog Front End. The Capacitor and Oscillator will be inside those blocks.
- the Analog font end 3 is an up-converter circuit basically to up-convert the binary ID to high frequency.
- Antenna and Energy Gather Circuit 4 is for receiving and sending the radiofrequency energy in and out the chip. Internal Block 5 and Pins 6 for testing or other reserved function.
- the chip may optionally contain a layer 7. SiO 2 protects most of area of IC and only the pins areas 6 are exposed to air. It can be added by the IC manufacturer but is not necessary.
- RF with "metal option” for ID with ECL application see Figures 3 and 4
- This embodiment also comprises an electrode 8.
- Both metal option ID and electrode are on the same current and use the same electricity source.
- the substance has contact with the electrode 8 on the chip to let the ECL labeled substance bind.
- the electricity will pass through the ECL labeled substance and emit for example, the wavelength at 600-620 nm for ECL Ru substrate.
- Both RF ID and ECL signal can be detected at the same time. Alternatively, they can be detected separately that is ECL signal first, then RF ID with two inputs of radiofrequency.
- the IC chip of the present invention will use the electricity ( ⁇ 3V) generated by RF to power the ECL conjugated target 13 when it binds to the substance 9 to an electrode on said chip (see Figure 4).
- This technology involves two components: the ECL-label, such as Tris (2,2' - bipyridine) ruthenium (Ru) that is coupled to a detection probe (chemical, DNA, protein, and drugs), and a substance that is oxidized, such as tripropylamine (TPA), present in the reaction buffer.
- the ECL-label such as Tris (2,2' - bipyridine) ruthenium (Ru) that is coupled to a detection probe (chemical, DNA, protein, and drugs)
- a substance that is oxidized such as tripropylamine (TPA)
- This form returns to its ground state with emission of a photon at wavelength at 620 nm and long excited state lifetime ( ⁇ 600ns) at room temperature.
- the amount of light produced is directly proportional to the amount of ECL label bound on the IC chip of the present invention and can be captured by the light detection systems 11 (e.g. photo detector, camera, microscope... etc.).
- the production of light indicates the ECL conjugated target binds to the chip powered by RF.
- Several commercial ECL reader systems are available (e.g. NucleiSens Reader from Organon Teknika company; IGEN).
- Figure 5 depicts the Vincogen chip without metal option ID.
- Modulator 2 makes the ID binary number to RF band.
- a Capacitor and Oscillator may also be inside the modulator.
- Analog font end 3 is an up-converter circuit basically to up-convert the binary ID to high frequency.
- the Antenna and Energy Gather Circuit 4 is used for receiving and sending the radiofrequency energy in and out the chip.
- Internal Block 5 and Pins 6 is used for testing or other reserved functions. It optionally contains a layer.
- SiO 2 protects most areas of IC and the I/O pins 6 and 8 area will expose to air. It can be added by the IC manufacture.
- Electrode 8 is the also the pins device.
- the pin device can provide very short time current for outside material.
- the chip of the present invention will use the electricity ( ⁇ 3V) generated by RF to power the ECL conjugated target 13 when it binds to the substance 9 on the electrode present on the chip.
- the light will produce during the electrochemical reaction of ECL and electricity and capture by the light detective system (e.g. photo detector, camera, microscope.. etc.).
- the light reaction indicates that the ECL conjugated target bound to the substance on the chip powered by RF.
- the IC chip of the present invention is a part of a system comprising a radio frequency identification system comprising: (i) an antenna which emits a radio signal; (ii) a transponder having a read-only tag, wherein said tag contains unique information and said transponder activated by said antenna of (i) and (iii) receiver which receives and decodes said information.
- the information contains binary code.
- the IC chip of the present invention can be used to detect the binding of a substance to a sample.
- the IC chip 9 of the present invention is contacted with a substance to determine whether this substance binds to the substance present on the IC chip.
- the substance present on the IC chip contains a detectable moiety.
- the substance that is contacted with the IC chip contains the detectable moiety (see Figure 7).
- the substance is a fluorophore labeled substance 12.
- a laser light and scanning device detects the fluorophore labeled substance and an RF ID reader 11 identifies the attached substance 9.
- the detectable moiety is added after the chip is contacted with the substance.
- an IC chip may contain an antibody that is bound to a transponder. The antibody is incubated with antigen in, for example, a vessel, to obtain a reaction mixture. A second fluorescent or ECL -labeled antibody that binds to antigen is added to the mixture. The IC chips are then washed to remove any unbound components and reagents. The labeled antibody is detected with a fluorometer or ECL reader to identify those chips that have antigen bound.
- the bound unlabeled antibody can also be detected with BIA label-free, surface plasmon resonance (SPR) technology [Karlsson et al, (2000) 278, 1-13; BIACORE AB, Sweden]. These chips are decoded using a receiver.
- SPR surface plasmon resonance
- the receiver 11 is a transceiver, which can transmit power to the RFID IC chip of the present invention through radiofrequency and receive ID from antenna and demodulate the ID from RF signal wireless. The ID can then send information to a PC or other post-processing unit 19.
- the assay of the present invention may, for example, be used to create the disease disorder protein profile in a patient's sample (blood, urine, saliva, sweat....etc.), and use it to diagnose a disorder.
- a sample from a patient may be screened with a panel of markers, for example, from a random peptide or antibody phage display chip library.
- the random peptide or antibody display library [Marks et al, (1991) J. Mol. Biol. 222, 581-597; Hoogenboom et al, (1992), J. Mol. Biol, 227, 381-388; Griffiths et al, (1993) EMBO J, 12, 725-734; Haard et al, (1999) J. Biol. Chem.
- the antibody or random peptide (12-15mer) phage display library can create more than 10 7 -10 9 individual clones enough to cover all possible epitopes.
- the random peptide or antibody IC chip display library 9 will screen the patient and normal person's serum 10. The patient will express several unique "disease associated proteins (antigens)" in the serum. Since the display library can cover 10 7 -10 9 individual epitopes, it should detect these unique “disease associated proteins (antigens)" in the serum to create the real profile and surrogate markers through binding of 9 and 10.
- the primary screening procedure can be applied with a mixed IC chip library 9 containing different 1000 phage clones on each individual chip.
- a chip library containing 10 4 -10 5 chips for the first screening can be obtained from 10 7 -10 9 individual clones.
- the screening procedure involves the incubation of a chip library with the sample for a period of e.g., 1 hr. The unbound sample is washed away thoroughly with the washing buffer and the bound chip is identified with BIA label-free, surface plasmon resonance (SPR) technology [Karlsson et al, (2000) 278, 1-13; BIACORE AB, Sweden]. The binding status of the chip can be detected and confirmed by SPR directly.
- the reader 11 can identify the RF ID.
- This process may be repeated in the mixture IC chip library with only one clone on each individual chip to determine the real clone or chip that can interact with patient's serum only. All of the positive clones' IDs will form the "expression profile of surrogate markers" for this disease may be analyzed by PC or other post-processing unit. This profile can be used as a diagnosis for disease progression, the new drug targets, or for a vaccine.
- a multiplex assay is conducted in a similar manner. Two or more IC chips of the present invention are placed in each assay vessel to detect two or more substances simultaneously. The IC chips are divided into two or more classes, with each class having a distinct index number.
- the multiplex assay of the present invention may be used to 1) identify an unknown antagonist or agonist from phage display library on chip; 2) identify an unknown antagonist or agonist from monoclonal display library on chip; 3) identify an unknown antagonist or agonist from the gene-expression IC chip library; 4) identify the unknown antagonist or agonist from the gene-expression IC chip library using a mixture of substances (e.g. extract of Herbs). Assays of gene expression libraries will primarily focus on promoter regions.
- the transponder used in the method of the present invention along with a nonradioactively labeled substance may be packaged as a kit.
- a kit An example of such a substance is a labeled antibody.
- the kit of the present invention may comprise the transponder and a detectable moiety, such a luminescent moiety, an enzyme, such as alkaline phosphatase and substrate.
- the kit may further comprise a standard.
- the kit of the present invention may also comprise a standard compound SPECIFIC EMBODIMENTS
- the IC Chip is small and designed with radio reflect (RF) ID that can be used in high throughput drug screening, real-time live cells monitoring processes, and gene expression profiles with different materials (DNA, proteins, chemicals, and cells) on it.
- RF radio reflect
- the chip can be embedded into different shapes (e.g., bead, square) made of SiO 2 .
- Target cells are cultured or attached on the surface of transponders/chips (bead shape), and then are treated with reagent for designated period of time.
- the surface of the chip is treated with poly-L-lysine.
- the reagents include but are not limited to drugs, chemicals, biological substances (e.g., fluorescent protein, cytokines, endocrines), pathogens (e.g., virus), and toxins.
- the chips are separated and recovered.
- the specific fluorescent reagents e.g., fluorescent probe, fluorescent protein
- the unbound fluorescent reagent is washed away.
- a cell sorter, reader, and multimode microscopy is used to measure the intensity and localization of fluorescence reagents for various biological processes occurring in live cells, such as the presence of cell surface antigens (e.g., MHC antigen, HIV gpl20, ...etc.), metabolic processes (e.g., changes in mitochondrial potential [Waggoner A.S. (1985) "Dye probes of cell, organelle, and vesicle membrane potentials" In The Enzymes of Biological Membranes, 2 nd Ed, Edited by Martonosi A. Plenum; pp.
- cell surface antigens e.g., MHC antigen, HIV gpl20, ...etc.
- metabolic processes e.g., changes in mitochondrial potential [Waggoner A.S. (1985) "Dye probes of cell, organelle, and vesicle membrane potentials" In The Enzymes of Biological Membranes, 2 nd Ed, Edited by Mart
- membrane receptors e.g., cytokine receptor, endocrine receptor number change
- gene activity e.g., transcription factors, translation factors, protein expression
- cell cycle identification e.g., GO, Gl, M, S phases time curve
- cellular components such as cellular organelles, cytoskeleton [Dailey etal, (1999) Methods 18, 222-230; Dai et al, (2000) J. Cell Biol.
- the recovered cell sample can also be used for further molecular analysis (e.g. PCR) or protein analysis (e.g. HPLC, GC/MS) by end-user.
- molecular analysis e.g. PCR
- protein analysis e.g. HPLC, GC/MS
- Target cells are cultured on the surface of IC chips, then different RF ID of cultured cells are treated with different reagents or different treatments.
- the HTV infected cells are on one ID chip and HIV na ⁇ ' ve cells are on different ID chips.
- different concentrations of HIV infected cells may be cultured on different chips; each chip has its own ID. All chips are cultured in the medium with or without reagents (e.g. drugs) and the gene expression of cellular proteins (e.g. chemokine receptor) and viral protein (e.g. HIV gpl20) is monitored.
- reagents e.g. drugs
- the HTV dynamic cycle in HTV secondary infected na ⁇ ve cells is studied.
- Cell samples are taken every hour to measure the HTV gpl60 on the cell surface for 24 hours.
- the RF receiver chooses the chip to include all the different concentration or strains infected cells and na ⁇ ve cells through their unique RF ID.
- the chosen chips are then analyzed by anti-HIV gpl60 (or other studied target protein) antibody conjugated or with fluorescence probe.
- the antibody is incubated with chips for a period of time and washed thoroughly to remove the unbound antibody.
- the fluorescence reader is used to determine flurorescence intensity over a 24 hour period.
- the whole experiment provides a whole picture of the dynamic time curve of interaction of cell response as well as viral expression between different strains in the same condition.
- the chips can also be used to perform mixed cell type co-culture. This is very important to evaluate the cytokines, promoter, and cellular biological interactions between different cell types or treatments.
- the different cell types of cells are cultured on the surface of transponders with different RF ID, then treated with reagents. During different time points, the transponders are recovered and separated by cell sorter to measure fluorescence for the function, characteristic and/or marker to be assayed from the live cells. The different RF ID of cultured cells can then be decoded. The analysis gives the time curve of biological processes under co-cultured conditions.
- HTV infected cells e.g. macrophage tropism or lymphocytes tropism
- different concentrations of anti-HTV drugs or the different combination of anti-HTV drugs may be treated with different concentrations of anti-HTV drugs or the different combination of anti-HTV drugs (cocktail treatment).
- the different kind of HTV infected cell will have a unique ID on the chip.
- the infected cell may be screened with anti-gpl60 or other related antibody conjugated with fluorescence probe as described above.
- HTV susceptible cells can be identified through HTV antigens on the cell surface. Mixed cells on the chip are then treated with anti-HTV cocktail drugs or drug candidates to identify the efficacy and model system for HTV treatment.
- an HTV biochip library can detect multi-HTV proteins (antigens) and other opportunistic pathogens' antigens in one assay.
- HTV proteins are Gag (pl7, p24, p7), Protease (pl5), Reverse Transcriptase (p66, p51), Integrase, Env (gpl60, gpl20, gp41), Tat (pl6/pl4), Rev (pl9), Vif (p23), Vpr, Vpu, ⁇ ef, Tev.
- the HIV wild type proteins and mutants' proteins are being assembled in phage expression display library or by synthesis in vitro (E. coli, yeast, other eukaryotic cells). It will also include all possible mutants of HIV proteins in this display library. All proteins will be attached on the surface of RF chip to form chip library as described previously.
- the sample from the patient is incubated with the chip library for a time period to let human anti-HTV antibodies to bind to the viral protein on the chip.
- the unbound sample is thoroughly washed with washing buffer and removed from the chip.
- the 2 nd anti-human antibody conjugated with fluorescence will be added to incubate with chip for a time period.
- the unbound anti-human antibody conjugated with fluorescence will be removed by washing buffer again.
- a laser light and scanning device detects the fluorophore labeled antibody and an RFTD reader.
- the SPR technology can also be applied here for without using 2 nd anti-human antibody conjugated with fluorescence.
- Each protein is attached on the surface of individual IC chip to create the display IC chip HIV library for screening purpose.
- the HTV patient's sample may be screened with this display chip library once a week to monitor the change of the HIV population. This will help patient, physician, and medical system to save cost on HIN health care and also benefit the patient to change the new combination of anti-HTV drugs therapy as early as possible. Most of all, the information of HIN mutants dynamic profile through the drug treatment will let to predict the HTN mutants even before these HTV drugs treatment. Then we can use this information for vaccine and new drugs development.
- the different target cells can be attached on different IC chips. Then all the cells can be treated or incubated with the drug candidate to observe the cytotoxicity in each cells under biological interaction conditions that mimic the real human physiological condition.
- Each IC chip with a different target protein contains a unique signal or number generated by the embedded IC.
- 2 14 16,384 kinds of IC Chips can be created to label different proteins or genes. This unique signal or ID can be used to identify which gene or protein is on the IC Chip.
- All proteins from human, bacteria, virus, and other microorganisms for potential drug targets can be expressed in vitro or phage display system and conjugated onto chips to create a drug-screening library.
- the drug-screening library can constitute 15,000 different kinds of proteins with different identification of IC chips in it.
- the sequence of the human Genome [Venter et al, (2001) Science 291, 1304-1351] has made the gene information available.
- the gene expression IC chip libraries from different organisms are constructed by protein expression technology or phage display system and each protein is attached to on single IC chip 9.
- Substance protein, antibody, ribozyme, toxin
- Substance without label or labeled by fluorescence directly, by fluorescence-conjugated antibody, or by different RF ID 17
- Figure 12 is incubated with the drug-screening library for 2 hours at 4°C.
- the library is then washed with 3 times of washing buffer (e.g. BSA-detergents) to remove free substance.
- washing buffer e.g. BSA-detergents
- the sample can be treated with protein cross-link reagents available commercially to create the covalent link between substance 9 and 17. Then reader 11 can determine both IDs.
- the drug-screening library bound with fluorescence labeled substance is sorted and recovered by the sorter.
- the SPR technology will be used to screen and recover the chemical-bound chip if no-labeled substance is used.
- the recovered chips can be decoded through its specific embedded IC number and a specific protein can be identified.
- the bound substance also can be analyzed for its identity (e.g GC/MS, HPLC).
- the identified protein on the chip that can bind to drug will be the candidate for further analysis.
- liver function of patients with chronic hepatitis B and acute exacerbation can be recovered due to the regeneration of hepatocytes by Ganoderma [Phounsavan, Say Fone, (1991) The 5 th International Conference on Immunopharmacology, Tampa, Florida, USA. Abstracts, p. 52].
- Gene expression IC chip libraries from humans are used to screen the Ganoderma extract.
- the screening procedure is similar to those given above. Briefly, the Ganoderma extract is incubated with the human gene expression RF IC chip libraries for a period of time to let Ganoderma ingredients bind to the human gene expression RF IC chip library.
- the bound chips can be detected by SPR technology due to unlabeled probe.
- the specific gene can be identified through its unique RF ID immediately.
- the bound ingredients from Ganoderma can be analyzed and purified later as a new drug candidate. Determining Ingredients in Herbs
- a phage display chip library is used to set up the ingredient profile of target herbs. This profile of ingredients of Herbs serves as an index to certify the efficacy of herbs. With this index profile, government, consumers, merchants will have a standard to judge the ingredients of the Herbs.
- the antibody or random peptide (12-15mer) phage display library can create more than 10 7 -10 9 individual clones enough to cover all possible binding possibility to all ingredients in herbs.
- the primary screening procedure will be applied to the IC chip library with 1000 different phage clones on each individual chip.
- a chip library containing 10 -10 5 chips for the first screening can be obtained from 10 7 -10 9 individual clones.
- the screening procedure is the incubation of chip library with sample for a period (1 hr). The unbound sample is washed away with the washing buffer thoroughly and identify the bound chip is identified with BIA label-free, surface plasmon resonance (SPR) technology [BIACORE AB, Sweden]. The binding status of the chip can be detected and confirmed by SPR directly.
- SPR surface plasmon resonance
- This process will be repeated in the mixed IC chip library with only one clone on each individual chip to determine the real clone or chip that can interact with patient's serum only.
- the combination of the positive ID of bound chips will be the index profile of the herbs in this case.
- the antibody display library from the positive chip can be used to make the antibody affinity column to purify the specific ingredients.
- Lymphoid hemocytes
- hemocytes gill cells from pregnant black tiger shrimp
- Penaeus monodon may be assayed to detect the presence of pathogens [Vargas et ⁇ l, (1998) Advances in Shrimp biotechnology, 5 th Asian Fisheries Forum, ppl61-167].
- pathogens There are more than 14 viral pathogens to infect the black tiger shrimp.
- the most serious viral pathogen is White Spot Syndrome Virus (WSSV) (Gene Bank #NC_003225).
- WSSV White Spot Syndrome Virus
- the presence of the pathogen's antigen on cell surface is detected using an antibody to the pathogen's specific antigen. Diagrams of general procedures used are depicted in Figures 10 and 11.
- the cells 14 are attached and cultured on the IC chips used in the method of the present invention.
- Each chip with unique ID only attaches one shrimp's cells 14. These cells on the chip are incubated with fixing solution (e.g., tetraformaldehyde, ethanol) to fix all the proteins on the cell membrane first. Then it is contacted with antibody against the pathogen's specific antigen. The antibody is labeled 15 or alternatively, the mixture is incubated with a secondary labeled antibody 18 bound to the primary antibody 16. The chips are washed with washing buffer to remove unbound antibody and scanned for fluorescence-positive chips to identify infection of the virus in shrimp.
- the advantage of chip technology is that over 20,000 shrimp samples can be checked within 2 days with low cost than any conventional methods.
Abstract
Description
Claims
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CA002480434A CA2480434A1 (en) | 2002-03-26 | 2003-03-25 | Novel integrated circuit chip for bioassays |
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AU2003218403A AU2003218403A1 (en) | 2002-03-26 | 2003-03-25 | Novel integrated circuit chip for bioassays |
IL16415003A IL164150A0 (en) | 2002-03-26 | 2003-03-25 | Novel integrated circuit chip for bioassays |
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2003
- 2003-03-21 PE PE2003000281A patent/PE20040015A1/en not_active Application Discontinuation
- 2003-03-21 AR ARP030100999A patent/AR039102A1/en not_active Application Discontinuation
- 2003-03-25 AU AU2003218403A patent/AU2003218403A1/en not_active Abandoned
- 2003-03-25 EP EP03714402A patent/EP1495483A2/en not_active Withdrawn
- 2003-03-25 WO PCT/US2003/009223 patent/WO2003083905A2/en not_active Application Discontinuation
- 2003-03-25 US US10/396,269 patent/US7338811B2/en not_active Expired - Fee Related
- 2003-03-25 NZ NZ536162A patent/NZ536162A/en unknown
- 2003-03-25 CN CNA03806734XA patent/CN1643128A/en active Pending
- 2003-03-25 CA CA002480434A patent/CA2480434A1/en not_active Abandoned
- 2003-03-25 IL IL16415003A patent/IL164150A0/en unknown
- 2003-03-26 TW TW092106784A patent/TWI283746B/en not_active IP Right Cessation
-
2004
- 2004-10-22 ZA ZA200408597A patent/ZA200408597B/en unknown
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US5874214A (en) * | 1995-04-25 | 1999-02-23 | Irori | Remotely programmable matrices with memories |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7609155B2 (en) | 2005-08-25 | 2009-10-27 | Hinkamp Thomas J | System providing medical personnel with immediate critical data for emergency treatments |
EP1785494A1 (en) * | 2005-11-09 | 2007-05-16 | Seiko Epson Corporation | Application of biosensor chips |
US7972494B2 (en) | 2005-11-09 | 2011-07-05 | Seiko Epson Corporation | Application of biosensor chips |
WO2008094173A2 (en) * | 2006-06-23 | 2008-08-07 | Becton, Dickinson And Company | Radio frequency transponder assay |
WO2008094173A3 (en) * | 2006-06-23 | 2008-12-11 | Becton Dickinson Co | Radio frequency transponder assay |
Also Published As
Publication number | Publication date |
---|---|
TWI283746B (en) | 2007-07-11 |
CA2480434A1 (en) | 2003-10-09 |
WO2003083905A3 (en) | 2004-07-15 |
TW200306419A (en) | 2003-11-16 |
ZA200408597B (en) | 2006-06-28 |
PE20040015A1 (en) | 2004-01-29 |
IL164150A0 (en) | 2005-12-18 |
AR039102A1 (en) | 2005-02-09 |
US20040029109A1 (en) | 2004-02-12 |
EP1495483A2 (en) | 2005-01-12 |
CN1643128A (en) | 2005-07-20 |
NZ536162A (en) | 2006-11-30 |
AU2003218403A1 (en) | 2003-10-13 |
US7338811B2 (en) | 2008-03-04 |
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