Nanoelectrode arrays

Details Nanoelectrode arrays Nanoelectrode arrays

2000-04-12

2001-12-04

Tung, T. (Department: 1743)

Chemistry: electrical and wave energy

Apparatus

Electrolytic

C204S400000, C436S086000, C436S164000

Reexamination Certificate

active

06325904

ABSTRACT:

TECHNOLOGICAL FIELD
The present invention relates generally to methods and apparatus for detecting and characterizing single biological molecules in solution and, more specifically, to detect and characterize individual proteins, protein mixtures, deoxyribonucleic acid (DNA) or other molecules on a chip.
BACKGROUND OF THE INVENTION
The characterization and quantification of individual proteins or complex biological molecules is extremely important in fields as distant as medicine, forensics and the military. For example in medicine the presence and concentration of given proteins can be used for disease or pre-disease diagnoses. In the military given proteins can be used to signal the presence or absence of given pathogens in the environment which is extremely important for example in potential germ warfare situations.
The detection of individual proteins or molecules in biological samples is currently complex and generally requires sophisticated and bulky equipment.
Several technologies have recently been disclosed to characterize given biological molecules. In particular success has been achieved in high density DNA chips build by Affymetrix as originally described in PCT International Publication No. WO 90/15070.
U.S. Pat. No. 5,624,537, entitled “BIOSENSOR AND INTERFACE MEMBRANE”, describes a protein-receiving matrix and a single electrode.
U.S. Pat. No. 5,395,587, entitled “SURFACE PLASMON RESONANCE DETECTOR HAVING COLLECTOR FOR ELUTED LIGATE”, describes a system to measure immobilized ligands using a plasmon resonance detector.
U.S. Pat. No. 5,607,567 entitled “PROTAMINE-RESPONSIVE POLYMERIC MEMBRANE ELECTRODE”, describes a membrane electrode.
U.S. Pat. No. 5,328,847 entitled “THIN MEMBRANE SENSOR WITH BIOCHEMICAL SWITCH”, describes a biosensor with a specific recognition biomolecule.
U.S. Pat. No. 4,777,019 entitled “BIOSENSOR”, describes a biosensor for biological monomers.
U.S. Pat. No. 5,532,128, entitled “MULTI -SITE DETECTION APPARATUS”, describes test wells combined with electrodes to detect given biological molecules.
U.S. Pat. No. 4,983,510 entitled “ENZYMES IMMOBILIZED ON LATEX POLYMER PARTICLES FOR USE WITH AN AMINO ACID ELECTROSENSOR”, describes an electrosensor with a latex polymer trap.
U.S. Pat. No. 5,384,028 entitled “BIOSENSOR WITH A DATA MEMORY”, describes a membrane biosensor with a memory module.
U.S. Pat. No. 5,567,301 entitled “ANTIBODY COVALENTLY BOUND FILM IMMUNOBIOSENSOR”, describes an antibody biosensor.
U.S. Pat. No. 5,310,469 entitled “BIOSENSOR WITH A MEMBRANE CONTAINING BIOLOGICALLY ACTIVE MATERIAL”, describes a membrane biosensor.
U.S. Pat. No. 5,019,238 entitled “MEANS FOR QUANTITATIVE DETERMINATION OF ANALYTE IN LIQUIDS”, describes a means to sequentially test the ionic concentration of fluids.
U.S. Pat. No. 4,981,572 entitled “ELECTRODE UNIT AND PACKAGE FOR A BLOOD ANALYZER”, describes an electrode and apparatus to analyze blood.
U.S. Pat. No. 4,452,682 entitled “APPARATUS FOR MEASURING CLINICAL EMERGENCY CHECK ITEMS OF BLOOD”, describes an apparatus to measure multiple elements in blood.
U.S. Pat. No. 4,568,444 entitled “CHEMICAL SUBSTANCE MEASURING APPARATUS”, describes an electrode to quantify chemical substances in a solution.
U.S. Pat. No. 5,281,539 entitled “IMMUNOASSAY DEVICE FOR CONTINUOUS MONITORING”, describes a two step immunoassay device.
U.S. Pat. No. 5,192,507 entitled “RECEPTOR -BASED BIOSENSORS”, describes a biosensor based on a polymeric film to detect opiates.
U.S. Pat. No. 5,156,810 entitled “BIOSENSORS EMPLOYING ELECTRICAL, OPTICAL AND MECHANICAL SIGNALS”, describes a thin layer biosensor.
U.S. Pat. No. 5,494,831 entitled “ELECTROCHEMICAL IMMUNOSENSOR SYSTEM AND METHODS”, describes an immunologic biosensor.
U.S. Pat. No. 5,332,479 entitled “BIOSENSOR AND METHOD OF QUANTITATIVE ANALYSIS USING THE SAME”, describes an electrode based sensor with a biologically active receptor.
U.S. Pat. No. 5,582,697 entitled “BIOSENSOR, AND A METHOD AND A DEVICE FOR QUANTIFYING A SUBSTRATE IN A SAMPLE LIQUID USING THE SAME”, describes a biosensor based on the measure of reduction between a substrate and an oxidoreductase.
U.S. Pat. No. 4,908,112 entitled “SILICON SEMICONDUCTOR WAFER FOR ANALYZING MICRONIC BIOLOGICAL SAMPLES”, describes a micro capillary separation device with detector capabilities.
U.S. Pat. No. 5,409,583 entitled “METHOD FOR MEASURINGCONCENTRATIONS OF SUBSTRATES IN A SAMPLE LIQUID BY USING A BIOSENSOR”, describes a two step biosensor.
U.S. Statutory Invention H201 entitled “BIOSENSORS FROM MEMBRANE PROTEINS RECONSTITUTED IN POLYMERIZED LIPID BILAYERS”, describes a method for incorporating and using cell membrane proteins in biosensors.
The above described technologies are generally used for the detection of a single type or a few different types of molecules. None of these technologies are particularly adapted to allow a very large number of different types of proteins, protein variants or other biological molecules to be detected and quantified simultaneously on a single chip. Furthermore none of the prior art provides a suitable technology to directly build protein-specific electronic receptors on a chip without the use of any biological binding agents, synthetic probes or complex micro-structures such as test wells.
I disclose herein a novel, smaller, faster and more cost effective technique to detect, characterize and quantify individual proteins or other complex molecules on a chip. The technology described herein may also serve as a new method for DNA sequencing.
SUMMARY OF THE INVENTION
In one aspect the present invention provides a sensor which is capable of distinguishing between different molecular structures in a mixture. The device includes a substrate on which nanoscale binding sites in the form of multiple electrode clusters are fabricated. Each binding site includes nanometer scale points which extend above the surface of a substrate. These points are preferably nanoelectrodes which are spatially configured to provide a three-dimensional electrochemical binding profile which mimics a chemical binding site. Thus, the binding sites have selective affinity for a complementary binding site on a target molecule or for the target molecule itself.
In one aspect, the binding sites are arranged in an array on the substrate. In one aspect, the spatial and electrochemical profiles of each site of the array are identical and provide an assay for a single target molecule. In another aspect, regions of the nanoelectrode array carry grouped arrays of electronically and/or spatially distinct binding sites for simultaneous detection and quantification of several molecular species.
In still another aspect, the materials used for the electrodes and surrounding surfaces are selected based on preferred intrinsic electrical and chemical properties.
The nanoelectrode array may be included in a chamber which can retain fluids. Several arrays may be used in a single chamber and several different chambers may be used on a single chip.
In still another aspect, the nanoelectrode array and chamber are attached to at least one micro-fluidic delivery and separation system such as a micro-capillary which allows both the delivery and separation by size and electrical properties of the proteins or other molecules to be analyzed.
In another aspect a microcontroller or microprocessor is provided to analyze signals from the nanoelectrodes and/or to time and control the fluidics separation of the molecules or proteins.
In another aspect the chip with the nanoelectrode arrays is associated with an electronic temperature control system such as a thermoelectric device having a thermistor to vary the bonding kinetics or the electro-chemical affinity of the molecules with given nanoelectrodes, as well as the flow kinetics and separation of the molecules.
In another aspect the nanoelectrodes are interspaced in a linear microtube to sequence DNA.
Thus, it is an object of the present invention to provide a novel and rapid method to analyze small biological molecules in solution such as proteins and to sequence DNA by using semiconductor chip techno

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