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WO2003054931A1 - Procede et dispositif de nanodetection - Google Patents

Procede et dispositif de nanodetection Download PDF

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Publication number
WO2003054931A1
WO2003054931A1 PCT/US2002/039937 US0239937W WO03054931A1 WO 2003054931 A1 WO2003054931 A1 WO 2003054931A1 US 0239937 W US0239937 W US 0239937W WO 03054931 A1 WO03054931 A1 WO 03054931A1
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WIPO (PCT)
Prior art keywords
conducting
layer
layers
capacitive device
particles
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English (en)
Inventor
Jorma Virtanen
Jukka Virtanen
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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
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/22—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating capacitance
    • G01N27/221—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating capacitance by investigating the dielectric properties
    • 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

Definitions

  • the present invention relates to sensors, and more particularly, to nanosensors.
  • Nanosensors are small devices that are capable of detecting and responding to certain stimuli, wherein the sensing part is limited to a nanometer scale at least in one dimension.
  • Stimuli may include biological and chemical substances, displacement, force, mass, acoustic, thermal or electromagnetic. Most nanosensors measure observables (as defined below) such as concentration of a chemical, temperature, pressure or acceleration within a given frame of reference .
  • Nanosensors may be used for various bio-medical applications, for example, in-vivo, i.e. within the body; and/or intra-cellular; in-vitro, i.e. exterior to the body; disease detection; cellular repair; drug delivery; and measurement of pH and various minerals and/or elements, for example calcium, sodium, potassium, oxygen, glucose, and magnesium.
  • Nanosensors may also be used for detecting various types of vapors, for example methanol, ethanol, 2-propanol, acetone and toluene. Nanosensors may also be used for detecting airborne chemical/biological agents, for example, the anthrax bacteria. Nanosensors may also be used in communications and various industrial applications.
  • nanosensors may be produced using porous silicon using various well-known processes, for example, electrochemical etching, chemical vapor deposition and physical vapor deposition etc., and are discussed in the foregoing prior art patents and/or publications.
  • Nanowire One example of a nanosensor is a "nanowire” .
  • a description of nanowires is provided in "Hydrogen Sensors and Switches from Electrodeposited Palladium Mesowire Arrays” by Fre'de'ric Favier et . al , published in the September 21, 2001 volume 293 of the “Science Magazine” incorporated herein by reference, in its entirety, (available via the Internet online at “sciencemag.org”) .
  • Nanowires however, have drawbacks, including, difficulty in large scale fabrication, controlled patterning, potential instability and contact problems.
  • the present invention enhances miniaturization compared to the present state-of-the-art.
  • the sensor (s) of the present invention may be electronic, and may be easily interfaced with processing and display devices.
  • a capacitive device for measuring at least one electrical property is provided.
  • the device includes, a first conducting layer; a second conductive layer; wherein the first and second layers are operationally coupled to a measuring device for measuring at least one electrical property that depends on a physical and/or chemical factor; and a third layer separating the first and second conducting layer. A part of the first and/or second layer is covered with a recognition molecule.
  • the recognition molecule may be an antibody, antigen, oligonucleotide or a DNA fragment enzyme.
  • the third layer may function as an electric insulator, covered with a recognition molecule which may be an antibody, antigen, oligonucleotide or a DNA fragment enzyme .
  • a method for fabricating a capacitive device for measuring at least one electrical property includes, depositing at least a first conducting layer operationally coupled to a conducting first lead; depositing a first spacer layer; and depositing at least a second conducting layer operationally coupled to a second conducting lead, such that the second conducting layer is separated from the first conducting layer.
  • the first spacer layer may be insulating, semi -conducting or of die-electric material.
  • the method includes depositing similar or dissimilar materials on the first and second conducting layers for building a conductive bridge between the first and second conducting layers.
  • a capacitive device for sensing antigens includes a first conducting layer; and a second conducting layer separated by a spacer layer, wherein antibodies are placed on the spacer layer that attracts antigens .
  • a capacitive device for testing DNA is provided.
  • the device includes, a first conducting layer with at least a complementary probe; a second conducting layer with at least a second complementary probe; wherein the first and second conducting layers are separated from the first conducting layer by a spacer layer; plural soluble probes that are operationally coupled to the first and/or second complementary probe; and a conducting bridge formed by a DNA fragment that is operationally coupled to the first and second complementary probe .
  • the present invention provides a device with plural layered structures, in which alternating layers have different conductivity, for example, in one implementation half the layers are metallic and the other half are insulating. In general, these layers are called conducting and spacer layers.
  • the conducting layer may act as an electrode.
  • the layers may be rectangular, and of the same size. However, because of the adaptive nature of the present invention, other shapes and sizes are well within the scope of this invention.
  • two alternating layers do not overlap completely.
  • the layers form a pattern where one metallic layer may be shifted left and the other to right.
  • the insulating layers may be centered.
  • metallic layers to the right are electrically connected with each other.
  • the two metal layer packs are insulated from each other. Right and left sides are connected to electrical wires.
  • the device may operate as a parallel capacitor.
  • the capacitor has two edges that are not in direct physical contact with the wires.
  • One or both the edges may perform the sensing function.
  • the edges may be etched and coated with various sensing molecules. The purpose is to change the capacitance or to make the capacitor leaky, when the capacitor is exposed to either chemical or physical observable (s) .
  • any other electrical property such as voltage, impedance, conductance, current, or phase shift, may be measured.
  • the present invention allows an easy and low cost fabrication of nano-sensors .
  • the dimensions and location of plural features are well controlled by fabrication methods that are already known in the art.
  • the stability of a two dimensional layered structure is superior to that of fragile nanowires.
  • the external contact for the nanosensors (hereinafter referred to as "nanoplates” ) may be produced in most implementations during fabrication.
  • the size of the contacts may be adjusted from nanometer to millimeter scale.
  • the conductivity between the conducting layers may be increased and the capacitive structure made leaky by an external factor.
  • the original structure is a leaky capacitor, and the external factor or stimuli may reduce the conductivity between the layers of the capacitor.
  • the small size of the sensors makes it possible to place the sensors in unconventional places.
  • a biological sensor may be placed into or onto a needle. The sensed results will be obtained after the needle reaches the tissue or blood of a patient. There is no actual need to take a sample.
  • the needle may be the only disposable part of the sensing device.
  • the device may be totally self-contained so that it contains measurement, processing and display units. The information may be transferred to a permanent storage unit, such as a PC hard drive, before the disposal.
  • the devices and methods may be used to measure the presence and concentration of analytes (defined below) suspected to be present in a sample or in a patient .
  • the classes of analytes that may be measured include but are not limited to peptides, proteins, glycoproteins, oligonucleotides, DNA, RNA, steroids, lipids, lipoproteins , carbohydrates, and compounds that may be detected by electrochemical means.
  • external particles are bound on or near the edge of the foregoing capacitive structure or device to induce a charge in the electrical properties of the structure.
  • the particle may be conductive or it may be made conductive after the binding.
  • the particles may have large dipole moment or be highly polarizable .
  • the nanosensors may be implanted into the skin or some other organ. They may also be injected into circulation.
  • the sensors may be very small, about the size of a cell, and actually placed inside a cell, if necessary. They may be made of materials, which are stable for years or alternatively dissolve in a body. Because of very small power consumption, a small battery may power the sensors. Information may be retrieved either using radio or microwaves. Alternatively, an external light may access an implanted sensor.
  • an array of sensors may be implanted. Each sensor in an array may perform a different task.
  • the implanted sensor may be powered by a fuel cell that utilizes chemicals that are abundant in a body. These chemicals may include glucose, cholesterol, ATP, and oxygen.
  • the implanted sensor may be coupled with the nervous system of a patient.
  • Most natural biochemical feed-back systems are independent of the nervous system. For instance, an increase in glucose concentration increases the production and secretion of insulin. Thus, biologically, it is not meaningful to couple chemo-receptor cells to the central nervous system.
  • our bodies are warned if there is excess pressure, heat, cold, light etc. It would be desirable to have continuous warning for every biochemical imbalance that is a serious threat to the well being of an individual .
  • heat there would be no feeling in the normal range, but immediately when something is out of normal physiological range, a conscious signal is obtained, the strength of signal is related to the magnitude of the deviation.
  • new possible senses may be created among humans.
  • Humans would be conscious of any disease state at the onset. For example, a small cluster of cancer cells would be recognized immediately, and that would cause a conscious unpleasant feeling that would be only slightly unpleasant early on, but will grow stronger if the cancer is allowed to grow. This would allow the detection of cancer years earlier than is currently possible.
  • a further aspect of the present invention provides devices and methods for food and water safety measurements, military, and anti -terrorist purposes.
  • Figures 1A-1D show various process steps to fabricate a nano- sensor, according to one aspect of the present invention.
  • Figures 2A-2D show various process steps to fabricate a nano-sensor, according to one aspect of the present invention.
  • Figures 3A-3C show various process steps to fabricate a nano-sensor, according to one aspect of the present invention.
  • Figures 4A-4J show various aspects of nano-sensors, shown in Figures 1A-1D, 2A-2C and 3A-3C, according to one aspect of the present invention.
  • Figures 5A-5F show a nano-sensor used with a testing needle, according to one aspect of the present invention.
  • Figures 6A-6B show a hydrogen sensor, according to one aspect of the present invention.
  • Figures 7A-7B show a localized attachment of oligonucleotide probes onto the nanosensor, according to one aspect of the present invention.
  • Figures 8A-8F show a capacitive structure with multiple conducting layers, according to one aspect of the present invention.
  • Figures 9A-9C show use of spin-coated particles, according to one aspect of the present invention.
  • Figures 10A-10F show a composite sensor structure, according to one aspect of the present invention.
  • Figures 11A-11C show the side view of Figure 8F, according to one aspect of the present invention.
  • Figures 12A-12B show use of magnetic patterns with the nano-sensors of the present invention.
  • Figures 13A-13B show affinity binding between conducting layers, according to one aspect of the present invention.
  • Figures 14A-14d show binding of bacteriophages, according to one aspect of the present invention.
  • Figures 15A-15B show formation of a conducting bridge with a DNA fragment, according to one aspect of the present invention.
  • Figure 16 shows circuitry for measuring voltage.
  • Figure 17 shows a circuit for measuring capacitance using the sensor of the present invention.
  • Figure 18 show multiple sensor modules, according to one aspect of the present invention.
  • Figures 19A-19B show a schematic representation of an implantable sensor, according to one aspect of the present invention.
  • Figures 20A-20C shows the implantable sensor of Figures 19A-19B coupled to a nerve cell, according to one aspect of the present invention.
  • Observable any physical or chemical factor that can be measured either qualitatively or quantitatively. These include, but are not limited to light intensity and wavelength, temperature, acceleration, temperature, radioactive particles, humidity, chemicals, biochemicals, cells, and pathogens.
  • Probe oligonucleotide or DNA fragment
  • Target oligonucleotide or DNA fragment
  • Figures 1A-1D show various stages of fabricating a nanosensor, according to one aspect of the present invention.
  • Figure 1A shows a semiconductor substrate 10 with two electrical leads 20 and 30.
  • Figure IB shows a conductive layer 40, for example, a gold layer, deposited onto substrate 10 so that layer 40 is in contact with lead 20, but not with the lead 30. Thereafter, an insulating (also referred to herein as "spacer") layer 50 is deposited between leads 20 and 30.
  • insulating also referred to herein as "spacer”
  • Figure IC shows a second conducting (e.g., gold) layer 60, which is deposited so that it is in contact with the lead 30, but not with the lead 20. Thereafter, a second spacer layer 70 is deposited on top of layer 60 and previously deposited spacer layer 50. It is noteworthy that the present invention is not limited to the foregoing two conducting and spacer layers, the adaptive nature of the present invention allows several deposition cycles that may be performed on substrate 10.
  • a second conducting (e.g., gold) layer 60 which is deposited so that it is in contact with the lead 30, but not with the lead 20.
  • a second spacer layer 70 is deposited on top of layer 60 and previously deposited spacer layer 50.
  • Figure ID shows a top view of the sensor 100A shown in Figure IC, with conductive layers 40 and 60 connected to leads 30 and 20, respectively.
  • the layered structure discussed above and shown in Figure 1A-1D is grown onto a solid substrate 10 that can be of amorphous or crystalline material, for example, glass, quartz, silicon, mica, polyethylene, polyvinylchoride, or polycarbonate.
  • Substrate 10 may be a composite or layered material.
  • Substrate 10 may be flat and smooth, cylindrical, and/or patterned.
  • Leads 20 and 30 may be coupled to substrate 10 before deposition of layers 40, 50, 60 and/or 70, or they can be attached after all the foregoing layers are formed. Leads 20 and 30 may be evaporated onto substrate 10 or attached by
  • leads 20 and/or 30 may be created by doping a desired pattern on substrate 10. Approximately a distance of 10 nanometer ( "nm” ) to 100 mm, or more advantageously between 500 nm and 1 mm may separate leads 20 and 30.
  • Both leads 20 and 30 may be made of the same or different material.
  • Leads 20 and 30 may be made of gold, silver, copper, iridium, palladium, and platinum and/or other conducting materials which include in some applications indium tin oxide, and plastics, such as polyaniline, polythiophene, tetrathiafulvalene, and polyacetylene. Amalgams and composite materials may also be used and are often more corrosion resistant, durable, and/or conductive than any pure element, for example, boron doped silver, several semiconductors, and other carbon composites. Leads 20 and 30 may also be created by several methods as described in "The Mechanics of Solder Alloy Interconnects by Eds. Frear, Burchett, Morgan, and Lau" incorporated herein by reference, in its entirety.
  • Conducting layers 40 and 60 in sensor 100A may be made of the same materials as leads 20 and 30, i.e., any metal, semiconductor, or photo-conductor.
  • Spacer layers 50 and 70 may be insulating or semiconducting, and may be fabricated from dielectric or semiconducting materials, provided that the material (s) in layers 50 and 70 are less conducting than layers 40 and 60. Examples of such materials without limitation are glass, quartz, silicon, cadmium selenide, mica, polyethylene, polyvinylchoride, polycarbonate.
  • Spacer layers 50 and 70 may also be made of composite materials, for example, polystyrene particles 70 that are optionally coated with a thin, approximately 20 nm, gold layer, dispersed onto a photo-resist (as shown in Fig. 9) .
  • Spacer layers 50 and 70 may include polystyrene or other plastic particles pre-coated by evaporating a thin metal layer.
  • spacer layers 50 and 70 may be created by attaching approximately 1-20 nm gold particles by streptavidin-biotin or other similar bonding mechanism onto plastic particles and chemically depositing a gold or other metallic layer. These methods are well known in the art as discussed by Hayat, in “Immunogold Silver Staining", CRC Press, 1995, incorporated herein by reference, in its entirety.
  • Chemical deposition methods may be a part of fabricating sensor 100A in Figures 1A-1D, or when sensor 100A is used for detection.
  • bacteriophages 1110 and 1120 may be used as discussed below in context with Figure 14.
  • bacteriophages 1110A and 1120A may be affinity bound onto specified areas, especially onto the edge of sensor 100A. After silver, gold or some other metal staining, they provide thin elongated nanowires between plates.
  • Carbon nanotubes, either single or multi -walled, may also be used to form conducting bridges between layers. The conductivity of carbon nanotubes is sensitive for many chemicals, especially for chemicals that are electron donors or acceptors (for example, ammonia and oxygen)
  • sensor 100A may have different structures with different chemical compositions. If spacer layers 50 and 70 contain conductive particles it is vertically conductive, which makes the entire structure 100A conducting. It is noteworthy that sensor 100A may not have bulk metal or conductor and is mostly surface, and accordingly, very sensitive to all kinds of physical and chemical factors. Sensor 100A may be made specific for a certain physical or chemical observable, as discussed below.
  • spacer layers 50 and/or 70 are electric insulators. In these cases conductivity is created between layers 40 and 60 by an observable, for example, a conducting particle that may be bound between two conducting layers (40 and 60) by an affinity binding as shown in Figure 13. Particle binding by affinity methods is also well known in the art.
  • sensor 100A is light sensitive. Electromagnetic field created by light can generate potential between adjacent layers 40 and 60. Also, spacer layers 50 and 70 may include light absorbing material that injects electrons on to conducting layers 40 and 60. These kinds of structures have applications beyond sensors.
  • sensor 100A may be utilized as solar cells converting light into electricity.
  • a light -receiving unit is small enough, only one photon at a time arrives into the unit, and the energy of that photon may be recovered.
  • semiconductors are advantageously added into sensor structure 100A.
  • layers such as p and n-doped silicon layers, or electric rectifier circuitry may be used to rectify the frequency of oscillating electric field of the light.
  • Sensor 100A may also be used to measure temperature by manufacturing layers 40 and 60 as bimetallic layers.
  • the binding of a bimetallic layer changes the contact and conductivity between adjacent layers 40 and 60.
  • attaching a small weight onto the edge of a conductive layer of sensor 100A imparts accelometric capacity. Bending of a layer, for example 40 and/or 60, due to acceleration changes the electrical properties, especially capacitance and conductance, of sensor 100A.
  • conducting layers 40 and 60, and spacer layers 50 and 70 may be fabricated by evaporation, sputtering, chemical vapor deposition, deposition, atomic layer epitaxy, spin coating, adsorbing, or formed using some other method commonly known in the art.
  • the Langmuir-Blodgett method may also be used to fabricate sensor 100A.
  • photochemical vapor deposition may be used to fabricate conducting layers 40 and 60, and/or spacer layers 50 and 70.
  • This process allows deposition at a relatively low temperature of plural elements, alloys, or ceramics.
  • some of the elements that may be deposited are boron, carbon, aluminum, arsenic, cadmium, gallium, germanium, iron, mercury, indium, iridium, molybdenum, nickel, phosphorus, lead, platinum, rhenium, sulfur, antimony, selenium, silicon, tin, thallium, tellurium, and tungsten.
  • Exemplary compounds include indium phosphide, silicon oxide, silicon nitride, aluminum oxide, zinc sulfide, zinc selenide, cadmium selenide, cadmium telluride, mercury telluride, gallium nitride, gallium phosphide, gallium arsenide, indium phosphide, indium antimonide, gallium aluminum arsenide, cadmium mercury telluride, yttrium barium copper oxide, and barium strontium titanate.
  • sensor 100A may include additional layers between conducting layers 40 and 60 and spacer layers 50 and 70.
  • an adhesive layer with chromium or incanal may be deposited between conducting layer 40 and insulating layer 50, or between conducting layer 60 and spacer layer 70. Some of the surfaces may be activated chemically.
  • chemically active layers may also be included between conducting layers 40 and 60, and spacer layers 50 and 70, using oxygen, halogen, ammonia, or some other plasma treatment.
  • the chemically active layer (s) may be used for recognition of certain molecules, as described below.
  • molecular layers may be adsorbed on plural layers of sensor 100A from gaseous, liquid, or liquid crystalline phase.
  • Several traditional surface treatment chemicals are listed in "Index of Chemicals Used for the Treatment of Metal Surfaces" by Benninghoff, Elsevier, New York, 1974, incorporated herein by reference, in its entirety, that may be used.
  • Examples of other useful compounds that may be used to produce additional layers in sensor 100A are 6-hydroxyhexane thiol, and 6-aminohexane thiol that form a self-assembled monolayer onto gold and silver surfaces.
  • Other techniques include silanization, which provides certain desired properties on surfaces (Virtanen et al . , US 4,756,971, incorporated herein by reference, in its entirety) , for example, organosilanes and their hydrolytic polymers may be used as surface treatment agents in chromatography and electronics applications of sensor 100A. Hydroxy group chemicals may also be used to make the surface (s) of sensor 100A hydrophilic, and amino group chemicals are useful for attracting various recognition molecules onto the sensing surface (s) of sensor 100A.
  • sensor 100A and the other embodiments described below may have two or several conducting layers like layer 40 and/or 60. All conducting layers may be made of the same material or several different materials may be used. The same applies to spacer layers, for example 50 and 70. The thickness of the plural layers may be
  • the conducting and spacer layers may have different thickness. Also the thickness of the layers may vary. For example, half of the conducting layers (for example layer40 and/or 60) may be approximately 50 nm thick, while the other half may be approximately 200 nm.
  • the thickness of the plural layers in sensor 100A increases incrementally, for example, from approximately 50 nm to 300 nm in approximately 10 nm steps.
  • These methods and structures may be used for multiplexing plural sensors, for example sensor 100A, to detect certain pre-defined observables .
  • the particle size may be different and match the separation of the corresponding layers.
  • some spacer layers may be conductive, while other layers are dielectrics.
  • the same assay may be performed simultaneously at both of these sites to increase the dynamic range. For example, increasing conductivity from zero to some small but measurable value is very sensitive to a presence of an analyte, while a decrease in conductivity is not equally sensitive, but has utility of detecting higher concentrations of an analyte .
  • Substrate 10 may be cut mechanically, for example, by a microtome that is designed to cut biological sample, or laser cutting may be used.
  • the cutting laser's wavelength is short to avoid any excessive heating during the cutting process.
  • the input cutting power must be high, to avoid excessive reflection from reflective layers.
  • substrate 10 may smear plural layers of sensor 100A.
  • sensor 100A may optionally be dipped in an etching solution. For example, if gold is used as a conductive material for layer 40 and/or 60, a potassium cyanide, or 6 M hydrochloric acid solution may be used for etching. Typically, the conductive layers of sensor 100A are etched for a short time.
  • insulating layers are etched so that grooves are formed between conductive layers 40 and 60.
  • the depth of the insulating layers are etched so that grooves are formed between conductive layers 40 and 60.
  • spacer layers 50 and 70 are composites containing particles. Entire spacer layer 50 and/or 70, except these particles, may be etched away. Etching method used depends on the insulating material. For example, silicon, glass, and quartz may be etched with hydrofluoric acid or ammonium fluoride, described by Hsiao, Virtanen, and Penner (1993) in Appl . Phys .
  • Metal oxides may be dissolved with acids and some, like aluminum oxide, may be removed with potassium hydroxide.
  • electroosmosis accelerates etching by increasing concentration of the etching chemical.
  • plasma may create an oxide or halogenide that does not evaporate, and may be removed by an etchant, such as an acid. This provides a controlled removal of spacer layer 50 and/or 70.
  • etchant such as an acid.
  • Most plastics may be dissolved by several organic solvents, such as acetone, methyl ethyl ketone, tetrahydrofurane, ethyl acetate, chloroform, toluene, or any mixture of the and other solvents.
  • applying a potential between conducting layers 40 and 60 may generate electric field, and optionally external electrode (s) may be used as a part of sensor 100A.
  • external electrode s
  • Figures 2A-2D show another aspect of the present invention where sensor 100B is similar to sensor 100A, except in this case, conducting layer 40A is deposited between leads 20 and 30, and a gap 80 is etched between leads 20 and 30. Spacer layer 50A is then deposited over layer 40A and thereafter, conducting layer 60 is deposited over layer 50A. It is noteworthy, that layer 60A in this aspect does not touch leads 20 and/or 30.
  • Figures 3A-3C show yet another aspect of the present invention with sensor 100C having plural sensing areas, 10A, 10B and IOC, as shown in Figure 3D.
  • Figure 3A shows substrate
  • Figure 3B shows a conducting layer
  • Spacer layer 50B (similar to layer 50) is fabricated on layer 40B.
  • conducting layer 60B (similar to layer 60) is fabricated with etched gaps 90 such that gap 90 is opposite to gap 80A.
  • Sensor 100C may have plural sensing regions, 10A, 10B and IOC. Electrical properties of each region 10A, 10B and 10C may be measured independently .
  • Figures 4A-4G show various implementations of the foregoing aspects of the present invention, as discussed above with respect to Figures 1A-1C, 2A-2C, and 3A-3C.
  • Figure 4A shows the side view of sensor 100A described above.
  • Figure 4B shows etched spacer layer 50, such that conducting layers 40 and 60 are exposed.
  • another material 200 is electro-chemically or otherwise, deposited between conducting layers 40 and 60.
  • Figure 4D shows a metallic or other substance 210 deposited on conducting layer 40.
  • the metallic or other substance may be deposited on conducting layer 60.
  • Figure 4E shows two different materials 210 and 220 deposited on conducting layers 40 and 60, respectively.
  • materials 210 and 220 may be substantially similar.
  • Figure 4F shows deposited materials 210 and 220 to be in contact with each other.
  • Figure 4G shows a conductive bridge 240 between conducting layers 40 and 60.
  • Figure 4H is the top view of Figure 4A
  • Figure 41 is the top view of Figure 4F
  • Figure 4J is the top view of Figure 4G with three conducting bridges 240, 250 and 260.
  • FIGS 5A-5F show another aspect of the present invention that uses sensors 100A through 100C to detect various chemical or biological molecules or organisms, for example, the anthrax bacteria.
  • Figure 5A shows one aspect of the present invention, where sensors 100A, 100B and/or 100C may be used to detect observables or analyze certain analytes.
  • Figure 5A shows needle 110 with deposited plural layers 120, 130 and 140 are, similar to layers 40, 50 and 60, described above.
  • Figure 5B shows a system where a plastic or ceramic coating is applied on needle 110. A small opening 180A is left to act as the sensing area.
  • Figure 5C shows a cross-section view with needle 110, plastic layer 150, conducting layer 120, spacer layer 130 and conducting layer 130.
  • Figure 5D shows another cross-sectional view based on Figure 5B with needle 110, plastic layer 150, conducting layer 120, spacer layer 130 and conducting layer 130.
  • Figure 5E shows the system of Figure 5D with electrical leads 160 and 170, similar to leads 20 and 30.
  • Figure 5E shows a system 180 with sensing area 180A.
  • System 180 may include a micro-processor and measurement circuitry that is used to sense change in electrical or other properties of sensing area 180A.
  • Figure 6A-6B show how sensor 100A may be used to detect hydrogen.
  • Palladium 300 may be deposited between conducting layers 40 and 60. When palladium absorbs hydrogen ( Figure 6B) , the contact between palladium layer 300 and conducting layers 40 and 60 improves. Improvement in contact may be detected as measured current, voltage or other electrical characteristics.
  • Figure 7 shows an implementation of the Figure 4B structure to sense and/or detect DNA fragments.
  • Figure 7A shows conducting layers 360, 370, 380 and 390, which are similar to layers 40 and 60 in Figure 4B.
  • Spacer layer 360A is etched (just like layer 50 in Figure 4B) .
  • Counter electrode 340 and layers 360 and 390 are negative, while layers 370 and 380 are positive.
  • Oligonucleotides probes 350 are adsorbed on the exposed areas of conducting layers 360, 370, 380 and 390.
  • Complimentary DNA fragments 350A are attracted to layers 370 and/or 380, as shown in Figure 15B.
  • Figures 8A through 8F show various other implementations of the sensors described above, according to one aspect of the present invention.
  • Figure 8A shows conducting layer 40 deposited on substrate 10 with contact 410, similar to Figure IC.
  • Figure 8B shows a dielectric layer 530 deposited on layer 40.
  • Multiple conducting layers as shown in Figures 8D to figure 8F may be fabricated with multiple contacts 410-520.
  • Spacer layers 530, 620 and 630 separate plural conducting layers.
  • Sensing area for sensing device 100D is 630A. It is noteworthy that plural conducting layers may be used to detect plural observables.
  • Figures 9A-9C show yet another aspect of the present invention where spin-coated particles are placed on conducting layer 40.
  • Particles 700 in polymer suspension 710 are applied on conducting layer 40.
  • Particles 700 may also include optional coating 750.
  • coating 750 may include gold.
  • Excess polymer 710 may be etched as shown in Figure 9B, and additional conducting layer 740 (similar to layer 60) may be deposited.
  • Figures 10A-10E show a composite structure 100E in which spacer layer, for example, layer 50, includes plastic particles 700.
  • Figures 10B-10E show various steps by which multiple conductive layers, similar to layer 40 and 60 separated by spacer layers with plastic particles 700 may be fabricated.
  • Figure 10E shows multiple conductive layers 40, 60, 810, 820 and 830, separated by spacer layers 50, 70, 810A, and 820, respectively.
  • Figure 10E structure may be sliced into plural slices 840, as shown in Figure 10F.
  • FIGS. 11A-11C show side view of Figure 10F with multiple conducting layers 40, 40, 40A and 60A separated by coated plastic particles 700.
  • Figure 11C shows sensor 100F where anti-bodies
  • Figures 12A-12B show another aspect of the present invention, that allows magnetic patterns using paramagnetic particles 900 and the sensing techniques of this invention.
  • Paramagnetic particles 900 are well known in the art and may be used as is or coated with a metal.
  • the magnetic field 900A is parallel to the surface of the paper. Magnetic particles 900 are separated by spacer layer 900C, which is similar to the spacer layers discussed above. If a magnetic field 900B, perpendicular to the paper plane is applied ( Figure 12B) , then the magnetic particles 700 are spread out, as shown in Figure 12B.
  • the density of rows or individual particles discussed may be adjusted by the strength of the magnetic field. If the field is perpendicular ( Figure 12B) to substrate 10 and there is excess paramagnetic particles 900, columns of the particles are formed in a regular pattern.
  • the structure may also be fixed by affinity binding methods. In this case the surface and particles contain moieties, which are complementary or bind with a common target .
  • Figures 13A-13B show yet another aspect of the present invention using sensor 100H similar to sensor 100A, described above.
  • Figure 13A shows conducting layers 40 and 60 separated by spacer layer 50, wherein spacer layer includes antibodies 1020 that may be grown during fabrication.
  • Particles 1000 are also coated with antibodies 1010, while the analyte in this example are antigens 1030.
  • An antigen 1030 binds itself to antibodies 1020 on the device and 1010 on the particle, hence closing the circuit between conducting layers 40 and 60.
  • Sensor 100H operates as a capacitor.
  • Particles 1000 may be coated, at least partially, with recognition molecules 1010 (Fig. 13) .
  • Molecules 1010 are often charged.
  • oligonucleotides are negatively charged in all common buffers.
  • a certain protein is negatively charged, if pH is above an isoelectric point and positively charged at a lower pH value.
  • the charge is balanced by soluble counterions, which form an electrical double layer. It is noteworthy that these particles move when an electric field is applied. Also the particles may repel
  • Particles The following provides a discussion on the various particles (700, 900 and/or 1000) that are described above with reference to plural aspects of the present invention
  • Gold particles may be used for the various applications described above, as metal particles, because of their stability in water, and constant size ranging from
  • plastic particles especially polystyrene spheres
  • ⁇ between approximately 20 nm and 100 ⁇ m may be used and are also commercially available.
  • Other commercially available particles include cellulose, silica, and diamond particles.
  • the quantitative interaction between charged colloidal particles is well known.
  • the charge of the particles may be adjusted by attaching charged molecules, other than recognition molecules, onto the particles.
  • charged molecules are polylysine, polyasparagine acid, polyallylamine, polyacrylate, histone, and DNA.
  • Oligonucleotides and DNA may be used to adjust the charge in immunoassays and also in DNA testing, as described below. Typically, in DNA tests the DNA that is used to regulate the charge may not contain a target sequence .
  • Particle charge may also be regulated, for example, by pH, ionic strength, counter ions, solvent, and additives, such as polyethyleneglycol.
  • Also charged molecules may be attached on to the particles so that the binding is reversible. For example, if the surface of a particle is sparsely covered by negative moieties, such as carboxylates, an excess of a positive polymer, such as polyallylamine, will bind on to the surface and give the surface a positive charge.
  • the negative charge of the carboxylates may be eliminated by adding acid so that pH is approxiately below 5. The binding of the positively charged polymer will be much weaker, and a significant part or possibly all of it will be detached from the particles.
  • the charge may be changed by a chemical reaction.
  • the positive charge of amino groups may be eliminated by acylation that may be done in water by active esters, such as acyl N-hydroxysuccinimides .
  • Conductive particles, as described above, may also be charged with static electricity, which may be adjusted to be either positive or negative. The charge may also be changed during the assay. An additional charging electrode may added to give the particles a charge before they enter into the assay area.
  • Particle charge may be utilized in many ways in assays, in various aspects of the present invention.
  • particles may be forced to move electrically through a sample, and while they are moving their recognition molecules interact with the sample and collect analyte molecules.
  • the particles may be attracted on to the surface of one electrode.
  • the particles may be concentrated on to the edges of certain layers.
  • the binding kinetics of particles is faster because of concentration and the physical contact induced by the electric field.
  • the present adaptive aspects allow the use of nearby conductive layers for attraction, while the layer that is coated with affinity molecules is electrically idle. This avoids electrochemical reactions of the affinity molecules and the sulfur-gold bond that is often used to bind affinity molecules.
  • the strength of an analyte mediated binding may be measured. This tests the specificity of the binding. Specific and non-specific binding in immunoassays may be differentiated. Moreover, the binding force may also be measured. For example, in DNA tests this allows to differentiate SNPs (Single Nucleotide Polymorphisms) .
  • the charge of the particles may be adjusted independently of an analyte.
  • the charge may be even opposite to that of an analyte.
  • DNA binding particles may be made positively charged. After interacting with a sample these particles may be attracted on to the negative electrode surface. The soluble DNA in the sample as well as DNA that is weakly bound on to the particles would be repelled from the electrode .
  • Antibody- antigen interaction may be used in many different ways either to bind or prevent the binding of particles onto the surface of an electrode.
  • a traditional sandwich type assay one member of a matching antibody pair is bound on to particles and the other on to an electrode.
  • the corresponding antigen forms a bridge between two antibodies and binds the particle on to the surface of the electrode as depicted in Figures 13A- 13B.
  • an antigen is a large enough molecule to have at least two spatially separated epitopes . Most proteins may be assayed by sandwich assay.
  • Non-conducting particle may be made a conductor by depositing metal layer onto its surface. This method may also be used in conjunction with conducting particles to improve the contact between the particle and the conducting layers. If the particle is a photo-conductor, exposure to optical light will increase its conductivity. If the conducting layers are connected with conducting bridges, the conductivity will decrease due to the binding of an analyte or a particle.
  • a cleavable spacer provides another way to perform a sandwich assay, Virtanen US Patent No. 6,312,901, which is incorporated by reference in its entirety.
  • the number of the bound conductive particles is directly proportional to the concentration of the antigen.
  • competitive assay may be used.
  • the antibody is attached, for example, on to a particle, and the antigen or an analog of the antigen is attached onto the electrode ( Figure 13B) .
  • the antigens in the sample saturate the antibody molecules on the particles.
  • the competitive assay is not as sensitive as the sandwich assays, because zero and very small concentrations of the antigen gives maximum or near maximum binding. Small changes are very difficult to differentiate from normal experimental error.
  • the preferred electrode material for example, 40 and/or 60
  • Gold surface may be first coated with streptavidin, which will adsorb spontaneously from an aqueous solution. Biotinylated antibody will bind with steptavidin providing a good coating.
  • Another method is to reduce the antibody with dithiotreitol or with some other reductant and allow the reduced antibody to chemisorb directly on to the gold surface.
  • a wide variety of immunoassays may be performed using the various sensors and processes under the present invention. For example, without limitation, hCG (pregnancy test) , prostate specific antigen (PSA) detection, insulin, proinsulin, glucagon, glycated hemoglobin, growth hormone, fetoprotein, TSH, C-reactive protein, CK-MB, myoglobin, troponin, interferons, interleukins, ferritin, tumor negrosis factor, trypsin, plasminogen, cardiolipin, cortisol, aldosterone, estradiol, digoxin, benzodiazepine, vancomycin, amphetamine, cocaine, morphine, tetrehydrocannabinol , phenobarbital, secobarbital , parathione, adenovirus
  • Figures 14A-14D show yet another aspect of the present invention, where sensor 100J similar to 100A in Figure ID, and 100J in Figure 4G, is used for binding bacteriophages 1110A and 1120A to complimentary molecules 1130 and 1140, respectively.
  • Sensor 100J similar to 100A in Figure ID, and 100J in Figure 4G, is used for binding bacteriophages 1110A and 1120A to complimentary molecules 1130 and 1140, respectively.
  • Proteins 1110 are a part of bacteriophage 1110A and protein 1120 are a part of bacteriophage 1120A.
  • Figure 14A shows molecules 1130 and 1140 attached to spacer layer 50 between conducting layers 40 and 60. It is noteworthy, that more than one pair of conducting layers 40 and 60 may be used.
  • Figure 14B shows complementary molecules 1130 and 1140 bound with bacteriophages 1110A and 1120A.
  • Figure 14C shows particles 1150, similar to particles 700 bound to bacteriophages 1110A and 1120A.
  • Figure 14D shows sensor 100J that is similar to the sensor 1001 in Figure 4G, where a conductive bridge 1160 (with particles 1150) are created between conducting layers 40 and 60.
  • Metal coated bacteriophages 1110A and 1120A may be used to operate as thin elongated nanowires between conducting layers 40 and 60.
  • FIGS 15A-15C shows, yet another aspect of the present invention with sensor 100K similar to sensors in Figure 1A and
  • Complementary probes 1200 and 1210 are placed between conducting layers 40 and 60 respectively.
  • Soluble probes, 1230, 1240, 1250 and 126, with gold particles 1270 are coupled to complementary molecules, as shown in Figure 15B.
  • Figure 15C shows conductive bridge 1280 between conducting layers 40 and 60, similar to sensor 1001 in Figure 4G.
  • DNA fragment 1220 may act as a template for conducting bridge 1280 that functions as a nanowire.
  • the use of gold particles may be avoided by ligation of the probes together.
  • a continuous DNA duplex is an electric conductor (as described by D. Porath et al . Nature 403:635, incorporated herein by reference in its entirety) . Weak conductance can be detected, for example, by measuring leakage current of the capacitor.
  • DNA fragment 1210 is bound between the conductive layers 40 and 60 with the stationary probes 1200 and 1210.
  • Soluble probes 1230-1260 contain at least one gold particle that may cover most of DNA fragment 1220, if the sequence has complementary segments. After a gold or silver amplification a continuous wire 1280 is created between the conductive layers 40 and 60. If the sequences do not match, there will be gaps and no conductivity is detected.
  • the present invention allows testing of plural sequences simultaneously.
  • the main large-scale application of oligonucleotide arrays is comparative expression analysis. Gene expression patterns in healthy as well as in diseased tissues and cells will greatly increase the understanding of the function of living organisms. The effect of drugs may be understood in much more detail than presently.
  • SNPs single nucleotide polymorphisms
  • DNA diagnostics Another example of DNA diagnostics is the detection of fetal DNA in maternal plasma as described by Lo (2000) , in “Clinical Chemistry", 46:1903-1906), incorporated herein by reference, in its entirety. DNA and RNA studies are not limited to humans. Plant genomics has enormous economical importance. Knowledge of pathogen genes and gene expression may be used in diagnostics and for the design of new drugs.
  • Oligonucleotide probes may synthesized so that they contain aliphatic amino, mercapto, or other groups.
  • Mercapto groups have a drawback that they tend to be oxidized by a positive electrode (anode) .
  • the positive charge is sometimes used to attract sample DNA to the close proximity of the electrode.
  • Particles or analytes themselves are attracted to electrode (s) .
  • the charge of the particles may be opposite to the charge of an analyte.
  • probes 1200 and 1210 will be nearly perpendicular to the surface and easily accessible (Fig. 15A) . In this case when positive charge is used, the probes are likely to lay flat on the surface being sterically hindered.
  • Probes 1200 and/or 1210 may have 5 to 10,000 nucleotides, and preferably 10 - 80 nucleotides. Long probes have generally genomic origin. The target is often a PCR product. Other amplification methods may be used, including isothermal and ligation amplification. The probes should have preferably about the same length as the amplicons.
  • Hybridization as shown in Figure 15C is well known in the art. Temperature should preferably be 20 °C below the melting temperature of the dublex. The salt concentration effects the melting temperature and kinetics of the hybridization. The melting temperature depends also on guanidine and cytidine contents of the probes and the target.
  • a higher salt concentration in the buffer and higher C/G- content will increase the melting temperature.
  • electric current will increase the temperature of the elecrolyte.
  • ⁇ T VIt/Cm, where t is the time and C is the thermal capacity of the medium of a mass m. A certain thin layer of walls may be included into mass m.
  • the method of the present invention is less sensitive to external conditions than the most currently used methods. This is due to the electric field that may be utilized to increase the rate of the hybridization as well as to test the stringency of the hybridization.
  • Polymerase and ligase chain reactions as well as isothermal amplification may be performed using sensors of the present invention.
  • the temperature cycling (not for isothermal) may obtained by electric potential induced heating between the electrodes or by embedding heating elements near the electrochemical cells. The heating is more effective, if instead of a direct current, an alternating current is used.
  • Oligonucleotide analogs such as peptidenucleotide acids (PNAs) , and thionucleotide acids, also offer increased stability and/or stringent hybridization.
  • PNAs peptidenucleotide acids
  • thionucleotide acids also offer increased stability and/or stringent hybridization.
  • Oligonucleotide probes may be prehybridized with complementary oligonucleotides.
  • the purpose of this kind of array is to study interaction of biomolecules with double helical DNA. Cell and Pathogen Detection;
  • Cells and pathogens may be detected either by assaying certain surface markers, or their DNA. The methods already described above for immunoassays and DNA testing are applicable.
  • the particles may also be bound onto the cell membrane, either before or after they are bound onto the surface of an electrode. Examples of cells include the human T&NK cells (CD2 and CD7) , T helper cells (CD4), T cells (CD5) , supressor cells (CD8) , E. Coli, Salmonelle, and Helicobacter pylori .
  • Circuit 1300A includes capacitor 1300F and resistor 1300E within module 1300 that gets input voltage 1300B. Voltage 1300C is measured at resistor 1300D. Parallel resistor 1300E and capacitor 1300F are analogous to the capacitive sensors, described above.
  • FIG. 17 shows measurement of capacitance and leakage of capacitor 1320 coupled in parallel to module 1300.
  • Transistor 1320A provides external charge to diode 1320B that powers capacitor 1320.
  • Voltage 1300C may be measured by device 1330. It is noteworthy, that module 1300, in this figure is similar to the capacitive sensors, described above.
  • Input voltage (1300B in Figure 17) is a constant voltage
  • a short pulse for example 50 ⁇ s, is given to the base
  • a very low leakage capacitor 1320 is charged via a diode 1320B.
  • a leaking capacitor module 1300 In parallel to capacitor 1320 is a leaking capacitor module 1300. If conductive particles are bound between the conducting layers, voltage is measured through a high impedance Op-Amp module 1330 that contains field-effect transistors. Without the measurement cell the capacitor 1320 would retain over 99% of its charge. Leakage due to cell 1300 will reduce the charge and voltage exponentially. This reduction may be sampled at desired intervals or continuously. The time constant of the leakage may be correlated with the number of conductive particles. This circuitry is referred to herein as a "Charge-and-Leak Amplifier" .
  • Figure 18 shows plural modules 1300 with the circuit shown in Figure 17 and described above.
  • the circuit of Figure 18 includes a switch 1400 that allows each subsystem of a sensor with various 1300 modules to be coupled to measuring device 1330.
  • the following discussion is based on using several electrochemical methods, which are known in prior art and discussed above with reference to the various figures including Figures 16-18.
  • the present invention utilizes primarily electrical measurements, for example, current, voltage etc.
  • other detection schemes may supplement electrical detection.
  • the light may be simultaneously used to get additional information on an analyte, recognition molecules, substrate, or conductive particles. Reflectance, scattering, fluorescence, or some other optical property of the particles or an associated unit, such as liquid crystalline display may be measured.
  • the plural sensors of the various aspects of the present invention may contain several conducting layers in close proximity.
  • the potential of each layer may be independently controlled.
  • This kind of device may serve as an electrochemical measurement device.
  • Working, counter and reference electrodes may be a part of one device.
  • electrochemistry may be performed, but in addition, multiplexing different sensors provide more options, than conventional means.
  • potential sweep study may be done without actual potential sweep, if there are enough layers so that all data may be collected simultaneously. Possibly, the potential of each conducting layer (40 or 60 or their multiples) is changed only few millivolts to cover the range of several volts with the whole device. As a result electrochemical analytical techniques may be utilized.
  • the electrodes may be coated with enzymes, such as glucose or cholesterol oxidase. Hydrogen peroxide that is released in the enzymatic reaction may be detected electrochemically. Examples of other small molecules that may be detected by enzymatic means are ethanol, lactic acid, and bilirubin described by Wieck et al . (1984) in "Anal. Chem.” Acta 158: 137. Alternatively hydrogen peroxide may enzymatically oxidize many compounds, such as benzidine, tetramethyl benzidine, p-fluorophenol, or p-fluoroaniline to produce fluoride ion, or some other a secondary stable species that may be detected by an ion selective electrode.
  • enzymes such as glucose or cholesterol oxidase.
  • Example of the compounds and groups of compounds that may be detected by electrochemical means are: cathecolamines, several drugs, oxygen, nitric oxide, nitrous oxide, carbon dioxide, nitro, nitroso, azo, heterocyclic compounds, isocyanates, phenols, amines, most sulfur containing compounds, such as disulphides, dithiocarbamates, thiobarbiturates, thioureas, thiols, sulphonates, sulphides, and sulphoxides, and also cations, anions, chelates, and organometallics .
  • electrical power may be provided by a battery (Galvanic cell), fuel cell, solar cell, electromagnetic radiation, magnetic induction, direct contact with external power source , or by any other commonly known means .
  • battery Galvanic cell
  • fuel cell fuel cell
  • solar cell electromagnetic radiation
  • magnetic induction direct contact with external power source , or by any other commonly known means .
  • Coupling electrical devices to computer processing units and to networks is well known in the art. Examples may be found in several books, including J.J. Barbarello "PC Hardware Projects, Volume 3” (Prompt Publications, Indianapolis, 1998); W.J. Tompkins and J.G. Webster “Interfacing Sensors to the IBM PC” (Prentice Hall PTR, Englewood Cliffs, 1998), S. McDowell and M.D. Seyer “USB Explained” (Prentice Hall, Upper Saddle River, 1999) , and J. Axelson "Serial Port Complete” (Lakeview Research, Madison, 1998), incorporated herein by reference, in entirety. Networks include Local -Area-Networks, Wide Area Networks, and the Internet.
  • Networks may also utilize among others, metal cables, fiberoptics, or be wireless.
  • Various protocols/mechanisms may be used for data transfer, including without limitation, Bluetooth ® (an industry standard, published by the Bluetooth Standards Organization) and Infra Red standards, incorporated herein by reference, in entirety.
  • Direct detection of a tunneling current using the plural sensor devices, described above is one choice, but Charge-and- Leak Amplifier system described above and shown Figures 17 and 18 may also be used.
  • a sample-and- Hold Amplifier as described in J.J. Brophy, Basic Electronics for Engineers, McGraw-Hill Publishing Co, New York, 1990, p. 234, incorporated herein by reference, in its entirety, may be modified so that it may be applied to measure electrical properties between pair of electrodes.
  • a substrate for example substrate 10, may be coated with a photoconductor .
  • Light may be used to create conductive pathways in the photoconductive layer. Any area in the photoconductive layer may be selectively addressed.
  • light forms a temporary pattern as required.
  • Light may be patterned in several ways. For example, masks are a traditional way of selectively exposing some areas for light. Traditional masks are fixed, and they should be either stored or inserted into the sensor device .
  • Micro-mirror arrays provide a method for patterning of light that is programmable. Another way to accomplish programmable light pattern is to apply liquid crystal display technology. Instead of black color the back plate may be coated with reflective layer, or be transparent. In both cases the light would be directed only to certain areas on substrate 10.
  • substrate 10 is a non-conductor
  • shining light on to the photoconducting layer may create nanowires.
  • the photoconductor is on a metallic layer, only an area of interest needs to be lighted.
  • the area may be whole assay area, or it may be only a small part of it.
  • the assay area may be scanned with a micrometer sized laser spot. This allows the localization of individual conductive particles, and also the measurement of the electrical properties of each particle individually.
  • Conductive particles may be photoconductive. Electrodes may be metallic, semi -conducting or photo-conducting in this case. The location of each particle may be found by scanning with a focused laser beam. Implantable Sensors:
  • Figures 19A-19B show another aspect of the present invention, where sensor 100A, modified into sensor 100L, as discussed below, and operates as an implantable device for detecting plural analytes.
  • Figure 19A shows electrodes 1710 and 1760 that are coated with enzymes, with conducting layers 40 and 60 (shown in Figure 19B) .
  • a liquid crystal area 1730 is also shown.
  • Figure 19B shows a cross-sectional view taken from the section shown in Figure 19A.
  • Figure 19B shows conducting layer 60, plural liquid crystal areas 1730, 1740 and 1750.
  • Sensing area for device 100L is shown as 1730A.
  • microscopic sensors 100L may be fabricated.
  • Sensor 100L may be smaller than one human cell, hence may be implantable.
  • the power consumption of these sensors is so low that a very small battery may be used.
  • Light such as laser light may be used to acquire information from sensor 100L.
  • a sensor and a liquid crystalline display may be coupled in series or parallel in a circuitry, as shown in Figure 19A or 19B. If they are parallel the potential in the LC display will decrease when the conductivity of the sensor increases. The situation is reversed in the serial coupling.
  • the reflection from a flat LC display depends on its orientation.
  • the display may be cylindrical. However, in order to avoid orientation problem, the display may be spherical or at least hemispherical .
  • a spherical display may be fabricated by emulsion coating gold or some other metal coated plastic particle on a liquid crystalline material. A very thin, about 5-50 nm, metal layer, such as gold or silver layer is chemically deposited on top of the liquid crystalline layer.
  • an additional metal layer about 50 nm, is evaporated onto one hemisphere of each particle. Immediately a dielectric layer is deposited on to the same hemisphere. After slightly etching the metal from the opposite hemisphere the process is complete. Short plasma etch or dissolution with organic solvent removes the liquid crystal and exposes the first gold layer in that hemisphere.
  • these particles may be bound onto the substrate so that they are properly oriented.
  • the dielectric protecting the upper hemisphere may be partially or totally etched away, allowing electrical contact with the upper metal hemisphere. Partial etching may be done, for example, by laser ablation.
  • Battery as a power source and LC display as a detector are well within the art. However, in the preferred implementations power may be harnessed from biological energy of a body. In some implementations the nervous system of the body is utilized as a detector, as described below. In these ultimate implementations a cell sized sensor 100L is continuously powered by a biochemical energy of a body and a signal is transmitted into a nervous system and to a brain. Biological fuel cells are well known in the art. The present invention describes a novel combination of fuel cells and sensors, and improvements of biologically powered fuel cells (Fig. 19) .
  • the chemical source of the energy is glucose. The concentration of the glucose is high and relatively stable. Glucose oxidase is a stable enzyme.
  • Hydrogen peroxide is formed in the enzymatic oxidation of glucose.
  • Platinum electrode 1710 is preferred, because of the stability and minimal over potential in the reduction of the hydrogen peroxide.
  • the counter electrode 1760 may be coated by a reducing enzymatic system.
  • One preferred enzyme is cytochrome c oxidase that reduces oxygen to water.
  • the system may also contain cytochrome c that actually transfers the electrons from the electrode to the cytochrome c oxidase. This fuel cell utilizes abundant chemical species and relatively stable enzymes. Encapsulating the electrodes in a polymeric matrix may further stabilize the enzymes.
  • a reversed microemulsion of enzymes and polymerizable material such as methyl methacrylate
  • an organic solvent for example, octane.
  • the monomer is polymerized.
  • the microemulsion is adsorbed onto the electrode.
  • the enzymes that are capsulated are often stable for years at ambient temperature .
  • FIGS 20A-20C show sensor 100M similar to the implantable sensor 100L of Figure 19B, according to one aspect of the present invention.
  • Sensor 100M may be coupled to a nerve celll 1900 with axon 1910.
  • Figure 20A shows plural swicthes 1770-1800, coupled next to opening 1800-1840. Nerve cells grow via openings 1770-1800 and plural switches 1810- 1840 are used to couple or de-couple a specific nerve cell electronically from sensor 100M.
  • Figure 20B is a side view of the device shown in Figure 20A, and Figure 20C shows nerve cell 1900 with axon 1910 growing through a hole.
  • Neurons and sensors may be connected by neural surgery as described by Agnew, McCreery, in “Neural Prostheses, Fundamental Studies", Prentice Hall, 1990), incorporated herein by reference, in its entirety.
  • sensor 100M may contain cavities that slowly release nerve growth factors.
  • Neurotrophic factors such as NGFs stimulate neural growth, especially after peripheral nerve lesion (Grothe, Nikkhah Anat. Embryol (2001) 202: 171) incorporated herein by reference, in its entirety and furthermore direct the growth toward sensor 100M (Fig. 20C) .
  • the nervous system consists of the central nervous and peripheral nervous system. Sensory nerves have a receptor at their end. Two main classes of receptors are exteroreceptors and enteroreceptors . Enteroreceptors measure observables, such as cholesterol, blood sugar and oxygen levels, and body temperature. These factors are very well controlled, although no conscious signal is given to the brain.
  • Exteroreceptors consist of photoreceptors, chemoreceptors, thermoreceptors, mechanoreceptors, and nocireceptors .
  • Sensory nerves act as transducers converting sound, mechanical, photonic, chemical, or thermal energy into electrical signal .
  • the ion fluxes across nerve cell membranes form the basis of impulse propagation in the Hodgin-Huxley model of depolarization-repolarization wave in neuronal fiber (Hodgin, Science 145: 1148, incorporated herein by reference, in its entirety) .
  • the potential of a membrane is approximately 50 mV, and the average action potential is about 110 mV.
  • the signal is all-or-nothing.
  • An impulse is initiated by increasing the membrane potential above a certain threshold value. The initiation may be done artificially.
  • the nerve signal may be digital .
  • Receptor potential is graded, unlike the action potential, which is all or none.
  • the magnitude of the receptor potential determines the frequency of the synaptic triggering, and thus the frequency of the pulses that are sent to the central nervous system.
  • Thermo-reception is also adaptable for chemical sensing, because temperature has low, normal, and high range.
  • the proposed glucose bio-sensor (100M) could be anywhere in a skin, but preferably in an area that is protected by clothing. Temperature variations in the general area would not affect glucose sensing, because sensory system is sensitive to differentials .
  • Mechanoreceptors are connected to the caudal medulla, where they terminate in the cracile or cuneate nuclei.
  • the second order neurons are connected to contralateral thalamus.
  • the third-order neurons in the thalamus are finally connected to the primary somatic sensory cortex located in the postcentral gyrus of the parietal lobe. Somatic cortex contains four areas.
  • Two of the foregoing receive information from the skin and two from muscles and joints. These have been mapped in detail. For example, it is known, which part of somatic cortex is responsive for the stimulus in the right forefinger. Touch of a finger activates at least four areas in the somatic cortex, first one indicates that a finger has been touched (may be any finger, except a thumb) , second tells in which hand this finger is, third gives the general area of the finger (for example, the tip of a finger) , finally the fourth defines the exact finger. These maps have been in animal studies using microelectrodes .
  • Cancer typically starts to be painful when death is near. In the past any early warning had been useless and actually prevented an individual acting at full capacity. The situation has reversed with the development of the modern medicine. If the pain due to cancer could be selectively amplified enormously, the cancer could be detected several years earlier than is possible currently. The situation is similar with radiation damage. If a person could feel even a small radiation damage (above the background radiation) , that person could seek protection. It is a part of this invention to develop selective methods to increase pain. This increase can be transient or semipermanent, unless the reason is removed.
  • Some chemoreceptors are highly sensitive and specific to certain chemicals, while others like olfactory chemoreceptors are sensitive to a class of chemicals. Thermoreceptors are also sensitive to many chemicals. Menthol and eucalyptol have cooling sensations, while many alkaloids, especially piperidine containing, produce heating sensations.
  • thalamic nuclei DM, AN, IL, and CM
  • ACGI and ACGI I Pain perception involves both "attention riveting" (selection) and "actual perception” (emotional aspect) .
  • Activation and de-activation of these centers can be followed in real time by functional Magnetic Resonance Imaging (fMRI) .
  • fMRI Magnetic Resonance Imaging
  • insertion of an acupuncture needle into a pain relief point causes first a transient signal in the thalamic nuclei and cingulate gyrus, but within seconds de-activates these centers.
  • a stimulus in a very small area may cause effects in the brain that are clearly discernible by f RI.
  • a point-like sensor may be effective enough to induce a signal that is detectable by a nervous system.
  • Example 1 Onto a flat and smooth glass plate (substrate 10) is sequentially evaporated layers of approximately 10 nm of chromium, approximately 200 nm of gold, and approximately 10 nm of chromium. The plate is then spin coated with approximately 150 nm layer of photo resist (Shipley Co) . The plate is covered by a mask, and exposed to UV- light for approximately a min. The plate is then developed and baked. Etching is performed with 6-M hydrochloric acid/nitric acid solution. The resist is washed away, although in some other applications the resist may serve as an insulating layer. An approximate 100 nm layer of silicon dioxide (layer 40) is deposited (chemical vapor deposition, CVD) so that it
  • a second chromium-gold-chromium layer (60) is deposited, and all other operations are repeated essentially the same way as in the first cycle. However, the mask is a mirror image of that used the first time.
  • the third cycle is identical to the first cycle, and similarly the fourth cycle is identical to the second one. Altogether six metal layers may be deposited.
  • the plate is
  • Example 2 The sensor unit of Example 1 is treated with aminopropyl triethoxysilane, which will activate the silicon dioxide bottom of each groove. Biotinyl N-hydroxysuccinimide will spontaneously conjugate with the amino groups. Streptavidine coated approximately 100 nm polystyrene particles are added. They will bind into the grooves. When a colloidal solution of approximately 10 nm biotinylated gold particles are allowed to interact with plastic particles, they will be partially covered with gold particles.
  • Gold colloid The unbound gold colloid is washed away. Gold chloride solution and hydroquinone is added. Gold may be deposited around the particles, which are bound onto the polystyrene spheres. Thus, nanowires are created between adjacent gold layers. Gold is coated with antibody molecules, which impart specific binding properties for the sensor. In the presence of antigen the conductivity of the device will change .
  • Example 3 Approximately 20 nm chromium and 200 nm gold
  • the film is coated with a suspension of approximately 1 ⁇ m polystyrene particles, which are coated with streptavidine.
  • a magnetic plate is brought from below onto close proximity with the substrate.
  • a gold colloid of approximately 10 nm biotinylated particles is added.
  • the solution on the top of the substrate is diluted and mostly removed.
  • Gold chloride and hydroquinone solution is added.
  • the plastic particles will be coated with gold.
  • the surface is washed and dried. After spin coating with photoresist the excess of the photoresist is removed by oxygen plasma, so that the gold coated particles are just exposed.
  • a new approximately 200 nm layer of gold is evaporated on top of the photoresist. The process is repeated plural times.
  • the plate is about 210 ⁇ m thick.
  • the edge is glued onto long rod that may have a square cross section having approximate dimensions of 0.6 mm x 0.6 mm. This rod has at intervals of approximately 6 mm rectangular openings of

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Abstract

L'invention concerne un dispositif capacitif permettant de mesurer au moins une propriété électrique. Le dispositif comprend une première couche conductrice et une seconde couche conductrice reliées fonctionnellement à un dispositif de mesure permettant de mesurer au moins une propriété électrique dépendant d'un facteur physique et/ou chimique. Le dispositif comprend également une troisième couche séparant la première couche conductrice de la seconde couche conductrice.
PCT/US2002/039937 2001-12-12 2002-12-12 Procede et dispositif de nanodetection Ceased WO2003054931A1 (fr)

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WO2006067276A1 (fr) * 2004-12-23 2006-06-29 Nanolab Systems Oy Utilisation de nanofils dans une analyse chimique et biologique
WO2006107312A1 (fr) * 2004-06-15 2006-10-12 President And Fellows Of Harvard College Nanocapteurs
US7211464B2 (en) 2000-08-22 2007-05-01 President & Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors and fabricating such devices
US7254151B2 (en) 2002-07-19 2007-08-07 President & Fellows Of Harvard College Nanoscale coherent optical components
US7256466B2 (en) 2000-12-11 2007-08-14 President & Fellows Of Harvard College Nanosensors
US7301199B2 (en) 2000-08-22 2007-11-27 President And Fellows Of Harvard College Nanoscale wires and related devices
US7858965B2 (en) 2005-06-06 2010-12-28 President And Fellows Of Harvard College Nanowire heterostructures
US7857959B2 (en) 2004-11-19 2010-12-28 The Trustees Of Boston College Methods of fabricating nanowires and electrodes having nanogaps
US8058640B2 (en) 2006-09-11 2011-11-15 President And Fellows Of Harvard College Branched nanoscale wires
US8154002B2 (en) 2004-12-06 2012-04-10 President And Fellows Of Harvard College Nanoscale wire-based data storage
US8232584B2 (en) 2005-05-25 2012-07-31 President And Fellows Of Harvard College Nanoscale sensors
US8575663B2 (en) 2006-11-22 2013-11-05 President And Fellows Of Harvard College High-sensitivity nanoscale wire sensors
EP2406621A4 (fr) * 2009-03-11 2014-08-20 Agency Science Tech & Res Capteur électrique permettant une détection ultrasensible d'acide nucléique
US9102521B2 (en) 2006-06-12 2015-08-11 President And Fellows Of Harvard College Nanosensors and related technologies
US9297796B2 (en) 2009-09-24 2016-03-29 President And Fellows Of Harvard College Bent nanowires and related probing of species
US9390951B2 (en) 2009-05-26 2016-07-12 Sharp Kabushiki Kaisha Methods and systems for electric field deposition of nanowires and other devices
WO2019191648A1 (fr) * 2018-03-29 2019-10-03 The Regents Of The University Of California Biorésistances virales
US20220364162A1 (en) * 2018-08-14 2022-11-17 Korea University Research And Business Foundation Method for synthesizing single metal nanobridged structure and method for manufacturing dna point mutation detection sensor by using same

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7915151B2 (en) 2000-08-22 2011-03-29 President And Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors and fabricating such devices
US8153470B2 (en) 2000-08-22 2012-04-10 President And Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors, and fabricating such devices
US7211464B2 (en) 2000-08-22 2007-05-01 President & Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors and fabricating such devices
US7666708B2 (en) 2000-08-22 2010-02-23 President And Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors, and fabricating such devices
US7595260B2 (en) 2000-08-22 2009-09-29 President And Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors, and fabricating such devices
US7301199B2 (en) 2000-08-22 2007-11-27 President And Fellows Of Harvard College Nanoscale wires and related devices
US7476596B2 (en) 2000-08-22 2009-01-13 President And Fellows Of Harvard College Doped elongated semiconductors, growing such semiconductors, devices including such semiconductors, and fabricating such devices
US7256466B2 (en) 2000-12-11 2007-08-14 President & Fellows Of Harvard College Nanosensors
US7619290B2 (en) 2000-12-11 2009-11-17 President And Fellows Of Harvard College Nanosensors
US7385267B2 (en) 2000-12-11 2008-06-10 President And Fellows Of Harvard College Nanosensors
US7911009B2 (en) 2000-12-11 2011-03-22 President And Fellows Of Harvard College Nanosensors
US7254151B2 (en) 2002-07-19 2007-08-07 President & Fellows Of Harvard College Nanoscale coherent optical components
WO2006107312A1 (fr) * 2004-06-15 2006-10-12 President And Fellows Of Harvard College Nanocapteurs
US7857959B2 (en) 2004-11-19 2010-12-28 The Trustees Of Boston College Methods of fabricating nanowires and electrodes having nanogaps
US8154002B2 (en) 2004-12-06 2012-04-10 President And Fellows Of Harvard College Nanoscale wire-based data storage
WO2006067276A1 (fr) * 2004-12-23 2006-06-29 Nanolab Systems Oy Utilisation de nanofils dans une analyse chimique et biologique
US8232584B2 (en) 2005-05-25 2012-07-31 President And Fellows Of Harvard College Nanoscale sensors
US7858965B2 (en) 2005-06-06 2010-12-28 President And Fellows Of Harvard College Nanowire heterostructures
US9102521B2 (en) 2006-06-12 2015-08-11 President And Fellows Of Harvard College Nanosensors and related technologies
US9903862B2 (en) 2006-06-12 2018-02-27 President And Fellows Of Harvard College Nanosensors and related technologies
US8058640B2 (en) 2006-09-11 2011-11-15 President And Fellows Of Harvard College Branched nanoscale wires
US8575663B2 (en) 2006-11-22 2013-11-05 President And Fellows Of Harvard College High-sensitivity nanoscale wire sensors
US9535063B2 (en) 2006-11-22 2017-01-03 President And Fellows Of Harvard College High-sensitivity nanoscale wire sensors
EP2406621A4 (fr) * 2009-03-11 2014-08-20 Agency Science Tech & Res Capteur électrique permettant une détection ultrasensible d'acide nucléique
US9390951B2 (en) 2009-05-26 2016-07-12 Sharp Kabushiki Kaisha Methods and systems for electric field deposition of nanowires and other devices
US9297796B2 (en) 2009-09-24 2016-03-29 President And Fellows Of Harvard College Bent nanowires and related probing of species
WO2019191648A1 (fr) * 2018-03-29 2019-10-03 The Regents Of The University Of California Biorésistances virales
US20210018463A1 (en) * 2018-03-29 2021-01-21 The Regents Of The University Of California Virus bioresistors
EP3775292A4 (fr) * 2018-03-29 2022-01-12 The Regents of the University of California Biorésistances virales
US20220364162A1 (en) * 2018-08-14 2022-11-17 Korea University Research And Business Foundation Method for synthesizing single metal nanobridged structure and method for manufacturing dna point mutation detection sensor by using same

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