WO1999012035A1 - A porous semiconductor-based optical interferometric sensor - Google Patents
A porous semiconductor-based optical interferometric sensor Download PDFInfo
- Publication number
- WO1999012035A1 WO1999012035A1 PCT/US1998/018331 US9818331W WO9912035A1 WO 1999012035 A1 WO1999012035 A1 WO 1999012035A1 US 9818331 W US9818331 W US 9818331W WO 9912035 A1 WO9912035 A1 WO 9912035A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- analyte
- substrate
- porous
- binder compound
- fabry
- Prior art date
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/41—Refractivity; Phase-affecting properties, e.g. optical path length
- G01N21/45—Refractivity; Phase-affecting properties, e.g. optical path length using interferometric methods; using Schlieren methods
-
- 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
- G01N33/5438—Electrodes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/41—Refractivity; Phase-affecting properties, e.g. optical path length
- G01N21/45—Refractivity; Phase-affecting properties, e.g. optical path length using interferometric methods; using Schlieren methods
- G01N2021/458—Refractivity; Phase-affecting properties, e.g. optical path length using interferometric methods; using Schlieren methods using interferential sensor, e.g. sensor fibre, possibly on optical waveguide
-
- 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/808—Optical sensing apparatus
-
- 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/973—Simultaneous determination of more than one analyte
-
- 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/805—Optical property
Abstract
The measurement of the wavelength shifts in the reflectometric interference spectra of a porous semiconductor substrate such as silicon, make possible the highly sensitive detection, identification and quantification of small analyte molecules. The sensor of the subject invention is effective in detecting multiple layers of biomolecular interactions, termed 'cascade sensing', including sensitive detection of small molecule recognition events that take place relatively far from the semiconductor surface.
Description
A POROUS SEMICONDUCTOR-BASED OPTICAL INTERFEROMETRIC SENSOR
Description
Governmental Support
This invention was made with governmental support under Contract No. NO0014 -95 -1-1293 by the ONR. The government has certain rights in the invention.
Technical Field
This invention is related to solid state sensors and, more particularly, to the use and preparation of a porous semiconductor such as a silicon wafer for the quantitative and qualitative analysis of an analyte such as an organic analyte.
Background of the Invention
Solid-state sensors and particularly biosensors have received considerable attention lately due to their increasing utility in chemical, biological, and pharmaceutical research as well as disease diagnostics. In general, biosensors consist of two components: a highly specific recognition element and a transducing structure that converts the molecular recognition event into a quantifiable signal.
Biosensors have been developed to detect a variety of biomolecular complexes including oligonucleotide pairs, antibody-antigen, hormone-receptor, enzyme-substrate and lectin-glycoprotein interactions. Signal transductions are generally accomplished with electrochemical, field-effect transistor, optical absorption, fluorescence or interferometric devices.
It is known that the intensity of the visible photoluminescence changes of a porous silicon film depend on the types of gases adsorbed to its surface. Based on this phenomenon, a simple and inexpensive chemical sensor device was developed and disclosed in U.S. Patent No. 5,338,415.
As disclosed in that patent, porous films of porous films of silicon (Si) can be fabricated that display well-resolved Fabry-Perot fringes in their optical reflectance properties. The production of a porous silicon (Si) layer that is optically uniform enough to exhibit these properties may be important for the design of etalons (thin film optical interference devices for laser spectroscopy applications) and other optical components utilizing porous Si wafers. Such interference-based spectra are sensitive to gases or liquids adsorbed to the inner surfaces of the porous Si layer.
Ever increasing attention is being paid to detection and analysis of low concentrations of analytes in various biologic and organic environments. Qualitative analysis of such analytes is generally limited to the higher concentration levels, whereas quantitative analysis usually requires labeling with a
radioisotope or fluorescent reagent . Such procedures are time consuming and inconvenient. Thus, it would be extremely beneficial to have a quick and simple means of qualitatively and quantitatively detect analytes at low concentration levels. The invention described hereinafter provides one such means .
Brief Summary of the Invention
The subject invention contemplates the detection and, if desired, measurement of the wavelength shifts in the reflectometric interference spectra of a porous semiconductor substrate such as a silicon substrate that make possible the highly sensitive detection, identification and quantification of small molecules and particularly, small organic molecules (i.e., carbon-containing molecules e.g., biotin, and the steroid digoxigenin) , short DNA oligonucleotides (e.g., 16-mers) , and proteins (e.g., streptavidin and antibodies) . The binding of inorganic species such as metal ions is also contemplated. Most notably, the sensor of the subject invention has been shown to be highly effective in detecting multiple layers of biomolecular interactions, termed "cascade sensing" , including sensitive detection of small molecule recognition events that take place relatively far from the silicon surface.
In an exemplary embodiment, a p-type silicon (Si) wafer (substrate) is galvanostatically etched in a hydrofluoric acid (HF) -containing solution. The etched wafer is rinsed with ethanol and dried under a stream of nitrogen gas. Reflection of white light off the
porous silicon results in an interference pattern that is related to the effective optical thickness. The binding of an analyte to a recognition partner immobilized in the porous silicon substrate results in a change in the refractive index, which is detected as a wavelength shift in the reflection interference pattern.
One benefit of the present invention is the provision of a device for detecting the presence of target (analyte) molecules such as biological or organic compound molecules at very low concentrations . An advantage of the present invention is the provision of a means for detecting the presence of multilayered molecular assemblies. Still another benefit of the present invention is a device that is capable of quantitatively detecting an analyte.
Still another advantage of the present invention is that the presence of an analyte in a sample solution can often be detected by visual inspection, and without the need for special apparatus. Still further benefits and advantages will be apparent to a worker of ordinary skill from the disclosure that follows.
Brief Description of the Drawings
An understanding of the present invention will be facilitated by consideration of the following detailed description of a preferred embodiment of the present invention, taken in conjunction with the
accompanying drawings, in which like reference numerals refer to like parts and in which:
FIG. 1 is a schematic representation of the porous semiconductor, e.g., silicon-based optical interferometric biosensor of the present invention.
FIGs. 2A and 2B are interferometric reflectance spectra of DNA-modified porous Si layers.
FIG. 3 shows the change in effective optical thickness in a DNA-A-modified porous Si layer as a function of DNA-A' concentration.
FIGs. 4A, 4B, 4C and 4D are cascade sensing and reflectometric interference spectra of multilayered molecular assemblies.
Detailed Description of the Invention
A contemplated interferometric sensor is depicted in FIG. 1 and is extremely sensitive in detecting the presence of a number of ligands (analytes) that bind specifically to a chemical binder on the sensor surface. For example, the lowest DNA concentration measured with a contemplated porous Si interferometric sensor was 9 fg/mm2. For comparison, the detection limits of current technologies are: Interferometry (100 pg/mm2) ; Grating Couplers (2.5 pg/mm2) ; Surface Plasmon Resonance (10 pg/mm2) .
The devices and methods of the present invention employ a porous semiconductor layer as an element of their interferometric sensors. A "porous semiconductor layer" is a porous layer having a relatively consistent thickness, relatively consistent porosity and made up of a semiconducting solid that is
relatively transparent. A "semiconducting" material is one having a bulk resistivity of from about 1 to about 1 x 107 ohms per cm.
The term "transparent" as used herein refers to the property of a material to transmit a fraction, such as at least about 20% of a suitable range of wave lengths of light from which Fabry-Perot fringes can be generated.
The term "light" is employed herein to include not only the visible portion of the electromagnetic spectrum, i.e. 350-800 nm, but also the infrared region of from say 800-3000 nm and the ultraviolet region of from about 50-350 nm. Longer and shorter wavelengths can be employed as well . The wavelengths employed can play a part in the selection of layer thickness and pore size of the porous semiconductor layer. As a general rule shorter wavelengths permit thinner layer thicknesses and smaller pore sizes while longer wavelengths permit thicker layer thicknesses and larger pose sizes.
The porous semiconductor layer can range in thickness from about 0.5 to about 30 microns with thicknesses of from about 1 or 2 to about 10 microns being preferred when visible light such as white light is employed and with thicknesses of from about 5 to about 30 microns being preferred with infrared wave lengths and thicknesses of from about 0.5 to 5 microns being preferred with ultraviolet wave lengths. The pores (or cavities) in the porous semiconductor layers are typically sized in terms of their nominal "diameter" notwithstanding the fact that
they are somewhat irregular in shape . These diameters range from about 2 nm to about 2000 nm with diameters of from about 10 to about 200 nm being preferred for visible light and 2-50 nm diameters being preferred for ultraviolet light and 100 to 2000 nm being preferred for infrared light. The surface of the solid semiconductor is flat with a substantial degree of porosity such as from about 10% to about 80% of the surface area and typically from 20 to 70% of the surface area.
The semiconducting porous layer can be formed of any semiconductor capable of being formed into the porous structure of the desired thickness and porosity. Silicon and silicon alloys are preferred semiconductors because of their amenability to the preferred galvanic etching process described herein for forming porous structures. These materials can include p-doped silicon, n-doped silicon, intrinsic (undoped) silicon, as well as alloys of these materials with, for example germanin in amounts of up to about 10% by weight as well as mixtures of these materials.
A representative device depicted in FIG. 1 is prepared from an electrochemical etch of a semiconductor such as single-crystal p-type (boron- doped) silicon wafers that produce microporous silicon that displays well-resolved Fabry-Perot fringes in its reflectometric interference spectrum. Silicon- containing (silicious) semiconductors are preferred herein, and although p-type silicon wafers are utilized herein as exemplary substrates, it is to be understood that n-type silicon and undoped, intrinsic silicon can
be used, as a silicon-germanium (Si-Ge) alloy containing up to about 10 mole percent germanium, Group III element nitrides and other etchable semiconductor substrates . Exemplary semiconductor substrates and dopants are noted below.
n dopant p dopant
H2Se (CH3)2Zn
H2S (C2H5)2 Zn
(CH3)3Sn (C2H5)2 Be
(C2H5)3Sn (CH3)2Cd
siH4 (ηC2H5)2Mg
Si2H6 B
P Al
As Ga
Sb In
The substrate can be GaAs, Si, Al203, MgO, Ti02, SiC, ZnO, LiGa02, LiA102, MgAl204 or GaN.
Reflection of light at the top (surface) and bottom of the exemplary porous semiconductor layer results in an interference pattern that is related to the effective optical thickness (product of thickness L and refractive index n) of the film by eq. 1, mk = 2 nL (1)
where m is the spectral order and λ is the wavelength of light. Binding of an analyte to its corresponding recognition partner, immobilized on the porous silicon substrate area results in a change in refractive index of the layer medium and is detected as a corresponding shift in the interference pattern.
The refractive index, n, for the porous semiconductor in use is related to the index of the semiconductor and the index of the materials present (contents) in the pores pursuant to eq. 2
n-(l P) nsemiconcjuctor + Pncontents (2)
Where P = porosity of porous semiconductor layer; nsemiconductor = refractive index of semiconductor; ncontents = refractive index of the contents of the pores.
The index of refraction of the contents of the pores changes when the concentration of analyte species in the pores changes. Most commonly, the analyte (target) species is an organic species that has a refractive index that is larger than that of the semiconductor. The replacement of a species of lower index of refraction (water) by another species of higher index of refraction (analyte) would be expected to lead to an increase in the overall value for index of refraction. An increase in index should result in a shift in the interference pattern wavelengths to longer
values; i.e., a bathochromic or "red" shift pursuant to equation 1. Contrarily, the observed shift in interference pattern wavelengths is opposite that which is expected; i.e., is toward shorter wavelengths exhibiting a hypsochromic or "blue" shift.
The basis for the observed wavelength blue shift is not understood with certainty. However, the observed, unexpected hypsochromic shift in wavelengths is believed to be the result of a reduction in the index of refraction of the semiconductor itself that is induced by the intimate association of the semiconductor with the bound analyte .
White light is preferred for carrying out reflectance measurements, and is used illustratively herein. The use of white light or other light in the visual spectrum can permit a determination of the presence of an analyte in a sample by visual inspection of a color change in the reflected light without the need of special apparatus. It should be understood, however, that reflected infrared (IR) and ultraviolet
(UV) light canals be utilized along with an appropriate spectral measuring device .
The sensors of the present invention include the binder molecule (also referred to as the "recognition partner") for the analyte and the like that is bound to or otherwise intimately associated with the porous semiconductor surface. This intimate association can be accomplished by any approach that leads to the tethering of the binder molecule to the semiconductor. This includes without limitation covalently bonding the binder molecule to the
semiconductor, ionically associating the binder molecule to the substrate, adsorbing the binder molecule onto the surface of the semiconductor, or the like. Such association can also include covalently attaching the binder molecule to another moiety, which in turn is covalently bonded to the semiconductor, bonding the target molecule via hybridization or another biological association mechanism to another moiety with is coupled to the semiconductor. The binding of an analyte to its corresponding recognition partner, immobilized on the porous silicon substrate, results in a change in refractive index of the layer medium and is detected as a corresponding shift in the interference pattern. Recognition partners or binding compounds can be peptides, small molecules (molecular weight of less than about 500) , metal ions and their preferably organic binding ligands, antibodies, antigens, DNA, RNA or enzymes. More broadly, a recognition partner can be any receptor of an acceptor molecule that can be adsorbed by the substrate and binds to a ligand provided by of another molecule or ion.
More specifically, the Examples that follow illustrate use of two different single strands of binder DNA (SEQ ID NOs : 1 and 2) bound to the porous silicon substrate, and two different single DNA strands (SEQ ID NOs : 3 and 4, respectively) as analyte (Examples 1 and 3) . Example 4 illustrates the use of a biotin- bound porous silicon substrate with strepavidin, as well as biotnylated anti-mouse antibodies that were used to analyze for mouse-anti-digoxigenin, and those
antibodies were then used to assay for the presence of digoxigenin. Further exemplary binding pairs include so-called polypeptide P-62 (SEQ ID N0:5) of U.S. Re. 33,897 (1992), whose disclosures are incorporated by reference, with human antibodies to the Epstein-Barr nuclear antigen (EBNA) as analyte; monoclonal antibodies ATCC HB 8742 or HB 8746 that immunoreact with human apolipoprotein B-100 as analyte, or monoclonal antibodies ATCC HB 9200 or HB 9201 that immunoreact with human apolipoprotein A-I as analyte as are described in U.S. Patent No. 4,828,986, whose disclosures are incorporated by reference; and the several deposited monoclonal antibodies listed at column 13 of U.S. Patent No. 5,281,710, and their listed binding partners as analyte, which disclosures are incorporated by reference.
Electrochemical etching of Si can generate a thin (approximately 1-10 μm) layer of porous Si on the silicon substrate with cavities of about 10 nm to about 200 nm in diameter, providing a large surface area for biomolecular interaction inside the porous Si layer. The porous films are uniform and sufficiently transparent to display Fabry-Perot fringes in their optical reflection spectrum. More particularly, a porous Si substrate is prepared by an electrochemical etch of a polished (100) -oriented p-type silicon (B-doped 3 Ohm-cm resistivity) wafer. The etching solution is prepared by adding an equal volume of pure ethanol to an aqueous solution of HF (48% by weight) . The etching cell is constructed of Teflon® and is open to air.
Si wafers are cut into squares with a diamond scribe and mounted in the bottom of the Teflon® cell with an 0-ring seal, exposing 0.3 cm2 of the Si surface. Electrical contact is made to the back side of the Si wafer with a strip of heavy aluminum foil, such as heavy duty household aluminum foil. A loop of platinum wire is used as a counter-electrode. The exposed Si face can be illuminated with light from a tungsten lamp for the duration of the etch in order to enhance the optical properties of the films. Etching is illustratively carried out as a 2 -electrode galvanostatic operation at an anodic current density of 5 mA/cm2 for 33 minutes. After etching, the samples are rinsed in ethanol and dried under a stream of N2 • Scanning electron microscopy and atomic force microscopy showed that porous silicon films so prepared were about 5-10 microns thick and contained an average of 200 nm diameter pores.
The porous semiconductor so prepared was modified by oxidation with bromine gas in an evacuated chamber for one hour, followed by hydrolysis in air. The molecular recognition elements were then attached to the resulting silicon dioxide surface using conventional techniques. The sensors of this invention can be employed as discrete, independent units. Multiple sensors can also be arrayed together. Where multiple sensors are desired to be arrayed together, a plurality of porous areas can be etched on to the surface of a single semiconductor substrate in much the same way as microchip patterns are prepared A plurality of
separate porous areas can also be combined to form a desired array.
An array of sensors can make it possible to have a plurality of concentrations of a single binder molecule on a single plate so as to provide a "dose- response curve" for a particular analyte. Multiple sensors also can make it possible to have a plurality of different binder molecules on the same plate so as to make multiple screenings in a single test. A sensor having a plurality of individual porous areas can be analogized to a multi-well microtiter plate, and can contain the same or different associated binder compound at any desired porous area so that the same or a different binding assay can be carried out on each porous area. The individual binder compound-porous areas are then illuminated. Binding studies with analytes are then carried out for those areas, followed by reillumination. Binding results are obtained in a manner similar to that used for the individual porous areas exemplified herein.
Spectral Measurement. To measure optical interference spectra, a Princeton Instruments CCD photodetector/Acton research 0.25 m monochrometer, fitted with a fiber optic and microscope objective lens to permit detection from small (< 1 mm2) sample areas was used for the studies described here, but similar equipment is well-known and can be used instead. The white light source for the experiments was a low intensity krypton, tungston or other incandescent bulb. A linear polarizing filter was used to enhance the appearance of the interference spectra.
The substrate can be pre-treated with a chemical receptor (binder compound) species (such as an antibody) to provide chemical specificity. For gas measurements, the sample was mounted in a Pyrex® dosing chamber and exposed to the gaseous analyte of interest . For liquid-phase measurements, as in an aqueous medium, a Teflon® and O-ring cell similar to the cell employed in etching the porous layer was used. Measurements have also been taken using a liquid flow-through chamber equipped with glass or plastic window.
The fringe pattern can be changed by replacing the air or liquid in the pores with a material of differing refractive index. The shift in fringe maxima corresponds to a change in the average refractive index of the thin film medium. Solution of the simultaneous equations provided by measurement of the fringe spacing provides a quantitative measurement that can be related to the analyte concentration. Chemical specificity can be introduced by incorporating or chemically bonding molecular recognition agents such as peptides, antibodies, antigens, single- or double- strand DNA or RNA, enzymes, a metal ion-binding ligand and the like onto the inner surfaces of the porous Si film. Control measurements can be performed on a similar sample that does not contain the molecular recognition elements. Further details as to the preparation of a porous silicon substrate and apparatus used for spectral measurements can be found in U.S. Patent No. 5,338,415, whose disclosures are incorporated by reference.
Thus, one aspect of the invention contemplates a process for detecting a analyte molecule such as an organic molecule analyte. In accordance with that process, a porous silicon substrate is provided and prepared, and that prepared substrate is provided and contacted with a binder compound to form a binder compound-bound substrate. The wavelength maximum of the Fabry-Perot fringes is determined upon illumination of the binder compound-bound substrate. That binder compound-bound substrate is thereafter contacted with a sample to be assayed that may contain an analyte that is an organic molecule that binds to the binder compound of the substrate. When the desired analyte is present in the sample, in distilled water or various buffer solutions that ligand binds to the binder compound to form a ligand-bound substrate. The contact between the sample and binder compound-bound substrate can be maintained for a few seconds to several hours, as desired to form the ligand-bound substrate. When the substrate is thereafter reilluminated with the same light source, a shift in the wavelength maximum of the Fabry-Perot fringes from that previously determined indicates the detection and therefore presence of the analyte in the sample. Without committing to any particular theory in support of the subject invention, it is believed that the unique sensitivity of the system involves selective incorporation or concentration of an analyte such as an illustrative organic analyte in the porous Si layer to modify the refractive index by two effects: increase of the average refractive index of the medium
in the pores by replacing water (refractive index 1.33) with organic matter (refractive index typically 1.45), and also decrease of the refractive index of the Si by modifying the carrier concentration in the semiconductor. A net increase in refractive index is expected to shift the interference spectrum to longer wavelengths, whereas a decrease in index is expected to shift the spectrum to shorter wavelengths. Without exception, a shift to shorter wavelengths in such cases has been observed, indicating that the induced change in the semiconductor overwhelms the refractive index change occurring in the solution phase.
Each of Examples 1-3 was carried out in 1.0 M aqueous NaCl at 25°C, whereas Examples 4 and 5 were carried out in 0.5 M NaCl .
EXAMPLE 1
Binder DNA oligonucleotide-derivatized porous silicon films were employed to test the selectivity and limits of detection of a contemplated sensor. For attachment of DNA, a trimethoxy-3-bromoacetamido- propylsilane linker was synthesized by reaction of bromoacetic acid with trimethoxy- (3-aminopropyl) silane in the presence of 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide-hydrochloride in methylene chloride as solvent The linker product was purified by column chromatography on silica gel . The oxidized porous silicon samples were then contacted with a toluene solution of the linker for 2 hours . The resulting linker-bound substrate was thoroughly rinsed with pure
toluene and methylene chloride, and dried for about 18 hours under reduced pressure.
HPLC-Purified 5 ' -phopsphorothiate oligonucleotides (DNA-A and DNA-B, illustrated hereinafter) were separately dissolved at about 50 nmol in a solution of 1:1:0.2; water/DMF/5%NaHC03 and admixed with the linker-bound porous semiconductor substrate for about 2 hours . The presence of the DNA- modification on the porous surface of the resulting binder compound -bound substrate was confirmed by FTIR spectroscopy.
In the presence of complementary analyte DNA sequences (DNA concentrations ranging from 2xl0"15 M to 2xl0"δ M) pronounced wavelength shifts in the interference pattern of the porous silicon films were observed (FIG. 2) . Under similar conditions but in the presence of noncomplementary DNA sequences, no significant shift in the wavelength of the interference fringe pattern was detected-only minor amplitude fluctuations were observed.
Specifically, measurements were made of two DNA sequences :
DNA-A: 5'-pGC CAG AAC CCA GTA GT-3'
SEQ ID NO:l and
DNA-B: 5'-CCG GAC AGA AGC AGA A-3'
SEQ ID NO: 2,
and corresponding complementary strands [ (DNA-A' (SEQ ID NO:3) and DNA-B'v (SEQ ID NO:4)] . For clarity, only one set of data are shown.
In FIG. 2A, the Fabry-Perot fringes 10 from a porous Si surface derivatized with DNA-A are shown to shift to shorter wavelength 11 upon exposure to a 2x10" 12 M solution of DNA-A' (the complementary sequence of DNA-A) in 1 M NaCl (aq) . The net change in effective optical thickness (from 7,986 to 7,925 nm) upon DNA-A' recognition is represented by the difference 12 between the two interference spectra.
EXAMPLE 2
FIG. 2B represents a control for Example 1, showing the Fabry-Perot fringes 10a of a DNA-A derivatized porous Si surface before and after exposure to a 2xl0"12 M solution of DNA-B (non-complementary sequence) in 1 M NaCl (aq) . No wavelength shift was observed up to the measured concentration of 10"9 M of DNA-B.
EXAMPLE 3
Fluorescence spectroscopy was used to independently investigate the surface coverage of immobilized DNA on porous Si and the rate of analyte diffusion into the Si substrate for the purposes of comparison with the subject invention. Solutions of fluorescein-labeled analyte complementary DNA oligonucleotides were placed in fluorescence cuvettes and the binder DNA-derivatized porous Si substrate was
then added to the cell without stirring. At lowest DNA concentrations employed in the study, the fluorescence intensity of the samples decreased to an asymptotic limit in 40 min (similar equilibration times were observed in the interferometric measurements described above) (FIG. 3) . The data indicate 1.1 x 10~12 mol of bound DNA in a 1 mm2 porous Si substrate (calculated from standardized fluorescence titration curves) . The data obtained from the reflectometric interference measurements also provided a similar coverage number.
EXAMPLE 4
The subject invention was used to sense multiple layers of biomolecular interactions (cascade sensing) and small molecule detection. A linker with attached biotin was prepared by reaction of Iodoacetyl- LC-biotin (Pierce Biochemicals) with 3-mercaptopropyl- trimethoxysilane (Aldrich Chemicals) in dimethylformamide (DMF) . After purification, the biotinylated linker was dissolved in ethanol or DMF and the oxidized, porous semiconductor was immersed in the solution for 12 hours. The sample was then rinsed thoroughly with ethanol, and dried under a stream of nitrogen to provide a binder compound-bound substrate .
Exposure of a biotinylated (binder) porous Si substrate to a 5xl07 M analyte streptavidin solution resulted in a large blue-shift of the interference fringes, corresponding to a decrease in the measured effective optical thickness from 12,507-11,994 nm (the lowest streptavidin concentration employed was 10~14 M) (FIG. 4A) . Control studies performed by exposing a biotinylated porous Si substrate to inactivated streptavidin (streptavidin pre-saturated with biotin) did not display perceptible shifts in interference pattern.
The biotin-streptavidin monolayer surface was contacted with aqueous 10"^ M biotinylated anti-mouse IgG (from goat IgG) . Binding of this secondary antibody to the surface was indicated by a decrease in effective optical thickness of the monolayer from 11,997 to 11,767 (lowest concentration employed with a detectable signal was 10"12 M) (FIG. 4B) . Treatment of the secondary antibody sample with anti-digoxigenin (mouse IgG) at a concentration of 10"^ M caused a further decrease in the effective optical thickness of the monolayer from 11,706 to 11,525 nm (FIG. 4C) . The interaction of digoxigenin (10"^ M) , a steroid with molecular weight of 392, with the anti-digoxigenin IgG- bound porous Si surface was also detected with a decrease of the effective optical thickness from 11,508 to 11,346 nm (FIG. 4D) .
EXAMPLE 5
To rule out the possibility of nonspecific interaction, a non-biotinylated surface was subjected to the same solution, and conditions as described in Example 4. No measurable change in the effective optical thickness was observed on treatment with streptavidin, secondary antibody, primary antibody, and digoxigenin. Detection of the relatively small biotin molecule (MW=244) at concentrations as low as 10"12 M has also been demonstrated using biotin-streptavidin- modified porous Si.
Although the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments and equivalents falling within the scope of the appended claims. Various features of the invention are set forth in the following claims.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: Ghadiri, M. Reza
Sailor, Michael J. Motesharei , Kianoush Lin, Shang-Yi Dancil, Keiki-Pua S.
(ii) TITLE OF INVENTION: A POROUS SILICON-BASED OPTICAL INTERFEROMETRIC BIOSENSOR
(iii) NUMBER OF SEQUENCES: 5
(iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Welsh & Katz, Ltd.
(B) STREET: 120 South Riverside Plaza, 22nd Floor
(C) CITY: Chicago
(D) STATE: IL
(E) COUNTRY: USA
(F) ZIP: 60606
(v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.30
(vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME:Gamson, Edward P.
(B) REGISTRATION NUMBER: 29,381
(C) REFERENCE/DOCKET NUMBER: 71578
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (312) 655-1500
(B) TELEFAX: (312) 655-1501
(2) INFORMATION FOR SEQ ID NO : 1 :
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS : single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(A) DESCRIPTION: /desc = "synthetic DNA sequences"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: GCCAGAACCC AGTAGT 16
(2) INFORMATION FOR SEQ ID NO: 2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS : single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(A) DESCRIPTION: /desc = "synthetic DNA sequence"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 2 : CCGGACAGAA GCAGAA IS
(2) INFORMATION FOR SEQ ID NO: 3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(A) DESCRIPTION: /desc = "synthetic DNA sequence"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: ACTACTGGGT TCTGGC 16
(2) INFORMATION FOR SEQ ID NO:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(A) DESCRIPTION: /desc = "synthetic DNA sequence"
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:4: TTCTGCTTCT GTCCGG 16
(2) INFORMATION FOR SEQ ID NO : 5 :
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: not relevant
(ii) MOLECULE TYPE: peptide
(x) PUBLICATION INFORMATION:
(A) AUTHORS: Vaughan, John H.
Carson, Dennis A. Rhodes, Gary Houghten, Richard A.
(B) TITLE: Synthetic Polypeptides and Antibodies Related to Epstein-Barr Virus Nuclear Antigen
(C) JOURNAL: U.S. Patent No. Re. 33,897 (G) DATE: Apr. 21-1992
(K) RELEVANT RESIDUES IN SEQ ID NO : 5 : FROM 1 TO 20
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:
Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly 1 5 10 15
Ala Gly Gly Ala Gly 20
Claims
1. A process for detecting an analyte in a sample to be assayed comprising the steps of :
(a) providing a porous semiconductor substrate having a bound binder compound that forms a binder compound-bound substrate and determining the wavelength of the Fabry-Perot fringes upon illumination of said binder compound-bound substrate;
(b) contacting said binder compound-bound substrate with a sample to be assayed, said analyte present in said binding to said binder compound to form a ligand-bound substrate; and
(c) thereafter reilluminating said substrate; whereby a shift in the wavelength maximum of the Fabry- Perot fringes indicates the detection of said analyte in the sample .
2. The process of claim 1 wherein said porous semiconductor substrate is silicon.
3. The process of claim 1 wherein said binder compound is an organic molecule.
4. The process of claim 1 wherein said analyte is an organic molecule.
5. A process for detecting an organic molecule analyte in a sample to be assayed comprising the steps of: (a) providing a porous silicon semiconductor substrate having a bound binder compound that forms a binder compound-bound substrate and determining the wavelength of the Fabry-Perot fringes upon illumination of said binder compound-bound substrate;
(b) contacting said binder compound-bound substrate with a sample to be assayed, said organic molecule analyte present in said sample binding to said binder compound to form a analyte-bound substrate; and (c) thereafter reilluminating said substrate; whereby a shift in the wavelength maximum of the Fabry- Perot fringes indicates the detection of said organic molecule analyte in the sample.
6. The process of claim 5 wherein said provided substrate is prepared by the steps of :
(a) etching said substrate; and
(b) washing said etched substrate.
7. The process of claim 5 wherein said binder compound is selected from the group consisting of peptides, antibodies, antigens, DNA, RNA, ligands that bind to metal ions and enzymes .
8. The method of claim 5 wherein said contacting of step (b) is carried out in an aqueous, liquid medium.
9. A process of quantitatively detecting organic analyte molecules in a sample comprising the steps of :
(a) preparing a porous silicon semiconductor substrate;
(b) contacting said substrate with a binder compound to form a binder compound-bound substrate and determining the wavelength of the Fabry-Perot fringes upon illumination of said binder compound-bound substrate;
(c) introducing a sample having an unknown concentration of an organic molecule analyte at a plurality of dilutions and measuring the shift in wavelength of the Fabry-Perot fringes at said dilutions to prepare a first dose response curve of the unknown concentration of the organic molecule analyte;
(d) providing a second, standard, dose response curve of Fabry-Perot fringe wavelength shifts of known concentrations of the organic molecule analyte; and
(e) comparing said first curve with said second curve on a log vs . log plot to thereby obtain the concentration of said organic molecule analyte in said sample.
10. In a solid state sensor for detecting Fabry-Perot fringes from the reflection of light from a semiconductor substrate, the improvement comprising a semiconductor substrate having a porous surface, said substrate surface having an organic binder compound adsorbed thereon.
11. The sensor of claim 10 further including a solution of an organic compound having an analyte that binds to said organic binder compound, said semiconductor substrate, when containing said analyte bound to said organic binder compound reflecting light to exhibit Fabry-Perot fringe wavelengths different from those exhibited when the analyte is not so bound.
12. A reflective sensor comprising a semiconductor substrate having a porous surface area, said substrate surface area having an organic binder compound intimately associated thereon, said binder compound binding selectively with said analyte.
13. The reflective sensor of claim 12 wherein said semiconductor is a silicious semiconductor .
14. The sensor of claim 13 wherein said silicious semiconductor is selected from the group consisting of intrinsic silicon, p-doped silicon, n- doped silicon, alloys of silicon and mixtures thereof.
15. The sensor of claim 14 wherein said alloys of silicon comprise silicon alloyed with up to about 10% by weight of germanium.
16. The reflective sensor of claim 12 wherein said binder compound is selected from the group consisting of peptides, antibodies, antigens, DNA, RNA, ligands that bind to metal ions and enzymes.
17. The reflective sensor of claim 12 wherein said semiconductor surface defines a plurality of said porous surface areas having an organic binder compound adsorbed thereon.
18. A reflective sensor for an analyte comprising a layer of porous semiconductor with a binder compound for the analyte intimately associated therewith, said layer being substantially transparent and having a top surface and a bottom surface which reflect light to exhibit Fabry-Perot fringes having a first set of characteristic wave lengths in the absence of analyte and a second set of characteristic wave lengths when analyte is present, said second set of characteristic wave lengths being detectably shifted from said first set of characteristic wavelengths.
19. The reflective sensor of claim 18 wherein said layer of porous semiconductor with a binder compound for the analyte intimately associated therewith exhibits a first index of refraction, wherein said analyte exhibits a second index of refraction which is greater than said first index of refraction, but wherein the second set of characteristic wavelengths is shorter than the first set of characteristic wave lengths.
20. The reflective sensor of claim 19 wherein said semiconductor comprises silicon.
21. An analytical sensor for detecting a target species comprising a porous semiconductor layer of a thickness selected to generate Fabry-Perot fringes from the reflection of light therefrom, said Fabry- Perot fringes having a first set of characteristic peak wavelengths in the absence of the target species and a second set of characteristic peak wavelengths in the presence of the target species with the second set of peak wave lengths being shifted toward shorter wavelengths relative to said first set of wavelengths.
22. The analytical sensor of claim 21 wherein said semiconductor comprises silicon.
23. The analytical sensor of claim 22 wherein the porous silicon has a first index of refraction and said target species has a second index of refraction which is higher than said first index of refraction.
24. The analytical sensor of claim 23 additionally comprising a binder material intimately associated with the porous silicon layer, said binder material specifically binding the target species.
25. A process for detecting a target species in a sample to be assayed comprising the steps of (a) selecting an assay sensor for the target species, the selected assay sensor comprising a layer of porous semiconductor and a binder material intimately associated therewith, said binder material specifically binding the target species, said layer of a thickness selected to generate Fabry-Perot fringes from the reflection of light therefrom, said Fabry- Perot fringes having a first set of peak wavelengths in the absence of the target species and a second set of peak wavelengths in the presence of the target species; and
(b) reflecting light off of the porous surface of the selected assay sensor in the presence of said sample and determining the presence or absence of the target species in the sample from the Fabry-Perot fringes in the reflected light.
26. The process of claim 25 wherein the porous semiconductor comprises porous silicon.
27. The process of claim 26 wherein the target species is an organic target species.
28. The process of claim 25 wherein said light comprises visible light.
29. The process of claim 25 wherein said light is white light.
30. The process of claim 25 wherein said light comprises infrared light.
31. The process of claim 25 wherein said light comprises ultraviolet light.
32. A reflective sensor array for at least one analyte comprising a layer of porous semiconductor with a plurality of discrete and separate regions having one or more binder compounds for at least one of the at least one analytes intimately associated therewith, said layer being substantially transparent and having a top surface and a bottom surface which reflect light in each of the plurality of regions to exhibit Fabry-Perot fringes for such regions having a first set of characteristic wave lengths in the absence of the at least one analyte and a second set of characteristic wave lengths when analyte is present, said second set of characteristic wave lengths being detectably shifted from said first set of characteristic wavelengths.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU91301/98A AU9130198A (en) | 1997-09-05 | 1998-09-04 | A porous semiconductor-based optical interferometric sensor |
US10/801,282 US6897965B2 (en) | 1997-09-05 | 2004-03-16 | Porous semiconductor-based optical interferometric sensor |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US92460197A | 1997-09-05 | 1997-09-05 | |
US08/924,601 | 1997-09-05 | ||
US08/961,308 US6248539B1 (en) | 1997-09-05 | 1997-10-30 | Porous semiconductor-based optical interferometric sensor |
US08/961,308 | 1997-10-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999012035A1 true WO1999012035A1 (en) | 1999-03-11 |
Family
ID=27129889
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/018331 WO1999012035A1 (en) | 1997-09-05 | 1998-09-04 | A porous semiconductor-based optical interferometric sensor |
Country Status (3)
Country | Link |
---|---|
US (3) | US6248539B1 (en) |
AU (1) | AU9130198A (en) |
WO (1) | WO1999012035A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1373894A1 (en) * | 2001-02-21 | 2004-01-02 | The University Of Rochester | Microcavity biosensor, methods of making, and uses thereof |
WO2013164659A1 (en) * | 2012-04-30 | 2013-11-07 | Tubitak | Methods for producing new silicon light source and devices |
WO2015024065A1 (en) * | 2013-08-23 | 2015-02-26 | Pregtech Pty Ltd | Methods and sensors for detecting a biological parameter |
EP2409136B1 (en) * | 2009-03-16 | 2017-05-17 | Ramot at Tel-Aviv University Ltd. | Device and method for optical sensing of substances or environmental conditions |
CN116363523A (en) * | 2023-03-10 | 2023-06-30 | 浙江省测绘科学技术研究院 | Pine wood nematode epidemic monitoring method, terminal and medium based on remote sensing information |
Families Citing this family (126)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6248539B1 (en) * | 1997-09-05 | 2001-06-19 | The Scripps Research Institute | Porous semiconductor-based optical interferometric sensor |
EP1056548B1 (en) * | 1998-01-22 | 2008-10-15 | Purdue Research Foundation | Functionalized porous silicon surfaces |
ATE423314T1 (en) | 1998-06-24 | 2009-03-15 | Illumina Inc | DECODING OF MATRIXED SENSORS BY MICROPARTICLES |
IL147531A0 (en) * | 1998-07-10 | 2002-08-14 | Iatroquest Corp | Photoluminescent semiconductor materials |
NZ515189A (en) * | 1999-05-01 | 2004-05-28 | Psimedica Ltd | Derivatized porous silicon as a biomaterial to use as a material for componets in or on the surface of the human body |
US7582420B2 (en) | 2001-07-12 | 2009-09-01 | Illumina, Inc. | Multiplex nucleic acid reactions |
US7955794B2 (en) | 2000-09-21 | 2011-06-07 | Illumina, Inc. | Multiplex nucleic acid reactions |
US20050214825A1 (en) * | 2000-02-07 | 2005-09-29 | John Stuelpnagel | Multiplex sample analysis on universal arrays |
US8076063B2 (en) | 2000-02-07 | 2011-12-13 | Illumina, Inc. | Multiplexed methylation detection methods |
US6519383B1 (en) * | 2000-11-28 | 2003-02-11 | Nortel Networks Limited | Photonic switch status tester |
US7018795B2 (en) * | 2001-03-23 | 2006-03-28 | Fuji Photo Film Co., Ltd. | Hybridization probe and target nucleic acid detecting kit, target nucleic acid detecting apparatus and target nucleic acid detecting method using the same |
US20030003476A1 (en) * | 2001-03-23 | 2003-01-02 | Fuji Photo Film Co., Ltd. | Waste water inspecting agent and waste water inspecting apparatus using the same |
US20020168756A1 (en) * | 2001-03-23 | 2002-11-14 | Fuji Photo Film Co., Ltd. | Particle size variable reactor |
US7077982B2 (en) * | 2001-03-23 | 2006-07-18 | Fuji Photo Film Co., Ltd. | Molecular electric wire, molecular electric wire circuit using the same and process for producing the molecular electric wire circuit |
US20020168667A1 (en) * | 2001-03-23 | 2002-11-14 | Fuji Photo Film Co., Ltd. | Antigen detecting agent and antigen detecting kit, antigen detecting apparatus and antigen detecting method using the same |
US20020168291A1 (en) * | 2001-03-23 | 2002-11-14 | Fuji Photo Film Co., Ltd. | Agent for health inspection and health inspection apparatus using the same |
JP4313959B2 (en) * | 2001-03-30 | 2009-08-12 | 日本電気株式会社 | Atomic reflection optical element |
US20040166593A1 (en) * | 2001-06-22 | 2004-08-26 | Nolte David D. | Adaptive interferometric multi-analyte high-speed biosensor |
WO2003036225A1 (en) * | 2001-10-26 | 2003-05-01 | University Of Rochester | Method for biomolecular sensing and system thereof |
DE10160987B4 (en) * | 2001-12-05 | 2005-08-04 | Siemens Ag | Assembly for simultaneous, optical illumination of a large number of samples |
AU2003207438A1 (en) * | 2002-01-02 | 2003-07-24 | Visen Medical, Inc. | Amine functionalized superparamagnetic nanoparticles for the synthesis of bioconjugates and uses therefor |
US7042570B2 (en) * | 2002-01-25 | 2006-05-09 | The Regents Of The University Of California | Porous thin film time-varying reflectivity analysis of samples |
US8765484B2 (en) * | 2002-02-07 | 2014-07-01 | The Regents Of The University Of California | Optically encoded particles |
WO2005062866A2 (en) * | 2003-12-22 | 2005-07-14 | The Regents Of The University Of California | Optically encoded particles, system and high-throughput screening |
US20030179381A1 (en) * | 2002-03-18 | 2003-09-25 | Fuji Photo Film Co., Ltd. | Sensor, color sensor and apparatus for inspection using the same |
GB0207431D0 (en) | 2002-03-28 | 2002-05-08 | Qinetiq Ltd | Signal analysis system |
US20060063178A1 (en) * | 2002-06-27 | 2006-03-23 | Trex Enterprises Corporation | Optical sensor and methods for measuring molecular binding interactions |
US7517656B2 (en) * | 2002-07-30 | 2009-04-14 | Trex Enterprises Corp. | Optical sensor and methods for measuring molecular binding interactions |
US6806543B2 (en) * | 2002-09-12 | 2004-10-19 | Intel Corporation | Microfluidic apparatus with integrated porous-substrate/sensor for real-time (bio)chemical molecule detection |
JP3786073B2 (en) * | 2002-10-10 | 2006-06-14 | 株式会社日立製作所 | Biochemical sensor kit and measuring device |
JP4294946B2 (en) * | 2002-12-13 | 2009-07-15 | 富士フイルム株式会社 | Target detection apparatus, target detection method, and target detection substrate |
CA2509909C (en) * | 2002-12-20 | 2011-05-24 | Fiso Technologies Inc. | Method and sensor for detecting a chemical substance using an optically anisotropic material |
US7076127B2 (en) | 2003-01-14 | 2006-07-11 | Fuji Photo Film Co., Ltd. | Optical switch and safety apparatus using the same |
US7713778B2 (en) * | 2003-02-13 | 2010-05-11 | Univ California | Nanostructured casting of organic and bio-polymers in porous silicon templates |
US7075642B2 (en) * | 2003-02-24 | 2006-07-11 | Intel Corporation | Method, structure, and apparatus for Raman spectroscopy |
WO2004111612A2 (en) | 2003-03-05 | 2004-12-23 | The Regents Of The University Of California | Porous nanostructures and methods involving the same |
US20040189982A1 (en) * | 2003-03-26 | 2004-09-30 | Institut National D'optique | Optical sensor for volatile organic compounds |
US7435391B2 (en) * | 2003-05-23 | 2008-10-14 | Lucent Technologies Inc. | Light-mediated micro-chemical reactors |
US20080102036A1 (en) * | 2003-06-04 | 2008-05-01 | Poss Kirtland G | Biocompatible Fluorescent Silicon Nanoparticles |
US20090081694A1 (en) * | 2003-07-08 | 2009-03-26 | Trex Enterprises Corp. | Modified well plates for molecular binding studies |
US7318903B2 (en) * | 2003-08-14 | 2008-01-15 | The Regents Of The University Of California | Photonic sensor particles and fabrication methods |
EP1516665A1 (en) * | 2003-09-18 | 2005-03-23 | Sony International (Europe) GmbH | A method of immobilizing and stretching a nucleic acid on a substrate |
US7394547B2 (en) * | 2003-11-06 | 2008-07-01 | Fortebio, Inc. | Fiber-optic assay apparatus based on phase-shift interferometry |
US7319525B2 (en) * | 2003-11-06 | 2008-01-15 | Fortebio, Inc. | Fiber-optic assay apparatus based on phase-shift interferometry |
US7019847B1 (en) | 2003-12-09 | 2006-03-28 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Ring-interferometric sol-gel bio-sensor |
EP1702414A4 (en) * | 2003-12-22 | 2008-04-23 | Univ California Office Of The | Optically encoded particles with grey scale spectra |
US20050148064A1 (en) * | 2003-12-29 | 2005-07-07 | Intel Corporation | Microfluid molecular-flow fractionator and bioreactor with integrated active/passive diffusion barrier |
US7271896B2 (en) * | 2003-12-29 | 2007-09-18 | Intel Corporation | Detection of biomolecules using porous biosensors and raman spectroscopy |
US20050148277A1 (en) * | 2004-01-02 | 2005-07-07 | Stephen Lister | Interactive command-repeater toy system |
DE102004034486B4 (en) * | 2004-07-16 | 2007-08-23 | Infineon Technologies Ag | Method for detecting luminescent light from a porous support structure |
US8097173B2 (en) * | 2004-07-19 | 2012-01-17 | The Regents Of The University Of California | Magnetic porous particles and method of making |
KR101137736B1 (en) * | 2004-09-30 | 2012-04-24 | 각코호진 와세다다이가쿠 | Semiconductor sensing field effect transistor, semiconductor sensing device, semiconductor sensor chip and semiconductor sensing device |
WO2006044957A2 (en) * | 2004-10-19 | 2006-04-27 | The Regents Of The University Of California | Porous photonic crystal with light scattering domains and methods of synthesis and use thereof |
ITNA20040067A1 (en) * | 2004-12-03 | 2005-03-03 | Consiglio Nazionale Ricerche | IMMOBILIZATION OF BIOMOLECULES ON POROUS SUPPORTS, VIA ELECTRONIC BEAM, FOR APPLICATIONS IN BIOMEDICAL AND ELECTRONIC FIELDS. |
US8206780B2 (en) * | 2004-12-14 | 2012-06-26 | The Regents Of The University Of California | Polymer composite photonic particles |
US7445887B2 (en) * | 2005-01-07 | 2008-11-04 | Fortebio, Inc. | Enzyme activity measurements using bio-layer interferometry |
US7391936B2 (en) * | 2005-01-21 | 2008-06-24 | Lucent Technologies, Inc. | Microfluidic sensors and methods for making the same |
US7910356B2 (en) * | 2005-02-01 | 2011-03-22 | Purdue Research Foundation | Multiplexed biological analyzer planar array apparatus and methods |
US20070023643A1 (en) * | 2005-02-01 | 2007-02-01 | Nolte David D | Differentially encoded biological analyzer planar array apparatus and methods |
US7405831B2 (en) * | 2005-02-01 | 2008-07-29 | Purdue Research Foundation | Laser scanning interferometric surface metrology |
US7875426B2 (en) * | 2005-02-04 | 2011-01-25 | University Of South Florida | DNA biochip and methods of use |
US20060234391A1 (en) * | 2005-02-18 | 2006-10-19 | University Of Rochester | Optical sensor based on resonant porous silicon structures |
US20070108465A1 (en) * | 2005-03-10 | 2007-05-17 | The Regents Of The University Of California | Porous microstructure multi layer spectroscopy and biosensing |
US20060276047A1 (en) * | 2005-03-14 | 2006-12-07 | University Of Rochester | Macroporous silicon microcavity with tunable pore size |
US20070007241A1 (en) * | 2005-04-20 | 2007-01-11 | University Of Rochester | Methods of making and modifying porous devices for biomedical applications |
US20070048731A1 (en) * | 2005-05-20 | 2007-03-01 | Neurosilicon | High throughput use-dependent assay based on stimulation of cells on a silicon surface |
US20070017530A1 (en) * | 2005-06-10 | 2007-01-25 | Syed Naweed I | Detecting electrical activity and assessing agents for the ability to influence electrical activity |
US20100261288A1 (en) | 2005-06-13 | 2010-10-14 | Fortebio, Inc. | Tip tray assembly for optical sensors |
US20060287660A1 (en) * | 2005-06-15 | 2006-12-21 | Syed Naweed I | Electrically Stimulating Nerve Regeneration |
US20060292549A1 (en) * | 2005-06-15 | 2006-12-28 | Neurosilicon | Psychotropic drug screening device based on long-term photoconductive stimulation of neurons |
US20070012574A1 (en) * | 2005-07-13 | 2007-01-18 | Trex Enterprises Corporation | Fabrication of macroporous silicon |
WO2007009235A1 (en) * | 2005-07-15 | 2007-01-25 | Neurosilicon (1145990 Alberta Ltd.) | Method and apparatus for guiding growth of neurons |
US7551294B2 (en) * | 2005-09-16 | 2009-06-23 | University Of Rochester | System and method for brewster angle straddle interferometry |
EP1973575B1 (en) | 2005-12-22 | 2019-07-24 | Visen Medical, Inc. | Biocompatible fluorescent metal oxide nanoparticles |
US7759129B2 (en) | 2006-01-11 | 2010-07-20 | The Regents Of The University Of California | Optical sensor for detecting chemical reaction activity |
JP4857820B2 (en) * | 2006-03-03 | 2012-01-18 | 学校法人早稲田大学 | DNA sensing method |
US7818264B2 (en) * | 2006-06-19 | 2010-10-19 | Visa U.S.A. Inc. | Track data encryption |
KR100869066B1 (en) * | 2006-04-17 | 2008-11-17 | 한국기술산업 (주) | Bio-chip of pattern-arranged in line, method for manufacturing the same, and method for detecting an analyte bound in the same |
US20070259366A1 (en) * | 2006-05-03 | 2007-11-08 | Greg Lawrence | Direct printing of patterned hydrophobic wells |
US20080011498A1 (en) * | 2006-07-12 | 2008-01-17 | Bruce Leon Catlin | Cultivator and blade |
US8067110B2 (en) * | 2006-09-11 | 2011-11-29 | 3M Innovative Properties Company | Organic vapor sorbent protective device with thin-film indicator |
US20100093106A1 (en) * | 2006-09-14 | 2010-04-15 | Fortebio, Inc. | Amine-Reactive Biosensor |
US7692798B2 (en) * | 2006-09-15 | 2010-04-06 | Adarza Biosystems, Inc. | Method for biomolecular detection and system thereof |
US20080144899A1 (en) * | 2006-11-30 | 2008-06-19 | Manoj Varma | Process for extracting periodic features from images by template matching |
US7522282B2 (en) * | 2006-11-30 | 2009-04-21 | Purdue Research Foundation | Molecular interferometric imaging process and apparatus |
US20080230605A1 (en) * | 2006-11-30 | 2008-09-25 | Brian Weichel | Process and apparatus for maintaining data integrity |
WO2008089495A2 (en) * | 2007-01-19 | 2008-07-24 | Purdue Research Foundation | System with extended range of molecular sensing through integrated multi-modal data acquisition |
US7787126B2 (en) * | 2007-03-26 | 2010-08-31 | Purdue Research Foundation | Method and apparatus for conjugate quadrature interferometric detection of an immunoassay |
CN102921003B (en) * | 2007-07-09 | 2014-11-26 | 艾德拉药物股份有限公司 | Stabilized immune modulatory RNA (SIMRA) compounds |
AU2008275181B2 (en) | 2007-07-10 | 2014-06-26 | The Regents Of The University Of California | Materials and methods for delivering compositions to selected tissues |
US7889954B2 (en) * | 2007-07-12 | 2011-02-15 | The Regents Of The University Of California | Optical fiber-mounted porous photonic crystals and sensors |
KR100888747B1 (en) * | 2007-09-10 | 2009-03-17 | 한국기술산업 (주) | System for non-labeling bio-chip analysis and method for analyzing bio-chip using the same |
US8003403B1 (en) | 2008-03-19 | 2011-08-23 | Emitech, Inc | Optochemical sensors for the detection of low pressure vapors based on porous semiconductors and emissive organics |
EP2307103B1 (en) * | 2008-06-30 | 2018-12-19 | 3M Innovative Properties Company | Respirator system comprising an exposure indicating device |
US8506887B2 (en) | 2008-10-17 | 2013-08-13 | Vanderbilt University | Porous membrane waveguide sensors and sensing systems therefrom for detecting biological or chemical targets |
EP2396409A2 (en) * | 2009-02-10 | 2011-12-21 | Idera Pharmaceuticals, Inc. | Synthetic rna-based agonists of tlr7 |
US20100227414A1 (en) * | 2009-03-05 | 2010-09-09 | Trex Enterprises Corp. | Affinity capture mass spectroscopy with a porous silicon biosensor |
CA2706063A1 (en) * | 2009-05-29 | 2010-11-29 | Vanderbilt University | Diffraction gratings comprising porous materials and diffraction-based sensors comprising porous materials |
CN101566597B (en) * | 2009-06-04 | 2012-07-18 | 浙江大学 | Preparation method of ammonia-sensitive material for detecting ammonia concentration in air |
WO2011064701A1 (en) * | 2009-11-27 | 2011-06-03 | Ecole Polytechnique Federale De Lausanne (Epfl) | Nanofluidic biosensor and its use for rapid measurement of biomolecular interactions in solution and methods |
EP2385057A1 (en) | 2010-05-05 | 2011-11-09 | Centre National de la Recherche Scientifique | Peptide derivatives for biofunctionalization of silicon substrates and their applications |
US8778690B2 (en) | 2010-08-31 | 2014-07-15 | The Regents Of The University Of California | Porous optical sensor with fiducial marker and method for detection of analytes |
KR101189076B1 (en) | 2010-09-14 | 2012-10-10 | 전남대학교산학협력단 | Porous silicon particles for immune proteins detection and sensors containing the same |
WO2012039764A1 (en) | 2010-09-20 | 2012-03-29 | Vanderbilt University | Nanoscale porous gold film sers template |
US9279770B2 (en) * | 2010-10-15 | 2016-03-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mid-infrared imaging of microarrays |
WO2012151306A2 (en) * | 2011-05-02 | 2012-11-08 | The Regents Of The University Of California | Electroadsorption and charge based biomolecule separation and detection in porous sensors |
US9360302B2 (en) * | 2011-12-15 | 2016-06-07 | Kla-Tencor Corporation | Film thickness monitor |
TWI624862B (en) * | 2012-06-11 | 2018-05-21 | 應用材料股份有限公司 | Melt depth determination using infrared interferometric technique in pulsed laser annealing |
US9889504B2 (en) | 2012-12-11 | 2018-02-13 | Vanderbilt University | Porous nanomaterials having three-dimensional patterning |
US10309958B2 (en) | 2013-03-25 | 2019-06-04 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Method and apparatus for bacterial monitoring |
US10656085B2 (en) | 2015-04-08 | 2020-05-19 | Bactusense Technologies Ltd. | High sensitivity real-time bacterial monitor |
US10077470B2 (en) | 2015-07-21 | 2018-09-18 | Omniome, Inc. | Nucleic acid sequencing methods and systems |
WO2017209817A2 (en) * | 2016-03-08 | 2017-12-07 | Massachusetts Institute Of Technology | Dynamic resonant circuits for chemical and physical sensing with a reader and rfid tags |
AU2017258619B2 (en) | 2016-04-29 | 2020-05-14 | Pacific Biosciences Of California, Inc. | Sequencing method employing ternary complex destabilization to identify cognate nucleotides |
WO2018034780A1 (en) | 2016-08-15 | 2018-02-22 | Omniome, Inc. | Sequencing method for rapid identification and processing of cognate nucleotide pairs |
JP6828140B2 (en) | 2016-08-15 | 2021-02-10 | オムニオム インコーポレイテッドOmniome, Inc. | Methods and systems for sequencing nucleic acids |
TWI592651B (en) | 2016-08-31 | 2017-07-21 | 國立清華大學 | Metal ion detection equipment and metal ion detection method |
WO2018125759A1 (en) | 2016-12-30 | 2018-07-05 | Omniome, Inc. | Method and system employing distinguishable polymerases for detecting ternary complexes and identifying cognate nucleotides |
CA3050695C (en) | 2017-01-20 | 2024-02-20 | Omniome, Inc. | Process for cognate nucleotide detection in a nucleic acid sequencing workflow |
US11125753B2 (en) * | 2017-03-29 | 2021-09-21 | Trutag Technologies, Inc. | Labeling using an optical thickness measurement of a biosensor |
US9951385B1 (en) | 2017-04-25 | 2018-04-24 | Omniome, Inc. | Methods and apparatus that increase sequencing-by-binding efficiency |
US10161003B2 (en) | 2017-04-25 | 2018-12-25 | Omniome, Inc. | Methods and apparatus that increase sequencing-by-binding efficiency |
CA3079411C (en) | 2017-10-19 | 2023-12-05 | Omniome, Inc. | Simultaneous background reduction and complex stabilization in binding assay workflows |
CN110887451B (en) * | 2019-11-20 | 2021-08-03 | 浙江工业大学 | Stripe detection method based on camera response curve |
WO2022136328A1 (en) * | 2020-12-22 | 2022-06-30 | Radiometer Medical Aps | Determining time response value of an analyte in a liquid |
IL310712A (en) * | 2021-08-12 | 2024-04-01 | The State Of Israel Ministry Of Agriculture & Rural Development Agricultural Res Organization Aro Vo | In situ optical biosensing system and method for monitoring serotypes |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5077210A (en) * | 1989-01-13 | 1991-12-31 | Eigler Frances S | Immobilization of active agents on substrates with a silane and heterobifunctional crosslinking agent |
US5804453A (en) * | 1996-02-09 | 1998-09-08 | Duan-Jun Chen | Fiber optic direct-sensing bioprobe using a phase-tracking approach |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US33897A (en) * | 1861-12-10 | Printing-press | ||
DE3135196A1 (en) * | 1981-09-05 | 1983-03-17 | Merck Patent Gmbh, 6100 Darmstadt | METHOD, MEANS AND DEVICE FOR DETERMINING BIOLOGICAL COMPONENTS |
SE8200442L (en) * | 1982-01-27 | 1983-07-28 | Forsvarets Forsknings | METHOD OF DETECTION OF ORGANIC MOLECULES, SUCH AS BIOMOLECULES |
DE3215484A1 (en) * | 1982-04-26 | 1983-11-03 | Sagax Instrument AB, 18302 Täby | MULTIPLE LAYERS OF LAYER AND PROCESS FOR DETECTING AND / OR MEASURING THE CONCENTRATION OF A CHEMICAL SUBSTANCE, IN PARTICULAR BIOLOGICAL ORIGIN |
US4654419A (en) | 1984-08-08 | 1987-03-31 | Scripps Clinic And Research Foundation | Synthetic polypeptides and antibodies related to epstein-barr virus nuclear antigen |
US5468606A (en) * | 1989-09-18 | 1995-11-21 | Biostar, Inc. | Devices for detection of an analyte based upon light interference |
US4828986A (en) | 1986-09-29 | 1989-05-09 | Scripps Clinic And Research Foundation | Assay method and diagnostic system for determining the ratio of APO B-100 to APO A-I in a blood sample |
US5281710A (en) | 1990-08-01 | 1994-01-25 | The Scripps Research Institute | Dynemicin analogs: synthesis, methods of preparation and use |
US5418136A (en) * | 1991-10-01 | 1995-05-23 | Biostar, Inc. | Devices for detection of an analyte based upon light interference |
US5338415A (en) | 1992-06-22 | 1994-08-16 | The Regents Of The University Of California | Method for detection of chemicals by reversible quenching of silicon photoluminescence |
US6248539B1 (en) * | 1997-09-05 | 2001-06-19 | The Scripps Research Institute | Porous semiconductor-based optical interferometric sensor |
-
1997
- 1997-10-30 US US08/961,308 patent/US6248539B1/en not_active Expired - Lifetime
-
1998
- 1998-09-04 AU AU91301/98A patent/AU9130198A/en not_active Abandoned
- 1998-09-04 WO PCT/US1998/018331 patent/WO1999012035A1/en active Application Filing
-
2001
- 2001-02-28 US US09/795,533 patent/US6720177B2/en not_active Expired - Lifetime
-
2004
- 2004-03-16 US US10/801,282 patent/US6897965B2/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5077210A (en) * | 1989-01-13 | 1991-12-31 | Eigler Frances S | Immobilization of active agents on substrates with a silane and heterobifunctional crosslinking agent |
US5804453A (en) * | 1996-02-09 | 1998-09-08 | Duan-Jun Chen | Fiber optic direct-sensing bioprobe using a phase-tracking approach |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1373894A1 (en) * | 2001-02-21 | 2004-01-02 | The University Of Rochester | Microcavity biosensor, methods of making, and uses thereof |
EP1373894A4 (en) * | 2001-02-21 | 2004-04-21 | Univ Rochester | Microcavity biosensor, methods of making, and uses thereof |
EP2409136B1 (en) * | 2009-03-16 | 2017-05-17 | Ramot at Tel-Aviv University Ltd. | Device and method for optical sensing of substances or environmental conditions |
WO2013164659A1 (en) * | 2012-04-30 | 2013-11-07 | Tubitak | Methods for producing new silicon light source and devices |
US9337395B2 (en) | 2012-04-30 | 2016-05-10 | Tubitak | Methods for producing new silicon light source and devices |
WO2015024065A1 (en) * | 2013-08-23 | 2015-02-26 | Pregtech Pty Ltd | Methods and sensors for detecting a biological parameter |
CN116363523A (en) * | 2023-03-10 | 2023-06-30 | 浙江省测绘科学技术研究院 | Pine wood nematode epidemic monitoring method, terminal and medium based on remote sensing information |
CN116363523B (en) * | 2023-03-10 | 2023-10-20 | 浙江省测绘科学技术研究院 | Pine wood nematode epidemic monitoring method, terminal and medium based on remote sensing information |
Also Published As
Publication number | Publication date |
---|---|
US6897965B2 (en) | 2005-05-24 |
US6720177B2 (en) | 2004-04-13 |
US20040152135A1 (en) | 2004-08-05 |
US6248539B1 (en) | 2001-06-19 |
US20010044119A1 (en) | 2001-11-22 |
AU9130198A (en) | 1999-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6248539B1 (en) | Porous semiconductor-based optical interferometric sensor | |
EP1373894B1 (en) | Microcavity biosensor, methods of making, and uses thereof | |
Hsiao et al. | Aminopropyltriethoxysilane (APTES)-functionalized nanoporous polymeric gratings: fabrication and application in biosensing | |
EP1711823B1 (en) | Detection of biomolecules using porous biosensors and raman spectroscopy | |
AU693666B2 (en) | Composite waveguide for solid phase binding assays | |
US5832165A (en) | Composite waveguide for solid phase binding assays | |
US6194223B1 (en) | Method for the simultaneous determination of biomolecular interactions by means of plasmon resonance and fluoresence detection | |
US6395558B1 (en) | Optical chemical/biochemical sensor | |
JP2818292B2 (en) | Analyte assay method and device | |
US7759114B2 (en) | Sensor chips | |
Lee et al. | Formation of a self-assembled phenylboronic acid monolayer and its application toward developing a surface plasmon resonance-based monosaccharide sensor | |
US20020146837A1 (en) | Method for detection of gases based on fluorescence enhancement in porphyrin aggregates | |
AU1391288A (en) | Improved assay technique and apparatus therefor | |
Chen et al. | Real-time multicolor antigen detection with chemoresponsive diffraction gratings of silicon oxide nanopillar arrays | |
Kim et al. | Salmonella detection with a direct-binding optical grating coupler immunosensor | |
EP0543842A1 (en) | Analytical device. | |
US20040248165A1 (en) | Nucleic acid immobilization method and manufacturing method of biosensor using same | |
Vo-Dinh | Biosensors and biochips | |
Zhao et al. | A novel optical immunosensing system based on measuring surface enhanced light scattering signals of solid supports | |
Leblanc et al. | Langmuir and Langmuir-Blodgett films of proteins and enzymes | |
Tsargorodska | Research and development in optical biosensors for determination of toxic environmental pollutants | |
JP2005283296A (en) | Optical detection method of specimen, and detection system | |
Lawrie et al. | Silicon Photonics for Biosensing Applications | |
Starodub | Some Features of Design, Functional Activity, and Practical Application | |
Starodub | Porous Silicon-Based Biosensors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AU BA BB BG BR CA CN CU CZ EE GE HU ID IL IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA UZ VN YU |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: KR |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |