WO2010039147A1 - Puce à protéines interférométrique à quadrature équilibrée - Google Patents

Puce à protéines interférométrique à quadrature équilibrée Download PDF

Info

Publication number
WO2010039147A1
WO2010039147A1 PCT/US2008/078692 US2008078692W WO2010039147A1 WO 2010039147 A1 WO2010039147 A1 WO 2010039147A1 US 2008078692 W US2008078692 W US 2008078692W WO 2010039147 A1 WO2010039147 A1 WO 2010039147A1
Authority
WO
WIPO (PCT)
Prior art keywords
regions
land
height
contrast
chips
Prior art date
Application number
PCT/US2008/078692
Other languages
English (en)
Inventor
David D. Nolte
Xuefeng Wang
Original Assignee
Purdue Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Purdue Research Foundation filed Critical Purdue Research Foundation
Priority to PCT/US2008/078692 priority Critical patent/WO2010039147A1/fr
Publication of WO2010039147A1 publication Critical patent/WO2010039147A1/fr

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

Definitions

  • the present invention generally relates to systems for detecting the presence of one or more target analytes or specific biological material in a sample, and more particularly to a microarray for detecting the presence of biological materials and/or analyte molecules bound to target receptors by sensing changes in the optical characteristics of a probe beam reflected from the surface by the materials and/or analytes.
  • One such technology for screening for a plurality of molecular structures is the so-called immunological compact disk, which simply includes an antibody microarray.
  • Conventional fluorescence detection can be employed to sense the presence in the microarray of the molecular structures under test.
  • Other approaches to immunological assays employ traditional Mach- Zender interferometers that include waveguides and grating couplers.
  • Interferometric optical biosensors have the intrinsic advantage of interferometric sensitivity, but are sometimes characterized by large surface areas per element, long interaction lengths, or complicated resonance structures. They also can be susceptible to phase drift from thermal and mechanical effects.
  • a land-contrast (LC) platform can use a spatially patterned substrate rather than protein patterns to produce image contrast.
  • An embodiment of the protein-patterned platform utilizes surface-enhanced reflectometry to detect protein immobilized on silicon wafers with 140 nm thermal oxide to maximize the sensitivity. The oxide layer establishes an interferometric quadrature condition, and a 1 nm protein layer (at a spot) induces 2.4% reflectance change ( ⁇ R/R) at a 633 nm wavelength and normal incidence.
  • the LC platform utilizes two complementary quadratures between the spot and the land to enhance the signal.
  • the spot and the land have equal reflectance but opposite quadrature responses for the protein layer.
  • This condition is called Land Contrast (LC).
  • Protein can be evenly immobilized on the entire chip and detected by reflectometry.
  • the contrast between spot and land can be directly converted to protein thickness. This is achieved because equal binding on the spot and the land produces equal but opposite responses.
  • the LC platform is sensitive for protein detection in either dry or liquid environments.
  • One embodiment of the present invention uses micro-patterning of thermal oxide on silicon to establish two opposite quadrature conditions for in-line common-path interferometry.
  • the micro-patterns eliminate the need for protein printers. This is realized by etching spot patterns into a silicon wafer.
  • the SiO 2 thickness within the spots is 140 nm while the SiO 2 thickness on the land is 77 nm.
  • Immunoassay tests have been done on LC platforms read respectively by Molecular Interferometric Imaging (MI2) and Spinning Disc Interferometry (SDI). The sensitivity for protein layer height is on the order of 3 pm.
  • MI2 Molecular Interferometric Imaging
  • SDI Spinning Disc Interferometry
  • a land contrast platform for interferometrically detecting the presence of a target analyte in a sample can include a spatially patterned substrate and a layer of recognition material immobilized on the spatially patterned substrate.
  • the spatially patterned substrate can include a plurality of high regions and a plurality of low regions, where the height of the plurality of high regions is substantially uniform at a first height, and the height of the plurality of low regions is substantially uniform at a second height. The first height is different from the second height.
  • the recognition material immobilized on the spatially patterned substrate is designed to bind with the target analyte.
  • the land contrast platform is designed such that the high regions and the low regions have approximately the same reflectance but have complementary quadrature conditions.
  • This complementary quadrature condition causes an equal target binding on the high and low regions to produce opposite responses; the target binding on the high regions producing one of a positive or negative reflectance difference, and the target binding on the low regions producing the other of a positive or negative reflectance difference.
  • the average of the first height and the second height can be an antinode condition that maximizes the phase contrast interferometric response.
  • the average height can be approximately ⁇ /4
  • the first height of the high regions can be approximately ⁇ /8 above the average height
  • the second height of the low regions can be approximately ⁇ /8 below the average height, where ⁇ is the wavelength of a probe beam used for interferometric detection of the target analyte.
  • the substrate of the land contrast platform can include a silicon layer covered by a thermal oxide layer.
  • the thickness of the thermal oxide layer in the high regions can be approximately 140 nm and the thickness of the thermal oxide layer in the low regions can be approximately 77 nm.
  • the land contrast platform can be balanced such that the surface area of the plurality of high regions is approximately equal to the surface area of the plurality of low regions of the land contrast platform.
  • the land contrast platform can be in the shape of a disc, a chip or other shape.
  • the land contrast platform can also include an identifier, such as a barcode.
  • the barcode can be formed using a portion of the plurality of high regions and the plurality of low regions such that the barcode can be read interferometrically.
  • the identifier can be used to indicate the type of recognition material immobilized on the land contrast platform. While barcodes have been incorporated into other optical disc platforms (see for instance, U.S. Patent No. 7,157,049), such barcodes are not readable interferometrically such as can be done by the embodiments of the present invention.
  • a method of producing a land contrast platform for interferometrically detecting the presence of a target analyte in a sample is also disclosed.
  • the method can include steps of obtaining a silicon wafer; creating on oxide surface on the silicon wafer; covering the oxide surface with a photomask; exposing the oxide surface covered by the photomask to create surface patterns on the oxide surface; etching the oxide surface to create a lower region and a higher region; and immobilizing recognition material on the lower region and the higher region.
  • the recognition material is designed to bind with the target analyte.
  • the etching of the oxide surface creates a lower region and a higher region.
  • Both the lower region and the higher region can have approximately the same reflectance but complementary quadrature conditions such that an equal target binding on the lower region and the higher region produces opposite responses, the target binding on the lower regions producing one of a positive or negative reflectance difference and the target binding on the higher regions producing the other of a positive or negative reflectance difference.
  • Ultraviolet light can be used in the exposing step.
  • the oxide surface can be made to have a surface thickness of approximately 140 nm, and the etching step can be used to create the lower region with a thickness of approximately 77 nm.
  • the method can also include a cleaning step following the etching step, where the cleaning step includes a wash with Piranha solution.
  • a method of detecting one or more target analyte in a sample using land contrast chips includes a first step of making a plurality of land contrast chips having a spatially patterned substrate which includes a plurality of high regions and a plurality of low regions.
  • the height of the high regions is substantially uniform at a first height
  • the height of the low regions is substantially uniform at a second height, the first height being different from the second height.
  • the high regions and the low regions have approximately the same reflectance but have complementary quadrature conditions such that an equal target binding on the high and low regions produces opposite responses; the target binding on the high regions producing one of a positive or negative reflectance difference and the target binding on the low regions producing the other of a positive or negative reflectance difference.
  • the method further includes steps of placing an identifier on each of the land contrast chips; immobilizing a layer of recognition material designed to bind with a first target analyte on the chips; exposing at least one chip to the sample; and interferometrically reading the at least one exposed chip to determine the presence or absence of the first target analyte.
  • the method can also include placing the at least one exposed chip on the surface of a disc; and interferometrically reading the disc using spinning disc interferometry.
  • the identifier can be a barcode formed using a portion of the high regions and low regions such that the barcode can be read interferometrically.
  • the method can also be used to detect multiple target analytes by immobilizing a layer of different recognition materials on different land contrast chips, where each of the recognition materials is designed to bind with a particular target analyte. Land contrast chips having different recognition materials immobilized thereon can then be exposed to the sample; and interferometrically read to determine the presence or absence of the multiple target analytes.
  • the identifier on each chip can identify the type of recognition material immobilized on the individual chip.
  • the identifier can be a barcode formed using a portion of the high and low regions such that the barcode can be read interferometrically.
  • the exposed chips can be placed on the surface of a disc, and the disc interferometrically read using spinning disc interferometry to determine the presence or absence of one or more of the multiple target analytes.
  • the barcode of any chip indicating the presence of its associated target analyte can be read to determine the type of recognition material immobilized on the chip.
  • Fig. 1 illustrates a surface relief of an embodiment of a land-contrast platform showing the two surface heights associated with opposite quadratures
  • Fig. 2 illustrates a "spot-based" pattern that can be etched into a land-contrast platform for spots and land;
  • Fig. 3 illustrates some exemplary alternative land-contrast patterns
  • Fig. 4 illustrates the uniform immobilization of recognition molecules on the two surface heights which removes the need for protein printers
  • Fig. 5 shows a sequence of experimental measurements for a land-contrast chip: image (1) shows the spot and land patterns etched on a silicon thermal oxide chip by photolithography under white light; image (2) shows a reflectance image of a blank chip (the spot and land regions have the same reflectance); image (3) shows a reflectance image after evenly applying an antibody layer on the entire chip; and image (4) shows a reflectance image after sandwich assay;
  • Fig. 6 shows a graph of the reflectance at 633 nm of a land-contrast chip in both air and water environments, and shows that the working conditions at 77nm and 140nm thicknesses for this embodiment is suitable for both environments;
  • Fig. 7 shows a graph illustrating that the reflectance changes at 77nm and 140nm thicknesses to a protein layer are opposite on the spot and land regions in both air and water environments;
  • Fig. 8 is a schematic of an exemplary layout of 8x8 spot patterns on a 100-mm diameter silicon wafer
  • Fig. 9 shows the kinetic curves for the complete process of immunoassays of rabbit IgG forward and sandwich assays at five concentrations monitored in real time using molecular interferometric imaging;
  • Fig. 10 shows a graph of the forward assay portions of the kinetic curves in Fig. 9 fitted by the real-time binding equation
  • Fig. 11 shows the response curve of a rabbit IgG sandwich assay read in a dry state using a spinning disk interferometry system, the differences of contrast images ( ⁇ C) before and after the sandwich are shown for 30, 100, 300, 1000, and 3000 ng/ml concentration groups;
  • Fig. 12 shows an embodiment of a land contrast chip with a land-contrast pattern and a unique land-contrast barcode;
  • Fig. 13 illustrates the dispersing of N different types of the land-contrast chips of Fig. 12 into a sample solution
  • Fig. 14 illustrates a plurality of the land-contrast chips shown in Figs. 12 and 13 arranged randomly on a disc for scanning.
  • quadrature might be narrowly construed as what occurs in an interferometric system when a common optical "mode” is split into at least 2 "scattered” modes that differ in phase by about N* ⁇ /2 (N being an odd integer).
  • an interferometric system is in quadrature when at least one mode "interacts" with a target molecule or varying surface height to produce a phase difference of about N* ⁇ /2 (N being an odd integer).
  • quadrature is also applicable to interferometric systems in which the "other mode(s)," referring to other reference waves or beams, interact with a different molecule or surface height.
  • the interferometric system may be considered to be substantially in the quadrature condition if the phase difference is ⁇ /2 (or N* ⁇ /2, wherein N is an odd integer) plus or minus approximately twenty or thirty percent.
  • the phrase "in-phase” is intended to describe in-phase constructive interference
  • out of phase is intended to describe substantially 180-degree-out-of-phase destructive interference. This is to distinguish these conditions, for both of which the field amplitudes add directly; from the condition of being "in phase quadrature" that describes a relative phase of an odd number of ⁇ /2.
  • a land-contrast (LC) platform produces the image contrast by a spatially patterned substrate rather than by the protein pattern.
  • Some embodiments of the original in-line BioCD utilize surface-enhanced reflectometry to detect protein immobilized on silicon wafers with 140 run thermal oxide to maximize the sensitivity.
  • the oxide layer establishes an interferometric quadrature condition, and a 1 nm protein layer (in a spot) induces 2.5% reflectance change ( ⁇ R/R) at a 633 nm wavelength and normal incidence.
  • the LC platform extends this concept by utilizing two complementary quadrature conditions between the spot and the land to enhance the signal. This is achieved because equal protein binding on the spot and the land produces equal but opposite responses.
  • the surface height profile of an exemplary embodiment is shown in Fig. 1 for a thermal oxide layer on silicon, where the patterns are etched in the thermal oxide using photolithography.
  • the average thermal oxide thickness is ⁇ /4, which is an antinode condition that maximizes the phase-contrast interferometric response.
  • the two surface heights are roughly (but not exactly) an eighth-wavelength above or below the average height, placing both surface heights in the condition of in-line phase quadrature, but with opposite signed responses to additional surface height.
  • a standard pattern that can be etched into the surface is a spot pattern, as shown in Fig. 2.
  • the starting thermal oxide thickness is 140 run (a quadrature condition) and the land is etched down to 77 nm (the opposite quadrature condition).
  • some exemplary alternative patterns are shown in Fig. 3.
  • the spot pattern in the upper-left of Fig. 3 is the most similar to conventional spotted arrays, but is not balanced between spot and land areas.
  • the other 3 patterns in Fig. 3 can be easily balanced between spot and land areas.
  • the checkerboard and stripe patterns have equal area component structures at each of the two heights.
  • the unit cell pattern in the lower-left balances the spot-based patterns.
  • a striped pattern can be compatible with chemical surface modification protocols. It is also possible to build up positive-negative versions of the spot pattern to balance the areas of the two surface heights, while retaining the spot-based pattern that is more conventional for array image analysis.
  • the reflection coefficients of the spot and land regions are conjugate to each other: 0.07- 0.383i and 0.07+0.383i, respectively.
  • the reflectances of both areas are equal to 0.152 at a 633 nm wavelength (normal incidence).
  • image (2) the spot-land contrast is zero. Black circles in image (2) are due to light scattering on the edge of the spots.
  • Fig. 6 shows that the reflectances are equal at a 633 nm wavelength in both air and water for heights of 77 and 140 nm.
  • Fig. 7 also shows a contrast-protein conversion factor of 0.51% in water.
  • Fig. 5 image (3) shows a reflectance image of the land contrast chip after antibody molecules are evenly immobilized across an entire well of the array, forming a dielectric layer.
  • the spot-land contrast continues to increase after a sandwich assay.
  • the antibody changes in layer thickness after a sandwich immunoassay, shown in Fig. 5, image (4), are measured by monitoring the spot-land contrast induced by the patterned substrate.
  • the initial contrast of a LC structure is not necessarily always to be zero.
  • the non-zero value occurs for the unprinted LC structure because of the thickness variation of the thermal oxide layer.
  • the contrast increment is the quantity which can be converted to protein thickness, not the contrast value itself.
  • the conversion between the spot-land contrast and protein thickness is derived using a general model of a biomaterial on a substrate. If the substrate has reflection coefficient r in an ambient medium with refractive index n m under conditions of light wavelength ⁇ (in vacuum) and incidence angle ⁇ o, then after applying a biomaterial layer with thickness d ( d « ⁇ ) and refractive index n p on the substrate, the reflection coefficient is changed to r ' and
  • ⁇ p is the refraction angle in the protein layer.
  • Eq. 1 can be simplified to: Based on Eq. 2, the reflectance change ratio due to the biomaterial layer is approximately
  • the reflection coefficients are r on the spot region and r (conjugate value of f) on the land region.
  • the spot-land contrast is defined as
  • Contrast is zero for a land-contrast platform without a protein layer.
  • the contrast increment due to a thickness d of biomaterial is:
  • a LC platform can be made by photolithography.
  • positive photoresist AZl 518, MicroChemicals Company
  • 140-nm oxide on silicon wafer can be spun on 140-nm oxide on silicon wafer (Addison Engineering, Inc.), covered by a photomask, exposed under ultraviolet light and developed to create spot patterns on the wafers.
  • a plasma etcher can be used to etch the land to 77 nm SiO2 film.
  • the photomask pattern can be designed by AutoCAD2000 software.
  • 96 wells are distributed on a 4 inch diameter wafer.
  • the platform can be cleaned using a sequence of Acetone, DI water, Piranha solution, and finally DI water.
  • the Piranha solution wash is recommended because the photoresist hardened after plasma etching is hard to clean with regular organic solution.
  • the platforms are soaked in 0.02 M chloro-octadecylsilane in toluene solution for 12 hours and rinsed with toluene, acetone, methanol and deionized water and dried with dry nitrogen gas.
  • Surface immobilization can be accomplished using other methods known in the art, such as by using butyraldehyde, isocyanate or di-iso, or by physical adsorption through covalent binding.
  • MI2 Molecular Interferometric Imaging
  • SDI spinning disk interferometry
  • the pixel resolution is 2.2 ⁇ m with a 7x objective lens.
  • the contrast value is calculated for each frame and converted to protein thickness, and the protein thickness change due to immuno-binding is monitored in real time.
  • the frame rate can be manipulated with a trade-off between shot-noise and image capture speed.
  • a microfiuidic channel is built by placing a cover- slip on the land-contrast chip with a 0.5 mm gap between the cover-slip and the chip. Protein solution is driven continuously through the channel and therefore provides a stable liquid environment with uniform protein concentrations.
  • the contrast conversion factor is 0.51% for 1 nm protein in this situation because the detection was done in a liquid environment (see Fig. 7).
  • Fig. 9 shows these curves for the complete process of the immunoassays (including antibody immobilization, forward assay and sandwich assay) at five concentrations monitored in real time.
  • the flow rate is 2 mL h " mm " .
  • Hmax 0.60 nm
  • k off 4.35x10 '5 sec "1
  • k on 435 g "1 ml sec "1
  • fo 100 ng/ml.
  • the sandwich assays in Fig. 9 show that amplification by the secondary antibody is not a constant for all concentrations.
  • AH s ⁇ n dw ⁇ c h / ⁇ Hf orw ⁇ rd equals 6.2, 4.9, 4.5, and 3.8 at 100, 200, 500, and 1000 ng/ml antigen concentrations respectively.
  • This phenomenon may be caused by the limited space on the chip surface.
  • One antigen has many binding sites for the polyclonal antibody, but the space around the antibody is limited. If the antigen molecules are already crowded after the forward assay at high concentration, then the secondary antibody molecules have less space to bind with the antigen, and the secondary antibody/antigen ratio would be less.
  • the detection limit of the protein thickness is 3 pm based on the area of 4 spots and the relevant land (overall, about 0.1 mm 2 ). This was estimated by subtracting a fitted curve from the 100 ng/ml forward assay data (Fig. 10) and calculating the standard deviation of the data points after subtraction. A 3 pm detection limit was also found by analyzing the standard deviation of the 0 ng/ml forward assay data without curve subtraction (where the curve is flat). From the results, LC chips can be used with an MI2 system to provide an accurate and efficient tool to perform protein interaction studies.
  • SDI spinning disk interferometry
  • the ability of the LC platform to detect protein concentration was also explored in the following assay in a dry condition.
  • a spinning disc interferometry (SDI) system was used to acquire the reflectance image of a LC disc for 1/f noise suppression and high throughput on the SDI system.
  • the LC disc is in the format of 96 wells on a silicon thermal oxide wafer with 100 mm diameter, each well consists of 8x8 spots which can serve for one type of protein detection. All spot regions have 140 nm thickness SiO 2 film while the land is etched to be 77 nm.
  • the disc is mounted on a motor fixed on a translational stage in a similar configuration to a CD reader.
  • the motor is spun at 1200 rpm and the stage moves at steps of 5 ⁇ m.
  • a 633 nm wavelength laser beam is focused on the LC platform with 5 ⁇ m resolution. Reflected laser intensity is detected by a silicon detector and the signal is sent to a computer where the reflectance image of the whole disc is reconstructed.
  • the LC disc was surface-silanized to immobilize antibodies by physical adsorption. 100 ⁇ g/ml anti-rabbit IgG in PBS was loaded on 8 wells of a LC disc with a pipette. The wells were fully and evenly incubated in antibody solution for 30 min to form an antibody layer. The disc was then washed and dried.
  • a pre-scan was performed to record the initial height of the antibody layer on all wells, and then the 8 wells were incubated with 0, 10, 30, 100, 300, 1000, 3000, and 10,000 ng/ml rabbit IgG (15006, Sigma Inc.) in PBS + 0.05% Tween 20 (PBST) for 30 min, and then washed by DI water and incubated with 10 ⁇ g/ml anti-rabbit IgG in PBST for 30 min. All incubations were static (ambient).
  • a post-scan was performed to record the protein height after assay. The height increment due to the sandwich assay was calculated and the response curve is shown in Fig. 11.
  • the differences of contrast images ( ⁇ C) before and after the sandwich are shown for 30, 100, 300, 1000, and 3000 ng/ml concentration groups.
  • the curve was fitted by the Langmuir equation.
  • the equilibrium constant was found to be 550 ng/ml, which is larger than the 100 ng/ml acquired by the MI2 system. This is because the protein transport in diffusion-limited incubation slows down the binding rate.
  • the ko here is an effective value for equilibrium constant between antigen and antibody binding.
  • the land contrast patterns etched into a wafer can be made into individual chips by dicing up the wafer.
  • a 100-mm diameter wafer has the potential to provide up to 10,000 mm chips.
  • Each chip can be composed of a land-contrast pattern and a two-level barcode. An exemplary embodiment is shown in Fig. 12.
  • the barcode can be a standard bar-code, but imprinted using the two heights of the etched chip and read out interferometrically.
  • the bar-code identifies the recognition molecule immobilized on the chip. A large number of chips can be placed in a single solution so that many of the chips have the same recognition molecules immobilized on their surfaces.
  • chips can all have the same bar-code, the bar-code relating to the type of immobilized species on the surface. Many different sets of these chips can be made, each with a different surface chemistry bar-coded appropriately. After chemical immobilization, they can be placed into containers, one for each kind of recognition molecule. In this way, the chips become barcoded "reagents" that can be added to a sample solution, as shown in Fig. 13. There can be L chips of type A, M chips of type B, etc. up to N different types of chips. These chips can be placed in the sample solution, incubated, and then retrieved.
  • the chips can be placed on the surface of a disc and read interferometrically using SDI with the land contrast mechanism.
  • Fig. 14 illustrates a random arrangement of these chips on a disc. The barcode of each chip will tell which recognition molecule the chip was prepared with. The chips can be arranged randomly and read by scanning the entire disc. There is room on a 100-mm diameter disc for over a thousand such chips.

Landscapes

  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

La présente invention concerne une plateforme de contraste de sol qui permet de détecter par interférométrie la présence d'une substance cible à analyser dans un échantillon. Ladite plateforme de contraste de sol comprend un substrat à motifs spatiaux avec une couche de matériau de reconnaissance immobilisé dessus. Ledit substrat à motifs spatiaux comprend une pluralité de régions hautes et de régions basses. Lesdites régions hautes sont à une première hauteur sensiblement uniforme et lesdites régions basses sont à une seconde hauteur sensiblement uniforme, cette première hauteur et cette seconde hauteur étant différentes. La couche de matériau de reconnaissance est conçue pour se lier à la substance cible à analyser. Les régions hautes et les régions basses présentent à peu près la même réflexion mais des états de quadrature complémentaires, de telle sorte que la substance cible à analyser se liant aux régions hautes et basses produise des réponses opposées; la substance cible à analyser se liant aux régions hautes produit une différence de réflexion positive ou négative et celle se liant aux régions basses produit l'autre réflexion, positive ou négative, non produite par la première substance.
PCT/US2008/078692 2008-10-03 2008-10-03 Puce à protéines interférométrique à quadrature équilibrée WO2010039147A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2008/078692 WO2010039147A1 (fr) 2008-10-03 2008-10-03 Puce à protéines interférométrique à quadrature équilibrée

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/078692 WO2010039147A1 (fr) 2008-10-03 2008-10-03 Puce à protéines interférométrique à quadrature équilibrée

Publications (1)

Publication Number Publication Date
WO2010039147A1 true WO2010039147A1 (fr) 2010-04-08

Family

ID=42073757

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/078692 WO2010039147A1 (fr) 2008-10-03 2008-10-03 Puce à protéines interférométrique à quadrature équilibrée

Country Status (1)

Country Link
WO (1) WO2010039147A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170274374A1 (en) * 2016-03-28 2017-09-28 Ilumina, Inc. Multi-plane microarrays
US11619806B2 (en) * 2011-12-16 2023-04-04 Taiwan Semiconductor Manufacturing Company, Ltd. Microscope apparatus

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5867297A (en) * 1997-02-07 1999-02-02 The Regents Of The University Of California Apparatus and method for optical scanning with an oscillatory microelectromechanical system
US20040166593A1 (en) * 2001-06-22 2004-08-26 Nolte David D. Adaptive interferometric multi-analyte high-speed biosensor
US20080129981A1 (en) * 2006-11-30 2008-06-05 David D Nolte Molecular interferometric imaging process and apparatus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5867297A (en) * 1997-02-07 1999-02-02 The Regents Of The University Of California Apparatus and method for optical scanning with an oscillatory microelectromechanical system
US20040166593A1 (en) * 2001-06-22 2004-08-26 Nolte David D. Adaptive interferometric multi-analyte high-speed biosensor
US20080129981A1 (en) * 2006-11-30 2008-06-05 David D Nolte Molecular interferometric imaging process and apparatus

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11619806B2 (en) * 2011-12-16 2023-04-04 Taiwan Semiconductor Manufacturing Company, Ltd. Microscope apparatus
US20170274374A1 (en) * 2016-03-28 2017-09-28 Ilumina, Inc. Multi-plane microarrays
WO2017172798A1 (fr) * 2016-03-28 2017-10-05 Illumina, Inc. Micro-réseaux multi-plans
CN108463287A (zh) * 2016-03-28 2018-08-28 亿明达股份有限公司 多平面微阵列
EP3377226A4 (fr) * 2016-03-28 2018-09-26 Illumina, Inc. Micro-réseaux multi-plans
CN108463287B (zh) * 2016-03-28 2021-01-15 亿明达股份有限公司 多平面微阵列
EP3831484A1 (fr) * 2016-03-28 2021-06-09 Illumina, Inc. Micro-réseaux multi-plans

Similar Documents

Publication Publication Date Title
US7158230B2 (en) Method and apparatus for detecting biomolecular interactions
US7023544B2 (en) Method and instrument for detecting biomolecular interactions
US7663092B2 (en) Method and apparatus for phase contrast quadrature interferometric detection of an immunoassay
US7582486B2 (en) Double resonance interrogation of grating-coupled waveguides
US7659968B2 (en) System with extended range of molecular sensing through integrated multi-modal data acquisition
US7202076B2 (en) Label-free high-throughput optical technique for detecting biomolecular interactions
US7101660B2 (en) Method for producing a colorimetric resonant reflection biosensor on rigid surfaces
US7615339B2 (en) Method for producing a colorimetric resonant reflection biosensor on rigid surfaces
JPH087139B2 (ja) 導波管センサ及び分析方法
KR20090128528A (ko) 바이오센서를 위한 교정 및 정규화 방법
JP2009282046A (ja) 光の回折に基づく検定のための方法および装置
JP2004529324A (ja) 生体分子相互作用の検出のためのラベル化不用ハイスループット光学技術
US20070047088A1 (en) Optical sensor based on surface electromagnetic wave resonance in photonic band gap materials and method for using same
JP2003507723A (ja) カンチレバーアレイブロックのパレットにより微小力を可視的に識別する装置及び方法
Wang et al. Prostate specific antigen detection in patient sera by fluorescence-free BioCD protein array
WO2010039147A1 (fr) Puce à protéines interférométrique à quadrature équilibrée
Zhao et al. Differential phase-contrast BioCD biosensor
Wang et al. Area-scaling of interferometric and fluorescent detection of protein on antibody microarrays
CN101151518A (zh) 用于免疫测定的相位差正交干涉测量检测的方法和设备
EP1856692A2 (fr) Procede et appareil de detection interferometrique en quadrature par contraste de phase d'un dosage immunologique
Striemer et al. Arrayed imaging reflectometry for inexpensive and label-free protein arrays
Zhao Interferometric detection of proteins
Wang et al. A novel concept for protein microarray: land-contrast BioCD

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08877204

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08877204

Country of ref document: EP

Kind code of ref document: A1