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WO2000079249A1 - Methode de balayage bidirectionnel - Google Patents

Methode de balayage bidirectionnel Download PDF

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Publication number
WO2000079249A1
WO2000079249A1 PCT/US2000/016514 US0016514W WO0079249A1 WO 2000079249 A1 WO2000079249 A1 WO 2000079249A1 US 0016514 W US0016514 W US 0016514W WO 0079249 A1 WO0079249 A1 WO 0079249A1
Authority
WO
WIPO (PCT)
Prior art keywords
specimen
location
set forth
assembly
drive mechanism
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2000/016514
Other languages
English (en)
Inventor
Herman Deweerd
Michael Beach
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virtek Vision Corp
Original Assignee
Virtek Vision Corp
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 Virtek Vision Corp filed Critical Virtek Vision Corp
Priority to GB0128261A priority Critical patent/GB2366116B/en
Priority to AU57418/00A priority patent/AU5741800A/en
Priority to CA002375489A priority patent/CA2375489A1/fr
Priority to US09/980,658 priority patent/US20040224421A1/en
Publication of WO2000079249A1 publication Critical patent/WO2000079249A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"

Definitions

  • the subject invention relates generally to an improved scanner of the type that scans specimens for performing subsequent computer analysis on the specimens.
  • Micro array biochips are being used by several biotechnology companies for scanning genetic DNA samples applied to biochips into computerized images. These chips have small substrates with thousands of DNA fragments that represent the genetic codes of a variety of living organisms including human, plant, animal, and pathogens. They provide researchers with information regarding the DNA properties of these organisms. Experiments can be conducted with significantly higher throughput than previous technologies offered by using these biochips. Biochip technology is used for genetic expression, DNA sequencing of genes, food and water testing for harmful pathogens, and diagnostic screening. Biochips may be used in pharmacogenomics and proteomics research aimed at high throughput screening for drug discovery.
  • DNA fragments are extracted from a sample and are tagged with a fluorescent dye having a molecule that, when excited by a laser, will emit light of various colors. These fluorescently tagged DNA fragments are then spread over the chip. A DNA fragment will bind to its complementary (cDNA) fragment at a given array location.
  • cDNA complementary
  • a typical biochip is printed with a two-dimensional array of thousands of cDNA fragments, each one unique to a specific gene. Once the biochip is printed, it represents thousands of specimens in an area usually smaller than a postage stamp.
  • a microscope collects data through a scanning lens by scanning one pixel of a specimen at a time.
  • the scanning lens projects emitted light from the specimen onto a scanner that is manipulated along a predetermined pattern across the chip scanning an entire biochip one pixel at a time.
  • the pixels are relayed to a controller that sequentially connects the pixels to form a complete, computerized biochip image.
  • the controller must determine where the lens is relative to the specimen. Frequently, drive mechanisms that manipulate the scanner do not relay accurate location information to the controller due to slippage of the mechanism's bearings and general wear.
  • the controller cannot connect the pixels in an accurate sequential manner resulting in a blurred, and sometimes unreadable, computerized biochip image. Therefore, a need exists for a scanning microscope that can accurately determine the location of the scanning mechanism relative to the specimen being scanned.
  • the assembly includes a transmitter for emitting an optical signal and a reflector for directing the optical signal onto the specimen.
  • a detector includes an objective lens that focuses the emitted optical signal from the specimen onto a sensor. The sensor transmits the emitted optical signal to a controller one pixel at a time.
  • a first drive mechanism varies the position of the optical signal transmitted onto the specimen.
  • a second drive mechanism varies the position of the specimen relative to the optical signal. In this manner, a complete scan of the specimen is performed and transmitted to a controller one pixel at a time.
  • a locator accurately determines the location of the first drive mechanism, and therefore of the scanner, relative to the specimen. The locator relays the location of the first drive mechanism to the controller with each pixel scanned.
  • the location information is used by the controller to improve the sequential connection of the scanned pixels when forming the computerized image of the specimen.
  • Figure 1 is a detailed view of an optical instrument of the present invention
  • Figure 2 is a plan view of a biochip specimen of the present invention showing the movement of the scanning objective lens
  • Figure 3a is a side view of the first drive mechanism showing the preferred embodiment of the locator of the subject invention
  • Figure 3b is a side view of the first drive mechanism showing a first alternative of the locator of the subject invention
  • Figure 3c is a side view of the first drive mechanism showing a second alternative embodiment of the subject invention.
  • Figure 4 is top view of the second drive mechanism.
  • optical instrument assembly of the present invention is generally shown in
  • the assembly includes a transmitter 12 for emitting an optical signal 14.
  • the transmitter 12 comprises a laser.
  • Figure 1 shows three transmitters 12a-c, each emitting an optical signal 14a-c having a different wavelength.
  • Additional transmitters 12 may be introduced to the assembly 10 as needed.
  • a reflector 30 directs the optical signal 14 onto a specimen 90.
  • the reflector 30 includes a plurality of turn mirrors 32.
  • Figure 1 shows three turn mirrors 32a-c corresponding to the same number of transmitters 12a-c.
  • Each optical signal 14a-c is reflected by the turn mirrors 32a-c into corresponding beam combiners 34a-c.
  • the beam combiners 34a-c known as dichroic filters transmit light of one wavelength while blocking other wavelengths.
  • the beam combiner 34a-c collect the individual optical signals 14a-c into a combined beam along a single path and direct the beam towards a beam splitting mirror 20.
  • the beam splitting mirror 20 includes an opening 22 through which the combined optical signals 14a-c travel.
  • the combined optical signals 14a-c reflect off a ninety degree fold mirror 36 located immediately above a scanning objective lens 52, which focuses the combined optical signals 14a-c onto a section of the specimen 90 in a forward and reverse direction.
  • a first drive mechanism 50 varies the position of the combined optical signal 14a-c on the specimen 90 as will be explained further herein below.
  • the specimen 90 is treated with dyes having fluorescent properties when subjected to the optical signal 14a-c.
  • the specimen 90 having been treated with the dye, and illuminated with the optical signal 14, emits the optical signal 44 at a wavelength corresponding to the dye selected.
  • Different dyes may be used to examine different specimen properties.
  • Multiple dyes may be used to examine different properties of the same specimen 90 simultaneously.
  • the assembly 10 includes a detector 40 with a sensor 42 for detecting a emitted optical signal 44 from the specimen 90.
  • the emitted optical signal 44 reflects off the opposite side of the beam splitting mirror 20 through a plurality of beam splitters 38a-b to separate the emitted optical signal 44 into individual signals 44a-c corresponding to different dyes.
  • Each individual signal passes though an emission filter 46a-c and is focused by a detector lens 48a-c into a pinhole.
  • the individual signals 44a-c proceed through the pinhole to contact the individual sensors 42a-c.
  • the sensors 42a-c are in communication with a controller 80, the purpose of which will be described in further detail hereinbelow.
  • the objective lens 52 is moved in forward and reverse directions along the x-axis of the specimen 90 collecting data in each direction.
  • the specimen 90 does not move in the x direction.
  • the specimen 90 is moved in the y direction incrementally each time a scan is about to be started in the x direction. In this manner, a rectangular zigzag scanning pattern is performed upon the specimen 90.
  • Figures 3a-c show a first drive mechanism 50 for varying the position of the combined optical signal 14a-c on the specimen 90.
  • the first drive mechanism 50 preferably employs a galvanometric torque motor 54 to rotate a sector-shaped cam 56 over an angle between plus forty degrees and negative forty degrees.
  • the circular portion of the cam 56 is connected to the carriage 58 via a set of roll-up, roll-off thin, high strength steel wires 66a-b.
  • the scanning objective lens 52 is attached to the carriage 54.
  • the radius of the cam 56 is such that its rotation will cause the carriage 58 to travel a linear distance along a rail 60 commensurate with the length of the scan along the x-axis.
  • Figure 4 shows a second drive mechanism 70 employing a stepper motor 72 to drive a precision screw 74 in a known manner.
  • a nut 76 on the screw 74 is attached to the carriage 58 so that any rotation of the screw 74 will cause the carriage 58 to move along a linear rail 60.
  • the carriage in turn is equipped with a tray 76 which includes retainers 78 to hold a specimen 90 slide in a position and orientation that is repeatable within an accuracy required by optical focus and alignment criteria.
  • the rail 60 and the stepper motor 72 are attached to the frame of the second drive mechanism 70.
  • the first and second drive mechanisms 50, 70 transmit location information to the controller 80.
  • the controller 80 uses the location information to map the scan data received from the sensors 42a-c. A scanning accuracy of one micron is required to accurately map the scan using data from both directions scanned on the x-axis.
  • mechanical couplings of the drive mechanisms tend to slip with increasing frequency as the assembly 10 ages. Therefore, it becomes increasingly difficult to match the scans in the forward and reverse directions resulting in inaccurate or blurred pixels being transmitted to and correlated by the controller 80.
  • a locator 100 is affixed to the first drive mechanism 50 for determining the location of the first drive mechanism 50 relative to the specimen 90.
  • the locator 100 takes the form of an encoder.
  • the encoder provides a precise location of the first drive mechanism 50, and therefore of the scanning objective lens 52 relative to the specimen 90 meeting the accuracy requirement of one micron.
  • the scan provides the controller 80 the degree of accuracy required to align the pixels for generating an accurate computer based image of the specimen 90.
  • the encoder 101 includes a linear grating scale 102 also mounted to the first drive mechanism 50. The encoder 101 establishes a reference location for the objective lens 52 from a reference point 104 disposed upon the linear grating scale 102.
  • a first alternative embodiment of the locator 100 is shown in Figure 3b as a laser range finder 105. Similar to the encoder 101, the laser range finder 105 signals the controller 80 with the location of the first drive mechanism 50 relative to the specimen 90. The laser range finder 105 transmits a laser beam 107 onto a sensor 106 for determining the precise location of the first drive mechanism 50.
  • the sensor 106 includes two embodiments a timing sensor and a position determining sensor. In the case of the timing sensor, the laser range finder 105 transmits the time of travel for the laser beam 107 to the controller 80 for determining the distance of the first drive mechanism 50 from the sensor 106 thereby establishing the location of the first drive mechanism 50. In the case of the position determining sensor, the location the laser beam 107 strikes the sensor 106 is measured and transmitted to the controller 80 for conducting a triangulation calculation thereby determining the location of the first drive mechanism 50.
  • a third alternative embodiment of the scanner 100 is shown in Figure 3c as an interferometer 108.
  • the interferometer 108 signals the controller the location of the first drive mechanism 50 as interpolated by the wavelength of the laser beam 107.

Landscapes

  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Microscoopes, Condenser (AREA)
  • Length Measuring Devices By Optical Means (AREA)

Abstract

Un ensemble instrument optique comprend un émetteur (12) destiné à émettre un signal optique sur un échantillon, un détecteur (40) destiné à détecter une lumière émise par l'échantillon, un premier mécanisme de commande (50) destiné à faire varier la position du signal sur l'échantillon, et un localisateur (100) destiné à déterminer l'emplacement du premier mécanisme de commande par rapport à l'échantillon.
PCT/US2000/016514 1999-06-18 2000-06-15 Methode de balayage bidirectionnel Ceased WO2000079249A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB0128261A GB2366116B (en) 1999-06-18 2000-06-15 Bi-directional scanning method
AU57418/00A AU5741800A (en) 1999-06-18 2000-06-15 Bi-directional scanning method
CA002375489A CA2375489A1 (fr) 1999-06-18 2000-06-15 Methode de balayage bidirectionnel
US09/980,658 US20040224421A1 (en) 2000-06-15 2000-06-15 Bi-directional scanning method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13996399P 1999-06-18 1999-06-18
US60/139,963 1999-06-18

Publications (1)

Publication Number Publication Date
WO2000079249A1 true WO2000079249A1 (fr) 2000-12-28

Family

ID=22489111

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/016514 Ceased WO2000079249A1 (fr) 1999-06-18 2000-06-15 Methode de balayage bidirectionnel

Country Status (4)

Country Link
AU (1) AU5741800A (fr)
CA (1) CA2375489A1 (fr)
GB (1) GB2366116B (fr)
WO (1) WO2000079249A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4626684A (en) * 1983-07-13 1986-12-02 Landa Isaac J Rapid and automatic fluorescence immunoassay analyzer for multiple micro-samples
US5091652A (en) * 1990-01-12 1992-02-25 The Regents Of The University Of California Laser excited confocal microscope fluorescence scanner and method
US5355215A (en) * 1992-09-30 1994-10-11 Environmental Research Institute Of Michigan Method and apparatus for quantitative fluorescence measurements
US5805342A (en) * 1995-10-31 1998-09-08 Gravely; Benjamin T. Imaging system with means for sensing a filtered fluorescent emission

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4626684A (en) * 1983-07-13 1986-12-02 Landa Isaac J Rapid and automatic fluorescence immunoassay analyzer for multiple micro-samples
US5091652A (en) * 1990-01-12 1992-02-25 The Regents Of The University Of California Laser excited confocal microscope fluorescence scanner and method
US5355215A (en) * 1992-09-30 1994-10-11 Environmental Research Institute Of Michigan Method and apparatus for quantitative fluorescence measurements
US5805342A (en) * 1995-10-31 1998-09-08 Gravely; Benjamin T. Imaging system with means for sensing a filtered fluorescent emission

Also Published As

Publication number Publication date
AU5741800A (en) 2001-01-09
CA2375489A1 (fr) 2000-12-28
GB0128261D0 (en) 2002-01-16
GB2366116B (en) 2003-10-22
GB2366116A (en) 2002-02-27

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