WO1998057148A1 - The optical detection and analysis of sub-micron particles - Google Patents
The optical detection and analysis of sub-micron particlesInfo
- Publication number
- WO1998057148A1 WO1998057148A1 PCT/GB1998/001591 GB9801591W WO9857148A1 WO 1998057148 A1 WO1998057148 A1 WO 1998057148A1 GB 9801591 W GB9801591 W GB 9801591W WO 9857148 A1 WO9857148 A1 WO 9857148A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- particles
- optical
- metal film
- metal
- sample
- Prior art date
Links
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Classifications
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- 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
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
- G01N21/553—Attenuated total reflection and using surface plasmons
-
- G01N15/1433—
-
- 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
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Electro-optical investigation, e.g. flow cytometers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Electro-optical investigation, e.g. flow cytometers
- G01N2015/1486—Counting the particles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Electro-optical investigation, e.g. flow cytometers
- G01N2015/1497—Particle shape
-
- 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
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
- G01N21/553—Attenuated total reflection and using surface plasmons
- G01N21/554—Attenuated total reflection and using surface plasmons detecting the surface plasmon resonance of nanostructured metals, e.g. localised surface plasmon resonance
-
- 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
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/805—Optical property
Definitions
- the present invention relates to the optical detection and analysis of particulates of nanometre, submicron or micron dimensions and in particular to particles of biological origin such as macromolecules, macromolecular assemblies, virus particles, microbial or animal cells or cell organelles
- the particle may selectively absorb certain wavelengths of the light such as in differential absorption, the technique most common in conventional transmission microscopy
- Other microscopical variants exist which selectively monitor specific wavelengths generated by the particle when illuminated by the incident illumination, such as fluorescent microscopy which is useful in reducing background interference and which can be used to identify specific structures through the use of fluorescent labels
- phase contrast or interference microscopy Other microscope techniques, such as epiluminescent microscopy, employ light scattering at high angles to allow low contrast particles to be visualised against a low background
- Other similar versions of this technique are used in microscopy, of which the most common is referred to as dark field microscopy
- the sample is illuminated by a high numerical aperture source and the central portion of the illuminating cone is blocked from entering the detection objective by an optical stop so that the particle is illuminated at an
- the sample typically an aqueous suspension of particles
- a transparent optical substrate which is illuminated by a suitably defined and collimated optical beam at a certain angle called the critical angle at which the incident light is refracted along the plane of the optical element on which the liquid sample is placed
- a small portion of the beam called the evanescent wave, propagates a small distance into the sample phase above the optical substrate and particles entering this evanescent region act to scatter some of this otherwise non-radiative field
- the light coupled out i e scattered by the particle within the evanescent field
- this technique is referred to as evanescent field microscopy and relies on the principle of frustrated total internal reflection
- EP 341927 claiming priority of GB881154 describes a biological or biochemical testing sensor comprising a surface plasmon resonance (SPR) sensor and a sample-antibody surface arranged to influence resonance characteristics
- SPR surface plasmon resonance
- the SPR sensor comprises a metallised glass slide onto the glass-metal interface of which is directed a beam of light at an angle at which surface plasmons are induced to resonate in the metal film Changes in the resonance angle on binding of analyte are determined by measuring the intensity or angle of the light internally reflected from the metal-glass interface
- these techniques are characterised by their reliance on measuring the intensity of light reflected from the surface or changes in the resonance angle on binding of specific sample components
- Such non-imaging reflectance techniques monitor only the binding of relatively large numbers of macromolecules through measurement of changes in the amount or position of the reflected light
- Such reflectance techniques cannot be used to locate, visualise, detect or count the presence of individual macromolecules or very sub- ⁇ m particulates because the optical effect of interaction of individual nm or very sub- ⁇ m scale structures with an optical beam is too small to be distinguished from the high levels of light reflected from the metal surface though images of the interaction of surfaces of larger (e g 1-50 ⁇ m cellular) structures can be obtained by observing the spatial distribution of light reflected from the underside of the metal film if they are sufficiently large to be able to distinguish from the main reflected beam
- generation of images of individual particles are not required, for instance when it is only necessary to determine the presence or otherwise of particles and to estimate their size, size distribution, number etc , then other principles in which light scattering phenomena predominate may be used Such methods rely on the measurement of the amplitude of optical signal generated by the interaction of particles with suitably intense and focused beams
- Such instruments are referred to as particle detectors or particle counters and are used widely in a variety of industrial and scientific applications
- One such technique known as flow cytometry, allows particles in a concentrated suspension, to be addressed on an individual basis by diluting the sample through adding it slowly to a rapidly flowing hydrodynamic sheath of substantially particle free liquid, the output of which is directed by a finely adjusted nozzle to flow accurately through a concisely focused measurement volume
- the fluorescence wavelength generated by the interaction of the particle with a suitably focused and intense optical sources particles as small as 0 2 ⁇ m can be quantified and various optical parameters relating to their size and differential absorption or fluorescence characteristics can be determined
- the present invention is based on the unexpected finding that when a small volume of a suspension of sub-micron particulates, exemplified by biological virus particles, are placed on a metallised optical element comprising an optically transparent (glass or silica) surface coated with a thin (10's nm) film of metal, for example chrome, silver or gold, and which is illuminated by a beam of light incident on the metal/glass interface at or close to the critical or SPR angle for that optical structure when in contact with the particle-bearing medium, individual sub-micron particles within the contacting fluid and in close proximity to the point at which the optical beam is incident on the metal film are found to scatter sufficient amounts of light so as to be individually discernible through a conventional microscope objective/lens combination, by eye or by a suitable photodetector such as a photon multiplier tube, solid state photodiode, CCD camera or other photosensitive device placed in an image plane in the far field and normal or at high angle to the plane of the otherwise non-radiative metallised surface
- a method and apparatus for the individual optical detection and characterisation of small (relative to the wavelength of light being used for illumination) particles suspended in a transparent fluid or gas medium for the purposes of determining particle characteristics such as size, size distribution, number concentration, shape or other optical characteristics such as fluorescence, polarisation, phase modulating properties, etc wherein the particulate suspension is contacted with one side of an optical element comprising a transparent optical substrate such as a glass or silica slide or prism the surface of which in contact with the particulate suspension has been coated with a thin film of metal such that when illuminated by a suitably intense and focused beam of light caused to be obliquely incident to the metal/glass interface at or close to critical or SPR angle, such that the beam of light is caused, by refraction, to propagate along or close to the plane of the metallised surface of the optical element, those particles in the vicinity of the illuminated region of the metal surface or the propagating beam in contact with the particle bearing fluid cause detectable amounts of light to
- microscope optics and instrumentation can be used to allow particles so small as to be otherwise undetectable by conventional optical microscopy techniques to be individually detected for the purposes of determination of particle presence, size, particle size distribution, concentration, number, fluorescent attributes, whether inherent or through the addition of fluorescent labels for measurement of specific parameters associated with the particle composition, polarisation modifying properties, phase modulating properties or any other parameter normally addressable by optical methods of analysis
- the particle suspension can be caused to flow over the surface of the optical element such that particulate suspensions that would otherwise be so dilute as to contain too few particles within the measurement volume for statistically accurate estimation of particle presence or number concentration or size distribution to be made, an increased volume of the particle-containing medium can be caused to flow over the detection region thereby increasing the number of particles capable of being accurately detected and analysed
- the present method may be employed in an optical particle measurement and analysis system exemplified by those instruments known as flow cytometers in which a suspension of particles is caused to pass through an optical measurement region by introducing, via a nozzle, the particulate-bearing sample into a stream of substantially particle free fluid moving at a higher velocity, known as a hydrodynamic sheath, such that the particle-bearing sample is diluted
- the process of the invention may thus be used to determine particle presence, size, particle size distribution, concentration, number, fluorescent attributes, whether inherent or through the addition of fluorescent labels for measurement of specific parameters associated with the particle composition, polarisation modifying properties, phase modulating properties or any other parameter normally addressable by optical methods of analysis but which is particularly useful for carrying out such analyses on particles that are so small as to be otherwise undetectable on an individual basis by optical systems incorporating bulk lens configurations such as conventional microscopes, flow cytometers or other optical particle measurement instruments
- the present invention by virtue of its sensitivity to detection of particle-associated events close to a surface, further allows the interaction of sub-micron particles with surface coatings and functionahsed layers to be individually monitored and analysed in time
- Such events may include the interaction of discrete virus particles with a coating on the optical element specifically designed to substantially reproduce the properties exhibited by a cell surface for the purposes of investigating virus-cell wall infection events
- the adhesion of sub-micron regions of cell walls and regions thereof with surfaces, chemically or biochemically modified or otherwise, may be monitored at resolutions and sensitivities exceeding those afforded by conventional optical microscopic techniques
- such events can be monitored in real time and in an aqueous environment unlike those lyophilised conditions necessary for visualisation of such interactions by electron microscopy
- the range of the types of particle which can be individually seen by the process of the invention is also varied and broad
- the use of the metallised optical element herein described by virtue of its ability to generate detectable optical signals from sub-micron particulates, allows the process of the invention to be applied to the estimation of contaminant levels in process or industrial fluids and liquids which are desired to be contaminant free, the detection of virus particles and other sub-micron biological entities in biological, environmental, biotechnological and clinical samples, such as blood and urine and other body fluids, purification media, pharmaceutical preparations, and the like
- Other particulates in solution or suspended in a gas phase that may be individually detected, counted and characterised in accordance with the invention include contaminating organic or inorganic particles in otherwise particle free fluids, smoke or other combustion product particles in gases, contaminants in oils, micro-emulsion (oil in water or water in oil) droplets, hposomes and vesicles, micelles, sub-microscopic cells such as mycoplasmas, colloids of
- the process of the invention is applicable to the analysis of individual macromolecules and macromolecular constructs which, through labelling with a suitable optical amplifier or fluorescent label capable allowing them to be distinguished from the background, would not otherwise be detectable on an individual basis using conventional optically based particle characterising instrumentation
- metallised optical element illuminated with a suitable optical source as described herein is particularly advantageous in that readily available light sources of modest power such as low cost gas, diode or solid state lasers can be used in conjunction with conventional detection optics and electronic photosensitive devices to detect particles which normally would only be capable of being individually visualised by very much more sophisticated and complex techniques such as electron microscopy
- Figure 1 illustrates apparatus according to the invention for the detection of sub- ⁇ particles such as viruses suspended in an aqueous fluid
- Figure 2 illustrates one use of the invention for application in a flow cytomnet ⁇ c configuration
- Figure 3 illustrates the use of the apparatus for studying the interaction of particles with a functional layer deposited on the optical element
- an instrument element 100 consists of an optically transparent substrate 1 , typically a glass or silica prism, onto which is deposited a thin film of metal 2, typically less than 50nm depth of gold, silver, aluminium or chrome deposited by any suitable sputtering, vapour phase, electrochemical or other means
- a light beam of suitable colhmation, intensity, polarisation and wavelength or wavelength range 3 is focused by lens 4 to be incident on the glass/metal interface at or close to the critical or SPR angle for that optical configuration such that when a sample of liquid 8 containing a suspension of particles 5 is placed onto the surface of the metal film 2, those particles 6, in close proximity to the point at which the optical beam is incident on and thus propagates along or close to the direction of the plane of the metal film, individually act to scatter light which can be detected in the far field by a suitably aligned and focused lens arrangement 7 such as a microscope objective, which could be an immersion lens, and associated lenses to be subsequently observed by eye or analysed using a photosensitive device and suitable signal
- the particle population 5 is comprised entirely or partially of particles which are inherently fluorescent or have been specifically labelled through the use of selected fluorescent labels, those particles which fluoresce on coming into close proximity to the region of the metal/glass interface illuminated by an exciting optical beam 3, may be specifically observed through the lens assembly 7 if the image is first filtered by a suitable fluorescence filter assembly 9
- the detection lens assembly 7 could, if required, be placed on the opposite side of the optical element 100, if the apex of the prism were to be removed or modified in shape to present an optically flat surface through which the scattered light of fluorescence from the particles could then be detected, the metal film being sufficiently thin at normal or high detection angles to allow sufficient amounts of radiation to pass through it to allow observation and analysis of the particle suspension
- Optical element 103 consists of an optically transparent planar substrate 11 , typically glass or silica, onto which is deposited a thin film of metal 12, typically less than 50nm depth of gold, silver, aluminium or chrome deposited by any suitable means
- a light beam of suitable colhmation and wavelength 10 is caused to be incident on the glass/metal interface of optical element 103 at or close to the critical or SPR angle for that optical configuration
- a hydrodynamically focused stream of fluid 13 emanating from a nozzle 14 and containing a stream of particles 13 introduced into the hydrodynamic sheath fluid by tube 15 is passed through the region at which the optical beam is incident on the glass/metal interface of optical element 103, particles directed, by fine adjustment of nozzle 14, to flow in close proximity to this region will either scatter light or be induced to fluoresce, the optical radiation of which is detected, through use of lens system 17 containing a fluorescent filter assembly 18 if required
- the detection lens assembly 17, or an additional lens and detector assembly could, if required, be placed on the opposite side of the optical element 103, through which the scattered light or fluorescence from the particles could then be detected, the metal film being sufficiently thin at normal or high detection angles to allow sufficient amounts of radiation to pass through it to allow observation and analysis of the particle suspension
- Figure 3 is shown an alternative configuration for the detection of interaction of particles with a functional surface
- an instrument element 102 consisting of an optically transparent planar or prism substrate 21 , typically glass or silica, onto which is deposited a thin film of metal 20, typically less than 50nm depth of gold, silver, aluminium or chrome deposited by any suitable means
- a functional layer 24 can be deposited onto the metal film 20 which may comprise a polymeric or biological material which substantially replicates the properties exhibited by a natural cell membrane or wall surface and from which the interaction of particles 26 in a liquid 27, which may, for instance, be infective virus particles, can be obtained information about the rate, number and behaviour of binding events between the particles and the functional surface
- the functional layer may comprise a chemically or biochemically modified layer onto which have been attached chemical or biological molecular moieties such as antibodies or other selective ligand binding structures which exhibit a specific affinity for target molecular or particulate structures, 26 the presence and number or behaviour of which is required to be established in the sample 27
- the detection lens assembly 28 could, if required, be placed on the opposite side of the optical element 102, through which the scattered light or fluorescence from the particles could then be detected the metal film being sufficiently thin at normal or high detection angles to allow sufficient amounts of radiation to pass through it to allow observation and analysis of the particle suspension
- the optical element is a silica quartz planar substrate onto which has been deposited by a sputtering method, an approximately 40-50nm thick layer of gold the surface first having been thinly coated with a 2nm layer of chrome to assist adhesion of the gold
- the optical element is illuminated at grazing incidence by a laser beam of modest power, for example 50mW and suitable wavelength, for instance 488nm
- a biological sample such as a throat swab diluted in phosphate buffered saline containing a population of unlabelled retractile virus particles of clinical significance (such as adenoviruses) is placed on the optical element surface and the light the virus particles scatter as they move under Brownian motion in the vicinity of the point at which the optical beam is incident on the metallised optical element is observed by eye down a conventional microscope fitted with a x40 immersion objective
- Images of the virus can, of course, be captured on film or on video recording by suitable instrumentation for subsequent viewing and analysis The presence and number concentration of virus particles in
- the invention can be used in a variety of other configurations and for a variety of other purposes
- the invention could be incorporated into any other optical detection apparatus in which the interaction of very small particles with and optical field is measured
- the invention could be incorporated into a scanning probe microscope, such as a scanning near-field microscope, as a means of visualising a surface and locating desirable or interesting features on that surface to assist in the efficient high resolution scanning and imaging of the surface by the scanning probe tip
- the invention could be used to enhance the performance of and derive more information from other analytical techniques such as Surface Plasmon Resonance (SPR) techniques allowing SPR device surface features and areas of interest to be identified and spatially located This would allow specific particulate-bearing regions of the SPR surface to be spectroscopically analysed instead of taking readings from a random or otherwise uncharacte ⁇ sed or undefined point on the measurement surface as is done presently
- SPR Surface Plasmon Resonance
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU76685/98A AU7668598A (en) | 1997-06-13 | 1998-06-01 | The optical detection and analysis of sub-micron particles |
US09/308,049 US6280960B1 (en) | 1997-06-13 | 1998-06-01 | Optical detection and analysis of sub-micron particles |
EP98924492A EP1044361A1 (en) | 1997-06-13 | 1998-06-01 | The optical detection and analysis of sub-micron particles |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9712202.2 | 1997-06-13 | ||
GB9712202A GB2326229A (en) | 1997-06-13 | 1997-06-13 | Detecting and analysing submicron particles |
Publications (1)
Publication Number | Publication Date |
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WO1998057148A1 true WO1998057148A1 (en) | 1998-12-17 |
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PCT/GB1998/001591 WO1998057148A1 (en) | 1997-06-13 | 1998-06-01 | The optical detection and analysis of sub-micron particles |
Country Status (5)
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---|---|
US (1) | US6280960B1 (en) |
EP (1) | EP1044361A1 (en) |
AU (1) | AU7668598A (en) |
GB (1) | GB2326229A (en) |
WO (1) | WO1998057148A1 (en) |
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WO2010097369A1 (en) * | 2009-02-27 | 2010-09-02 | Leibniz - Institut Für Analytische Wissenschaften - Isas - E.V. | Method for high-resolution registration of nanoparticles on two-dimensional measurement surfaces |
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Also Published As
Publication number | Publication date |
---|---|
GB2326229A (en) | 1998-12-16 |
EP1044361A1 (en) | 2000-10-18 |
GB9712202D0 (en) | 1997-08-13 |
AU7668598A (en) | 1998-12-30 |
US6280960B1 (en) | 2001-08-28 |
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