Optical detection and analysis of sub-micron particles

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...

Reexamination Certificate

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C356S317000, C356S318000, C356S335000, C356S336000, C356S244000, C356S246000, C422S051000, C422S068100, C422S082050, C422S082080, C422S082110, C435S287100, C435S287200, C435S287900, C435S288700, C435S808000, C436S164000, C436S165000, C436S172000, C436S518000, C436S524000, C436S525000, C436S805000

Reexamination Certificate

active

06280960

ABSTRACT:

The present invention relates to the optical detection and analysis of particulates of nanometre, sub-micron 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.
A large number of principles and techniques exist by which particles can be analysed in terms of their number, size, shape, composition and motion.
Historically, the observation and charaterisation of particles lies in the domain of microscopy in which highly magnified images of particles are generated through the use of high powered lensed systems and which can be seen directly by eye or can be captured by camera for subsequent interpretation by the operator or by an image analysis system.
There are many types of microscope systems capable of characterising the particle in terms of its interaction with the incident illumination. For instance, 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. Yet other microscopical techniques utilise the way in which the particle induces a phase shift in the incident light, such as 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. In this case, 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 oblique angle only.
Methods of illumination vary greatly and in certain circumstances the sample (typically and aqueous suspension of particles) can be placed on a transparent (typically glass or silica) 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 place. A small portion of the beam, called the evanescent wave, propagates a small 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 with the evanescent field) can then be detected in the far field either by eye or by a suitable detector situated normal or at high angle to the plane of the surface. When employed in a microscope configuration this technique is referred to as evanescent field microscopy and relies on the principle of frustrated total internal reflection Other techniques, such as confocal microscopy, benefit from the specific properties exhibited by light sources such as lasers in which the light can be highly collimated, monochromatic, coherent and very intense.
All the above techniques suffer, however, from being limited by the classical diffraction or Rayleigh limit which restricts, in practice, the useful resolving power of optical microscopes to approximately &lgr;/2 which precludes the imaging of particles of less than 0.2-0.5 &mgr;m diameter.
Numerous non-imaging methods exist for the optical analysis of suspensions &mgr;m or sum-&mgr;m particles or solutions of nm scale particles such as biological molecules or macromolecules. Many such techniques monitor the interaction between biological molecules and in order to define a region within such interactions can be specifically detected within minimal interference from other species in the bulk of the solution phase, such analyses are frequently carried out at the interface of an optical waveguide or fibre optic structure onto the surface of which have been immobilised biological capture molecules such as antibodies, specific for the target analyte. In conventional waveguide or fibre optic systems use is made of the changes in the refractive index properties at the surface interface following binding of specific biological molecules in the surface associated evanescent field region of the optical structure. This field extends, however, only some 100-200 nm into the bulk solution phase and is accordingly limited in its ability to monitor weak interactions involving limited numbers of molecular interactions. Such a method is disclosed in DE 4307042 (930305), in which a single or multilayer of receptor molecules are deposited on and evanescent waveguide sensor device and which is capable of sensing and quantifying various chemical and biochemical species in solution. A similar method is disclosed in WO 9005295 claiming priority of SE 884075 (881110) in which a wedge shaped prism is used to allow light reflected at different angles off the underside of the optical sensor element to be imaged and analysed to quantify specific species in solution. Similarly, EP677735 claiming priority of U.S. Pat. No. 228233 (940415) describes and optical resonator cavity in which light is reflected from a total internal reflector cavity in contact with a solution components of which interact with the evanescent field within the TIR allowing quantification of species in the solution These techniques are characterised by their reliance on the analysis of light which is reflected from the underside of a sensing element surface.
The ability to follow such low numbers of interactions or binding events can, however, be significantly enhanced, by one or two orders of magnitude, by employing Surface Plasmon Resonance techniques in which the surface of the optical waveguide structure is coated with a thin film of a conductive metal, such as gold, silver, chrome or aluminum, in which electromagnetic waves, called Surface Plasmons, can be induced by a beam of light incident on the metal glass interface at a specific angle called the Surface Plasmon Resonance angle. Modulation of the refractive index of the interfacial region between the solution and the metal surface following binding of the captured macromolecules causes a change in the SPR angle which can either be measured directly or which causes the amount of light reflected from the underside of the metal surface to change. Such changes can be directly related to the mass and other optical properties of the molecules binding to the SPR device surface. Several biosensor systems based on such principles have been disclosed. Thus WO 9005305 claiming priority of SE884074 (881110) describes the use of a metal film deposited on one side of a block unit of optical instrumentation, one multi-functionalised side of which is in contact with a solution of reagents or samples to be measured, the other side is illuminated by an optical beam within the block unit of optical instrumentation caused to reflect off the metal surface at an angle such that reflectance is modified by selective binding of ligands on the functionalised surface. Measurement of the reflected beam can be correlated to concentrations of specific species binding to the functionalised sensor surface.
Similarly EP 341927 claiming priority of GB881154 (880510) describes a biological or biochemical testing sensor comprising a surface plasmon resonance (SPR) sensor and a sample-antibody surface arranged to influence resonance characteristics. 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

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