Chemistry: analytical and immunological testing – Optical result – With claimed manipulation of container to effect reaction or...
Patent
1992-05-06
1994-11-08
Johnston, Jill A.
Chemistry: analytical and immunological testing
Optical result
With claimed manipulation of container to effect reaction or...
324 711, 324 714, 356441, 356442, 356335, 356311, 422 73, 422 8205, 422 8211, 436149, G01N 2117, G01N 2900
Patent
active
053626532
DESCRIPTION:
BRIEF SUMMARY
This invention relates to methods and apparatus for examining individual objects the size of which is of the general order of magnitude of macromolecules and their aggregates, or smaller. These objects may consist of particles, or of other materials or structures of generally similar dimensions. Where they are particles, they may in fact actually be macromolecules, for example enzymes or other proteins, or biological macromolecules or other larger structures such as viruses. The field covered by the invention does not however exclude the examination of particles of generally sub-micron size. Objects for examination, or being examined, will sometimes herein be called "samples", for convenience.
Current techniques, such as scanning tunnelling microscopy, atomic force microscopy and scanning near field optical microscopy, are already well known, and have considerably lowered the limit of molecular resolution that is now possible. In all these techniques, the image is built up from a scanned signal which is generated by interaction of the structure of the sample particle with a probe tip having dimensions comparable with that of the sample.
In scanning tunnelling microscopy (STM) an ultra-fine, chemically etched electrode is brought very close to the sample, so that electrons can pass by quantum tunnelling across the free space between the electrode tip, or part thereof, and the surface of the sample. The samples are mounted on a conductive substrate, and the probe is scanned across the substrate in order to find a sample for examination. Piezoelectric transducers are used to control the movement of the probe. One disadvantage of STM is that the sample must be sufficiently electrically conductive, and with many types of particle, particularly biological particles, this requires pretreatment of the sample macromolecule in order to improve its conductivity. This has been achieved by using metal shadowing or doping with conductive salt ions; such treatment can however alter the characteristics of the sample, so that in some cases it becomes self-defeating.
Another, somewhat similar, device is the scanning capacitance microscope, which measures the capacitive, changes associated with sample structures but on a much lower resolution. It can operate to the same order of magnitude of sample size as conventional optical microscopy, or larger.
In atomic force microscopy (AFM), an ultra-fine, very lightly spring loaded probe tip is scanned across an area containing a sample, and then across the sample itself. The movement of the tip as it is deflected by repulsion between the Van der Waals forces between the tip and the sample is monitored so as to generate a topographical image of the surface of the sample. A major disadvantage of AFM is that with most biological macromolecular structures, particularly in solution, the forces generated by the probe tip will tend to damage or destroy the sample. The AFM technique is therefore somewhat limited in scope, and, as is also generally true of STM, it is really only suitable for use where the sample can be shadowed, i.e. coated, with metal.
Electromagnetic radiation can be greatly amplified when interacting with strongly curved parts of a surface due to quasi-static concentration of field lines (the so-called "lightning rod" effect). This effect is responsible for the development of surface-enhanced Raman scattering or roughness-induced electrical breakdown. It is also responsible for the strong elastic light scattering associated with microscopic holes in a film (apertures) or protrusions (asperities) from a surface, a process closely related to Mie scattering from small spheres which act as "short optical antennae" (SOA). The degree of scattering from these SOA is related to their size (curvature) and dielectric properties.
The method employed in a scanning near field optical microscope (SNOM) is a variant on the STM technique, and is essentially optical in character. The SNOM includes a component which serves as an optical source of suitably small dimensions and which perfor
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Atkinson Anthony
Carr Robert J. G.
Clarke David J.
Johnston Jill A.
Middleton James B.
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