Chemistry: electrical and wave energy – Apparatus – Electrophoretic or electro-osmotic apparatus
Reexamination Certificate
2000-07-31
2004-08-24
Bell, Mark L. (Department: 1755)
Chemistry: electrical and wave energy
Apparatus
Electrophoretic or electro-osmotic apparatus
Reexamination Certificate
active
06780300
ABSTRACT:
The invention relates to the field of analyzing samples by multichannel capillary electrophoresis.
BACKGROUND OF THE INVENTION
It relates more particularly to devices comprising firstly a multiplicity of capillaries for analyzing samples in parallel, secondly receiver means for receiving at least the central portions of the capillaries remote from their ends, and thirdly regulator means co-operating with the receiver means to regulate the temperature of the capillaries.
A device of this type is described in particular in U.S. Pat. No. 5,045,172. The capillaries of that device are used in a hollow case within which a cooling fluid circulates for temperature regulation purposes.
That method of temperature regulation requires a complex hydraulic circuit comprising at least a pump, a fluid reservoir, sealing means, means for regulating the fluid flow rate, and possibly also a heat exchanger.
Such a circuit increases the size of the device, requires regular maintenance, and disturbs the capillaries because of the turbulence that exists inside the case.
Furthermore, that type of regulation by means of a fluid is unsatisfactory in terms of reproducibility between capillaries.
Also, it is difficult to replace a faulty capillary because all of the capillaries are housed in the same case.
Finally, that type of device requires a large amount of manipulation, in particular of the samples to be analyzed, thereby making it impossible to perform analyses at a rate sufficient for use in a clinical chemical laboratory.
Other solutions have been proposed, for example in document U.S. Pat. No. 5,413,686, however they do not provide entire satisfaction.
OBJECTS AND SUMMARY OF THE INVENTION
An object of the invention is thus to resolve the above-mentioned drawbacks in full or in part.
To this end, the invention provides a device of the type described in the introduction in which, firstly, the capillary receiver means comprise a multiplicity of independent units closely enclosing the central portions of the capillaries and made of a material that is thermally conductive and electrically insulating, and secondly the temperature regulation means are arranged to provide heat exchange with the units via a solid/solid exchange in such a manner as to regulate the temperature of the capillaries via said units.
The term “closely enclosing” is used herein to mean that the material of the unit is in surface contact with the outside surface of a capillary. The term “solid/solid exchange” is used to mean that heat exchange takes place by transfer from one solid surface to another solid surface, and not from a solid surface to a liquid or gaseous surface.
This provides very effective temperature regulation and enables any faulty capillary to be replaced independently of the others.
In an advantageous embodiment, first link means are provided formed of thermally conductive walls that define housings for closely receiving the units. Still more preferably, the first link means are constituted by a multiplicity of independent second link means comprising at least three walls that are substantially mutually perpendicular and leaving an opening for housing a unit, each second link means co-operating with its unit to constitute an independent cartridge.
The unit can be made of resin, e.g. of the Stycast type (trademark registered by National Search and Chemical Company). It can be flexible or rigid. It can be shaped prior to being introduced into the housing formed by the first link means, or it can be injected directly into the housing. The unit can be extractable or not, depending on how it is made.
According to another characteristic of the invention, detector means are provided capable of supplying information about the samples traveling in a selected zone of each capillary.
Preferably, these detector means comprise a source delivering light radiation at a selected wavelength, a light radiation detector, a multiplicity of first optical fibers each having a first end receiving the light radiation and a second end delivering the light radiation to the selected zone of a capillary, and a multiplicity of second optical fibers each comprising a first end picking up the light radiation from the associated first optical fiber after it has interacted with the sample components traveling through the selected zone of the capillary, and a second end delivering said light radiation that has interacted to the detector.
Such a detector can advantageously be implemented in the form of a charge-coupled device (CCD) having a multiplicity of detector elements each coupled to the second end of a corresponding second optical fiber. The term “element” is used herein to mean one or more detection pixels. Detection is performed using a single detector simultaneously on the various capillaries such that the response coefficient of the detector is substantially constant regardless of which capillary is involved, thereby making it possible for the reproducibility of analysis to be improved considerably from one capillary to another.
Preferably, in the selected zone, each capillary has an internal cross-section of area that is greater than in its other portions. This can be achieved either by coupling together capillaries of different dimensions, or else by using “bubble” capillaries of the type described in U.S. Pat. No. 5,061,361 and sold by Agilent Technologies. As a result, the path followed by the light through the capillary is lengthened, thus considerably increasing the sensitivity of detection.
According to yet another characteristic of the invention, first and second reservoirs are provided each fitted with a single first or second electrode and capable of receiving the first or the second ends respectively of the capillaries together with high voltage power supply means enabling a selected potential difference to be established between the first and second electrodes. All of the first ends of the capillaries are thus placed at substantially the same depth in the analysis fluid, and the electric field is distributed in uniform and substantially symmetrical manner over the ends, thereby further improving the reproducibility of analyses.
Preferably, means are provided that are capable of establishing a selected pressure difference between the first and second reservoirs that is either positive or negative, such that fluid flow can take place from the first reservoir to the second reservoir and vice versa (which fluid is generally a liquid, but could be a gas, e.g. to unplug a capillary). This enables the capillaries to be cleaned under pressure, preferably using a counterflow, and consequently enables the time required for cleaning the capillaries to be reduced considerably, while also improving the quality of such cleaning.
The invention also provides a method of analyzing samples by capillary electrophoresis, the method comprising at least the following steps:
introducing samples into a multiplicity of capillaries each having a central portion closely incorporated in an independent unit made of a material that is thermally conductive and electrically insulating;
applying a selected potential difference between the opposite ends of the capillaries in order to separate the components of the samples, while regulating the temperature of the capillaries by heat exchange via a solid/solid exchange between said units and regulator means, preferably of the Peltier type; and
detecting the components in a selected zone of the capillaries.
REFERENCES:
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Bell Mark L.
Brown Jennine M.
Lerner David Littenberg Krumholz & Mentlik LLP
Sebia
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