Etching a substrate: processes – Etching to produce porous or perforated article
Reexamination Certificate
1997-07-21
2001-04-10
Gulakowski, Randy (Department: 1746)
Etching a substrate: processes
Etching to produce porous or perforated article
C216S044000, C216S094000, C216S024000
Reexamination Certificate
active
06214246
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates, in general, to a method and apparatus for analysis of chemical species separated by differences in flow rate through a porous medium, and, more particularly, to a method and apparatus for analysis of such species through optical absorption, reflection, refraction or fluorescence simultaneously in multiple micron-scale optical channels. The invention further relates to a microfabricated porous medium for such channels.
Optical systems for use in chemical analysis are well known, and the use of such systems in electrophoretic DNA sequencing is a particularly important application because of the intense interest in the sequencing of the human genome. This is a multiyear, multibillion dollar project which is directed to improving, if not revolutionizing, the ability to diagnose and treat illness.
Significant progress is being made in this field, and commercial optical systems are now available which are capable of sequencing DNA by gel electrophoresis of fluorescently labeled DNA fragments.
Because DNA sequencing is a highly complex procedure which requires a great deal of time and involves high cost, a considerable amount of research is being done into techniques and devices for reducing the time required for such sequencing, with one technique including the parallel reading of fluorescence from multiple capillaries. However, problems still remain in processing the DNA, in supplying it to the capillaries, in causing the DNA to pass through the capillaries, and in optically reading out the results, for currently available systems are relatively large, are expensive, and, although capable of operating faster than previous systems, still require very long time periods to sequence DNA fractions. Thus, the time required to sequence the three billion base pairs which comprise the human genome is still measured in years, and, there is an urgent need for an improved optical system for carrying out such procedures. Such an improved system would also have application in the analysis of other chemical species, particularly where the species are separated by differences in flow rate through a porous medium.
In electrophoretic analysis, chemical species are separated by an electric field which produces varying flow rates, and the separated products may then be detected optically. In typical DNA sequencing applications, the DNA fragments to be analyzed are added to a gel material which carries the fragments through electrophoresis channels. Such gels create problems, however, since it is difficult to fill narrow capillaries with the gel material, thereby increasing the time required and the expense of carrying out the sequencing process. Efforts have been made to develop an artificial gel material in the form of a porous medium, but the dimensions of such structures have been limited to those obtainable by photolithography. In addition, the production of artificial gel structures by such a process is too expensive for practical use. Thus, there is a need for an artificial gel structure which can be formed by processes that are easily carried out over large areas and which can be fabricated in inexpensive materials. Such a gel material would find wide use in a miniaturized, compact, and proportionately less expensive systems for chemical analysis.
SUMMARY OF THE INVENTION
Briefly, the present invention relates to a miniaturized optical system for chemical analysis and to a microfabricated gel material usable in such a miniaturized system. The invention utilizes multiple parallel microoptical illumination paths from one or more light sources leading to individual sample channels. The illumination from the light source may be divided and directed in parallel to corresponding channels, or may be a single beam scanned sequentially over the channels without a need for mechanically translatable optics or the need for moving the sample channels. Preferably, the illumination source is a laser.
Each optical path directs the illumination to a corresponding sample channel where components of the sample material to be detected may be caused to fluoresce, for example. Light emitted from the sample is collected and focussed onto a detector array which may include individual detectors for each sample channel, the detectors being responsive to selected wavelengths in the emitted light for identification of the sample material components. By using miniaturized optical components, illumination and collection lenses and other optical elements can be reduced to less than 1 mm diameter, and the illumination and collection path length can be reduced to a total of about 1 cm. An array of aspheric illumination and/or collection microlenses provides high optical efficiency and further provides a complete set of optics for each of the multiple sample channels.
By providing multiple sets of microptic illumination and collection paths and multiple sample channels, the structure is completely scalable without the need to extend the optical path length for any channel as the number of sample channels increases. Further, the microoptical system of the invention is easily mass produced by current commercial technologies, and in large quantities can be produced relatively inexpensively.
Preferably, the optical system incorporates a carrier block which incorporates a plurality of parallel sample channels. The carrier block may be replicated in optically clear plastic from a master die, as by a conventional molding process, to allow the sample channels to be readily produced with precise dimensions at a low cost so as to provide disposable sample holders. The block preferably is molded in two parts, one part, which may be referred to as the channel block, including the parallel sample channels on a first surface and the other part, which may be referred to as the cover block, providing a cover for the channels. If desired, channels or parts of channels, can be formed in both parts of the carrier block, with the channels being completed and enclosed when the two parts of the block are assembled.
In one form of the invention, one part of the carrier block, for example the channel block, may incorporate multiple miniaturized illuminating lenses on a second surface spaced from and parallel to the first surface on which the sample channels are located. Preferably one lens is provided for each channel, or for a small group of channels, for directing light from an external source such as a laser (or multiple lasers) through the channel block to the respective sample channels. The illuminating lenses are molded as an integral part of the channel block in a preferred form of the invention, although they may be adhesively secured to a surface of the channel block, if desired.
In this embodiment, the second part of the carrier block, for example the cover block, carries collection optics, preferably including a collection lens for each channel for collecting output light passing through, emitted by, or reflected from, sample material in the sample channels. The collection optics also preferably include diffraction elements, to separate the output light by wavelength, and directs this output light to suitable detectors. The collection optics preferably are molded as an integral part of the cover block, which also is optically clear plastic in the preferred form of the invention, this fabrication process enabling rapid and inexpensive replication of the cover block and optics.
The carrier block may incorporate suitable electrodes for supplying electric potentials to sample material in the sample channels, to permit electrophoretic analysis of this material. In this configuration the structure of the present invention is particularly advantageous when used in the fluorescent detection and analysis of sample material such as dye-labeled DNA fragments in electrophoretic DNA sequencing. Accordingly, the following description of preferred forms of the invention will be particularly directed to this process, although it will be understood that the described optical system lends itself to
Ahmed Shamim
Cornell Research Foundation
Gulakowski Randy
Jones Tullar & Cooper P.C.
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