Optics: measuring and testing – Sample – specimen – or standard holder or support – Fluid containers
Reexamination Certificate
1999-06-11
2002-12-03
Evans, F. L. (Department: 2877)
Optics: measuring and testing
Sample, specimen, or standard holder or support
Fluid containers
C356S440000
Reexamination Certificate
active
06490034
ABSTRACT:
The present invention relates to optical transmission measuring cells and reactors with an integrated optical detection mechanism and, especially, to a micromechanical transmission measuring cell for determining an optical absorption of a sample fluid.
Reactors with an without integrated evaluation components are presently used in various fields of analytical and synthetic chemistry. One embodiment which is frequently used in the field of analytical chemistry is the microtitration plate, which is used for immunological testing methods, e.g. the enzyme-linked immunosorbent assay (ELISA). Microtitration plates normally consist of an optically transparent plastic body provided with a number of depressions used as reaction vessels. The inner wall of said reaction vessels is coated with a suitable biochemical receptor layer which, when the sample fluid has been filled in, permits selective bonding of the analyte molecule to be determined to at least one reactor wall. In further reaction steps, a change in colour is produced in the reaction vessel as an indicator reaction, said change in colour representing a measurable variable for the amount of bonded analyte molecules. The quantitative determination of the alteration of colour is normally carried out by an optical transmission measurement through the interior volume of the reactor and through the plastic body.
Further embodiments of microreactors consist of a volume through which a flow passes, e.g. a capillary or a flow passage filled with a carrier material, on the inner surface of which (the inner wall or surface of the carrier material) a receptor layer is immobilized. Such a system is described in E. Yacoub-George, H. Wolf, S. Koch, P. Woias, A Miniaturized ISFET-ELISA System with a Pretreated Fused Silica Capillary as Reaction Cartridge, Proc. of the Transducers '95—Eurosensors IX, Stockholm, Sweden, 1995, pp. 898-901. The chemical reaction mechanism used in this case is similar to the above-described course of action and produces as the last step again an indicator reaction in the volume of fluid contained in the reactor. The inner volume of the reactor is then supplied to a subsequent evaluation component, e.g. a photometer or an electrochemical sensor, for carrying out the quantitative determination of the indicator reaction.
Like reactors with an without integrated evaluation components, also a great variety of optical transmission cells is presently used in the field of analytical and synthetic chemistry. Simple embodiments consist of measuring cuvettes which are filled with the liquid to be analyzed and introduced in the ray path of an array comprising a light source and an optical detector. Flow-through cuvettes, however, comprise a flow passage which is introduced in the ray path of the optical array in the direction of flow or transversely to the direction of flow, said optical array consisting of a light source and of an optical detector.
E. Verpoorte, A. Manz, H. Lüdli, H. M. Widmer, B. H. van der Schoot, N. F. de Rooij, A Novel Optical Detector for Use in Miniaturized Total Chemical Analysis Systems, Transducers '91, Book of Abstracts, pp. 796-799, describes a micromechanical flow-through cuvette, which consists of a channel realized by means of anisotropic etching processes and covered on the upper surface thereof by a silicon chip provided with windows. Due to the use of silicon wafers with an <100> crystal orientation, the lateral walls of the channel, which have been produced by anisotropic etching, have the orientation of the etch-resistant <111> crystal plane. As is known to those skilled in the art, this plane extends at an angle of approx. 54° to a horizontal reference plane. In the known micromechanical flow-through cuvette, light is coupled in by being radiated in approximately perpendicularly through an optical entrance window by means of a light waveguide, which is directed onto an inclined end face of the etched channel. Perpendicularly means in this context a direction perpendicular to the direction of flow of the sample fluid. Due to the reflection at one end face of the channel, light is guided into the cell interior and, due to multiple reflections on the lateral walls, it is guided to the second end face, where it is coupled out of the channel through an optical window, i.e. through the cover chip, and fed into a glass fibre arranged at right angles to the direction of flow of the sample fluid. It follows that the light is coupled out at the second end face, the outcoupling glass fibre leading to a detector which may have a conventional structural design.
One disadvantage of commercially available microtitration plates is that they have typical inner volumes of the reactor in the range of some ml and diffusion path lengths in the range of some mm. This has the effect that the development of the chemical processes in the interior of the reactor, i.e. the bonding of the analyte molecules to the receptor layer, the generation of the indicator value, etc., is mainly determined by the comparatively long diffusion paths and the resultant long diffusion times. The time required for an analysis can therefore be in the range of some hours.
Furthermore, microtitration-plate tests are processed by automated anlysis apparatus which must have a comparatively high mechanization degree (e.g. pipetting robots, plate transport mechanisms), whereby the costs and the error rate are increased.
The use of reactors without integrated evaluation components normally requires additional transport steps at the end of the indicator reaction, and these additional transport steps may result in a higher expenditure and, depending on the respective structural design, in signal losses, e.g. due to mixing processes during transport in a flow-through system.
Optical transmission cells operating according to the cuvette principle have a comparatively large fluid volume in the range of some ml and are not suitable for flow-through operation. It follows that automatic processing of sample series can only be carried out with a high mechanical outlay making use of a robot system or of automatic handling machines.
Optical flow-through cuvettes are often produced by conventional techniques, e.g. injection moulding of plastic material, whereby miniaturization is only possible to a certain degree.
The micromechanical flow-through cuvette in silicon technology, which has been mentioned hereinbefore, additionally has, as has been described hereinbefore, an intentionally chosen perpendicular coupling-in direction of the light so that a ray path with multiple reflections on the channel walls is obtained. The large number of multiple reflections is intended to substantially increase the effective optical path length of the cell in comparison with the channel diameter by factors of 10 to 50, whereby an improved detection sensitivity is to be achieved. Since the etched silicon channel walls permit, however, only lossy reflections, a high light power must be coupled into this known transmission measuring cell so that a measurable light power can be coupled out at the outlet.
U.S Pat. No. 4,908,112 discloses a silicon semiconductor wafer for analyzing micronic biological samples. The analytical device comprises a separation channel having an elongate shape, electrodes formed in said channel, and a storage reservoir as well as a reception reservoir. The single separation channel or a plurality of separation channels are formed in a silicon wafer and have bevelled walls which are typically produced when etching by means of a potassium hydroxide solution is carried out. A silicon dioxide layer is formed on the channel. The electrodes are used for activating a movement of the sample fluids through said channel by means of electroosmosis. For analyzing the sample, a laser beam is directed onto a bevelled side wall of the channel; from said bevelled side wall, the laser beam is reflected transversely across the channel transversely to the opposite wall, and from said opposite wall it is reflected out of the channel. By means of
Hillerich Bernd
Woias Peter
Evans F. L.
Fraunhofer-Gesellschaft zur Foerderung der angewandten Forschung
Smith Zandra
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