Optics: measuring and testing – For light transmission or absorption – Of fluent material
Reexamination Certificate
2000-03-03
2003-04-01
Rosenberger, Richard A. (Department: 2877)
Optics: measuring and testing
For light transmission or absorption
Of fluent material
C356S440000
Reexamination Certificate
active
06542241
ABSTRACT:
BACKGROUND OF THE INVENTION
a) Field of the Invention
For tasks appertaining to the biotechnical analysis (screening) of large quantities of samples, e.g. for genetic analysis (e.g. viral diagnosis), the use of so-called microtiter plates and associated manipulation technology (e.g. automatic machines for filling the individual cavities in the microtiter plate) is an established technology (pharmacological research, clinical practice etc.).
b) Description of the Related Art
This technology is distinguished by the fact that in a microtiter plate with a size of 8 cm×12 cm, depending on the embodiment, 96 (most common type), 384 or 1536 (probably the maximum possible value for microtiter plate technology with only minor application heretofore) different sample substances can be accommodated. In order to fill the individual cavities, sample quantities of the order of magnitude of 100 &mgr;l are necessary depending on the type of microtiter plate.
In the course of increasing the effectiveness, international research and development work is currently underway with the aim of significantly increasing the number of cavities (that can be processed in parallel) in conjunction with significantly reducing the required sample quantities and significantly increasing the sample throughput. These aims are intended to be achieved by the transition from microtiter plates to biochips (e.g. manufactured using microphotolithographic technologies) and fast read-out and processing (high throughput screening, HTS) of the biochips.
An individual biochip may comprise spots (comparable with the cavities in the microtiter plate) numbering tens of thousands on an area of a few mm
2
to cm
2
, sample quantities of the order of magnitude of a few nanoliters being necessary altogether over all the spots.
In order to read biochips (and also microtiter plates or any other chemical sample carriers), the sample material is irradiated with light in the UV through to the NIR region, depending on the type of samples, and the influence on the radiation by the sample material (e.g. absorption) or the effect of the illumination radiation on the sample material (e.g. excitation of a luminescent radiation) is measured.
In order to read the matrix-type arrangement of the pixels on a biochip, the following two techniques are known in principle:
1. Serial illumination by means of a laser scanner and read-out of the individual sample images (pixels) of the sample carrier using a single optoelectronic photoreceiver, e.g. photon counter/secondary electron multiplier (SEM)/photo multiplier tube (PMT).
2. Parallel illumination and simultaneous read-out of many or all of the pixels of the sample carrier using an optoelectronic receiver matrix (e.g. CCD).
Reading units that have been disclosed for microtiter plates operate (due to the dimensions of these plates) practically exclusively according to the scan principle. In the case of this principle, the individual samples (cavities) of the sample carrier are each excited separately (successively in time). Laser scanners are used for this purpose because narrowband coherent laser radiation, in contrast to broadband incoherent radiation, can be focused without difficulty onto small pixel areas (a few &mgr;m
2
).
The narrowband nature of the laser radiation used is advantageous, on the one hand, since narrowband excitation is necessary in order to excite a specific marker (e.g. fluorescent marker) in a targeted manner, which is disadvantageous on the other hand, if different excitation wavelengths are required for different markers and it is thus necessary to change the laser light source (or use cost-intensive tunable lasers).
In the case of the camera principle, it is fundamentally possible also to use cost-effective broadband (thermal) light sources for the illumination, with the result that only one excitation filter has to be exchanged when the marker is changed. Using broadband light sources is expedient for a host of applications, which speaks in favor of the use of the camera principle for cost reasons.
One example of the application of the camera principle is a nanotiter plate read-out unit described in the technical paper “Optische Mikrosysteme für die Umweltme&bgr;technik” [Optical microsystems for environmental metrology] (in: Laser und Optoelektronik, 30(1), 1998, pp. 33-35).
On the other hand, the scan principle is recommended on account of the use of highly sensitive SEMs, which results, in particular, in especially good detection sensitivity in the case of weak secondary radiation, which is regularly absent from the camera principle owing to the less sensitive matrix receivers used and has to be compensated for by relatively long integration times (a few tens of seconds through to a few minutes) and the use of costly cooled receiver matrices (for largely suppressing the generation of thermal charge carriers during the integration time).
From this standpoint there have also been endeavors to combine a broadband radiation source with a sensitive SEM as radiation receiver in a measuring apparatus which has been disclosed, in terms of equipment engineering, as an ultrahigh throughput screening system (from Carl Zeiss Jena GmbH) for processing 96-type microtiter plates with 96 optical transmission channels and an SEM for each channel. However, this solution leads to very high costs and seems inconceivable for pixel numbers of the order of magnitude of several thousands to tens of thousands of pixels.
The invention is based on the object of finding a new possibility for optically reading out the information from matrix-type substrates having a multiplicity of individual samples which allows a fast read-out of a radiation which is characteristically influenced by the individual sample substances with a high degree of sensitivity. In addition, the intention is to find a possible way of departing from the storage of a complete (image) file of the local distribution of the radiation intensities on the matrix-type substrate and, for specific objectives (e.g. comparison of the present radiation distribution with a catalog of possible distributions), of performing, as early as in the optical channel, a suitably adaptable data reduction or an initial evaluation situated upstream (with respect to the subsequent digital evaluation by means of a PC or the like).
The object is achieved according to the invention, in the case of an arrangement for optically reading out the information from a matrix-type substrate having a multiplicity of individual samples, which represent metrically ordered pixels on the substrate and emit a radiation which is characteristically influenced by the respective sample substance, having a transfer optical arrangement for separately transferring the radiation emitted by individual substrate pixels to a receiver, by virtue of the fact that the receiver is an individual receiver which has high sensitivity and a uniform receiver area and is able to take up the radiation from each substrate pixel, that the transfer optical arrangement has an electrooptical matrix, which has the function of a variable light valve for separately transferring radiation from each substrate pixel to the receiver, and also an imaging optical system, each substrate pixel being assigned to a matrix region, comprising at least one matrix pixel, by means of the imaging optical system, and that the matrix can be driven in such a way that matrix regions of such a size which allow exclusively the feeding of radiation from a substrate pixel to the receiver can be switched separately, radiation quantities from in each case at least one substrate pixel successively impinging on the receiver over a suitably chosen time interval, with the result that it is possible to evaluate a series of measured radiation quantities from selected sequences of substrate pixels at the output of the receiver.
Intensive illumination is preferably provided for generating the radiation which is characteristically influenced by the substrate pixels. This illumination is expediently chosen such that th
Reiland Werner
Thorwirth Guenter
Jena-Optronik GmbH
Reed Smith LLP
Rosenberger Richard A.
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