Registers – Coded record sensors – Particular sensor structure
Reexamination Certificate
2001-08-23
2002-12-17
Lee, Michael G. (Department: 2876)
Registers
Coded record sensors
Particular sensor structure
C235S462230, C235S470000
Reexamination Certificate
active
06494373
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a biochip reader for reading the wavelengths of fluorescence resulting from the excitation of samples on a biochip with excitation light. More specifically, the invention relates to improvements made in order to increase the speed of measurement, simplify the biochip reader, reduce damage to the samples, and make uniform the distribution of intensity within a spot of light that is formed when excitation laser light is condensed with a microlens.
2. Description of the Prior Art
There has been apparatus for detecting and analyzing DNA or protein segments by marking the segments with a fluorescent substance, emitting laser light onto them, and reading fluorescent light thus produced. In this type of apparatus, a biochip on which such samples as DNA or protein segments marked with a fluorescent substance are spotted in arrays is used.
FIG. 1
is a conceptual schematic view showing one example of a conventional epi-illuminated biochip reader. In this biochip reader,
1
) a plurarity of DNA molecules (genes) A, B, C, . . . with known sequences are combined and arranged on a substrate PL to form a biochip
6
, as shown in
FIG. 1
a,
2
) the biochip
6
is hybridized with an unknown gene a, as shown in
FIG. 1
b,
and
3
) the result of hybridization is read using such a mechanism as shown in
FIG. 1
c.
In
FIG. 1
c,
light (laser light) emitted from a light source
1
is collimated by a lens
2
, made to pass through a dichroic mirror
4
, and then condensed onto the biochip
6
by a lens
3
. Light returning from the biochip
6
is changed back to parallel light by means of a lens
3
, is reflected by the dichroic mirror
4
, and forms an image on a detector
9
by means of a lens
8
.
In this case, a stage (not shown in the figure) on which the biochip
6
is mounted is moved in the X/Y-axis direction by drive means (not shown in the figure) so that the surface of the biochip
6
is optically scanned and a surface image is obtained.
However, such a prior art biochip reader as described above has had problems. One problem is that the stage is scanned using a single spot of light beamed at the biochip
6
, in order to obtain the surface image of the biochip. This method is disadvantageous since a stage drive mechanism is complex and it takes a long time to obtain the image.
Another problem is that the intensity of a light beam must be high in the case of the prior art biochip reader. This is also disadvantageous since a high level of light intensity causes fluorescent stain to bleach more easily.
Yet another problem is that a spot of high-intensity light is liable to cause the detector
9
or a subsequent A/D converter to saturate. For this reason, the gain of the detector or converter must be lowered. This is also disadvantageous since lowering the gain prohibits the measurement of weak light and, therefore, results in a narrower dynamic range of measurement.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the above-mentioned problems by providing a biochip reader that eliminates the need for moving a stage on which samples are placed, as practiced in the prior art, and that involves virtually no risk of bleaching fluorescent stain. Thus, the present invention is intended to provide a simple-structured biochip reader capable of measuring even weak light.
In order to attain the above-described object, a biochip reader is provided for reading image information appropriate for a plurality of samples with an optical detector, by emitting a plurality of light beams onto a biochip on which the plurality of samples are arranged in spots or linear arrays, wherein the biochip reader is configured so that the spatial positions of the plurality of samples and the plurality of light beams agree with each other, as defined in claim
1
of the present invention.
This biochip reader configuration eliminates the need for moving a stage and permits non-scanned reading of image information from a plurality of samples. Furthermore, as long as a comparison is made with reference to the same duration of reading, the required level of light intensity decreases as the number of beams increases. Thus, there is no need for emitting high-intensity beams of laser light, as seen in the prior art and, therefore, there is virtually no risk of bleaching fluorescent stain. Consequently, it is possible to realize a biochip reader capable of measuring even weak light.
As described in claim
2
of the present invention, in the above-mentioned biochip reader configuration, it is also possible for a light beam emitted onto any one of the plurality of samples to form an image at a position on the optical axis different from any position on the surface of the sample. As a result, a spot of light on the biochip will have an almost uniform intensity distribution across its entirety, and the distribution of excitation light intensity will no longer affect the sample.
Note that when a biochip is mounted at a position on the optical axis beyond the focal point of an objective lens, the working distance increases and therefore the efficiency of such work as mounting or removing the biochip improves.
As described in claim
3
of the present invention, it is also possible for a fluorescent image from the above-mentioned sample to form at a position on the optical axis different from any position on the surface of a detector. As a result, it is possible to reduce intensity bias in the detector or an A/D converter, and thus widen the dynamic range of measurement.
As described in claim
4
of the present invention, the above-mentioned emitted light beam may be made obliquely incident on the sample, so that the fluorescent image from the sample and the image of excitation light are separated from each other. As a result, background noise due to the excitation light can be removed.
As described in claim
5
of the present invention, the fluorescent image and the image of excitation light from the sample may be formed at positions on the detector distant from each other. As a result, it is possible to easily remove the reflection image of excitation light during the image processing stage.
REFERENCES:
patent: 4888756 (1989-12-01), Shikichi et al.
patent: 5122644 (1992-06-01), Hasegawa et al.
patent: 5128528 (1992-07-01), Heninger
patent: 6160618 (2000-12-01), Garner
patent: 6371370 (2002-04-01), Sadler et al.
Sugiyama Yumiko
Tanaami Takeo
Cyr Daniel St.
Lee Michael G.
Moonray Kojima
Yokogawa Electric Corporation
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