Radiant energy – Infrared-to-visible imaging – Including detector array
Reexamination Certificate
2001-06-02
2003-05-27
Hannaher, Constantine (Department: 2878)
Radiant energy
Infrared-to-visible imaging
Including detector array
C250S339020, C250S461200
Reexamination Certificate
active
06570158
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an apparatus and method for imaging infrared-spectrum radiation that is emitted during cellular and molecular events, such as chemical reactions.
BACKGROUND OF THE INVENTION
In assay screening, a large number of cellular events (e.g., calcium flux, etc.), physiological events and/or molecular events (e.g., chemical reactions, etc.) are monitored and analyzed. These events, hereinafter referred to as “target events,” are usually carried out in parallel in an array of deposits on specimen plates. The specimen plates are typically glass or plastic slides, or multi-well (e.g., micro-titer) plates.
Due to the large number of events taking place on the plates, time-consuming methods that directly examine each deposit (e.g., microscopic examination, etc.) are unsuitable for data acquisition. Rather, a “snap shot” of the whole plate is advantageously taken via imaging systems.
Area visible-spectrum imaging techniques, such as fluorescence imaging and luminescence imaging, can be used for data acquisition. In fluorescence imaging, when a target event occurs, a detection reagent emits light (i.e., fluoresces) when excited by an appropriate excitation source, e.g., ultraviolet light, etc. The detection reagent is chosen for its ability to interact (e.g., bind, etc.) with a target or to respond to a specific stimulus that is present only if the target event occurs. The emitted light, which provides quantitative information about the event, is captured and converted to electrical signals using, for example, a charge coupled device (“CCD”). The CCD comprises an array of thousands of sensor cells that are capable of receiving radiation from multiple wells at the same time. The signals are analyzed, via suitable software, to recover information concerning the target events.
Area fluorescent imaging devices are very complex and, hence, very expensive (c.a., $100,000 to $400,000). These imaging devices typically include an excitation light source, complicated optics, filters, a CCD, in some cases a cooler for the CCD, a control unit, software, positioners, and other elements. See, for example, the fluorescence imagers (FLIPR systems) available from Molecular Devices Corporation (www.moldev.com).
Luminescent imaging (chemi- or bio-) is similar to fluorescence imaging, except that excitation radiation is not required; the target event itself emits light. But many of the luminescent reactions have such low intensity emissions that a highly optimized imaging system, including the most sensitive form of cooled CCD camera and very efficient lenses, are required.
In addition to the high cost of these imaging devices, fluorescence imaging is complicated by the requirement of having a suitable detector reagent. While specific detector reagents have been developed for various applications, there are no universally applicable reagents. See, for example, Molecular Probes, Inc. (www.probes.com).
Consequently, a less costly and less complicated alternative to visible spectrum (i.e., fluorescence and luminescence) imaging is desirable. One possible alternative is thermal or infrared (IR) imaging.
All chemical reactions and physiological processes are accompanied by a change in energy; in other words, heat is generated or absorbed. Useful information can be obtained by monitoring/measuring such thermal changes.
Several methods are available for measuring thermal changes, including, for example, calorimetry and infrared thermography. Regarding the latter technique, published PCT application WO 99/60630 discloses a method of using infrared thermography to monitor physiological and molecular events.
According to that application, a high-resolution infrared imaging system is used to monitor heat output.
FIG. 1
depicts a simplified schematic of the imaging system disclosed in WO 99/60630. Imaging system
100
comprises an infrared camera
102
, including optics
104
, that is spaced apart (i.e., the lens has a 6 centimeter focal length) from target
106
(e.g., a multi-well plate containing reagents, cellular or non-cellular material, a living animal, etc.). Target
106
is contained within isothermal chamber
108
that reduces temperature variations. The infrared camera monitors radiated heat production from target
106
and images are recorded by central processing unit
110
for data capture and analysis.
Infrared camera
102
advantageously provides a thermal image of the entire scene. That is, if a multi-well plate with its two-dimensional array of wells is being monitored, a thermal image of each well is preferably obtained. To do this, camera
102
must either (1) incorporate a scanning mechanism that sequentially focuses radiation from each well (or groups of wells) onto the detector or (2) use a focal plane array or “staring” array.
Infrared cameras that incorporate scanning mechanisms are quite complicated. Scanning mechanisms typically comprise multiple movable reflective surfaces, a drive system to move the reflective surfaces and several lenses to focus incoming IR radiation onto the reflective surfaces. Furthermore, infrared cameras having scanning mechanisms cannot support ratiometric or comparative analysis of target events in each well, since this requires simultaneous image acquisition across all locations on the specimen plate. A focal plane array (“FPA”)
212
, depicted in
FIG. 2
, is a monolithic microelectronic device that incorporates thousands of sensing elements
214
that continuously receive IR radiation, capturing an image of the entire scene. FPA-based infrared cameras, such as camera
302
depicted in
FIG. 3
, do not require a scanning system. Rather, they include a single monolithic FPA detector
212
and optics
104
. Consequently, FPA-based cameras are lighter, quieter, consume less power, are more reliable, more durable and have a lower parts count than scan-based cameras. Furthermore, FPA-based cameras support ratiometric analysis. Ray tracing
318
depicts the relatively straight optical path of IR radiation from a target to detector
212
in FPA-based camera
302
.
Regardless of whether the imaging system disclosed in WO 99/60630 uses a scanning system or an FPA-based camera as described above, the imaging system has certain characteristic drawbacks, which are discussed in conjunction with FIG.
4
.
FIG. 4
depicts a simplified representation of the path
420
of IR radiation from target
106
, through optics
104
to FPA
212
. As shown in
FIG. 4
, the IR radiation must traverse medium
422
(e.g., air, etc.) between target
106
and optics
104
, pass through optics
104
and then travel through medium
424
between optics
104
and FPA
212
. The passage of IR radiation through media
422
and
424
, and optics
104
attenuates the IR radiation, thereby compromising the sensitivity and resolution of the detector. Furthermore, passage of IR radiation through optics
104
introduces parallax-related aberrations.
The art would therefore benefit from infrared spectrum-imaging systems that avoid the complexity, performance deficits (e.g., reduced signal-to-noise ratio), expense and other drawbacks of prior art infrared-system imaging systems.
SUMMARY OF THE INVENTION
The present invention is an imaging apparatus and a method for imaging by which target events are monitored. Some infrared-spectrum imaging systems in accordance with the illustrative embodiment of the present invention comprise a two-dimensional detector array (hereinafter “detector”), which receives infrared radiation emitted from a specimen plate where target events are occurring. The detector is electrically connected to processing electronics that are operable to analyze the image data.
REFERENCES:
patent: 4777525 (1988-10-01), Preston, Jr.
patent: 5265169 (1993-11-01), Ohta et al.
patent: 5846708 (1998-12-01), Hollis et al.
patent: 6055095 (2000-04-01), Bawolek
patent: 6083763 (2000-07-01), Balch
patent: 6187267 (2001-02-01), Taylor et al.
DeMont & Breyer LLC
Gagliardi Albert
Hannaher Constantine
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