Sample holders with reference fiducials

Details Sample holders with reference fiducials Sample holders with reference fiducials

1998-09-18

2001-07-10

Tung, T. (Department: 1743)

Chemical apparatus and process disinfecting, deodorizing, preser

Control element responsive to a sensed operating condition

C422S091000, C422S105000, C422S105000, C435S287300, C435S297100, C435S300100, C435S301100, C436S164000, C436S165000

Reexamination Certificate

active

06258326

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to sample holders. More particularly, the invention relates to sample holders with reference fiducials configured to provide information that facilitates sample handling and/or analysis.
BACKGROUND OF THE INVENTION
Certain techniques in biology, chemistry, and medicine require processing large numbers of samples; such techniques include the high-throughput luminescence screening of candidate drug compounds, which may involve sequentially illuminating and monitoring the photoluminescence emission light transmitted from hundreds of thousands of samples. Processing large numbers of samples as in high-throughput screening may be facilitated by packaging samples together into high-density holders, such as “microplates” and “biochips,” so that the samples may be analyzed together in an automated device.
Microplates are substantially rectilinear thermoplastic holders that include a plurality of sample wells for holding a plurality of samples. These sample wells typically are disposed in regular arrays, which may be of rectangular, hexagonal, or other geometry. Currently, the standard microplate includes 96 sample wells disposed in an 8×12 rectangular array on 9 millimeter (mm) centers.
Microplates may have other numbers of sample wells.
FIG. 1
shows a stack of overlapping microplates having similar sizes and dissimilar numbers of sample wells. Microplate
30
has 96 sample wells. Microplate
32
has 384 sample wells. Microplate
34
has 1536 sample wells. Microplate
36
has 3456 sample wells. Microplate
38
has 9600 sample wells. The fluid volumes associated with these sample wells vary from several hundred microliters (&mgr;L) in the 96-well microplate to less than one microliter in the 9600-well microplate. The sample well dimensions associated with these sample well vary from several millimeters on a side in the 96-wells microplate to less than one millimeter on a side in the 9600-well microplate.
Biochips are substantially planar semiconductor devices used to hold and study biomolecules; a familiar example is a gene chip used to hold nucleic acids. Biochips may include many discrete sample positions, like microplates. Indeed, microplates begin to merge with biochips, such that the concept of a sample well begins to merge with the concept of a feature on a biochip, for microplates having very small sample wells.
Although microplates and biochips are of demonstrated utility in automated screening, they suffer from a number of shortcomings. Some shortcomings result from variations within the microplate and biochip. For example, microplates and biochips typically are made of plastic and may suffer distortions in the positions of sample wells and features due to shrinkage or expansion of the plastic. Other shortcomings result from inherent inaccuracies in the alignment mechanisms used to position microplates and biochips for sample analysis. Yet other shortcomings result from holder-to-holder variations in the microplate and biochip. For example, the overall size, sample well or feature size, construction material, and sample well or feature number and arrangement may vary, as shown for microplates in FIG.
1
. To circumvent holder-to-holder variations, devices may limit sample analysis to only a single type of sample holder, such as a 96-well microplate.
If the positional error due to plastic deformation, inaccurate alignment mechanisms, or holder-to-holder variations in sample holders is a significant fraction of the feature size, then sample analysis will be adversely affected. For example, fluorescence signals may be decreased, and crosstalk from adjacent sites may be increased, especially when the array of sample wells or features is read with a step-and-repeat optical reader, which relies on moving to predetermined locations to perform fluorescence intensity measurements. These problems will be particular severe as the sample wells and features become smaller.
SUMMARY OF THE INVENTION
The present invention addresses these and other shortcomings by providing microplates having reference fiducials configured to provide information that facilitates sample handling and/or analysis.
The invention provides a sample holder for holding a plurality of samples for a preselected optical assay. Generally, the sample holder comprises (1) a frame, (2) a plurality of sample wells disposed in the frame, each sample well configured to hold a sample so that light transmitted from the sample during the preselected optical assay may be detected by a detection system, and (3) at least one reference fiducial that is not a sample well disposed in the frame, each reference fiducial configured to provide information that facilitates the preselected optical assay and to be interpretable by the same detection system that detects light transmitted from the sample.
The reference fiducial may be configured to provide a variety of information. For example, the reference fiducial may be configured to reduce cross-plate drift, or to facilitate alignment of the sample holder and the detection system. The reference fiducial also may be configured to provide information regarding microplate layout, including the manufacturer, overall size, sample well or feature size, construction material, and sample well or feature number and arrangement for the sample holder. The reference fiducial also may be configured to provide information regarding background luminescence from the microplate.
The invention also provides methods of performing assays involving sample holders, wherein reference fiducials provide information that facilitates conducting the assay.


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