Integrated sample processing devices

This application is a division of U.S. patent application Ser. No. 10/325,723, filed Dec. 19, 2002, which is hereby incorporated herein by reference.

Modem scientific investigations frequently involve the use of large number of chemical reactions. For efficient implementation, these reactions are preferably run using systems that minimize setup times and cost while ensuring the quality of their results.

In many cases, a multiplicity of reactions are performed on systems in which a small set of reactants are combined with a much larger set of reactants. For example, a single biological sample may be subjected to a multiplicity of polymerase chain reactions, each of which address the expression level of a single gene.

Many different chemical, biochemical, and other reactions are also sensitive to small temperature variations. The reactions may be enhanced or inhibited based on the temperatures of the materials involved. In many such reactions, a temperature variation of even 1 or 2 degrees Celsius may have a significantly adverse impact on the reaction. Although it may be possible to process samples individually and obtain accurate sample-to-sample results, individual processing can be time-consuming and expensive.

One approach to reducing the time and cost of processing multiple samples is to use a device including multiple chambers in which different portions of one sample or different samples can be processed simultaneously. However, this approach presents several temperature control related issues. When using multiple chambers, the temperature uniformity from chamber to chamber may be difficult to control. Another problem involves the speed or rate at which temperature transitions occur when thermal processing, such as when thermal cycling. Still another problem is the overall length of time required to thermal cycle a sample(s).

The multiple chamber device may include a distribution system. However, the distribution system presents the potential for cross-contamination. Sample may inadvertently flow among the chambers during processing, thereby potentially adversely impacting the reaction(s) occurring in the chambers. This may be particularly significant when multiple samples are being processed. In addition, the distribution system may present problems when smaller than usual samples are available, because the distribution system is in fluid communication with all of the process chambers. As a result, it is typically not possible to prevent delivery of sample materials to all of the process chambers to adapt to the smaller volume samples.

Thermal processing, in and of itself, presents an issue in that the materials used in the devices may need to be robust enough to withstand repeated temperature cycles during, e.g., thermal cycling processes such as PCR. The robustness of the devices may be more important when the device uses a sealed or closed system. Also, it is often required that the process chambers remain in adequate alignment with instrument optics despite temperature changes and the attendant thermal expansion.

Various sample processing devices of the present invention are described in U.S. Provisional Patent Application Ser. No. 60/214,508 filed on 28 Jun. 2000 and titled THERMAL PROCESSING DEVICES AND METHODS (Attorney Docket No. 55265USA19.003); U.S. Provisional Patent Application Ser. No. 60/214,642 filed on 28 Jun. 2000 and titled SAMPLE PROCESSING DEVICES, SYSTEMS AND METHODS (Attorney Docket No. 55266USA99.003); U.S. Provisional Patent Application Ser. No. 60/237,072 filed on 2 Oct. 2000 and titled SAMPLE PROCESSING DEVICES, SYSTEMS AND METHODS (Attorney Docket No. 56047USA29); U.S. Pat. No. 6,627,159, titled CENTRIFUGAL FILLING OF SAMPLE PROCESSING DEVICES, U.S. Pat. No. 6,814,935, and titled SAMPLE PROCESSING DEVICES AND CARRIERS; U.S. Pat. No. 7,026,168, and titled SAMPLE PROCESSING DEVICES.

The documents identified above all disclose a variety of different constructions of sample processing devices that could be used to manufacture sample processing devices according to the principles of the present invention. For example, although many of the sample processing devices described herein are attached using adhesives (e.g., pressure sensitive adhesives), devices of the present invention could be manufactured using heat sealing or other bonding techniques.

Although the devices and their carriers identified in the above-listed patent documents may provide many advantages over the prior art, further improvements may still be possible. For example, the use of a carrier separate from the sample processing device may add cost to the sample processing devices as delivered to customers because of the need to manufacture different components separately from each other and then accurately assemble the components. In addition to adding cost, inaccurate assembly may cause performance problems due to misalignment of interrogation zones with the optics train of the analytical device. Further variability in the assembly process may induce unwanted part-to-part variability in the way the assembly fits to the thermal platen and hence thermal variations between process chambers.

The present invention provides integrated sample processing devices for thermal processing of multiple samples at the same time. The sample processing devices may include compression structures that provide for the transfer of force from a platen to a thermal block on which the sample processing device is located during processing. By distributing the compression structures over a compliant sample processing device, intimate contact between substantially all of the processing chambers in the sample processing device and the thermal block can be achieved in spite of variations in the thickness of the sample processing device due to, e.g., manufacturing tolerances.

Such compression structures may also be useful in ensuring that the reaction chambers of the sample processing device are located on a common plane during optical interrogations performed during, or after, thermal or other processing. For example, the sample processing devices may be thermally processed and then placed on an optical detection system for assessment of reaction products. This situation is encountered when performing “end-point reads” following thermal-cycling on Peltier blocks that do not provide for real-time monitoring of the processing, e.g., PCR.

In some embodiments, the compression structures may include permanently deformable compression structures that may help to equilibrate the force with which the processing chambers of the sample processing device are urged against a platen. The permanently deformable structures may include, e.g., frangible elements that permanently deform in a manner that provides an indication that a sample processing device has been used. The frangible element may, in some instances, include a chromic indicator that changes color when deformed to further enhance unaided visual determination of use of the sample processing device.

The sample processing devices may include a fill reservoir structure with various features such as arcuate edges, radially aligned exit channels, support structures, and selectively variable heights (and corresponding volume distribution) to enhance even distribution of fluid sample materials to the main channels and processing chambers of a sample processing device according to the present invention.

The sample processing devices of the present invention preferably have a form factor that is compatible with conventional microtiter plates such that conventional microtiter plate processing equipment and systems may be used to process sample processing devices of the present invention. For example, it may be preferred that that the sample processing devices have a height of five millimeters or more. Furthermore, it may be preferred that that the sample processing devices of the present invention have a maximum height as defined by the Society for Biomolecular Screening Standard “SBS-2 for Microplates—Height Dimensions” (9 May 2002).

A further advantage of the present invention may come from more precise control of fill port locations. The use of multiple fill ports on a sample processing device is particularly advantageous if the fill ports are compatible with standard laboratory robotic equipment for liquid dispensing. For example, eight or more micropipettes are frequently arranged in a linear array with uniform spacing to efficiently fill standard microplates. Use of such micropipette arrays to fill particular embodiments of the present invention could provide a significant benefit to users requiring highly automated laboratory operations using existing equipment.

Use of the present invention with such automated operations is further facilitated if the particular embodiment complies with the standardized form-factor for microplates. In such cases, the handling of the microplate subsequent to loading can be performed by commonly available robotic equipment.

Finally, because many of the reactants used with the present invention are often expensive and available only in small quantities, it is important to utilize sample processing devices which minimize the amounts of samples necessary to achieve satisfactory results. In particular, this requires loading mechanisms which efficiently distribute the sample to each of the reaction chambers and that reduce the risk of spillage during loading and handling of the devices.