Continuous form microstructure assay array

Details Continuous form microstructure assay array Continuous form microstructure assay array

2000-05-09

2004-12-07

Ludlow, Jan M. (Department: 1743)

Chemical apparatus and process disinfecting, deodorizing, preser

Control element responsive to a sensed operating condition

C422S051000, C422S066000, C422S082010, C422S105000, C204S601000, C204S603000

Reexamination Certificate

active

06827906

ABSTRACT:

BACKGROUND
This invention relates to methods and apparatus for high throughput sample analysis.
In a range of technology-based industries, including the chemical, bioscience, biomedical, and pharmaceutical industries, it has become increasingly desirable to develop capabilities for rapidly and reliably carrying out chemical and biochemical reactions in large numbers using small quantities of samples and reagents. Carrying out a massive screening program manually, for example, can be exceedingly time consuming and may be entirely impracticable where only a very small quantity of an important sample or component of interest is available, or where a component of a synthesis or analysis is very costly.
Developments in a variety of fields have resulted in an enormous increase in the numbers of targets and compounds that can be subjected to screening.
Rapid and widespread advances in the scientific understanding of critical cellular processes, for example, has led to rationally designed approaches in drug discovery. Molecular genetics and recombinant DNA technologies have made possible the isolation of many genes, and the proteins encoded by some of these show promise as targets for new drugs. Once a target is identified and the gene is cloned, the recombinant protein can be produced in a suitable expression system. Often receptors and enzymes exist in alternative forms, subtypes or isoforms, and using a cloned target focuses the primary screen on the subtype appropriate for the disease. Agonists or antagonists can be identified and their selectivity can then be tested against the other known subtypes. The availability of such cloned genes and corresponding expression systems require screening methods that are specific, sensitive, and capable of automated very high throughput.
Similarly, an emergence of methods for highly parallel chemical synthesis has increased the need for high throughput screening (“HTS”). Conventionally, preparation of synthetic analogs to the prototypic lead compound was the established method for drug discovery. Natural products were usually isolated from soil microbes and cultured under a wide variety of conditions. The spectrum of organisms employed by the pharmaceutical industry for isolation of natural products has now expanded from actinomycetes and fungi to include plants, marine organisms, and insects. More recently, the chemistry of creating combinatorial libraries has vastly increased the number of synthetic compounds available for testing. Thousands to tens or hundreds of thousands of small molecules can be rapidly and economically synthesized. See, e.g., U.S. Pat. No. 5,252,743 for a discussion of combinatorial chemistry. Thus, combinatorial libraries complement the large numbers of synthetic compounds available from the more traditional drug discovery programs based, in part, on identifying lead compounds through natural product screening.
Accordingly, considerable resources have been directed to developing methods for high-throughput chemical syntheses, screening, and analyses. A considerable art has emerged, in part from such efforts.
Competitive binding assays, originally developed for immunodiagnostic applications, continue to be commonly employed for quantitatively characterizing receptor-ligand interactions. Despite advances in the development of spectrophotometric- and fluorometric-based bioanalytical assays, radiolabeled ligands are still commonly employed in pharmaceutical HTS applications. Although non-isotopic markers promise to be environmentally cleaner, safer, less expensive, and generally easier to use than radioactive compounds, sensitivity limitations have prevented these new methods from becoming widespread. Another major disadvantage of the competition assay is the number of steps, most notably washing steps, required to run assays.
Scintillation proximity assays, discussed for example in U.S. Pat. No. 4,271,139 and U.S. Pat. No. 4,382,074, were developed as a means of circumventing the wash steps required in the above heterogeneous assays. The homogeneous assay technology, which requires no separation of bound from free ligand, is based on the coating of scintillant beads with an acceptor molecule such as, for example, the target receptor.
In another approach to avoiding the use of radioactive labels, especially useful in high-throughput assays, lanthanide chelates are used in time-resolved fluorometry. See, e.g., U.S. Pat. No. 5,637,509.
Automated laboratory workstations have contributed significantly to advances in pharmaceutical drug discovery and genomic science. See, e.g., U.S. Pat. No. 5,104,621 and U.S. Pat. No. 5,356,525, Particularly, robotics technology has played a major role in providing practical means for carrying out HTS methods. See, e.g., U.S. Pat. No. 4,965,049.
Robotic-based high-throughput tools are now routinely used for screening libraries of compounds for the purpose of identifying lead molecules for their therapeutic potential. For example, a screening method for characterizing ligand binding to a given target employing a variety of separation techniques is described in WO 97/01755, and a related method is described in U.S. Pat. No. 5,585,277.
Highly parallel and automated methods for DNA synthesis and sequencing have also contributed significantly to the success of the human genome project, and a competitive industry has developed. Examples of automated DNA analysis and synthesis include, e.g., U.S. Pat. No. 5,455,008; U.S. Pat. No. 5,589,330; U.S. Pat. No. 5,599,695; U.S. Pat. No. 5,631,734; and U.S. Pat. No. 5,202,231.
Computerized data handling and analysis systems have also emerged with the commercial availability of high-throughput instrumentation for numerous life sciences research and development applications. Commercial software, including database and data management software, has become routine in order to efficiently handle the large amount of data being generated.
With the developments outlined above in molecular and cellular biology, combined with advancements in combinatorial chemistry, there has been a huge increase in the number of targets and compounds available for screening. In addition, many new human genes and their expressed proteins are being identified by the human genome project and will therefore greatly expand the pool of new targets for drug discovery. A great need exists for the development of more efficient ultrahigh throughput methods and instrumentation for pharmaceutical and genomic science screening applications.
Miniaturization of chemical analysis systems, employing semiconductor processing methods, including photolithography and other wafer fabrication techniques borrowed from the microelectronics industry, has attracted increasing attention and has progressed rapidly. The so-called “lab-on-a-chip” technology enables sample preparation and analysis to be carried out on-board microfluidic-based cassettes. Moving fluids through a network of interconnecting enclosed microchannels of capillary dimensions is possible using electrokinetic transport methods.
Applications of microfluidics technology embodied in the form of analytical devices has many attractive features for pharmaceutical high throughput screening. Advantages of miniaturization include greatly increased throughput and reduced costs, in addition to low consumption of both samples and reagents and system portability. Implementation of these developments in microfluidics and laboratory automation hold great promise for contributing to advancements in life sciences research and development.
Of particular interest are microfluidics devices in which very small volumes of fluids are manipulated in microstructures, including microcavities and microchannels of capillary dimension, at least in part by application of electrical fields to induce I electrokinetic flow of materials within the microstructures. Application of an electric potential between electrodes contacting liquid media contained within a microchannel having cross-sectional dimensions in the range from about 1 &mgr;m to upwards of about 1 mm results in

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