Chemistry: analytical and immunological testing – Including sample preparation
Reexamination Certificate
1998-09-14
2001-12-18
Ludlow, Jan (Department: 1743)
Chemistry: analytical and immunological testing
Including sample preparation
C436S086000, C436S089000, C436S094000, C436S180000
Reexamination Certificate
active
06331439
ABSTRACT:
The present invention relates to a method and system for accomplishing various combinatorial processes, including syntheses, screening and chemical diagnostic assays. More particularly, this invention relates to a system and method that incorporates a layered array for inhibiting cross-contamination of reagent fluids used in such combinatorial processes.
BACKGROUND OF THE INVENTION
Traditional methods in the field of combinatorial chemistry for making a homologous series of compounds or testing of new potential drug compounds were often slow and tedious. The underlying reason is that each member of the series or each potential drug compound must be created individually and tested individually. During this testing stage, it is common that the exact composition and/or behavior of a compound or new potential drug is unknown. In order to discover the proper composition of a compound or to observe the behavior of a new potential drug, a multitude of experiments must be conducted. For example, a plurality of potential drug compounds is tested by using an agent to test a plurality of materials that may differ only by a single amino acid or nucleotide base, or have a different sequence of amino acids or nucleotides. Furthermore, these experiments may investigate the effectiveness of the compound in different concentrations or its reaction to other reagents. This process for discovering and developing compounds or a new potential drug by combinatorial chemistry is labor intensive and costly.
Traditionally, these experiments are conducted by manually injecting reagent fluids or other agents into a multimode of vials. Each vial is filled manually by a laboratory technician. The solution within each vial may differ only slightly from an adjoining vial so that permutations of the solution are investigated simultaneously. Generally, a receptor having a fluorescent tag is introduced to each vial and the solution is incubated with the receptor. When a proper reaction is obtained where the receptor reacts with the solution, the result can be detected optically by observing the site of the fluorescent tag. The fluorescent data is transmitted to a computer which identifies the compound reacted and the degree of the reaction. Thus, combinatorial chemistry allows screening of thousands of compounds for the desired activity.
Recently, the process has been improved to some degree with the introduction of robotics into the field. Robotic arms are employed to automate the process of depositing materials into the multitude of vials. This improvement relieves the laboratory technical from a tedious task and increases the efficiency and accuracy of the process. A robotic arm is able to more accurately deposit a precise amount of material repeatedly into different vials.
However, the process continues to face problems in the area of cost and space. With thousands of compounds being tested and in some cases incubated over a period of time, the process requires a large quantity of space to house the multitude of trays of vials. In addition, these vials are generally large and cumbersome to handle.
Furthermore, the process generally consumes a large quantity of reagents for testing thousands of compounds. These reagents and other materials used in the process are often very expensive or difficult to obtain. Thus, to reduce the cost and increase the efficiency of the process, it is necessary to replace the vials with other smaller reaction cells. By reducing the size of the reaction cell, the process consumes a smaller quantity of reagents. In addition, a proper control and delivery system is necessary for regulating and distributing minute amount of reagents to the reaction cells.
Recently, there are developments where traditional semiconductor techniques are combined with the synthesis of various compounds having potential biological activity. For example, a semiconductor or dielectric substrate is coated with a biologic precursor having such amino groups with a light-sensitive protective chemical. A series of masks are placed over the substrate with each mask having an opening. By introducing photosensitive amino acid through the openings, the reaction creates a particular compound that can be detected optically.
However, the synthesis of each reaction is not always complete and the process may need additional layers of mask for introducing new agents. Creating new masks is a complex and expensive process. In addition, the process of aligning a plurality of masks and forming openings in the mask in sequence requires careful alignment and is time consuming.
Nevertheless, the advantages in terms of size and efficiency of traditional semiconductor techniques are extremely attractive. Specifically, through the use of microchannels, the process of combinatorial chemistry is effectively conducted on a microcell scale. This approach addresses the problems of size and cost attributed to the traditional combinatorial process.
Therefore, a need exists in the art for a system and method that incorporates a microelectronic and fluidic array for accomplishing the process of combinatorial chemistry.
SUMMARY OF THE INVENTION
The system of the present invention comprises a microelectronic and fluidic array (device array) having micron sized reservoirs, connecting microchannels and reaction cells etched into a substrate. The device array is supported by a station which serves to interface and perform electrooptic measurements of material in the reaction cells of the device array. The station also controls the fluid flow of reagents to the reaction cells.
The device array incorporates a modular configuration with three distinct layers or plates. The device array comprises a top feedthru plate, a center distribution plate and a bottom cell plate. The three plates are stacked vertically and coupled together to form a liquid-tight seal. The top feedthru plate is bonded or fused to the center distribution plate, while the center distribution plate is detachably coupled to the bottom cell plate. The plates can be made from glass, fused silica, quartz or a silicon wafer. Reservoirs, microchannels and reaction cells are controllably etched onto the plates using traditional semiconductor fabrication techniques with a suitable chemical or laser etchant.
The top feedthru plate serves as a cover for the device array and contains apertures selectively positioned above the reservoirs located in the center distribution plate. These apertures provide the necessary openings for a loading module to fill the reservoirs with a plurality of reagents or other materials. The top feedthru plate further comprises a plurality of micropump electrodes that extend completely through the top feedthru plate. The micropump electrodes are coupled to a plurality of electrical contacts on one end and are geometrically shaped to act as electrofluidic pumps on the other end. These miniature pumps (micropumps) are activated by selectively applying a voltage source to the electrical contacts located on the top surface of the top feedthru plate.
The center distribution plate comprises a plurality of micron-sized reservoirs, microchannels, reservoir feeds, cell feeds and overflow feeds, which are selectively etched on both sides (top and bottom) of the center distribution plate. These channels and reservoirs form a grid delivery system where reservoirs are grouped into column reservoirs, row reservoirs and matrix reservoirs. Column reservoirs are coupled to microchannels that deliver reagents to a location vertical from the column reservoirs, while row reservoirs are coupled to microchannels that deliver reagents to a location horizontal from the row reservoirs. Finally, matrix reservoirs are coupled to microchannels that deliver reagents to a location both vertical and horizontal from the matrix reservoirs.
Thus, the center distribution plate is defined into a plurality of sectors in a grid configuration. Each sector on the center distribution plate is directly positioned above a reaction cell located on the bottom cell plate. The reagents channeled to a sector
Cherukuri Satyam Choudary
Demers Robert Richard
Fan Zhong Hui Hugh
Levine Aaron W.
McBride Sterling Edward
Ludlow Jan
Mierzwa Kevin G.
Orchid BioSciences, Inc.
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