Chemical apparatus and process disinfecting – deodorizing – preser – Control element responsive to a sensed operating condition
Reexamination Certificate
2000-04-12
2002-05-14
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Control element responsive to a sensed operating condition
C436S180000, C073S864000, C073S863320, C073S864010, C073S864110, C073S864130, C073S864160, C073S864170, C073S864310, C141S102000, C141S104000, C222S135000, C222S136000
Reexamination Certificate
active
06387330
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a method and device capable of storing and dispensing specified subsets of materials from large collections (tens, hundreds, or thousands) of different reagents into specified locations within microtitre trays or the like.
2. Description of the Related Art
During the last half of the 20th century, and especially in the 1980's and 1990's, technology has been developed to illuminate the molecular basis of life and disease. Illnesses with homogeneous molecular underpinnings such as sickle cell anemia were the first to be elucidated on a molecular level. More complex diseases, such as cancer, are more difficult to disentangle because their molecular origins involve interaction of multiple defects which may be unique to individual patients.
Researchers working to understand complex diseases or other complex biological issues often start with a general hypothesis, asking a specific molecular question of multiple stored tissue reagent samples such as DNA, RNA, protein, or other materials isolated from diseased or normal tissues. In current practice, these stored samples are stored in liquid form in individual receptacles usually made of plastic, either individually or in groups of 96, 384, or even 1536 wells, for example. The placement of these tissue reagents in fixed positions in storage plates facilitates the use of automated and non-automated multi-headed pipettors to move aliquots of the tissue reagent sample from the storage container to a reaction container.
In current practice, the liquid tissue reagent samples contained in such gridded storage devices are held in place at the bottom of each storage vessel by gravity, and the upper surface of each liquid sample is in contact with air, or in some cases, with pure nitrogen. Ambient air contains 21% oxygen, which over time has a marked, damaging oxidative effect on biological samples. Exposure of each liquid sample to air is inevitable in this current practice because the fill level of each storage receptacle must be kept well below the upper limit of the container to avoid spill-over of the liquid when pipette tips enter the vessel to effect transfer of the liquid to a reaction vessel, causing upward displacement of the liquid within the vessel. Gaseous nitrogen or other less reactive pure gases can be blown into the storage vessel prior to closure, but such systems are not in wide use because of their expense and relative complexity.
When not in use, each gridded or non-gridded liquid reagent storage container must be capped or otherwise sealed, which in current practice usually involves the use of pressure fitted plastic closures, or adhesive films. Each time the pressure fitted closures or adhesive films must be removed to gain access to the stored sample, opposing forces must be applied to the closure land the storage vessel, often leading to vibration or sudden movement which can aerosolize liquid within the storage vessel, increasing the risk of cross-contamination between samples.
In Current practice, transfer of liquid reagent from such a storage device inevitably requires use of a “vector” device, such as a pipette tip, or hollow needle, that enters the sample, removes a volume of liquid and then is moved to a recipient receptacle where a volume of the tissue reagent is dispensed. During subsequent rounds of reagent liquid pickup and dispensing with other samples, new pipette tips must be used, or the needles or pipette tips must be washed to prevent cross-contamination. Use of disposable pipettes is associated with large volumes of unrecyclable plastic waste that must be disposed of, and use of washable needles or pipette tips even under ideal conditions is associated with an irreducible minimum possibility of cross-contamination, which is unacceptable in many research and clinical settings.
For researchers trying to untangle complex biological processes, the current practice of storing liquid reagent samples becomes most troublesome after results are obtained from a first experiment designed to test a general hypothesis. Often this initial experiment will reveal findings in specific subsets of the original tissue samples that require a series of experiments to be performed on only these subsets. To obtain aliquots of the subset of stored reagents needed for these secondary experiments, the researcher must either manually remove the samples needed from the gridded reagent samples, or must have a method of automating this process. Manual removal of liquid samples from such gridded reagents is difficult and error-prone, because it entails identification of small isolated tubes or individual cells within hundreds of cells, careful removal of the cap or adhesive closure for that specific tube or cell, and selective aliquotting using a manual pipettor. Most laboratories, even relatively large ones, find it too expensive to automate this “subset aliquotting”, because of the difficulty of addressing individual cells accurately and without risk of contamination to other cells.
In summary, libraries of biological reagents such as cDNA solutions are often stored in collections of passive vessels such as microbitre trays. Such collections typically contain 100's, 1000's or even in excess of 10,000 different reagents. It is necessary to select and transfer specific subsets of these libraries to other vessels or titre trays for subsequent operations or experiments. This is typically done in the present art by pipetting or aspirating and dispensing the required volumes from the storage containers in to the desired recipient locations. This pipetting can be done by hand or by computer controlled robots or laboratory workstations.
Hand pipetting, although involving only inexpensive tools, is obviously prone to human operator error. Only one error in 100 can be very expensive in terms of the invalidity of the results of subsequent experiments. Hand pipetting also shares many of the drawbacks of automated pipetting mentioned below.
Automated pipetting, although avoiding some of the errors of hand pipetting, still involves first aspirating a controlled volume from the storage reservoir (e.g. a microtitre tray) into an intermediate reservoir (the pipette), and then dispensing some or all of that volume into the desired recipient container (e.g. another microtitre tray). This procedure wastes some of the valuable reagent on the walls of the intermediate container, risks cross-contaminating the primary storage volumes, and involves a continuing cost of replacing disposable pipette tips. In addition, this procedure, whether manual or automated, exposes the primary storage volumes to the ambient atmosphere with attendant evaporative losses and contamination including oxidation.
Crude attempts in the prior art to improve the speed of dispensing operations have utilized multiple dispensing heads. However, these devices (manual and automatic) still involve waste of disposable pipette tips and/or cross contamination. Some of these devices employ vibration to create small droplet sizes, but the vibrating unit is at or near the dispensing tip and the plungerl for bulk fluid movement is separated from the dispensing tip by a flexible tube. This results in a cumbersome arrangement and separate plunger actuators and vibrators must be used for each dispensing head. There are no examples in the prior art of more than 4 such heads being used in any such instrument because it was known that the cost would be prohibitive.
U.S. Pat. No. 5,658,802 (Hayes et al.) teaches arrays of electromechanical dispensers to form extremely fine drops of fluid and locate them precisely on substrate surfaces in miniature arrays, wherein a positioning support such as an X-Y table moves the dispensing devices and substrate surfaces relative to each other to locate the drops on the substrates. However, the valving scheme is cumbersome and requires purging each time a switch is made to a different reagent. This wastes time and reagent and is more expensive to build, since a netw
Bova George Steven
Leighton Stephen B.
Bova George Steven
Gordon Brian R.
Pendorf & Cutliff
Warden Jill
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