Chemistry: analytical and immunological testing – Optical result – With fluorescence or luminescence
Reexamination Certificate
1995-06-06
2001-09-04
Ludlow, Jan (Department: 1743)
Chemistry: analytical and immunological testing
Optical result
With fluorescence or luminescence
C250S458100, C422S066000, C422S082050, C422S091000, C436S044000, C436S174000
Reexamination Certificate
active
06284546
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods and apparatus for handling small liquid volumes. As used herein and throughout the description and claims directed to this invention, the term “liquid” encompasses liquids alone and liquids containing particulate matter of whatever kind.
The apparatus and method of the present invention have particular application to situations where small liquid volumes are utilized and processed. One such example is the clinical laboratory, in which chemical analyzers are used with liquid samples which are added to reagents and mixed in discrete reaction cups. These reaction-cups are typically molded plastic about the size and shape of a sewing thimble. Sometimes they are of a special shape to include multiple compartments, viewing windows for optics, or shaped for centrifugation. They are usually loaded by hand into some form of automated mechanism although automatic loaders have been built. Complicated mechanisms have been built to move the cups between different locations so that various operations can be performed as required by the analysis method. At the end of the analysis, they must be carefully removed to prevent spilling of materials that may constitute a biohazard. The volumes of the cups are usually quite large, consisting of hundreds of microliters. Mixing of sample and reagents can be done in several ways: employment of centrifugal forces, turbulence due to hydraulic discharge, magnetic stir bars or mixing blades or paddles that require cleaning between successive samples. Discrete plastic cups have moderately thick walls and have poor thermal conductivity, making rapid temperature equilibration difficult even with waterbaths. Additionally, discrete cups can be relatively expensive costing from one to several cents each.
As described more fully below, several approaches have been developed to avoid the use of the above-described containers. One of the more difficult problems encountered in avoiding such containers if providing for adequate mixing when fluids are combined. In one approach small fluid volumes are placed on a deformable support, which can be deformed into a cavity, thus achieving mixing of the liquids contained in the small volume. In another approach liquids are applied in small pools to a support to form a mixture, which is agitated by directing a gas on the liquid.
As will be seen more fully from the description of the invention that follows, the present invention affords a liquid handling system that minimizes, obviates or totally overcomes problems presented by the prior art devices. For example, it is possible to handle very small volumes of liquid, even sample volumes below 50 microliters. The apparatus promotes mixing of the liquid sample within itself or, if mixed with one or more reagents, without using any external mixer that is in contact with the reaction mixture. Additionally, the system yields an apparatus that promotes good thermal conductivity such that temperature gradients throughout the mixed system are minimized. The system additionally exhibits simple and safe disposal of used materials and facilitates lower costs through the use of disposables and reduced labor costs or machine costs due to the absence of discrete reaction cups.
Present day clinical assay instrumentation typically requires numerous disposable components, relatively large amounts of reagents, multiple steps to ensure that all reused components are washed and relatively large amounts of sample. The purpose of the present invention is to minimize reagents and sample use, eliminate buffers, washing solutions, and most of the disposables, decrease the size, complexity and cost of instrumentation, and reduce the volume of waste without interfering with assay performance. All of this is accomplished without evaporation of the liquids or the use of a deformable support.
2. Description of the Related Art
U.S. Pat. No. 3,854,703 (Gibbs, et al.) discloses a method of, and apparatus for, promoting a reaction between a liquid specimen and a liquid reagent. Such reaction is promoted by applying the liquids to a liquid-impermeable support surface to form a mixture thereon. The liquid mixture is agitated by directing a jet of gaseous fluid from a supply duct outlet to impinge thereon, bringing about relative movement between the outlet and the support surface.
A fluid handling system is described in U.S. Pat. No. 4,676,656 (Cook, et al.). A small fluid volume is placed on a reversibly deformable support, which is deformed to form a cavity. As the fluid clings to the surface of the support, it is physically agitated and mixed as the support is deformed. The deformable support can be utilized to provide fluid containers of varying sizes, to accommodate different fluid volumes and as a transport mechanism to move fluid from one location to another.
U.S. Pat. No. 3,479,141 (Smythe, et. al.) discloses a transport system for an automatic analysis apparatus for a series of aqueous liquid samples processed as a flowing stream with no or minimal contamination between samples. A fluorinated hydrocarbon conduit and intersample segments of silicone are employed. The silicone wets and adheres to the fluorinated hydrocarbon conduit, while the aqueous liquid samples do not do so. Where wetting and contacting of the conduit by the samples is required, and in dialysis, glass and/or cellophane are used, which the aqueous liquid samples wet, and the silicone does not.
A metering apparatus is disclosed in U.S. Pat. No. 4,121,466 (Reichler, et. al.). The apparatus is adaptable either as a dispenser or a sampler, the surface of the aspirating probe being coated with a thin film of liquid immiscible with the liquids to be aspirated. The thin immiscible film prevents contamination between segments of successively aspirated liquids and, also, their respective sources. Further, segments of the immiscible liquid can be aspirated between successive liquid segments to maintain such liquid segments discrete.
Smith, et. al., discuss “An innovative technology for ‘random-access’ sampling” in
clin. Chem.,
28(9): 1867-1872 (1982). An immiscible, non-reactive fluid is used as a positive barrier between the liquid sample and reagent and the interior and exterior surfaces of their respective probes providing an inert, deformable surface that both prevents carryover and ensures accurate delivery.
U.S. Pat. No. 3,526,480 discusses an automatic chemical analyzer wherein measured portions of sample material are transferred from a sample carrier to discrete reagent-containing sites on an analytical tape. The apparatus is particularly adapted for the transfer of a plurality of different discrete reagent-containing sites. Apertured analytical tapes are disclosed as well as reagent-containing sites that have the reagents chemisorbed therein.
U.S. Pat. No. 4,575,485 (Sizto, et al.) describes ultrasonic enhanced immunoreactions. Rates of binding between members of a specific binding pair, e.g., ligand-receptor, are greatly enhanced by short-term ultrasonication of an aqueous medium containing the specific binding pair. The enhanced rates find particular use in specific binding protein assays.
SUMMARY OF THE INVENTION
One aspect of the present invention is a method of mixing two or more liquids. The method comprises forming a liquid droplet containing two or more liquids on a substantially planar and substantially inelastic surface in containerless containment on the surface and causing the droplet to deform in an essentially zero air flow environment thereby mixing the liquids.
Another aspect of the present invention is a method of mixing two or more liquids wherein a liquid droplet containing the two or more liquids is formed on a substantially planar surface. Electrostatic energy or acoustic energy is applied to the droplet thereby mixing the liquids.
Another method in accordance with the present invention for mixing two or more liquids comprises forming a liquid droplet containing two or more liquids on a substantially planar surface. Th
Bryning Zbigniew T.
Irvin Benjamin R.
Kirakossian Hrair
Ullman Edwin F.
Dade Behring Marburg GmbH
Jordan Leland K
Leitereg Theodore J
Ludlow Jan
Ruszala Lois K
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