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  Method and device for mixing samples on a supportUSPTO Application #: 20060019243Title: Method and device for mixing samples on a support Abstract: A method for detecting analytes in a liquid is provided in which the liquid is subjected to a mixing treatment on an area of a support which has in particular immobilized reactants, wherein in the mixing treatment the liquid is impinged upon by a stream of gas that sweeps across at least some areas of the support surface in a scanning manner by means of a jet directed towards the support surface. The invention also concerns a method for mixing a liquid sample comprising an analyte and a device for carrying out the method. (end of abstract) Agent: Roche Diagnostics Corporation - Indianapolis, IN, US Inventors: Karl-Heinz Mann, Thomas Mayer, Friedhelm Vieth USPTO Applicaton #: 20060019243 - Class: 435005000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Virus Or Bacteriophage The Patent Description & Claims data below is from USPTO Patent Application 20060019243. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application claims priority to German patent application no. 102004028303.6 filed Jun. 11, 2004. FIELD OF THE INVENTION [0002] The invention concerns a method for detecting analytes in a liquid in which the liquid is subjected to a mixing treatment on an area of a support preferably of a biochip which in particular has immobilized reactants. BACKGROUND [0003] The invention especially concerns methods for improving the mixing treatment of a liquid and in this connection methods for improving the way in which analytes in the liquid are brought to reactants that are immobilized on an area of the support and in particular of the biochip that is occupied by the liquid. [0004] The following problem occurs in biochip applications and especially in immunoassay applications in which binding reactions are detected between reactants that are immobilized on a support surface and analytes that are present in a liquid that wets the support surface. The binding of analytes to immobilized reactants lowers the concentration of analytes in the liquid in a boundary layer on the support surface resulting in a depletion of analytes in the sample liquid in a boundary layer. Due to the usually low analyte diffusion rate which is normally only a few .mu.m/s or less, new analyte molecules are not resupplied rapidly enough from the sample liquid volume so that long incubation times are required for immunological tests or such like to achieve an adequate measuring effect. There are various approaches for solving this problem in the prior art. [0005] A mixing process is described in U.S. Pat. No. 6,485,918 for a microarray biochip with a deformable cover which is placed over the surface of the microarray. Deformation of the cover generates a flow movement in the liquid between the cover and microarray surface. Although this known method is suitable for flat biochips having a reactant immobilized on the bottom, it has the disadvantage that the cover must always be in contact with the sample liquid during the mixing process. Additional processing steps such as washing steps, reagent addition etc. may necessitate an opening of the cover with the associated risk of losing sample liquid and contamination. [0006] A method and device for mixing samples near the interface in biosensor systems, namely biochips is known from WO 00/10011. In order to increase the sensitivity the liquid in the biochip is excited in this known method by mechanical waves (sound, ultrasound or surface waves) which is intended to improve mixing of the sample liquid especially at the chip/liquid boundary layer in order to enhance the diffusion of the analyte. [0007] A device for controlling the temperature and mixing the contents of vessels of a microtitration plate for immunological tests is known from EP 0 281 958 A2. This known device comprises a cover which defines a hollow space into which a gas line discharges. A boundary wall of the cover that faces the titration plate is provided with gas outlet openings which are arranged eccentrically relative to the vessel axes of the individual vessels of the microtitration plate and are aligned at an angle to the surfaces of the liquids in the individual vessels. Temperature control and generation of a rotary mixing movement of the liquid in the individual vessels is achieved by blowing in warm air through the gas outlet openings. [0008] U.S. Pat. No. 6,063,564, U.S. Pat. No. 4,479,720 and U.S. Pat. No. 5,009,998 for example also concern the improved mixing of sample liquids in sample tubes as liquid containers. [0009] The mechanical mixing processes known from the prior art such as shaking, application of ultrasound, vortexing etc. have proven to be not particularly effective and advantageous for biochips with a flat support or planar support surface with an array of reactants. SUMMARY OF THE INVENTION [0010] The present invention relates to a method for mixing a liquid sample comprising an analyte, the method comprising providing a support comprising an area comprising a reactant immobilized thereon and the sample, wherein the sample wets the area, and providing a stream of gas that impinges upon and sweeps across at least a part of the area in a scanning manner, the stream of gas being provided by means of a jet directed toward the area, thereby causing a mixing of the liquid sample and thereby causing the analyte to be available for reaction with the immobilized reactant. [0011] The invention further relates to a method for detecting an analyte in a liquid sample comprising providing a support comprising an area comprising a reactant immobilized thereon and the sample, wherein the sample wets the area, providing a stream of gas that impinges upon and sweeps across at least a part of the area in a scanning manner, the stream of gas being provided by means of a jet directed toward the area, thereby causing a mixing of the liquid sample and thereby causing the analyte to be available for binding with the immobilized reactant, and detecting the binding of the analyte with the immobilized reactant. [0012] The invention further relates to a device for detecting an analyte in a liquid sample, the device comprising a holder, a support held by the holder and comprising an area comprising a reactant immobilized thereon, the support containing the liquid sample which wets the area, a gas supply device comprising a jet for supplying a stream of gas to the area, and a drive device for generating relative movement between the jet and the holder whereby the stream of gas sweeps across at least a part of the area in a scanning manner, thereby mixing the sample and causing the analyte to be available for reaction with the immobilized reactant. BRIEF DESCRIPTION OF THE DRAWINGS [0013] The invention is further elucidated in the following with reference to the figures. [0014] FIG. 1 shows a greatly simplified schematic representation of a diagrammatic sketch to illustrate the method comprising a trough-shaped biochip and a gas jet that can be moved above it and [0015] FIG. 2 shows a greatly simplified schematic representation of a device according to the invention. DESCRIPTION OF THE INVENTION [0016] The object of the invention is to propose a method of the type stated above which increases the measuring sensitivity or reduces the incubation time required to achieve an adequate measuring effect when performing tests based on binding reactions between analytes in a sample liquid and reactants on a support wetted by the sample liquid and thus for typical biochip applications. Furthermore, the binding reaction between analytes and reactants should occur homogeneously and independently of the location over the entire chip. This means that reactants that are in the middle or at the edge of the support or microarray chip can bind the analyte essentially at the same rate and efficiency. [0017] In order to achieve this object in the case of the aforementioned method for detecting analytes in a liquid the invention proposes that the liquid is impinged upon by a stream of gas that sweeps across at least some areas in a scanning manner by means of a jet directed towards the support surface during the mixing treatment. [0018] This process which is extremely suitable especially when using trough-shaped biochips having an essentially flat bottom as the support surface results in an efficient local mixing of the sample liquid containing the analytes in the area of the zone that is currently being impinged upon by the gas stream. It is expedient to direct the jet from above onto the sample liquid in such a manner that the gas stream locally displaces sample liquid in its impact area. As a result the level of sample liquid in the impact area of the gas stream is reduced to a very low value of for example only a few .mu.m and the sample liquid is efficiently homogenized by vortexing in a zone encompassing this area with the reduced liquid level. Since the impact point of the gas stream sweeps across the support surface in a scanning manner the zone where the sample liquid is intensively mixed on the bottom of the chip migrates across the support surface such that new analytes are supplied in an accelerated manner to the boundary layer that is initially depleted of analyte due to prior binding reactions. This increases the probability of further binding reactions between the analytes and the immobilized reactants which can thus increase the sensitivity or reduce the incubation period and improve the homogeneity and especially the position-independent homogeneity of analyte binding compared to conventional methods. Continue reading... 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