EP2388067A1 - Procédé et dispositif de mélange d'un liquide avec un élément de test micro-fluidique, et élément de test - Google Patents

Procédé et dispositif de mélange d'un liquide avec un élément de test micro-fluidique, et élément de test Download PDF

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Publication number
EP2388067A1
EP2388067A1 EP10005124A EP10005124A EP2388067A1 EP 2388067 A1 EP2388067 A1 EP 2388067A1 EP 10005124 A EP10005124 A EP 10005124A EP 10005124 A EP10005124 A EP 10005124A EP 2388067 A1 EP2388067 A1 EP 2388067A1
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EP
European Patent Office
Prior art keywords
test element
rotation
angular velocity
cycle
accelerations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10005124A
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German (de)
English (en)
Inventor
Dr. Carlo Effenhauser
Susanne Würl
Christoph Böhm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH filed Critical F Hoffmann La Roche AG
Priority to EP10005124A priority Critical patent/EP2388067A1/fr
Priority to PCT/EP2011/055891 priority patent/WO2011144396A1/fr
Publication of EP2388067A1 publication Critical patent/EP2388067A1/fr
Withdrawn legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/10—Mixers with shaking, oscillating, or vibrating mechanisms with a mixing receptacle rotating alternately in opposite directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/20—Mixing the contents of independent containers, e.g. test tubes
    • B01F31/22—Mixing the contents of independent containers, e.g. test tubes with supporting means moving in a horizontal plane, e.g. describing an orbital path for moving the containers about an axis which intersects the receptacle axis at an angle
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/71725—Feed mechanisms characterised by the means for feeding the components to the mixer using centrifugal forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0418—Geometrical information
    • B01F2215/0431—Numerical size values, e.g. diameter of a hole or conduit, area, volume, length, width, or ratios thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0436—Operational information
    • B01F2215/0454—Numerical frequency values
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0803—Disc shape
    • B01L2300/0806—Standardised forms, e.g. compact disc [CD] format
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces

Definitions

  • the present invention relates to a method for mixing a liquid by means of a microfluidic test element, which has a substrate and a channel structure and rotates at an angular velocity about an axis of rotation.
  • the invention also relates to a device for mixing a liquid and the test element itself.
  • Microfluidic test elements are used, for example, for analyzing liquid samples and for mixing a liquid, primarily in diagnostic tests (in-vitro diagnostics). In such tests, for example, body fluid samples are examined for an analyte for medical purposes contained therein.
  • microarrays or solid-phase tests based on solid-phase binding reactions are so-called microarrays or solid-phase tests based on solid-phase binding reactions.
  • One group of such assays are sandwich assays in which a solid phase-bound first binding partner undergoes a specific binding reaction enters with an analyte in the liquid.
  • the analyte in turn, can be visualized by "docking" a label molecule.
  • the visualization may be by, for example, luminescence or fluorescence or other forms of labeling, such as by enzymes in enzyme immunoassays.
  • mock tests are carried out in which the solid-phase-bound reactant does not cover the entire bottom surface of an incubation chamber but only individual regions or points thereof.
  • the use of spots thus results in a concentration of the analyte and the label at the individual spots in the chamber.
  • the density of the analyte and the label in the area of the spots is considerably higher than with full-surface application of the solid phase-bound reactant.
  • an arrangement of several (three to ten) spots for the same parameter (analyte) has proved suitable. The spots are evaluated individually. The results are averaged. In some tests, another, preferably higher number of spots per parameter is advantageous.
  • the analytes and labels must be distributed as evenly as possible over all spots.
  • microarrays even in biochemical reaction chambers with surface sensors and a corresponding measuring technique uniform binding of the analytes is necessary, especially if optical evaluation takes place, for example by image recognition.
  • fully coated (active) surfaces may be, for example, a gel (solid phase reaction partner hydrogel) at the bottom of the chamber or a large pore 3D matrix as an alternative to a planar surface.
  • microfluidic test elements are also used in tests in which a reagent in the reagent chamber in liquid form or as a solid is present, which is dried on the test element.
  • a reagent in the reagent chamber in liquid form or as a solid is present, which is dried on the test element.
  • Such dry reagents must be dissolved and homogenized prior to analysis. It is necessary in each case a uniform mixing or solving.
  • the term "mixing” in addition to the dissolution of a solid in a liquid also includes the possibility that two liquids are mixed together when the reagent is present for example in liquid form.
  • test carriers on which microfluidic test elements with channel structures for receiving a liquid sample are arranged or integrated.
  • the channel structures often include a plurality of channel sections, chambers, and fluidic valves for sequencing.
  • Test carriers and microfluidic test elements consist of a carrier material, often a substrate made of plastic material. Suitable materials include COC (cyclo-olefin copolymer) or plastics such as PMMA (polymethyl methacrylate), polycarbonate or polystyrene.
  • the channel structure of the test carrier is enclosed by the substrate and a cover or a cover layer.
  • Such a channel structure is manufactured by a three-dimensional structuring of the plastic parts, for example by injection molding techniques or other methods. It is also possible to introduce the structure by material-removing methods, such as milling or laser ablation.
  • control of the liquid transport within the channel structures and the control of the process flow can be done with internal (within the fluidic test element) or with external (outside the fluidic test element) measures.
  • the control can be caused by applying pressure differences or by changing forces, for example by changing the effective direction of gravity.
  • a targeted control of the liquid flow can be achieved within the channel structure by the rotation of a test element.
  • the generated forces may be made by controlling the change in rotational speed or direction of rotation, or by the distance from the axis of rotation, or by utilizing density differences in the liquid (eg, dissolving a solid).
  • the microfluidic test elements can be arranged in a rotating disk in the form of a compact disc (CD).
  • CD compact disc
  • the object of the present invention is thus to propose an improved method and an improved apparatus for mixing liquids.
  • the present object is achieved by a method having the features of claim 1 and by an apparatus having the features of claim 12 and by a test element having the features of claim 13.
  • the method according to the invention for mixing a liquid by means of a microfluidic test element comprising a substrate and a microfluidic channel structure with a mixing chamber requires that the microfluidic test element rotate at an angular velocity ⁇ about an axis of rotation which can preferably extend through the test element.
  • the axis of rotation can be a central axis of rotation the center of the test element or by the center of gravity.
  • the test element is designed as a test carrier or integrated into a test carrier.
  • the test carrier rotates about an axis of rotation, which preferably extends through the test carrier and is preferably arranged centrally.
  • the microfluidic test element rotates according to a rotation profile that comprises at least two cycles and in which the angular velocity changes within one cycle.
  • the rotation profile is to be understood as a time sequence of several Winkelend beauen, which are divided into cycles.
  • One cycle comprises accelerating the rotation of the test element with at least a first acceleration a1 until reaching a first end angular velocity ⁇ 1 and, after reaching the first end angular velocity ⁇ 1, accelerating the rotation of the test element with at least one second acceleration a2 until reaching a second one End angular velocity ⁇ 2.
  • the two accelerations a1 and a2 are opposite.
  • One cycle is defined to define the timing of angular velocity, for example, where the first end angular velocity is contained twice in a cycle.
  • a cycle can be defined by the zero crossings.
  • One cycle then connects three zero crossings, with two consecutive cycles Z 1 , Z 2 having a common zero crossing.
  • the cycle thus corresponds to a period, ie the smallest temporal interval, after a process repeats itself.
  • the end angular velocities and / or the accelerations need not be the same or constant.
  • the rotation profile has a plurality of cycles, wherein the rotation profile can also be repeated periodically, so that the sequence of the cycles is repeated after a predetermined number of cycles (greater than 2). However, this is not mandatory.
  • At least one of the accelerations a1, a2 and / or at least one of the end angular velocities ⁇ 1, ⁇ 2 are changed from one cycle to the next in order to produce a (preferably homogeneously) mixed liquid. It was recognized that the homogeneity of the mixed liquid can be significantly improved by the juxtaposition of different cycles. Also, the use of different cycles has positive effects on the mixing time, which is reduced.
  • the method according to the invention also solves the problem that the analyte becomes "depleted" in the analyte if the analyte in the liquid sets, for example, on the solid phase of the microarray and therefore the portion of the liquid near to the solid phase has few or fewer analyte molecules .
  • the method according to the invention it is ensured that (continuously) analyte is replenished from the liquid phase regions of the chamber which are remote from the phase to the depleted liquid regions.
  • the mass transport within the liquid is optimized by the method as well as the mixing.
  • the constant shaking causes the flow pattern on the array surface to "burn in".
  • the array spots Detection locations
  • the array spots are not introduced at any location in the chamber, but would have to be selected depending on the flow pattern and thus depending on the rotation profile.
  • the coupling of an equal amount of analyte in the liquid at different locations on the chamber surface is thus different efficient.
  • multiple array spots are evaluated by averaging the actual actual spot values to increase biosensor precision in array format.
  • the formation of flow patterns distorts the measurement result, so that this method has significant disadvantages here.
  • the round chamber is preferably circular and not elliptical. Since the shape of a flat disk is selected for the rotating test elements and an optical evaluation is carried out over the surface of the disk, it was recognized that a chamber in the form of a cylindrical disk is optimal. Particularly preferably, this has a circular floor plan. A ratio of chamber diameter to chamber height of 1 to 1 has been found to be ideal. This "aspect ratio" should therefore preferably be close to 1 and, taking into account the typical systemic boundary conditions, be at most 4. The quotient from surface A to volume V should be based on the investigations at constant volume have a value between 1 and 3.5.
  • the liquid chamber is to be arranged such that the rotation axis (preferably extending through the test element) around which the test element rotates does not extend through the liquid chamber. Rather, the liquid chamber is preferably spaced from the axis of rotation.
  • the amounts of the accelerations a1 and a2 are different in one cycle.
  • the formation of constant flow patterns in the liquid chamber is prevented within a cycle.
  • At least one of the accelerations a1, a2 is variable during a cycle.
  • the one or both accelerations a1, a2 thus change within the cycle.
  • at least one of the accelerations a1, a2 can be constant during one cycle, preferably both accelerations.
  • the change in the angular velocity within the cycle thus changes continuously (constant). Since a cycle is relatively short in relation to the rotation profile and thus to the entire mixing time, no stationary, constant flow patterns are formed within the period (cycle duration).
  • the mixing results are of (nearly) the same quality as with changing accelerations during the cycle.
  • the control of the rotation with a constant acceleration is much easier to realize.
  • the mixing efficiency with higher amplitudes is more effective than the mixing efficiency with low amplitudes ( ⁇ 1, ⁇ 2). Consequently, with the same acceleration, the mixing efficiency with a longer period duration and fewer cycles (assay interval) is more effective than with a consequently short period duration and many cycles per examination, ie with the same total mixing time.
  • the direction of rotation of the test element is equal to or opposite to the direction of rotation of the test element when the second end angular velocity ⁇ 2 is reached.
  • the direction of rotation is opposite. Consequently, a reversal of the direction of rotation takes place while an acceleration is exerted on the rotating test element between the first and second end angular speeds.
  • the "vibration" thus takes place around the zero point of the frequency.
  • the rotating test element is consequently decelerated by reaching a second acceleration a2 until it comes to a standstill and then accelerated further with the same second acceleration a2 until the second final angular velocity ⁇ 2 is reached.
  • the term "mixing” means not only the dissolution of a solid in a liquid and the mixing of several liquids, but also the uniform transport of dissolved in the liquid components, for example, a depletion of the solution with reagent or analyte to avoid a binding phase (solid phase). After the reaction of individual analyte molecules with capture molecules of the binding phase, the analyte in the liquid is depleted in the Area of the binding phase.
  • the transport of analyte molecules within the liquid is ensured such that a continuous subsequent delivery of the analyte molecules from remote areas to the liquid zones near the binding phase takes place in order as possible all possible in the context of the relevant equilibrium reaction analyte molecules to the binding phase (or their catcher molecules), which increases the sensitivity of the detection method.
  • the goal thus achieved is enrichment of all possible analyte molecules from the liquid phase at the binding phase.
  • the term "mixing" thus also includes this balancing of the analyte molecules within the liquid.
  • FIG. 1 shows a device 1 for homogeneously mixing a liquid with a test element 2, which is held in the device 1.
  • the device 1 comprises a holder 3 for receiving the test element 2, which is rotatable about a rotation axis 4.
  • the two test elements 2 are integrated in a test carrier 16.
  • the rotatable holder 3 with its shaft 3 a is moved by a drive 5 in such a way that the holder 3 together with the held test carrier 16 rotates about the rotation axis 4 at an adjustable variable angular velocity.
  • the drive 5 is controlled by a control unit 6, wherein a movement sequence can be defined, which is preferably stored as a rotation profile in the control unit 6.
  • the rotation profile may consist of a plurality of control commands which set the rotation speed (angular velocity), the acceleration, the hold time during which the end angular velocity is kept constant, and the rotation direction.
  • the rotation profile can either be stored in a memory of the device 1 or adjusted by manual adjustment of the above parameters on the device or generated from the parameters.
  • the device 1 comprises an optical measuring and evaluation unit 7 with an optical sensor 8.
  • a liquid recorded in the test element 2 can be analyzed and measured.
  • the known in the prior art investigation can be applied.
  • the microfluidic test element 2 comprises a microfluidic channel structure 10, which has a channel section 11 which extends from an opening 12 to a microfluidic fluid chamber 13.
  • the liquid chamber 13 is fluidically connected via a siphon channel 14 with a collection chamber 15, which is also referred to as waste chamber.
  • the test elements 2 are embedded in the test carrier 16, which is formed as a round disk (disc) and through which the axis of rotation 4 extends.
  • the channel structure 10 is enclosed by a substrate and a cover layer, not shown, which covers the test carrier 16 from above.
  • the holder 3 in the device 1 is designed as a shaft 3 a, which runs concentrically to the axis of rotation 4.
  • holders 3 for example, a retaining disk, a rotor or a clamping device with outer brackets, in which the test element is clamped.
  • the central shaft 3a it is possible to rotate the test carrier with one or more test elements about an eccentric (eccentric) axis of rotation.
  • the axis of rotation may extend, for example, through the center of gravity of the test carrier 16, in order to take into account spatial structures in the test carrier 16 or the test elements 2 and to avoid an imbalance during rotation.
  • the rotation axis does not necessarily have to be aligned vertically. It can also run obliquely in space at a solid angle ⁇ ⁇ 0 with respect to the vertical.
  • the test carrier 16 in FIG. 2 for homogeneous mixing of a liquid comprises a test element 2 with a channel structure 10.
  • the channel structure 10 has two openings 12a, 12b, to which two adjacent channel sections 11a, 11b extend up to two intermediate chambers 17a, 17b.
  • the intermediate chambers 17a, 17b are in fluid communication via a further channel 18a or 18b, each with an opening 19a, 19b.
  • An adjoining the intermediate chambers 17a, 17b Channel section 20a, 20b leads to a fluidic valve 21, through which liquids from the intermediate chambers 17a, 17b can be directed into the liquid chamber 13.
  • the fluidic valve 21 has an air outlet 22 for venting, which provides an air channel 23 for the venting of the fluidic valve 21 and connected thereto fluidic regions (eg, chamber 13).
  • the liquid chamber 13 is adjoined by a siphon channel 14, which connects the liquid chamber 13 to a collecting chamber 15.
  • the shaping of the liquid chamber 13 has an influence on the mixing speed.
  • a round liquid chamber 13 is advantageous.
  • the liquid chamber 13 is smaller than a round cylindrical disk with a height the height of the test carrier 16th
  • a circular floor plan of the cylinder disc is particularly preferred. The quotient of the diameter of the circular cylindrical disk and the height of the cylinder should be as close as possible to one.
  • a chamber diameter r1 of 2.5 mm and a height h1 of 2 mm homogeneous mixing of two liquids containing plasma is achieved after just 5 seconds, while with a diameter r2 of 4 mm and a height h2 of 0.8 mm a homogeneous mixing takes place only after 10 seconds.
  • the ratio of surface A to volume V is crucial.
  • the quotient is close to 1.
  • the chamber with the smaller quotient achieves homogenous mixing faster.
  • the mixing efficiency can be further increased. It has thus been recognized that, according to the invention, at least one of the accelerations a1, a2 and / or at least one of the end angular velocities ⁇ 1, ⁇ 2 has to be changed from one cycle Z 1 to the next cycle Z 2 .
  • the incubation time with mixing over the solid phase of the microarray can thus be reduced to a few minutes, while the quality of the subsequent delivery of analytes to the detection surface and the homogeneity of the setting on the solid phase are markedly improved.
  • FIG. 4 shows a rotation profile in which only the end angular velocities ⁇ 1, ⁇ 2 have been changed from cycle to cycle.
  • the accelerations a1, a2 are the same in all cycles.
  • the first and second accelerations a1, a2 are equal in magnitude.
  • FIGS. 5a to c each show a section of a rotation profile for the angular velocity.
  • both the accelerations a1, a2 and the final angular velocities ⁇ 1, ⁇ 2 change in the respective cycles.
  • two cycles Z 1 , Z 2 are shown .
  • the first acceleration a11 in the first cycle Z 1 is different from the first acceleration a12 in the second cycle Z 2 .
  • the first end angular velocity ⁇ 11 of the first cycle is different from the first end angular velocity ⁇ 12 of the second cycle.
  • the second acceleration a21, a22 and the second end angular velocity ⁇ 21 and ⁇ 22 are constant and does not change.
  • At least one of the accelerations a1, a2 is variable during a cycle Z.
  • the respective acceleration a1, a2 consist of two partial accelerations a1 a , a1 b and a2 a , a2 b .
  • the respective accelerations a a , a b may each be constant. Preferably, they are different from each other.
  • the accelerations a a , a b can also be variable, so that in the diagram no straight line, but a curve would be shown.
  • a cycle consists of a first partial cycle Z T1 until reaching the first end angular velocity ⁇ 1 and from an adjoining second partial cycle Z T2 until reaching the second final angular velocity ⁇ 2.
  • the rotation of the test element takes place in at least one of the two partial cycles Z T1 , Z T2 with at least two accelerations a a , a b .
  • FIG. 5b It can be seen that the first cycle Z 1 consists of the two partial cycles Z T11 and Z T21 .
  • the rotation of the test element takes place first with the acceleration a11 a and then with a second acceleration a11 b , which in this embodiment is different from the first partial acceleration a11 a .
  • the second subcycle Z T21 of the first cycle also has two accelerations a21 a and a21 b .
  • At least one of the two partial accelerations a a , a b in at least one of the partial cycles Z T1 , Z T2 is equal to zero.
  • T P plateau time, hold time
  • the Acceleration a a , a b is equal to zero
  • the test element rotates at a constant speed.
  • at least one of the partial accelerations a a , a b is not equal to zero.
  • Such a rotation profile has proven to be advantageous, in particular in biochemical tests and tests in immunology, when setting takes place during the phases with a constant rotation (acceleration equal to zero).
  • the acceleration in a subcycle a1, a2 also consist of more than two partial accelerations a a , a b , a c ... exist. It is conceivable that even before reaching the final angular velocity, the rotation of the test element with a constant angular velocity (not equal to the final angular velocity), ie with an acceleration equal to zero, and then again the rotation is accelerated until the final angular velocity is reached ,
  • At least one of the partial accelerations when reaching one of the end angular velocities is equal to zero.
  • the test element is then constantly rotated at the final angular velocity of the cycle for a predetermined period of time T P , ie not accelerated.
  • FIG. 5c shows such a rotation profile in which the accelerations a11 b and a21 b in the first cycle are equal to zero.
  • the rotation of the test element at a constant speed takes place here when the final angular velocities ⁇ 11, ⁇ 21 are reached in the first cycle Z 1 .
  • the durations T P1 and T P2 within one cycle may be the same or different from each other. They can vary from cycle to cycle or repeat themselves.
  • the accelerations of the rotation profile are coded with a random number; they are formed from the random number.
  • the end angular velocities ⁇ 1, ⁇ 2 are preferably formed from a random number.
  • a random number is used which is within the systemic limits of the device.
  • the amount of the final angular velocity is limited to 100 Hz due to the system, so that the final angular velocities determined by a random number can likewise not be greater than 100 Hz in terms of magnitude.
  • the magnitude of the final angular velocity must be greater than or equal to 20 Hz as a result of the system, since otherwise the siphon channel 14 adjoining the liquid chamber 13 breaks through and liquid escapes.
  • the random number is preferably a "true random number".
  • the random number is used as a matrix for choosing the "random" process parameters. For example, values of the accelerations and / or the end angular velocities may be formed from two consecutive digits of the random number. Alternatively, any number may be used that is constant with a factor, e.g. B. 10, is multiplied.
  • This process also includes braking, a (short) standstill with reversal of the direction of rotation and an acceleration.
  • the first acceleration a1 is opposite to the second acceleration a2 and consequently has a positive sign.
  • This first end angular velocity ⁇ 1 already belongs to the second cycle Z 2 of the rotation profile.
  • This rotational profile of a " ⁇ -shake mode" ( ⁇ -Euler mixing) is in FIG. 6 shown.
  • both the end angular velocities ⁇ 1, ⁇ 2 and the accelerations a1, a2 will be changed from cycle to cycle.
  • the amount of the maximum occurring end angular velocity ⁇ 1, ⁇ 2 in this application example is 100 Hz due to the system. It can be clearly seen that the cycles have different cycle times, which follows from the different accelerations or end angular velocities.
  • FIG Fig. 7 Evidence of improved mixing of an analyte in a liquid by using a chaotic Euler rotation profile in which both the accelerations and the final angular velocities are varied from one cycle to the next is shown in the table in FIG Fig. 7 shown.
  • three spots of a solid phase-bound reaction partner were placed in a liquid chamber 13.
  • FIG. 8 the standard Euler mixing (curve A) is compared with the chaotic Euler mixing (curve B) on the basis of the number ⁇ ( ⁇ -Euler mix).
  • a BI-DIG model system was used in which the bottom of the liquid chamber 13 is coated with a TRSA-BI streptavidin. On the floor, individual spots are placed with a BI-RPLA-DIG (BI-bovine plasma albumin DIG) with the bottom surface blocked (coated) around the spots with biotin. An anti-DIG latex is detected as a model analyte in a sample fluid.
  • BI-RPLA-DIG BI-bovine plasma albumin DIG
  • FIG. 9 shows the comparison of two measurements in a "chaotic Euler-mixing".
  • the median of the measured, signaling fluorescence signals (FS) counts
  • S individual spots
  • FS signaling fluorescence signals
  • the coefficient of variation is low.
  • the two outliers were expected in this attempt because they are systemic.
  • the fact that both outliers were detected at different spots is due to the fact that no ideal matrices (coated liquid chambers) were available.

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EP10005124A 2010-05-17 2010-05-17 Procédé et dispositif de mélange d'un liquide avec un élément de test micro-fluidique, et élément de test Withdrawn EP2388067A1 (fr)

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DE102014019526A1 (de) * 2014-12-23 2016-06-23 Testo Ag Untersuchungsverfahren, scheibenförmiger Probenträger und Verwendung eines Probenträgers
EP3383628A4 (fr) * 2016-04-30 2019-08-21 Hewlett-Packard Development Company, L.P. Mélange d'un matériau de construction en poudre pour fabrication additive
CN109030165A (zh) * 2018-07-02 2018-12-18 昆明金域医学检验所有限公司 一种用于微生物内毒素检测的旋涡混匀装置

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