EP2783747B1 - Procédé et dispositif destinés au mélange sans contact de liquides - Google Patents

Procédé et dispositif destinés au mélange sans contact de liquides Download PDF

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Publication number
EP2783747B1
EP2783747B1 EP14162100.3A EP14162100A EP2783747B1 EP 2783747 B1 EP2783747 B1 EP 2783747B1 EP 14162100 A EP14162100 A EP 14162100A EP 2783747 B1 EP2783747 B1 EP 2783747B1
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Prior art keywords
liquid
particles
radiation
interaction
layer
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German (de)
English (en)
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EP2783747A1 (fr
Inventor
Philipp Baaske
Stefan Duhr
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Nano Temper Technologies GmbH
Nano Temper Tech GmbH
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Nano Temper Technologies GmbH
Nano Temper Tech GmbH
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    • 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
    • B01F33/05—Mixers using radiation, e.g. magnetic fields or microwaves to mix the material
    • B01F33/053—Mixers using radiation, e.g. magnetic fields or microwaves to mix the material the energy being magnetic or electromagnetic energy, radiation working on the ingredients or compositions for or during mixing them
    • 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
    • B01F33/05—Mixers using radiation, e.g. magnetic fields or microwaves to mix the material
    • B01F33/055—Mixers using radiation, e.g. magnetic fields or microwaves to mix the material the energy being particle radiation working on the ingredients or compositions for or during mixing them
    • 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
    • B01F33/12—Mixers in which the mixing of the components is achieved by natural convection
    • 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
    • B01F33/3034—Micromixers using induced convection or movement in the mixture to mix or move the fluids without mechanical means, e.g. thermodynamic instability, strong gradients, etc.
    • 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
    • B01F35/20—Measuring; Control or regulation
    • 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
    • B01F2215/0472—Numerical temperature values

Definitions

  • the invention generally relates to a method and a device for non-contact mixing of liquids or for mixing particles in a liquid and in particular for mixing aqueous solutions.
  • directed liquid radiation is generated by targeted irradiation of electromagnetic radiation into the liquid in order, for example, to transport particles, preferably particles dissolved in the liquid, to a surface or boundary surface of a sample chamber or a surface of a liquid volume in order to mix the particles the liquid, in particular at the surface / interface to provide.
  • the invention is advantageous in that a "depletion layer" or an "enhancement layer” with a reduced or increased particle concentration at the surface / interface is avoided, so that surface-based measurement methods can be improved.
  • the invention is also advantageous in that it allows small volumes (micro-volumes), which are difficult to mix, for example, due to mechanical effects such as shaking or shaking, to be mixed.
  • the invention also relates to a method and a device for investigating specific and nonspecific interactions or interactions of particles, which are preferably dissolved in a liquid, with surfaces or interfaces.
  • fluorescence measurements are fluorescence measurements, fluorescence anisotropy measurements, Förster resonance energy transfer measurements (FRET), total internal reflection fluorescence microscopy (TIRFM), backscattering interferometry measurements (BSI), absorption measurements, spectroscopic measurements, AlphaScreen® assays , MicroScale Thermophoresis Measurements (MST), Patch Clamp Measurements.
  • FRET Förster resonance energy transfer measurements
  • TRFM total internal reflection fluorescence microscopy
  • BSI backscattering interferometry measurements
  • absorption measurements spectroscopic measurements
  • AlphaScreen® assays are MicroScale Thermophoresis Measurements (MST), Patch Clamp Measurements.
  • Another method of avoiding the depletion layer moves or "shakes" the sample chamber macroscopically with respect to a surface sensor.
  • a problem with this method is that the sample chamber must be open to the outside and so can evaporate the aqueous solution and / or can be contaminated by external influences.
  • the mechanical "shaking" of the open sample chamber is also problematic, since the shaking overflow liquids / "spill" and so can penetrate into adjacent open sample chambers.
  • the invention generally relates to a method for mixing fluids, preferably liquids or for mixing particles in a fluid or a liquid.
  • the invention relates to a method for mixing of dissolved and / or undissolved particles in the liquid.
  • the present invention relates to the mixing of any kind of particles or particles such as (bio) molecules, (nano) particles, (micro) beads, (bio) polymers, paints, emulsifiers, cells (biological cells), viruses, bacteria, Lipids, vesicles, liposomes, nanodiscs, pigments, dispersing additives, pastes.
  • the liquid is provided as a liquid volume in at least one sample chamber, wherein the sample chamber may be open or closed.
  • the liquid can also be provided in the form of a drop, wherein according to the invention a thermal convection flow is generated within the droplet.
  • the liquid drop may be provided on a suitable slide (see discussion below) and, for example, surrounded by an oil layer to prevent evaporation. According to a preferred embodiment, the provision of very small volumes of liquid in glass capillaries already suffices.
  • a convection flow is achieved in the liquid volume by irradiation of electromagnetic radiation in the liquid volume and in particular a mixing of Liquid with the particles present therein at a surface of the liquid volume or at an interface or boundary layer between the liquid volume and a material layer of the sample chamber achieved.
  • the inventive method and the associated apparatus is thus applicable to measuring methods in which preferably measured at the surface or interface of a liquid, since according to the invention a depletion zone, depletion layer, enrichment zone, enrichment layer or a concentration shift at the surface or interface is avoided.
  • a good mixing in contact surfaces between solids for example inner surface of a sample chamber or of glass capillaries
  • a surface or contact surface according to the invention is not limited to a flat surface, but may also be three-dimensional or fractal, e.g. when dextran or dendrimer coated glass substrates are used and the interaction between e.g. Antibody and antigen takes place on / in the dextran layer.
  • the thermal convection flow is generated by means of at least one electromagnetic radiation source, preferably a light source.
  • the thermal convection flow is generated by means of an infrared (IR) radiation source.
  • IR radiation can be generated with known IR radiation sources and preferably positioned locally by an optical means (eg, lens and / or mirror / reflector) in the liquid also be focused.
  • an optical means eg, lens and / or mirror / reflector
  • IR LEDs are used as the radiation source.
  • the liquid is preferably heated locally at the location of the radiated beam and thus generates the thermal convection flow.
  • the present invention preferably produces liquid streams directly, and preferably purely optically and in particular completely contactless, directly in the liquid / solution with the particles. Since liquids to be examined are often aqueous solutions, it is particularly advantageous in these cases to select the electromagnetic radiation in the infrared wavelength range, due to the advantageous absorption behavior.
  • an aqueous solution not only absorbs the energy of the IR laser radiation, but also the pulse of the photons of the IR laser radiation (light pressure) has an influence on the convection behavior (see FIGS. 2A, 2B ).
  • the energy absorption heats the aqueous solution locally at the location where the IR laser radiation is radiated into the aqueous solution, which leads to thermal convection.
  • the momentum of the photons of the IR laser radiation is transferred to the aqueous solution.
  • the flow velocity of the thermal convection can be amplified (antiparallel to gravitation) or attenuated (parallel to gravitation).
  • the laser radiation can also be aligned vertically or obliquely to the gravitation.
  • the wavelength of the preferred IR radiation is preferably in the range 1200 nm to 2000 nm. More preferred are the specific IR laser wavelengths: 980 nm (+/- 10 nm); 1450 nm (+/- 20 nm); 1480 nm (+/- 20 nm); 1550 nm (+/- 20 nm) and 1920 nm (+/- 20 nm).
  • the invention also relates to a device for carrying out the method according to the invention.
  • the method according to the invention is preferably used in combination with surface / interface-based measuring methods / measuring devices.
  • This allows, for example, specific chemical, biochemical Interactions at interfaces are safely and reliably investigated, preferably in extremely small volumes.
  • non-specific effects such as "sticking", physisorption, chemisorption, sorption, adsorption, absorption, electrochemical processes, catalytic processes, etc. can also be investigated
  • the mixing method according to the invention can be used, for example, in combination with measuring device for determining optical properties on a thin layer, whereby, for example, chemical, biochemical, medical and / or physical reactions, binding and / or addition processes as well as other interactions on the thin layer are detected can.
  • measuring methods for example, light, preferably light of a specific wavelength, is irradiated onto a sample to be examined, the sample being bound to a thin layer. Changes in the optical layer thickness are detected or measured, for example, by means of interference phenomena, which results in conclusions on reactions of the examined sample with a suitably pretreated thin layer.
  • volume consumption can be reduced from a few 100 microliters to a few milliliters to a few nanoliters to a few microliters. Volumes of from 1 microliter to 10 microliters are preferably used as the volume according to the invention.
  • Elaborate flow cells, microfluidics, pumps, valves and hoses are preferably eliminated, whereby a device according to the invention is very robust and preferably can not be contaminated by any residues in hoses and / or valves and it also prevents loss of sample / particles in the sample Adherence (adsorption / chemsorption / physorption) of the particles to the surfaces of the hoses and valves (more generally: to the surfaces of the dead volumes).
  • both open and closed sample chambers can be used, whereby vaporization / evaporation of the (aqueous) solution can also be avoided by closed sample chambers. This is advantageous, for example, in that significantly longer measurement times are possible.
  • convection is caused by a flow that can carry particles.
  • Cause of the transporting flow can basically be different forces, such. As weight or forces resulting from pressure, density, temperature or concentration differences.
  • the method of the invention preferably produces a free or natural convention, i.e., convection caused by a temperature gradient.
  • the temperature increase is preferably so low that the particles or the sample are not damaged and / or negatively affected.
  • free convection due to thermal density differences may be described as follows: When heated, fabrics tend to expand (except, for example, the density anomaly of the water). Under the influence of the gravitational force, areas of lower density rise within the fluid against the gravitational field (buoyancy), while areas of higher density sink therein. For example, if heat is applied to the bottom of a sample chamber and the top of the sample is allowed to cool, a continuous flow is created: the liquid heats up, expands, and rises. Once there, the liquid cools down, contracts again and sinks to be heated again below.
  • the velocity of the liquid streams of the thermal convection according to the invention can preferably be determined by varying the optical energy or power, the focusing or defocusing, the intensity, the direction, the parallelism (or also the convergence and divergence) and / or the position of the focus relative to surface / thin film, the number of beams (laser beam can be split to heat several places at the same time), the duration of irradiation, pulse width modulation (pulse height, pulse duration, repetition rate), wavelength, moving beam velocity, irradiated radiation and / or be changed or controlled relative to the direction of gravity relative to gravity.
  • the position of the irradiated radiation can vary, for example the focus can be positioned in all three spatial directions by means of mirror systems (see laser scanner) and be moved at different speeds. Since the present invention can also generate liquid streams perpendicular to the surfaces of sample chambers by means of optically generated thermal convection (as opposed to liquid streams generated by external pumps), mixing the liquid and reducing a depletion layer is very efficient.
  • the rate of thermal convection depends, among other things, on the chamber thickness (height in the direction of gravity) of the sample chamber and, in particular, on the chamber geometry.
  • edge surfaces of a sample chamber can significantly influence the speed of thermal convection.
  • Preference is given to sample chambers that are thick enough (for example> 0.05 mm) to achieve a desired rapid flow velocity of the thermal convection in order to avoid the " depletion layer" or an enrichment layer.
  • a thermal convection such that preferably a laminar flow is generated, preferably at low Reynolds numbers (Reynolds number Re ⁇ 1000).
  • sample chambers also liquid drops or water drops
  • a layer thickness of at least 0.05 mm is preferred because at lower layer thicknesses or smaller thicknesses of the sample chamber, the convection effect is too weak to achieve a desired mixing.
  • layer thicknesses of the liquid or thicknesses of the sample chamber not greater than 11.5 mm (well depth in the case of multiwell plates).
  • An exemplary convection velocity for a sample chamber that is 1 mm in height and 5 mm in diameter, 20 ⁇ l in volume, 52 ° C chamber temperature, 1480 nm IR laser with 75 mW light output is at medium speed of about 0.4 mm / s.
  • a typical or average extent of the convection flow lines in this example is about 2 mm in diameter.
  • exemplary diffusion constants D of biomolecules are between 1 ⁇ m 2 / s and 400 ⁇ m 2 / s.
  • the movement / displacement / mixing of the particles due to the convection flow is adapted to the movement of the particles (Brownian motion) due to their diffusion (diffusion constant D).
  • diffusion constant D diffusion constant of the particles to be examined
  • there is a preferred average flow velocity of the thermal convection to be used and thus, for example, preferably also radiation intensities or configurations for the irradiation of the radiation to be used. Due to the very flexible and easily variable and preferably purely optical construction according to the invention, the convection flow and thus the mixing can preferably be adjusted to the particles to be examined, without a new structure having to be built specifically for each particle.
  • rate constants can be exemplified as follows. Assume a chemical reaction of molecule A of concentration [A] with molecule B of concentration / surface density [B] to complex D of concentration [D].
  • mixing according to the invention are “diagnostics” (mixing also important in ELISA), the field of electrochemistry, the range of catalysts, or the area of quality control ("sticking" to surfaces to avoid it).
  • rates of “sticking” of particles or measuring the strength of "sticking"("sticking", physorption, chemsorption, adsorption, absorption) can be measured.
  • thermal convection is to be generated for mixing by means of IR LEDs.
  • IR LEDs are cheap; one can e.g. Insert 384 LEDs or 96, or 24 or 16 to mix many wells simultaneously.
  • IR LEDs typically have less light output than IR lasers, but since the layer thickness of the aqueous solution in the wells is very large (typically> 1 mm), the IR radiation is very well absorbed (Beer-Lambert's Law) and so are IR LEDs powerful enough.
  • the method according to the invention is advantageous for reaction kinetics measurements or biomolecule analysis.
  • the method can be used with NanoTemper® capillaries (for example, glass capillaries with inner diameter of 0.05 mm to 0.8 mm), preferably with inner diameters of 0.2 mm, 0.35 mm, 0.5 mm and 0.8 mm and outer diameters less than or equal to 1.0 mm.
  • no flow cells are necessary and filling of the capillaries can be carried out purely passively by capillary forces.
  • the inner surface of the glass capillary may be untreated or at least partially specifically coated / modified (e.g., with antibody, antigen, DNA, RNA, PNA, TNA, proteins, peptides, cells, polymers, etc.) or not.
  • the disclosed method can generally be carried out with sample compartments having at least one region which is transparent.
  • Transparency in physics is the ability of matter to transmit electromagnetic waves (transmission). In everyday life, the term is usually related to light, that is, to the spectral range of electromagnetic radiation visible to humans.
  • the transparent material is preferably in a wavelength range between 200 nm to 2000 nm permeable, ie preferably also for infrared light and / or UV light.
  • the transparent material is transparent to light in the range of 200 nm to 900 nm, preferably 250 nm to 900 nm, preferably 275 nm to 850 nm.
  • the transparent material is also transparent to light of the following wavelength: 940 nm to 1040 nm (preferably 980 nm +/- 10 nm), 1150 nm to 1210 nm, 1380 nm to 1600 nm (preferably 1450 nm +/- 10 nm and / or 1480 nm +/- 10 nm and / or 1550 nm +/- 10 nm), 1900 nm to 2000 nm (preferably 1930 nm +/- 10 nm).
  • the transparent material may comprise, for example, glass and / or a polymer.
  • Possible materials are borosilicate or borosilicate glass such as Brosilikatglas 3.3 (for example DURAN glass), quartz glass, such as Suprasil, Infrasil, Synthetic quartz glass or silica glass, soda lime glass, Bk-7, ASTM Type 1 Class A glass, ASTM type 1 Class B glass.
  • the polymer may be PTFE, PMMA, Zeonor TM, Zeonex TM, Teflon AF, PC, PE, PET, PP (polypropylene), PPS, PVDF, PFA, FEP, and / or acrylic glass].
  • the disclosed method can also be used with pipette tips, in particular with at least partially transparent pipette tips, for example made of polypropylene.
  • the process according to the invention can also be used with reaction vessels, for example reaction vessels made of glass or plastic ("Eppis"), preferably transparent glass and plastic.
  • reaction vessels for the "Realtime PCR (Polymerase Chain Reaction)" for example, with reaction vessels for the "Realtime PCR (Polymerase Chain Reaction)".
  • the method according to the invention can also be used with chambers / capillaries for electrophoresis, preferably capillary electrophoresis.
  • the method according to the invention can also be used in the detection range of HPLC / UHPLC (High Performance Liquid Chromatography (HPLC).)
  • HPLC High Performance Liquid Chromatography
  • the disclosed method can also be used with microfluidic chambers / microfluidic chips
  • the method according to the invention can be used with sealed / sealed multititre plates (multiwell plates).
  • the disclosed method can be used in sealed / sealed ampoules, for example glass ampoules or plastic ampoules, preferably transparent ampoules, for example substances in the ampoules for forensic or diagnostic tests be enclosed, which must not be contaminated and therefore preferably should not be opened.
  • the inventive method can also be done with multi-well plates (multiwell plates) which have a non-transparent bottom.
  • multititer plates (multiwell plates) for filling with pipettes or pipetting robots are open, preferably open at the top.
  • the process according to the invention can also be used everywhere, for example, where mixing / flow generation by means of external flow (pumping) and / or mechanical shaking is not possible (for example all closed reaction vessels / microcavities) or useful, but the aqueous solution is optically accessible.
  • the method according to the invention can be used in diagnostics, also for mixing in ELISA plates. Another exemplary application is quality control.
  • the mixing method according to the invention can be combined with a multiplicity of different known measuring and reading techniques, in particular for measuring specific and unspecific interactions of particles at surfaces / interfaces.
  • the following typical surface techniques are mentioned by way of example: For measurement, methods such as reflectometric interference spectroscopy (RlfS), Bio-Layer Interferometry (BLI), the surface plasmon resonance (English Surface Plasmon Resonance, SPR), the quartz crystal microbalances (English Quartz Crystal Microbalance, QCM), surface acoustic wave (SAW), enzyme-linked immunosorbent assay (ELISA) or nanopores or transistors (Next Generation Sequencing). For example, these measuring methods may be performed by a combination of e.g.
  • Glass capillaries of certain diameter as a sample chamber of the aqueous solution with the particles, IR laser / LED for generating a thermal convection in the aqueous solution in the glass capillaries and a corresponding measurement or experimental arrangement can be improved.
  • the disclosed method for mixing liquids or particles with a liquid relates to the steps of providing a volume of liquid and generating a thermal convection flow on at least one surface / interface of the liquid volume by irradiating electromagnetic radiation into the liquid volume.
  • the liquid volume may be provided, for example, in a sample chamber that is open or closed.
  • a microcavity may serve as the sample chamber, more preferably a capillary or a pipette tip.
  • a sample chamber should have at least one region that is at least partially transparent.
  • the sample chamber has a thickness of 0.01 mm to 25 mm, preferably 0.05 mm to 12 mm, preferably 0.05 mm to 1 mm.
  • capillaries have an inner diameter of 0.01 mm to 3 mm, preferably 0.05 mm to 0.8 mm, wherein the capillaries are preferably at least partially made of glass or other at least partially transparent materials.
  • the volume of liquid may also be provided as drops on a slide.
  • the sample chamber has a volume of 0.001 ⁇ l to 1000 ⁇ l, preferably from 0.1 ⁇ l to 200 ⁇ l, preferably from 1 ⁇ l to 10 ⁇ l, preferably from 1 ⁇ l to 6 ⁇ l.
  • the surface of the liquid volume is preferably formed by the interface between liquid volume and a surface of the sample chamber or, for example, by the interface between liquid volume and a surface of the slide.
  • the liquid used is preferably an aqueous solution, but is not limited thereto.
  • the electromagnetic radiation preferably has IR radiation or only wavelengths in the IR range and is preferably generated by a laser and / or an LED.
  • the incident radiation may be parallel and / or anti-parallel to gravity and / or may include a component oriented perpendicular to gravity.
  • the temperature gradient is generated in a small range, preferably in a range of 0.00001 mm 2 to 1 cm 2 , preferably generated in a range of 0.0001 mm 2 to 12 mm 2 .
  • a detection area for measuring properties of the liquid or particles in the liquid may be spaced from the area in which the radiation is irradiated.
  • the detection area may be spaced at least 0.01 mm from the incident beam, the distance preferably being measured perpendicular to the direction of irradiation.
  • the detection area and the irradiation area may also overlap.
  • the detection surface is often larger than a well-focused laser beam (for example, 2 ⁇ m diameter can be achieved with IR). Therefore, in this embodiment, preferably the entire detection surface is swept by the convection flow.
  • the overlap of the detection area and the irradiation area is, for example, in the structures Fig. 5 or Fig. 6 applicable. Since everything is focused by the same optics, the heating focus of the IR radiation is preferably within the detection range
  • Preferred flow velocities of the convection flow are in the range of 0.0001 mm / s to 10 mm / s, preferably 0.0005 mm / s to 2 mm / s.
  • the mixing method according to the invention is particularly advantageous when it is combined with additional measuring methods.
  • the present invention also relates to a method for investigating molecular interactions on and / or in a thin layer in a liquid volume according to claim 7.
  • a sample chamber is provided for carrying out such a measurement in the form of a capillary, pipette tip, multiwell plate or a microfluidic chip.
  • the interaction is preferably measured by means of reflectometric interference spectroscopy (RlfS), surface plasmon resonance (SPR), enzyme-linked immunosorbent assay (ELISA), quartz crystal microbalances (QCM), and / or surface acoustic wave, (surface acoustic wave; SAW).
  • the measurement of the interaction may be at least one method from the group: Reflectometric Interference Spectroscopy (RlfS), Bio-Layer Interferometry (BLI), Surface Plasmon Resonance (SPR), Quartz Crystal Microbalance (QCM), Surface Acoustic Wave, SAW, Enzyme linked immunosorbent assay (ELISA), nanopores or transistors (Next Generation Sequencing).
  • the present invention also relates to a device for mixing liquids or particles with a liquid, in particular for carrying out a method described above, according to claim 9.
  • a system with a device for mixing and a device for measuring is disclosed, wherein the Measuring device preferably for measuring a specific or nonspecific interaction of the particles with a surface / interface of a sample chamber or a slide is used.
  • FIG. 3 shows by way of example the detection area 80 for measurements of the specific and unspecific interaction of particles.
  • the sample chamber 45 shown is an example of a capillary.
  • the detection area 80 is preferably located at the surface / interface of the measurement volume within the capillary 45, i. on the inside of the sample chamber 45.
  • the detection area 80 can be selected around the area of an irradiated IR radiation 30 such that it is smaller, larger or the same size as the area swept by the thermal convection 90.
  • the detection region 80 may be, for example, a thin layer and contain, for example, antibodies for the specific detection of antigens. In other words, the detection region is located on the surface of the liquid or the surface of the capillary 45.
  • the detection region 80 may, for example, also be composed of several different thin layers, which differ, for example, in their refractive index, polarizability or their fluorescence.
  • the convection is preferably adjusted so that no depletion layer or enrichment layer is formed in the detection area.
  • the thermal convection can be adjusted so that it particles from far outside the Detection area, for example, a few millimeters away, transported into the detection area.
  • Order can be varied, but it is crucial that there is a certain distance between IR laser focus (determines the "convection rollers") and the place where the interaction is detected on the surface. The distance between them is important as the IR laser produces different thermal convection currents depending on the power and chamber thickness and chamber geometry. You have to set it all up so that you have the right thermal convection currents at the interaction site (to avoid the depletion layer of the molecules).
  • FIG. 4 shows an exemplary arrangement in which the inventive method is applied.
  • Infrared laser radiation 30 is radiated from below into a sample chamber 45 having a liquid volume, here an aqueous solution with particles 50, and generates a thermal convection 90 in the sample chamber 45.
  • the flow velocities in the liquid are represented by corresponding vectors.
  • a symmetrical convection around the irradiated laser beam 30 can be seen.
  • the reflectometric interference spectroscopy (RIfS) method is used as a detection method for measuring the interaction of the particles 105 dissolved in the liquid with a thin layer (shown hatched) of functionally immobilized molecules / particles 103.
  • RIfS is a physical method based on the interference of white light on thin layers. This method is used in practice, for example, to investigate molecular interactions.
  • the basic measuring principle corresponds to the Fabry-Perot interferometer.
  • RIfS is mainly used as a detection method in chemo- and biosensors.
  • As sensitive layers mostly non-selective measuring polymers are used, which sort analytes either by their size (so-called molecular sieve effect in microporous polymers) or due to different polarities (eg functionalized polydimethylsiloxanes).
  • polymers such as polyethylene glycols or dextranes are applied to the layer system and immobilized thereon recognition structures for biomolecules.
  • all substance classes can be used as recognition structures (proteins such as antibodies, DNA / RNA such as aptamers, small organic molecules such as estrone, but also lipids such as phospholipid membranes).
  • a carrier 46 which may be part of the sample chamber 45.
  • the sample to be examined is provided as a drop or liquid layer on the carrier.
  • the carrier 46 may be made of glass or plastic, for example.
  • the thin layer to be examined comprising a layer 103 of functionally immobilized molecules and another layer 102 of molecules, which is arranged between the layer 103 and the carrier 46, is shown schematically.
  • the layer 102 serves, in particular, for better adhesion of the thin layer on the carrier 46.
  • the layer / layer 102 of molecules (eg PEG or dextran, etc.) which is arranged between the layer 103 and the carrier 46 (illustrated schematically) can be referred to, for example Spacer and / or serve as immobilization aid for the functional molecules of layer 103.
  • the layer 102 also serves in particular for better adhesion of the layer / thin layer 103 on the carrier.
  • sample particles 105 can bind.
  • the thickness of the thin layer increases, the distance of its upper boundary surface 104 to the phase boundary between the thin layer and the support (or the lower boundary surface of the thin layer) is larger.
  • irradiated light 31 which is used for the measurement, we now also reflected at the boundary surface 104 after connection of the sample particles 105.
  • the boundary surface 104 is formed opposite to the solution with particles 50, for example, when the particles from the aqueous solution bind to the functionally immobilized molecules in the thin layer 103.
  • the reflected beam 113 at this boundary surface 104 is shown schematically.
  • the reflected beams 112, 111a, 111b and 110 are also shown, which are reflected at interfaces that lie below the boundary surface 104. Since the incident light has to cover a greater path length up to the boundary surface 104, a shift of the interferogram, which is produced by the superimposition of the reflected electromagnetic radiation 110, 111 a, 111 b, 112 and 113, results. This shift can be measured with time resolution, which allows conclusions about the change in layer thickness and thus the interaction of the dissolved particles 105 with the functionally immobilized particles 103.
  • the particles 105 in the aqueous solution are biomolecules such as DNA, RNA, proteins, antibodies, antigens, etc. Small molecules, nanoparticles, polymers, peptides, PNA, etc. or even cells, viruses, bacteria, vesicles, Liposomes, microbeads, nanobeads, nanodiscs, etc.
  • FIG. 5 shows by way of example the application of the method in a concrete experimental arrangement, but without being limited thereto.
  • the reference numeral 1 denotes a light source used for the measurement.
  • the light source 1 may be one or more LEDs, one or more lasers and / or one or more SLEDs (superluminescent LED).
  • the light of the light source 1 serves primarily to irradiate a sample 50 to be examined, preferably to irradiate it vertically.
  • the light emitted by the light source 1 can be changed by means of known optical means, for example by means of a diffuser 4 and / or a lens system (not shown).
  • a diffuser 4 can be used to evenly distribute the light and a lens system can be used to focus the light as desired.
  • the light passes through a polarizer 5, for example for producing linearly polarized light.
  • the light can also pass through a filter 14, so that a light beam 31 with defined properties is irradiated onto the sample 50.
  • the filter 14 may, for example, be a wavelength filter, for example a bandpass filter, or a longpass filter or a shortpass filter.
  • the beam splitter 7 is used to divide the light beam into a measuring beam or measuring beam path 9 and a reference beam or reference beam path 11, the measuring beam path being shown at the bottom and the reference beam path 11 pointing to the left to the reference beam.
  • Detector assembly 19 ' is shown.
  • the beam splitter 7 preferably has a polarizing property. However, the beam splitter 7 may also be omitted in certain embodiments. Then also eliminates the reference beam path 11, or the whole reference branch of reference beam path 11, reference lens system 17 ', reference detector filter 23' and reference detector 19 '.
  • the reference detector array 19 ' may be, for example, a photodiode, a photomultiplier (photomultiplier, photomultiplier tube, PMT), a charge coupled device (CCD) camera, a complementary metal (CMOS) CMOS Oxide Semiconductor; complementary metal oxide semiconductor), a diode array, or an avalanche photodiode.
  • the reference branch may have a reference lens system 17 'in front of the reference detector arrangement 19' for imaging / focusing on the reference detector arrangement 19 'and / or a reference detector filter 23', for example a bandpass filter, or a longpass filter or a short-pass filter.
  • the measuring beam path 9 can, before it hits the sample 50, be changed with additional optical means, which are arranged after the beam splitter 7.
  • additional optical means which are arranged after the beam splitter 7.
  • a second optical correction element 36 is shown, which can optionally be extended with a lens or a lens / lens system, for example, the phase shift, polarization change and / or optical path change may be accompanied by the (second) beam splitter 34 for coupling the infrared laser radiation, to compensate / correct.
  • the second optical correction element 36 and / or the optional lens or the optional lens system can also serve to focus the beam paths on the sample 50.
  • the sample 50 may be deposited on a carrier 46 as a droplet or in a sample chamber 45, as in FIGS FIGS. 2 to 4 shown provided.
  • a sample chamber may be a capillary, a microcavity, a reaction vessel ("Eppi"), a microfluidic device, or a pipette tip without being limited thereto.
  • the sample 50 to be investigated is preferably a liquid, preferably an aqueous solution, with particles 105 present therein (see US Pat Fig. 4 ), which may be in dissolved or undissolved form.
  • the support 46 is preferably at least partially transparent, with the illustrated support 46 being a slide glass formed from a glass on which a thin layer 103 is formed.
  • the thin layer 103 to be examined comprises, for example, a layer of functionally immobilized molecules.
  • the thin layer 103 is influenced by the sample 50 to be examined. For example, interaction of the molecules on the thin layer 103 with the corresponding particles 105 in the sample leads to a layer thickness change (see Fig. 4 ). This change in layer thickness influences the light conducted via the measuring beam path 9 onto the carrier 46 and reflected on the surface of the thin layer, which light is deflected by the beam splitter 7 and imaged on a detector arrangement 19.
  • the measuring branch (to the right of the beam splitter 7) is preferably similar to the detector arrangement 19 or even identical to the reference branch (to the right of the beam splitter 7).
  • the detector assembly 19 for example, a Photodiode, a photomultiplier (photomultiplier tube, photomultiplier tube, PMT), a CCD camera (Charge-Coupled Device), a complementary metal oxide semiconductor (CMOS), a diode array or an avalanche Be photodiode.
  • the measuring branch may have a lens system 17 in front of the detector arrangement 19 for imaging / focusing on the detector arrangement 19 and / or a detector filter 23, for example a bandpass filter, or a longpass filter or a shortpass filter.
  • the multiple reflection is preferably used at the interfaces of the thin layer for the measurement, wherein the reflected steel with the two detector arrays 19, 19 'are detected.
  • the second beam splitter 34 is arranged below the first beam splitter 7.
  • the second beam splitter 34 is shown above the first beam splitter 7 by way of example.
  • the infrared laser radiation 30, which is emitted by the laser 32 and optionally with an optical means 33, for example lenses, or lens system, for example, collimator for parallelization and / or focusing of the infrared laser radiation is changed, in the measuring beam path 9 coupled.
  • the beam splitter 34 may be similar to the beam splitter 7, be the same, or have other properties.
  • the beam splitter 34 may be a dichroic mirror or a "hot mirror". It is again explicitly emphasized here that the irradiated electromagnetic radiation 31 is used for the measurement, whereas the irradiated electromagnetic radiation 30 serves to generate a convection.
  • the experimental arrangement described above is only one of many examples according to the invention and the invention is by no means restricted to a specific arrangement of the optical means described above.
  • the experimental setup is not limited to the orientation shown. So the light can come from the bottom left or right instead of from above and the corresponding optical Means be moved or rotated accordingly.
  • the order of the optical means is not limited to the illustrated embodiment and can be changed according to the desired irradiation and measurement characteristics.
  • a transmission can also be measured according to the invention.
  • the convection generation method of the present invention can be easily implemented even in such a transmission test setup.
  • the one to Fig. 5 shows very similar experimental arrangement, but irradiates the light of the IR laser at a different location.
  • FIGS. 2A and 2B show by way of example the influence of the orientation of an irradiated IR laser beam 30 relative to gravity on the thermal convection within a sample chamber 45, in which an aqueous solution 50 with particles dissolved therein (not shown) is located. Also marked are the velocity vectors (arrows) and the flow lines (lines) of the thermal convection 90.
  • FIGS. 7A and 7B show by way of example the irradiation of radiation, preferably IR radiation, for example of laser radiation 30 in the filled with an aqueous solution 50 "well" 45 a multiwell plate, such as a 96, 384 or 1536 well multiwell plate.
  • the irradiated IR radiation 30 generates a thermal convection 90 in the irradiated sample chamber "well" 45.
  • the IR radiation 30 is irradiated through a transparent bottom 47 of a multiwell plate.
  • this multiwell plate may have a non-transparent bottom 48, but also, for example, a transparent bottom or even a partially transparent bottom.
  • FIG. 8 shows by way of example the application of the disclosed method in a concrete experimental arrangement, but without being limited thereto.
  • the reference numeral 1a denotes a light source used for the measurement.
  • the light source 1a may be one or more LEDs, one or more lasers, and / or one or more SLEDs (Super Luminescent LED).
  • Reference numeral 1b denotes a light source used for the measurement.
  • the light source 1b may be one or more LEDs, one or more lasers, and / or one or more SLEDs (Super Luminescent LED).
  • the light source 1b has a different wavelength or a different wavelength range than the light source 1a.
  • the light of the light source 1a and / or 1b is preferably used to irradiate a sample 50 to be examined.
  • the light emitted by the light sources 1a and / or 1b can be changed by means of known optical means, for example by means of a lens 26 and / or a lens system (not shown) or an aperture (not shown) or a polarizing filter.
  • the light of the light source 1a preferably passes through an excitation filter 25, preferably a bandpass filter
  • the light of the light source 1b preferably passes through an excitation filter 24, preferably a bandpass filter.
  • the excitation filter 24 has a different transmission range than the excitation filter 25.
  • Reference numeral 23 refers to an optional detector filter, for example a bandpass filter or a longpass filter or a shortpass filter or a dualpass or multipass filter. In the case of fluorescence, the filter 23 may also be referred to as an emission filter.
  • the light of the two excitation light sources is preferably combined, for example, reflected by the dichroic mirror 28 and then preferably by another dichroic mirror 29 in the direction of the object lens system 38.
  • the dichroic mirror 29 is also preferably used to separate the excitation light from the detection light.
  • the excitation light preferably passes through another dichroic mirror 34 ("hot mirror") and is then preferably from the object lens system 38 through the transparent bottom 47 of the multiwell plate into the aqueous solution 50, in the sample chamber 45, preferably a " Well "a multiwell plate, focused.
  • the excitation light excites the fluorescence of fluorescent particles 105, for example proteins with intrinsic fluorescence and / or fluorescence-labeled biomolecules or other fluorescent substances.
  • the fluorescent light is collected by the object lens system 38, preferably a lens, a combination of lenses or a microscope objective, then passes through the dichroic mirrors 34 and 29, then the detection filter 23, preferably an emission filter, for example a bandpass filter, dual pass filter or multipass filter, and is then focused by a lens 17, for example an asphere, onto the detector 19, for example a photodiode, a PMT, a CCD camera, a CMOS camera, a diode array, an avalanche photodiode.
  • the detection filter 23 preferably an emission filter, for example a bandpass filter, dual pass filter or multipass filter, and is then focused by a lens 17, for example an asphere, onto the detector 19, for example a photodiode, a PMT, a CCD camera, a CMOS camera, a diode array, an avalanche photodiode.
  • the infrared radiation for generating the thermal convection is preferably generated by means of a fiber-coupled infrared laser 32.
  • the fiber of the laser is coupled, for example by means of a fiber coupling 27, preferably with collimating functionality, in the optics or the optical system.
  • the infrared radiation may be changed by known optical means, for example by means of a lens 26 and / or a lens system (not shown) or an aperture (not shown) or a polarizing filter. For example, it may be parallelized or focused by the lens 26, for example an asphere.
  • the infrared radiation is mirrored by the dichroic mirror 34 ("hot mirror") in the object lens system 38.
  • the object lens system 38 then focuses the infrared radiation 30 through the transparent bottom 47 of the multiwell plate into the aqueous solution 50 of the sample chamber 45, preferably a "well" of a multiwell plate.
  • the multiwell plate is preferably a 96 well plate or 384 well plate or 1536 well plate.
  • the infrared radiation 30 generates a defined thermal convection 90 there for the mixing of the particles 105 in the aqueous solution 50.
  • the particles are, for example, biomolecules such as DNA, RNA, PNA, proteins, antibodies, antigens or small molecules, cells, viruses, bacteria, microbeads, nanobeads, nanoparticles, polymers, peptides.
  • the device can also be used for the detection and quantification of biomolecule aggregation, for example, the aggregation of proteins or therapeutic Antiköprern.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Electromagnetism (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Claims (9)

  1. Procédé de mélange de liquides (50) ou de particules avec un liquide (50), comprenant les étapes suivantes :
    a. préparation d'un volume de liquide (50) dans une micro-cavité d'une micro-plaque de 384 ou de 1536 cavités ;
    b. préparation de plusieurs LED IR
    c. production d'un écoulement à convection thermique au niveau d'au moins une interface entre le volume de liquide et la micro-cavité par irradiation simultanée d'un rayonnement IR (30) des plusieurs LED dans plusieurs des cavités,
    moyennant quoi, l'écoulement à convection permettant de réduire une couche d'appauvrissement au niveau de l'interface ou d'augmenter une couche d'enrichissement au niveau de l'interface, de façon à ce que les procédés de mesure basés sur les interfaces soient améliorés.
  2. Procédé selon la revendication 1, le liquide (50) étant une solution aqueuse.
  3. Procédé selon l'une des revendications précédentes, le rayonnement (30) étant dirigé parallèlement et/ou anti-parallèlement par rapport à la gravité et/ou comprenant une composante qui est orientée perpendiculairement à la gravité.
  4. Procédé selon l'une des revendications précédentes, le rayonnement (30) appliqué permettant d'obtenir un gradient de température de 0,001 K/µm (=1 K/mm) à 2 K/µm (=2000 K/mm).
  5. Procédé selon la revendication 4, un intervalle de détection (80) pour la mesure de propriétés du liquide ou des particules dans le liquide étant éloigné de l'intervalle dans lequel le rayonnement (30) est appliqué.
  6. Procédé selon l'une des revendications précédentes, des vitesses d'écoulement de 0,0005 mm/s à 2 mm/s étant obtenues à l'intérieur de l'écoulement à convection.
  7. Procédé d'examen d'interactions moléculaires sur et/ou dans une couche mince (80) dans un volume de liquide au moyen d'un procédé basé sur les interfaces, comprenant les étapes suivantes :
    - préparation d'au moins un volume de liquide (50) avec des particules à l'intérieur dans une micro-cavité d'une micro-plaque de 384 ou de 1536 cavités ;
    - préparation de plusieurs LED IR ;
    - application d'un rayonnement IR des plusieurs LED IR dans les volumes de liquide (50) des plusieurs micro-cavités de la micro-plaque pour la génération de l'écoulement à convection,
    - mesure d'une interaction spécifique ou non spécifique des particules avec une interface de la micro-cavité à l'aide du procédé de mesure basé sur les interfaces,
    - caractérisation de l'interaction des particules à l'aide de la mesure.
  8. Procédé selon la revendication 7,
    i) la mesure de l'interaction ayant lieu au moyen d'une spectroscopie à interférence réflectométrique (RifS) ;
    ii) la mesure de l'interaction ayant lieu au moyen d'une résonance de plasmon de surface (en anglais : Surface Plasmone Resonance SPR) ;
    iii) la mesure de l'interaction ayant lieu au moyen d'une Immunosbasorption par Enzyme Liée (ELISA) ;
    iv) la mesure de l'interaction ayant lieu au moyen de micro-balances à cristaux de quartz (Quartz Crystal Microbalance ; QCM) ;
    v) la mesure de l'interaction ayant lieu au moyen d'une onde acoustique de surface (surface acoustic wave ; SAW) ; ou
    vi) la mesure de l'interaction étant au moins un procédé sélectionné dans le groupe constitué de : spectroscopie à interférence réflectométrique (RifS), Interférométrie Bio-Layer (BLI), résonance de plasmon de surface (Surface Plasmone Resonance SPR), micro-balances à cristaux de quartz (Quartz Crystal Microbalance ; QCM), onde acoustique de surface (surface acoustic wave ; SAW), Immunosbasorption par Enzyme Liée (ELISA), nanopores ou transistors (Next Generation Sequencing).
  9. Dispositif de mélange de liquides (50) ou de particules avec un liquide (50), pour l'exécution d'un procédé selon l'une des revendications 1 à 8, avec :
    a. une micro-plaque de 384 ou de 1536 cavités pour le logement d'un volume de liquide (50) ; et
    b. plusieurs LED IR pour l'émission d'un rayonnement IR (30) ;
    c. un dispositif pour l'application du rayonnement IR (30) à plusieurs volumes de liquide de la micro-plaque.
EP14162100.3A 2013-03-27 2014-03-27 Procédé et dispositif destinés au mélange sans contact de liquides Active EP2783747B1 (fr)

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US20140293731A1 (en) 2014-10-02
ES2677975T3 (es) 2018-08-07

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