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    • 专利摘要:
    In a method for determining biological or other properties of samples by means of a microplate reader, the samples are arranged in wells (112) of a microtiter plate (110). The method comprises filling wells of a microtiter plate with samples that contain at least one sample substance in a liquid medium, heating samples by means of a heating device, arranging the microtiter plate in a measuring position within a measuring chamber of the microplate reader and examining samples during and / or after heating in at least one operating mode of the microplate reader by measuring radiation emitted from the samples. The method is characterized in that microwave radiation is used to heat the samples. A system (100) suitable for carrying out the method has a heating device (190) for heating samples which are located in wells (112) of a microtiter plate (110). The heating device comprises at least one microwave source (160-1, 160-2) for generating microwave radiation, which can be radiated onto samples for heating.
    公开号:CH711376B1
    申请号:CH00962/16
    申请日:2016-07-26
    公开日:2021-02-15
    发明作者:Frank Schleifenbaum Dr
    申请人:Berthold Tech Gmbh & Co Kg；
    IPC主号:
    专利说明:

    AREA OF APPLICATION AND STATE OF THE ART
    The invention relates to a method for determining properties of samples by means of a microplate reader, wherein the samples are arranged in a matrix arrangement in wells of a microtiter plate, and a system for performing the method. A preferred field of application is the determination of biological properties of samples.
    In modern biology, a variety of sample multiplex methods are used in which the samples to be examined are arranged in a matrix arrangement in wells of a microwell plate and are examined either sequentially or in parallel with different, mostly contact-free optical analysis methods . The types of samples examined are extremely diverse and can range from homogeneous solutions to immobilized cells. The latter in particular, but also other special sample systems (“assays”), require a temperature that is set as precisely as possible for an optimal reaction or for optimal growth. Modern microplate readers therefore have heating functions by means of which the samples in the microplate can be brought to a defined temperature and kept at this temperature.
    In conventional systems, this temperature control is achieved by electrical current flowing through heating coils, which generate a temperature radiation due to conduction losses through the ohmic resistance of the heating element. The heat generated by means of this electrical resistance heating is transferred into the interior of a heating chamber by natural air flow and is thus transferred to the sample located there. Sometimes a fan is used to homogenize the heat distribution, which distributes the heated air evenly in the heating chamber. The amount of current that flows through the heating resistor is regulated by an electrical thermal sensor, which compares a set target temperature with the current actual temperature recorded by means of a thermocouple and adjusts the current accordingly. In this way, e.g. living cells can be examined at an ideal 37 ° C. Furthermore, kinetic studies can be carried out at different temperatures and DNA hybridizations can be controlled. Furthermore, some assay formats require operating at elevated temperatures for optimal performance.
    US 2012/0300194 A1 shows a universal multidetection system for microtiter plates with heating devices for temperature control of samples.
    TASK AND SOLUTION
    [0005] It is an object of the invention to provide a method and a system for determining properties of samples which, compared to conventional methods and systems, create improved examination possibilities using temperature control of samples. In particular, the method and the system should be suitable for determining biological properties of the samples.
    This object is achieved by a system according to claim 1 and a method according to claim 14. Advantageous further developments are given in the dependent claims. The wording of all claims is incorporated into the content of the description by reference.
    In the method, microwave radiation is used to heat samples that are to be examined before heating, at the same time as heating and / or after heating by means of at least one optical examination method by measuring the radiation emitted by the sample. The samples (some or all) are preferably heated or warmed exclusively by irradiating in microwave radiation.
    A system suitable for carrying out the method has a heating device for heating samples that are located in the well of a microtiter plate. The heating device comprises at least one microwave source for generating microwave radiation, which can be radiated onto samples for heating. In addition to the devices for generating the microwave radiation, the system does not require any further heating devices, in particular no radiant heating device and no heating device operating via convection or heat conduction.
    The use of microwave radiation for heating samples to determine biological and / or other properties of the samples offers specific advantages over the methods and systems previously used for this purpose. The advantages are based, among other things, on the type of heat generation and the type of heat transfer. Since with the conventional methods the heat reaches the sample (s) only indirectly via the ambient air, the heating of the sample (s) usually takes place relatively slowly. The area around the sample is also heated. Conversely, a later cooling down to room temperature can take a long time, since a large volume and large surface areas (e.g. bounding walls) with a correspondingly high heat capacity have to be cooled by heat radiation, convection and / or active air transport. Because of the slow warm-up and cool-down times, setting an exact temperature and / or temperature control can be difficult.
    In the claimed invention, microwave radiation is used for sample heating and / or for temperature control of samples. This can increase the efficiency of the sample heating. In the ideal case, practically only the sample to be examined can be heated, while the environment can be kept essentially at ambient temperature. This can also be referred to as direct heating and is achieved in that energy is deposited directly, without contact and essentially exclusively in the sample.
    By using suitable microwave radiation it can also be achieved that the biological and / or chemical integrity of the samples is not affected, in particular because there is no fear of resonant excitation of individual molecular bonds.
    Since, for example, biological samples are usually examined in low-viscosity liquids with a permanent dipole moment (especially in water, aqueous solutions, possibly also in ethanol), it is advantageous to use radiation for heating that essentially only interacts with the liquid which in turn acts as a direct energy carrier.
    Since with this type of energy transfer on the one hand the distances to be bridged are very small, since the heat only has to be transported within the sample volume, and at the same time the shock transfer in the condensed phase is much more efficient than in gases, one obtains a high degree of efficiency for the Energy transfer from the solvent (eg water) to the sample.
    In this application, the term “microwave radiation” refers to electromagnetic radiation from the frequency range from approx. 1 GHz to 300 GHz, which corresponds to wavelengths of approx. 300 mm to 1 mm. Within the scope of the claimed invention, wavelengths of the so-called 23 cm band, i.e. wavelengths between 2320 and 2450 MHz, are preferably used to heat the samples to be examined. In particular, microwave radiation with a frequency of approximately 2.45 GHz can be used. For these frequencies, the penetration depth in aqueous or alcoholic media is sufficiently great for a largely uniform heating of a sample in the typical format of microtiter plates. If necessary, microwave radiation with frequencies up to approx. 900 MHz can also be used.
    It may be sufficient to use a single microwave radiation source and to use it for heating. In some method variants, it is provided that in a heating phase microwave radiation from a first microwave source and at least one separate second microwave source are radiated at the same time. This enables better control of the spatial field distribution of the microwave radiation in the area of the samples. If necessary, it can be achieved that, on average over time, essentially the same amount of energy is deposited in several or all samples, so that the respective samples concerned are tempered under comparable conditions. A selective heating of individual samples or of subgroups of the samples is also possible. Two separately controllable microwave sources can also be used alternatively to one another or staggered in time.
    In some embodiments of the system, the heating device has a first microwave transmitter antenna and a second microwave transmitter antenna that is spatially separated therefrom. This enables better control of the spatial field distribution and thus an adaptation to the distribution of samples in a microtiter plate.
    It is possible that the spatial field distribution does not change significantly during a heating phase. For this purpose, the heating device can contain a microwave source or a plurality of microwave sources which work with fixed, preset control parameters.
    It is also possible for the first and the second microwave source to be controlled in an amplitude-modulated and / or phase-modulated manner in such a way that the first and the second microwave source generate a time-dependently varying field distribution of microwave radiation. In a given time window, for example, individual samples or spatially connected subgroups of samples can be heated, while other samples are not heated at the same time. The spatial position of the sample (s) captured by microwave radiation can be varied with the aid of a time-dependent control. This can increase the flexibility when specifying temperature profiles.
    This variable control of the heating effect can be achieved in a system in that the heating device has a first microwave source and at least one separate second microwave source. An associated microwave control device can be configured so that the first and the second microwave source can be controlled in an amplitude-modulated and / or phase-modulated manner so that the first and the second microwave source can generate a time-dependently varying field distribution of microwave radiation.
    In one class of systems, the heating device has a heating chamber with a metallic shield which is substantially impervious to microwave radiation. The heating chamber can be dimensioned so that one or more microtiter plates can be accommodated within the heating chamber for heating. The metallic shield can ensure that the microwave radiation used to heat samples remains within the area of the shield and does not penetrate to the outside. In this way, components of the system that are outside the heating chamber can be protected against microwave radiation.
    In some variants, the heating chamber is a separate chamber from the measuring chamber. In these cases a transfer device can be provided for transferring microtiter plates between the heating chamber and the measuring chamber. The heating and the measurement are spatially and temporally separated in these cases. The heating chamber can be provided within a separate heating unit, which can be combined with the microplate reader as an additional device to form a system. It is also possible to accommodate a heating chamber and a separate measuring chamber in a common housing. A solution with separate chambers offers, among other things, the possibility of retrofitting.
    In other variants, the measuring chamber is designed as a heating chamber with a metallic shield which is essentially impervious to microwave radiation. This allows a combined measuring and heating chamber to be created. In these cases a microtiter plate does not have to be moved between heating and measuring. The heating can precede the actual measurement, so that the heating is completed before the measurement begins. It is also possible to carry out at least part of the heating during a measurement or to carry out a measurement during a heating phase.
    In many variants, the microwave radiation is generated in such a way that the samples (one or more) are located in the region of the far field of the associated microwave generation. However, this is not mandatory. Heating in the near field is also possible.
    In some method variants, a non-propagating microwave evanescent field is generated for heating samples, which has a spatial extent that allows selective heating of individual samples. In a corresponding system, this can be achieved in that the heating device has a near-field hollow waveguide which is coupled to a microwave source and has a radiation exit opening which has an effective diameter of less than half the wavelength of the microwave radiation. The diameter can for example be in the range from approx. 0.5 mm to approx. 6 mm. The geometry is chosen so that the microwave radiation cannot propagate out of the near-field hollow waveguide into the surroundings, but is reflected back into the near-field hollow waveguide. Only an evanescent portion can couple out in the area of the radiation exit opening and its field strength decreases exponentially with increasing distance from the radiation exit opening. As a result, the spatial resolution of the area exposed to microwave radiation in this way is determined exclusively by the size of the radiation exit opening and is no longer diffraction-limited. The evanescent microwave field can be used for local heating of a sample.
    For the most accurate possible setting of sample temperatures, it is useful to measure the temperature of samples. Although contact-based measurement is possible using measuring sensors that can be in contact with the samples and / or the microtiter plate, preferred method variants are characterized by a contactless measurement of the temperature of samples to determine sample temperature values.A contactless temperature measurement can impair the sample as a result of the temperature measurement can be avoided even with small sample volumes. It is possible to determine the temperature of individual samples or subgroups of samples.
    [0026] The determined sample temperature values are preferably used to regulate the temperature. For this purpose, the microwave radiation can be controlled as a function of the sample temperature values or values derived therefrom.
    When using microwave radiation as an energy source for heating samples, the samples can be heated locally. The temperature can be measured without contact, for example using an infrared camera or an infrared diode or an infrared diode array and, if necessary, regulated on the basis of the sample temperature values. Since this radiation-based temperature measurement works in a different wavelength range (infrared range) than the microwave radiation used for heat excitation, the two types of radiation do not influence each other and the temperature measurement can be carried out continuously or intermittently, even while the sample is exposed to microwave radiation. This promotes particularly precise temperature control.
    As already mentioned, there are exemplary embodiments in which the measuring chamber is designed as a heating chamber with a metallic shield which is essentially impervious to microwave radiation, so that the heating can take place within the measuring chamber. In this case, separate measures can be provided to ensure that components of the measuring devices for examining the samples that are sensitive to microwave radiation cannot be impaired in their function and / or damaged by the microwave radiation.
    Some measuring devices include, for example, a polychromatic light source from which an optical excitation path for the transmission of spectral components of light from the light source is guided as excitation light into a measuring position in which a sample is or can be arranged. Furthermore, an optical emission path is provided for the transmission of emission light emitted by the sample to a detector. With such devices, for example, fluorescence properties of samples can be determined. Some measuring devices of this type have at least one optical path (excitation path and / or emission path) which leads through an opening in the metallic shielding of the heating chamber that is impervious to microwave radiation. Suitable dimensioning and / or shielding of the opening can ensure that no microwave radiation can penetrate outside of the heating chamber in the area of the opening. In some variants, the optical path leads through a light guide, which is guided through an opening in the metallic shielding of the heating chamber that is impervious to microwave radiation.
    In some exemplary embodiments, it is provided that microchemical processes, for example simple reaction or separation steps, are carried out in a multi-label device (microplate reader) with a microwave source as the central energy source. The system can have suitable facilities for this purpose.
    These microchemical processes are not limited to biological systems, but can in particular also include reactions in which test conditions such as the stoichiometry of the reactants, the temperature, the temperature gradient and / or the reaction time are permuted. An exemplary embodiment from the field of non-biological samples provides for polymerisation reactions to be carried out, since a relatively small number of reaction partners are used in this type of reaction and the specific properties of the polymer end product are achieved by varying the test parameters listed. A microplate reader with microwave heating is particularly suitable for carrying out these reactions, since the microplate format allows several samples to be examined in parallel and the combination with microwave heating provides the specific advantages described above. The possibility of directly following the reaction or checking the reaction result is given in microplate readers, since polymer reactions often change optical material properties such as the refractive index, absorption or autofluorescence, which are recorded and quantified with the optical measuring devices integrated in a microplate reader according to the invention can be.
    Some method variants are characterized in that the heating of the microwave radiation is used to modify the sample in its molecular structure. This is preferably done indirectly, in that the solvent is heated up and processes are set in motion by increasing the temperature which can modify the molecular structure of the sample substance. Among other things, it is possible to use the heating by microwave radiation to separate heterogeneous sample systems into individual components, e.g. by means of a distillation between directly or indirectly neighboring wells of a microtiter plate. The energy introduced into the sample via microwave radiation can be kept so low that direct modification of the sample substance by microwave radiation can be avoided.
    In the system, such method variants can be made possible, for example, that an attachment is or is arranged over one or more wells (sample receptacles) in such a way that evaporated liquid condense on the walls of the attachment and drip back into the wells or the sample receptacle can. It is also possible that an attachment is or is arranged above one or more wells (sample receptacles) in such a way that evaporated liquid can condense on the walls of the attachment and is deflected so that it can at least partially drip into an indirectly or directly adjacent sample receptacle . The corresponding attachments should be made of a material that cannot be heated by microwave radiation (e.g. glass or plastic) and can be viewed as accessories or as part of the system.
    By appropriate dimensioning, the attachments can be adapted to the relatively small dimensions of wells of a microtiter plate. In particular, an outer diameter of an attachment in its inlet area that can be placed on a bowl should be slightly smaller than an inner diameter of the bowl at its open end, so that the attachment with its inlet area can be inserted into a bowl.
    BRIEF DESCRIPTION OF THE DRAWINGS
    Further advantages and aspects of the invention emerge from the claims and from the following description of preferred exemplary embodiments of the invention, which are explained below with reference to the figures. 1 shows schematically components of a system which has a heating chamber that is separate from a measuring chamber; 2 shows schematically components of a system which has a combined measuring and heating chamber; 3 shows schematically components of a system which has a measuring device which has light guides for guiding excitation light into a measuring and heating chamber and emission light from the measuring and heating chamber; 4 shows schematically an exemplary embodiment of a near-field hollow waveguide for local heating of individual samples; 5 shows schematically a system with a near-field hollow waveguide for local heating of individual samples; 6 shows a further exemplary embodiment of a system with a near-field hollow waveguide; 7 shows a further exemplary embodiment of a system with a near-field hollow waveguide; 8 shows, in FIGS. 8A to 8C, different variants of a microchemical process that is carried out in a heating chamber using microwave radiation for the selective heating of individual samples; and FIG. 9 shows, in FIGS. 9A to 9C, different variants of another microchemical method which is carried out in a heating chamber using microwave radiation for the selective heating of individual samples.
    DETAILED DESCRIPTION OF THE EMBODIMENTS
    In Fig. 1 some components of a first embodiment of a system 100 for determining biological or other properties of samples are shown schematically.
    The samples to be examined are arranged in a rectangular matrix arrangement in wells 112 of a rectangular microtiter plate 110 and are to be examined sequentially or in parallel using one or more different non-contact optical analysis methods. The commercially available microtiter plate can for example consist of a plastic material such as polyvinyl chloride or polystyrene, or of glass and has a number of identically dimensioned wells in straight rows and columns, e.g. between 6 and 1536 wells, in the example 12 * 8 = 96 wells.
    The system 100 is set up, inter alia, to carry out methods of fluorescence spectroscopy. In addition to fluorescence measurements, other radiation-based measurement methods, for example luminescence measurements or absorption measurements, can also be carried out. The components used for this are not shown for reasons of clarity.
    The system 100 has a substantially cuboid, light-tight, lockable measuring chamber 120, which is dimensioned so that at least one microtiter plate can be accommodated within the measuring chamber so that one of the samples contained in the wells is in a measuring position using a positioning system can be brought. The positioning system has a cross table that can be moved horizontally in two dimensions with an integrated lifting device, so that the samples can be positioned in three dimensions.
    The measuring chamber is assigned measuring devices with the aid of which samples can be examined in at least one operating mode of the system by measuring radiation emitted from the samples.
    A primary light source 130 in the form of a xenon flash lamp with a short electrode spacing is arranged outside the measuring chamber. Depending on the application, it can also be a continuous wave lamp. The light source has a wide emission spectrum in the visible spectral range.
    An optical excitation path 132 with a flat deflecting mirror 133 leads from the light source to a measuring position 134 in which a sample 135 to be measured can be positioned for a measurement by positioning the microtiter plate (shown in dashed lines in a measuring position). The sample is located in a depression or a well of the microtiter plate. The optical elements of the optical excitation path 132, not shown in detail, serve to transmit spectral components of light from the primary light source as excitation light into the measurement position. The excitation light is radiated vertically from above into a well or into the sample.
    In the sample 135 there is a sample substance in aqueous solution. With the aid of the excitation light, the sample substance can be excited to emit fluorescent light which is shifted to lower energies or greater wavelengths compared to the excitation light. The extent of the spectral redshift is specific to the sample substance.
    The emission light (the emitted radiation) passes via an optical emission path 136 equipped with a parabolic mirror 137 to a detector 140 which, depending on the incident light, generates electrical signals which are fed to an evaluation unit (not shown) in order to characterize the emission light Evaluate sample spectrally. In the example, the detector comprises a photomultiplier.
    Furthermore, 100 absorption measurements can be carried out with the system. For this purpose, the light can be guided via the optical excitation path 132 through the sample, which is located in a microtiter plate with a transparent bottom. After passing through the sample, the passing light hits a light detector (not shown), typically a silicon photodiode with a broad spectral range.
    The system 100 is also suitable for measuring luminescence emission that is generated chemically, biologically or biochemically. For this purpose, starter substances that initiate light emission in a sample can be injected via injectors (not shown). The emitted light is guided to the detector 140 via the parabolic mirror 137 via the optical emission path 136.
    The system 100 includes a heating device 190 with which the samples held in a microtiter plate can be heated with the aid of microwave radiation. The heating device 190 includes a heating chamber 150 which is separate from the measuring chamber 120 and which is arranged next to the measuring chamber at a distance therefrom at the same height within the housing 105 of the system. A chamber wall 155 of the heating chamber encloses an essentially cuboid interior 152, which is dimensioned such that at least one microtiter plate fits completely into it. A metallic shield 154 is attached to the inside of the chamber wall in such a way that the interior 152 is sealed off from the environment with regard to the emission of microwave radiation. The shield 154 can, for example, comprise metal sheets which are joined together without any gaps and which are fastened to the inside of the chamber walls.
    In the interior 152 there is a first microwave transmitter antenna 162-1 which is connected to a first microwave source 160-1 and can emit microwave radiation generated by this into the interior 152. An optional second microwave transmitter antenna 162-2 is spatially separated from the first microwave transmitter antenna 162-1, for example on the opposite side, and is excited by a second microwave source 160-2 to emit microwave radiation into the interior. The microwave sources 160-1, 160-2 are connected to a control device 170 which is configured such that the first and the second microwave sources can be controlled in amplitude-modulated and / or phase-modulated manner independently of one another.
    In the example, the microwave sources are semiconductor-based microwave sources that can generate microwave radiation with a frequency of approximately 2.45 GHz and a nominal power in the range of approximately 50W. Alternatively, magnetrons of suitable power and frequency could also be used, for example.
    The heating device 190 includes a temperature measuring device 180 for the contactless measurement of the temperature of samples by detecting and evaluating infrared radiation. As a result, sample temperature values can be determined, on the basis of which the heating device can be controlled in order to achieve temperature regulation. In the example, the temperature measuring device 180 comprises an infrared diode array 182 which is attached above the receptacle for the microtiter plate outside the shielding and is connected to the control device 170. Small holes are made in the shield in the area of the infrared diode array, through which the infrared radiation can pass while the longer-wave microwave radiation is blocked.
    For the transfer of a microtiter plate between the heating chamber 150 and the measuring chamber 120, a transfer unit 175 is provided which can be controlled via the control device 170 of the system. The transfer unit has a plate holder 176 which can be moved horizontally on guide rails and which can hold a single microtiter plate in each case. The plate holder has a vertically movable frame 177 on which the microtiter plate can rest with two opposite edges. The microtiter plate can thus be transferred to other components, e.g. by placing it on a platform in the heating chamber. The transfer unit 175 also has drives for fine positioning of the microtiter plate received, so that a plate manipulator is present that can take over both the transfer and the fine positioning. The transfer unit can thus form a common unit with the cross table for sample positioning.
    The samples are heated exclusively by means of microwave radiation. Due to the dipole moment of the water molecules, exposure to electromagnetic radiation in the lower GHz range (corresponding to wavelengths in the range of a few centimeters), so-called microwave radiation, causes a force to act on the water molecule so that a torque acts on the water molecule and forces it to rotate. Heat is generated through friction with neighboring water molecules. With this consideration it is important that the radiation frequency used does not have to correspond to a rotational resonance frequency of the water molecule.
    With the help of the arrangement it can be ensured that the heating or the incubation of samples takes place in a separate, metallically conductive enclosed space (interior 152) which represents a cavity for the microwave excitation and thus corresponds to a hollow waveguide closed on all sides. A microtiter plate with the samples to be examined is moved into this cavity with the aid of the movable plate holder 176 and can be placed there in a heating position. The transfer unit can then leave the heating chamber. The interior 152 can then be closed off from the outside in a radiation-tight manner with the aid of a likewise shielded drawer. At the circumference of the drawer there are gaps that are a maximum of 1 mm wide and at least 1 cm long, which are impermeable to the microwave radiation excited inside. The gaps can be realized, for example, by a rear panel on the sample drawer. With such an arrangement it is achieved that reproducible and controllable electromagnetic conditions prevail in the interior 152 and the propagation of microwave radiation from the microwave transmitting antennas to the samples does not depend on the further configuration of the device, since, for example, possible field deflections due to electrically conductive components are excluded . The heating device 190 can be constructed as an independent assembly that can be integrated into suitably dimensioned devices in addition to a measuring chamber.
    A field distribution within the cavity that is at least homogeneous over time can be achieved by controlling the amplitude and phase of the two independent microwave transmitting antennas 162-1, 162-2 placed in the interior in such a way that, if possible, no radiation hot spots. Spots arise or they can be moved over time over the microtiter plate and thus ensure a homogeneous energy input (on average over time).
    After the microtiter plate with the heated samples has been transferred into the measuring chamber, radiation measurements can be carried out there in a manner known per se, e.g. fluorescence measurements.
    In Fig. 2 some components of a second embodiment of a system 200 for determining biological properties of samples are shown schematically. Similar to the first exemplary embodiment, the system can be used to carry out fluorescence measurements and also luminescence measurements or absorption measurements on samples which are accommodated in wells of a microtiter plate 210 which can be identical or similar to the microtiter plate of the first exemplary embodiment.
    A special feature of the system 200 is that the light-tight, lockable measuring chamber 220 is designed at the same time as a heating chamber of a heating device 290, so that it can serve as a combined measuring and heating chamber that allows the samples located in the measuring chamber with the help of To heat or heat up microwave radiation. This means that heating or temperature control and measurement can be carried out simultaneously if required.
    The substantially cuboid measuring and heating chamber can be dimensioned similarly or identically to the heating chamber 120 of the first embodiment. In order to ensure that the measuring chamber can also serve as a heating chamber that is essentially impervious to microwave radiation, a metallic shield, only partially shown, is provided which, when the measuring chamber is closed, essentially completely encloses the interior 252 of the measuring chamber in such a way that microwave radiation does not come from the interior the measuring chamber or heating chamber can penetrate to the outside. To build up the metallic shielding, metal sheets can be attached to the inner walls of the measuring chamber, which are joined to one another without gaps or with very narrow gaps at the joints.
    At least part of the metallic shielding is formed by perforated sheets 255-1, 255-2, which have a regular pattern of holes, the diameter of which is in the range from 1 mm to 30 mm, in particular in the range from 2 mm to 20 mm, is so small that microwave radiation cannot penetrate these perforated sheets. However, the holes allow optical paths from measuring devices to be guided through the metallic shield.
    The measuring devices that are assigned to the measuring chamber 220 include a primary light source 230 which is arranged outside the measuring chamber and which emits a continuous emission spectrum in the visible spectral range. An optical excitation path 232 leads through an opening (hole) in the side perforated plate 255-1 via a planar deflecting mirror arranged inside the measuring chamber from the light source 230 to the measuring position 234, in which a sample to be measured can be positioned. The radiation emitted by the sample excited in this way (the emission light) arrives via an optical emission path 236 equipped with a parabolic mirror to a detector 240 which is arranged outside the measuring chamber and which comprises a photomultiplier. The emission path leads through holes or openings in the perforated plate 255-2, which is attached to the inside wall of the chamber above the measurement position.
    Those components of the heating device 290 which are provided for irradiating the microwave radiation onto the samples can be identical or similar to corresponding components of the first exemplary embodiment, which is why reference is made to the description of the first exemplary embodiment. Here, too, there are two independently controllable microwave transmitter antennas 262-1, 262-2, which are each arranged within the metallic shielding in order to generate microwave radiation directed onto the sample, which can be controlled via a control device with regard to amplitude and phase, that the desired field distribution for heating the samples results in the area of the samples.
    The components of the contactless temperature measuring device can also correspond to those of the first exemplary embodiment, for which reason reference is made to the description there. In particular, an infrared diode array 282 for the contactless measurement of the temperature of the samples is attached above the receiving position for the microtiter plate outside the shielding (perforated plate 255-2). The measurement is carried out through holes in the perforated plate.
    In FIG. 3, some components of a third exemplary embodiment of a system 300 for determining biological properties of samples are shown schematically. Here, too, the measuring chamber 320 is designed at the same time as a heating chamber of a heating device 390 which enables the samples located in the measuring chamber to be heated or tempered by means of microwave radiation. The heating device with at least one microwave transmitter antenna 360-1 in the interior of the measuring chamber can be constructed identically or similarly to the heating devices of the previous exemplary embodiments.
    The main differences from the second exemplary embodiment lie in the way in which the optical paths of the measuring device assigned to the measuring chamber are designed. The excitation path 332, which leads from the light source 330 arranged outside the measuring chamber to the measuring position 334, leads through a first light guide 333, which leads through a hole in the perforated plate 355-2 of the metallic shielding arranged above the measuring position. The emission path 336, in which emitted radiation is guided from the measuring position to the detector 340 arranged outside the measuring chamber, runs through a second light guide 337, which is also guided through a hole in the perforated plate 355-2 arranged above the measuring position.
    In this embodiment, a common chamber for incubation and measurement is combined with measuring devices that have light guides from the light source to the sample position and from the sample position to the detector. A variant is illustrated in which the light guides are designed as a y-split, so that the excitation path and emission path are run side by side in sections. It is also possible to make optical fibers for the excitation path coaxially on the emission path in such a way that both paths can be guided through the same opening within the metallic shield. The detail in FIG. 3 shows a cross section through a coaxial fiber bundle 350 in which a central optical fiber guides the light of the emission path and the outer optical fibers arranged around the central optical fiber are provided for guiding the excitation light. It is also possible to use the coaxial fiber bundle in the reverse arrangement, so that a central optical fiber guides the excitation light, while the emission light is guided through the outer optical fibers arranged around the central optical fiber. The division of optical fibers to which excitation or emission light is applied can also be arbitrary, so that a homogeneous intermixing of excitation and emission optical fibers is achieved.
    If a light guide ends inside the heating chamber, the ferrule of the light guide should ideally be made of plastic or another electrically non-conductive material so as not to disturb the microwave field distribution. Metal ferrules are also conceivable, but should then be included in the design of the heating chamber and the calculations for optimizing the field distribution of the microwave radiation.
    In the exemplary embodiments illustrated so far, the heating device has a heating chamber equipped with a metallic shield into which at least one microtiter plate with samples must be inserted in order to warm up the samples by means of microwave radiation. The samples are located in the far field range of the microwave transmitting antennas.
    Chamber-free systems are also possible, that is to say systems without a separate heating chamber for receiving a microtiter plate. The systems described below use a non-propagating evanescence field of the microwave radiation for sample heating. For illustration, FIG. 4 schematically shows an exemplary embodiment of a near-field hollow waveguide 400 that can be used for this purpose, and FIG. 5 schematically shows a system 500 which is equipped with such a near-field hollow waveguide for sample heating.
    In the case of evanescence microwave excitation, the microwave radiation is initially generated, similar to the other exemplary embodiments, with the aid of a microwave source 460 and emitted into the interior of the metallic near-field hollow wave laser 400 via an antenna 410. In the exemplary embodiment, the near-field hollow waveguide tapers exponentially at its end opposite the antenna for continuous impedance matching and ends in a round or angular radiation exit opening 420, the effective diameter D of which is significantly smaller than the wavelength of the microwave radiation. The diameter can, for example, be in the range from 0.5 to 3 cm. The microwaves cannot propagate into the far field here, but an evanescent field with an exponentially decaying field strength is formed immediately in front of the radiation exit opening, which can be used for local heating of a sample.
    In an embodiment not shown in the figure, the near-field hollow waveguide has a geometry through which the reflected microwave radiation is not reflected back to the source, but instead passes it. By appropriately deflecting the microwave radiation, the process described above can be repeated several times, so that a large number of samples in the well of a microtiter plate can be heated simultaneously. By moving the microtiter plate laterally relative to the radiation exit openings, microwave radiation can thus be applied to all of the microtiter plate's wells.
    In FIG. 5, an application example of a chamber-free system 500 with microwave evanescence irradiation and beam guidance of the measuring system via light guides is shown schematically. The microtiter plate 510 is located within a measuring chamber of the system, not shown, which does not have or requires no inner metallic shielding against the escape of microwave radiation. It can therefore be the measuring chamber of a conventional system. The excitation light reaching the measurement position from the light source 530 via the excitation path 532 is radiated into the sample from above, and the emitted radiation emits upwards, which arrives at the detector 540 through the emission path 536.
    The heating device 590 of the system 500 comprises at least one near-field hollow waveguide 400, which is arranged in the example below the receiving plane for the microtiter plate so that the upwardly directed exit opening 420 is in a plane directly below the plane in which the floors of the wells 512 of the microtiter plate are arranged. The distance between the radiation outlet opening and the bottom of a well is dimensioned such that the microwave evanescent field emerging from the radiation outlet opening can penetrate from below through the material of the microtiter plate into the aqueous sample and heat it up.
    Advantageously, the diameter of the radiation exit opening is so small that, with typical microtiter plates, only a single sample can be warmed up by means of microwave radiation in this way, while the other samples are practically unaffected by microwave radiation at ambient temperature (or another previously set temperature) stay. A selective heating of individual samples is thus possible in a targeted manner. The heating can be monitored and controlled by the contactless temperature measuring device. Similar to the other exemplary embodiments, this has an infrared sensor 582 arranged above the receiving position for the microtiter plate. With the aid of a three-dimensionally movable sample manipulation device 575 for moving the microtiter plate 510 relative to the radiation outlet opening 420, individual samples can be successively positioned in front of the outlet opening.
    In the systems 600 in FIG. 6 and 700 in FIG. 7, the devices for positioning the microtiter plate, for heating samples by means of near-field hollow waveguides and for temperature control are identical to the exemplary embodiment in FIGS. 4 and 5. The only differences are here regarding the structure of the measuring equipment.
    In the system 600 of FIG. 6, the light from the light source 630 is radiated onto the sample from above via an inclined deflecting mirror without the use of light guides, while the emission light reaches the detector via a parabolic mirror (see, for example, first embodiment).
    In the variant of FIG. 7, the excitation path 732 and the emission path 736 are separated via a geometric beam splitter 770 in the form of a perforated mirror, which is arranged above the measurement position and has a central opening through which the excitation light is directly drawn from the above Measuring position arranged light source 730 can be irradiated into a sample. The emission light arrives at the detector 740 via a reflective surface of the geometric beam splitter.
    8A shows an exemplary embodiment for a configuration for heating a sample in a microtiter plate to a maximum of the boiling point of the solvent used for a longer period of time. An attachment 820, which essentially consists of an upwardly open tube made of a non-metallic material, e.g. plastic or glass permeated with carbon fibers, is placed on a well 812 of a microtiter plate 810 in a substantially gas-tight manner.
    The outer diameter of the attachment is slightly smaller in its inlet area that can be placed on a bowl 812 than the inner diameter of the bowl at its upper open end, so that the attachment with its inlet area can be inserted a little bit into the bowl. Then an outwardly projecting shoulder is formed on the inlet area, the outer diameter of which is somewhat larger than the diameter of the cup opening, so that the attachment seals the cup in a substantially gas-tight manner.
    By heating the sample 835 by means of microwave radiation from a lower temperature T1 to a higher temperature T2> T1 according to one of the methods described above, the solvent begins to boil and rises as vapor upwards into the interior of the attachment. Since the use of microwave radiation as an energy source essentially does not heat the attached pipe, the steam cools down on the pipe walls and condenses. The liquid condensate can drip back into the well 812.
    In a further embodiment according to FIG. 8B, the tube is such that it tapers upwards. This arrangement achieves a more efficient recondensation of the solvent vapor.
    In another embodiment, as shown in FIG. 8C, the tube has an upwardly increasing wall thickness. In this way, due to the high heat capacity of the pipe, a greater thermal gradient from T2 to T1 is achieved and thus more efficient gas condensation for a given pipe length.
    9A shows an exemplary embodiment for the separation of liquid substance mixtures by distillation in microtiter plates. Two adjacent wells 812-1, 812-2 are connected to one another via a bridge 830 sloping towards the second well, in such a way that the bridge is on the first well 812-1, in which the substance mixture is located and which can be referred to as a distillation well , rests in a substantially gas-tight manner, while it rests on the second cup 812-2, which can be referred to as a template cup, in such a way that a gas exchange with the environment can take place. When the sample is heated with microwave radiation using one of the methods described above, the solvent begins to boil and rises as vapor. Since the attached bridge is essentially not heated by using microwave radiation as an energy source, the steam cools down on the bridge walls and condenses. The condensate flows off on the sloping side of the bridge and thus enters the sample cell. Using different boiling points of a substance mixture, two fractions can be separated from one another in this way. The separation efficiency can be increased by having webs (not shown) in the bridge that protrude into the gas space above the distillation bowl. The steam can recondense on these webs, drip down and return to the gas phase.
    This increases the number of effective distillation steps and the separation efficiency is increased. In classical preparative chemistry, this process is referred to as increasing the number of theoretical plates by introducing a distillation column (column distillation).
    In an exemplary embodiment shown in FIG. 9B, the bridge has a wall thickness that increases in the direction of the template cup. In this way, due to the high heat capacity of the bridge, a greater thermal gradient from T2 to T1 is achieved and thus, for a given bridge length, more efficient gas condensation.
    Another embodiment shown in Fig. 9C uses a curved tube as a bridge, which has a substantially horizontal opening to the gas space on the side of the distillation cup and a substantially vertical opening on the side of the template cup, so that in the pipe condensed gas can drip into the platen.
    In both of the methods described above for heating samples in microtiter plates with microwave radiation to modify the molecular structure or to separate a homogeneous mixture of substances, the microwave radiation is not used in such a way that the exposure to the microwave radiation directly influences the molecular integrity of the sample. Rather, the microwave radiation only serves to heat the solvent by orienting the dipoles contained therein. This guarantees that the knowledge gained will also scale for larger amounts of substances.
    Current research investigates the extent to which intensive microwave radiation can directly influence the chemical properties of substances. This influence is not provided for in the examples described, but can also be used if powerful microwave sources are used.
    Embodiments of the claimed inventions may provide one or more of the following advantages.
    Exclusively local heating of the sample: This enables significantly shorter heating times in the range of a few seconds to be achieved. At the same time, the interior of the device is not heated up and therefore does not have to cool down slowly. Therefore measurements at different temperatures can be carried out in direct succession.
    Exact temperature control: If the temperature of the sample is tracked in real time via an IR diode or another IR sensor, this can be controlled very precisely via feedback by setting the microwave power (in cw or in pulse mode) (feedback control). In this way, a high-precision sample thermostatting is achieved, which is not possible in a comparable way with conventional methods.
    A generation of temperature profiles: An active temperature control loop can, in conjunction with the short reaction times, ensure that user-specific temperature profiles can be run. On the one hand, this is advantageous for two-dimensional kinetics studies and, on the other hand, opens up the field of DNA hybridization: by precisely defining the heating and cooling profile, hybridization errors can be virtually avoided.
    An expansion of the range of applications for the devices. According to the inventors' considerations, it is possible, within the framework of μ-chemical processes, to carry out simple reaction and separation steps in a multilabel device with a microwave source as the central energy source. In combination with injectors or dispersion units, the appropriate attachments can be used to heat and stir under reflux and to distill from one well into a neighboring well. The prerequisite for this is a large temperature gradient, which is achieved by preventing the distillation bridge from heating up (e.g. designed as a simple bent tube). Local heating with the help of microwave radiation meets this requirement.
    In this way, a multi-label reader or microplate reader can develop from a pure measuring device to an integrated synthesis robot with an analysis unit. Such an approach is extremely helpful for systemic approaches, e.g. in polymer research, since reaction conditions and concentrations are permuted with a limited number of starting substances in order to achieve the desired product properties.
    权利要求:
    Claims (25)
    [1]
    1. System (100, 200, 300, 500, 600, 700) for determining properties of samples (135) which are arranged in wells (112) of a microtiter plate (110, 210, 510), comprising:a measuring chamber (120) for receiving at least one microtiter plate in a measuring position;a heating device (190, 290, 390, 590) for heating samples which are located in wells of the microtiter plate;Measuring devices contain a microplate reader for examining samples arranged in the measuring chamber during and / or after heating in at least one operating mode by measuring radiation emitted from the samples;characterized in thatthe heating device (190, 290, 390, 590) has at least one microwave source (160-1, 160-2) for generating microwave radiation which can be radiated onto samples for heating.
    [2]
    2. System according to claim 1, characterized in that the heating device (190) has a heating chamber (150) which is substantially impermeable to microwave radiation and has a metallic shield (154).
    [3]
    3. System according to claim 2, characterized in that the heating chamber (150) is a separate chamber from the measuring chamber (120) and that a transfer device (175) for transferring microtiter plates (110) between the heating chamber (150) and the measuring chamber ( 120) is provided.
    [4]
    4. System according to claim 2, characterized in that the measuring chamber (120) is designed as a heating chamber with a metallic shield which is substantially impermeable to microwave radiation.
    [5]
    5. System according to claim 1 or 2, characterized in that the heating device (190, 290) has a first microwave transmitting antenna (162-1, 262-1) and a spatially separated second microwave transmitting antenna (162-2, 262- 2).
    [6]
    6. System according to claim 1 or 2, characterized in that the heating device (190) has a first microwave source (160-1) and at least one separate second microwave source (160-2).
    [7]
    7. System according to claim 6, characterized by a control device (170) which is configured such that the first microwave source (160-1) and the second microwave source (160-2) can be controlled in an amplitude-modulated and / or phase-modulated manner in such a way that they are coordinated with one another a time-dependently varying field distribution of microwave radiation can be generated by the first and the second microwave source.
    [8]
    8. System according to claim 1, characterized in that the heating device has a near-field hollow waveguide (400) which is coupled to a microwave source (460) and which has a radiation exit opening (420) which has an effective diameter (D) of less than that Half the wavelength of the microwave radiation, the diameter preferably being in the range from 0.5 mm to 6 mm.
    [9]
    9. System according to claim 8, characterized by a sample manipulation device (575) for moving the microtiter plate (520) relative to the radiation exit opening (420).
    [10]
    10. System according to one of claims 1 to 9, characterized by a temperature measuring device (180) for contactless measurement of the temperature of samples to determine sample temperature values, wherein the temperature measuring device preferably has at least one temperature sensor (182, 282, 582) selected from the group infrared diode, infrared diode array and infrared camera.
    [11]
    11. System according to claim 10, characterized by a temperature control device which is configured to control the microwave radiation as a function of the sample temperature values or values derived therefrom.
    [12]
    12. System according to one of claims 2 to 7 or 10 to 11, characterized in that the measuring devices have at least one optical path (232, 332, 336) which passes through an opening in the metallic shielding (255-1, 355-2) of the heating chamber (290, 390), the optical path preferably leading through a light guide (333, 337).
    [13]
    13. System according to claim 1, characterized by at least one first attachment (820) which can be arranged above one or more wells in such a way that evaporated liquid of the sample can condense on the walls of the attachment and drip back into the well or wells and / or at least a second attachment (830) which can be arranged over one or more cups in such a way that evaporated liquid condenses on the walls of the attachment and can be deflected so that the liquid can at least partially drip into an indirectly or directly adjacent cup.
    [14]
    14. A method for determining properties of samples by means of a system according to claim 1, wherein the samples are arranged in wells of a microtiter plate, with the following steps:Filling wells of a microtiter plate with samples which contain at least one sample substance in a liquid medium;Heating of samples by means of a heating device;Arranging the microtiter plate in a measuring position within a measuring chamber of the microplate reader;Examining samples before, during and / or after the heating in at least one operating mode of the microplate reader by measuring radiation emitted from the samples;characterized in thatmicrowave radiation is used to heat the samples.
    [15]
    15. The method according to claim 14, characterized in that microwave radiation from a frequency range of 2320 MHz to 2450 MHz is radiated in for heating.
    [16]
    16. The method according to claim 14 or 15, characterized in that in a heating phase at least temporarily microwave radiation from a first microwave source and at least one separate second microwave source is irradiated simultaneously.
    [17]
    17. The method according to any one of claims 14 to 16, characterized in that a first microwave source and a second microwave source are amplitude-modulated and / or phase-modulated controlled in such a way that the first and second microwave sources generate a time-dependently varying field distribution of microwave radiation.
    [18]
    18. The method according to any one of claims 14 to 17, characterized in that essentially the same amount of energy is deposited in several or all samples during heating on average over time.
    [19]
    19. The method according to any one of claims 14 to 18, characterized in that at least part of the heating is carried out during a measurement.
    [20]
    20. The method according to any one of the preceding claims 14 to 19, characterized in that a non-propagating microwave evanescent field is generated, which has a spatial extent that allows selective heating of individual samples.
    [21]
    21. The method according to any one of the preceding claims 14 to 20, characterized by a contactless measurement of the temperature of samples to determine sample temperature values, wherein infrared radiation emanating from the samples is preferably measured to measure the temperature.
    [22]
    22. The method according to claim 21, characterized by controlling the microwave radiation as a function of the sample temperature values or values derived therefrom.
    [23]
    23. The method according to any one of claims 21 or 22, characterized in that a measurement of the temperature of samples is carried out at least in phases during the heating.
    [24]
    24. The method according to any one of claims 14 to 23, characterized in that the heating by microwave radiation is used to modify the sample in its molecular structure.
    [25]
    25. The method according to any one of claims 14 to 24, characterized in that the heating by microwave radiation is used to separate heterogeneous samples into individual components, in particular by means of a distillation between directly or indirectly adjacent wells of a microtiter plate.
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    同族专利:
    公开号 | 公开日
    DE102015214414A1|2017-02-02|
    CH711376A2|2017-01-31|
    DE102015214414B4|2020-10-22|
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    法律状态:
    优先权:
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    DE102015214414.3A|DE102015214414B4|2015-07-29|2015-07-29|Method and system for determining biological properties of samples|
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