EP3229965A2 - Corps de régulation de température pour plaque multipuits et procédé et dispositif pour congeler et/ou décongeler des échantillons biologiques - Google Patents

Corps de régulation de température pour plaque multipuits et procédé et dispositif pour congeler et/ou décongeler des échantillons biologiques

Info

Publication number
EP3229965A2
EP3229965A2 EP15798324.8A EP15798324A EP3229965A2 EP 3229965 A2 EP3229965 A2 EP 3229965A2 EP 15798324 A EP15798324 A EP 15798324A EP 3229965 A2 EP3229965 A2 EP 3229965A2
Authority
EP
European Patent Office
Prior art keywords
tempering
cavities
fingers
temperature
multiwell plate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP15798324.8A
Other languages
German (de)
English (en)
Inventor
Günter R. Fuhr
Heiko Zimmermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Publication of EP3229965A2 publication Critical patent/EP3229965A2/fr
Pending legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/50—Cryostats
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0236—Mechanical aspects
    • A01N1/0242—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components
    • A01N1/0252—Temperature controlling refrigerating apparatus, i.e. devices used to actively control the temperature of a designated internal volume, e.g. refrigerators, freeze-drying apparatus or liquid nitrogen baths
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0278—Physical preservation processes
    • A01N1/0284—Temperature processes, i.e. using a designated change in temperature over time
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/54—Heating or cooling apparatus; Heat insulating devices using spatial temperature gradients
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/523—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for multisample carriers, e.g. used for microtitration plates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M45/00—Means for pre-treatment of biological substances
    • C12M45/22—Means for packing or storing viable microorganisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/44—Sample treatment involving radiation, e.g. heat
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1827—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using resistive heater
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B01L2300/185—Means for temperature control using fluid heat transfer medium using a liquid as fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1894—Cooling means; Cryo cooling
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00346—Heating or cooling arrangements
    • G01N2035/00445—Other cooling arrangements

Definitions

  • the invention relates to a tempering body for a multiwell plate.
  • the invention further relates to an apparatus and a method for freezing biological samples, in particular for cryopreservation, and / or for thawing biological samples, in particular a cryopreserved sample.
  • Such multi-well substrates are also referred to as multi-well plates or microtiter plates.
  • the exact dimensions are 127.76 mm ⁇ 85.48 mm * 14.35 mm according to the ANSI standard recommended by the Society for Biomolecular Screening (SBS).
  • Standards for microtiter plates have been published by the ANSI on the recommendation of the Society of Biomolecular Screening (SBS), in particular concerning the dimensions and positions of the wells in 96, 384 and 1536 well microtiter plates. These are the standards ANSI / SBS 1 to 4 - 2004 and the standard SBS-6 - 2009.
  • cryobiobanks in which the samples, especially living cells and here
  • Stem cells are deposited by animals and humans and fed back into use if needed. This usually takes place via cryopreservation, defined freezing and thawing protocols as well as a storage temperature below minus 140 ° C, however, in individual tubs, straws, individual plastic containers, etc., so that the suspensions contained in the corrugated substrates must be removed and transferred.
  • cryopreservation defined freezing and thawing protocols as well as a storage temperature below minus 140 ° C, however, in individual tubs, straws, individual plastic containers, etc., so that the suspensions contained in the corrugated substrates must be removed and transferred.
  • the quality of a biological sample in particular when cells grow adhering to surfaces, decreases with each transfer, since they have to be detached by enzyme treatment or mechanical treatment and are therefore subject to considerable stress. It is also important that all samples of a corrugated plate, z. B. at 96 wells, treated in the same or predeterminable manner and thus also frozen, stored and thawed.
  • cryo Freezers from Planar Plc with programmable temperature programs or simple cryoboxes, such as the cryobox of the type sold under the name "Mr. Frosty"
  • ThermoFisher Scientific Inc . In particular, in important medical cell types, such as immune cells, stem cells, especially the Induced Pluripotent Stem cells, recently controlled freeze and thaw protocols have proven to be extremely important for the quality of the sample and its vitality. Very good results are achieved with very quick cooling and warming. All this and in particular rapid cooling and heating below 1 ° / sec are not yet available for multiwell substrates, which is why the bioprobes have to be transferred to other vessels. But even in the conventional plastic tubes, due to the thickness of the plastic wall and the arrangement of the volumes, such exact, but above all, rapid temperature profiles can not be achieved.
  • a further object is to provide such a device which is process efficient in automated high throughput methods, e.g. As high-throughput screening method, can be integrated.
  • Samples in particular cryopreserved samples to provide, are overcome with the vitality-affecting disadvantages of conventional techniques and in particular a simplified post-processing of the thawed bi- yogn sample allows.
  • a temperature body is provided for a multi-well plate, for
  • the multiwell plate has, in a manner known per se, a plurality of cavities arranged in rows and columns.
  • the tempering body according to the invention comprises a body which can be flowed through by a tempering fluid, preferably of a thermally conductive material, preferably high heat. mekapaztician, and a plurality of arranged on an upper surface of the body in rows and columns protruding tempering fingers, which are thermally conductively connected to the base body, wherein a grid spacing of the tempering corresponds to a grid spacing of the cavities of the multiwell plate.
  • the distance between adjacent tempering fingers thus corresponds to the distance between adjacent cavities.
  • the invention comprises the general technical teaching to provide a tempering, which is adapted to the matrix-like, regular arrangement of the cavities of the multiwell plate and for this purpose has a corresponding maxtrix shame arrangement of tempering fingers in the pitch of the arrangement of the cavities.
  • the cooling fingers can be brought with their end faces with the bottom plates of the cavities in connection, wherein preferably each tempering finger of a cavity is assigned.
  • the tempering fingers can be made rod-shaped or suppository-type, and the end faces of the tempering fingers are designed such that they form planar supports for the bottoms of the cavities of the multiwell plate.
  • a particular advantage of the invention is therefore that samples for freezing and thawing no longer in Einzeltubes, Straws or special plastic containers, etc. must be transferred, but frozen by means of the tempering according to the invention directly into and with the multiwell plate and subsequently thawed again , This can increase the vitality rate in the cryopreservation of biological samples.
  • Another advantage is that a tempering body designed in this way allows a rapid freezing and / or thawing, since the tempering fingers can be positioned very close to the sample and high cooling and Heating rates can be generated directly in the bioprobe on the bottom wall of the cavities.
  • sample any article which undergoes cryopreservation in the cavity.
  • the sample material typically includes biological material such as cells, tissues, cell components or biological macromolecules and optionally a nutrient solution, reagents, cryoprotectants or other substances.
  • an electrically controllable heating and / or cooling element may be integrated in at least some of the tempering fingers, preferably in all.
  • heating elements can also be microwave or high-frequency elements, which can set a defined heat input with appropriate control against the fluid cooling of the body.
  • This variant offers the advantage that individual tempering fingers or subgroups of tempering fingers, for example individual rows and / or columns, can be tempered differently. As a result, the heat or cold input can be selectively varied via the arrangement of the cavities and adapted to the samples stored in the individual cavities.
  • thermoelectric sensor for monitoring the heat or cold entry into the cavities in the front region of at least one of the tempering fingers a temperature sensor, such as.
  • a thermoelectric sensor is integrated.
  • the temperature sensor may be designed as a flat design of a platinum resistance temperature sensor, such as a PT 100 or PT 1000 sensor.
  • the end faces of the tempering fingers are highly polished, preferably with roughnesses below 20 pm, and / or have a coating of high thermal conductivity, preferably with a thermal conductivity comparable to that of copper or silver, preferably a coating of graphite or diamond.
  • the tempering fingers can be arranged within an area with a length of 127.8 mm and a width of 85.5 mm.
  • the number of tempering fingers may correspond to the number of wells of the multi-well plate and preferably have one of the following values: 6, 8, 12, 16, 24, 48, 96, 384 or 1536.
  • the tempering fingers are preferably made of a material of high heat capacity and high thermal conductivity, preferably of a metallic material.
  • the heat capacity of the tempering fingers is higher than that of a commercially available multiwell plate.
  • the main body of the tempering body comprises at least one line through which a cooling fluid can flow, with a supply connection and an outflow connection for connecting the at least one line to a cooling circuit and / or a heating circuit.
  • the line course of the at least one line is preferably meander-shaped or spiral in order to achieve a desired temperature profile evenly distributed over the base body.
  • An advantageous variant provides in this case that the flow of a tempering fluid through the at least one line is controllable so that predetermined individual tempering fingers and / or at least one predetermined subgroup of Temperierfinger different in temperature compared to the rest of the tempering fingers are tempered.
  • This can be realized, for example, by means of a plurality of fluid lines or line sections which can be connected and disconnected for different regions of the heat sink, in order to temper sub-groups of tempering fingers differently.
  • the end faces of the tempering fingers can be flat or slightly curved.
  • This embodiment is preferably suitable for the tempering of multi-well plates which have cavities with a flat bottom or a slightly curved round bottom.
  • a further variant of this embodiment is characterized by an inclination of the end faces of the tempering fingers, which increases from the middle to two opposite edge regions of the temperature body, with respect to a planar upper side of the base body.
  • the increasing inclination may be formed by an increasing inclination of the tempering fingers arranged on the planar upper side of the main body or by an increasing bevel of the end faces of the tempering fingers.
  • uses that multiwell plates mostly made of plastic, z. B. made of polystyrene or polyvinyl chloride, are manufactured and bend slightly under pressure. This bending can be exploited by the increasingly inclined outwardly embodiment of the end faces of the tem- perierfinger advantageously to determine safe ⁇ that all cavities come into planar contact with the temperature conditioning.
  • a further alternative embodiment provides that an outer wall of the bottoms of the cavities and an end face of the tempering fingers for forming a local positive connection each have a shape-corresponding non-planar surface shape complementary to one another.
  • the end face of the tempering finger according to the key-lock principle is designed as a counter contour to the contour of the underside of the cavities.
  • a surface shape of the end faces of the tempering fingers and a surface shape of the outer walls of the bottoms of the cavities to form a local form fit can be designed as interlocking toothing.
  • This alternative embodiment has the advantage that even with cavities with small diameters, a large surface contact between the cavity and corresponding cooling finger and thus a comparatively large cooling surface and faster temperature control are made possible.
  • the invention further relates to an arrangement of a tempering, as disclosed herein, and a multi-well plate whose pitch of their arranged in rows and columns cavities corresponds to the pitch of the tempering fingers.
  • a temperature control device for freezing samples, in particular for cryopreservation, and / or for thawing samples, in particular particular of a cryopreserved sample.
  • the samples may in particular be biological samples.
  • the tempering device comprises a tempering as disclosed in this document.
  • the temperature control device comprises WEI direct a positioning means for positioning the Tem ⁇ perier stressess a multiwell plate in a predetermined position relative to each other, wherein the pitch of the ⁇ hen in Rei and columns arranged cavities of the multiwell plate correspond to the grid spacing of the Temperierfinger and wherein in the predetermined position, the multi-well plate above the tempering and the cavities are each positioned in alignment with the longitudinal axis of one of the tempering fingers.
  • the tempering device further comprises a device for contacting the tempering fingers of the tempering with the bottoms of the cavities of a positioned in the predetermined position multiwell plate.
  • the device for contacting brings about a pressing body which can be pressed from above onto a multiwell plate positioned above the tempering body, as a result of which the bottoms of the cavities of the multiwell plate are to bring the contact pressure in contact with the end faces of the tempering fingers.
  • the pressing body preferably comprises a contact surface with the multiwell plate of at least the same
  • Length and width as the matrix-like arrangement of the cavities of the multiwell plate.
  • the device for bringing into contact comprises a plurality of electrically controllable actuators, which are designed to indirectly on the top of a positioned above the temperature control multiwell plate, z. B. on the aforementioned Anpress stresses, or directly to attack in order to change a relative distance between the multi-well plate and the tempering when driving the actuators to bring the temperature control fingers and the bottoms of the cavities in contact and / or out of contact.
  • the electrically controllable actuators may be embodied as micromechanical actuators or as piezoelectric actuators.
  • the tempering fingers can all be pressed or returned to the underside of the cavities of the multiwell plate at the same time or in groups, in some cases only a single tempering finger, so that a temperature bridge is established between the bottom of the multiwell plate and the tempering fingers and dissolved, so that the heat can be led out of or into the sample.
  • Another advantage of the embodiment in which the electrically controllable actuators as high-precision micro ⁇ mechanical actuators or piezoelectric actuators are carried out, is that such actuators by a control unit of the device for in-contacting can be controlled so that a sequential in-contact matching, an out-contacting and re-in-contact accommodating multiwell plate and tempering frame within a time can be carried out in the range of 1 ms (milli ⁇ seconds) to 1 s (second ) and this is feasible with a distance ⁇ accuracy ⁇ .
  • the tempering device for handling a multi-well plate the grid spacing of which is arranged in rows and columns cavities corresponds to the grid spacing of the tempering of a tempering of the temperature control executed.
  • the temperature control device may comprise such a multiwell plate.
  • the multiwell plate may be a commercially available multiwell plate. Furthermore, the multiwell plate may differ from commercial multiwell plates and be adapted for use for cryopreservation and for use with the tempering body and / or the tempering device.
  • each one electrically controllable heating and / or cooling element preferably a Peltier element
  • a temperature sensor is integrated in the bottoms of the cavities.
  • the bottoms of the cavities can be made thin and made of a heat-conducting material or be provided with a structure on the underside, resulting in a larger surface contact with the tempering.
  • the tempering device may further comprise, in a manner known per se, a temperature-controlled cooling chamber or housing which can be filled and / or filled with a dry gas and, when cooled, has a vertical temperature stratification in the temperature-control chamber with a lower cold layer and an upper warm layer. and at least one provided on a housing wall of the Temperierkaramer lock for introducing and / or carrying out a multiwell plate.
  • two such locks are provided: a first lock, via which a multiwell plate can be introduced or carried out in the chamber in the warm state, and a second lock, via which a multiwell plate is introduced into the chamber in the cold state or can be executed.
  • the tempering device comprises a tempering body according to the invention.
  • the tempering device may be arranged in the lower cold layer of the temperature control chamber, connected to a cooling circuit first temperature control body for cryopreserving biological samples and / or arranged in the upper warm layer, attached to a heat cycle.
  • a cooling circuit first temperature control body for cryopreserving biological samples and / or arranged in the upper warm layer, attached to a heat cycle.
  • a mounted in the lower cold layer of the temperature-control chamber we ⁇ tendonss containing a thawed sample multiwell plate may be positioned above the second temperature conditioning means of the positioning device.
  • a multi-well plate which is introduced into the temperature-control chamber via the at least one lock and contains at least one sample to be frozen can be positioned above the first temperature-control body by means of the positioning device.
  • the positioning device may have a suitably designed guide mechanism in order to move the multiwell plate within the temperature chamber.
  • a multi-well plate positioned above the first and / or second temperature control body can be lowered or raised in a controlled manner by means of the device for bringing it into contact and / or out of contact with the thermal element to become.
  • the positioning device can also be designed instead to move the or the tempering body toward the multiwell plate.
  • the tempering chamber may be cooled with liquid gases such as LN2, N2 gas or a Sterling engine.
  • liquid gases such as LN2, N2 gas or a Sterling engine.
  • liquid nitrogen in a trough at the bottom of the tempering chamber open or introduced into a spongy material liquid nitrogen can be stored, resulting in the vertical temperature stratification.
  • the vertical Temperaturver ⁇ running is set within the temperature chamber so that the warm layer having a temperature which corresponds essentially to a predetermined starting temperature of a freezing process or a specified target temperature of a thawing process corresponds, while the cold layer has a temperature which Substantially corresponds to a predetermined target temperature of the freezing process or a predetermined starting temperature of the thawing process.
  • a further aspect of the invention relates to a method for freezing biological samples, in particular for cryopreserving, and / or thawing biological samples, in particular cryopreserved samples, using a tempering body as disclosed in this document, and / or a tempering device, as in disclosed in this document.
  • the method comprises applying a substance to a sample stored in a cavity of the multiwell plate.
  • the applied substance is a solution which, when it solidifies, terminates a surface of the cavity contents with respect to the outer space, preferably closes in a gastight manner, so that no lid or the like is required as a closure.
  • the substance may be, for example, a natural or synthetic oil, a liquid or a gel which is immiscible with an aqueous solution, or solid CO 2.
  • the substance is applied to the already frozen sample, wherein the substance after and / or thawing of the sample causes a predetermined reaction or interaction with the sample.
  • a substance is used, from the state of which it can be deduced whether, after freezing the sample, an intermediate thawing has taken place.
  • the substance has a higher density than the nutrient solution surrounding the sample, so that the sequence of the sample and the substance turns over after thawing, so that, for example, floating cells can be easily removed in a nutrient solution.
  • a substance is applied, wherein information about the sample can be derived from the state of the introduced substance and / or the substance causes a predetermined reaction or interaction with the sample during the thawing of the sample.
  • liquids which give rise to a specific pattern during freezing or have a temperature sensor function from which it is possible to detect whether thawing has occurred in the meantime or by which the structure, color, mixture, etc. have been changed.
  • these can also be recrystallization processes which are not visible macroscopically but can easily be detected and quantified by means of scattered light, fluorescence, Raman measurements or the like.
  • the substance may be a diluent and wash solution or antifreeze, act as a differentiation factor with respect to the sample, or be a substance containing antioxidants, anti-apoptotic substances, and / or live-dead dyes.
  • multi-well plates can be used directly for cryopreservation, so that every transfer into new containers is omitted.
  • Figure 1 is a perspective view of a multi-well plate and a tempering according to an embodiment of the invention; an arrangement of a multi-well plate and a tempering, from which a section is enlarged and reproduced in section; a cross section of a multi-well plate and a tempering according to another embodiment of the invention; schematically a tempering and a tempering according to an embodiment of the invention;
  • FIG. 5 schematically shows the application of a substance according to an embodiment of the method
  • FIGS. 6A and 6B show a unit consisting of a tempering finger and a filled cavity
  • FIGS. 7A and 7B show a cross-section of a multi-well plate on a tempering body according to another embodiment.
  • FIGS. 8A and 8B show a cross section of a multiwell plate and a tempering element according to a further embodiment.
  • Figure 1 shows a multiwell plate 1 and a first Auspar tion form of the tempering 4 according to the invention in a perspective view.
  • a commercially available plastic multiwell plate 1 in the standardized 96-well format is shown schematically in an oblique view. shows.
  • the cavities (wells) 2 are arranged side by side in matrix form in eight rows of twelve cavities each and represent depressions for receiving the test pieces) on such a multiwell plate 1.
  • the grid spacing of adjacent cavities is for a 9 mm 96-well multiwell plate.
  • Such multi-well plates 1 can be covered with a plastic lid 3, which can also be omitted in the machine for filling, emptying and other manipulations.
  • the cavities 2 are planarly closed with a thin plastic disc or foil, which generally allows microscope images of adherent cells in their optical quality.
  • the tempering body 4 comprises a cuboid basic body 6, through which a tempering fluid can flow, and a plurality of projecting cylindrical tempering fingers 5 arranged in rows and columns in rows and columns in rows and columns exactly in the pattern of the 96-well multiwell plate.
  • the tempering body 4 is made of one Material made of high heat capacity or good heat conduction. Usually these are metals, such as silver or alloys.
  • tempering fingers 5 are arranged in a matrix-like manner in eight rows of twelve tempering fingers 5 each.
  • the grid spacing of the tempering fingers 5 corresponds to a grid spacing of the cavities 2 of the multiwell plate 1, ie, the distance between adjacent tempering fingers thus corresponds to the spacing of adjacent cavities and is therefore also 9 mm in the present case.
  • the tempering fingers 5 are in each case of essentially the same shape and are regularly divided in two into the contact area with the multi-surface Well plate 1 spanning and substantially perpendicular to each other surface directions each arranged substantially equidistantly.
  • the tempering fingers 5 can be provided in one piece with the main body 6.
  • the Temperierfinger 5 are in very good, usually thermi ⁇ rule contact with the arranged below tempering
  • the base body 6 can be flowed through by at least two openings 7a, 7b with a temperature control gas or a temperature control liquid.
  • a meandering or even spiral course of a fluid guide connecting the two openings is realized in the tempering body 6 so that a uniform or desired temperature profile is achieved, via which the tempering fingers 5 each assume the temperature prevailing at their location.
  • the temperature control fingers 5 have the highest possible heat capacity, which is far greater than that of the bottom regions of the multi-well plates, so that they dominate and determine the temperature of the cavity region with the bioprobe when in contact with them. D. h., The cooling and heating are essentially limited only by the thermal conductivity of the bottom regions of the multiwell plate 1 and the bioprobe.
  • a corresponding This format adapted tempering are used, which then according to 8, 12, 16, 24, 48, 96, 384 or 1536 Temperierfinger 5 whose pitch is adapted to the pitch of the multiwell plate.
  • the principle of cooling a 96-well multiwell plate 1 from room temperature to a target temperature of z. B. minus 150 ° C is explained below using the example of a similar cooling all 96 cavities 2.
  • Tempering fingers 5 heating elements located (not shown) and different temperatures at the individual Temperierfingern 5 can be realized.
  • the pressing body 8 it is also possible to use a piezo-controlled device for bringing the tempering fingers 5 into contact with the bottoms of the cavities 2 for pressure (shown in FIG. 3), which permits contact of the multiwell substrate with the tempering fingers 5 to open by vertical movement and close again. For this only small gaps in the micrometer range are required. By repeated repetition alone on this way a temperature profile of the entire plate can be driven. Additionally or alternatively, the temperature of the gas stream can be changed by the base body 6, which can drive slow T-profiles, as they are also common in the cryopreservation of cells (for example in the range of a few fractions ° C per minute, some ° C per Minute). In the case of heating, the procedure is contrary: Very quickly, the multiwell plate 1 is brought into contact with a temperature control body 4 brought to a high temperature. This can be with a warm or
  • the multi-well plate 1 is also pressed rapidly to the tempering 4.
  • the tempering 4 is brought to 40 ° C to 300 ° C and only as long brought into thermal contact with the multiwell plate 1, until the target temperature is reached. Even during heating, the temperature profiles can be controlled by opening and closing the thermal contact between the tempering fingers 5 and the cavities 2.
  • FIG. 2 shows, in section, in the lower part, a tempering body 24, which in turn has a base body 6, through which a tempering fluid can flow, and a plurality of projecting tempering fingers 25 arranged in rows and columns on the upper side 6a of the base body 6.
  • the grid spacing of the tempering fingers 25 again corresponds to the grid spacing of the cavities 2 of the multiwell plate 1, which is enlarged in the middle in a detail in FIG. 2 and reproduced in section.
  • the multiwell plate 1 is inclined Top view shown with the marked area used as a cut.
  • the multiwell plate 1 is still covered with a cover 3.
  • the tempering fingers 25 are according to this embodiment not vertically standing on the surface 6a of the base 6, but increasingly inclined to the edges of the multiwell plate 1 , This is exaggerated in the figure by the dashed line 5c and the two longitudinal axes 5b of tempering fingers 25 arranged in the outer region, which are tilted outward in comparison with the longitudinal axis 5d of a centrally arranged tempering finger 25. Due to the surface pressure from above or below the multiwell plate 1 is bent a little lenticular, which ensures that all cavities 2 get with their bottom bottom 11 in the same good planar contact with the tempering fingers 25.
  • the surface of the temperature control fingers in particular the end face 25a, as exemplified by an example cylinder in Figure 2, with a good thermal conductivity
  • Layer 9 can be covered, whereby very rapid cooling and heating are possible.
  • heating or cooling elements 10 may be integrated in the tempering fingers 25, via which individual elements are controlled in temperature.
  • tempering 5 temperature sensors 12, z. B. in flat design of a platinum resistance temperature sensor, such as a PT 100 or PT 1000 sensor.
  • a platinum resistance temperature sensor such as a PT 100 or PT 1000 sensor.
  • FIG. 3 shows, in analogy to FIG. 2, a cross section of a multiwell plate 1, which is in contact with the temperature control body 24.
  • the peculiarity of this embodiment is that piezoelectric actuators 30 are fixedly arranged on the cover of the multiwell plate 1, so that over the expansion or shrinkage of the piezoelectric actuators 30 (shown by the arrows), the contact of the cavities 2 to the tempering fingers 25 is made or interrupted. These are deflections in the range of 1 to a few 100 ⁇
  • FIG. 4 shows by way of example a tempering device 40 for the automated and direct cryopreservation of biological samples stored in multi-well plates 1.
  • the device 40 includes fully a temperature-controlled chamber 48, no moisture- ⁇ ness is in the "so that no humidity may condense as ice.
  • the chamber 48 comprises further regions which at least the output temperature of the multiwell plate and the have desired target temperature.
  • a trough 43 in which open or in a sponge-like material, for.
  • a sponge-like material for.
  • liquid nitrogen (LN2) is located at the bottom of the temperature chamber 48.
  • This is covered with a perforated plate 44, which should prevent that parts can fall into the nitrogen lake at a temperature of -196 ° C.
  • two locks 47a and 47b are shown, which are arranged on the housing wall of the temperature-control chamber 48.
  • a multi-well plate 1 Via the lock 47a, a multi-well plate 1 is warmly introduced or carried out in the temperature-control chamber 48.
  • a multiwell plate 1 Via the lock 47b, a multiwell plate 1 can be cold introduced or performed in the temperature control chamber 48. If, due to the introduction or removal of a multi-well plate 1, moist air enters the tempering chamber from the outside
  • Temperature chamber 48 and via the locks 47a, 47b are placed, through which the gaseous dry nitrogen escapes.
  • the overall system 40 is not sealed pressure-tight, but has a siphon-like outlet tube at the top (not shown here).
  • the area of the end faces in the heating temperature control unit 42 of the shrunken multiwell substructure geometry can be adapted at -150 ° C., ie the area the end faces of the tempering 42 for heating are made slightly smaller than the end faces of the tempering 41 for cooling.
  • the device 40 further comprises a positioning device (not shown), by means of which the multiwell plates 1 to be tempered within the chamber 49 can be moved in accordance with the travel paths illustrated by the arrows 45a-c or by the arrows 46a-c, and by means of which the multi-well plates can be positioned in particular exactly aligned above the tempering bodies 41 and 42.
  • the arrows 45a-c show here the temporal and spatial sequence when heating a cryogenic multiwell plate 1.
  • the arrows 46a-c illustrate the course of a cooling of a multiwell plate 1.
  • the paths indicated by the arrows are by means of mechanical elements of the Go through positioning, the drives are preferably outside the temperature control chamber 48 and a conventional guide mechanism, such. As rods, coils, etc. (not shown), the multi-well plates - l - method.
  • a multiwell plate 1 containing bioprobes to be frozen is introduced via the lock 47a into the temperature control chamber 48 (arrow 46a) and moved by means of the positioning device into the cold layer 43a and there above the first, standing on the perforated plate 44 Temperature control 41 positioned (arrow 46b).
  • the positioning takes place in such a way that the cavities of the multi-well plate 1 are each positioned in alignment with the longitudinal axis of one of the temperature control fingers of the temperature-control body 41.
  • the thus positioned multiwell plate by means for contacting (not shown), such as. B. described above in connection with Figure 3, controlled or regulated lowered to be brought into contact with the tempering 41,
  • the multiwell plate 1 can either be stored for storage in the lower cold layer 43a or for further processing via the second
  • FIG. 5 schematically illustrates the application of a substance to the biological samples stored in the cavities 2, and shows a series of cavities 2 with a liquid filling 20 and cells 21 on the cavity bottoms 11 the temperature control fingers 5.
  • a substance 51 with a pipetting 50, z. B. with a pipetting robot, added to the cavities 2.
  • These may be, for example, antifreeze agents, particle suspensions, gels and the like which solidify, which are helpful in freezing, but may also be closure material which, when solidified, seals the surface of the actual cavity contents with respect to the exterior so that there is no cover or other is needed as a closure, which simplifies the automation processes.
  • These can also be recrystallization processes which are not visible macroscopically but can easily be detected and quantified by means of scattered light, fluorescence, Raman measurements or the like.
  • substances in solid or liquid form in the cavities 2, when the contents 20 is already frozen This can be differentiation factors for stem cells that become effective immediately after thawing, protective materials, or genetic material that only binds after thawing with the underlying solution. These can also be diluent media that reduce the concentration of antifreeze after thawing.
  • Figures 6A shows an arrangement of a tempering finger 5 and a cavity 2.
  • a filling which consists of three materials.
  • the culture medium 60 in which the bioprobes (here shown as cells on the bottom plate) are located, is a medium 61 which has been applied after freezing of the medium 60, so that it is not mixed with it , The whole is covered with another medium 62 which provides a gas tight seal to the outside atmosphere.
  • the medium 62 can be a natural or synthetic oil, a liquid-immiscible liquid, a gel, or solid CO 2. The advantage of such arrangements is that they can be optimally adapted to the process of thawing or freezing.
  • the type and arrangement of the media determines the reaction during thawing. Thus, staggered liquefaction takes place at different temperatures. Depending on the composition of the filling media can shift so that a new order arises, as shown in Figure 6B.
  • FIG. 6B shows two different states of an arrangement of a tempering finger 5 and a cavity 2.
  • the arrangement In the first state, designated “I”, the arrangement is in the cold state.
  • the second state designated “II” the arrangement in the warm state in which the nutrient solution 60 has thawed is shown, for example, when frozen, a silicone oil 63 is applied to the solid culture medium 60, which has a higher density than the nutrient solution 60, then this layer will turn over in sequence after the two phases have become liquid as the cells 64 easily detach from the surface during thawing and go into suspension, after thawing, they float in the upward-rising, final-layered nutrient solution 60, which can be easily removed from a vending machine without having to remove a cover
  • Alternative variants can be developed for freezing, for example by using glycerol solutions which remain liquid up to temperatures of -40 ° C and lower or which do not assume a solid state at all
  • a particular advantage of this arrangement and method is the possibility of checking the maintained
  • FIGS. 7A and 7B show two classic corrugated sheets 70, 71 with larger cavities 72, with a diameter of approximately 2 to 3 cm.
  • the corrugated sheets 70, 71 are made as an injection-molded part in a modified form for freezing in the entirety of the multiwell plate.
  • the bottom plate 75 is made of a heat-conducting thin material, for. B. of a polymer, a metal, a metal coating or diamond, so that the heat well above the cooling or
  • Warming room 74 which is located in a stable cooling or heating body 73, can be initiated or initiated.
  • the corrugated sheets 70, 71 are pressed from above onto the tempering unit 73 and can be bent over the cavities 76 in the corrugated sheet by creating a slight negative pressure.
  • This variant of the total cooling of the Multiwellsub- strate is a simplified form that combined with the Temperierkör ⁇ perstepn corresponding to FIGS 1 to 6 who can ⁇ .
  • Such a possibility of the combination is the introduction of the tempering 4, 24 in the space 74. This is traversed by a cooling or heating liquid or the tempering gas, whereby the corresponding temperature profiles are transmitted via the multiwell substrate bottom 75 in the cavities 72.
  • temperature sensors can be integrated, for.
  • FIGS. 8A and 8B show a cross-section of a multi-well plate and a tempering body according to a further embodiment.
  • Figure 8A shows a cross section of an arrangement of a multi-well plate 1 and a tempering 4, both of which are not yet in contact with each other.
  • FIG. 8B shows a single cavity 2 with the tempering cylinder 25 below.

Abstract

La présente invention concerne un corps de régulation de température (4) destiné à une plaque multipuits (1) qui présente une pluralité de cavités (2) disposées en lignes et en colonnes, pour congeler et/ou décongeler des échantillons biologiques. Le corps de régulation de température (4) comprend un corps de base (6) en matière thermo-conductrice pouvant être parcouru par un fluide de régulation de température ; et une pluralité d'ergots de régulation de température (5) en saillie, disposés en lignes et en colonnes sur un côté supérieur du corps de base (6), lesdits ergots étant reliés de manière thermo-conductrice au corps de base (6), un espace de grille entre les ergots de régulation de température (5) correspondant à un espace de grille entre les cavités (2) de la plaque multipuits (1). La présente invention concerne également un dispositif et un procédé pour congeler des échantillons biologiques, notamment pour réaliser la cryoconservation et/ou la décongélation d'échantillons biologiques, notamment d'un échantillon cryoconservé.
EP15798324.8A 2014-12-10 2015-11-06 Corps de régulation de température pour plaque multipuits et procédé et dispositif pour congeler et/ou décongeler des échantillons biologiques Pending EP3229965A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102014018308.4A DE102014018308A1 (de) 2014-12-10 2014-12-10 Temperierkörper für eine Multiwell-Platte und Verfahren und Vorrichtung zum Einfrieren und/oder Auftauen von biologischen Proben
PCT/EP2015/002232 WO2016091344A2 (fr) 2014-12-10 2015-11-06 Corps de régulation de température pour plaque multipuits et procédé et dispositif pour congeler et/ou décongeler des échantillons biologiques

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EP3229965A2 true EP3229965A2 (fr) 2017-10-18

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EP (1) EP3229965A2 (fr)
JP (1) JP6715841B2 (fr)
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CN (1) CN107257710B (fr)
DE (1) DE102014018308A1 (fr)
WO (1) WO2016091344A2 (fr)

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US10987673B2 (en) 2021-04-27
WO2016091344A3 (fr) 2016-08-04
DE102014018308A1 (de) 2016-06-16
KR102103237B1 (ko) 2020-04-22
KR20170093173A (ko) 2017-08-14
US20170333905A1 (en) 2017-11-23
JP2018510321A (ja) 2018-04-12
WO2016091344A2 (fr) 2016-06-16
CN107257710B (zh) 2020-07-31
CN107257710A (zh) 2017-10-17
JP6715841B2 (ja) 2020-07-01

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