METHOD AND DEVICE FOR CONTROLLING THE TEMPERATURE OF REACTION MIXTURES IN AN AGITATION OPERATION

Abstract

The invention relates to a method for controlling the temperature of reaction mixtures (2) in an agitation operation, wherein at least two reaction mixtures (2) in at least two reaction vessels (1) are individually temperature-controlled, said reaction mixtures (2) in said reaction vessels (1) being subjected to a common agitation movement (3), the individual temperature control of at least two reaction mixtures (2) being carried out by means of a separate heat transfer (6) between each at least one reaction mixture (2) and at least one temperature control zone (4) associated with said reaction mixture (2).

Claims

1-14. (canceled)

15. A method for controlling temperature of reaction mixtures during an agitation operation, the method comprising: subjecting at least two reaction mixtures in at least two reaction vessels to a common agitation movement; and individually controlling temperature of the at least two reaction mixtures by means of a separate heat transfer between at least one of the at least two reaction mixtures and at least one temperature control zone associated with the at least one of the at least two reaction mixtures.

16. The method according to claim 15, wherein the temperature is controlled using a plurality of individually controllable temperature control elements.

17. The method according to claim 15, wherein the at least two reaction mixtures or temperature control zones are temperature controlled by individually controlling temperature control elements.

18. The method according to claim 15, wherein the at least two reaction mixtures are separated from one another by at least one isolation zone so that maximum achievable heat transfer between the at least two reaction mixtures is less than maximum achievable heat transfer between one of the at least two temperature control zones and a corresponding reaction mixture.

19. The method according to claim 15, wherein the at least two temperature control zones are separated from one another by at least one isolation zone so that maximum achievable heat transfer between the at least two temperature control zones is less than maximum achievable heat transfer between one of the at reaction mixtures and a corresponding control zone.

20. The method according to claim 15, wherein at least two temperature control zones are combined to form a larger temperature control zone or that at least two temperature control elements are combined to form a larger temperature control element.

21. The method according to claim 15, wherein for a combination of temperature control zones, a first number of temperature control elements are controlled identically while a second number of temperature control elements are controlled differently.

22. The method according to claim 15, wherein a temperature control element locally associated with an isolation zone is switched to inactive in order to form the isolation zone.

23. The method according to claim 22, wherein the combination of the at least two temperature control zones or temperature control elements is associated with positioning or shape of reaction vessels, optionally, by means of a targeted control of the temperature control elements.

24. The method according to claim 15, wherein the at least one temperature control zone or at least one temperature control element is controlled on a basis of measurement information that was recorded by at least one temperature sensor.

25. The method according to claim 15, wherein the at least one temperature control zone or at least one temperature control element is controlled on a basis of measurement data or information that was recorded during a process in, on or in a vicinity of the reaction mixture to be temperature-controlled.

26. A device for carrying out the method according to claim 15, the device comprising: at least one agitation platform driven by an agitation drive, on which the at least two reaction mixtures are exposed to a common agitation movement in the at least two reaction vessels; and at least two temperature control elements or temperature control zones which are each associated with one of the at least two reaction mixtures in each of the at least two reaction vessels and by means of which the individual temperature control of at least two reaction mixtures is carried out.

27. The device according to claim 26, further comprising at least one isolation zone which separates the at least two reaction mixtures in such a way that maximum achievable heat transfer between at least two reaction mixtures is smaller than maximum achievable heat transfer between at least one temperature control zone and at least one associated reaction mixture.

28. The device according to claim 27, further comprising a plurality of temperature control zones or temperature control elements which can be freely combined with one another.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIG. 1 is a schematic representation of the method, according to the invention, with two reaction vessels 1, which are filled with two reaction mixtures 2 to be individually temperature-controlled and separated by an isolation zone 5.

[0039] FIG. 2A and FIG. 2B are schematic representations of an embodiment of the device, according to the invention, for performing the method, according to the invention, for shaking flasks and reaction tubes as reaction vessels 1 on an orbital shaker with individually combined arrays of small temperature control elements 9 and temperature control zones 4.

[0040] FIG. 3 is a schematic representation of an embodiment of the device, according to the invention, for performing the method according to the invention for microtiter plates using infrared lighting for the individual temperature control of each well.

DETAILED DESCRIPTION

Definitions

[0041] To ensure the clarity of some terms used in the description, they are defined and explained below and throughout the description.

[0042] Reaction vessels in the context of the invention are all equipment and vessels that are suitable for receiving and storing reaction mixtures. They can be open or closed. Reaction vessels within the meaning of the invention are, in particular but not exclusively, shaking flasks, reaction tubes, falcons, T-flasks, microtiter plates, agitation bags and agitation vessels of any geometry, material composition and filling quantity.

[0043] Reaction mixtures within the meaning of the invention are mixtures of at least two components and are, in particular but not exclusively, liquids, solutions, emulsions, dispersions, slurries, suspensions, foams, gas mixtures or powder mixtures. Biological, chemical or physical processes or reactions take place in reaction mixtures. Reaction mixtures within the meaning of the invention, therefore, include, in particular but not exclusively, mixtures of culture mediums and cells, starting materials, catalysts and products, various states of aggregation, etc.

[0044] For the purposes of the invention, agitation movements are movements which are suitable for moving or mixing the reaction mixtures contained in them by moving the reaction vessels. Agitation movements within the meaning of the invention are, in particular but not exclusively, orbital agitation, rocking agitation and tumbling agitation. Agitation movements within the meaning of the invention can be carried out continuously or discontinuously, depending on the process requirements.

[0045] The temperature control of a reaction mixture in the context of the invention is the setting of a specific temperature in the reaction mixture via the transfer of heat into or out of the reaction mixture. The heat can be transferred directly into or from the reaction mixture or indirectly via the reaction vessel, in particular but not exclusively, via convection, thermal conduction or thermal radiation.

[0046] Temperature control zones within the meaning of the invention are all zones, regions, surfaces or volumes that are involved in the targeted heat transfer between the reaction mixture and the temperature control element.

[0047] Temperature control elements within the meaning of the invention are all devices that are suitable for generating heat from other forms of energy or for generating temperature gradients, which can be used for controlling the temperature of the reaction mixtures, by heat transport. Temperature control elements within the meaning of the invention are, in particular but not exclusively, electrical heating elements, heating foils, Peltier elements, heat emitters, IR LEDs, heat engines, heat pumps, fans and pumps.

[0048] Isolation zones within the meaning of the invention are all zones, regions, surfaces or volumes that limit or prevent the transfer of heat between different reaction mixtures or temperature control zones.

[0049] According to the invention, the maximum achievable heat transfer denotes the amount of heat that can be exchanged per time between at least two inventive components, regions, zones, surfaces or volumes under the given conditions (e.g., heating or cooling capacity, temperature difference), regardless of the heat transfer mechanism.

Described Embodiments

[0050] Turning now to the drawings, FIG. 1 shows a schematic representation of the method, according to the invention. Two reaction vessels 1 exposed to the same agitation movement 3 are respectively filled with different reaction mixtures 2 and are individually temperature-controlled by means of the method, according to the invention. To this purpose, each reaction vessel 1 with the reaction mixture 2 contained therein is located in the effective range of a separate temperature control zone 4 that individually carries out the temperature control of the associated reaction mixture 2 by means of a heat transfer 6 between the temperature control zone 4 and the reaction mixture 2.

[0051] The reaction mixtures 2 in their reaction vessels 1 are at least partially separated by at least one isolation zone 5 in such a way that the maximum achievable heat transfer 7 between the reaction mixtures 2 is less than the maximum achievable heat transfer 6 between the respective associated temperature control zone 4 and the reaction mixture 2. The temperature control zones 4 are also advantageously separated from one another by at least one isolation zone in such a way that the maximum achievable heat transfer 8 between the temperature control zones 4 is lower than the maximum achievable heat transfer 6 between the temperature control zone 4 and reaction mixture 2 associated with each other. According to the invention, this allows for an individual and process-optimal temperature control of each reaction mixture 2 without a negative influence on the respective individual reaction processes by the temperature or the temperature control of adjacent reaction mixtures 2.

[0052] FIGS. 2A-2B show a schematic representation of an embodiment of the device, according to the invention, for performing the method, according to the invention, for shaking flasks and reaction tubes as reaction vessels 1 on an orbital shaker, which comprises at least one agitation drive 11 and one agitation platform 10. FIG. 2A is a top view of the agitation platform 10 whereas FIG. 2B is a side view of the embodiment. FIGS. 2A-2B contain some schematic simplifications that serve to clarify and better illustrate the features, according to the invention. In particular, the reaction mixtures 2 that are present in the reaction vessels 1 and the holder for reaction tubes 14 are not shown in FIG. 2A in order to emphasize the arrangement of the temperature control zones 4 and the temperature control elements 9. Furthermore, for illustration clarity reasons, no complete side view of the arrangement in FIG. 2A is shown in FIG. 2B, but instead only its first row of reaction vessels 1 is shown. The fastening of the reaction vessels 1, in particular the shaking flasks, on the agitation platform 10 is not shown either in FIGS. 2A-2B for illustration clarity reasons.

[0053] On an agitation platform 10, which is driven by an agitation drive 11, a plurality of reaction mixtures 2 to be individually temperature-controlled are positioned in different reaction vessels 1. The reaction vessels 1 shown include shaking flasks of various sizes as well as culture tubes. The reaction mixtures 2 in their reaction vessels 1 are all exposed to a common agitation 3 on the agitation platform 10. According to the invention, a plurality of temperature control elements 9 are integrated into the agitation platform 10, said temperature control elements each generating separately controllable temperature control zones 4 or being used as insulation zones 5 by being switched off.

[0054] FIG. 2A illustrates the combination, according to the invention, of a plurality of temperature control elements 9 or temperature control zones 4 to form combined arrays of small temperature control zones 4 and temperature control elements 9. According to the invention, this combination is performed on the basis of the size of the reaction vessels 1, as shown in FIG. 2A, on the basis of the cross-sections of the reaction vessels 1. Further temperature control elements 9, which are used as isolation zones 5 by being switched off or being used as an active counter-regulation, are found between the combined temperature control zones 4 specific to each reaction vessel. According to the invention, the temperature control elements 9 on the agitation platform 10 can be linked to one another to form temperature control zones 4 or isolation zones 5 to be recombined depending on the loading and positioning of reaction vessels 1 with reaction mixtures 2.

[0055] The temperature control zones can be combined by means of a synchronous control of adjacent temperature control elements. If a group of individual temperature control elements is controlled identically, a larger temperature control zone can be formed as a result. An isolation zone can be created by deactivating individual temperature control elements; the gas phase above said zone is then not heated and thus insulates the adjoining temperature control zone.

[0056] The reaction vessels 1 with the reaction mixtures 2 contained in them are surrounded by a gaseous phase as the isolation zone 5, which consists of either ambient air or an atmosphere regulated with regard to its composition, pressure, temperature and humidity. In some embodiments of the invention, this gas phase functions simultaneously as an isolation zone 5 and as a weak temperature control zone 4, which performs a heat transfer-limited basic temperature control of all reaction mixtures 2, which is then individually adapted locally by the temperature control elements 9 on the agitation platform 10.

[0057] FIG. 2B also shows a holder for reaction tubes 14, which itself in turn has regions with high thermal conductivity as temperature control zones 4 and regions with low thermal conductivity as isolation zones 5. In an advantageous embodiment of the invention, the temperature control elements 9 under the holder for the reaction tubes 14 are adapted to the position of its temperature control zones 4 and isolation zones 5.

[0058] The fastening of the shaking flasks as reaction vessels 1 on the agitation platform 10 is not shown in FIGS. 2A-2B for illustration clarity reasons. According to the invention, reaction vessels 1 with the devices customary for them are attached to the agitation platform 10 so that, in an advantageous embodiment of the invention, the heat transfer 6 between the temperature control zone 4 and the reaction mixture 2 is greater than the heat transfer 7 between at least two reaction mixtures 2. In some embodiments of the invention, the fastening device itself can be used as a temperature control zone 4 in order to allow for a suitable heat transfer between at least one temperature control element 9 and the reaction mixture 2 by means of its reaction vessel 1. This applies, for example, to clips and adhesive mats with which shaking flasks are attached to agitation platforms 10. According to the invention, metallic clips or thermally conductive adhesive mats thus function as temperature control zones 4, which allow for a heat transfer between one or more Peltier elements as temperature control element 9 and the reaction mixture 2 through their contact surface with the reaction vessel 1. According to the invention, the same also applies to other devices which are suitable for fastening at least one reaction vessel 1 on the agitation platform 10.

[0059] According to the invention, the agitation platform 10 also includes temperature sensors 12 in addition to the temperature control elements 9. In an advantageous embodiment of the invention, the temperature sensors 12 directly detect the temperature of the reaction mixture 2 associated with them, in particular but not exclusively, by means of its emitted infrared radiation. In further embodiments of the invention, the temperature sensors 12 detect the temperature of the reaction vessel 1 associated with them and thus indirectly the temperature of the reaction mixture 2 in the equilibrium. In some configurations of the invention, the temperature sensors also detect the temperature of the temperature control zones 4 or isolation zones 5 or temperature control elements 9.

[0060] According to the invention, the temperatures detected by temperature sensors 12 are used to individually regulate the temperature control of individual reaction mixtures 2 in their reaction vessels 1. According to the invention, the detection of temperature gradients between reaction vessels 1, reaction mixtures 2, temperature control zones 4, isolation zones 5 or temperature control elements 9 allows for a particularly precise temperature control. According to the invention, temperature sensors 12 can be attached in a wide variety of planes and positions in order to be able to detect such temperature gradients.

[0061] FIG. 3 is a schematic representation of an embodiment of the device, according to the invention, for performing the method, according to the invention, for microtiter plates using infrared lighting for the individual temperature control of each well. According to the invention, a microtiter plate represents an array of interconnected reaction vessels 1 with each well corresponding to a reaction vessel 1 and being filled with a reaction mixture 2 to be individually temperature-controlled. The microtiter plate is attached to a shaken agitation platform 10, which is moved by an agitation drive 11, so that all reaction vessels 1 of the microtiter plate are subjected to a common agitation movement 3.

[0062] In order to be able to control the temperature of each well separately, the walls of the microtiter plate and thus the walls of the reaction vessels 1 are designed here as isolation zones 5. The temperature of the individual reaction mixtures 2 is therefore not controlled by means of contact surfaces but rather directly by means of radiation-based heat transfers 6 between the temperature control element 9 and the reaction mixture 2. FIG. 3 is a device, according to the invention, in which infrared radiators (in particular, as IR LEDs) are arranged as temperature control elements 9 in a holder 13 with at least a partial field of view of their associated reaction mixture 2 with at least one infrared radiator individually transferring heat as infrared radiation in an associated reaction mixture 2.

[0063] Just as in FIGS. 2A-2B, the reaction vessels 1 with the reaction mixtures 2 contained in them are surrounded by a gaseous phase as the isolation zone 5, which consists of either ambient air or an atmosphere regulated with regard to its composition, pressure, temperature and humidity. In some embodiments of the invention, this gas phase functions simultaneously as an isolation zone 5 and as a weak temperature control zone 4, which performs a heat transfer-limited basic temperature control or cooling of all reaction mixtures 2, which is then individually adapted locally by the infrared radiators as temperature control elements 9.

[0064] In some embodiments of the invention, the walls of at least one reaction vessel 1 are partially or completely able to strongly reflect or absorb infrared radiation in order to increase the heat transfer into the reaction mixture 2 either in the mixture itself or on the heated walls of the reaction vessel 1. According to the invention, this is achieved through the selection of suitable reaction vessel materials, colors or coatings.

[0065] FIG. 3 shows temperature sensors 12 both in the agitation platform 10 and in an additional holder 13. The temperature sensors 12 in the agitation platform 10 primarily determine the temperature of the reaction vessels 1 whereas the temperature sensors 12 in the holder directly determine the temperature of the reaction mixtures 2 associated with them by means of their IR emission. In an advantageous embodiment of the invention, these IR temperature sensors 12 are either visually clearly separated from the temperature control elements 9 or are modulated and operated in a manner that is matched to the temperature control elements 9. In some embodiments of the invention, these IR temperature sensors 12 are also used to measure and adapt the radiation power of the temperature control elements 9.

[0066] In some embodiments of the invention, the holder 13 is also agitated so that there is no relative movement between the reaction vessels 1 and the holder 13. In other embodiments, the holder is fixed externally 13 so that a relative movement occurs between the reaction vessels 1 and the holder 13. In some embodiments of the invention, the association changes the temperature control elements 9 and the temperature sensors 12 to at least one reaction mixture 2 as a result of the relative movement so that, with a suitable control, a plurality of reaction mixtures 2 can be individually temperature-controlled by means of a single combination of a temperature control element 9 and a temperature sensor 12.

LIST OF REFERENCE NUMBERS

[0067] 1 Reaction vessel [0068] 2 Reaction mixture [0069] 3 Agitation movement [0070] 4 Temperature control zone [0071] 5 Isolation zone [0072] 6 Heat transfer between the temperature control zone 4 or the temperature control element 9 and the reaction mixture 2 [0073] 7 Heat transfer between at least two reaction mixtures 2 [0074] 8 Heat transfer between at least two temperature control zones 4 [0075] 9 Temperature control element [0076] 10 Agitation platform [0077] 11 Agitation drive [0078] 12 Temperature sensor [0079] 13 Holder [0080] 14 Holder for reaction tubes