METHOD AND DEVICE FOR CARRYING OUT REACTION PROCESSES

Abstract

A method for carrying out a reaction process, in particular for setting the mixing and/or aeration of a reaction liquid while the reaction process is being carried out, which includes filling at least one reaction vessel with at least one reaction liquid, wherein an internal volume of the reaction vessel is not completely filled by the at least one reaction liquid at all times during the reaction process, and changing the internal volume of the reaction vessel in the course of the reaction process, in particular in a targeted manner, which causes a movement of the at least one reaction liquid.

Claims

1. A method for carrying out a reaction process, in particular for setting the mixing and/or aeration of a reaction liquid (2) while the reaction process is being carried out, the method comprising: filling at least one reaction vessel (1) with at least one reaction liquid (2), wherein an internal volume (4) of the reaction vessel (1) is not completely filled by the at least one reaction liquid (2) at all times during the reaction process, and changing (5) the internal volume (4) of the reaction vessel (1), in the course of the reaction process, in particular in a targeted manner, which causes a movement (6) of the at least one reaction liquid (2).

2. The method according to claim 1, characterized in that the change in the internal volume is used to set the mixing and/or aeration of the at least one reaction liquid (2) in a targeted manner.

3. The method according to either of the preceding claims, characterized in that the internal volume is changed by 5%, optionally at least 10%, or at least 20% or 50%.

4. The method according to claim 1, characterized in that in addition to the at least one reaction liquid (2), at least one headspace (3) is also provided in the internal volume, which is filled with a gas phase, and in that the internal volume is changed such that the volume of the at least one headspace is changed by 5%, optionally at least 10%, or at least 20% or 50%.

5. The method according to claim 1, characterized in that the change (5) in the internal volume (4) is accompanied by a change in shape of the reaction vessel (1).

6. The method according to claim 1, characterized in that the change (5) in the internal volume (4) or in shape of the reaction vessel (1) takes place repeatedly, periodically or continuously in the course of the reaction process.

7. The method according to claim 1, characterized in that the change (5) in the internal volume (4) causes at least one gas transfer (8) via at least one opening (7) of the reaction vessel (1).

8. The method according to claim 1, characterized in that at least one flexible wall (10) is deformed by at least one actuator (9) in order to achieve a change (5) in the internal volume (4) or in the shape of the reaction vessel (1) and thus to cause the at least one reaction liquid (2) to move (6) and to mix said at least one reaction liquid (2).

9. The method according to claim 1, characterized in that the change (5) in the internal volume (4) or in the shape of the reaction vessel (1) is adjusted to requirements of the reaction process in the course of said process.

10. A device for carrying out the method according to claim 1, comprising at least one reaction vessel (1) which contains at least one reaction liquid (2), wherein the internal volume (4) of the reaction vessel (1), at at least one point in time of the reaction process, also comprising, in addition to the at least one reaction liquid (2), at least one headspace (3), characterized in that the reaction vessel comprises at least one flexible wall or at least one flexible wall region (10) and in that the device comprises at least one actuator (9) which is designed, in particular for the targeted setting of the mixing and/or aeration of a reaction liquid, to bring about a change (5) in the internal volume (4) or in the shape of the reaction vessel (1).

11. The device according to claim 10, further comprising an actuator drive (11) and an actuator controller (12).

12. The device according to claim 10, characterized in that the reaction vessel (1) comprises at least one opening (7) which is suitable for bringing about at least one gas transfer (8).

13. The device according to claim 10, characterized in that at least one opening (7) of the reaction vessel (1) is closed by means of a sterile barrier (14).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG. 1 is a schematic representation of the method according to the invention.

[0036] FIG. 2 is a schematic representation of the method according to the invention with a change in the shape of the reaction vessel.

[0037] FIG. 3 is a schematic representation of the method according to the invention with gas transfer.

[0038] FIG. 4 is a schematic representation of a device according to the invention for carrying out the method according to the invention.

[0039] FIG. 5 is a schematic representation of a device according to the invention for carrying out the method according to the invention with a magnetic actuator.

DETAILED DESCRIPTION

[0040] The present invention is explained in more detail with reference to the figures and embodiments. Reference signs in the figures designating components of the invention that have already been used in the same figure or in another figure under the same circumstances or in the same representation are partially omitted in order to maintain clarity of the figures. Graphic elements without reference signs are therefore to be interpreted in consideration of the list of reference signs, the other figures, the designated representations within the same figure, the patterning or structuring of already designated graphic elements and with reference to the entire description and the claims.

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

[0042] A reaction vessel within the meaning of the invention is any device and any vessel that is suitable for receiving or storing reaction liquid. It can be open or closed. Reaction vessels within the meaning of the invention are therefore in particular, but not exclusively, shake flasks, reaction tubes, falcons, T-flasks, microtiter plates, shaking bags and shaking vessels of any geometry, material composition and filling capacity.

[0043] A reaction liquid within the meaning of the invention is a fluid in which at least one reaction relevant to the particular reaction process takes place. Reaction liquids within the meaning of the invention are therefore in particular, but not exclusively, culture broths, mixtures of culture medium and cells, chemical or biochemical reaction mixtures of solvents, starting materials, catalysts and products, and in principle all types of solutions, emulsions, dispersions, slurries, suspensions, foams, or powder mixtures with fluid properties.

[0044] Within the meaning of the invention, the headspace denotes the part of the internal volume of a reaction vessel which is not filled with reaction liquid. Said headspace is mostly filled with a gas phase and can therefore in particular, but not exclusively, contain air as well as any random or well-defined other gas mixture or pure gas, or can be completely or almost completely free of matter (vacuum).

[0045] Within the meaning of the invention, the internal volume denotes the inner volume of a reaction vessel that is enclosed by the reaction vessel. In the case of reaction vessels having at least one opening, the internal volume corresponds to the inner volume that would be enclosed if each existing opening were closed with the smallest possible area.

[0046] A change in the internal volume or in the shape of a reaction vessel is present within the meaning of the invention when the internal volumes or the shapes of a reaction vessel of at least two considered states of the reaction vessel or points in time of the reaction process are not identical.

[0047] Movements of the reaction liquid within the meaning of the invention are all movements that are suitable for mixing the reaction liquid or maintaining the mixing state of the reaction liquid.

[0048] Gas transfer within the meaning of the invention refers to any conceivable type of transport of at least one gas or gaseous molecule between two locations in space. Gas transfer within the meaning of the invention thus takes place in particular, but not exclusively, via diffusion, convection or via reactions such as evaporation, sublimation, condensation, solvation, desolvation, adsorption or desorption.

[0049] An actuator within the meaning of the invention is any device that is suitable for bringing about a change in the internal volume or in the shape of the reaction vessel. Actuators act in particular, but not exclusively, on flexible walls or wall components of the reaction vessel and on movably mounted components of the reaction vessel. Actuators within the meaning of the invention are in particular, but not exclusively, lifters, arms, pushers, slides, axes, eccentrics, permanent magnets, temperature-control elements, bimetal strips, hydraulic or pneumatic actuators, cranks, screws, liquids and piezo crystals.

[0050] A flexible wall or a flexible wall region within the meaning of the invention is any wall region of the reaction vessel that can be deformed, shifted or rotated by a suitable actuator. Flexible walls or flexible wall regions within the meaning of the invention are in particular wall regions made of flexible polymers, rubber, silicone, woven fabric, fleece, metal sheets, or foils. Flexible walls or flexible wall regions can have support structures or comprise optically transparent windows in order to allow optical sensors access to the reaction liquid in the reaction vessel. Flexible walls or flexible wall regions can contain or include, but in particular not exclusively, mechanical, capacitive, resistive, inductive, magnetic or optical sensors that allow characterization of the shape and distribution as well as other parameters of the reaction liquid or of the flexible wall itself

[0051] An actuator drive within the meaning of the invention is any device that is suitable for bringing about, conveying or adjusting the action of an actuator according to the invention. Actuator drives within the meaning of the invention are, in particular, motors, coils, electromagnets, pumps, heating and cooling elements, as well as voltage sources or current sources.

[0052] An actuator controller within the meaning of the invention is any device that is suitable for configuring, controlling or adjusting actuators or actuator drives according to the invention. Actuator controllers are often either analog control chains or computers, the latter including all devices, in particular electronic devices, that can store data (in particular arithmetic and logic data) and process said data on the basis of programmable rules. In particular, but not exclusively, microcontrollers, microprocessors, system-on-a-chip computers (SoC), PCs and servers, as well as networks of computers, are considered to be computers and thus also actuator controllers within the meaning of the invention.

[0053] A sterile barrier within the meaning of the invention is a gas-permeable device which is used in particular to prevent, reduce or completely stop the penetration of undesired cells, viruses or other contamination into the interior of the device according to the invention through at least one opening. Sterile barriers according to the invention allow at least one gas transfer between the headspace and the environment or the reaction liquid and the environment, in particular via diffusion or convection. Sterile barriers within the meaning of the invention are in particular, but not exclusively, sterile filters, porous membranes (e.g., PTFE, cellulose, hydrophilic or hydrophobic, etc.), cotton plugs or pads, and open-pore foams made of silicone, polyurethane or other plastics materials. Sterile barriers within the meaning of the invention are mostly connected to the wall of the reaction vessel, in particular, but not exclusively, by direct bonding or welding, as well as indirectly via suitable closure systems having a screw closure or locking closure or other interlocking or bonded connections.

[0054] A fastening device within the meaning of the invention is any device that is suitable for attaching at least one reaction vessel to another device, in particular, but not exclusively, to a table or a shaking platform. Fastening devices establish a mechanically loadable connection between at least one reaction vessel and at least one further device (in particular by means of an interlocking or bonded connection, negative pressure and by means of all types of gluing and adhesion).

[0055] Turning now to the drawings, FIG. 1 is a schematic representation of the method according to the invention. For this, a reaction vessel 1 is filled with at least one reaction liquid 2 that is to be mixed in the course of the reaction process. However, the reaction liquid 2 does not fill the reaction vessel 1 completely at each point in time of the reaction process, but rather, in the reaction vessel 1, there is at least temporarily a headspace 3 in which there is no reaction liquid 2, but which is usually filled with a gas phase, in particular, but not exclusively, air. The entire internal volume 4 of the reaction vessel 1 thus comprises all regions of the reaction vessel 1 that are filled with reaction liquid 2 or that are part of the headspace 3. The method according to the invention is characterized by at least one change 5 in the internal volume 4 of the reaction vessel 1, the change 5 causing a movement 6 of the reaction liquid 2 and thus the mixing thereof.

[0056] In some embodiments of the invention, the internal volume 4 comprises, throughout the entire reaction process, at least one headspace 3, the gas phase of which can be compressed or decompressed by changes 5 according to the invention in the internal volume 4.

[0057] In an advantageous embodiment of the invention, as shown in FIG. 1, there are at least two different limit states of the internal volume 4, between which all internal volume changes 5 take place periodically continuously, such that the reaction liquid 2 performs movements 6 throughout the entire reaction process and is thus continuously mixed.

[0058] In an advantageous embodiment of the invention, the method according to the invention comprises the formation of a reaction liquid film 17 on the differential area of the different limit states of the internal volume 4. According to the invention, this reaction liquid film 17 is produced by the adhesion of the reaction liquid 2 to the inner walls of the reaction vessel 1. Said film can advantageously increase the gas exchange between the headspace 3 and the reaction liquid 2.

[0059] FIG. 2 is a schematic representation of the method according to the invention as in FIG. 1 but, in addition to the change 5 in the internal volume 4, also has a change in the shape of the reaction vessel 1. The movements 6 according to the invention of the reaction liquid 2 can thereby advantageously be intensified, or directed and influenced in a targeted manner. Thus, in an advantageous embodiment of the invention, the formation of inhomogeneously mixed regions in the reaction liquid 2 can be avoided by means of targeted deformation of the reaction vessel 1.

[0060] In an advantageous embodiment of the invention, the deformation of the reaction vessel 1 also takes place periodically continuously, so that the reaction liquid 2 performs movements 6 throughout the entire reaction process and is thus continuously mixed.

[0061] FIG. 3 is a schematic representation of the method according to the invention with deformation of the reaction vessel 1 as in FIG. 2, the reaction vessel 1 here also comprising an opening 7. According to the invention, changes 5 in the internal volume 4 of the reaction vessel 1 cause pressure changes in the headspace 3 which, as shown in FIG. 3, lead to a gas transfer 8 via the opening 7 of the reaction vessel 1.

[0062] According to the invention, therefore, increases in the internal volume 4 lead to gases flowing into the reaction vessel 1, and reductions in the internal volume 4 lead to gases flowing out of the reaction vessel 1. According to the invention, the intensity and speed of the gas transfer 8 and thus the aeration of the reaction liquid 2 can therefore be adjusted by adjusting the change 5 in the internal volume 4 of the reaction vessel 1, and controlled according to the requirements of the reaction process taking place therein.

[0063] The change in the internal volume can be considerable in order to achieve the desired aeration and/or mixing. A change in the internal volume by more than 5%, even more than 50%, is possible. It is also possible to change the volume of the headspace by this amount.

[0064] This type of aeration advantageously results in an oscillating aeration process similar to human breathing. The formation of foams is avoided here, but at the same time there is a significantly more efficient active gas exchange between the headspace 3 and the environment of the reaction vessel 1 compared with passively aerated shaking reactions. In addition, the division into the at least two shown states—with a large and a smaller headspace volume—advantageously results in a two-phase gas exchange process in which, in the inflow phase (left-hand side), a large surface area is available for gas exchange between the headspace 3 and the reaction liquid 2 due to the simultaneous formation, according to the invention, of a reaction liquid film 17, while the outflow phase (right-hand side) takes place using a gas mixture which, for example, has delivered oxygen to the reaction liquid 2 and has absorbed carbon dioxide from said liquid. Here too, the method according to the invention behaves similarly to human breathing.

[0065] FIG. 4 shows a schematic representation of a device according to the invention for carrying out the method according to the invention. The device comprises a reaction vessel 1 which is filled with a reaction liquid 2. The reaction vessel 1 furthermore comprises a headspace 3. This, together with the reaction liquid 2, fills the internal volume 4 of the reaction vessel 1. At least one wall or at least one part of at least one wall of the reaction vessel 1 is designed to be flexible, here in the form of a flexible wall 10. In order to carry out the method according to the invention, this flexible wall 10 is at least temporarily in contact with at least one actuator 9, by means of which the flexible wall 10 is shifted or deformed in order to bring about the change 5 according to the invention in the internal volume 4 or in the shape of the reaction vessel 1 and thus the movement 6 of the reaction liquid 2 necessary for the mixing.

[0066] FIG. 5 is a schematic representation of a device according to the invention for carrying out the method according to the invention with a magnetic actuator 9. The reaction vessel 1 is designed based on an Erlenmeyer flask and is filled with reaction liquid 2. The design of the base of the reaction vessel 1 as a flexible wall makes it possible to carry out the method according to the invention. A permanent magnet is firmly connected to the flexible wall 10 as the actuator 9. This actuator 9 is moved up and down via a current-carrying coil, which is switchable and controllable by means of an actuator controller 12 and is in the form of an actuator drive 11, and the switchable external magnetic field 13 produced thereby. As a result, the shape and extent of the flexible wall 10 and thus the internal volume 4, and the shape of the reaction vessel 1, is changed according to the invention so as to produce a mixing movement 6 of the reaction liquid 2 and formation of the gas-exchange-promoting reaction liquid film 17.

[0067] The reaction vessel 1 shown also has an opening 7 through which, as already described for FIG. 3, the gas transfer 8 according to the invention between the headspace 3 and the environment of the reaction vessel 1 takes place. The opening 7 is closed by a gas-permeable sterile barrier 14 which prevents contamination of the reaction liquid 2.

[0068] Fastening devices 15 are also located on the reaction vessel 1, which devices allow the reaction vessel 1 to be attached to a shaking platform in order to achieve basic mixing of the reaction liquid 2 by means of shaking.

[0069] Furthermore, capacitive or resistive strain gauges 16 are located on or in the flexible wall 10 in order to detect the mass, shape and distribution of the reaction liquid 2 during the reaction process. These data can advantageously be integrated into the control and actuation of the actuator drive 11 via the actuator controller 12 and thus into the implementation of the method according to the invention.

[0070] In an advantageous embodiment of the invention with shaking operation, the actuator drive 11, the actuator controller 12 and the electrical circuits and computers necessary for detecting and analyzing the data from the strain gauges 16 are integrated into the shaking platform to which the reaction vessel 1 is attached by means of the fastening devices 15.

LIST OF REFERENCE SIGNS

[0071] For the relevant interpretation of the reference signs, reference is made to the description and claims.

[0072] 1 Reaction vessel

[0073] 2 Reaction liquid

[0074] 3 Headspace

[0075] 4 Internal volume

[0076] 5 Change in the internal volume or in the shape of the reaction vessel

[0077] 6 Movement of the reaction liquid

[0078] 7 Opening

[0079] 8 Gas transfer

[0080] 9 Actuator

[0081] 10 Flexible wall or flexible wall region

[0082] 11 Actuator drive

[0083] 12 Actuator controller

[0084] 13 External magnetic field

[0085] 14 Sterile barrier

[0086] 15 Fastening device

[0087] 16 Strain gauges