WO2009132616A2 - Système d'amenée - Google Patents

Système d'amenée Download PDF

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Publication number
WO2009132616A2
WO2009132616A2 PCT/DE2009/000528 DE2009000528W WO2009132616A2 WO 2009132616 A2 WO2009132616 A2 WO 2009132616A2 DE 2009000528 W DE2009000528 W DE 2009000528W WO 2009132616 A2 WO2009132616 A2 WO 2009132616A2
Authority
WO
WIPO (PCT)
Prior art keywords
supply system
layer
channels
mixing chamber
flow element
Prior art date
Application number
PCT/DE2009/000528
Other languages
German (de)
English (en)
Other versions
WO2009132616A3 (fr
Inventor
Claus FÜTTERER
Hans-Ulrich Fried
Arne Brombas
Original Assignee
Forschungszentrum Jülich GmbH
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 Forschungszentrum Jülich GmbH filed Critical Forschungszentrum Jülich GmbH
Publication of WO2009132616A2 publication Critical patent/WO2009132616A2/fr
Publication of WO2009132616A3 publication Critical patent/WO2009132616A3/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/71745—Feed mechanisms characterised by the means for feeding the components to the mixer using pneumatic pressure, overpressure, gas or air pressure in a closed receptacle or circuit system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/71805—Feed mechanisms characterised by the means for feeding the components to the mixer using valves, gates, orifices or openings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/30—Driving arrangements; Transmissions; Couplings; Brakes
    • B01F2035/35—Use of other general mechanical engineering elements in mixing devices
    • B01F2035/351—Sealings

Definitions

  • the invention relates to a supply system, in particular a supply system for perfusion.
  • Prior art supply systems are known for perfusion, consisting of several reservoirs for liquids, each of which is connected via a conduit to a mixing chamber which supplies the mixed liquid to a substrate to be perfused via a drain.
  • These devices are confusing in structure, take up a lot of space, are therefore not easy and a germ-free operation can not be guaranteed.
  • the prior art devices require a high experimental design skill in order to ensure the tightness of the devices. Furthermore lead the supply systems according to the prior art
  • the tightness of the device should allow pressurization of, for example, 7 bar without escaping gas or liquid to the outside.
  • the supply system should be immune to interference and a simple predictability of the flow parameters, such as flow rate
  • the liquid supplied to the substrate should be easy and as accurate as possible to temper.
  • the invention comprises a supply system to a substrate or a sample, comprising at least two feed lines to a mixing chamber and a discharge from the mixing chamber, wherein the feed system is formed by a layer system of at least two layers, of which the first layer is a flow element, into which the mixing chamber, at least two channels leading into the mixing chamber and an exit channel leading from the mixing chamber to a sample or a substrate, are embedded and the second layer is sealingly applied to the first layer.
  • Operation is inexpensive and the supply system is easy to manufacture and build.
  • the liquid-carrying flow element is easy to replace.
  • the supply system according to the invention can be applied to higher pressures, such as 7 bar, without affecting the tightness and reliability. Cross-contamination between different channels can be prevented.
  • the feed system according to the invention is robust against external influences, and the flow parameters in each channel can be easily calculated. A temperature control is also possible in a simple manner and very accurately. Through a simple-to-produce flow element of the experimental setup can be customized to the problem or the desired conditions.
  • Fig. 1 A side view of the device according to the invention
  • Fig. 2a A plan view of the inventive device
  • Fig. 2b An advantageous embodiment of the reservoir
  • FIG. 1 shows a supply system with storage containers 1, Ia, Ib, which are intended for receiving a liquid. They are each equipped with a pressure source 2, 2a, 2b, which are connected via a pressure regulator 3, 3a, 3b with the reservoirs 1, Ia, Ib. At the storage containers 1, Ia, Ib, there is in each case a supply line 4, 4a, 4b which is equipped with a valve 5, 5a, 5b.
  • the feed lines 4, 4a, 4b equipped with the valves 5, 5a, 5b lead into a layer system 6 with a layer 7 serving as a flow element and a cover layer 8 mounted above.
  • a further layer 9 is attached underneath the layer 7 serving as a flow element the serving as a flow element layer 7 presses against the cover layer.
  • channels 10, 1 Oa, 1 Ob are admitted, which connect the leads 4, 4a, 4b with a mixing chamber 11, which is also embedded in the serving as a flow element layer 7.
  • a mixing chamber 11 which is also embedded in the serving as a flow element layer 7.
  • Reference numeral 13 refers to temperature control.
  • Figure 2b shows a side view of an alternative embodiment of the reservoir.
  • the various storage vessels 1, Ia, Ib are stacked on top of each other.
  • the supply system comprises at least two layers, of which the first layer is a layer serving as a flow element 7, in which at least two Channels 10, 10a, which open into a mixing chamber 11, and an output channel 12 are recessed.
  • the fluidizing layer 7 may be a rigid plate which has been cast or into which the channels 10, 10a, the mixing chamber 11 and the outlet conduit 12 have been milled or otherwise recessed.
  • the materials used are rigid materials such as glass, plastic, e.g. Polymethyl methacrylate (PMMA) PTFE or other plastics and metal, preferably steel, into consideration.
  • PMMA Polymethyl methacrylate
  • the cover layer 8 is placed, which is liquid-sealingly connected to the flow element forming layer 7.
  • the seal can be ensured by an elastic intermediate layer of rubber, silicone or grease.
  • the layers 7 and 8 are secured together by means for holding the layers together. These means of holding together can be screwed or clamped.
  • the layer 7 serving as a flow element consists of an elastic material, such as rubber or silicone, which is cast.
  • an elastic material such as rubber or silicone
  • the leadership of the channels 10, 10a, 10b can be made according to the desired conditions for each experiment.
  • the preparation can be carried out by simple known methods, in particular, the layer can be cast but also milled. It cleaning operations of the fluidizing layer 7 are saved for reuse.
  • the layer 7 serving as a flow element consists of an elastic material, then it can be pressed against the cover layer 8 by a further layer 9, so that it seals off gas-tight or liquid-tight against the cover layer 8.
  • the same means for holding together the layers 7 and 8 can be used, as in the embodiment in which the serving as a flow element layer 7 is formed of rigid material.
  • a rigid or elastic layer as a flow element 7 For both embodiments, namely the use of a rigid or elastic layer as a flow element 7 is that these can be made individually for each new application according to the requirements of the experiment to be performed.
  • the newly produced, serving as a flow element layers 7, can be produced germ-free or under sterile conditions.
  • the liquid flow is limited to a plane, so that the computational effort for the calculation of the flow behavior is significantly reduced. With straight management of the channels 10, 10a and / or the output channel 12, the computational effort continues to reduce.
  • the flow resistance can therefore be easily calculated.
  • the simple and inexpensive way to recreate a layer serving as a flow element 7 for each use allows a one-time use of the layer. This eliminates additional cleaning work or the hassle of sterilization.
  • the fluidizing layer 7 is easy to manufacture, especially when cast from an elastomer such as polydimethylsiloxane (PDMS). Due to the interchangeability of layer 7, the delivery system can be adapted to the requirements of each experiment.
  • the serving as a flow element layer 7 comprises at least two channels 10, 10 a, which are freely selectable in number.
  • the channels 10, 10a and / or the output channel 12 may be equipped with means for interrupting the liquid flow.
  • These means for interrupting the liquid flow may be bores in the cover layer 8, which are located above the channels 10, 10a and / or the output channel 12, are embedded in the stamp, which can be lowered to either reduce the liquid flow or completely closed interrupt.
  • snaps or screw connections can be provided which are located in the bores and which are lowered or screwed in the direction of the channels 10, 10a... And / or of the outlet channel 12.
  • the means for interrupting the liquid flow may also be valves which, for example, presses down an elastomer layer over the cover layer 8 and the channel 10, 10a, 12 and / or the mixing chamber in such a way that the channel is closed.
  • the cover layer 8 can be made of transparent or transparent material, such as PMMA, glass or transparent plastic. This has the advantage that the liquid flowing through the channels 10, 10a, 10b, the mixing chamber 11 and the outlet channel 12 can be observed to detect blistering which could affect the liquid flow. This allows timely intervention in the course of the experiment.
  • the layer forming the flow element 7 may also be made of transparent or transparent material. In principle, the same materials can be used as in the cover layer, but transparent or transparent silicone is particularly preferred. This also has the consequence that the liquid flowing through the channels 10, 10a, 10b, the mixing chamber 11 and the outlet channel 12 can be observed to be e.g. Bubble formation that affects the flow of liquid.
  • the layer 9 can be transparent or transparent.
  • the advantages are the same as in layers 7 and 8.
  • a further chamber can be located behind the mixing chamber 11 in the outlet channel 12, which receives the sample to be supplied to the perfusion.
  • the device according to the invention may be equipped with detection means which detect certain observables of the sample in the chamber in the outlet conduit 12 which is perfused.
  • an optical detector may be provided which detects changes in the sample located in the chamber and optionally stores them as a film.
  • at least the cover layer 8 and / or the lower layer 9 must be transparent, so that an optical observation is possible.
  • all layers 7, 8, 9 can also be transparent.
  • the chamber located in the exit channel 12 may be equipped with other detectors which allow electrical or magnetic measurements.
  • Electrodes As detectors then electrodes, Ampersonden or means for impedance measurement are used. Furthermore, Hall sensors or squids can be used for magnetic measurements.
  • the transparent design of the layers 7 and / or 8 and / or 9 is optional.
  • At least a portion of the channels 10, 10a, and / or the output channel 12 has a cross-sectional geometry, wherein the width of the recessed channels 10, 10a and / or the output channel 12 is greater than the depth.
  • This cross-sectional geometry has the advantage that a particularly good heat exchange with the environment takes place.
  • the cross-section of the channels 10, 10a, and / or the output channel 12 is then, for example, rectangular, wherein the depth is smaller than the width of the cross section or the cross section forms a shallow groove with curves.
  • the output region of the output channel 12 may be designed to be wide, so that there is a particularly good heat exchange.
  • This cross-sectional geometry has the advantage that a particularly good heat exchange with the environment takes place, which favors a targeted and efficient temperature control.
  • Deep channels 10, 10a, and / or a deep outlet channel 12 have the advantage that a particularly good flow is possible. For example, with a deep channel or channel, the depth-to-width ratio is 1 or greater.
  • the cross section may also have curves. Between large heat exchange and small flow resistance must be weighed according to the application.
  • a heating plate or a cooling element for example a Peltier element or other tempering means, such as tempered liquid streams, can be introduced, which provide the desired temperature.
  • the tempering means may for example be applied or embedded between the layer forming the flow element 7 and the layer 9, but also at other locations, such as in the cover layer 8 or the lower layer 9.
  • the temperature control means can be arranged as desired in the region of the channels 10, 10a, 10b and / or in the region of the mixing chamber 11 and / or in the region of the outlet line 12, for example between the layer 9 and the layer 7 forming the flow element. It is also possible to introduce additional lines into the layer forming the flow element 7 and / or the cover layer 8 and / or the layer 9, which allow a circulation of Temperier deviskeiten.
  • Different channels 10, 10a, 10b can also be kept at different temperatures. Desirable temperatures are physiological temperatures which are generally higher than 32 ° C, for example 37 ° C. However, all temperature ranges of interest can be adjusted. For example, temperatures below 0 ° C, but also high temperatures, eg. B. 8O 0 C can be selected. If liquids, for example living cells, are supplied as substrate, extreme temperatures can also be selected for the respective cells in order to investigate their reaction.
  • the channels 10, 10a, 10b are connected via supply lines 4, 4a, 4b with the storage containers 1, Ia, Ib in connection.
  • the supply lines 4, 4a, 4b can be shut off by the valves 5, 5a, 5b from the channels 10, 10a, 10b ....
  • valves solenoid valves are preferably used.
  • the storage container 1, Ia, Ib can be arranged side by side or substantially side by side.
  • the storage containers 1, Ia, Ib are stacked on top of one another and furthermore preferably of a flat geometry.
  • the result of the flat geometry is that the liquid surface forming in the reservoir is comparatively large compared to a geometry with a greater depth in relation to the bottom surface.
  • the liquid forms a large surface, which is in optimal exchange with the surrounding gas phase.
  • a maximum saturation of the liquid can be achieved with the surrounding gas. This is particularly advantageous if the liquid is to contain defined dissolved gas fractions.
  • gases compositions are mixtures with defined oxygen content and / or defined CO 2 content for pH buffering.
  • Other gases include hydrogen sulfide, sulfur dioxide, ammonia, nitrogen or artificial air.
  • valves 5, 5a, 5b may be designed so that an optional return of the liquid to be conveyed to the storage containers 1, Ia, Ib is possible.
  • the storage container 1, Ia, Ib are connected to a pressure source 2.
  • This pressure source is preferably a pressurized gas supply or a pump with pressure vessel which is filled with gas.
  • each storage container 1 can be connected to a respective pressure source or at least two storage containers are connected to a pressure source.
  • the connection of the reservoir to a gas source allows the supply of liquid for a channel 10 with the respective desired gas, with which the liquid is to be acted upon.
  • Different liquid streams corresponding to different channels 10, 10a, 10b can be supplied with different gases and / or pressures.
  • gas reservoirs of different filling are provided as pressure sources.
  • gases are in particular CO 2 , or oxygen, nitrogen but also other gases into consideration.
  • valves 3, 3 a, 3 b are provided for pressure regulation between the pressure source 2 and the storage containers 1, 1 .
  • the valves 3, 3a, 3b are preferably solenoid valves.
  • pressure regulating modules in particular solenoid valves, a particularly accurate pressure regulation can be realized. Controlled pressure regulation can minimize the stress and thus the impairment of tissue during the experiment. Fluctuations in flow rates, especially when switching from In this way, gases or gases can be excluded so that continuous experimental conditions can be maintained. If at least two storage containers 1, Ia are connected to a pressure source, the channels 10, 10a assigned to these storage containers I 5 Ia can be charged with the same gas and the same pressure.
  • the solenoid valves can be controlled so that a constant flow or a targeted variation is possible.
  • the feed system according to the invention can be used for example for the following applications.
  • Structure of the supply system allows fast switching and easy and very fast replacement of the components in contact with the solution (contamination).
  • All substances of interest in particular biological material, can be used as examination objects, depending on the problem.
  • examination objects are cell cultures, even under unusual pressure and temperature conditions, biological tissue, surfaces to be treated, different organic or inorganic materials, for example in crystal growth.
  • the device according to the invention advantageously comprises only two or three elements, namely the layers 7, 8 and 9, instead of a plurality of tubes, which are cumbersome to handle and which have the disadvantages listed in the prior art.
  • the device according to the invention is compact and has good operational reliability even at elevated pressures of, for example, 7 bar.
  • the dimensions may vary as needed, however, the present invention joined layers have dimensions in the order of millimeters or centimeters in terms of side lengths.
  • the flow element 7 can allow flow rates of typically a few ⁇ l / min to 100 ml / min, depending on the channel geometry and pressure. .
  • the first part consists of several storage tanks that contain the liquids (nutrient solution, buffer, pharmaceuticals, etc.).
  • the second part consists of a very compact layered three-component system. It combines electrically controllable valves, a miniaturized mixing chamber and a temperature control and can be easily integrated into a wide variety of already existing experimental setups (patch-clamp setup, confocal
  • Liquids can be selected from the storage tanks via the valves and directed into the perfusion chamber.
  • a pneumatic pressure system allows a very precise flow regulation and simultaneous fumigation with CO 2 -O 2 at 37 degrees (physiological conditions) at elevated levels
  • control element The system is made up of only 3 components layered: control element, flow element, heating element.
  • the assembly is easy.
  • the elastomer layer has dual function: Carrier of the channel system and seal.
  • the flow element is easily replaceable in case of contamination or desired channel system change. Its production is simple and can be performed by non-experts.
  • the channel system can be designed as desired and manufactured using standard techniques.
  • the first part consists of several storage tanks that contain the liquids (nutrient solution, buffer, pharmaceuticals, etc.).
  • the second part consists of a very compact, layered, three-component system. It combines electrically controllable valves, a miniaturized mixing chamber and a temperature control and can be easily integrated into a wide variety of existing experimental setups (patch-clamp setup, confocal microscopes, two-photon microscopes). Liquids can be selected from the storage tanks via the valves and directed into the perfusion chamber.

Abstract

L'invention concerne un système d'amenée comportant au moins deux conduites d'amenée s'étendant vers une chambre de mélange pourvue d'une conduite de sortie pour les liquides mélangés. Le système d'amenée est composé d'un système de couches comportant au moins deux couches dont la première (7) est un élément d'écoulement intégrant la chambre de mélange (11), au moins deux canaux (10, 10a) menant à la chambre de mélange, et un canal de sortie (12) s'étendant de la chambre de mélange (11) à un échantillon ou un substrat; et la deuxième couche (8) est appliquée de façon étanche sur la première (7). Le système d'amenée est employé pour l'alimentation de tissus ou de cultures cellulaires en liquides.
PCT/DE2009/000528 2008-04-29 2009-04-17 Système d'amenée WO2009132616A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008021483.3 2008-04-29
DE102008021483A DE102008021483A1 (de) 2008-04-29 2008-04-29 Zuleitungssystem

Publications (2)

Publication Number Publication Date
WO2009132616A2 true WO2009132616A2 (fr) 2009-11-05
WO2009132616A3 WO2009132616A3 (fr) 2010-04-15

Family

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PCT/DE2009/000528 WO2009132616A2 (fr) 2008-04-29 2009-04-17 Système d'amenée

Country Status (2)

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DE (1) DE102008021483A1 (fr)
WO (1) WO2009132616A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076441A1 (fr) 2010-12-07 2012-06-14 F. Hoffmann-La Roche Ag Dispositif de mélange de nutriments et utilisation de celui-ci
WO2019074951A1 (fr) * 2017-10-09 2019-04-18 Altopa, Inc. Dispositif microfluidique portatif sécurisé, à la demande, pour mélanger et distribuer des mélanges de liquides, de solutions, de suspensions, d'émulsions et de colloïdes
US11666875B2 (en) 2016-04-11 2023-06-06 Altopa, Inc. Secure portable, on-demand, microfluidic mixing and dispensing device

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DE19728520A1 (de) * 1997-07-04 1999-01-07 Imb Inst Fuer Molekulare Biote Schaltbarer dynamischer Mikromischer mit minimalem Totvolumen
US20030107946A1 (en) * 2001-10-25 2003-06-12 Cosby N. Guy Cover slip mixing apparatus and method
EP1623760A2 (fr) * 2004-08-06 2006-02-08 Hitachi Industries Co., Ltd. Système microfluidique sur un chip.
US20060199260A1 (en) * 2002-05-01 2006-09-07 Zhiyu Zhang Microbioreactor for continuous cell culture

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Publication number Priority date Publication date Assignee Title
DE19728520A1 (de) * 1997-07-04 1999-01-07 Imb Inst Fuer Molekulare Biote Schaltbarer dynamischer Mikromischer mit minimalem Totvolumen
US20030107946A1 (en) * 2001-10-25 2003-06-12 Cosby N. Guy Cover slip mixing apparatus and method
US20060199260A1 (en) * 2002-05-01 2006-09-07 Zhiyu Zhang Microbioreactor for continuous cell culture
EP1623760A2 (fr) * 2004-08-06 2006-02-08 Hitachi Industries Co., Ltd. Système microfluidique sur un chip.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076441A1 (fr) 2010-12-07 2012-06-14 F. Hoffmann-La Roche Ag Dispositif de mélange de nutriments et utilisation de celui-ci
CN103221534A (zh) * 2010-12-07 2013-07-24 弗·哈夫曼-拉罗切有限公司 进料混合装置及其用途
JP2014500025A (ja) * 2010-12-07 2014-01-09 エフ．ホフマン−ラ ロシュ アーゲー 供給物混合装置およびその使用
JP2016028596A (ja) * 2010-12-07 2016-03-03 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 供給物混合装置およびその使用
US10837042B2 (en) 2010-12-07 2020-11-17 Hoffman-La Roche Inc. Feed mixing device and its use
US11666875B2 (en) 2016-04-11 2023-06-06 Altopa, Inc. Secure portable, on-demand, microfluidic mixing and dispensing device
WO2019074951A1 (fr) * 2017-10-09 2019-04-18 Altopa, Inc. Dispositif microfluidique portatif sécurisé, à la demande, pour mélanger et distribuer des mélanges de liquides, de solutions, de suspensions, d'émulsions et de colloïdes

Also Published As

Publication number Publication date
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DE102008021483A1 (de) 2009-12-03

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