DEVICE, MICROFLUIDIC CIRCULATION SYSTEM AND USES THEREOF

Abstract

Device containing or consisting of: a) a first reservoir suitable for receiving a liquid cell culture medium and having at least one first opening, wherein a first flow barrier is arranged in the at least one first opening of the first reservoir; b) a second reservoir which is suitable for receiving a liquid which contains or consists of at least one active ingredient and has at least one first opening, wherein a second flow barrier is arranged in the at least one first opening of the second reservoir; wherein the first and second flow barriers are each suitable for reducing a flow of an aqueous liquid through the respective at least one first opening of the respective reservoir and for allowing a diffusion of water and dissolved components of an aqueous liquid through the respective at least one first opening of the respective reservoir; characterized in that the first flow barrier is a different flow barrier than the second flow barrier, and the first reservoir is connected to the second reservoir via a conditionally detachable or non-detachable connection.

Description

A device and microfluidic circulation system are provided and uses thereof are proposed. The device contains a first reservoir, which is suitable for receiving a liquid cell culture medium and has at least one first opening with a first flow barrier, and a second reservoir, which is connected to the first reservoir in a conditionally detachable or non-detachable manner and is suitable for receiving an active substance liquid and has at least one first opening with a second flow barrier. The first and second flow barriers are distinct from each other and are each capable of reducing flow of an aqueous liquid and allowing diffusion of water and dissolved constituents of an aqueous liquid. The device is very long-term stable and allows an economical and reproducible investigation of a desired PK over a very broad range with low risk of contamination.In cell culture systems, so-called microphysiological systems (MPS for short), organ-on-chip systems (OOC systems for short) and "microscale cell culture analog" systems (mCCA systems for short), the pharmacokinetics must be mapped correctly for the testing of active substances (e.g. medicaments). Pharmacokinetics describes the concentration of a substance over a given time course in the bloodstream of an organism. A pharmacokinetic curve can be predicted well via the pharmacologically important properties of a molecule, such as plasma binding (albumin affinity), blood stability, permeability, IC 50, etc., which can be determined before testing in the cell culture system, and the type of dosage. The pharmacokinetics (PK) is strongly dependent here on the mode of application of an active substance (e.g. intravenously, subcutaneously or rectally) and can also be the target of a test via a device suitable for this purpose in order to test in what manner administration of an active substance should take place. For assays on cell or tissue cultures, the pharmacokinetic curve must be mapped exactly to predict realistically a potential toxic effect or tissue accumulation of said substance.In general, pharmacokinetics are influenced by a plurality of processes which take place in parallel in the body and are also referred to as ADME (absorption, distribution, metabolization, excretion). These processes are in most cases significantly influenced by specific organs of the body. Whereas absorption takes place via the mucous membranes of the body in the case of an oral dosage (e.g. in the form of a tablet or a dragée) or rectal dosage (e.g. in the form of a suppository), this takes place primarily via the skin at a cutaneous dosage (e.g. in the form of an ointment or cream). In the case of subcutaneous dosing (e.g. in the form of a syringe or short cannula), the dosing takes place directly into the connective and adipose tissue below the skin, which determines the subsequent absorption process.After the absorption, the active ingredient is distributed in the body, i.e. the distribution describes a distribution process of an absorbed active ingredient in the body. Usually, active ingredients (e.g. medicaments) are distributed in the body via the cardiovascular system and thus enter the target tissue and other tissues. For this process, both the blood plasma binding of the active ingredient and the binding of the active ingredient in the tissue play a decisive role.The distribution process has hitherto been the most difficult to image in microphysiological systems. This is for several reasons. Firstly, a prediction of blood plasma binding of active substances in the cell culture medium of microphysiological systems has so far been inadequate. Secondly, tissue accumulation of active ingredients takes place in addition to the target tissue, depending on the type of active ingredient, also in various other tissues of the body, wherein imaging of all relevant tissue types in microphysiological systems involves enormous resource expenditure, time expenditure and cost expenditure, as a result of which correct imaging of these effects via tissue equivalents in microphysiological systems is not economically possible. Thirdly, a scaling of microphysiological systems cannot take place correctly for all physiological parameters, whereby a mathematical distortion of the determined distribution necessarily takes place. There is thus a need for improvement in these aspects.The metabolism of an active ingredient absorbed in the body takes place primarily via the liver. As a result of the enzymatic degradation of all active ingredients absorbed into the body, these are pharmacologically modified and partially degraded, which is also referred to as "hepatic clearance".The excretion of an active ingredient absorbed in the body takes place primarily via the kidney, which is also referred to as "renal clearance". The active ingredients absorbed are precipitated glomerularly depending on their size and subsequently absorbed tubularly depending on their molecular structure. This process determines, on the one hand, the excretion and, on the other hand, toxic effects are also induced in the case of specific binding to the functional transporters of the tubule.Microfluidic systems are known in the prior art, which have a syringe pump and a flow chip and thus permit, in a time-controlled manner, an adjustment of the concentration of an active substance according to a pharmacologically relevant profile. Such microfluidic systems have at least two fluidic inlets, wherein a cell culture medium is supplied to the microfluidic system via a first inlet and an active substance is metered in at a predefined concentration via the second inlet. By varying the volume flows in the first inlet and the second inlet with respect to one another, the concentration of the active substance can be varied over time. However, the disadvantage of these microfluidic systems is that they have a complicated structure due to the requirement of a syringe pump and are very susceptible to contamination due to the associated tubing (Guerrero, Y. A. et al., The AAPS journal, 22(3):53).Furthermore, microfluidic systems are known in the prior art which contain tissue equivalents of the organs (e.g. of the liver and / or of the kidney) which are most important for pharmacokinetics. The tissue equivalents of the liver metabolize the active substances and thus reduce the concentration of the added active substances over time in these systems. The tissue equivalents of the kidney secrete the active substances (or degradation products thereof) and thus also reduce the concentration of the added active substances over time in these systems (Zhao, Y. et al. Molecules, 24(4):675). A disadvantage of these microfluidic systems is that the use of tissue equivalents in these systems increases the complexity and susceptibility to errors of the systems and increases the effort and costs for providing the systems. Moreover, a joint culture of different tissue equivalents is frequently limited in that it is first necessary to find a cell culture medium which satisfies all organotypic tissue culture equivalents. A further disadvantage of such systems is that the aspects absorption and distribution of pharmacokinetics and binding to other tissues and to blood plasma are totally ignored.At the latter point, it is known in the art that absorption of an active agent can be mapped in microphysiological models by using an equivalent of mucosa or skin in a microfluidic system (Zoio, P. et al., Pharmaceutics, 14(3):682). However, this measure further increases the complexity of the microfluidic system, as a result of which the susceptibility to errors is further increased and the outlay and the costs for the provision of the microfluidic system are driven further into the higher level.WO 2007 / 021343 A2 discloses a device which has a first and a second reservoir, wherein the two reservoirs each have an opening at which a flow barrier is arranged. The first and second reservoirs are here merely assembled to one another, i.e. are detachably connected to one another. As a result, the device does not have a high long-term stability and there is a certain susceptibility to errors and a risk of contamination when using the device.Proceeding from this, it was the object of the present invention to provide a device and a microfluidic circulation system which overcomes at least one disadvantage from the prior art. In particular, the device should be more stable over a long term and minimize errors and contamination risks during use of the device. Furthermore, it should be possible with the device and the microfluidic system to investigate pharmacokinetics (PK), preferably also pharmacodynamics (PD), of an active substance in biological cell systems (e.g. biological cell tissues) in a simple, rapid and cost-effective (i.e. economic) manner. In particular, it should be possible with the device and the microfluidic system to be able to set a desired PK, preferably also a desired PD, over a wide range in order to be able to realize a multiplicity of possible PK profiles, preferably also PD profiles (e.g. PK in the case of intravenous, subcutaneous or rectal administration of active compound). Further, uses of the device and microfluidic circulation system should be proposed.The object is achieved by the device having the features of claim 1, the microfluidic circulation system having the features of claim 17 and the use having the features of claim 18.According to the invention, a device is provided, containing or consisting of: a) a first reservoir which is suitable for receiving a liquid cell culture medium and has at least one first opening, wherein a first flow barrier is arranged in the at least one first opening of the first reservoir; b) a second reservoir which is suitable for receiving a liquid which contains or consists of at least one active substance and has at least one first opening, wherein a second flow barrier is arranged in the at least one first opening of the second reservoir; wherein the first and second flow barriers are each suitable for reducing a flow of an aqueous liquid through the respective at least one first opening of the respective reservoir (with respect to a flow through the first opening without the flow barrier) and for allowing a diffusion of water and dissolved constituents of an aqueous liquid through the respective at least one first opening of the respective reservoir, characterized in that the first flow barrier is a flow barrier different from the second flow barrier, and the first reservoir is connected to the second reservoir via a conditionally detachable or non-detachable connection.The device according to the invention is more stable over a long term than devices known in the prior art. This is because the first and second reservoirs of the device are connected via a conditionally detachable or non-detachable connection. Furthermore, this eliminates possible errors during assembly of the device and simplifies the use of the device. This also enables more reproducible measurement results to be achieved with the device. In addition, this reduces the risk of contamination when using the device. This represents an immense advantage, for example, in the examination and / or cultivation of antibiotic-free stem cell cultures. Moreover, culturing stem cells frequently requires a time-delayed addition of substances which can be adjusted by a targeted selection of a difference between the first and the second flow barrier of the device according to the invention.The two different flow barriers of the two reservoirs make it possible to investigate a time-dependent exposure of biological cells to at least one active substance over a broader range over the course of time than with identical flow barriers in the case of both reservoirs, i.e. a broad range of pharmacokinetics for an active substance to be investigated can be investigated (e.g. set and / or determined) by selecting a difference between the two flow barriers (e.g. selection of the permeation properties thereof).The device according to the invention does not require any complicated technical aids, such as a syringe pump for metering the active substance. This further reduces the risk of contamination when using the device and more reliable and reproducible results can be achieved. A user can easily and quickly carry out an examination with the device, since only at the beginning and end of an examination with the aid of the device according to the invention is a direct interaction necessary with the device according to the invention.In summary, the device according to the invention is thus more stable over a long term and allows a desired PK to be investigated (e.g. adjusted and / or determined) in a simple, fast and cost-effective (i.e. economic) manner, wherein different PKs can be investigated over a broader range than with devices from the prior art (e.g. PK with intravenous, subcutaneous or rectal administration of active substance etc.) and the device minimizes contamination risks and enables more reproducible results compared with known devices.The feature that the first flow barrier is a flow barrier different from the second flow barrier can be understood to mean that the permeation properties of the first flow barrier differ from the permeation properties of the second flow barrier. This can also apply to further current barriers mentioned here. Permeation properties can be understood to mean a suitability of the respective flow barrier for reducing a flow of an aqueous liquid through the respective at least one first opening of the respective reservoir (with respect to a flow through the first opening without the flow barrier) to a certain extent (or to a certain extent) and / or for permitting a diffusion of water and dissolved constituents of an aqueous liquid through the respective at least one first opening of the respective reservoir to a certain extent (or to a certain extent). If the permeation properties are different, said strength or said measure differs.A conditionally detachable connection (e.g. between the first reservoir and the second reservoir) can be understood to mean a connection (e.g. between the first and the second reservoir) which can be destroyed without destroying the reservoirs, but by destroying at least one auxiliary joining part which establishes the connection between the reservoirs (e.g. a force-fit connection such as an adhesive connection, or a connection via a holding device which fixes the reservoirs in a force-fit manner and is damaged when a reservoir is removed). A non-detachable connection (e.g. between the first reservoir and the second reservoir) can be understood to mean a connection (e.g. between the first and the second reservoir) which can be released only by destroying at least one of the (at least two) reservoirs (e.g. a cohesive connection).An active substance is preferably understood to mean all substances which exert at least one effect on a biological cell. Examples are pharmaceutical active ingredients (i.e. medicaments), cosmetics and / or growth factors. The active ingredient is preferably selected from the group consisting of organic molecules with a mass ≤1 kDa, peptides, proteins, RNA, DNA and combinations thereof.The first and / or second reservoir can have (in each case) at least two, preferably at least three, particularly preferably at least four, first openings, i.e. openings in which a flow barrier is arranged in each case. Preferably, the flow barriers in the first openings of the first reservoir are first flow barriers identical to one another and / or the flow barriers in the first openings of the second reservoir are second flow barriers identical to one another. The advantage of a plurality of openings with respective flow barriers in the respective reservoirs is that a more uniform (homogeneous) and optionally also faster dispensing of substances from the (second) reservoir and receiving of substances into the (first) reservoir is possible. The pharmacokinetics with respect to absorption and / or distribution can thus be adjusted more uniformly and rapidly occurring pharmacokinetics with respect to absorption and / or distribution can be realized.The first and / or second flow barrier of the device according to the invention can contain or consist of at least one hydrogel, wherein the hydrogel is optionally a swelling hydrogel.Furthermore, the first and / or second flow barrier can contain or consist of at least one capillary.Apart from this, the first and / or second flow barrier can contain or consist of at least one filter flow.The second flow barrier may allow for a faster diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the second reservoir than the first flow barrier through the at least one first opening of the first reservoir. This has the advantage that an active substance located in the second reservoir can be dispensed quickly from the second reservoir (e.g. into a cell culture compartment with biological cells to which the device is fluidically connected) and is taken up more slowly into a liquid (e.g. a cell culture medium) in the first reservoir (e.g. from a cell culture compartment with biological cells to which the device is fluidically connected). By a targeted selection of the permeability properties of the two flow barriers, a desired pharmacokinetics (PK) of the active substance can thus be set for a cell culture compartment with biological cells connected to the device, i.e. for example a PK can be set and thus emulated in the case of oral, rectal or subcutaneous administration of the active substance.Alternatively, the second flow barrier may allow for a slower diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the second reservoir than the first flow barrier through the at least one first opening of the first reservoir. The advantage here is that a cell culture medium located in the first reservoir can be dispensed quickly from the first reservoir (e.g. into a cell culture compartment with biological cells to which the device is fluidically connected) and is dispensed more slowly into a liquid with active substance from the first reservoir (e.g. from a cell culture compartment with biological cells to which the device is fluidically connected). This is a great advantage especially in cell cultivation (e.g. of stem cells).The first reservoir and / or second reservoir can (in each case) contain a device for filling the (respective) reservoir with a liquid. The device preferably contains or consists of a closable, second opening and / or an elastomer membrane. The elastomer membrane is preferably liquid-tight and gas-permeable. If the device consists of an elastomer membrane, filling can be effected by puncturing the elastomer membrane with a needle. The advantage is that no separate steps of opening and closing the second opening are necessary to fill the reservoir(s) with a liquid, which means a time saving and reduces the risk of contamination.Furthermore, the first reservoir and / or second reservoir may (each) contain a gas-permeable filter, preferably a gas-permeable filter membrane. The filter membrane preferably has a pore width in the range from 0.1 to 0.4 μm. The advantage here is that a gas exchange of an interior of the respective reservoirs with the environment is possible via the gas-permeable filter. This makes it possible to avoid the formation of a negative pressure or positive pressure in the reservoirs, as a result of which corruption of the mass transfer via the flow barriers of the reservoirs caused as a result can be ruled out. Thus, a desired PK can be adjusted more accurately and more reproducible results can be obtained.In addition, the first reservoir and / or second reservoir can contain a liquid cell culture medium or contain a liquid which contains or consists of at least one active substance. Preferably, the first reservoir contains a liquid cell culture medium and / or the second reservoir contains a liquid which contains or consists of at least one active substance. As a result, the second reservoir is defined as the reservoir that defines a release of active agent (to a fluidly connected cell culture compartment having biological cells) and thus defines the absorption aspect of the PK ("A" in ADME) via its flow barrier, and the first reservoir al defines the reservoir that defines a take-up of active agent (from a fluidly connected cell culture compartment having biological cells) and thus defines the distribution aspect of the PK ("D" in ADME) via its flow barrier.The device may comprise a third reservoir suitable for containing a liquid containing or consisting of at least one metabolite of at least one active substance and having at least one first opening, wherein a third flow barrier is arranged in the at least one first opening of the third reservoir, said third flow barrier being suitable for reducing a flow of an aqueous liquid through the at least one first opening of the third reservoir and allowing a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the third reservoir. By said third reservoir with the flow barrier in its first opening it is possible to examine a metabolizing aspect of the PK ("M" in ADME).The third reservoir can be connected to the first reservoir and / or second reservoir via a connection that can be released or non-released to a limited extent.The third flow barrier of the third reservoir preferably allows a slower diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the third reservoir than the first flow barrier and / or the second flow barrier allows through the at least one first opening of the respective reservoir. The advantage here is that the metabolizing aspect can be depicted more correctly (i.e. physiologically relevant), since the metabolizing takes place with a time delay and thus biological cells (here: in a cell culture compartment which is fluidically connected to the device according to the invention) are only faced with the metabolite after a certain time.The third flow barrier of the third reservoir preferably contains or consists of at least one switchable hydrogel.Furthermore, the third flow barrier of the third reservoir can contain or consist of at least one (non-electrically activatable) nonreturn valve, which is preferably selected from the group consisting of duck bill valves, mushroom valves, cross valves and combinations thereof. The check valve particularly preferably contains or consists of an elastomeric material, wherein the elastomeric material is optionally selected from the group consisting of silicone, thermoplastic polyurethane and combinations thereof.Moreover, the third flow barrier can contain or consist of at least one swelling (non-electrically activatable) valve. The swelling valve preferably contains or consists of an elastomeric material, wherein the elastomeric material is optionally selected from the group consisting of silicone, thermoplastic polyurethane, regenerated cellulose, agarose, PEG-based hydrogel, gelatin, collagen and combinations thereof.The third reservoir can contain a device for filling the third reservoir with a liquid, wherein the device preferably contains or consists of a closable, second opening and / or an elastomer membrane.Furthermore, the third reservoir can contain a gas-permeable filter, preferably a gas-permeable filter membrane. The filter membrane preferably has a pore width in the range from 0.1 μm to 0.4 μm.Apart from this, the third reservoir can contain a liquid which contains or consists of at least one metabolite of at least one active substance, wherein the at least one metabolite of at least one active substance is preferably at least one metabolite of at least one active substance which is contained in the second reservoir.The third reservoir can have at least two, preferably at least three, particularly preferably at least four, first openings, i.e. openings in which a third flow barrier is arranged in each case. The flow barriers in the first openings of the third reservoir are preferably third flow barriers identical to one another. The advantage is that a more uniform (homogeneous) and optionally also faster release of metabolites from the third reservoir is possible. The pharmacokinetics with respect to the metabolism can thus be adjusted more uniformly and pharmacokinetics which take place rapidly with respect to the metabolism can also be realized.The device may include a fourth reservoir suitable for containing a liquid and having at least one first opening, wherein a fourth flow barrier is disposed in the at least one first opening of the fourth reservoir, said fourth flow barrier being suitable for reducing a flow of an aqueous liquid through the at least one first opening of the fourth reservoir and allowing a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fourth reservoir. By said fourth reservoir with the flow barrier in its first opening it is possible to examine an excretion aspect of the PK ("E" in ADME).The fourth reservoir can be connected to the first reservoir and / or second reservoir (optionally also to the third reservoir) via a connection that can be released or non-released to a limited extent.The fourth flow barrier of the fourth reservoir may be suitable to slow down a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fourth reservoir over time from contact with an aqueous liquid. The advantage here is that the excretion aspect can be depicted more correctly (i.e. physiologically relevant), since the excretion (i.e. excretion) of active ingredient or at least one metabolite thereof initially proceeds rapidly and then increasingly slowly and thus biological cells (here: in a cell culture compartment which is fluidically connected to the device according to the invention) experience only a rapid and then increasingly slow reduction in the concentration of the active ingredient or of its at least one metabolite.The fourth flow barrier of the fourth reservoir may contain or consist of at least one membrane which increases its diffusion resistance over time after contact with an aqueous liquid, wherein the at least one membrane is preferably a membrane whose properties substantially correspond to a filtration tissue of a kidney, wherein the kidney is in particular a human kidney. The advantage here is that a excretion of active ingredient and at least one metabolite thereof can be mapped as physiologically as possible correctly and corruptions of the results can be avoided.Furthermore, the fourth flow barrier of the fourth reservoir may contain or consist of at least one filter flow which increases its diffusion resistance over time after contact with an aqueous liquid. This measure also makes it possible to achieve the most correct possible mapping of the physiologically occurring excretion of the active ingredient and of at least one metabolite thereof.The fourth reservoir can contain a device for filling the fourth reservoir with a solid, wherein the device preferably contains or consists of a closable, second opening.Furthermore, the fourth reservoir can contain a liquid-impermeable and gas-permeable filter, preferably a liquid-impermeable and gas-permeable filter membrane. The filter preferably has a pore width in the range from 0.1 to 0.4 μm.In a preferred embodiment, the fourth reservoir contains no liquid. The advantage is that the excretion aspect of the PK (i.e. the excretion) can be mapped more exactly.In a particularly preferred embodiment, the fourth reservoir contains albumin, preferably human serum albumin. The advantage here is that, in addition to excretion, the PK can be investigated under still more physiological conditions, since, as a result of the presence of albumin, a binding of active substance or at least one metabolite thereof to a substantial blood constituent is also taken into account in the PK. This is of particular importance, for example, for active ingredients or their metabolites which show a strong binding to the albumin of the blood serum (e.g. HSA), since said binding can drastically reduce the concentration of active ingredient or its metabolite which biological cells actually experience in the body. The PK in the living body can thus be mapped even more accurately, as a result of which even more accurate statements can be made about the actual influences of active substances or of their metabolites on body cells and incorrect conclusions can be avoided. The albumin is preferably present in a dry state in the fourth reservoir. This increases the long-term stability of albumin and thus of the device according to the invention.The fourth reservoir can have at least two, preferably at least three, particularly preferably at least four, first openings, i.e. openings in which a fourth flow barrier is arranged in each case. The flow barriers in the first openings of the fourth reservoir are preferably fourth flow barriers identical to one another. The advantage is that a more uniform (homogeneous) and optionally also faster absorption of active substance and optionally its metabolites into the fourth reservoir is possible. The pharmacokinetics with respect to excretion can thus be adjusted more uniformly and pharmacokinetics which take place rapidly with respect to excretion can be realized.The device may further include a fifth reservoir suitable for containing a liquid and having at least one first opening, wherein a fifth flow barrier is disposed in the at least one first opening of the fifth reservoir and is suitable for reducing a flow of an aqueous liquid through the at least one first opening of the fifth reservoir and for allowing a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fifth reservoir. The advantage here is that a absorption of active substance or at least one metabolite thereof via a skin or mucosa can be imaged via the fifth reservoir.The fifth reservoir can be connected to the first reservoir and / or second reservoir (optionally also to the third reservoir and / or fourth reservoir) via a connection that is releasable or non-releasable to a limited extent.The fifth flow barrier of the fifth reservoir may contain or consist of at least one hydrogel, optionally wherein the hydrogel is a swelling hydrogel.Furthermore, the fifth flow barrier of the fifth reservoir can contain or consist of at least one capillary.Apart from this, the fifth flow barrier of the fifth reservoir may contain or consist of at least one filter flow.The fifth reservoir can contain a device for filling the fifth reservoir with a liquid, wherein the device preferably contains or consists of a closable, second opening and / or an elastomer membrane.Furthermore, the fifth reservoir can contain a liquid-impermeable and gas-permeable filter, preferably a liquid-impermeable and gas-permeable filter membrane. The filter preferably has a pore width in the range from 0.1 μm to 0.4 μm.In addition, the fifth reservoir may contain a liquid containing at least one component of the extracellular matrix of a skin or mucosa, preferably the skin or mucosa being human skin or mucosa.The fifth reservoir can have at least two, preferably at least three, particularly preferably at least four, first openings, i.e. openings in which a fifth flow barrier is arranged in each case. The flow barriers in the first openings of the fourth reservoir are preferably fifth flow barriers identical to one another. The advantage is that a more uniform (homogeneous) and optionally also faster absorption of active substance and optionally its metabolites into the fifth reservoir is possible. The pharmacokinetics with respect to the absorption into the skin or mucous membrane can thus be set more uniformly and rapidly occurring pharmacokinetics with respect to the absorption into the skin or mucous membrane can also be realized.The device according to the invention can furthermore have a continuous opening without a flow barrier, which extends at least between the first and / or second reservoir of the device, optionally also between at least one further reservoir of the device, preferably between all reservoirs of the device. The advantage of the through-opening without a flow barrier is that a user of the device can add at least one active substance (e.g. in a liquid) past a flow barrier of the device (i.e. directly and directly) biological cells of a cell culture compartment (e.g. in a well of a 6-well microtiter plate). As a result, a very rapid addition of active substance to the biological cells can be achieved and pharmacokinetics which take place very rapidly can be mapped (for example to map intravenous administration of at least one active substance).Particularly preferably, at least one wall of the first and / or second reservoir of the device, optionally of at least one further reservoir of the device, preferably of all reservoirs of the device, represents at least one wall of the continuous opening without a flow barrier (i.e. the continuous opening without a flow barrier shares at least one wall with at least one reservoir of the device). The advantage of the common wall of the through opening without a flow barrier and of at least one reservoir of the device is a more cost-effective provision of the device, wherein the device can be provided more compactly or, given a defined size, the reservoirs thereof can have a larger volume.In particular, the through-opening without a flow barrier is arranged centrally in the device. The advantage here is that the device has greater stability than in the case of a lateral arrangement of the through opening (for example an arrangement on a lateral edge of the device).In a preferred embodiment, the device is suitable by its dimensions for being inserted into a single well of a microtiter plate, optionally being inserted in a liquid-tight manner, so that the openings of the reservoirs of the device are directed in the direction of an interior of the well of the microtiter plate. The microtiter plate is preferably a 6-well microtiter plate, 12-well microtiter plate, 24-well microtiter plate, 48-well microtiter plate or 96-well microtiter plate. The advantage of this embodiment is that it is possible in a very simple, rapid, cost-effective manner and in a manner which is not very susceptible to contamination to investigate at least one pharmacokinetic of an active substance in biological cells which are present in wells of a microtiter plate (wells of the microtiter plate as cell culture compartments).The device according to the invention can also contain or consist of an arrangement (i.e. an array) of at least six devices according to the invention, wherein the at least six devices in the arrangement (i.e. in the array) are connected to one another. The dimensions of the arrangement make it suitable to be inserted into a microtiter plate, optionally to be inserted in a liquid-tight manner, so that the openings of the reservoirs of the individual devices of the arrangement are each directed in the direction of an interior of an individual well of the microtiter plate. The microtiter plate is preferably a 6-well microtiter plate, 12-well microtiter plate, 24-well microtiter plate, 48-well microtiter plate or 96-well microtiter plate. The advantage of the arrangement is that it is possible to investigate at least one pharmacokinetic of different active substances in identical biological cells which are present in wells of a microtiter plate and / or to investigate at least one pharmacokinetic of an identical active substance in different biological cells which are each present in separate wells of a microtiter plate in a simpler, faster, more cost-effective and less susceptible to contamination.The device can have at least one spacer, preferably at least two spacers, particularly preferably at least three spacers, on a wall of the device in which the at least one first opening of the device is arranged. The advantage is that when the device is inserted into a well of a microtiter plate (in particular when the device is placed on a bottom of a well of a microtiter plate), it can be better ensured that the flow barriers of the device are not closed by the bottom of the well of the microtiter plate. Thereby, possible errors in the functioning of the device can be better avoided and more reproducible results can be achieved.In the device according to the invention, the openings of the (respective) reservoirs of the device can (already) be fluidically connected to a cell culture compartment which is suitable for receiving a liquid cell culture medium. This embodiment has the advantage that it is possible to begin more quickly with the investigation of an influence of an active substance on biological cells and at least from its PK.The cell culture compartment can be a well of a microtiter plate. Furthermore, the cell culture compartment can (already) contain a liquid cell culture medium and biological cells, wherein the biological cells are preferably immobilized on a wall of the cell culture compartment. The advantage here is that it is possible to begin directly with the investigation of an influence of an active substance on biological cells and at least from its PK.According to the invention, there is further provided a microfluidic circulation system comprising a) a device according to the invention; b) a cell culture compartment suitable for receiving a liquid cell culture medium; c) a channel which is fluidically connected to the first openings of the reservoirs of the device and to the cell culture compartment and which is suitable for circulating a liquid in the microfluidic circulation system; and d) a pump which is suitable for conveying a liquid in the channel of the microfluidic circulation system; e) optionally: a control unit which is configured to control a pump activity of the pump, wherein the control unit is preferably configured to control the pump in such a way that a liquid in the channel is conveyed in a pulsing manner, particularly preferably with a pulse frequency in the range from 1 to 2.5 Hz.The microfluidic circulation system according to the invention has the advantages of the device according to the invention. Another advantage of the microfluidic circulation system is the presence of the pump. By means of the pump it is possible (by convection effects) to achieve a more rapid exposure of biological cells in the cell culture compartment to active substance, as a result of which the pharmacokinetics can be influenced, i.e. pharmacokinetics which take place more rapidly can be mapped (for example to map intravenous administration of at least one active substance).The cell culture compartment of the microfluidic circulation system can contain (already) biological cells, wherein the biological cells are preferably immobilized on a wall of the cell culture compartment. Furthermore, the channel of the microfluidic device may (already) contain a liquid cell culture medium which can be circulated in the microfluidic circulation system. The advantage here is that it is possible to begin directly with the investigation of an influence of an active substance on biological cells and at least from its PK.According to the invention, a use of the device according to the invention or of the microfluidic circulation system according to the invention for delivering an active substance to a cell culture compartment is also proposed.In this case, the use can comprise the following steps: a) filling the first reservoir of the device with a liquid cell culture medium; b) filling the second reservoir of the device with a liquid which contains or consists of at least one active substance; c) optionally: filling a third reservoir of the device with a liquid which contains or consists of at least one metabolite of at least one active substance; d) optionally: filling a fourth reservoir of the device with albumin, preferably with human serum albumin; e) optionally: filling a fifth reservoir of the device with a liquid which contains at least one constituent of the extracellular matrix of a skin or mucosa, wherein the skin or mucosa is preferably human skin or human mucosa; f) establishing fluidic contact of the first openings of the reservoirs of the device with a cell culture compartment; g) optionally: conveying a liquid through a microfluidic circulation system via a pump of the microfluidic circulation system.The object according to the invention is intended to be explained in more detail on the basis of the following figures and the following examples, without wishing to restrict it to the specific embodiments shown here. FIG. 1 schematically shows an apparatus according to the invention. The device contains a first reservoir 1 which is suitable for receiving a liquid cell culture medium and has at least one first opening, wherein a first flow barrier 2 is arranged in the at least one first opening of the first reservoir 1. Furthermore, the device contains a second reservoir 3 which is suitable for holding a liquid which contains or consists of at least one active substance and has at least one first opening, wherein a second flow barrier 4 is arranged in the at least one first opening of the second reservoir 3. The first reservoir 1 is connected to the second reservoir 3 via a non-detachable connection, i.e. in this case the two reservoirs 1, 3 share a common wall (i.e. they are connected in a materially integral manner or configured in one piece). The first and second flow barriers 2, 4 are each suitable for reducing a flow of an aqueous liquid through the respective at least one first opening of the respective reservoir 1, 3 and for permitting a diffusion of water and dissolved constituents of an aqueous liquid through the respective at least one first opening of the respective reservoir 1, 3. FIGS. 2A to 2C schematically show different views of a further device according to the invention. The device shown here is suitable by its dimensions for insertion into a single well of a microtiter plate. Like the device from FIG. 1, the device contains a first reservoir 1 with at least one first opening, in which a first flow barrier 2 is arranged, and a second reservoir 3 with at least one first opening, in which a second flow barrier 4 is arranged, wherein the flow barriers have the properties described above with reference to FIG. 1. Here too, the first reservoir 1 is connected to the second reservoir 3 via a non-detachable connection, i.e. in this case the two reservoirs 1, 3 share a common wall (i.e. they are connected in a materially integral manner or configured in one piece). This device also includes a flow-barrier through opening 12 extending centrally in the device between the first and second reservoirs of the device, one wall of the first and second reservoirs of the device constituting at least one wall of the flow-barrier through opening. In addition, the device has at least one spacer 13 (e.g. three spacers 13) which, when the device is placed on a base of a well of a microtiter plate, can / can ensure that the flow barriers 2 and 4 are not closed over the base of the well. FIG. 3 schematically shows a microfluidic circulation system according to the invention. The microfluidic circulation system contains a device according to the invention which, like the device from FIGS. 1 and 2, contains a first reservoir 1 having at least one first opening in which a first flow barrier 2 is arranged and a second reservoir 3 having at least one first opening in which a second flow barrier 4 is arranged, wherein the flow barriers have the properties described above with respect to FIG. 1. Furthermore, the device according to the invention of the microfluidic circulation system contains a third reservoir 5 with at least one first opening, in which a third flow barrier 6 is arranged, and a fourth reservoir 7 with at least one first opening, in which a fourth flow barrier 8 is arranged. The third flow barrier 6 allows a slower diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the third reservoir 5 than the first flow barrier 2 and the second flow barrier 4 through the at least one first opening of the respective reservoir 1, 3. The fourth flow barrier 8 of the fourth reservoir 7 is suitable to slow a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fourth reservoir 7 over time from contact with an aqueous liquid. The microfluidic circulation system further comprises a cell culture compartment 9 suitable for receiving a liquid cell culture medium and for culturing biological cells. Moreover, the microfluidic circulation system comprises a channel 14 which is fluidically connected to the flow barriers of the reservoirs 1, 3, 5, 7 of the device and to the cell culture compartment 9 and which is suitable for circulating a liquid in the microfluidic circulation system. Moreover, the microfluidic circulation system comprises a pump 10 suitable for conveying a liquid in the channel 14 of the microfluidic circulation system. Apart from this, the microfluidic circulation system comprises a control unit 11 configured to control a pump activity of the pump 10 (e.g. such that a liquid in the channel 14 is conveyed in a pulsating manner, particularly preferably with a pulse frequency in the range of 1 to 2.5 Hz). FIG. 4 shows a concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which compartment is fluidically connected to the device according to the invention, as a function of time for three different effective exchange surfaces in the first reservoir, i.e. three different surfaces of the first flow barrier in the first opening of the first reservoir. It can be seen that the area of the flow barrier exerts an influence on the PK, i.e. the larger the area, the faster the active substance which is dispensed from the second reservoir into the cell culture medium of the cell culture compartment is absorbed by the first reservoir and is thus depleted in the cell culture compartment. FIG. 5 shows a concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which compartment is fluidically connected to the device according to the invention, as a function of time for three different volumes of active ingredient-containing liquid in the second reservoir. It can be seen that the volume of the liquid in the first reservoir exerts an influence on the PK, i.e. the larger the volume, the faster the active ingredient is released from the second reservoir into the cell culture medium of the cell culture compartment and the higher the final concentration of the active ingredient in the cell culture medium of the cell culture compartment. FIG. 6 shows a concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which compartment is fluidically connected to the device according to the invention, as a function of time for three different heights (or thicknesses) of a first flow barrier (here: a hydrogel) in the first opening of the first reservoir. It can be seen that the height (or thickness) of the first flow barrier exerts an influence on the PK, i.e. the greater the height (or thickness), the faster the active ingredient concentration in the cell culture medium of the cell culture compartment increases and the slower the active ingredient is absorbed by the first reservoir and thus depleted in the cell culture compartment. FIG. 7 shows a concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which compartment is fluidically connected to the device according to the invention, as a function of time for certain parameters of the device, which parameters map a PK in the case of oral dosing of active ingredient (see curve "OD") and, in the case of direct, active dosing of the liquid containing active ingredient into the cell culture medium of the cell culture compartment via a continuous opening without a flow barrier, which the device has (see curve "IV"). It can be seen that the direct, active metered addition of the liquid containing active ingredient (i.e. metered addition without a flow barrier) has an influence on the PK, i.e. the active ingredient concentration in the cell culture medium of the cell culture compartment rises significantly more rapidly than is possible with the indirect, passive metered addition through the second flow barrier in the first opening of the second reservoir (cf. curves "IV" and "OD").Example 1 - Construction of microfluidic circulation systemsA microfluidic circulation system is provided that includes a device according to the invention. The device according to the invention contains: a) a first reservoir, which is suitable for holding a liquid cell culture medium, contains liquid cell culture medium and has at least one first opening, wherein a first flow barrier is arranged in the at least one first opening of the first reservoir; and b) a second reservoir, which is suitable for holding a liquid which contains or consists of at least one active substance, contains said liquid, and has at least one first opening, wherein a second flow barrier is arranged in the at least one first opening of the second reservoir.The first reservoir is connected to the second reservoir and the first and second flow barriers are each suitable for reducing a flow of an aqueous liquid through the respective at least one first opening of the respective reservoir and for permitting a diffusion of water and dissolved constituents of an aqueous liquid through the respective at least one first opening of the respective reservoir.Furthermore, the microfluidic circulation system contains a cell culture compartment which is suitable for receiving a liquid cell culture medium and contains said liquid cell culture medium and a biological cell culture.In addition, the microfluidic circulation system contains a channel which is fluidically connected to the first openings of the reservoirs of the device according to the invention and to the cell culture compartment and which is suitable for circulating a liquid in the microfluidic circulation system.Moreover, the microfluidic circulation system comprises a pump suitable for conveying a liquid in the channel of the microfluidic circulation system.In this case, the microfluidic circulation system further includes a control unit configured to control a pump activity of the pump.The first flow barrier in the first opening of the first reservoir and the second flow barrier in the first opening of the second reservoir allow a defined mass transfer between the two reservoirs and the channel and thus also the cell culture compartment to take place, as a result of which a desired concentration of an active substance can be adjusted as required over time in the microfluidic system. The respective flow barrier can be configured, for example, as a capillary, filter flow and / or hydrogel, i.e. does not require an electrical supply in comparison with a syringe pump and is less susceptible to contamination.The use of such a microfluidic circulation system can be divided into various fields of application:1) Only pharmacokinetics (PK for short) is investigated (i.e. only adsorption and distribution is investigated)For this purpose, the microfluidic circulation system has only two reservoirs-as described above. The first reservoir contains only cell culture medium and the second reservoir contains the active substance to be examined (e.g. in an aqueous buffer). Adjusting pharmacokinetics is controlled via the type of flow barrier in the first opening of the first reservoir.For examining a uptake of the active substance via the skin or the mucosa (e.g. for examining oral medication or rectal medication), this flow barrier contains or consists of a hydrogel. Alternatively, this flow barrier contains or consists of a hydrogel and a capillary for this purpose.For testing intravenous dosing or intramuscular dosing, this flow barrier contains or consists of a capillary.For subcutaneous dosage testing, this flow barrier contains or consists of a swelling hydrogel and / or a filter mesh whose diffusion resistance decreases over time.2) PK and some pharmacodynamics (PD for short) are studied (i.e. only adsorption, distribution and metabolism are studied)For this purpose, the device according to the invention, which is part of the microfluidic system, has a third reservoir. The third reservoir contains at least one metabolite of the active agent located in the second reservoir and includes a first opening in which a flow barrier is disposed. By selecting the type of these flow barriers, a release of the metabolite to the channel and thus to the cell culture compartment of the microfluidic system can be controlled over time.The metabolite of the active ingredient must be released with a time delay, since the active ingredient must also be reacted first in the body. Thus, a flow barrier having a "turn-on delay" is needed. For example, switchable hydrogels, a duck bill valve or a swelling fungal valve are suitable for this purpose. Fine adjustment of the permeability properties of this flow barrier to a specific active substance to be investigated can be effected by ascertaining a rate of liver metabolization of the active substance to be investigated in advance (for example via liver microsomes) and selecting the permeability properties of the flow barrier of the third reservoir on the basis of this information.3) PK and PD are studied (i.e., adsorption, distribution, metabolization, and excretion are studied)For this purpose, the device according to the invention, which is part of the microfluidic system, additionally has a fourth reservoir in addition to the third reservoir. The fourth reservoir does not contain liquid and includes a first opening in which a flow barrier is disposed. By selecting the type of these flow barriers, it is possible to control the uptake of the active substance or a metabolite thereof from the channel and thus from the cell culture compartment of the microfluidic system over time (dilution of the active substance / metabolite into the fourth reservoir). This emulates removal of the active ingredient / metabolite from the body.In this case, the flow barrier in the first opening of the fourth reservoir may contain or consist of a membrane and / or a filter mesh which increases its diffusion resistance over time. This flow barrier enables the concentration of the active ingredient or its metabolite in the channel and thus in the cell culture compartment to be rapidly reduced (emulation of high renal clearance). Ideally, this flow barrier contains a dialysis membrane which is very similar or corresponds in its permeation properties to the filtration of a kidney.4) PK and PD with regard to blood plasma binding is studied (i.e. adsorption, distribution, metabolisation and excretion under still more physiological conditions is studied)For this purpose, the cell culture medium in the fourth reservoir comprises serum albumin (e.g. in a dry form). The flow barrier in this case must be suitable to prevent a delivery of serum albumin to the channel of the microfluidic circulation system, i.e. the flow barrier must ensure that the serum albumin remains in the fourth reservoir.The reservoirs of the microfluidic circulation system according to the invention preferably each have a second opening via which gas exchange can take place and / or via which the reservoirs can be filled with a liquid. The possibility of gas exchange allows the time exchange of substances between the reservoirs and the channel of the microfluidic circulation system to be further influenced (avoidance of negative pressure in the respective reservoir).Example 2 - Use of the Device or Circulation SystemWith the device according to the invention and the microfluidic circulation system according to the invention, active ingredients (e.g. medicaments and / or cosmetics) can be tested.In this case, a physiological effect of organs of a body can be emulated, which allows an examination of the PK, optionally also the PD, of the active substance to be examined on a very small scale (e.g. in the size of a business card). This makes it possible, for example, to carry out toxicity tests quickly, simply, economically and in a realistic manner.Furthermore, it is possible to achieve a site-specific and time-specific release of at least one growth factor as active substance over the course of time with the device according to the invention and the microfluidic circulation system according to the invention and thus to examine a structure of artificial tissue structures as an organ substitute.Example 3 - Effect of Area of Flow Barriers on PKIn order to examine an influence of the area of the flow barriers (effective exchange area) on the time-dependent concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which is fluidically connected to the device according to the invention, the concentration of active ingredient in the cell culture medium of a cell culture compartment was examined as a function of time for three different effective areas of the first flow barrier in the first opening of the first reservoir of a device according to the invention.The parameters of the apparatus are shown in Table 1 below. Table 1 Table 1Volume of the first reservoir (medium)131,13 mm 3 mmVolume of the second reservoir (active ingredient-containing liquid)10,93 mm 3 mmVolume of the Through Opening1043 mm 3 mmEffective Replacement Area of First Flow Barrier0,6; 2,4; 52 mmEffective Replacement Area of Second Flow Barrier3,12 mmConcentration of Drug in Second Reservoir5mol / m 3Diffusion coefficient of the active ingredient (in water)2. 10 -9m 2 / sThe results are shown in Fig. 4.Example 4 - Effect of Liquid Volume in a Reservoir on PKIn order to examine an influence of the liquid volume in the reservoirs on the time-dependent concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which compartment is fluidically connected to the device according to the invention, the concentration of active ingredient in the cell culture medium of a cell culture compartment was examined as a function of time for three different volumes of active ingredient-containing liquid in the second reservoir of a device according to the invention.The parameters of the apparatus are shown in Table 2 below. Table 2 Table 2Volume of the first reservoir (medium)131,13 mm 3 mmVolume of the second reservoir (active ingredient-containing liquid)43,7; 21,8; 10,93 mm 3 mmVolume of the Through Opening1043 mm 3 mmEffective Replacement Area of First Flow Barrier0,62 mmEffective Replacement Area of Second Flow Barrier3,12 mmConcentration of Drug in Second Reservoir5mol / m 3Diffusion coefficient of the active ingredient (in water)2·10 -9m 2 / sThe results are shown in Fig. 5.Example 5 - Effect of Height of First Flow Barrier on PKIn order to examine an influence of the height (or thickness) of the first flow barrier on the time-dependent concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which is fluidically connected to the device according to the invention, the concentration of active ingredient in the cell culture medium of a cell culture compartment was examined as a function of time for three different heights (or thicknesses) of the first flow barrier in the first opening of the first reservoir of a device according to the invention.The parameters of the apparatus are shown in Table 3 below. Table 3 Table 3Volume of the first reservoir (medium)131,13 mm 3 mmVolume of the second reservoir (active ingredient-containing liquid)10,93 mm 3 mmVolume of the Through Opening1043 mm 3 mmEffective Replacement Area of First Flow Barrier2,42 mmEffective Replacement Area of Second Flow Barrier3,12 mmHeight (or thickness) of the first flow barrier (hydrogel)0,1; 0,5; 1mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mmConcentration of Drug in Second Reservoir5mol / m 3Diffusion coefficient of the active ingredient (in water)2·10 -9m 2 / sDiffusion coefficient of the active ingredient (in hydrogel)2·10 -10m 2 / sThe results are shown in Fig. 6.Example 6 - Effect of a Continuous Orifice Without Flow Barrier on PKIn order to examine an influence of a continuous opening of the device, which does not have a flow barrier, on the time-dependent concentration of an active ingredient in a cell culture compartment filled with cell culture medium, which compartment is fluidically connected to the device according to the invention, the concentration of active ingredient in the cell culture medium of a cell culture compartment was examined as a function of time on the one hand directly after a direct, active metered addition of an active ingredient-containing liquid via the continuous opening and on the other hand without the direct, active metered addition of an active ingredient-containing liquid via the continuous opening.The parameters of the apparatus are shown in Table 4 below. Table 4 Table 4Volume of the first reservoir (medium)131,13 mm 3 mmVolume of the second reservoir (active ingredient-containing liquid)10,93 mm 3 mmVolume of the Through Opening1043 mm 3 mmEffective Replacement Area of First Flow Barrier2,42 mmEffective Replacement Area of Second Flow Barrier3,12 mmConcentration of Drug in Second Reservoir5mol / m 3Diffusion coefficient of the active ingredient (in water)2·10 -9m 2 / sDiffusion coefficient of the active ingredient (in hydrogel)2·10 -10m 2 / sThe results are shown in Fig. 7.List of reference characters1 The method of the invention is described in detail in the following claims: A first reservoir; 2 First flow barrier (in the first opening of the first reservoir); 3 Second reservoir; 4 Second flow barrier (in the first opening of the second reservoir); 5 Third reservoir; 6 Third flow barrier (in the first opening of the third reservoir); 7 Fourth reservoir; 8 Fourth flow barrier (in the first opening of the fourth reservoir); 9 Cell culture compartment; 10 Pump: 11 Control unit; 12 Continuous opening without flow barrier; 13 Spacer; and 14 Channel.

Claims

A device comprising or consisting of: a) a first reservoir suitable for containing a liquid cell culture medium and having at least one first opening, wherein a first flow barrier is arranged in the at least one first opening of the first reservoir; b) a second reservoir suitable for containing a liquid comprising or consisting of at least one active substance and having at least one first opening, wherein a second flow barrier is arranged in the at least one first opening of the second reservoir; wherein the first and second flow barriers are each suitable for reducing a flow of an aqueous liquid through the respective at least one first opening of the respective reservoir and for allowing a diffusion of water and dissolved constituents of an aqueous liquid through the respective at least one first opening of the respective reservoir; characterized in that the first flow barrier is a flow barrier different from the second flow barrier, and the first reservoir is connected to the second reservoir via a conditionally detachable or non-detachable connection.Device according to the preceding claim, characterized in that the first and / or second flow barrier i) contains or consists of at least one hydrogel, wherein the hydrogel is optionally a swelling hydrogel; and / or ii) contains or consists of at least one capillary; and / or iii) contains or consists of at least one filter flow.Device according to one of the preceding claims, characterized in that the second flow barrier preferably permits i) a more rapid diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the second reservoir than first flow barrier through the at least one first opening of the first reservoir; or ii) a more slow or time-delayed diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the second reservoir than first flow barrier through the at least one first opening of the first reservoir.Device according to one of the preceding claims, characterized in that the first reservoir and / or second reservoir i) contains a device for filling the reservoir with a liquid, wherein the device preferably contains or consists of a closable, second opening and / or an elastomer membrane; and / or ii) contains a gas-permeable filter, preferably a gas-permeable filter membrane, wherein the filter membrane preferably has a pore width in the range from 0.1 to 0.4 μm; and / or iii) contains a liquid cell culture medium or contains a liquid which contains or consists of at least one active substance, wherein the first reservoir preferably contains a liquid cell culture medium and / or the second reservoir preferably contains a liquid which contains or consists of at least one active substance.Device according to any one of the preceding claims, characterized in that the device comprises a third reservoir suitable for containing a liquid containing or consisting of at least one metabolite of at least one active substance and having at least one first opening, wherein a third flow barrier is arranged in the at least one first opening of the third reservoir, said third flow barrier being suitable for reducing a flow of an aqueous liquid through the at least one first opening of the third reservoir and allowing a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the third reservoir.The device according to claim 5, characterized in that the third flow barrier of the third reservoir allows a slower diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the third reservoir than the first flow barrier and / or the second flow barrier through the at least one first opening of the respective reservoir, wherein the third flow barrier preferably contains or consists of at least one switchable hydrogel; and / or ii) contains or consists of at least one check valve, wherein the check valve is preferably selected from the group consisting of duck bill valves, mushroom valves, cross valves and combinations thereof, wherein the check valve particularly preferably contains or consists of an elastomeric material, wherein the elastomeric material is optionally selected from the group consisting of silicone, thermoplastic polyurethane and combinations thereof; and / or iii) contains or consists of at least one swelling valve, wherein the swelling valve preferably contains or consists of an elastomeric material, wherein the elastomeric material is optionally selected from the group consisting of silicone, thermoplastic polyurethane and combinations thereof.Device according to one of claims 5 or 6, characterised in that the third reservoir i) contains a device for filling the third reservoir with a liquid, wherein the device preferably contains or consists of a closable, second opening and / or an elastomer membrane; and / or ii) contains a gas-permeable filter, preferably a gas-permeable filter membrane, wherein the filter membrane preferably has a pore width in the range of 0.1 μm to 0.4 μm; and / or iii) contains a liquid which contains or consists of at least one metabolite of at least one active substance, wherein the at least one metabolite of at least one active substance is preferably at least one metabolite of at least one active substance contained in the second reservoir.Device according to any one of the preceding claims, characterized in that the device contains a fourth reservoir suitable for holding a liquid and has at least one first opening, wherein a fourth flow barrier is arranged in the at least one first opening of the fourth reservoir, said fourth flow barrier being suitable for reducing a flow of an aqueous liquid through the at least one first opening of the fourth reservoir and allowing a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fourth reservoir.Device according to claim 8, characterised in that the fourth flow barrier of the fourth reservoir is suitable for slowing down a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fourth reservoir over time from contact with an aqueous liquid, wherein the fourth flow barrier preferably contains or consists of at least one membrane which increases its diffusion resistance over time after contact with an aqueous liquid, wherein the at least one membrane is preferably a membrane whose properties substantially correspond to a filtration tissue of a kidney, wherein the kidney is in particular a human kidney; and / or ii) contains or consists of at least one filter flow which increases its diffusion resistance over time after contact with an aqueous liquid.Device according to one of claims 8 or 9, characterized in that the fourth reservoir i) contains a device for filling the fourth reservoir with a solid, wherein the device preferably contains or consists of a closable, second opening; and / or ii) contains a liquid-impermeable and gas-permeable filter, preferably a liquid-impermeable and gas-permeable filter membrane, wherein the filter preferably has a pore width in the range of 0.1 to 0.4 μm; and / or iii) contains no liquid; and / or iv) contains albumin, preferably human serum albumin, wherein the albumin is preferably present in a dry state.Device according to one of the preceding claims, characterized in that the device contains a fifth reservoir which is suitable for holding a liquid and has at least one first opening, wherein a fifth flow barrier is arranged in the at least one first opening of the fifth reservoir, said fifth flow barrier being suitable for reducing a flow of an aqueous liquid through the at least one first opening of the fifth reservoir and allowing a diffusion of water and dissolved constituents of an aqueous liquid through the at least one first opening of the fifth reservoir.The device of claim 11, characterized in that the fifth flow barrier of the fifth reservoir i) contains or consists of at least one hydrogel, optionally wherein the hydrogel is a swelling hydrogel; and / or ii) contains or consists of at least one capillary; and / or iii) contains or consists of at least one filter flow.Device according to one of claims 11 or 12, characterised in that the fifth reservoir contains i) a device for filling the fifth reservoir with a liquid, wherein the device preferably contains or consists of a closable, second opening and / or an elastomer membrane; and / or ii) a liquid-impermeable and gas-permeable filter, preferably a liquid-impermeable and gas-permeable filter membrane, wherein the filter preferably has a pore width in the range of 0.1 μm to 0.4 μm; and / or iii) a liquid which contains at least one constituent of the extracellular matrix of a skin or mucosa, wherein the skin or mucosa is preferably human skin or human mucosa.Device according to one of the preceding claims, characterized in that the device has a continuous opening without a flow barrier, which extends at least between the first and / or second reservoir of the device, optionally also between at least one further reservoir of the device, preferably between all reservoirs of the device, wherein particularly preferably at least one wall of the first and / or second reservoir of the device, optionally of at least one further reservoir of the device, preferably of all reservoirs of the device, constitutes at least one wall of the continuous opening without a flow barrier, wherein the continuous opening without a flow barrier is arranged in particular centrally in the device.Device according to one of the preceding claims, characterized in that the dimensions of the device i) make it possible to insert it into a single well of a microtiter plate, optionally to insert it in a liquid-tight manner, such that the openings of the reservoirs of the device are directed in the direction of an interior space of the well of the microtiter plate, the microtiter plate preferably being a 6-well microtiter plate, 12-well microtiter plate, 24-well microtiter plate, 48-well microtiter plate or 96-well microtiter plate; or ii) contains or consists of an arrangement of at least six devices according to one of claims 1 to 14, wherein the at least six devices in the arrangement are connected to one another, wherein the arrangement is suitable by its dimensions to be inserted into a microtiter plate, optionally to be inserted liquid-tight, such that the openings of the reservoirs of the individual devices of the arrangement are each directed in the direction of an interior of an individual well of the microtiter plate, wherein the microtiter plate is preferably a 6-well microtiter plate, 12-well microtiter plate, 24-well microtiter plate, 48-well microtiter plate or 96-well microtiter plate.Device according to one of the preceding claims, characterized in that the openings of the reservoirs of the device are fluidically connected to a cell culture compartment which is suitable for receiving a liquid cell culture medium, wherein the cell culture compartment optionally represents i) a well of a microtiter plate; and / or ii) contains a liquid cell culture medium and biological cells, wherein the biological cells are preferably immobilized on a wall of the cell culture compartment;A microfluidic circulation system comprising a) a device according to any of claims 1 to 14; b) a cell culture compartment suitable for containing a liquid cell culture medium; c) a channel fluidly connected to the first openings of the reservoirs of the device and to the cell culture compartment and suitable for circulating a liquid in the microfluidic circulation system; and d) a pump suitable for conveying a liquid in the channel of the microfluidic circulation system; e) optionally: a control unit configured to control a pump activity of the pump, wherein the control unit is preferably configured to control the pump such that a liquid in the channel is conveyed in pulsing fashion, particularly preferably with a pulse frequency in the range of 1 to 2.5 Hz; wherein preferably i) the cell culture compartment contains biological cells, wherein the biological cells are preferably immobilized on a wall of the cell culture compartment; and / or ii) the channel contains a liquid cell culture medium which can be circulated in the microfluidic circulation system.Use of the device according to any one of claims 1 to 16 or the microfluidic circulation system according to claim 17 for delivering an active substance to a cell culture compartment, wherein the use preferably comprises the following steps: a) filling the first reservoir of the device with a liquid cell culture medium; b) filling the second reservoir of the device with a liquid containing or consisting of at least one active substance; c) optionally: filling a third reservoir of the device with a liquid containing or consisting of at least one metabolite of at least one active substance; d) optionally: filling a fourth reservoir of the device with albumin, preferably with human serum albumin; e) optionally: filling a fifth reservoir of the device with a liquid containing at least one constituent of the extracellular matrix of a skin or mucosa, wherein the skin or mucosa is preferably human skin or human mucosa; f) establishing fluidic contact of the first openings of the reservoirs of the device with a cell culture compartment; g) optionally: conveying a liquid through a microfluidic circulation system via a pump of the microfluidic circulation system.

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