Apparatus, microfluidic circulation system and uses thereof

Abstract

An apparatus and a microfluidic circulation system are provided and uses thereof are proposed. The apparatus includes a first reservoir, which is suitable for receiving a liquid cell-culture medium and has at least a first opening with a first flow barrier, and also includes a second reservoir, which is conditionally detachably or undetachably connected to the first reservoir, is suitable for receiving an active-substance liquid and has at least a first opening with a second flow barrier. The first and second flow barriers are different from one another and are each suitable for reducing a flow of an aqueous liquid and allowing diffusion of water and dissolved constituents of an aqueous liquid. The apparatus is stable for a very long time and allows an economical and reproducible investigation of a desired PK over a very wide range with little risk of contamination.

Description

[0001] Device, microfluidic circulation system and uses thereof

[0002] A device and a microfluidic circulation system are provided, and uses thereof are proposed. The device contains a first reservoir suitable for holding a liquid cell culture medium and having at least one first opening with a first flow barrier, as well as a second reservoir, which is connected to the first reservoir in a conditionally detachable or non-detachable manner and is suitable for holding a liquid drug substance and has at least one first opening with a second flow barrier. The first and second flow barriers are different from one another and are each suitable for reducing the flow of an aqueous liquid and allowing the diffusion of water and dissolved components of an aqueous liquid. The device is very long-term stable and allows economical and reproducible testing of a desired PK over a very broad range with a low risk of contamination.In cell culture systems, so-called microphysiological systems (MPS), organ-on-chip systems (OOC systems) and microscale cell culture analogue systems (mCCA systems), the pharmacokinetics must be correctly mapped for the testing of active substances (e.g. drugs). Pharmacokinetics describes the concentration of a substance over a given time course in the bloodstream of an organism. A pharmacokinetic curve can be well predicted using the pharmacologically important properties of a molecule, such as plasma binding (albumin affinity), blood stability, permeability, IC50, etc., which can be determined before testing in the cell culture system, as well as the type of dosage. The pharmacokinetics (PK) is strongly dependent on the type of application of an active substance (e.g.The pharmacokinetics of a drug depend on the route of administration (e.g., intravenous, subcutaneous, or rectal) and can also be the target of a test using a suitable device to determine the appropriate route for administering a drug. For cell or tissue culture tests, the pharmacokinetic curve must be accurately mapped to realistically predict potential toxic effects or tissue accumulation of the substance in question.

[0003] In general, pharmacokinetics are influenced by several processes that occur in parallel in the body, which are also referred to as ADME (absorption, distribution, metabolism, excretion). In most cases, these processes are significantly influenced by specific organs of the body. While absorption occurs via the mucous membranes in the case of oral dosing (e.g. in the form of a tablet or coated tablet) or rectal dosing (e.g. in the form of a suppository), cutaneous dosing (e.g. in the form of an ointment or cream) primarily occurs via the skin. With subcutaneous dosing (e.g. in the form of a syringe or short cannula), the dose is administered directly into the connective and fatty tissue beneath the skin, which determines the subsequent absorption process.

[0004] After absorption, the active ingredient is distributed throughout the body, i.e., distribution describes the distribution process of an absorbed active ingredient within the body. Active ingredients (e.g., medications) are usually distributed throughout the body via the cardiovascular system, reaching the target tissue and other tissues. Both the blood plasma binding of the active ingredient and the binding of the active ingredient within the tissue play a crucial role in this process. The distribution process has so far been the most difficult to model in microphysiological systems. There are several reasons for this. First, predicting blood plasma binding of active ingredients in the cell culture medium of microphysiological systems has so far been inadequate.Second, depending on the type of active ingredient, tissue accumulation of active substances occurs not only in the target tissue but also in various other tissues of the body. Imaging all relevant tissue types in microphysiological systems requires enormous resources, time, and expense, making accurate mapping of these effects via tissue equivalents in microphysiological systems economically unfeasible. Third, scaling of microphysiological systems cannot be performed accurately for all physiological parameters, which inevitably leads to a mathematical distortion of the determined distribution. Therefore, there is a need for improvement in these aspects.

[0005] The metabolism of an absorbed drug occurs primarily via the liver. Through the enzymatic degradation of all absorbed drugs, they are pharmacologically altered and partially degraded, a process also referred to as "hepatic clearance."

[0006] The excretion of an absorbed drug in the body occurs primarily via the kidneys, which is also referred to as "renal clearance." Depending on their size, the absorbed drugs are excreted glomerularly and subsequently reabsorbed tubularly depending on their molecular structure. This process determines excretion on the one hand, but on the other hand, toxic effects are also induced upon specific binding to the functional transporters of the tubule.

[0007] Microfluidic systems are known in the art that comprise a syringe pump and a flow chip, thus allowing the concentration of an active ingredient to be adjusted in a time-controlled manner according to a pharmacologically relevant profile. Such microfluidic systems have at least two fluidic inlets, with a cell culture medium being supplied to the microfluidic system via a first inlet, and an active ingredient being dosed at a predetermined concentration via the second inlet. By varying the volume flows in the first and second inlets relative to each other, the concentration of the active ingredient can be varied over time. The disadvantage of these microfluidic systems, however, is that they have a complex design due to the requirement of a syringe pump, and the associated tubing makes them highly susceptible to contamination (Guerrero, YA et al., The AAPS journal, 22(3):53).

[0008] Furthermore, microfluidic systems containing tissue equivalents of the organs most important for pharmacokinetics (e.g., the liver and / or kidney) are known in the prior art. The liver tissue equivalents metabolize the active ingredients and thus reduce the concentration of the added active ingredients over time in these systems. The kidney tissue equivalents excrete the active ingredients (or their degradation products) and thus also reduce the concentration of the added active ingredients 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 error-proneness of the systems and increases the effort and cost of providing them.Furthermore, the co-cultivation of different tissue equivalents is often limited by the need to first find a cell culture medium that meets the needs of all organotypic tissue culture equivalents. A further disadvantage of such systems is that the aspects of absorption and distribution of pharmacokinetics, as well as binding to other tissues and blood plasma, are completely ignored.

[0009] Regarding the latter point, it is known in the art that drug absorption can be simulated in microphysiological models by using a mucosal or skin equivalent in a microfluidic system (Zoio, P. et al., Pharmaceutics, 14(3):682). However, this measure further increases the complexity of the microfluidic system, thereby further increasing the susceptibility to errors and further increasing the effort and cost of deploying the microfluidic system.

[0010] WO 2007 / 021343 A2 discloses a device comprising a first and a second reservoir, each of which has an opening at which a flow barrier is arranged. The first and second reservoirs are merely assembled, i.e., detachably connected. As a result, the device does not exhibit high long-term stability, and there is a certain susceptibility to errors and a risk of contamination during use.

[0011] Based on this, the object of the present invention was to provide a device and a microfluidic circulation system that overcomes at least one disadvantage of the prior art. In particular, the device should be more stable over the long term and minimize errors and contamination risks when using the device. Furthermore, the device and the microfluidic system should make it possible to investigate the pharmacokinetics (PK), preferably also the pharmacodynamics (PD), of an active ingredient in biological cell systems (e.g., biological cell tissues) in a simple, rapid, and cost-effective (i.e., economical) manner. In particular, the device and the microfluidic system should make it possible to set a desired PK, preferably also a desired PD, over a wide range in order to be able to realize a multitude of possible PK profiles, preferably also PD profiles (e.g.,PK during intravenous, subcutaneous, or rectal drug administration). Furthermore, uses of the device and the microfluidic circulation system should be proposed.

[0012] 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. The dependent claims show advantageous developments.

[0013] 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 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 (with respect to a flow through the first opening without the flow barrier) 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;

[0014] The device according to the invention is more stable over the long term than devices known from the prior art. This is due to the fact that the first and second reservoirs of the device are connected via a partially detachable or non-detachable connection. Furthermore, this eliminates possible errors during assembly of the device and simplifies use of the device. This also allows more reproducible measurement results to be achieved with the device. Furthermore, the risk of contamination during use of the device is reduced. This represents an immense advantage, for example, in the examination and / or cultivation of antibiotic-free stem cell cultures. Furthermore, the cultivation of stem cells often requires a time-delayed addition of substances, which can be adjusted by specifically selecting a difference between the first and second flow barriers of the device according to the invention.

[0015] The two different flow barriers of the two reservoirs allow the time-dependent exposure of biological cells to at least one active ingredient to be investigated over a broader range than with identical flow barriers in both reservoirs. This means that by selecting a difference between the two flow barriers (e.g., selecting their permeation properties), a wide range of pharmacokinetics for an active ingredient under investigation can be investigated (e.g., adjusted and / or determined). The device according to the invention does not require complicated technical aids, such as a syringe pump for dosing the active ingredient. This further reduces the risk of contamination when using the device, and more reliable and reproducible results can be achieved.A user can carry out an examination with the device easily and quickly, since direct interaction with the device according to the invention is only necessary at the beginning and end of an examination using the device according to the invention.

[0016] In summary, the device according to the invention is thus more stable in the long term and allows a desired PK to be investigated (e.g., adjusted and / or determined) in a simple, rapid and cost-effective (i.e., economical) manner, whereby different PKs can be investigated over a wider range than with devices from the prior art (e.g., PK during intravenous, subcutaneous or rectal drug administration, etc.) and the device minimizes contamination risks and enables more reproducible results compared to known devices.

[0017] The feature that the first flow barrier is a different flow barrier 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 other flow barriers mentioned here. Permeation properties can be understood to mean the suitability of the respective flow barrier to reduce the 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 degree) and / or to allow the 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 degree).If the permeation properties are different, the said strength or degree differs.

[0018] A conditionally detachable connection (e.g., between the first reservoir and the second reservoir) can be understood as a connection (e.g., between the first and the second reservoir) that can be destroyed without destroying the reservoirs, but by destroying at least one auxiliary joining part that establishes the connection between the reservoirs (e.g., a force-locking connection such as an adhesive connection, or a connection via a holding device that fixes the reservoirs force-lockingly 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 as a connection (e.g., between the first and the second reservoir) that can only be broken by destroying at least one of the (at least two) reservoirs (e.g., a material-to-material connection).

[0019] An active ingredient is preferably understood to mean all substances that exert at least one effect on a biological cell. Examples include pharmaceutical active ingredients (i.e., medications), 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.

[0020] The first and / or second reservoir can (each) have at least two, preferably at least three, particularly preferably at least four, first openings, i.e. openings in each of which a flow barrier is arranged. Preferably, the flow barriers in the first openings of the first reservoir are identical first flow barriers to one another and / or the flow barriers in the first openings of the second reservoir are identical second flow barriers to one another. The advantage of multiple openings with respective flow barriers in the respective reservoirs is that a more uniform (homogeneous) and possibly also faster release of substances from the (second) reservoir and uptake of substances into the (first) reservoir is possible.The pharmacokinetics with regard to absorption and / or distribution can thus be adjusted more uniformly and rapid pharmacokinetics with regard to absorption and / or distribution can be achieved.

[0021] 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.

[0022] Apart from that, the first and / or second flow barrier may contain or consist of at least one filter fleece.

[0023] The second flow barrier can allow a faster diffusion of water and dissolved components 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 ingredient located in the second reservoir can be released quickly from the second reservoir (e.g., into a cell culture compartment containing biological cells to which the device is fluidically connected) and absorbed more slowly into a liquid (e.g., a cell culture medium) in the first reservoir (e.g., from a cell culture compartment containing 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 ingredient can be adjusted for a cell culture compartment containing biological cells connected to the device, ie, for example, a PK can be adjusted and thus emulated during oral, rectal or subcutaneous administration of the active ingredient.

[0024] Alternatively, the second flow barrier can allow a slower diffusion of water and dissolved components 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 released quickly from the first reservoir (e.g. into a cell culture compartment containing biological cells, to which the device is fluidically connected) and released more slowly into a liquid containing an active ingredient from the first reservoir (e.g. from a cell culture compartment containing 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 (each) 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 achieved by piercing the elastomer membrane with a needle. The advantage is that no separate steps of opening and closing the second opening are required to fill the reservoir(s) with a liquid, which saves time and reduces the risk of contamination.

[0025] Furthermore, the first reservoir and / or second reservoir (each) can contain a gas-permeable filter, preferably a gas-permeable filter membrane. The filter membrane preferably has a pore size in the range of 0.1 to 0.4 pm. The advantage of this is that gas exchange between the interior of the respective reservoirs and the environment is possible via the gas-permeable filter. This prevents the formation of negative or positive pressure in the reservoirs, thus precluding any resulting distortion of the mass transfer via the flow barriers of the reservoirs. Thus, a desired PK can be set more precisely, and more reproducible results can be obtained.

[0026] Furthermore, the first reservoir and / or second reservoir can contain a liquid cell culture medium or a liquid that contains or consists of at least one active ingredient. Preferably, the first reservoir contains a liquid cell culture medium and / or the second reservoir contains a liquid that contains or consists of at least one active ingredient. Thus, the second reservoir is defined as the reservoir that determines the release of active ingredient (to a fluidically connected cell culture compartment with biological cells) and thus, via its flow barrier, determines the absorption aspect of the PK ("A" in ADME), and the first reservoir is defined as the reservoir that determines the uptake of active ingredient (from a fluidically connected cell culture compartment with biological cells) and thus, via its flow barrier, determines the distribution aspect of the PK ("D" in ADME).The device may contain a third reservoir suitable for holding a liquid containing or consisting of at least one metabolite of at least one active ingredient, 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 the flow of an aqueous liquid through the at least one first opening of the third reservoir and allowing the diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the third reservoir. By means of said third reservoir with the flow barrier in its first opening, it is possible to investigate a metabolism aspect of the PK ("M" in ADME).

[0027] The third reservoir may be connected to the first reservoir and / or second reservoir via a conditionally detachable or non-detachable connection.

[0028] The third flow barrier of the third reservoir preferably allows a slower diffusion of water and dissolved components 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. The advantage here is that the metabolism aspect can be represented more accurately (i.e., more physiologically relevant), since metabolism occurs with a time delay and thus biological cells (here: in a cell culture compartment fluidically connected to the device according to the invention) are only confronted with the metabolite after a certain time.

[0029] The third flow barrier of the third reservoir preferably contains or consists of at least one switchable hydrogel.

[0030] Furthermore, the third flow barrier of the third reservoir can contain or consist of at least one (non-electrically activated) check valve, which is preferably selected from the group consisting of duckbill 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.

[0031] Furthermore, the third flow barrier may contain or consist of at least one swellable (non-electrically activated) valve. The swellable 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.

[0032] The third reservoir may 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.

[0033] Furthermore, the third reservoir can contain a gas-permeable filter, preferably a gas-permeable filter membrane. The filter membrane preferably has a pore size in the range of 0.1 pm to 0.4 pm.

[0034] Apart from that, the third reservoir may contain a liquid which contains or consists of at least one metabolite of at least one active ingredient, wherein the at least one metabolite of at least one active ingredient is preferably at least one metabolite of at least one active ingredient which is contained in the second reservoir.

[0035] The third reservoir can have at least two, preferably at least three, particularly preferably at least four, first openings, i.e., openings in each of which a third flow barrier is arranged. The flow barriers in the first openings of the third reservoir are preferably identical third flow barriers. The advantage is that a more uniform (homogeneous) and possibly also faster release of metabolites from the third reservoir is possible. The pharmacokinetics with respect to metabolism can thus be adjusted more uniformly, and rapid pharmacokinetics with respect to metabolism can also be achieved.The device may include a fourth reservoir suitable for holding a liquid and having 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 the flow of an aqueous liquid through the at least one first opening of the fourth reservoir and allowing the diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the fourth reservoir. By means of said fourth reservoir with the flow barrier in its first opening, it is possible to investigate an excretory aspect of the PK ("E" in ADME).

[0036] The fourth reservoir may be connected to the first reservoir and / or second reservoir (optionally also to the third reservoir) via a conditionally detachable or non-detachable connection.

[0037] The fourth flow barrier of the fourth reservoir can be suitable for slowing down the diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the fourth reservoir over time, starting from contact with an aqueous liquid. The advantage here is that the excretion aspect can be represented more accurately (i.e., more physiologically relevant), since the excretion (i.e., elimination) 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 fluidically connected to the device according to the invention) first experience a rapid and then increasingly slow reduction in the concentration of the active ingredient or its at least one metabolite.

[0038] The fourth flow barrier of the fourth reservoir can contain or consist of at least one membrane that increases its diffusion resistance over time after contact with an aqueous liquid. The at least one membrane is preferably a membrane whose properties essentially correspond to the filtration tissue of a kidney, the kidney being, in particular, a human kidney. The advantage of this is that the excretion of the active ingredient and at least one metabolite thereof can be modeled as physiologically accurately as possible, and falsification of the results can be avoided.

[0039] Furthermore, the fourth flow barrier of the fourth reservoir can contain or consist of at least one filter fleece that increases its diffusion resistance over time after contact with an aqueous liquid. This measure can also achieve the most accurate possible representation of the physiologically occurring excretion of the active ingredient and at least one of its metabolites.

[0040] The fourth reservoir may contain a device for filling the fourth reservoir with a solid, wherein the device preferably contains or consists of a closable second opening.

[0041] 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 size in the range of 0.1 to 0.4 pm.

[0042] In a preferred embodiment, the fourth reservoir contains no liquid. The advantage is that the excretory aspect of the PK (i.e., excretion) can be more accurately modeled.

[0043] 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 even more physiological conditions, since the presence of albumin also takes into account the binding of the active ingredient or at least one of its metabolites to an essential blood component. This is of particular importance, for example, for active ingredients or their metabolites that bind strongly to the albumin in the blood serum (e.g. HSA), since this binding can drastically reduce the concentration of active ingredient or its metabolite actually experienced by biological cells in the body. The PK in the living body can thus be mapped even more precisely, allowing even more precise statements to be made about the actual effects of active ingredients orof their metabolites on body cells, thus avoiding false conclusions. 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.

[0044] The fourth reservoir can have at least two, preferably at least three, particularly preferably at least four, first openings, i.e., openings in each of which a fourth flow barrier is arranged. The flow barriers in the first openings of the fourth reservoir are preferably identical fourth flow barriers. The advantage is that a more uniform (homogeneous) and possibly faster uptake of active ingredient and, if applicable, its metabolites into the fourth reservoir is possible. The pharmacokinetics with respect to excretion can thus be adjusted more uniformly, and rapid pharmacokinetics with respect to excretion can be achieved.

[0045] The device can further contain a fifth reservoir suitable for holding a liquid and having at least one first opening, wherein a fifth flow barrier is arranged in the at least one first opening of the fifth reservoir, which fifth flow barrier is suitable for reducing the flow of an aqueous liquid through the at least one first opening of the fifth reservoir and allowing the diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the fifth reservoir. The advantage here is that the absorption of active ingredient or at least one metabolite thereof through a skin or mucous membrane can be imaged via the fifth reservoir.

[0046] The fifth reservoir may be connected to the first reservoir and / or second reservoir (optionally also to the third reservoir and / or fourth reservoir) via a conditionally detachable or non-detachable connection.

[0047] The fifth flow barrier of the fifth reservoir may contain or consist of at least one hydrogel, wherein the hydrogel is optionally a swelling hydrogel.

[0048] Furthermore, the fifth flow barrier of the fifth reservoir may contain or consist of at least one capillary. Furthermore, the fifth flow barrier of the fifth reservoir may contain or consist of at least one filter fleece.

[0049] The fifth reservoir may 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.

[0050] 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 size in the range of 0.1 μm to 0.4 μm.

[0051] Furthermore, the fifth reservoir may contain a liquid that contains at least one component of the extracellular matrix of a skin or mucous membrane, wherein the skin or mucous membrane is preferably human skin or human mucous membrane.

[0052] The fifth reservoir can have at least two, preferably at least three, particularly preferably at least four, first openings, i.e. openings in each of which a fifth flow barrier is arranged. The flow barriers in the first openings of the fourth reservoir are preferably identical fifth flow barriers. The advantage is that a more uniform (homogeneous) and possibly also faster absorption of active ingredient and possibly its metabolites into the fifth reservoir is possible. The pharmacokinetics with regard to absorption into the skin or mucous membrane can thus be adjusted more uniformly and rapid pharmacokinetics can also be achieved with regard to absorption into the skin or mucous membrane.

[0053] The device according to the invention can further comprise 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 continuous opening without a flow barrier is that a user of the device can add at least one active ingredient (e.g. in a liquid) past a flow barrier of the device (i.e. directly and immediately) to biological cells of a cell culture compartment (e.g. in a well of a 6-well microtiter plate). This enables very rapid addition of active ingredient to the biological cells and very rapid pharmacokinetics to be mapped (e.g. to map an intravenous administration of at least one active ingredient).

[0054] 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 through-opening without a flow barrier (i.e., the through-opening without a flow barrier shares at least one wall with at least one reservoir of the device). The advantage of the shared 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 in a more compact manner or, given a defined size, its reservoirs can have a larger volume.

[0055] In particular, the through-opening is arranged centrally in the device without a flow barrier. The advantage of this is that the device is more stable than if the through-opening were arranged laterally (e.g., at a lateral edge of the device).

[0056] In a preferred embodiment, the device's dimensions make it suitable for insertion into a single well of a microtiter plate, optionally in a liquid-tight manner, so that the openings of the reservoirs of the device are directed toward the 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 to investigate at least the pharmacokinetics of an active ingredient in biological cells present in wells of a microtiter plate (microtiter plate wells as cell culture compartments) in a very simple, rapid, cost-effective, and less susceptible to contamination manner.

[0057] The device according to the invention can additionally 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. Due to its dimensions, the arrangement is suitable for insertion into a microtiter plate, optionally for insertion in a liquid-tight manner, such that the openings of the reservoirs of the individual devices of the arrangement are each directed toward the 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 easier, faster, more cost-effective and less susceptible to contamination to investigate at least one pharmacokinetics of different active substances in identical biological cells present in wells of a microtiter plate and / or to investigate at least one pharmacokinetics of an identical active substance in different biological cells, each present in separate wells of a microtiter plate.

[0058] 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 the 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. This makes it easier to prevent possible errors in the function of the device and achieve more reproducible results. 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 suitable for receiving a liquid cell culture medium.This design has the advantage that the investigation of the influence of an active substance on biological cells and at least of its PK can begin more quickly.

[0059] 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, with the biological cells preferably immobilized on a wall of the cell culture compartment. The advantage of this is that the investigation of the effect of an active ingredient on biological cells, and at least its PK, can begin immediately.

[0060] According to the invention, a microfluidic circulation system is further provided, comprising a) a device according to the invention; b) a cell culture compartment suitable for receiving 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 pumping activity of the pump, wherein the control unit is preferably configured to control the pump such that a liquid is conveyed in the channel in a pulsating manner, particularly preferably with a pulse frequency in the range of 1 to 2.5 Hz.

[0061] The microfluidic circulation system according to the invention has the advantages of the device according to the invention. A further advantage of the microfluidic circulation system is the presence of the pump. The pump makes it possible (through convection effects) to achieve a faster exposure of biological cells in the cell culture compartment to the active ingredient, which can influence the pharmacokinetics, i.e., faster pharmacokinetics can be mapped (e.g., to map the intravenous administration of at least one active ingredient).

[0062] The cell culture compartment of the microfluidic circulation system may (already) contain biological cells, with the biological cells preferably being immobilized on a wall of the cell culture compartment. Furthermore, the channel of the microfluidic device may (already) contain a liquid cell culture medium that can be circulated in the microfluidic circulation system. The advantage of this is that the investigation of the effect of an active ingredient on biological cells, and at least its PK, can begin immediately.

[0063] According to the invention, a use of the device according to the invention or the microfluidic circulation system according to the invention for delivering an active substance to a cell culture compartment is also proposed.

[0064] 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 that contains or consists of at least one active ingredient; c) optionally: filling a third reservoir of the device with a liquid that contains or consists of at least one metabolite of at least one active ingredient; 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 that contains at least one component of the extracellular matrix of a skin or mucous membrane, wherein the skin or mucous membrane is preferably human skin or human mucous membrane; f) establishing fluidic contact between the first openings of the reservoirs of the device and a cell culture compartment;g) optionally: conveying a liquid through a microfluidic circulation system via a pump of the microfluidic circulation system;

[0065] The subject matter of the invention will be explained in more detail with reference to the following figures and the following examples, without wishing to restrict it to the specific embodiments shown here.

[0066] Figure 1 shows a schematic view of a device according to the invention. The device contains a first reservoir 1, which is suitable for holding 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 that contains or consists of at least one active ingredient, 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 permanent connection, i.e. in this case the two reservoirs 1, 3 share a common wall (i.e. they are integrally connected or designed as a single 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 allowing a diffusion of water and dissolved components of an aqueous liquid through the respective at least one first opening of the respective reservoir 1, 3.

[0067] Figures 2A to 2C schematically show various views of a further device according to the invention. The device shown here is suitable due to its dimensions for being inserted into a single well of a microtiter plate. Like the device from Figure 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 for Figure 1. Here too, the first reservoir 1 is connected to the second reservoir 3 via a permanent connection, i.e. in this case the two reservoirs 1, 3 share a common wall (i.e. they are integrally connected or designed as a single piece).This device also has a through-opening 12 without a flow barrier, which extends centrally in the device between the first and second reservoirs of the device, wherein a wall of the first and second reservoirs of the device represents at least one wall of the through-opening without a flow barrier. Furthermore, the device has at least one spacer 13 (e.g., three spacers 13) which can ensure that the flow barriers 2 and 4 are not closed above the bottom of the well when the device is placed on the bottom of a microtiter plate.

[0068] Figure 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 Figures 1 and 2, 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 for Figure 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 components 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 for slowing the diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the fourth reservoir 7 over time, starting from contact with an aqueous liquid. The microfluidic circulation system further comprises a cell culture compartment 9, which is suitable for receiving a liquid cell culture medium and for cultivating biological cells.In addition, the microfluidic circulation system includes a channel 14 that 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 that is suitable for circulating a liquid in the microfluidic circulation system. Furthermore, the microfluidic circulation system includes a pump 10 that is suitable for conveying a liquid in the channel 14 of the microfluidic circulation system. Furthermore, the microfluidic circulation system includes a control unit 11 that is configured to control the pumping activity of the pump 10 (e.g., such that a liquid is conveyed in the channel 14 in a pulsating manner, particularly preferably with a pulse frequency in the range of 1 to 2.5 Hz).

[0069] Figure 4 shows a 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, as a function of time for three different effective exchange areas in the first reservoir, i.e., three different areas of the first flow barrier in the first opening of the first reservoir. It can be seen that the area of ​​the flow barrier influences the PK, i.e., the larger the area, the faster the active ingredient released from the second reservoir into the cell culture medium of the cell culture compartment is absorbed by the first reservoir and thus depleted in the cell culture compartment.

[0070] Figure 5 shows the 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, 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 liquid in the first reservoir influences 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.

[0071] Figure 6 shows a 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, 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 influences 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.

[0072] Figure 7 shows a 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, as a function of time for certain parameters of the device, which represent a PK in the case of an oral dosage of active ingredient (see curve "OD") and in the case of a direct, active dosage of the active ingredient-containing liquid 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 dosage of the active ingredient-containing liquid (i.e. dosage 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 increases significantly faster than is possible with the indirect, passive dosing through the second flow barrier in the first opening of the second reservoir (cf. curves "IV" and "OD").

[0073] Example 1 - Structure of the microfluidic circulation systems

[0074] A microfluidic circulation system is provided which contains a device according to the invention. The device according to the invention contains: a) a first reservoir which is suitable for receiving 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 receiving a liquid which contains or consists of at least one active ingredient, 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.

[0075] 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 allowing a diffusion of water and dissolved components of an aqueous liquid through the respective at least one first opening of the respective reservoir.

[0076] Furthermore, the microfluidic circulation system contains a cell culture compartment suitable for receiving a liquid cell culture medium and containing said liquid cell culture medium and a biological cell culture.

[0077] In addition, the microfluidic circulation system contains a channel that is fluidically connected to the first openings of the reservoirs of the device according to the invention and to the cell culture compartment, and that is suitable for circulating a liquid in the microfluidic circulation system.

[0078] In addition, the microfluidic circulation system contains a pump that is suitable for transporting a liquid in the channel of the microfluidic circulation system.

[0079] In this case, the microfluidic circulation system further includes a control unit configured to control a pumping activity of the pump.

[0080] 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 enable a defined mass transfer between the two reservoirs and the channel, and thus also the cell culture compartment, allowing a target concentration of an active ingredient to be adjusted over time as needed in the microfluidic system. The respective flow barrier can be designed, for example, as a capillary, filter fleece, and / or hydrogel. Thus, unlike a syringe pump, it does not require an electrical supply and is less susceptible to contamination.

[0081] The use of such a microfluidic circulation system can be divided into different application areas: 1) Only pharmacokinetics (short: PK) is investigated (i.e. only adsorption and distribution is investigated)

[0082] For this purpose, the microfluidic circulation system—as described above—has only two reservoirs. The first reservoir contains only cell culture medium, and the second reservoir contains the drug to be investigated (e.g., in an aqueous buffer). The pharmacokinetics are controlled by the type of flow barrier in the first opening of the first reservoir.

[0083] To investigate the absorption of the active ingredient through the skin or mucous membranes (e.g., to investigate oral or rectal drug administration), this flow barrier contains or consists of a hydrogel. Alternatively, this flow barrier contains or consists of a hydrogel and a capillary.

[0084] For the investigation of intravenous dosing or intramuscular dosing, this flow barrier contains or consists of a capillary.

[0085] To investigate subcutaneous dosing, this flow barrier contains or consists of a swelling hydrogel and / or a filter fleece whose diffusion resistance decreases over time.

[0086] 2) PK and part of the pharmacodynamics (PD for short) is investigated (i.e. only adsorption, distribution and metabolism is investigated)

[0087] 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 ingredient located in the second reservoir and contains a first opening in which a flow barrier is arranged. By selecting the type of these flow barriers, the release of the metabolite to the channel and thus to the cell culture compartment of the microfluidic system can be controlled over time.

[0088] The drug's metabolite must be released with a time delay, as the drug must first be metabolized in the body. Consequently, a flow barrier with a "switch-on delay" is required. Examples of suitable devices include switchable hydrogels, a duckbill valve, or a swelling mushroom valve. The permeability properties of this flow barrier can be fine-tuned to a specific drug under investigation by determining the rate of liver metabolism of the drug under investigation in advance (e.g., via liver microsomes). Based on this information, the permeability properties of the flow barrier of the third reservoir are selected.

[0089] 3) PK and PD are investigated (ie adsorption, distribution, metabolism and excretion are investigated)

[0090] For this purpose, the device according to the invention, which is part of the microfluidic system, comprises a fourth reservoir in addition to the third reservoir. The fourth reservoir contains no liquid and contains a first opening in which a flow barrier is arranged. By selecting the type of these flow barriers, the uptake of the active ingredient or a metabolite thereof from the channel and thus from the cell culture compartment of the microfluidic system can be controlled over time (dilution of the active ingredient / metabolite in the fourth reservoir). This emulates the removal of the active ingredient / metabolite from the body.

[0091] In this case, the flow barrier in the first opening of the fourth reservoir can contain or consist of a membrane and / or a filter fleece that increases its diffusion resistance over time. This flow barrier allows the concentration of the active ingredient or its metabolite in the channel and thus in the cell culture compartment to be rapidly reduced (emulating high renal clearance). Ideally, this flow barrier contains a dialysis membrane whose permeation properties are very similar to or equivalent to the filtration of a kidney.

[0092] 4) PK and PD are investigated taking blood plasma binding into account (i.e., adsorption, distribution, metabolism, and excretion under even more physiological conditions). For this purpose, the cell culture medium in the fourth reservoir contains serum albumin (e.g., in a dry form). In this case, the flow barrier must be suitable to prevent the release of serum albumin into the channel of the microfluidic circulation system, i.e., the flow barrier must ensure that the serum albumin remains in the fourth reservoir.

[0093] The reservoirs of the microfluidic circulation system according to the invention preferably each have a second opening through which gas exchange can take place and / or through which the reservoirs can be filled with a liquid. The possibility of gas exchange can further influence the temporal exchange of substances between the reservoirs and the channel of the microfluidic circulation system (avoiding negative pressure in the respective reservoir).

[0094] Example 2 - Use of the device or circulation system

[0095] The device according to the invention and the microfluidic circulation systems according to the invention can be used to test active ingredients (e.g. medications and / or cosmetics).

[0096] This allows the physiological effect of a body's organs to be emulated, allowing the PK, and optionally also the PD, of the drug under investigation to be investigated on a very small scale (e.g., the size of a business card). This makes it possible, for example, to conduct toxicity tests quickly, easily, cost-effectively, and realistically.

[0097] Furthermore, with the device according to the invention and the microfluidic circulation system according to the invention, it is possible to achieve a site-specific and time-specific release of at least one growth factor as an active ingredient over time and thus to investigate the construction of artificial tissue structures as organ replacements. Example 3 - Influence of the area of ​​the flow barriers on the PK

[0098] In order to investigate the 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 investigated 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.

[0099] The parameters of the device are shown in the following Table 1.

[0100] Table 1

[0101] The results are shown in Figure 4.

[0102] Example 4 - Influence of the liquid volume in a reservoir on the PK

[0103] In order to investigate the 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 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 investigated 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.

[0104] The parameters of the device are shown in the following Table 2.

[0105] Table 2

[0106] The results are shown in Figure 5.

[0107] Example 5 - Influence of the height of the first flow barrier on the PK

[0108] In order to investigate 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 investigated 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.

[0109] The parameters of the device are shown in the following Table 3.

[0110] Table 3

[0111] The results are shown in Figure 6.

[0112] Example 6 - Influence of a continuous opening without flow barrier on the PK

[0113] In order to investigate the influence of a continuous opening of the device, which does not have a flow barrier, on the time-dependent concentration of an active substance 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 substance in the cell culture medium of a cell culture compartment was investigated as a function of time, on the one hand immediately after a direct, active addition of an active substance-containing liquid via the continuous opening and, on the other hand, without the direct, active addition of an active substance-containing liquid via the continuous opening.

[0114] The parameters of the device are shown in the following Table 4.

[0115] Table 4

[0116] The results are shown in Figure ?

[0117] 1: first reservoir;

[0118] 2: first flow barrier (in the first opening of the first reservoir);

[0119] 3: second reservoir;

[0120] 4: second flow barrier (in the first opening of the second reservoir);

[0121] 5: third reservoir;

[0122] 6: third flow barrier (in the first opening of the third reservoir);

[0123] 7: fourth reservoir;

[0124] 8: fourth flow barrier (in the first opening of the fourth reservoir);

[0125] 9: Cell culture compartment;

[0126] 10: Pump:

[0127] 11: control unit;

[0128] 12: continuous opening without flow barrier;

[0129] 13: spacer; and

[0130] 14: Channel.

Claims

Patent claims 1. A 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 suitable for receiving a liquid containing or consisting of at least one active ingredient 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 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 from the second flow barrier, and the first reservoir is connected to the second reservoir via a conditionally detachable or non-detachable connection; 2. 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 fleece.

3. Device according to one of the preceding claims, characterized in that the second flow barrier preferably i) allows a faster diffusion of water and dissolved components 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; or ii) allows a slower or time-delayed diffusion of water and dissolved components 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.

4. 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 of 0.1 to 0.4 pm; and / or iii) contains a liquid cell culture medium or contains a liquid which contains or consists of at least one active ingredient, 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 ingredient.

5. Device according to one of the preceding claims, characterized in that the device contains a third reservoir which is suitable for receiving a liquid which contains or consists of at least one metabolite of at least one active ingredient, and has at least one first opening, wherein in the at least a first opening of the third reservoir, a third flow barrier is arranged, which is suitable for reducing a flow of an aqueous liquid through the at least one first opening of the third reservoir and for allowing a diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the third reservoir.

6. Device according to claim 5, characterized in that the third flow barrier of the third reservoir allows a slower diffusion of water and dissolved components 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 i) 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 duckbill 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.

7. Device according to one of claims 5 or 6, characterized 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 ingredient, wherein the at least one metabolite of at least one active ingredient is preferably at least one metabolite of at least one active ingredient that is contained in the second reservoir.

8. Device according to one of the preceding claims, characterized in that the device contains a fourth reservoir which is suitable for receiving a liquid and has at least one first opening, wherein in the at least one first opening of the fourth reservoir a fourth flow barrier is arranged which is suitable for reducing a flow of an aqueous liquid through the at least one first opening of the fourth reservoir and for allowing a diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the fourth reservoir.

9. Device according to claim 8, characterized in that the fourth flow barrier of the fourth reservoir is suitable for slowing down a diffusion of water and dissolved components of an aqueous liquid through the at least one first opening of the fourth reservoir over time, starting from contact with an aqueous liquid, wherein the fourth flow barrier preferably i) 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 in Essentially 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 fleece which increases its diffusion resistance over time after contact with an aqueous liquid.

10. 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 pm; and / or iii) contains no liquid; and / or iv) contains albumin, preferably human serum albumin, wherein the albumin is preferably in a dry state.

11. Device according to one of the preceding claims, characterized in that the device contains a fifth reservoir which is suitable for receiving a liquid and has at least one first opening, wherein in the at least one first opening of the fifth reservoir a fifth flow barrier is arranged which 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 components of an aqueous liquid through the at least one first opening of the fifth reservoir.

12. Device according to claim 11, characterized in that the fifth flow barrier of the fifth reservoir 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 fleece.

13. Device according to one of claims 11 or 12, characterized 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) 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 pm to 0.4 pm; and / or iii) contains a liquid which contains at least one component of the extracellular matrix of a skin or mucous membrane, wherein the skin or mucous membrane is preferably human skin or human mucous membrane.

14. Device according to one of the preceding claims, characterized in that the device has a through 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, represents at least one wall of the through opening without a flow barrier, wherein the through opening without a flow barrier is arranged in particular centrally in the device.

15. Device according to one of the preceding claims, characterized in that the device i) is suitable due to its dimensions to be inserted into a single well of a microtiter plate, optionally to be inserted in a liquid-tight manner, so that the openings of the reservoirs of the device are directed towards an interior of the 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;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 are connected to one another in the arrangement, wherein the arrangement is suitable due to its dimensions for being inserted into a microtiter plate, optionally for being inserted in a liquid-tight manner, so that the openings of the reservoirs of the individual devices of the arrangement are each directed towards an interior space 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; 16. 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 suitable for receiving a liquid cell culture medium, wherein the cell culture compartment optionally i) represents 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; 17. A microfluidic circulation system, comprising a) a device according to any one of claims 1 to 14; b) a cell culture compartment suitable for receiving a liquid cell culture medium; c) a channel fluidically 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 pumping activity of the pump, wherein the control unit is preferably configured to control the pump such that a liquid is conveyed in the channel in a pulsating manner, 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 that is circulatable in the microfluidic circulation system.

18. Use of the device according to any one of claims 1 to 16 or of the microfluidic circulation system according to claim 17 for delivering an active ingredient 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 ingredient; 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 ingredient; 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 component of the extracellular matrix of a skin or mucous membrane, wherein the skin or the mucous membrane is preferably human skin or human mucous membrane; f) establishing fluidic contact between the first openings of the reservoirs of the device and 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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