Fluid conveying arrangement, recipient system and method for providing a fluid flow in a recipient system

Abstract

A fluid conveying arrangement (100), preferably for use in a recipient system (200), in particular a cell culture system (200), comprises a main reservoir (1), an impelling unit (2) for establishing a rotational flow (3) of a fluid (4) providable inside said main reservoir (1), at least a first and second auxiliary reservoir (7, 8) and a channel system (9), wherein said channel system (9) fluidly connects said auxiliary reservoirs (7, 8) with an outlet opening (5´) and an inlet opening (5´´) of said main reservoir (1) in a way, that a circulating supply flow (10) of said fluid (4) can be established by said rotational flow (3), wherein said channel system (9) and / or at least one of said reservoirs (1, 7, 8) is adapted for fluidly connecting one or more recipient arrangements (11), preferably one or more cell culture arrangements (11), to be supplied with said fluid (4) by means of said circulating supply flow (10). Furthermore, the invention relates to recipient system (200), preferably a cell culture system (200), and a method for providing a fluid flow in recipient system (200), preferably a cell culture system (200).

Description

[0001] Fluid conveying arrangement, recipient system and method for providing a fluid flow in a recipient system

[0002] The present invention relates to a fluid conveying arrangement, preferably for use in a recipient system, in particular a cell culture system.

[0003] Further, the present invention relates to a recipient system, preferably a cell culture system, and a method for providing a fluid flow in a recipient system, preferably a cell culture system.

[0004] Cell culturing is a widely used laboratory technique for growing and maintaining living cells in environments with controlled conditions, allowing to study the cellular behaviour outside of an organism. In particular, cell culturing may be used for the investigation of biological processes, for example in the context of drug development and the investigation of disease mechanisms. By providing controlled conditions, cell culturing enables a precise manipulation of different growth factors, like temperature, growth medium or growth substrate.

[0005] In conventional 2D and 3D static cell culture systems, cells are grown in batches with a growth medium comprising nutrients. However, the chemical environment changes over time, as nutrients are depleted and toxic metabolites accumulate. Therefore, the growth medium has to be periodically replaced, which each time abruptly changes the environment. Hence, the cells are not in the same chemostatic environment as they are in vivo and static cell culture systems often fail to replicate the dynamic environment of living tissues. To address these limitations, various techniques have been developed, wherein a continuous fluid flow of growth medium is introduced in cell culture systems.

[0006] Such cell culture systems providing a continuously flowing medium for example comprise

[0007] - perfusion bioreactors (Martin et al., 2004; Wendt et al., 2006; Zhao et al., 2016;

[0008] Porter et al., 2005; Lovett et al., 2009),

[0009] - rotating wall vessels (RWVs) (Goodwin et al., 1993; Unsworth and Lelkes, 1998; Hammond and Hammond, 2001 ),

[0010] - orbital shakers (Kuhn et al., 2010; Zhang et al., 2010), wave bioreactors (Singh, 1999; Eibl et al., 2009; Merten, 2004), and microfluidic platforms (Whitesides, 2006; Bhatia and Ingber, 2014; Zhang et al., 2018; Beebe et al. 2014).

[0011] In this context, magnetically coupled microfluidic fluid pumping systems have become known, wherein magnetic stir bars and / or magnetic bead actuation are used for generating a specific fluid flow. Magnetic stir bars placed in a fluid rotate under an external magnetic field, generating a fluid flow (Liu et al. 2004). Magnetic bead actuation uses external magnetic fields to move beads suspended in a fluid, creating specific flow patterns (Puyol et al. 2014). However, the known systems are challenging to manufacture and set up. Additionally, the known systems often pose challenges in scaling for larger experiments as it is difficult to manufacture pumping systems integrated into devices that are manufactured by means of standard industrial procedures, such as injection molding. In such cases, the systems typically need to be manufactured by means of soft lithography or 3D printing resulting in a high manufacturing effort and high manufacturing costs. Pompano et al. 2021 discloses an impeller pump that uses a 3D-printed device and an impeller to recirculate fluid in organs-on-chip and microreactors.

[0012] One of the objectives of the present invention is to improve and further develop a fluid conveying arrangement, a recipient system, in particular a cell culture system, and a method for providing a fluid flow in a recipient system, in particular a cell culture system, in particular with respect to fluid flow characteristics, manufacturability and versatility regarding different use cases, with easy means.

[0013] In a first aspect, the present invention provides a fluid conveying arrangement, preferably for use in a recipient system, in particular a cell culture system, comprising a main reservoir, an impelling unit for establishing a rotational flow of a fluid providable inside said main reservoir, at least a first and second auxiliary reservoir and a channel system, wherein said channel system fluidly connects said auxiliary reservoirs with an outlet opening and an inlet opening of said main reservoir in a way, that a circulating supply flow of said fluid can be established by said rotational flow, wherein said channel system and / or at least one of said reservoirs is adapted for fluidly connecting one or more recipient arrangements, preferably one or more cell culture arrangements, to be supplied with said fluid by means of said circulating supply flow. In a second aspect, the present invention provides a recipient system, preferably a cell culture system, comprising a fluid conveying arrangement according to the first aspect of the invention and said one or more recipient arrangements, preferably said one or more cell culture arrangements, that are fluidly connected to said channel system and / or to at least one of said reservoirs, preferably wherein said one or more recipient arrangements, preferably said one or more cell culture arrangements, are fluidly interconnected between said first and second auxiliary reservoirs.

[0014] In a third aspect, the present invention provides a method for providing a fluid flow in a recipient system, preferably a cell culture system, according to the second aspect of the invention comprising the steps of: providing said fluid inside said main reservoir, establishing said rotational flow of said fluid inside said main reservoir by means of said impelling unit, and establishing said circulating supply flow of said fluid by said rotational flow.

[0015] In other words, the channel system fluidly connects the auxiliary reservoirs with the outlet opening and the inlet opening of the main reservoir, so that a circulating supply flow through the channel system, the reservoirs and the one or more recipient arrangements, preferably one or more cell culture arrangements, can be established by means of the rotational flow. The rotational flow causes fluid to flow from the main reservoir through the outlet opening into the channel system and consequently through the auxiliary reservoirs as well as the one or more recipient arrangements before flowing back into the main reservoir through the inlet opening. This process is continuously repeated when the rotational flow is maintained, thereby establishing the circulating supply flow of the fluid.

[0016] It has been recognized, that by providing at least two auxiliary reservoirs a constant difference in column height between the two auxiliary reservoirs can be achieved. This difference in column height results in a difference in hydrostatic pressure that drives the flow of fluid from one auxiliary reservoirs to another. Thus, pulsatility of the fluid flow is reduced. Furthermore, fluid in one of the auxiliary reservoirs is constantly replenished while fluid in the other auxiliary reservoir is constantly withdrawn. Thereby, a particularly uniform and constant flow of fluid, for example during cell culture procedures, can be achieved. Furthermore, a constant fluid supply and mechanical stimuli without the need for external pumps or complex setups can be directed at the one or more recipient arrangements, preferably one or more cell culture arrangements. In addition, the column heights in the two auxiliary reservoirs can be altered to create a specific hydrostatic pressure, for example acting on cell cultures in the one or more cell culture arrangements. This hydrostatic pressure can be chosen in correspondence with in vivo physiological conditions, for example a hydrostatic pressure in blood vessels. It is noted that the fluid conveying arrangement may comprise additional auxiliary reservoirs, for example a third and a fourth auxiliary reservoirs.

[0017] It is noted that the fluid conveying arrangement may be designed as a single piece. For example, the fluid conveying arrangement may be moulded into a single piece of plastic. Alternatively, the fluid conveying arrangement may comprise a multi-part design.

[0018] Additionally, it is noted that the rotational flow may be established in two opposite senses of rotation. Hence, also the circulating supply flow could be established with two opposite senses of circulation depending on the sense of rotation of the rotational flow. Therefore, the fluid conveying arrangement could be operatable with two conveying directions, meaning that the fluid could be conveyed through the channel system and the one or more recipient arrangements, preferably one or more cell culture arrangements, in opposite directions. Depending on the sense of rotation / circulation, the outlet opening could alternatively function as an inlet opening. This also applies to the inlet opening, which could function as an outlet opening.

[0019] The fluid may comprise a culture medium that enables to influence the growth conditions for the cells to be cultured. The culture medium may comprises at least one of the following: one or more nutrients, for example amino acids, carbohydrates, vitamins and / or minerals; one or more growth factors; one or more hormones. Nutrients may for example serve as essential substrates and cofactors for enzymatic reactions, biosynthesis, and energy production, supporting cell viability and proliferation. Growth factors may for example bind to specific cell surface receptors to activate intracellular signaling cascades, promoting processes such as mitogenesis, differentiation, and apoptosis inhibition. Hormones may for example act as signaling molecules that modulate cellular physiology and homeostasis by influencing gene transcription, protein synthesis, and metabolic pathways. The culture medium may for example comprise at least one of the following commercially available culture mediums: Minimal essential medium (MEM); Dulbecco's modified Eagle's medium (DMEM); RPMI medium (RPMI 1640); Ham's tissue culture medium (Ham's F-12); Iscove’s Modified Dulbecco’s Medium (IMDM); Leibovitz L-15 medium; Glasgow's Minimum Essential Medium (GMEM).

[0020] The term “recipient arrangement” is to be understood in the broadest sense and refers, in particular in the claims, preferably in the description, to an arrangement configured to receive the fluid. Such a recipient arrangement may comprise an arrangement used in diagnostics and / or in vitro assays and / or cell culturing. The term “cell culture arrangement” is to be understood in the broadest sense and refers, in particular in the claims, preferably in the description, to an arrangement configured to accommodate cells to be cultured and supplied with the fluid. The cell culture arrangement may comprise an inlet and an outlet connection for fluidly connecting the channel system therewith. Hence, the circulating supply flow can run from the inlet connection, through the cell culture arrangement to the outlet connection. The inlet and outlet connection may for example form part of a microfluidic channel system of the cell culture arrangement. The one or more cell culture arrangements may, for example, comprise at least one of the following:

[0021] - A perfusion cell culture arrangement, for example comprising one or more wells, one or more chambers or a bioreactor for receiving cell cultures, being continuously perfusable by the fluid, in particular a culture medium; The perfusion cell culture arrangement may for example comprise a well plate format, such as a single-well or multi-well cell culture plate with multiple wells being connected with each other by means of a microfluidic channel network;

[0022] - A single-channel or multi-channel flow cell culture arrangement, for example for studying endothelial cells or simulate vascular conditions, wherein cell cultures may be seeded along one or more channels through which the fluid, in particular a culture medium, can flow; The multi-channel flow cell culture arrangement may comprise a co-culture arrangement with parallel channels or an interconnected channel network, for example for growing multiple cell types under separate but interacting fluid flows, or may comprise a cross-flow arrangement enabling a fluid flow across membranes or through cell layers for transport studies;

[0023] - An organ-on-chip arrangement, which may comprise microfluidic channels and a microchip for simulating organ functions, for example by applying mechanical forces to cell cultures placed on the chip; The organ-on-chip arrangement may comprise a lung-on-chip arrangement for mimicking air-liquid interfaces and perfused blood vessels, a kidney-on-chip arrangement incorporating a tubular fluid flow for modelling nephron-like filtration and reabsorption or a heart-on- chip arrangement using perfused chambers to study cardiac tissues under mechanical and nutrient flow;

[0024] - A lab-on-chip arrangement, which may include multiple chambers and microfluidic channels and is configured for a high-throughput, continuous-flow cell analysis;

[0025] It is emphasized that the use of the fluid conveying arrangement according to the first aspect of the invention is not limited to cell culture systems. The fluid conveying arrangement may be used in any application that requires the provision of flow rates comparable to flow rates for cell culture systems. Such applications may for example comprise diagnostics and / or in vitro assays.

[0026] Further features, advantages and preferred embodiments are disclosed or may become apparent in the following.

[0027] According to a preferred embodiment of the invention, said one or more recipient arrangements, preferably said one or more cell culture arrangements, are fluidly interconnectable between said first and second auxiliary reservoirs. This configuration facilitates an especially uniform and stable circulating supply flow between the auxiliary reservoirs, thereby ensuring consistent and sustained culturing conditions over an extended duration.

[0028] According to a further preferred embodiment of the invention, said fluid conveying arrangement comprises a flow modulation unit configured to modulate said fluid flow in a way that a definable pattern of the fluid flow can be generated. This allows to better mimic physiological conditions. It is conceivable that the flow modulation unit is configured to increase and / or decrease a flow rate of the fluid flow, in particular to stop and / or resume the fluid flow, and / or to change the direction of the fluid flow. Furthermore, said pattern of the fluid flow may comprise a cyclical flow pattern.

[0029] According to a further preferred embodiment of the invention, said main reservoir and said first and second auxiliary reservoirs are fluidly connected in series by means of said channel system, preferably wherein said one or more recipient arrangements, preferably said one or more cell culture arrangements, are fluidly connectable in series. This design allows for the fluid conveying arrangement to be installed with remarkable ease and efficiency, streamlining the setup process.

[0030] According to a further preferred embodiment of the invention, said channel system comprises at least one of the following channel sections: a first channel section fluidly connecting said main reservoir, in particular said outlet opening, with said first auxiliary reservoir; a second channel section fluidly connecting said first with said second auxiliary reservoir; a third channel section fluidly connecting said second auxiliary with said main reservoir, in particular said inlet opening. This configuration can ensure the channel system is not only straightforward to install but also efficiently maintainable. It is emphasized that the channel sections may be discontinuous, meaning that for example one or more recipient arrangements, preferably one or more cell culture arrangements, or any other elements may be interconnected.

[0031] According to a further preferred embodiment of the invention, an inner bottom face and / or an inner side wall face, preferably a lower portion of an inner side wall face, of said first and / or second auxiliary reservoir is fluidly connected to said channel system. By doing so, the manufacturing process of the fluid conveying arrangement can be facilitated. Preferably, an inner bottom face of the first auxiliary reservoir and a lower portion of an inner side wall face of the second auxiliary reservoir are fluidly connected to the channel system.

[0032] According to a further preferred embodiment of the invention, said inlet and / or outlet opening is formed on an inner side wall face of said main reservoir. The rotational flow comprises a tangential flow with a very high flow rate along the inner side wall face of the main reservoir. Therefore, by positioning the inlet and / or outlet opening on this inner side wall face, the high flow rates of the tangential flow can be harnessed to achieve a circulating supply flow with correspondingly high flow rates. Hence, the efficiency of fluid circulation can be improved and the power requirements of the impeller unit can be reduced. Consequently, the difference in hydrostatic pressure between the auxiliary reservoirs together with the harnessed tangential flow drive the fluid flow through the channel system.

[0033] According to a further preferred embodiment of the invention, said channel system comprises an outlet section being fluidly connected to said outlet opening and / or an inlet section being fluidly connected to said inlet opening, wherein said outlet section extends substantially tangentially from said inner side wall face in a rotation direction of said rotational flow and / or wherein said inlet section extends substantially tangentially from said inner side wall face in a direction opposite to said rotation direction of said rotational flow. This facilitates an efficient establishment of the circulating supply flow, as the direction of the tangential flow is aligned with the circulating supply flow in the outlet and inlet sections. Moreover, both high flow rates within the circulating supply flow and a significant reduction in the power requirements of the impeller unit can be achieved, enhancing the efficiency of the fluid conveying arrangement.

[0034] According to a further preferred embodiment of the invention, at least one of said first and second auxiliary reservoirs is configured for introducing an externally provided fluid therein, preferably wherein at least one of said first and second auxiliary reservoirs comprises at least one introduction port. The term “externally provided fluid” is to be understood in the broadest sense and refers, in particular in the claims, preferably in the description, to a fluid provided outside of the circulation system formed by the reservoirs, the channel system and the one or more recipient arrangements, preferably the one or more cell culture arrangements. The externally provided fluid may be the same fluid that is providable inside the main reservoir. This way, a composition and / or an amount of the fluid inside the fluid conveying arrangement the can be easily modified, in particular when said circular supply flow is established. Furthermore, the externally provided fluid may comprise cells.

[0035] According to a further preferred embodiment of the invention, said channel system is configured for establishing an auxiliary supply flow by means of a hydrostatic pressure difference between said first and second auxiliary reservoirs, when said externally provided fluid is introduced into said first and / or second auxiliary reservoir. This auxiliary supply flow facilitates the precise delivery or treatment of the one or more recipient arrangements, preferably the one or more cell culture arrangements with small volumes of specific fluids, particularly when the circulating supply flow is inactive or the main reservoir is empty. This way, specific vascular or interstitial flows can be simulated in the one or more cell culture arrangements. Furthermore, chemical can be established in the one or more cell culture arrangements for studying cell migration, angiogenesis or the diffusion of pharmaceutical agents. Establishing the auxiliary supply flow can be regarded as a second mode of operation, wherein establishing the circulating supply flow that can be regarded as a first mode of operation.

[0036] According to a further preferred embodiment of the invention, said channel system comprises a connecting channel section fluidly connecting a first opening of said first auxiliary reservoir with a second opening of said second auxiliary reservoir, wherein said first and second openings are arranged below a bottom level of said main reservoir. When the main reservoir is empty and the column height in the auxiliary reservoirs is below the bottom level of the main reservoir, an auxiliary supply flow can be provided, which only flows between the auxiliary reservoirs and not to the main reservoir. Hence, the amount of externally provided fluid that needs to be introduced for a sufficient supply of the one or more recipient arrangements, preferably the one or more cell culture arrangements, by means of the auxiliary supply flow can be reduced.

[0037] According to a further preferred embodiment of the invention, said impelling unit comprises at least one magnetic element providable in said fluid and an actuation unit for providing a spinning motion of said at least one magnetic element inside said main reservoir, preferably wherein said at least one magnetic element comprises a magnetic bar. With a magnetic element powered by an actuation unit, the need for direct physical connections can be obviated, thereby minimizing the risk of contamination and mechanical wear. Additionally, this design can ensure the generation of a uniform rotational flow within the main reservoir, enhancing the overall efficiency and reliability of the fluid conveying arrangement. The impelling unit may preferably be adapted to generate a rotating rate of the at least one magnetic element ranging from 0 to 1200 RPM. Additionally or alternatively, it is conceivable that the impelling unit comprises at least one stir element and an actuation unit, wherein said at least one stir element is mechanically connected to said actuation unit for providing a spinning motion of said at least one stir element inside said main reservoir.

[0038] According to a further preferred embodiment of the invention, said channel system comprises a channel width, in particular a channel diameter, of at least 10 pm and a maximum of 5000 pm, preferably of at least 100 pm and a maximum of 500 pm, more preferably of 300 pm. Such dimensions enable the establishment of flow rates within the channel system and / or the one or more recipient arrangements, preferably the one or more cell culture arrangements, that closely resemble in vivo physiological conditions, in particular with regard to shear stresses caused by fluidic flow and acting on cell cultures, thereby enhancing the relevance and accuracy of experimental investigations performed with the fluid conveying arrangement. The channel system may comprise at least one of the following cross-sectional shapes: a circular crosssection; an elliptical cross-section; a polygonal cross-section, in particular a triangular, square or rectangular cross-section.

[0039] According to a further preferred embodiment of the invention, said fluid conveying arrangement comprises a control unit for controlling a flow rate of said circulating supply flow inside said channel system and / or a fluid column height in said first and / or second auxiliary reservoir. This way, the amount of fluid supplying the one or more recipient arrangements, preferably the one or more cell culture arrangements, and / or the magnitude of shear stresses and / or the hydrostatic pressure acting on cell cultures in the one or more recipient arrangements, preferably the one or more cell culture arrangements, can be altered.

[0040] According to a further preferred embodiment of the invention, an inner side wall face of said main reservoir and / or of said first and / or second auxiliary reservoir comprises a substantially cylindrical shape. With such a shape, turbulences in the fluid flow can be reduced ensuring a uniform fluid flow through the reservoirs and the channel system. Preferably, a diameter of the main reservoir is larger than a diameter of the first and / or second auxiliary reservoir. However, it is also conceivable that the diameter of the main reservoir is smaller than or equal to a diameter of the first and / or second auxiliary reservoir. The diameter of the main reservoir may range from 3 mm to 20 mm. The diameter of the first and / or second auxiliary reservoir may range from 1 mm to 10 mm. For achieving a particularly uniform circulating supply flow, the channel system, preferably the channel section fluidly connecting the outlet opening of the main reservoir with one of the auxiliary reservoirs, may comprise at least the same height as the respective auxiliary reservoirs. Additionally or alternatively, the channel system, preferably the channel section fluidly connecting the outlet opening of the main reservoir with one of the auxiliary reservoirs, may comprise an open top.

[0041] According to a further preferred embodiment of the invention, said fluid conveying arrangement is configured to provide a flow rate of said circulating supply flow ranging from 0 to 500 pL / s inside said channel system, in particular wherein said channel system comprises a channel width, in particular a channel diameter, of at least 10 pm and a maximum of 5000 pm, preferably of at least 100 pm and a maximum of 500 pm, more preferably of 300 pm. With such flow rates, shear stresses and / or hydrostatic pressures can be applied to the cell cultures in the one or more recipient arrangements, preferably the one or more cell culture arrangements, that closely resemble in vivo physiological conditions.

[0042] The invention is further described by the following items:

[0043] 1. Fluid conveying arrangement, preferably for use in a recipient system, in particular a cell culture system, comprising a main reservoir, an impelling unit for establishing a rotational flow of a fluid providable inside said main reservoir, at least one auxiliary reservoir and a channel system, wherein said channel system fluidly connects said at least one auxiliary reservoir with an outlet opening and an inlet opening of said main reservoir in a way, that a circulating supply flow of said fluid can be established by said rotational flow, wherein said channel system and / or at least one of said reservoirs is adapted for fluidly connecting one or more recipient arrangements, preferably one or more cell culture arrangements, to be supplied with said fluid by means of said circulating supply flow, characterized in that said at least one auxiliary reservoir is configured for introducing an externally provided fluid therein.

[0044] 2. Fluid conveying arrangement according to item 1 , characterized in that said at least one auxiliary reservoir comprises at least one introduction port for introducing said externally provided fluid therein. 3. Fluid conveying arrangement according to item 1 or 2, characterized in that said at least one auxiliary reservoir comprises a first and a second auxiliary reservoir.

[0045] 4. Fluid conveying arrangement according to item 3, characterized in that said one or more recipient arrangements, preferably said one or more cell culture arrangements, are fluidly interconnectable between said first and second auxiliary reservoirs.

[0046] 5. Fluid conveying arrangement according to item 3 or 4, characterized in that that said channel system comprises at least one of the following channel sections: a first channel section fluidly connecting said main reservoir, in particular said outlet opening, with said first auxiliary reservoir; a second channel section fluidly connecting said first with said second auxiliary reservoir; a third channel section fluidly connecting said second auxiliary with said main reservoir, in particular said inlet opening.

[0047] 6. Fluid conveying arrangement according to any one of items 3 to 5, characterized in that said channel system comprises a connecting channel section fluidly connecting a first opening of said first auxiliary reservoir with a second opening of said second auxiliary reservoir, wherein said first and second openings are arranged below a bottom level of said main reservoir.

[0048] 7. Fluid conveying arrangement according to any one of items 1 to 6, characterized in that said channel system is configured for establishing an auxiliary supply flow through said one or more recipient arrangements, preferably said one or more cell culture arrangements, by means of a hydrostatic pressure difference between at least two of said reservoirs, preferably between said first and second auxiliary reservoirs, when said externally provided fluid is introduced into said at least one auxiliary reservoir.

[0049] 8. Fluid conveying arrangement according to any one of items 1 to 7, characterized in that an inner bottom face and / or an inner side wall face, preferably a lower portion of an inner side wall face, of said at least one auxiliary reservoir is fluidly connected to said channel system. 9. Fluid conveying arrangement according to any one of items 1 to 8, characterized in that said inlet and / or outlet opening is formed on an inner side wall face of said main reservoir.

[0050] 10. Fluid conveying arrangement according to item 9, characterized in that said channel system comprises an outlet section being fluidly connected to said outlet opening and / or an inlet section being fluidly connected to said inlet opening, wherein said outlet section extends substantially tangentially from said inner side wall face in a rotation direction of said rotational flow and / or wherein said inlet section extends substantially tangentially from said inner side wall face in a direction opposite to said rotation direction of said rotational flow.

[0051] 11. Fluid conveying arrangement according to any one of items 1 to 10, characterized in that said impelling unit comprises at least one magnetic element providable in said fluid and an actuation unit for providing a spinning motion of said at least one magnetic element inside said main reservoir, preferably wherein said at least one magnetic element comprises a magnetic bar.

[0052] 12. Fluid conveying arrangement according to any one of items 1 to 11 , characterized in that said channel system comprises a channel width, in particular a channel diameter, of at least 10 pm and a maximum of 5000 pm, preferably of at least 100 pm and a maximum of 500 pm, more preferably of 300 pm.

[0053] 13. Fluid conveying arrangement according to any one of items 1 to 12, characterized in that said fluid conveying arrangement comprises a control unit for controlling a flow rate of said circulating supply flow, in particular with regard to said channel system, and / or a fluid column height in said at least one auxiliary reservoir.

[0054] 14. Fluid conveying arrangement according to any one of items 1 to 13, characterized in that an inner side wall face of said main reservoir and / or of said at least one auxiliary reservoir comprises a substantially cylindrical shape.

[0055] 15. Fluid conveying arrangement according to any one of items 1 to 14, characterized in that that said main reservoir and said first and second auxiliary reservoirs are fluidly connected in series by means of said channel system, preferably wherein said one or more recipient arrangements, preferably said one or more cell culture arrangements, are fluidly connectable in series.

[0056] 16. Recipient system, preferably cell culture system, comprising a fluid conveying arrangement according to any one of items 1 to 15 and said one or more recipient arrangements, preferably said one or more cell culture arrangements, fluidly connected to said channel system and / or to at least one of said reservoirs.

[0057] 17. Recipient system, preferably cell culture system, according to item 16, characterized in that said fluid conveying arrangement is configured to provide a flow rate of said circulating supply flow ranging from 0 to 100 pL / s, in particular wherein said channel system comprises a channel width, in particular a channel diameter, of at least 10 pm and a maximum of 5000 pm, preferably of at least 100 pm and a maximum of 500 pm, more preferably of 300 pm.

[0058] 18. Method for providing a fluid flow in a recipient system according to item 16 or 17 comprising the step of introducing said externally provided fluid into said at least one auxiliary reservoir, preferably through said at least one introduction port.

[0059] 19. Method according to item 18, characterized in that said main reservoir is provided in an empty state before introducing said externally provided fluid.

[0060] There are several ways how to design and further develop the teaching of the present invention in an advantageous way. To this end, it is to be referred to the patent claims subordinate to the patent claims directed to the first, second and third aspect of the invention on the one hand and to the following explanation of preferred examples of embodiments of the invention, illustrated by the drawing on the other hand. In connection with the explanation of the preferred embodiments of the invention by the aid of the drawing, generally preferred embodiments and further developments of the teaching will be explained.

[0061] In the drawing

[0062] Fig. 1 shows a fluid conveying arrangement according to an embodiment of the present invention with a circulating supply flow established in a cross-sectional top view and a schematic diagram, illustrating the constant circulating supply flow over time,

[0063] Fig. 2a-c show the fluid conveying arrangement according to the embodiment of Fig. 1 with a circulating supply flow established in a cross-sectional top view (Fig. 2a), a cross-sectional side view (Fig. 2b) and a cross-sectional front view (Fig. 2c),

[0064] Fig. 2d shows a representation of a rotational flow and a circulating supply flow established in a fluid conveying arrangement according to a further embodiment of the present invention,

[0065] Fig. 3a-d show the fluid conveying arrangement according to the embodiment of Fig. 1 with an auxiliary supply flow established in a cross-sectional top view (Fig. 3a and 3b), a cross-sectional side view (Fig. 3c) and a cross- sectional front view (Fig. 3d),

[0066] Fig. 4 shows the fluid conveying arrangement according to the embodiment of Fig. 1 with an auxiliary supply flow established in two cross-sectional side views with different states and a schematic diagram, illustrating the auxiliary supply flow over time,

[0067] Fig. 5 shows a cell culture system with the fluid conveying arrangement according to the embodiment of Fig. 1 with a circulating supply flow established in a cross-sectional top view,

[0068] Fig. 6 shows steps of a method for providing a fluid flow in a cell culture system according to an embodiment of the present invention, and

[0069] Fig. 7 shows a minimum pixel intensity of 10 pm beads contained in a fluid and subjected to a circulating supply flow (left) and a contour maps of flow rates for 10 pm beads flowing through a channel section with a channel diameter of 300 pm according to their distance from the channel walls (right). Fig. 1 shows a fluid conveying arrangement according to an embodiment of the present invention with a circulating supply flow established in a cross-sectional top view and a schematic diagram, illustrating the constant circulating supply flow over time.

[0070] The fluid conveying arrangement 100 is suitable for use in a cell culture system 200 and comprises a main reservoir 1 and an impelling unit 2 for establishing a rotational flow 3 of a fluid 4 provided inside the main reservoir 1 . The main reservoir 1 comprises an outlet opening 5' and an inlet opening 5", which are formed on an inner side wall face 6 of the main reservoir 1. Furthermore, the fluid conveying arrangement 100 comprises a first and second auxiliary reservoir 7, 8 and a channel system 9, wherein the channel system 9 fluidly connects the auxiliary reservoirs 7, 8 with the outlet and inlet openings 5', 5" of the main reservoir 1 in a way, that a circulating supply flow 10 of the fluid 4 is established by the rotational flow 3. The channel system 9 and / or the reservoirs 1 , 7, 8 are adapted for fluidly connecting one or more cell culture arrangements 11 to be supplied with the fluid 4 by means of the circulating supply flow 10. The one or more cell culture arrangements 11 are not shown in Fig. 1 -4.

[0071] The main reservoir 1 and the first and second auxiliary reservoirs 7, 8 are fluidly connected in series by means of the channel system 9. The channel system 9 comprises a first channel section 12' fluidly connecting the outlet opening 5' with the first auxiliary reservoir 7, a second channel section 12" fluidly connecting the first with the second auxiliary reservoir 7, 8 and a third channel section 12"' fluidly connecting the second auxiliary reservoir 8 with the inlet opening 5". The channel sections 12', 12", 12'" are fluidly connected to openings 13 in inner side wall faces 14', 14" of the auxiliary reservoirs 7, 8. In particular, the one or more cell culture arrangements 11 are fluidly interconnectable between the first and second auxiliary reservoirs 7, 8.

[0072] Furthermore, the channel system 9 comprises an outlet section 15' being fluidly connected to the outlet opening 5' and an inlet section 15" being fluidly connected to the inlet opening 5". The outlet section 15' extends substantially tangentially from the inner side wall face 6 in a rotation direction 16 of the rotational flow 3, whereas the inlet section 15" extends substantially tangentially from the inner side wall face 6 in a direction opposite to this rotation direction 16 of the rotational flow 3. In Fig. 1 , the rotational flow 3 comprises an anti-clockwise rotation direction 16. Therefore, the circulating supply flow 10 runs from the main reservoir 1 through the outlet opening 5' to the first auxiliary reservoir 7, further to the second auxiliary reservoir 8 and consequently through the inlet opening 5" back into the main reservoir 1 . The fluid 4 builds up at the inner side wall face 6 of the main reservoir 1 in the region of the outlet and inlet openings 5', 5". At the bottom of Fig. 1 , a schematic diagram is shown, illustrating that the circulating supply flow 10 generates a constant flow over time.

[0073] The impelling unit 2 comprises a magnetic bar 17, which is positioned in the fluid 4 inside the main reservoir 1 , and an actuation unit 18 for providing a spinning motion of the magnetic bar 17. However, it is noted that other embodiments of the impelling unit are conceivable.

[0074] In this embodiment, the channel system 9 comprises a channel diameter 9' of 300 pm between the auxiliary reservoirs 7, 8. The inner side wall faces 6, 14', 14" of the main reservoir 1 and of the first and second auxiliary reservoirs 7, 8 comprise a substantially cylindrical shape. The main reservoir 1 comprises a diameter 19 of 10 mm, whereas each auxiliary reservoir 7, 8 comprises a diameter 20 of 3 mm.

[0075] Fig. 2a-c show the fluid conveying arrangement according to the embodiment of Fig. 1 with a circulating supply flow established in a cross-sectional top view (Fig. 2a), a cross-sectional side view (Fig. 2b) and a cross-sectional front view (Fig. 2c).

[0076] In contrast to Fig. 1 , the rotational flow 3 comprises a clockwise rotation direction 16 (see Fig. 2a). Therefore, the circulating supply flow 10 runs from the main reservoir 1 through an outlet opening 5', which in Fig. 1 functions as the inlet opening 5", and runs back into the main reservoir 1 through an inlet opening 5", which in Fig. 1 functions as the outlet opening 5'. Furthermore, the fluid 4 of the circulating supply flow 10 is first conveyed through the second auxiliary reservoir 8 and then through the first auxiliary reservoir 7. Thus, fluid 4 in the second auxiliary reservoir 8 is constantly replenished while fluid 4 in the first auxiliary reservoir 7 is constantly withdrawn. From Fig. 2b and 2c, it becomes apparent that the fluid 4 builds up at the inner side wall face 6 of the main reservoir 1 in the region of the outlet and inlet opening 5', 5". In the second auxiliary reservoir 8, a higher column height 21 is achieved compared to the column height 22 in the first auxiliary reservoir 7. This difference in column heights 21 , 22 between the two auxiliary reservoirs 7, 8 is maintained when the circulating supply flow 10 is maintained.

[0077] Fig. 2d shows a representation of a rotational flow and a circulating supply flow established in a fluid conveying arrangement according to a further embodiment of the present invention.

[0078] This embodiment of the fluid conveying arrangement 100 associated with the circulating supply flow 10 shown in Fig. 2d corresponds to the embodiment of the fluid conveying arrangement 100 shown in Fig. 2a-c, with the exception that the second channel section 12" is fluidly connected to the second auxiliary reservoir 8 via an opening 13 in its inner bottom face 23. However, the functional principles are the same.

[0079] In Fig. 2d, a detailed form of the rotational flow 3 and the circulating supply flow 10 is shown. Inside the main reservoir 1 , the rotational flow 3 of the fluid 4 is characterized by a central axis 24 of rotation, around which the fluid 4 spirals outward. The fluid 4 builds up at the inner side wall face 6 of the main reservoir 1 in the region of the outlet and inlet openings 5', 5". The fluid height which causes circulating supply flow 10 builds up on its way from the outlet opening 5' of the main reservoir 1 to the second auxiliary reservoir 8. From the second auxiliary reservoir 8 the fluid 4 flows through the first auxiliary reservoir 7 and back into the main reservoir 1 , resulting in different column heights 21 , 22 in the auxiliary reservoirs 7, 8 as described above.

[0080] Fig. 3a-d show the fluid conveying arrangement according to the embodiment of Fig. 1 with an auxiliary supply flow established in a cross-sectional top view (Fig. 3a-b), a cross-sectional side view (Fig. 3c) and a cross-sectional front view (Fig. 3d).

[0081] For establishing the auxiliary supply flow 25, the first and second auxiliary reservoirs 7, 8 are configured for introducing an externally provided fluid 26 therein. The channel system 9 is configured for establishing the auxiliary supply flow 25 by means of a hydrostatic pressure difference between the first and second auxiliary reservoirs 7, 8, when the externally provided fluid 26 is introduced into the first or the second auxiliary reservoir 7, 8. In particular, the channel system 9 comprises a connecting channel section 12", which in this embodiment corresponds to the second channel section 12", fluidly connecting a first opening 13' of the first auxiliary reservoir 7 with a second opening 13" of the second auxiliary reservoir 8. Therein, the first and second openings 13', 13" are arranged below a bottom level 27 of the main reservoir 1 . Since the main reservoir 1 does not comprise fluid 4, this arrangement of the first and second openings 13', 13" results in an auxiliary supply flow 25 only running between the auxiliary reservoirs 7, 8 (see Fig. 3d).

[0082] Fig. 4 shows the fluid conveying arrangement according to the embodiment of Fig. 1 with an auxiliary supply flow established in two cross-sectional side views with different states and a schematic diagram, illustrating the auxiliary supply flow over time.

[0083] In a first state (Fig. 4, left), externally provided fluid 26 is introduced into the first auxiliary reservoir 7, resulting in a rising column height 21. Consequently, a difference in column heights 21 , 22 and therefore a hydrostatic pressure difference builds up between the first and second auxiliary reservoir 7, 8.

[0084] Due to the hydrostatic pressure difference caused by gravity, fluid 26 flows from the first to the second auxiliary reservoir 7, 8 in the form of the auxiliary supply flow 25. When an equilibrium of the hydrostatic pressure is achieved in a second state (Fig. 4, right), the auxiliary supply flow 25 stops. At the bottom of Fig. 4, a schematic diagram is shown, illustrating the auxiliary supply flow 25 over time as described above.

[0085] Fig. 5 shows a cell culture system with the fluid conveying arrangement according to the embodiment of Fig. 1 with a circulating supply flow established in a cross-sectional top view.

[0086] In addition to the fluid conveying arrangement 100, the cell culture system 200 comprises a cell culture arrangement 11 in the form of a multi-well cell culture plate with a microfluidic channel system, which is not shown in Fig. 5. The microfluidic channel system is configured to supply the wells of the cell culture plate 11 with fluid 4, 26.

[0087] The multi-well cell culture plate 11 is fluidly interconnected between the first and second auxiliary reservoirs 7, 8. In particular, the microfluidic channel system comprises an outlet and an inlet connection 28', 28", which are fluidly connected to the connecting channel section 12" between the first and second auxiliary reservoirs 7, 8. Hence, a circulating supply flow 10 and / or an auxiliary supply 25 flow can run through the microfluidic channel system and consequently supply cell cultures contained in the wells of the multi-well cell culture plate 12.

[0088] Fig. 6 shows steps of a method for providing a fluid flow in a cell culture system according to an embodiment of the present invention.

[0089] In a first step S1 , the fluid 4 is provided inside the main reservoir 1 . Subsequently, a magnetic bar 17 is placed in the fluid 4 inside the main reservoir 1 and an actuation unit 18 of the impelling unit 2 is activated for providing a spinning motion of the magnetic bar 17. Thereby, a rotational flow 3 of the fluid 4 inside the main reservoir 1 is established (S2). As a result of the rotational flow 3, a circulating supply flow 10 of the fluid 4 is established in step S3.

[0090] Example

[0091] 1.1 Aim of the Experiment

[0092] The aim of this experiment is to test an optimized design of a fluid conveying arrangement, in particular for use in a cell culture system, that can reliably provide fluidic shear stresses comparable to those found in a common vasculature in vivo environment. A specific goal is to identify a combination of a suitable channel diameter of the channel system and suitable power inputs generated by the impelling unit that can generate a wide range of flow rate values enabling the establishment of such fluidic shear stresses. 1 .2 Experimental Protocol

[0093] The experimental procedure involved testing six different rotating rates of a magnetic bar placed inside the main reservoir of the fluid conveying arrangement. The investigated rotating rates were 200, 400, 600, 800, 1000 and 1200 RPM. A channel diameter of the channel system was 300 pm. A diameter of the main reservoir was 10 mm and diameters of first and second auxiliary reservoirs were 3 mm. The following steps were involved:

[0094] Fluid was introduced into the main reservoir of the fluid conveying arrangement, wherein the fluid contained beads with a size of 10 pm for determining the flow rate of the fluid. Consequently, a spinning motion of the magnetic stir bar in the fluid with varying rotating rates was established, resulting in a circulating supply flow through the channel system and the auxiliary reservoirs. The fluid flow in the channel system was imaged in intervals of 100 ms.

[0095] Consequently, the minimum pixel intensity of the beads as well as contour maps of flow rates of the fluid were derived from the images of the fluid flow. Minimum pixel intensity is used to illustrate the position of each bead over a sequence of recorded images, allowing viewers to observe the motion of each bead over time in a static image. Each bead appears as a dark spot on a white background and their location in each image can therefore be represented by projecting the lowest value of each pixel from a sequence of images onto a single image. Essentially the minimum pixel intensity is a means of representing rates of motion in a static image and was used to determine the flow rates of the fluid.

[0096] Furthermore, shear stresses, which are an important parameter in many biological systems, were determined. Shear stresses can be estimated from the flow rate combined with the known geometry of the system.

[0097] 1 .3 Results

[0098] Fig. 7 shows the minimum pixel intensity of the beads contained in the fluid and subjected to the circulating supply flow generated by the impelling unit with rotating rates of 200, 400, 600, 800, 1000 and 1200 RPM (left). Furthermore, contour maps of flow rates for the beads flowing through the channel system according to their distance from the channel walls are shown in Fig. 7 (right). The flow rates follow the expected pattern of parabolic flow due to fluidic drag caused by the channel walls and vary predictably depending on the rotating rate of the magnetic bar. The results show that reliable flow rates between 0 and 100 pL / s can be generated while the magnetic bar rotates between 0 and 1200 RPM. The combination of these flow rates through a channel system with a channel diameter of 300 pm indicates shear stresses comparable to those found in a common vasculature in vivo environment.

[0099] References

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[0101] Ryu, K. S., Shaikh, K., Goluch, E., Fan, Z. & Liu, C. Micro magnetic stir-bar mixer integrated with parylene microfluidic channels. Lab a Chip 4, 608-613 (2004).

[0102] Cook, S. R., Musgrove, H. B., Throckmorton, A. L. & Pompano, R. R. Microscale impeller pump for recirculating flow in organs-on-chip and microreactors. Lab a Chip 22, 605-620 (2021 ).

[0103] Zhao, F. & Ma, T. Perfusion bioreactor system for human mesenchymal stem cell tissue engineering: Dynamic cell seeding and construct development. Biotechnol. Bioeng. 91 , 482-493 (2005).

[0104] Zhang, Y. S. et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc. Natl. Acad. Sci. 114, E2293- E2302 (2017).

[0105] Whitesides, G. M. The origins and the future of microfluidics. Nature 442, 368-373 (2006).

[0106] Wendt, D., Marsano, A., Jakob, M., Heberer, M. & Martin, I. Oscillating perfusion of cell suspensions through three-dimensional scaffolds enhances cell seeding efficiency and uniformity. Biotechnol. Bioeng. 84, 205-214 (2003).

[0107] Unsworth, B. R. & Lelkes, P. I. Growing tissues in microgravity. Nat. Med. 4, 901-907 (1998).

[0108] Singh, V. Disposable bioreactor for cell culture using wave-induced agitation. Cytotechnology 30, 149-158 (1999). Qin, D., Xia, Y. & Whitesides, G. M. Soft lithography for micro- and nanoscale patterning. Nat. Protoc. 5, 491-502 (2010).

[0109] Porter, B., Zauel, R., Stockman, H., Guldberg, R. & Fyhrie, D. 3-D computational modeling of media flow through scaffolds in a perfusion bioreactor. J. Biomech. 38, 543-549 (2005).

[0110] Merten, O.-W. Advances in cell culture: anchorage dependence. Philos. Trans. R. Soc. B: Biol. Sci. 370, 20140040 (2015).

[0111] Martin, I., Wendt, D. & Heberer, M. The role of bioreactors in tissue engineering. Trends Biotechnol. 22, 80-86 (2004).

[0112] Lovett, M., Lee, K., Edwards, A. & Kaplan, D. L. Vascularization Strategies for Tissue Engineering. Tissue Eng. Part B: Rev. 15, 353-370 (2009).

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Claims

- 24 -C l a i m s1. Fluid conveying arrangement (100), preferably for use in a recipient system (200), in particular a cell culture system (200), comprising a main reservoir (1 ), an impelling unit (2) for establishing a rotational flow (3) of a fluid (4) providable inside said main reservoir (1 ), at least a first and second auxiliary reservoir (7, 8) and a channel system (9), wherein said channel system (9) fluidly connects said auxiliary reservoirs (7, 8) with an outlet opening (5') and an inlet opening (5") of said main reservoir (1 ) in a way, that a circulating supply flow (10) of said fluid (4) can be established by said rotational flow (3), wherein said channel system (9) and / or at least one of said reservoirs (1 , 7, 8) is adapted for fluidly connecting one or more recipient arrangements (11 ), preferably one or more cell culture arrangements (11 ), to be supplied with said fluid (4) by means of said circulating supply flow (10).

2. Fluid conveying arrangement (100) according to claim 1 , characterized in that said one or more recipient arrangements (11 ), preferably said one or more cell culture arrangements (11 ), are fluidly interconnectable between said first and second auxiliary reservoirs (7, 8).

3. Fluid conveying arrangement (100) according to claim 1 or 2, characterized in that that said main reservoir (1 ) and said first and second auxiliary reservoirs (7, 8) are fluidly connected in series by means of said channel system (9), preferably wherein said one or more recipient arrangements (11 ), preferably said one or more cell culture arrangements (11 ), are fluidly connectable in series.

4. Fluid conveying arrangement (100) according to any one of claims 1 to 3, characterized in that said channel system (9) comprises at least one of the following channel sections (12', 12", 12"'): a first channel section (12') fluidly connecting said main reservoir (1 ), in particular said outlet opening (5'), with said first auxiliary reservoir (7); a second channel section (12") fluidly connecting said first with said second auxiliary reservoir (7, 8); a third channel (12'") section fluidly connecting said second auxiliary (8) with said main reservoir (1 ), in particular said inlet opening (5").

5. Fluid conveying arrangement (100) according to any one of claims 1 to 4, characterized in that an inner bottom face (23) and / or an inner side wall face (14', 14"), preferably a lower portion of an inner side wall face(14', 14"), of said first and / or second auxiliary reservoir (7, 8) is fluidly connected to said channel system (9).

6. Fluid conveying arrangement (100) according to any one of claims 1 to 5, characterized in that said inlet and / or outlet opening (5", 5') is formed on an inner side wall face (6) of said main reservoir (1 ), preferably wherein said channel system (9) comprises an outlet section (15') being fluidly connected to said outlet opening (5') and / or an inlet section (15") being fluidly connected to said inlet opening (5"), wherein said outlet section (15') extends substantially tangentially from said inner side wall face (6) in a rotation direction (16) of said rotational flow (3) and / or wherein said inlet section (15") extends substantially tangentially from said inner side wall face (6) in a direction opposite to said rotation direction (16) of said rotational flow (3).

7. Fluid conveying arrangement (100) according to any one of claims 1 to 6, characterized in that at least one of said first and second auxiliary reservoirs (7, 8) is configured for introducing an externally provided fluid (26) therein, preferably wherein at least one of said first and second auxiliary reservoirs (7, 8) comprises at least one introduction port, preferably wherein said channel system (9) is configured for establishing an auxiliary supply flow (25) by means of a hydrostatic pressure difference between said first and second auxiliary reservoirs (7, 8), when said externally provided fluid (26) is introduced into said first and / or second auxiliary reservoir (7, 8).

8. Fluid conveying arrangement (100) according to claim 7, characterized in that said channel system (9) comprises a connecting channel section (12") fluidly connecting a first opening (13') of said first auxiliary reservoir (7) with a second opening (13") of said second auxiliary reservoir (8), wherein said first and second openings (13', 13") are arranged below a bottom level (27) of said main reservoir (1 ).

9. Fluid conveying arrangement (100) according to any one of claims 1 to 8, characterized in that said impelling unit (2) comprises at least one magnetic element (17) providable in said fluid (4) and an actuation unit (18) for providing a spinningmotion of said at least one magnetic element (17) inside said main reservoir (1 ), preferably wherein said at least one magnetic element (17) comprises a magnetic bar (17).

10. Fluid conveying arrangement (100) according to any one of claims 1 to 9, characterized in that said channel system (9) comprises a channel width (9'), in particular a channel diameter (9'), of at least 10 pm and a maximum of 5000 pm, preferably of at least 100 pm and a maximum of 500 pm, more preferably of 300 pm.

11. Fluid conveying arrangement (100) according to any one of claims 1 to 10, characterized in that said fluid conveying arrangement (100) comprises a control unit for controlling a flow rate of said circulating supply flow (10) inside said channel system (9), and / or a fluid column height (21 , 22) in said first and / or second auxiliary reservoir (7, 8).

12. Fluid conveying arrangement (100) according to any one of claims 1 to 11 , characterized in that an inner side wall face (6) of said main reservoir (1 ) and / or of said first and / or second auxiliary reservoir (7, 8) comprises a substantially cylindrical shape.

13. Recipient system (200), preferably cell culture system (200), comprising a fluid conveying arrangement (100) according to any one of claims 1 to 12 and said one or more recipient arrangements (11 ), preferably said one or more cell culture arrangements (11 ), that are fluidly connected to said channel system (9) and / or to at least one of said reservoirs (1 , 7, 8), preferably wherein said one or more recipient arrangements (11 ), preferably said one or more cell culture arrangements (11 ), are fluidly interconnected between said first and second auxiliary reservoirs (7, 8).

14. Recipient system (200), preferably cell culture system (200), according to claim 13, characterized in that said fluid conveying arrangement (100) is configured to provide a flow rate of said circulating supply flow (10) ranging from 0 to 500 pL / s inside said channel system (9), in particular wherein said channel system (9) comprises a channel width (9'), in particular a channel diameter (9'), of at least 10 pm and a maximum of 5000 pm, preferably of at least 100 pm and a maximum of 500 pm, more preferably of 300 pm.

15. Method for providing a fluid flow in a recipient system (200), preferably a cell culture system (200), according to claim 13 or 14 comprising the steps of: providing (S1 ) said fluid (4) inside said main reservoir (1 ), - establishing (S2) said rotational flow (3) of said fluid (4) inside said main reservoir (1 ) by means of said impelling unit (2), and establishing (S3) said circulating supply flow (10) of said fluid (4) by said rotational flow (3).

Images