Microcarrier for cultivating and / or expanding cells

Abstract

The invention relates to a microcarrier (1) for cultivating and / or expanding cells (Z) in a bioreactor, comprising an at least partly fluid-permeable outer shell (2) and an inner volume (3) for receiving the cells (Z). The microcarrier is characterized in that the outer shell (2) has a geometric shape with a flow resistance which has a minimum in a spatial direction and a fluid permeability which has a minimum in the front region of the outer shell (2), when viewed in said spatial direction.

Description

[0001] Microcarriers for the cultivation and / or expansion of cells

[0002] The invention relates to a microcarrier for the cultivation and / or expansion of cells in a bioreactor, comprising an at least partially fluid-permeable outer shell and an inner volume for receiving the cells.

[0003] The invention further relates to a system for cultivating and / or expanding cells comprising a bioreactor and at least one microcarrier, and a method for cultivating and / or expanding cells.

[0004] In the field of biotechnology, a bioreactor is a container in which microorganisms, cells, or small plants are cultivated under optimal conditions. A bioreactor thus makes biological processes usable in a technical setting.

[0005] Bioreactors are typically filled with a nutrient medium into which cells to be cultivated are placed. To ensure a constant supply of nutrients and oxygen to the cells, it is necessary to continuously or periodically replenish the contents of the container with new nutrients, introduce oxygen, and / or stir the contents during operation. This creates flow forces that act on the cells being cultivated within the bioreactor. These forces can damage the cells, subject them to additional stress, and / or inhibit their growth.

[0006] The large-scale cultivation of mammalian cells is essential for cell therapy and the production of many therapeutic protein drugs. Since most mammalian cell types exhibit adherent growth, the combination of a microcarrier and a bioreactor is a common choice for large-scale mammalian cell cultivation. To mitigate previously described damage to the cells caused by mechanical stress during cultivation in the bioreactor, various microcarriers for cell cultures are known in the art. These provide an outer shell around an inner volume into which the cells can be placed. The microcarriers can also be opened to allow for cell removal.

[0007] However, to ensure adequate nutrient supply to the cells they contain, microcarriers must exhibit a certain degree of fluid permeability. When the fluid in a bioreactor is set in motion, certain flow forces inevitably act on the cells contained within the microcarriers, despite the protection afforded by their outer shell. Furthermore, this subjectes the microcarriers themselves to additional mechanical stress. This can lead to damage to both the microcarriers and the cells contained within them.

[0008] The invention is based on the objective of avoiding these disadvantages of the prior art.

[0009] According to the invention, the problem is solved by providing a microcarrier for the cultivation and / or expansion of cells in a bioreactor, comprising an at least partially fluid-permeable outer shell and an inner volume for receiving the cells. The outer shell of the microcarrier according to the invention has a geometric shape whose flow resistance is minimized in one spatial direction and, in a front region of the outer shell viewed in this spatial direction, also exhibits a minimum fluid permeability. This causes the microcarriers in the bioreactor to align with the flow direction, while simultaneously preventing the contents of the inner volume, and thus the cells, from being directly exposed to the fluid flow. This reduces the shear forces acting on the cells in the microcarrier within the bioreactor.

[0010] The inner volume of the microcarrier according to the invention is preferably substantially completely or entirely surrounded by the outer shell. This achieves the advantage that the contents of the inner volume are protected from shear forces from all spatial directions, which can be generated, for example, by turbulent fluid flows.

[0011] According to the preferred embodiment of the microcarrier according to the invention, the flow resistance of the outer shell is minimal in one spatial direction, and in a forward region of the outer shell viewed in this spatial direction, the outer shell exhibits its absolute minimum fluid permeability. This achieves the advantage that the outer shell has its lowest fluid permeability in this forward region. Since the microcarrier according to the invention aligns itself in the flow direction, the forward region of the outer shell is exposed to the greatest shear forces. The lowest fluid permeability of the outer shell in the aforementioned forward region protects the contents of the inner volume from these shear forces.

[0012] Preferably, the outer shell forms at least one flow-guiding element, and / or the microcarrier comprises a flow-guiding element connected to the outer shell. This offers the advantage that the microcarrier can be precisely aligned in the fluid flow. According to the preferred embodiment of the microcarrier according to the invention, a protective shield is also provided on the front region of the outer shell. This provides an additional protective mechanism against mechanical stresses and collisions with other microcarriers and / or the walls of the bioreactor.

[0013] The outer shell is preferably made at least partially of a hydrolytically, enzymatically, thermally, and / or light-degradable material. This provides a simple way to open the microcarrier according to the invention for the removal of the cultured cells. Preferably, the degradable material is a polymer, more preferably a photopolymer. Alternatively, a thermo-responsive polymer can be chosen. This allows for the targeted degradation of the material through exposure to light or temperature changes.

[0014] Suitable polymers for the additive manufacturing of the inventive microcarrier or its outer shell, flow guide element, protective shield, weakening points, and / or spacers can, for example, be based on or consist of polylactic acid (PLA), polystyrene (PS), polyamide (PA), or polycarbonate (PC). Polymers based on hydrolytically / enzymatically degradable building blocks are particularly preferred. Examples include polylactic acid (PLA), polyhydroxyalkanoates (PHA), polycaprolactone (PCL), poly(trimethylene carbonate) (PTMC), and poly(3-hydroxybutyrate) (PHB), or modified versions thereof, for example, acrylate- and / or methacrylate-functionalized (see Arslan A et al. Materials Today, 44(2021): 25-39; Weisgrab G. et al. Biofabrication 12(2020):045036). Enzymes capable of breaking down polymers are familiar to experts.A light-degradable polymer, particularly one that is biodegradable by sunlight, preferably comprises at least one photocleavable linker such as o-nitrobenzyl (Liu T et al. Progress in Polymer Science 146(2023): 101741; Lunzer M et al. 130 (2018): 15342-15347). Another possibility is the use of thermoresponsive polymers (e.g., poly(N-isopropylacrylamide)) that exhibit hydrophobic or hydrophilic properties depending on the temperature. By changing the ambient temperature, the surface properties of the microcarriers according to the invention can be altered, for example, to release cells contained within them. The use of such materials would also make it possible to reuse / recycle the microcarriers.

[0015] The outer shell preferably has a series of weakening points (i.e., at least one weakening point). This defines specific positions at which the outer shell can be disassembled to extract the cells contained therein. According to a preferred embodiment of the microcarrier according to the invention, the series of weakening points forms a weakening line. This offers the advantage that the microcarrier can be, for example, disassembled into two clearly defined parts to extract the cells contained therein. The outer shell at the weakening points can again be made of a hydrolytically, enzymatically, and / or light-degradable material, thus providing a simple and rapid means of disassembling the microcarrier. The degradable material at the series of weakening points can, for example, be a polymer, preferably a photopolymer.

[0016] According to one embodiment of the microcarrier according to the invention, the outer shell can also be made of a single material. This offers the advantage of enabling simple, cost-effective, and rapid production of the microcarrier according to the invention.

[0017] According to an alternative embodiment, the outer shell can be made of at least two different materials, with the material at the weakening points preferably differing from the material of the rest of the outer shell. This allows for the selection of a material at the weakening points that, for example, deteriorates more quickly or is less mechanically resistant than the material of the rest of the outer shell. Furthermore, the outer shell can also have a reduced thickness and / or volume at the weakening points than outside of these weakening points.

[0018] According to the preferred embodiment of the microcarrier according to the invention, the outer shell is porous. This achieves the advantage of optimal permeability for oxygen and nutrients to supply the cells in the inner volume.

[0019] Preferably, the outer shell comprises at least one opening with a size of 10 to 100 pm, more preferably 10 to 70 pm, and even more preferably 10 to 30 pm. Preferably, the outer shell has a maximum outer diameter of 200 pm to 500 pm. Furthermore, the outer shell preferably has an average thickness of 3 pm to 50 pm, more preferably 35 pm. These dimensions have proven advantageous for the cultivation of mammalian cells.

[0020] According to the preferred embodiment of the microcarrier according to the invention, the outer shell and optionally the flow-guiding elements (or elements) optionally connected thereto are manufactured or can be manufactured using an additive manufacturing process (i.e., a 3D printing process). This offers the advantage that the dimensions and parameters of the microcarrier according to the invention can be selected specifically for particular applications. According to one embodiment, the outer shell and optionally the flow-guiding elements (or elements) optionally connected thereto are manufactured or can be manufactured using additive manufacturing and / or lithography-based manufacturing. Preferred lithography-based manufacturing processes include multi-photon lithography processes, in particular two-photon lithography processes. Alternatively, the outer shell and optionally the flow-guiding elements (or elements) can be manufactured using additive manufacturing and / or lithography-based manufacturing processes.The flow-guiding elements, optionally associated with this microcarrier, are manufactured using a casting process, an injection process, or soft lithography. These processes also make it possible to modify the surface of the microcarrier according to the invention so that it has a defined topography or can perform defined mechanical functions. This can lead to cells or other chemical compounds, such as proteins, adhering better to the microcarrier, or conversely, to the surface of the microcarrier exhibiting reduced adhesion. The topographic functionalization of microcarriers can also serve to influence the adhesion behavior and thus the growth of cells in their environment.

[0021] Surface modification can influence the interactions between cells and the microcarrier. One of the most important functions of chemical surface modification is to enhance or prevent cell binding to the microcarrier material. By specifically tailoring surface chemistry, adhesion proteins or ligands can be presented that bind specifically to cell surface receptors. This allows cells to be selectively bound to the microcarrier material. Conversely, chemical surface modification can also prevent undesired cell adhesions. For example, the presentation of antifouling layers can prevent unwanted cell types or proteins from binding to the microcarrier material. Another important aspect of chemical surface modification is the control of cell proliferation and differentiation.By presenting specific molecules or peptides on the surface, cellular signals that influence cell behavior can be modulated. This makes it possible to regulate cell proliferation or differentiation to a desired extent.

[0022] Furthermore, chemical modification of surfaces can also influence the physical properties of the microsupport material. For example, the presentation of hydrophilic or hydrophobic groups can alter the surface's wetting properties and thus affect cell adhesion.

[0023] Another advantage of chemical surface modification is the ability to selectively present bioactive molecules on the surface and, if desired, release them into the environment. This also makes it possible to control the release of active ingredients and thus achieve a local and long-lasting effect. Mechanical, topographic, and chemical surface modifications can be present across the entire microcarrier or limited to the inner or outer surface of the microcarrier or its outer shell.

[0024] According to the preferred embodiment of the microcarrier according to the invention, the outer shell of the microcarrier has at least one spacer facing away from the inner volume. This provides additional protection of the outer shell against collisions with other microcarriers and / or the vessel wall of the bioreactor. The spacer can also be formed integrally with the shell. Thus, the shell and the spacer can be manufactured together in a single production step, preferably using a previously described additive manufacturing process.

[0025] Preferably, the at least one spacer has a geometric shape that tapers towards the inner volume. This offers the advantage that the spacer protects a larger area of ​​the outer shell from collisions.

[0026] The outer shell of the microcarrier can also include at least two spacers, where the minimum distance between the two spacers at the end of the spacers facing away from the inner volume is smaller than the maximum diameter of the spacers at the end facing away from the inner volume. This reduces the risk of spacers from different microcarriers becoming entangled with each other.

[0027] The microcarrier according to the invention can be used in a system according to the invention for the cultivation and / or expansion of cells, comprising a bioreactor and at least one microcarrier according to the invention, wherein the bioreactor is configured to accommodate the microcarrier and a nutrient medium. Preferably, the bioreactor of the system according to the invention can be configured as an airlift bioreactor, bubble column reactor, stirred tank reactor, or fluidized bed reactor.

[0028] The microcarrier according to the invention can also be used in a process according to the invention for the cultivation and / or expansion of cells, wherein the process comprises the step of cultivating cells in a container filled with a nutrient medium and with a microcarrier according to the invention. According to the preferred embodiment of the process according to the invention, the cells are animal cells, preferably human or mammalian cells. The container can be a bioreactor, preferably an airlift bioreactor, bubble column reactor, stirred tank reactor, or fluidized bed reactor. The outer shell of the microcarrier according to the invention used in the process according to the invention can be made at least partially of a hydrolytically, enzymatically, or light-degradable material that can be degraded by the addition of appropriate enzymes. This allows the cells to be removed from the microcarrier(s).

[0029] In a further step, which the method according to the invention comprises in the preferred embodiment, the cells and / or the secretome of the cells are isolated after cultivation. "Secretome," as used here, comprises peptides, proteins, and other biomolecules that are released, i.e., secreted, by a cell into the culture medium. The secretome, or those biomolecules that one wishes to enrich or obtain, can then be recovered from the culture medium using methods known to those skilled in the art.

[0030] Advantageous embodiments of the microcarrier, the system and the method according to the invention will be explained in more detail below with reference to the figures.

[0031] Figure 1 shows a microcarrier according to the invention in a fluid flow.

[0032] Figure 2 shows the microcarrier according to the invention with weakening points of the outer shell.

[0033] Figure 3 shows the microcarrier according to the invention after the weakening points have been cut through.

[0034] Figure 4 shows an alternative embodiment of the microcarrier according to the invention.

[0035] Figure 5 shows the microcarrier according to the invention with an outer shell which has a spacer facing away from the inner volume.

[0036] Figure 6 shows another embodiment of the microcarrier according to the invention with spacers.

[0037] Figure 7 shows a system for cultivating and / or expanding cells comprising a bioreactor filled with a nutrient solution, with several microcarriers according to the invention dispersed in the nutrient solution.

[0038] Figure 1 shows a schematic representation of the microcarrier 1 according to the invention in a fluid flow. The microcarrier 1 according to the invention for cultivating and / or expanding cells Z is designed to be used in a bioreactor B, which contains, for example, a nutrient medium N. The cells Z are not shown in Figure 1, but are shown in Figures 2 to 4. An exemplary bioreactor B, which is filled with nutrient medium N and contains several microcarriers 1 according to the invention floating in the nutrient medium N, is shown in Figure 7. The fluid flow shown with small arrows in Figure 1 represents, by way of example, the flow of the nutrient medium N in the bioreactor B. The microcarrier 1 according to the invention comprises an outer shell 2 that is at least partially fluid-permeable, and an inner volume 3 for receiving the cells. The outer shell 2 can, for example, be a semipermeable or fully permeable membrane.The outer shell 2 can be designed as a barrier or a casing. According to the preferred embodiment of the microcarrier 1 according to the invention, the outer shell 2 is porous. As can be seen in Figure 1, this can be achieved by essentially regularly distributed holes across the outer shell 2, which provide a passage from outside the microcarrier 1 to its inner volume 3. The inner volume 3 can further contain an internal structure, not shown separately in the figures, such as a grid, for the attachment of the cells Z. The internal structure can, for example, be made of the same material as the outer shell 2. This offers the advantage that the microcarrier 1 according to the invention can be manufactured particularly cost-effectively. Alternatively, the internal structure can also be made of a material different from that of the outer shell 2.This allows the material of the internal structure to be specifically selected for different cell types in order to ensure particularly good cell attachment to the internal structure.

[0039] The outer shell 2 of the microcarrier 1 according to the invention has a geometric shape whose flow resistance is minimal in one spatial direction. This spatial direction represents the flow direction of nutrient medium N in a bioreactor B. Furthermore, the outer shell 2 has a minimum fluid permeability in a front region of the outer shell 3 as viewed in this spatial direction. This causes the microcarrier 1 to align itself in this spatial direction, and thus in the flow direction of the fluid flow, as illustrated by way of example in Figure 1. The orientation of the microcarrier 1 according to the invention in the fluid flow is also evident in Figure 7, where the fluid flow is represented by a curved arrow.This, combined with the minimal fluid permeability in the front area, or rather in the direction of flow, means that the cells contained in inner volume 3 are exposed to only very low fluid flow and thus only minimal mechanical stress. This allows the cells contained in inner volume 3 to develop optimally.

[0040] According to the preferred embodiment of the microcarrier 1 shown in Figure 1, the inner volume 3 of the microcarrier 1 is preferably substantially completely enclosed by the outer shell 2. The inner volume 3 of the microcarrier 1 can also be completely enclosed by the outer shell 2. This achieves the advantage that the contents of the inner volume 3 are protected from shear forces in all spatial directions, which can be generated, for example, by turbulent fluid flows.

[0041] According to the preferred embodiment of the microcarrier 1 according to the invention, the flow resistance of the outer shell 2 is minimal in one spatial direction, and in a forward region of the outer shell 2, viewed in this spatial direction, the outer shell 2 exhibits its absolute minimum fluid permeability. This achieves the advantage that the outer shell 2 has its lowest fluid permeability in this forward region. Since the microcarrier 1 according to the invention aligns itself automatically in the flow direction, the forward region of the outer shell 2 is exposed to the greatest shear forces. The lowest fluid permeability of the outer shell 2 in the aforementioned forward region protects the contents of the inner volume 3 from these shear forces.

[0042] The outer shell 2 of the microcarrier 1 according to the preferred embodiment shown in Figure 1 comprises at least one flow-guiding element 4. Alternatively, or additionally, the microcarrier 1 can also comprise a flow-guiding element 4 connected to the outer shell 2. This provides the advantage of achieving rapid and efficient alignment of the microcarrier 1 with the flow. The minimum flow resistance in one spatial direction, or the direction of flow, can generally be achieved, as explained above, by the geometric shape of the outer shell 2. This is illustrated by way of example in Figure 4, which shows a microcarrier 1 according to the invention whose outer shell 2 has at least a partially cylindrical shape.According to one embodiment of the inventive microcarrier 1, the flow-guiding element 4 can be configured to rotate the microcarrier 1 in the spatial direction in which the flow resistance of the inventive microcarrier is at its minimum when a fluid, in particular the nutrient medium N in a bioreactor B, flows over it. This stabilizes the orientation of the inventive microcarrier 1 in the fluid flow. The flow-guiding element 4 can, for example, be designed as a fin 4 or as a sphere connected to the outer shell 2, as shown in Figure 1, and have a different size than the outer shell 2. The flow-guiding element 4 offers the advantage of ensuring a stable path for the microcarrier 1 in the fluid flow, and it aligns itself automatically in the flow direction. The stabilized path reduces collisions between the microcarriers 1.

[0043] As can be seen in Figures 1 and 4, the microcarrier 1 according to the invention can also include a protective shield 5 at the front region of the outer shell 2. The protective shield 5 can, for example, have the shape of a cone, as shown in Figure 1. Alternatively, the protective shield 5 can also be designed in a streamlined shape, as shown by way of example in Figure 4. The protective shield 5 provides additional protection for the microcarrier against mechanical damage. By attaching the protective shield 5 to the front region, or the front region in the direction of airflow, of the outer shell 2, the advantage is achieved that this mechanical reinforcement is provided at the position where the greatest risk of collisions with other microcarriers 1 in the bioreactor B prevails. In addition, the protective shield 5 provides improved protection against shear forces.

[0044] The outer shell 2 of the microcarrier 1 according to the invention encloses the cells Z cultivated therein during operation of the microcarrier 1 in a bioreactor B. To provide the simplest and quickest possible method for removing the cells Z from the microcarrier 1, the outer shell 2 of the microcarrier 1 can, according to the preferred embodiment, be made at least partially of a hydrolytically, enzymatically, and / or light-degradable material. This degradable material can, for example, be a polymer, preferably a photopolymer. As can be seen in Figures 2 and 4, the outer shell 2 of the microcarrier 1 according to the invention can also comprise at least a series of weakening points 6. This series of weakening points 6 enables the microcarrier 1 to disintegrate at reproducible and clearly defined points during cell Z removal, thus allowing optimal removal of the cells Z without damaging them.The weakening points 6 can also be arranged such that the microcarrier 1 unfolds, as shown in Figure 3. Preferably, the series of weakening points 6 can also form a continuous weakening line. This divides the microcarrier 1 into at least two parts when the cells Z are extracted. Figure 3 shows a microcarrier 1 according to the invention after the outer shell 2 has been cut at the weakening points 6. The outer shell 2 can be designed to unfold after being cut at the weakening points 6. Figure 3 shows the outer shell 2 in such an unfolded state. Preferably, the outer shell 2 is thus made, at least at the weakening points 6, of a hydrolytically, enzymatically, and / or light-degradable material, which can, for example, be a polymer, preferably a photopolymer.Other materials that are hydrolytically, enzymatically and / or light-degradable are generally known to those skilled in the art.

[0045] According to one embodiment, the outer shell 2 of the microcarrier 1 according to the invention can be made of a single material. This offers the advantage that the microcarrier 1 can be manufactured quickly and cost-effectively. According to an alternative embodiment, the outer shell 2 can be made of at least two different materials, wherein the material at the weakening points 6 differs from the material of the rest of the outer shell 2. This allows the material at the weakening points 6 to be specifically selected so that the outer shell 2 separates at the weakening points 6 under certain influences. In general, the material at the weakening points 6 can have a smaller thickness than outside the weakening points 6, regardless of whether the outer shell 2 is made of one or different materials.This ensures that the weakening points 6 represent those points of the outer shell 2 where the outer shell 2 first breaks down or disintegrates. Furthermore, the material may also exhibit a lower degree of cross-linking at the weakening points 6.

[0046] According to the preferred embodiment of the microcarrier 1 according to the invention, the outer shell 2 has a maximum outer diameter of 200 pm to 500 pm. Furthermore, the outer shell 2 preferably has an average thickness of 3 pm to 50 pm, particularly preferably approximately 35 pm. This ensures that the microcarrier 1 according to the invention has a sufficiently large internal volume 3 to accommodate the cells Z, and at the same time exhibits sufficient stability of the outer shell 2.

[0047] The outer shell 2 of the microcarrier 1 according to the invention is manufactured or producible by means of an additive or lithography-based manufacturing process, according to the preferred embodiment. This offers the advantage that the dimensions and parameters of the microcarrier 1 according to the invention can be specifically selected for particular applications, while at the same time a cost-effective and easily scalable manufacturing process for the production of the microcarrier 1 is available. According to one embodiment, the outer shell 2 is manufactured or producible by means of additive manufacturing. Alternatively, the outer shell 2 is manufactured or producible by means of a lithography-based manufacturing process, preferably a multi-photon lithography process, in particular a two-photon lithography process.

[0048] According to an embodiment of the microcarrier 1 shown in Figure 5, the outer shell 2 of the microcarrier 1 can have at least one spacer 7 facing away from the inner volume 3. As shown in Figure 5, the spacer 7 can form an additional protective layer around the outer shell 2. Furthermore, the at least one spacer 7 can be formed integrally with the outer shell 2. The spacer 7 can be provided as an alternative or additional element to the protective shield 5. The at least one spacer 7 can also have a geometric shape that tapers towards the inner volume 3. This achieves the advantage that the spacer 7 covers a larger area of ​​the outer shell 2 while simultaneously using the least possible amount of material.

[0049] According to a further embodiment of the microcarrier 1 shown in detail in Figure 6, the outer shell 2 of the microcarrier 1 can comprise at least two spacers 7, wherein a minimum distance A between the two spacers 7 in the region of an end of the spacers 7 facing away from the inner volume 3 is smaller than a maximum diameter D of the spacers 7 in the region of the end of the spacers 7 facing away from the inner volume 3. This reduces the risk of the spacers 7 of different microcarriers 1 becoming entangled with each other. A system 10 according to the invention for cultivating and / or expanding cells Z is shown in Figure 7 and comprises the bioreactor B and at least one microcarrier 1 according to the invention. In the embodiment of the system 10 according to the invention shown in Figure 7, the bioreactor B is filled with several microcarriers 1.The bioreactor B is designed to accommodate the microcarrier 1 and a nutrient medium N, which is also shown in Figure 7. The bioreactor B can be, for example, an airlift bioreactor, bubble column reactor, stirred tank reactor, or fluidized bed reactor. When the nutrient medium N in the bioreactor B is set into rotation by stirring, as indicated by a curved arrow in Figure 7, the microcarriers 1 according to the invention align themselves in the fluid flow of the nutrient medium N.

[0050] A method according to the invention for cultivating and / or expanding cells Z comprises the step of cultivating the cells Z in a container filled with a nutrient medium N and with at least one microcarrier 1 according to the invention. According to a preferred embodiment of the method according to the invention, the cells Z are animal cells Z, preferably human or mammalian cells. The container is preferably a bioreactor B, in particular an airlift bioreactor, bubble column reactor, stirred tank reactor, or fluidized bed reactor.

[0051] According to a preferred embodiment of the inventive method, the outer shell 2 of the microcarrier 1 and / or the weakening points 6 of the outer shell 2 are at least partially made of hydrolytically, enzymatically, which can be degraded by adding appropriate enzymes and / or of light-degradable material.

[0052] In a further step, which in the preferred embodiment of the inventive method comprises the cells and / or the secretome of the cells are isolated after cultivation.

Claims

Patent claims:

1. Microcarrier (1) for cultivating and / or expanding cells (Z) in a bioreactor, comprising an at least partially fluid-permeable outer shell (2) and an inner volume (3) for receiving the cells (Z), characterized in that the outer shell (2) has a geometric shape whose flow resistance has a minimum in one spatial direction and has a minimum of its fluid permeability in a front region of the outer shell (2) as seen in this spatial direction.

2. Microcarrier (1) according to claim 1, characterized in that the inner volume (3) is substantially completely surrounded by the outer shell (2).

3. Microcarrier (1) according to one of claims 1 or 2, characterized in that the flow resistance of the outer shell (2) has a minimum in one spatial direction, and in a front region of the outer shell (2) seen in this spatial direction has the absolute minimum of its fluid permeability.

4. Microcarrier (1) according to one of claims 1 to 3, characterized in that the outer shell (2) forms at least one flow guide element (4) and / or the microcarrier (1) comprises a flow guide element (4) connected to the outer shell (2).

5. Microcarrier (1) according to one of claims 1 to 4, characterized in that a protective shield (5) is provided on the front area of ​​the outer shell (2).

6. Microcarrier (1) according to one of claims 1 to 5, characterized in that the outer shell (2) has a series of weakening points (6), wherein the series of weakening points (6) preferably forms a continuous weakening line.

7. Microcarrier (1) according to one of claims 1 to 6, characterized in that the outer shell (2) and / or the weakening points (6) of the outer shell (2) comprise at least one hydrolytically, enzymatically, thermally and / or light-degradable material, preferably at least one hydrolytically, enzymatically, thermally and / or light-degradable polymer.

8. Microcarrier (1) according to claim 6 or 7, characterized in that the outer shell (2) is made of at least two different materials, wherein the material at the weakening points (6) preferably differs from the material of the remaining outer shell (2).

9. Microcarrier (1) according to one of claims 6 to 8, characterized in that the outer shell (2) has a lesser thickness at the weakening points (6) than outside the weakening points (6).

10. Microcarrier (1) according to claim 7, characterized in that the polymer at the weakening points (6) of the outer shell (2) has a lower degree of crosslinking than the outer shell.

11. Microcarrier (1) according to one of claims 1 to 10, characterized in that the outer shell (2) is porous.

12. Microcarrier (1) according to any one of claims 1 to 11, characterized in that the outer shell comprises at least one opening with a size of 10 to 100 pm, preferably 10 to 70 pm, more preferably 10 to 30 pm.

13. Microcarrier (1) according to any one of claims 1 to 12, characterized in that the outer shell (2) has a maximum outer diameter of 200 pm to 500 pm and / or an average thickness of 3 pm to 50 pm.

14. Microcarrier (1) according to one of claims 1 to 13, characterized in that the outer shell (2) is manufactured or can be manufactured by means of an additive or a lithography-based manufacturing process, wherein the lithography-based manufacturing process is preferably a multi-photon lithography-based process, more preferably a two-photon lithography-based process.

15. Microcarrier (1) according to one of claims 1 to 14, characterized in that the outer shell (2) of the microcarrier (1) has at least one spacer (7) facing away from the inner volume (3), wherein the at least one spacer (7) is preferably formed integrally with the outer shell (2).

16. Microcarrier (1) according to one of claims 1 to 15, characterized in that the outer shell (2) of the microcarrier (1) comprises at least two spacers (7), wherein a minimum distance (A) between the two spacers (7) in the region of an end of the spacers (7) facing away from the inner volume (3) is smaller than a maximum diameter (D) of the spacers (7) in the region of the end facing away from the inner volume (3).

17. System (10) for cultivating and / or expanding cells (Z) comprising a bioreactor (B) and at least one microcarrier (1) according to any one of claims 1 to 16, wherein the bioreactor (B) is configured to accommodate the microcarrier (1) and a nutrient medium (N).

18. Method for cultivating and / or expanding cells (Z) comprising the step of cultivating the cells (Z) in a container filled with a nutrient medium (N) and with a microcarrier (1) according to any one of claims 1 to 16.

19. Method according to claim 18, characterized in that the outer shell (2) of the microcarrier (1) and / or the weakening points (6) of the outer shell (2) is at least partially made of at least one hydrolytically, enzymatically and / or light-degradable material, wherein the enzymatically degradable material is preferably degraded by the addition of enzymes.

20. Method according to claim 18 or 19, characterized in that the cells (Z) and / or the secretome of the cells (Z) are isolated after cultivation.

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