Extrusion device, method for manufacturing a hollow structure, and use of an extrusion device

Abstract

The invention relates to an extrusion device (2) for manufacturing a hollow structure (4) by coaxial extrusion of a plurality of media, wherein the extrusion device has a plurality of mountings (6, 8, 10), each for a nozzle (12, 14, 16) for extruding one of the media, wherein the mountings (6, 8, 10) extend in an axial direction (A) along a central axis (Z) and are arranged coaxially, for coaxial arrangement of the nozzles (12, 14, 16) in one another, wherein at least two of the mountings (6, 8, 10) follow one another in a radial direction (R) and are mounted against one another in the radial direction (R) by means of a bearing such that the at least two mountings (6, 8, 10) can be displaced relative to one another in the axial direction (A) in order to adjust the relative axial positions of the respective nozzles (12, 14, 16). The invention also relates to a method for manufacturing a hollow structure (4) and to a use of an extrusion device (2).

Description

[0001] Description

[0002] Extrusion device, method for producing a hollow structure and use of an extrusion device

[0003] The invention relates to an extrusion device, in particular for the biofabrication of a hollow structure. Furthermore, the invention relates to a method for producing a hollow structure and to the use of an extrusion device.

[0004] Biofabrication involves using one or more bioinks (e.g., cells dispersed in a hydrogel matrix) to create a biostructure, such as an organ or a piece of tissue. Various biofabrication methods are described, for example, in Zhang et al. 2015, “In vitro study of directly bioprinted perfusable vasculature conduits,” Biomaterials Science, 3, 134-143, Liu et al. 2017, “Synthesis of cell composite alginate microfibers by microfluidics with the application potential of small diameter vascular grafts,” Biofabrication, 9, 025030, Zhang et al. 2017, “Microfluidic Bioprinting for Engineering Vascularized Tissues and Organoids,” J Vis Exp., Constantini et al.2018, „Co-axial wet-spinning in 3D bioprinting: state of the art and future perspective of microfluidic integration“, Biofabrication, 11 , 012001 , Liu et al 2019, „Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet-Containing Constructs“, Adv Healthc Mater, e1801181 , Jia et al. 2016, „Direct 3D bioprinting of perfusable vascular constructs using a blend bioink“, Biomaterials, 106, 58-68, Cornock et al. 2014, „Coaxial additive manufacture of biomaterial composite scaffolds for tissue engineering“, Biofabrication, 6, 025002 und Meng et al. 2016, „Microfluidic generation of hollow Ca-alginate microfibers“, Lab Chip, 16, 2673-81. Weitere Systeme werden beschrieben in US 10,857,260 B2, US 2016 / 0288414 A1 , CN 112 659 551 A, CN 206 528 075 U, WO 2020 / 056517 A1 .One possible device-based solution for the biofabrication of a hollow structure is based on the use of medical cannulas or pipette tips as nozzles for coaxial extrusion, whereby the cannulas are aligned by hand and joined and sealed with adhesives. While such solutions are comparatively simple to use, they are usually manufactured for a specific purpose and also typically exhibit poor surface quality, limited print resolution, and very large diameters. With these nozzles, only minimal extrusion diameters well above several hundred microns, typically around 1 mm, can be achieved. Such solutions do not offer any possibility of diameter minimization or flow optimization and are therefore generally unsuitable for producing small and / or complex hollow structures.In other words, there are corresponding limitations regarding the biostructures that can be produced, especially with regard to the achievable structural, mechanical, and rheological properties of the biostructure. Furthermore, the process-technical design of the described solutions is more of a prototype and certainly not suitable for targeted, reproducible, and automated production, as would be desirable for biofabrication—both for individual and mass production of biostructures. The described solutions also lack flexibility and can only be used to produce a specific biostructure. Thus, the production of a complex biostructure, i.e., a biostructure with locally varying shapes and / or properties, particularly branching, is not possible.

[0005] Against this background, it is an object of the invention to improve the production of hollow structures, in particular in the context of biofabrication, in which the produced hollow structure is a biostructure made of a biomaterial. The production should be as flexible, reproducible and automatable as possible. For this purpose, a correspondingly suitable extrusion device, a method for producing a hollow structure and a use of an extrusion device are to be specified. The object is achieved by an extrusion device having the features according to claim 1, by a method having the features according to claim 13 and by a use having the features according to claim 14. Advantageous embodiments, further developments and variants are the subject of the dependent claims. The statements in connection with the extrusion device also apply analogously to the method and to the use and vice versa.If steps of the method are specified below, advantageous embodiments for the extrusion device result from the fact that it is designed to carry out one or more of these steps, preferably in an automated manner.

[0006] The extrusion device is used to produce a hollow structure (also called a hollow body) by coaxial extrusion of a plurality of media. In this case, the media are each extruded and in particular brought together in order to form the hollow structure by combination and / or reaction with one another. At least one of the media is preferably a biomaterial, so that the hollow structure is then accordingly a biostructure. Preferably, at least one of the media also contains cells whose vitality is ensured during the extrusion operation. However, this is not mandatory in itself, i.e. the extrusion device described here is particularly suitable both for the biofabrication of biostructures and for other biotechnological areas such as the production of hollow fiber bioreactors or microchannel arrangements for cell culture.

[0007] In a suitable embodiment, the extrusion device described here comprises three subassemblies, namely an extrusion assembly (also referred to as a microfluidic assembly), a tool change assembly and a drive unit (also referred to as a linear unit).

[0008] The extrusion assembly forms in particular a core part of the device and has several (i.e. at least two) holders, each for a nozzle for extruding one of the media. The nozzle is not part of the holder, but is in particular replaceable and a consumable. However, the nozzles are in particular a part of the extrusion device as a whole. The holders extend in an axial direction along a central axis and are arranged coaxially, in particular also concentrically, for the coaxial arrangement of the nozzles within one another. At least two of the holders, preferably all of the holders, follow one another in a radial direction (i.e. perpendicular to the axial direction) and are mounted on one another in this radial direction by means of a bearing, such that the at least two holders are displaceable relative to one another in the axial direction, for adjusting the relative axial positions of the respective nozzles (i.e.The arrangement of the nozzles relative to one another is also referred to as "relative displaceability," "relative displacement," or "axial relative displacement" of the holders / nozzles. In particular, one or more of the holders have a corresponding bearing. Preferably, the holders are continuously or continuously displaceable relative to one another. Preferably, the holders are automatically displaceable relative to one another.

[0009] The one of the several supports that is closest to the central axis is also called the innermost support, and all other supports are called outer supports relative to it. Similarly, the one of the several supports that is furthest from the central axis is also called the outermost support, and all other supports relative to it are also called inner supports. Those supports that are neither the innermost nor the outermost support are - if present - also called middle supports. Occasionally the supports are also numbered from the inside out, with the innermost support being the first support, the next support being the second support, and so on. Accordingly, the same support can have different names depending on the context.The above-mentioned designations also apply analogously to the nozzles, media and other components, which are available in corresponding numbers.

[0010] Overall, a nested structure results in which the holders are assembled with their respective nozzles along the axial direction, resulting in a layered structure in the radial direction, through which the media is then concentrically extruded during the process. The holders are each preferably cylindrical and / or rotationally symmetrical. The outer holders are each suitably designed as hollow cylinders (i.e., generally U-shaped in cross-section along the central axis) in order to insert one or more holders therein.

[0011] The extrusion device has a front and a rear side and extends axially generally from the front to the rear. The front side is located at the front, where the nozzles are also located, with their openings also located at the front to produce the hollow structure. The rear side, in particular, is used to feed the various media used in production.

[0012] The relative displaceability of at least two of the holders, and thus also of at least two of the nozzles, is achieved in particular by mounting the holders on one another, i.e., the bearings fix the holders relative to one another in the radial direction, but allow movement in the axial direction. In other words, at least two of the nozzles are displaceable independently of one another along the central axis. In particular, the holders are displaceable during the process, i.e., during the manufacture of the hollow structure, and are expediently also displaced relative to one another during manufacture in order to produce a hollow structure with locally different shapes and / or properties.

[0013] Each nozzle has an opening on the front through which the respective medium ultimately exits during extrusion. Viewed in the axial direction, there is a distance between the openings of two nozzles which can be adjusted by moving the holders. This results in various advantages: Firstly, the relative displaceability allows the merging of the various media during extrusion and thus also the production of the hollow structure to be controlled with particular precision. This makes production correspondingly flexible and even complex hollow structures with locally different shapes and / or properties can be manufactured. The mechanical, geometric, fluidic and rheological properties of the hollow structure are regularly dependent on the interaction (e.g. reaction or mixing) of the media with one another. This means that by controlling this interaction, the aforementioned properties of the hollow structure can be advantageously adjusted.This becomes immediately apparent, for example, with two media, one of which is a hardener, with which the other medium cures upon contact. The relative mobility allows the merging of the media and thus their interaction to be precisely and reproducibly controlled, so that the aforementioned properties of the hollow structure can also be adjusted accordingly precisely and reproducibly.

[0014] In addition, the relative displacement also makes it particularly easy to compensate for axial manufacturing and / or assembly tolerances of the nozzles. Since the nozzles are consumables subject to corresponding manufacturing tolerances and are replaced regularly, a change in length when replacing a nozzle can be responded to accordingly, resulting in improved reproducibility in the production of the hollow structure. Finally, the relative displacement in the axial direction, combined with the fixation in the radial direction, also enables automation of production.

[0015] To compensate for concentricity tolerances of the nozzles (i.e., tolerances of the nozzles in the radial direction), the holders are expediently rotatable relative to one another about the central axis. Concentricity tolerances are then suitably compensated for by rotating an outer holder, and thus also its nozzle, relative to the next, inner holder in such a way that the two concentricity tolerances are radially aligned in the same direction, thus minimizing their effects. After assembly, concentricity tolerances of two nozzles arranged radially one after the other are therefore compensated for by the two concentricity tolerances being radially aligned in the same direction. The concentricity tolerance is preferably measured at the orifice of each nozzle.For example, a runout tolerance of 10 pm at the orifice of an inner nozzle and a runout tolerance of 12 pm at the next outer nozzle with such an adjusted alignment results in only a theoretical deviation of the concentricity of the orifices of 2 pm.

[0016] In a particularly preferred embodiment, the plurality of holders are at least three holders, i.e. the extrusion device has at least three holders. These extend, as already described above, in the axial direction along the central axis and are arranged coaxially for the coaxial arrangement of the now at least three nozzles inside each other. The holders are also preferably displaceable in pairs relative to each other in the axial direction for adjusting the axial positions of the nozzles relative to each other. For this purpose, the three holders follow one another in the radial direction, as described, and are mounted on one another in the radial direction, so that, viewed from the central axis in the radial direction outwards, the three holders / nozzles are an innermost, a middle and an outermost holder / nozzle.

[0017] In the present case, without limiting the generality, a configuration as described above with three holders and correspondingly three nozzles for three media is assumed. However, the statements generally apply to any number of holders, nozzles, and media (i.e., even just two nozzles for two media). Another advantage of the invention is that the extrusion device is easily scalable by simply adding additional holders and nozzles as needed to produce any number of multilayer hollow structures by extrusion from a wide variety of media.

[0018] Each holder is assigned in particular exactly one nozzle and in particular also exactly one medium which is extruded by means of the nozzle. In a suitable embodiment, each nozzle is made of glass. Preferably, the nozzles are designed such that the hollow structure is produced with an internal diameter of a maximum of 1 mm, preferably less than 500 pm, preferably less than 200 pm and particularly preferably in the range from 10 pm to 200 pm, particularly preferably 10 pm to 100 pm or even only 10 pm to 50 pm. For this purpose, each nozzle has a maximum internal diameter of 1 mm, at least on the front side, i.e. in the region of the mouth, preferably less than 200 pm and particularly preferably in the range from 10 pm to 200 pm. Especially for this purpose, but also generally, a design is suitable in which each nozzle is a drawn and / or post-processed micronozzle made of a glass capillary.In other words: a nozzle is produced starting from a glass capillary by first heating the glass capillary and then pulling it out in the axial direction, whereby its inner and outer diameters are reduced towards the front. In this way, for example, starting from a glass capillary with an inner diameter of several hundred μm and an outer diameter of 1 mm or more, a nozzle with particularly small inner diameters, e.g. in the range of < 200 μm, is then produced. The original diameter of the glass capillary is retained at least in the area near and / or in the holder, so that the nozzle as a whole is tapered towards the front (i.e. at the front). The nozzles are drawn in particular outside the extrusion device and independently of it using a separate pulling device, so that the nozzle is manufactured first and then the finished drawn nozzle is mounted in the extrusion device.Advantageously, the nozzles are generally tapered as described and are thus designed to be particularly aerodynamic, ie in particular that during extrusion the most laminar flow of the respective medium and a uniform pressure drop along the nozzles are achieved.

[0019] Which media are extruded with which nozzles is basically arbitrary and can be adapted as required. In a preferred embodiment, which is assumed here without loss of generality, a first of the media is a support medium, in particular a cell suspension, for filling a lumen of the hollow structure, a second of the media is a wall material, in particular a biomaterial, for forming a wall of the hollow structure, and a third of the media is a hardener (e.g. a crosslinker) for hardening the second medium when brought together with the latter. Preferably, the support medium is fed to the first, innermost nozzle and extruded with it, the wall material is fed to the second, middle nozzle and extruded with it, and the hardener is fed to the third, outermost nozzle and extruded with it.During production, the wall material is then used to create a wall for the hollow structure by bringing the wall material into contact with the hardener, thus curing the wall material. The hardener is applied to the wall material from the outside. The support medium, on the other hand, is applied to the wall material from the inside, thus supporting it during extrusion.

[0020] A suitable wall material is a hydrogel, e.g., alginate; a suitable hardener is calcium chloride (CaCl2). A suitable support medium is water, but a preferred functional support medium is a cell suspension, e.g., with endothelial cells for the production of blood vessels or other cells (e.g., cell lines, stem cells, primary cells). This allows for the internal functionalization of the wall during production by depositing cells on the inside of the wall to create a cell-coated hollow structure.

[0021] Apart from the embodiment described above, in one variant, no two-component system consisting of wall material and hardener is used, but the wall is produced directly by extrusion of just a single medium. Accordingly, only two holders, nozzles, and media are then required. The use of a two-component system, however, has the advantage that it allows the production of significantly smaller hollow structures than with a single-component system. Furthermore, it is possible to use very low-viscosity wall materials, thus avoiding high viscosity and thus shear stress on living cells. A design in which the hardener is introduced from the inside to the wall material, which then cures from the inside out, is also suitable. In this design, the hardener also serves as a supporting medium, so that here too only two holders, nozzles, and media are required. Hardening from the inside, e.g.as described with a support medium acting as a hardener, however, it can also be combined with external hardening, for example by an external stream of a hardener, as described. The extrusion device preferably has a combination of two or more of the four operating modes mentioned below. A first operating mode is the extrusion mode, in which the hollow structure is produced. A second operating mode is the assembly mode, in which the individual holders of the extrusion device with mounted nozzles are pushed into one another. A third operating mode is a tool change mode, i.e. a receiving and fixing in the tool change assembly and in particular its release and release. A fourth operating mode is an adjustment mode, i.e. a fine adjustment of the nozzles in the assembled extrusion device in the axial direction in order to compensate for tolerances during production and when joining the nozzles into the holders.

[0022] A core concept of the invention is, in particular, a special mechanical design and configuration of the extrusion device such that the production of particularly small, preferably even multilayered hollow structures for automated and preferably fully additive biofabrication is enabled. This is achieved by the axial displaceability of the nozzles relative to one another, so that these nozzles can be reproducibly and precisely coaxially mounted with minimal inner diameters, preferably on the order of the diameter of a single cell (i.e., from ~10 pm) to 200 pm. In biofabrication, this advantageously enables new production cycles, for example, for the production of perfusable branches.

[0023] The extrusion device described here is also particularly suitable for the coaxial microextrusion of particularly small, filamentous hollow structures made of cell-coated biomaterials. "Particularly small" refers in particular to hollow structures with an inner diameter of less than 200 pm, preferably 10 pm to 100 pm, particularly preferably 10 pm to 50 pm. Production takes place, for example, at a process speed in the range of 50 pm / s to 500 pm / s. A further advantage of the extrusion device according to the invention is that this coaxial microextrusion of biomaterials is not limited in terms of equipment, because the nozzles are selected as tools suitable for a particular production step, fixed in a respective holder, and axially adjusted by means of axial displacement.The coaxial alignment is advantageously not dependent on the user's technical skill, but is ensured by the design and manufacture of the extrusion device presented here. This enables a reproducible manufacturing process that is fully automated.

[0024] As already described, the extrusion device preferably has three subassemblies. The extrusion assembly contains the aforementioned holders and enables the nozzles to be accommodated, the media to be guided and connected to the nozzles, and in particular, the precise, repeatable, and adjustment-free assembly of the regularly sensitive nozzles. By mounting the holders against one another, the described relative displacement of the nozzles to one another is also enabled, especially during operation, i.e., during manufacturing. This advantageously opens up entirely new operating modes and thus manufacturing possibilities, for example for the biofabrication of branched hollow structures, especially hierarchical vascular systems, e.g., intended vessels and vascular networks. Furthermore, the bearings also advantageously align the holders and nozzles precisely coaxially, meaning that no centering by the user is required.Accordingly, storage and the design of the warehouses are of particular importance in this case.

[0025] The tool change assembly and the drive unit are initially optional, but advantageously realize a high degree of automation and precision with ease of use. In particular, the tool change assembly enables the automated changing of multiple extrusion assemblies, thus ensuring a fully automated and fully additive manufacturing process for biological microstructures. By means of the drive unit, the holders can be moved relative to one another, preferably automatically, i.e. manual guidance of the nozzles is not necessary. The drive unit guarantees, in particular, the relative displaceability of the nozzles in the axial direction during operation, the compensation of tolerances of the nozzles used in the axial direction, and the highly precise, individual, automated control for picking up and fixing an extrusion assembly during a tool change.As already indicated, the axial displaceability enables the production of one or more branches (also called ramifications) as a new manufacturing step or cycle. Generally, one of the holders is an inner holder and another of the holders is an outer holder. In a suitable embodiment, the inner holder, preferably even the innermost holder, is displaceable in the axial direction relative to the outer holder to such an extent that the nozzle of the inner holder protrudes relative to the nozzle of the outer holder, namely at the front, for piercing an existing hollow structure for the purpose of forming a branch by molding a hollow structure onto the existing hollow structure.The inner nozzle is therefore used on the one hand to create an opening in an existing hollow structure, and on the other hand as a placeholder for a lumen of a subsequently produced, additional hollow structure which is formed onto the existing hollow structure. The axial displaceability is used as follows: firstly, the inner nozzle is moved forward so far that it protrudes from the outer nozzle, i.e. the inner nozzle is moved out of the outer nozzle. The existing hollow structure is then pierced (or perforated) with the inner nozzle by moving the inner nozzle into a wall of this hollow structure. If still necessary, the outer nozzle is pushed further up to the wall of the existing hollow structure and the distance between the openings of the two nozzles is reduced again.The corresponding medium is then extruded through the outer nozzle so that a connection to the existing hollow structure is created. In the process, the outer nozzle is pushed back again if necessary and the distance between the orifices of the two nozzles is increased accordingly. The inner nozzle keeps a connection to the lumen of the existing hollow structure open. From a certain point, e.g. marked by a predetermined distance between the orifices of the two nozzles, there is no further relative displacement and the inner nozzle is pulled out of the existing hollow structure and carried along with the outer nozzle. The production of the hollow structure then continues in the normal way. The same applies analogously to the production of the additional hollow structure with several outer nozzles and holders, e.g. in a two-component system for producing the wall.The extrusion of the various media from the multiple outer nozzles is then delayed if necessary.

[0026] In particular, the holders, their mutual mounting by means of suitable bearings, and their relative displaceability form a core element of the present invention and address a technically demanding range of tasks, including: on the one hand, the most precise, reproducible, coaxial alignment of multiple nozzles for coaxial extrusion of multiple media to produce a hollow structure; on the other hand, the possibility of the simplest, reproducible, and non-destructive assembly of the nozzles, which are usually particularly sensitive; and, in addition, a connection of the nozzles with correspondingly small inner diameters at the orifice with a macroscopic media connection, preferably fittings from the HPLC (high-performance liquid chromatography) field. This range of tasks is addressed by the various embodiments and further developments of the extrusion device described here.

[0027] The holders are preferably each designed as a rotationally symmetrical component. Each holder has, in particular on the front, a receptacle (e.g. fit) for one of the nozzles, so that a respective nozzle is then mounted in a respective holder on the front. All receptacles are located one behind the other on the central axis. The respective receptacle is preferably designed as a transverse press fit, so that when the holder is heated up due to its thermal expansion, the nozzle can be pushed into the receptacle. Upon cooling, a high-strength, high-precision and tight connection is created, which can advantageously be released again by reheating. Advantageously, the nozzles on the one hand and the holders on the other hand have as different thermal expansion coefficients as possible, so that it is possible to heat the holders slowly in a commercially available laboratory drying oven, so that special induction devices, such asfrom the machine tool sector, are not required. Suitable materials with very different thermal expansion coefficients include borosilicate glass for the nozzles and PEEK (polyether ether ketone) or stainless steel for the mounts.

[0028] The innermost holder forms the center of the entire extrusion assembly and, in contrast to the other holders, is comparatively solid, namely preferably as a solid cylinder and not merely as a hollow cylinder. Irrespective of the preferred rotational symmetry, several channels for guiding the various media are then preferably incorporated into this innermost holder. The channels are each designed, for example, as a bore in the innermost holder. The channels ultimately lead to one of the nozzles in the various holders. One of the channels initially leads to the innermost nozzle; this channel runs suitably along the central axis and is therefore also referred to as the central channel. The remaining channels then run eccentrically, i.e.in the radial direction at a distance from the central axis, and either parallel or inclined to this, depending on the dimensions of the holders and any space requirements, particularly for standardized media connections. Each channel has a diameter of 0.5 mm to 1 mm, for example. The media connections, e.g. HPLC fittings, are preferably formed on the back of the innermost holder. Alternatively, each of the holders has its own media connection, which is connected to the receptacle and the nozzle attached therein via a channel in the corresponding holder. However, combining the media connections and channels in one of the holders, especially in the innermost holder, is preferred.

[0029] In a configuration with three holders / nozzles, one of the channels expediently leads through the innermost holder and opens at the front into a headspace formed in the axial direction between the innermost holder and the following middle holder. In combination with the innermost nozzle, this headspace is annular. The second medium, which exits from the front of the innermost holder via the aforementioned channel, then enters the headspace and is guided from the outside along the innermost nozzle, before finally exiting through the corresponding middle nozzle, particularly in a ring shape. The same applies analogously to the next outermost nozzle, with the difference that the associated third medium does not exit from the front of the innermost holder, but expediently laterally, i.e. in the radial direction, and is initially guided into an annular channel in the middle holder, from where the third medium, for example,through one or more channels in an axial direction into a headspace between the middle and outermost brackets. From there, the third medium is then guided in a circular pattern between the middle and outermost nozzles, similar to the second medium, and finally discharged from the front.

[0030] As already described, at least two of the holders, preferably all of the holders, are mounted on one another by means of a bearing. In this case, two holders arranged radially one after the other are mounted on one another, in particular by means of a single bearing. With three holders, two bearings are therefore formed. Each bearing is suitably formed from an inner bearing surface and an outer bearing surface which encompasses the inner bearing surface. Preferably, the outer bearing surface bears radially against the inner bearing surface, so that the bearing is a plain bearing. The outer bearing surface is suitably a bearing bore. With two holders mounted on one another, the bearing bore is formed within the outer of the two holders and in particular an inner wall of this holder. This inner wall then corresponds to the outer bearing surface of the bearing.At the same time, the inner holder is inserted into the bearing bore, resulting in the layered structure of the holders already mentioned. The bearing inner surface, in contrast, is a part of an outer wall of the inner of the two holders. In principle, it is possible for the bearing inner surface to correspond completely or predominantly to the outer wall, but a design is preferred in which the bearing inner surface is only formed in sections, namely only as one or more bearing areas in which the outer wall has an enlarged diameter, i.e. the bearing inner surface protrudes from the remaining outer wall at one or more positions in the radial direction, so that bearing areas are formed here (equivalent to this is a reverse design in which the bearing areas are formed as parts of the bearing outer surface, i.e.then as annular and radially inward-projecting areas of the inner wall of the outer holder, which is, however, more difficult to manufacture). The bearing bore is a bore machined as precisely as possible, the inner surface of the bearing has one or more appropriately machined and preferably narrow, load-bearing, cylindrical areas, namely the aforementioned bearing areas, as part of an outer wall of the respective inner holder. Each bearing area is therefore in particular annular. Without limiting the generality, the following assumes bearings which each have several, in particular two, bearing areas. In the case of a bearing with several bearing areas, these preferably have the same diameter. Each bearing serves in particular for axial displacement during extrusion operation, during adjustment operation and for the stable cohesion of the extrusion assembly in the radial direction during tool change operation.Another key factor is the stabilization of the two brackets when they are put together during assembly.

[0031] Accordingly, in a suitable embodiment, the bearing serves to stabilize and guide the holders and to align them coaxially when they are fitted together during assembly (i.e. during assembly operation). The bearing has at least one bearing area which is designed and arranged in such a way that when the holders are fitted together, the bearing area always ensures guidance in such a way that in the radial direction, the play of an inner, in particular cantilevered, nozzle in no area exceeds a predetermined gap to an outer one of the nozzles in order to avoid damage to the nozzles when they are fitted together. Accordingly, the bearing area is positioned and designed in such a way that it interacts with the bearing bore of the bearing during fitting at the latest when the predetermined gap is undershot.In other words, the bearing is expediently designed to prevent damage to the often very fragile nozzles during assembly. Due to the anticipated small extrusion diameters, the minimum (and thus specified) gap between the coaxially mounted nozzles during extrusion, tool change, and adjustment operations is ideally always less than 200 μm, and depending on the shape and diameter of the nozzles used, often only a few micrometers. The bearings are therefore sufficiently rigid and free of play to avoid, under all circumstances, an asymmetrical position and thus irregular wall thickness during extrusion operation or even contact between the nozzles, despite the aforementioned small gap dimensions. Therefore, the fits between the inner and outer bearing surfaces are advantageously designed as close-tolerance transition fits.

[0032] In order to keep friction low and improve tribological properties, in a suitable embodiment, the inner surface of at least one bearing is divided into two, particularly narrow, regions which are as far apart as possible while still ensuring the highest possible rigidity. In other words, and more generally: the bearing has two, particularly narrow, bearing regions which are as far apart as possible in the axial direction. The bearing bore is, in particular, designed to be long enough for the bearing to have sufficient rigidity. This means that at least part of the inner surface of the bearing (i.e. at least one of possibly several bearing regions) is retracted into the bearing bore when the mouth of the inner nozzle moves into the shaft region (rear section of a nozzle) of the outer nozzle.The permissible radial play at the projecting tip (front section of a nozzle) of the nozzle towards the inner wall of the outer nozzle is based on the limited rigidity of the bearing and the tolerance of the fit and is therefore expediently smaller than the gap between the inner and outer nozzle. At the latest when the mouth of the inner nozzle moves into the drawn, narrower part of the outer nozzle, the entire bearing is supporting the bearing, with at least two and preferably all bearing areas being retracted into the bearing bore. With particularly small gaps already in the shaft area of ​​the outer nozzle, however, at least two or all bearing areas are already supporting the bearing when the inner nozzle moves into the shaft area.

[0033] The bearing preferably has at least two bearing areas, namely a front bearing area arranged at the front in the axial direction, and a rear bearing area arranged at the rear in the axial direction. The front and rear bearing areas are arranged one behind the other in the axial direction and spaced from one another such that at all times during extrusion (i.e., during extrusion operation), both bearing areas support, i.e., engage and are in contact with the outer bearing surface. This ensures sufficient guidance and rigidity of the bearing, and thus the coaxial alignment of the mounted nozzles is guaranteed at all times.

[0034] In a particularly expedient embodiment, the front bearing area is interrupted in the axial direction by an annular groove, i.e. divided into two, each particularly annular, partial areas. This makes it easier to insert the inner holder into the outer holder and prevents canting in the first few millimeters. Measured in the axial direction, the groove is preferably 0.5 to 3 times as long as one of the two adjacent partial areas of this front bearing area. The groove is not necessarily as deep as the bearing area protrudes from the rest of the outer wall. The bearing is thus designed to suit the various operating modes. During extrusion, the holders are only moved relative to each other to the extent that both the front and rear bearing areas engage at all times, thus ensuring maximum stability during extrusion.During tool change and adjustment operations, both bearing areas always engage to ensure maximum stability and protect the sensitive nozzles. In assembly operations, however, the front bearing area stabilizes the brackets as early as possible during assembly, while the rear bearing area engages later as the brackets are further pushed together.

[0035] In particular, the outer of the two holders has a maximum displacement path compared to the inner of the two holders during assembly operation, which preferably corresponds to at least the length of the nozzle of the outer holder. In order to ensure maximum guidance accuracy and rigidity, the distance between the two bearing areas of the bearing is also selected to be as large as possible in the axial direction. This distance between the two bearing areas, in conjunction with a projection of the bearing bore of the outer of the two holders beyond the rear bearing area, defines in particular the maximum displacement path between the two holders during assembly operation when the bearing is fully guided (i.e. when all bearing areas engage). This then results in the maximum possible length of the drawn area of ​​the outer nozzle, and with small gap dimensions between the inner and outer nozzles in the shaft area, even the maximum length of the entire outer nozzle.

[0036] The required and used displacement depends in particular on the operating mode. The maximum displacement differs between the operating modes by several orders of magnitude, with the maximum displacement being smaller in extrusion mode than in adjustment mode and significantly smaller than in assembly mode. In extrusion mode, the maximum displacement is preferably a few micrometers to a few hundred micrometers. In adjustment mode, the displacement is up to a few millimeters. In assembly mode, the maximum displacement is at least the entire length of the outer nozzle including the shaft, i.e. several millimeters, suitably in the range of 10 mm to 40 mm. The bearings are each designed with their two load-bearing bearing areas in such a way that static overdetermination is avoided. The displacement paths described here only describe the displacement of the brackets relative to one another.In contrast, the entire extrusion device can essentially be moved as far as desired, so that hollow structures of any length can be produced.

[0037] In general, the bearings described here are expediently designed as plain bearings. The smallest possible tolerances between the bearings, both relative to one another and with respect to the central axis and the nozzle mounts, are ensured by a suitable manufacturing process for the bearings, e.g., high-precision turning and / or cylindrical grinding, lapping, and honing. The resulting surface quality or roughness is selected to achieve the best possible tribological properties. In addition to the plain bearings mentioned, the bearings can also be designed as hydrostatic or aerostatic bearings; the statements made here specifically regarding arrangement and dimensioning also apply accordingly to these and other types of bearings.

[0038] In an advantageous embodiment, one of the bearing areas functions as a sealing area, which further underpins the requirements for surface quality, surface roughness, tight shape and dimensional tolerances and fits. To improve the sealing effect, at least one of the bearings suitably has a bearing area which is divided in two by an annular channel for one of the media, so that another of the media, which penetrates through a sealing gap in the bearing into the annular channel, is brought together with the medium in the annular channel to seal the sealing gap. This is particularly advantageous if a bearing area divided in two by a narrow groove is already present for stabilization during assembly, as described above, so that this can then also be used for sealing purposes. The sealing gap is formed between the inner and outer surfaces of the bearing, which bear against one another but are typically not arbitrarily tight.The annular channel mentioned here therefore preferably corresponds to the annular channel for the second medium described above in the case of three holders / nozzles. Sealing is achieved in particular by forming a reactive seal when the two media come together. The two-part bearing area is preferably the front bearing area mentioned above. The two media mentioned are preferably the wall material mentioned above and the hardener, which react on contact so that the wall material hardens and thus forms a reactive seal that seals the bearing. Such a seal is particularly useful as the inner diameter of the nozzles decreases, since this requires higher pressure to extrude the media and increases the risk of leakage through the bearing area.

[0039] In the embodiment with three holders, the innermost holder preferably has the two-part, front bearing area for sealing purposes, for storage on the middle holder. The third medium, preferably the hardener, is guided laterally from the channel of the innermost holder into the annular channel, and from there into the head space between the middle and outermost holders. Accordingly, the annular channel is delimited in the radial direction by the outer wall of the innermost holder and the inner wall of the middle holder, and in the axial direction by two partial surfaces of the front bearing area. The front partial surface of the front bearing area forms the sealing gap with the inner wall of the middle holder, which connects the annular channel to the head space between the inner and middle holders. The second medium is guided into this head space.In the event of a leak, the first and second media can then be brought together via the sealing gap. In the event of a potential leak in the bearing, the leak is then sealed at least in the area of ​​the sealing gap at the front part of the bearing area by the resulting reactive seal. Apart from the design described here, other configurations are also conceivable, e.g. exchanging the two media. The design presented here, in which the hardener is extruded via the outermost nozzle, has the advantage that a leakage of the hardener is less detrimental than a leakage of the wall material, so that sealing only the front bearing area with the reactive seal is sufficient and additional sealing of the rear bearing area is not necessary.

[0040] The front bearing area, regardless of whether it is split or not, is preferably designed as close as possible to one end face of the bracket in question, i.e. it is immediately flush with the end face of the bracket or is arranged at least on the first 1 to 3 mm of the outer wall. This has the advantage that, very early on when one bracket is placed on the other, the bearing ensures statically determined guidance of the two brackets relative to each other, and tilting is prevented. This advantage is further enhanced with the aforementioned split bearing area, regardless of the limitation of the annular channel and the described sealing.

[0041] In another advantageous embodiment, a separate sealing area is arranged axially upstream of the two bearing areas. This is preferably done to reduce the head volume between the two supports, thus achieving a smaller diameter of the fluid-conducting head area and thus the dead volume in the extrusion assembly. To avoid static overdetermination, this sealing area is advantageously designed to be significantly softer and more flexible in shape and material than the bearing area. This can be achieved, for example, by narrower contact areas in the axial direction or by incorporating an additional dynamic seal made of a softer material.To match the outer geometry of the inner holder in this sealing area, which can otherwise be implemented as described above despite the smaller diameter, the outer holder also features a pre-arranged bore in the axial direction with a matching diameter for the outer sealing areas. The displacement travel of the sealing area is appropriately at least equivalent to the required displacement travel during extrusion and adjustment operations.

[0042] If the reduced diameter in the sealing area of ​​the bracket is insufficient for a transverse interference fit, e.g., because there is not enough material for a purely elastic, reversible clamp, the nozzle receptacle is expediently extended into the bearing area behind the additional sealing area. However, this lengthens the respective nozzle in the shaft area. The length of the bearing (i.e., in particular, the distance between the front and rear bearing areas) is still dependent on the length of the nozzles, resulting in an extended assembly.

[0043] As already indicated, one of the holders, preferably the innermost holder, has a channel for one of the media, particularly along the central axis. This channel expediently has a constriction with a diameter corresponding to an inner diameter of the nozzle connected to the channel. This ensures a particularly low-shear transfer of the medium from the channel to the nozzle. Viewed in cross-section along the central axis, the constriction is, for example, simply a constant, reduced inner diameter, so that a simple step is formed in the channel as a transition to the constriction. Such a step is particularly easy to produce using appropriate drills.In connection with the step, a design is also advantageous in which a hose, which is intended to guide the medium into the holder, is pushed into the channel up to the constriction and abuts against the step. It then has the same inner diameter as the constriction and the nozzle, so that the medium does not experience any change in diameter until it reaches the nozzle. The inner diameter then changes, in particular, only along the nozzle.

[0044] In a suitable design, two brackets mounted on one another are made of different materials. In other words, the brackets are alternately made of at least two different materials, e.g., PEEK on the one hand and stainless steel on the other. This achieves optimal tribological properties and improves relative displacement. This design is particularly advantageous when the brackets are mounted on one another using plain bearings. Alternatively, all brackets are made of the same material, resulting in increased stability. This is particularly advantageous in combination with hydrostatic or aerostatic bearings.

[0045] The extrusion assembly suitably has one or more features for automated tool changing, i.e., an automated change of extrusion assemblies in the extrusion device. A suitable feature is, for example, a circumferential groove to enable a form-fitting, easily removable storage in a magazine, e.g., a rotary tool magazine with retaining clips.

[0046] The tool change assembly serves in particular as a holding device for the extrusion assembly during operation (in particular extrusion and adjustment operation), i.e. during the production of a hollow structure and the preparatory fine adjustment. The tool change assembly clamps the holders, in particular to the linear unit, in such a way that these holders can be precisely displaced relative to one another in the axial direction as required and are otherwise fixed as optimally as possible and centered relative to the linear unit. For this purpose, in a suitable embodiment, the extrusion device, in particular the tool change assembly, has a clamping device for each holder for holding and fixing the respective holder. Each clamping device has a pull arm and a push arm which encompass a respective holder around the circumference, such that each holder is clamped in the axial direction between the pull arm and the push arm.Accordingly, “circumferentially encircling” is primarily understood to mean that the pulling arm and the pushing arm run around the holder and hold it between them.

[0047] The tension arm and the pressure arm are each tubular and are then also referred to as the tension tube and the pressure tube. In the outer brackets, the pressure arm is inserted into the tension arm, whereas in the innermost bracket the tension arm is inserted into the pressure arm. Each outer bracket then has a suitable circumferential contour which is clamped between the tension arm and the pressure arm. In the innermost bracket, however, this is the other way around; there the tension arm pulls the bracket into the pressure arm and thereby clamps the bracket firmly. For this purpose, a groove or undercut is suitably formed behind the circumferential contour of the innermost bracket to allow the tension arm to engage. The tension arm and the pressure arm of a respective clamping device are mounted against one another by means of a bearing, e.g. a plain bearing, and can be moved relative to one another in the axial direction to clamp the respective bracket.In particular, in each external clamping device the pressure arm is mounted in the tension arm so that this tension arm can be moved precisely to the respective holder by the drive unit in order to fix it in place. The corresponding pressure arm is moved together with the tension arm and then pre-tensions the holder synchronously, without moving the corresponding holder relative to the other holders and thus without unintentionally extruding or even sucking in one of the media when changing tools (i.e. during assembly). The tension arms are each connected in particular to the drive unit so that the relative displaceability is ultimately achieved with the tension arms. A displacement of the pressure arm relative to the tension arm in order to pre-tension or release the respective holder is carried out using compressed air, for example.The clamping device is preferably used to tighten the clamping device at the front, whereas its bearings and pneumatic cylinders are suitably arranged at the rear.

[0048] In a suitable embodiment, the circumferential contour for clamping is formed by a cone of a respective holder, and the clamping device has a corresponding inner cone. In the case of the outer holders, the inner cone is formed, for example, on the respective tension arm, and in the case of the innermost holder, conversely on the pressure arm, so that the respective holder is fixed and centered in the tool change assembly by axial tension. Furthermore, a respective cone, especially of the outer holders, expediently has a flat surface which extends in the radial direction and is accordingly designed, in particular, in a ring shape. The flat surface serves as a stop for the pressure arm, so that it is then advantageously possible to preload the corresponding holder and thus enable a play-free connection.A reversed design is also suitable, in which the inner cone is formed on the respective pressure arm of the outer brackets and, conversely, on the tension arm of the innermost bracket. In this case, the respective cone and its flat surface are oriented in the opposite direction. The angle of the cone and the inner cone relative to the central axis is selected such that, on the one hand, it is not self-locking, but, on the other hand, also allows for the best possible centering. For example, an angle of 9° is suitable, and generally an angle in the range of 5° to 20°.

[0049] The cone of the innermost holder is preferably formed axially behind the above-mentioned shape feature (e.g. groove) for the tool change. The cones of the outer holders are expediently inclined opposite to the cone of the innermost holder, so that the respective internal pressure in the head spaces between the holders pushes the innermost holder and the outer holders in opposite directions and is thereby more strongly clamped via the cones in the tool change assembly. This ensures optimal fixing and centering. During tool change operation, the outer clamping devices are first unlocked by moving the associated push arms and pull arms apart, thereby releasing the outer holders. The extrusion assembly is then only fixed by the innermost clamping device.The extrusion device is then moved by the machine kinematics toward a tool magazine or tool changer, and the extrusion assembly is pushed into the magazine's retaining clamp, particularly along the groove described above. The last, innermost clamping device is then also unlocked, so that the extrusion assembly is completely released and is now held only by the retaining clamp of the tool changer or magazine. The tool change assembly then moves away from the extrusion assembly, thus releasing it. To lock an extrusion assembly in the tool change assembly, the procedure is reversed.

[0050] Suitably, the clamping devices of the tool change assembly each have a lateral recess (also referred to as a window) in the area of ​​the extrusion assembly to allow lateral entry and exit of the extrusion assembly and media connections in the form of polymer hoses into the tool change assembly, thus also enabling a tool change. The recesses suitably extend circumferentially by one-quarter to one-third of the circumference of the respective clamping device.

[0051] The tension arms are preferably freely swinging and are suitably fixed and positioned in the axial direction by the aforementioned drive unit. In this way, the relative displaceability of the holders is also realized. The drive unit is particularly designed in such a way that axial tensile and compressive rigidity is ensured for the absorption of forces and for precise positioning, i.e. displacement, while at the same time allowing slight radial flexibility to avoid static overdetermination. This would lead to radial forces on the bearings of the extrusion assembly and thus to poor tribological behavior. The relative displaceability of the holders and clamping devices is realized in particular by means of the drive unit, whereas a preload force of the clamping devices is realized separately from the relative displaceability, preferably pneumatically, e.g.by means of double-acting pneumatic cylinders. In other versions, mechanical preload is also achieved using suitable mechanical elements, such as threads or locking lugs actuated by electric motors (stepper or servo motors).

[0052] The drive unit is suitably connected to the tension arms of at least the outer clamping devices of the tool change assembly, e.g., by means of screw flanges. The drive unit is, in particular, a connection of two linear axes that is as compact as possible to realize the relative displaceability of the holders. Since the extrusion device presented here, in a suitable embodiment, is part of an additive manufacturing machine (e.g., a bioprinter) and must regularly be moved entirely by the machine kinematics of this manufacturing machine, a design that is as compact as possible is advantageous. Furthermore, the respective force applied by both linear axes should be transmitted as precisely as possible in the axial direction to the extrusion assembly.Especially in the design assumed here with three holders / nozzles for a support medium inside, a wall material in the middle and a hardener outside, a relative displacement of the innermost holder to the middle and outermost holder is regularly carried out during operation, whereas a relative displacement of the outermost holder to the middle holder is required less frequently in comparison. The same applies to the described manufacturing cycle for producing branches in hollow structures. Therefore, in a suitable design, the drive unit is designed as a linear axis with a ball screw drive with a threaded spindle with a particularly low pitch as well as with a fixed nut and a driven nut. Rotational fixation and linear guidance of the nuts is achieved, for example, by means of a profile rail guide. Drive is achieved, for example, via stepper motors and belt drives.The fixed nut is connected to the middle bracket via a suitable connection, whereas the driven nut is also connected to the outer bracket via a suitable connection. In order to move the innermost bracket relative to the other brackets, only the threaded spindle is driven. The relative positions of the other brackets to one another are maintained. In order to move only the outermost bracket relative to the other brackets, the driven nut is moved, whereby the relative positions of the other brackets to one another are again maintained. Alternatively, drive is achieved by motors with a respective hollow shaft or by rotary direct drives (e.g. torque motors) which are integrated into the drive unit. A design with linear motors is also suitable in principle.

[0053] The entire extrusion device is advantageously designed in such a way that by adding additional, appropriate brackets to the extrusion assembly, additional nozzles can be added, coaxially positioned, moved, and operated. Accordingly, additional clamping devices can be added to the tool change assembly, and the drive unit can be further developed, e.g., with additional driven nuts. Such an expansion then enables, for example, the production of multilayer microstructures for the reproduction of larger blood vessels (>100 μm) with more complex morphologies.

[0054] Suitable pumps (e.g., syringe pumps), valves (e.g., rotary valves), and connecting elements, e.g., from the chromatography field, such as fittings and hoses, ensure, in particular, the supply of the extrusion device with advantageously precisely metered, pulsation-free volume flows. A suitable pump control system for this purpose is connected or coupled, in particular, to a drive unit control system in order to compensate for the resulting volume change of the respective headspace, particularly in real time, in the event of a relative displacement of the holders in the axial direction.

[0055] In the following, exemplary embodiments of the invention are explained in more detail with reference to a drawing. In each case, the following schematically show:

[0056] Fig. 1 shows an extrusion device in a side view, Fig. 2 shows the extrusion device from Fig. 1 in another side view,

[0057] Fig. 3 shows the extrusion device from Fig. 1 in a perspective view,

[0058] Fig. 4a shows an extrusion assembly of the extrusion device of Fig. 1,

[0059] Fig. 4b a detailed view of Fig. 4a,

[0060] Fig. 5a shows a tool changing assembly of the extrusion device from Fig. 1 in the locked state,

[0061] Fig. 5b the tool change assembly from Fig. 5a in partially locked state,

[0062] Fig. 5c the tool change assembly from Fig. 5a in unlocked state,

[0063] Fig. 6 the production of a branch by means of the extrusion device from Fig. 1 ,

[0064] Fig. 7 shows a hollow structure produced by means of the extrusion device of Fig. 1.

[0065] 1, 2 and 3 show different views of an embodiment of an extrusion device 2 which is used to produce a hollow structure 4 by coaxial extrusion of a plurality of media. In this case, the media are each extruded and brought together to form the hollow structure 4. An exemplary hollow structure 4 is shown in Fig. 7. In the embodiment shown, one of the media is a biomaterial and at least one of the media contains cells, so that the hollow structure 4 is then a biostructure containing living cells. The extrusion device 2 described here is, however, suitable both for biofabrication and for other biotechnological areas, such as the production of hollow fiber bioreactors or microchannel arrangements for cell culture. An extrusion assembly 38, e.g. as shown in Fig.4a is a subassembly of the extrusion device 2 and has several, here three, holders 6, 8, 10, each for a nozzle 12, 14, 16 for extruding one of the media. This is shown in detail in a sectional view in Fig. 4a. The respective nozzle 12, 14, 16 is replaceable and a consumable. Fig. 4b shows a detailed view of the nozzles 12, 14, 16, which are arranged on the front side F of the holders 6, 8, 10. The holders 6, 8, 10 extend in an axial direction A along a central axis Z and are arranged coaxially and concentrically for the coaxial arrangement of the nozzles 12, 14, 16 inside one another.All holders 6, 8, 10 follow one another in a radial direction R perpendicular to the axial direction A and are mounted on one another in this radial direction R by means of a respective bearing, so that the holders are displaceable relative to one another in the axial direction A, for adjusting the relative axial positions of the respective nozzles 12, 14, 16. This is also referred to as “relative displaceability” or “relative displacement”.

[0066] The one of the brackets 6, 8, 10 that is closest to the central axis Z is also called the innermost bracket 6, all other brackets 8, 10 are referred to as outer brackets 8, 10 relative to this. Accordingly, the one of the brackets 6, 8, 10 that is furthest from the central axis Z is also called the outermost bracket 10, all other brackets 6, 8 are referred to as inner brackets 6, 8 relative to this. Those brackets 8 that are neither the innermost nor the outermost bracket 6, 10 are - if present - also referred to as middle brackets 8. Occasionally, the brackets 6, 8, 10 are also numbered from the inside out, with the innermost bracket 6 being the first bracket 6, the following bracket 8 being the second bracket 8, and so on. Accordingly, the same bracket 6, 8, 10 can have different names depending on the context.The above designations also apply analogously to the nozzles 12, 14, 16, media and other components, which are present in corresponding numbers. In Fig. 4a, the holders 6, 8, 10 are shown in a cross-sectional view along the central axis Z. As can be seen from Figs. 4a and 4b, a nested structure results in which the holders 6, 8, 10 are assembled with their respective nozzles 12, 14, 16 along the axial direction A, so that a layered structure is created in the radial direction R, through which the media is then concentrically extruded during the process. The holders 6, 8, 10 are each cylindrical and rotationally symmetrical here. The outer holders 8, 10 are each designed as hollow cylinders in order to insert one or more holders 6, 8 therein.

[0067] The relative displaceability of the holders 6, 8, 10 and thus also of the nozzles 12, 14, 16 is realized here by two bearings. Each of these bearings has a front bearing area 18, 20 and a rear bearing area 22, 24. Each front bearing area 18, 20 and a rear bearing area 22, 24 form an inner bearing surface, which rests against an outer bearing surface, which here is an inner wall 30 of a respective outer holder 8, 10. Conversely, the inner bearing surfaces are part of an outer wall 31 of the respective inner holder 6, 8. The bearings fix the holders 6, 8, 10 relative to one another in the radial direction R, but allow movement in the axial direction A. This is possible especially in the process, i.e. during the production of the hollow structure 4, and is used accordingly to produce a hollow structure 4 with locally different shapes and / or properties.

[0068] Each nozzle 12, 14, 16 has an orifice 26 on the front side F, through which the respective medium ultimately exits during extrusion. For simplicity, the various orifices 26 are provided with the same reference numerals. Viewed in the axial direction A, a distance 28 results between the orifices 26 of two nozzles 12, 14, 16, which distance can be adjusted by moving the brackets 6, 8, 10.

[0069] Although a configuration with three holders 6, 8, 10 and correspondingly three nozzles 12, 14, 16 for three media is shown here, the explanations generally apply to any number of holders 6, 8, 10, nozzles 12, 14, 16, and media. In fact, the extrusion device 2 is easily scalable by simply adding additional holders 6, 8, 10 and nozzles 12, 14, 16 as needed.

[0070] In the illustrated embodiment, each nozzle 12, 14, 16 is made of glass and is designed such that the hollow structure 4 is produced with an inner diameter of 10 μm to 200 μm. For this purpose, each nozzle has a corresponding inner diameter at least on the front side F, i.e., in the area of ​​the orifice 26. The nozzles 12, 14, 16 shown here are each a drawn and post-machined micronozzle made from a glass capillary. The nozzle 12, 14, 16 is therefore tapered toward the front, as can be seen particularly clearly in Fig. 4b.

[0071] Which media are extruded with which nozzles is basically arbitrary and can be adapted as needed. In the embodiment shown here, a first of the media is a support medium, specifically a cell suspension, for filling a lumen 32 of the hollow structure 4 and lining its inner wall with cells, a second of the media is a wall material for forming a wall 34 of the hollow structure 4, and a third of the media is a hardener for hardening the second medium when brought together with it. The support medium is extruded with the first, innermost nozzle 12, the wall material is extruded with the second, middle nozzle 14, and the hardener is extruded with the third, outermost nozzle 16. The wall 34 is then produced from the wall material by bringing the wall material into contact with the hardener, so that the wall material hardens. The hardener is introduced to the wall material from the outside.In contrast, the support medium is introduced to the wall material from the inside and thus supports it during extrusion. By way of example, the wall material in the present case is a hydrogel, e.g. alginate, the hardener is calcium chloride (CaCl), and the support medium is a cell suspension, e.g. with endothelial cells, in order to functionalize the wall 34 from the inside during production as shown in Fig. 7, by depositing cells 36 on the inside of the wall in order to obtain a cell-coated hollow structure 4. In a variant not shown, no two-component system consisting of wall material and hardener is used, but the wall 34 is produced directly by extrusion of just a single medium. Alternatively, the hardener is introduced to the wall material from the inside and this is then cured from the inside out. In this embodiment, the hardener also serves as a support medium.

[0072] The extrusion device 2 described here comprises three subassemblies, namely an extrusion assembly 38, a tool change assembly 40, and a drive unit 42. The extrusion assembly 38 contains the holders 6, 8, 10 and enables the nozzles 12, 14, 16 to be accommodated, the media to be guided and connected to the nozzles 12, 14, 16, and their precise, repeatable, and adjustment-free assembly. The bearings with the bearing areas 18, 20, 22, 24 ensure that the holders 6, 8, 10 and the nozzles 12, 14, 16 are precisely coaxially aligned. An exemplary extrusion assembly 38 has already been described in connection with Fig. 4a. An exemplary embodiment of the tool change assembly 40 is shown in Figs. 5a, 5b, and 5c in various states and also in a sectional view along the central axis Z (the extrusion assembly 38 is not shown for clarity). An exemplary embodiment of the drive unit 42 is shown in Figs.1 , 2 and 3 can be seen.

[0073] The tool change assembly 40 and the drive unit 42 are optional for the basic function of continuous extrusion, but guarantee high precision and reproducibility and are thus advantageous for adjustment operations, tool change operations, and advanced extrusion functions such as dynamic changes in flow conditions or the creation of branches. Thus, the tool change assembly 40 enables the automated changing of multiple extrusion assemblies 38, thus ensuring a fully automated and fully additive manufacturing process. By means of the drive unit 42, the holders 6, 8, 10 can be automatically displaced relative to one another, meaning manual adjustment or fixing of the nozzles 12, 14, 16 during operation is not required.The drive unit 42 guarantees the automated relative displaceability of the nozzles 12, 14, 16 in the axial direction A during operation, the compensation of tolerances of the nozzles 12, 14, 16 used in the axial direction A and the high-precision, individual, automated control for receiving and fixing an extrusion assembly 38 during tool change.

[0074] The axial displaceability enables the production of one or more branches 44 as a new manufacturing step or cycle, as illustrated by way of example in Fig. 6. When using the extrusion device as described above, the innermost (also inner) holder 6 is displaced in the axial direction A relative to the middle holder 8 (which, viewed relative to the innermost holder 6, is also an outer holder 8) such that the innermost nozzle 12 protrudes relative to the middle nozzle 14, namely at the front F, for piercing an existing hollow structure 4 for the purpose of forming the branch 44 by molding a further hollow structure 4 (indicated by a dashed line in Fig. 6) onto the existing hollow structure 4.The innermost nozzle 12 is thus used, on the one hand, to create an opening in the wall 34 of an existing hollow structure 4, and, on the other hand, as a placeholder for the lumen 32 of the subsequently produced, further hollow structure 4, which is molded onto the existing hollow structure 4. For this purpose, if necessary, the middle nozzle 14 is pushed up to the wall 34 of the existing hollow structure 4, and in the process, the distance 28 between the orifices 26 of the two nozzles 12, 14 is reduced again. The wall material is then extruded via the middle nozzle 12, so that a connection to the existing hollow structure 4 is created. In this case, the middle nozzle 14 is pushed back again if necessary, and the distance 28 is increased again accordingly. The innermost nozzle 12 maintains a connection to the lumen 32 of the existing hollow structure 4. From a certain point, e.g.At the point marked by a predetermined distance 28, no further relative displacement occurs, and the innermost nozzle 12 is withdrawn from the existing hollow structure 4 and carried along with the middle nozzle 14. The outermost nozzle 16 for the hardener is continuously carried along with the middle nozzle 14, so that these two nozzles 14, 16 are not displaced relative to one another. The entire extrusion device 2 is then moved further, starting from the beginning of the molded branch, under continuous extrusion in a coordinated movement of the machine kinematics (bioprinter), whereby the lateral branch can be extruded further as an independent hollow structure 4 as desired.

[0075] The brackets 6, 8, 10 are each designed as a rotationally symmetrical component. Each bracket 6, 8, 10 has a receptacle 48 for one of the nozzles 12, 14, 16 on the front side F, so that these are then each mounted in a respective bracket 6, 8, 10 on the front side, as can be seen, for example, in Fig. 4. All receptacles 48 are arranged one behind the other on the central axis Z. The receptacles are each designed as a transverse press fit.

[0076] The innermost holder 6 forms the center of the entire extrusion assembly 38 and, in contrast to the other holders 8, 10, is comparatively solid, namely as a solid cylinder and not merely as a hollow cylinder. Irrespective of rotational symmetry, several channels 50, 52, 54 for guiding the various media are then incorporated into this innermost holder 6. The channels 50, 52, 54 each ultimately lead to one of the nozzles 12, 14, 16 in the various holders 6, 8, 10. The channel 50 initially leads to the innermost nozzle 12 and runs along the central axis Z. The remaining channels 52, 54 run in the radial direction R at a distance from the central axis Z and, in this case, are inclined to it in order to achieve the smallest possible dimensions towards the front and to ensure sufficient installation space at the rear B for corresponding media connections 56. The media connections 56 are, for example, HPLC fittings.

[0077] In the embodiment shown here with three holders 6, 8, 10, the channel 52 leads through the innermost holder 6 and opens at the front F into a head space 58 which is formed in the axial direction A between the innermost holder 6 and the middle holder 8. In combination with the innermost nozzle 12, this head space 58 is annular. The second medium, which exits from the innermost holder 6 at the front F via the aforementioned channel 52, enters the head space 58 and is guided from the outside along the innermost nozzle 12, finally exiting in a ring shape through the corresponding middle nozzle 14. The same applies analogously to the outermost nozzle 16, with the difference that the associated third medium does not exit from the innermost holder 6 at the front F, but laterally, i.e. in the radial direction R, and is initially guided into an annular channel 60 in the middle holder 8, from where the third medium, for example,through one or more channels 62 in the axial direction A into a head space 64 between the middle holder 8 and the outermost holder 10. From there, the third medium is then guided in a ring shape between the middle nozzle 14 and the outermost nozzle 16, analogous to the second medium, and finally discharged at the front F.

[0078] The extrusion device 2 shown here has four operating modes. A first operating mode is an extrusion mode, in which the hollow structure 4 is produced. A second operating mode is an assembly mode, in which the individual holders 6, 8, 10 of the extrusion assembly 38 with shrink-fitted nozzles 12, 14, 16, i.e., thermally joined by a cross-press fit, are inserted into one another in order to subsequently be connected to the media lines and clamped in a tool magazine or directly into the tool change assembly 40. A third operating mode is then a tool change mode, i.e., fixing in the tool change assembly 40, in which the tool change assembly 40 is unlocked in order to remove the extrusion assembly 38 from a holder or magazine, fix it therein, and connect it to the drive unit 42.A fourth operating mode is an adjustment mode, i.e., the fine adjustment of the nozzles 12, 14, 16 in axial direction A to compensate for tolerances during manufacturing and when joining the nozzles 12, 14, 16 into the holders 6, 8, 10. For this purpose, the holders 6, 8, 10 are axially displaced or positioned such that all orifices 26 are in one plane. In the fourth operating mode, the position can be checked visually, for example. From there, they can be moved according to the requirements of the extrusion operation. As already indicated, at least two and in the present case even all of the holders 6, 8, 10 are mounted on one another by means of a bearing each, which is formed from a precisely machined bearing bore and the inner wall 30 formed thereby in the interior of the outer holders 8, 10 and two narrow, circumferential bearing areas 18, 20, 22, 24 (bearing inner surface) on the outer wall 31 of the inner holders 6, 8.Bearing areas 18, 20, 22, 24 enable statically determined and sufficiently rigid guidance in the bearing bore of the respective outer brackets 8, 10, with friction being minimized due to the small contact surfaces. These bearing areas 18, 20, 22, 24 are arranged one behind the other in the axial direction A; more precisely, each of the two bearings has a front bearing area 18, 20 and a rear bearing area 22, 24, and a front bearing area 18, 20 and a rear bearing area 22, 24 are arranged one behind the other. The bearing areas 18, 20, 22, 24 are part of the inner brackets 6, 8 and, together with the inner walls 30 of the outer brackets 8, 10, function as plain bearings.

[0079] The bearings are designed in such a way that damage to the usually very fragile nozzles 12, 14, 16 is prevented as far as possible when they are fitted together. To this end, the respective bearing is designed and arranged in such a way that when the two holders 6, 8, 10 are fitted together, at least its front bearing area 18, 20 engages before the respective inner nozzle 12, 14 moves into the shaft area of ​​the respective outer nozzle 14, 16. At the latest when the inner nozzle 12, 14 moves into the drawn conical area of ​​the outer nozzle 14, 16, both the front bearing area 18, 20 and the rear bearing area 22, 24 engage in order to ensure sufficient guidance and rigidity of the bearing and to prevent contact between the nozzles 12, 14, 16.

[0080] In the case of particularly narrow gaps between the nozzles 12, 14, 16, in particular in their shaft area, it may be necessary for both bearing areas 18, 20, 22, 24 of a respective bearing to engage before the mouth 26 of the respective inner nozzle 12, 14 moves into the shaft area of ​​the outer nozzle 14, 16. This design is shown in Fig. 4a, b with the illustrated geometries of holders 6, 8, 10 and nozzles 12, 14, 16. In this case, the middle holder 8 has a maximum displacement path 68 for assembly operation relative to the innermost holder 6, which must correspond at least to a length 78 of the outer nozzle 14.The distance between the two bearing areas 18, 22 in the axial direction A is selected to be as large as possible due to the stability and rigidity of the bearing and, in conjunction with a projection 72 of the middle bracket 8 beyond the rear bearing area 22, defines the maximum displacement path during assembly operation 68 of the middle bracket 8 in the axial direction A, relative to the innermost bracket 6. The same applies analogously to the brackets 8, 10 and the nozzle 16 in conjunction with the bearing areas 20, 24.

[0081] The front bearing area 18, 20 is arranged as far as possible at the front side F. For easier assembly and to avoid jamming, the front bearing area 18, 20 is divided into two parts by a narrow circumferential groove.

[0082] During extrusion, adjustment, and tool change operations, the holders 6, 8, 10 are only displaced relative to each other to the extent that both the front and rear bearing areas 18, 20, 22, 24 engage at all times, thus ensuring maximum stability. In assembly operations, however, the front bearing area 18, 20 stabilizes the holders 6, 8, 10 as early as possible during assembly, while the rear bearing area 22, 24 engages later during further assembly.

[0083] In the design shown here, the front bearing area 18 also acts as a seal for the head space 58 in front of it. In addition to a suitable choice of material, close tolerances and high surface qualities in this area to ensure the sealing effect, fluid guidance is also used to improve the sealing effect. The front bearing area 18 of the innermost holder 6 is divided into two by a circumferential groove, with the assembly advantages mentioned. The groove is also used to convey the third medium (here the hardener). For this purpose, the third medium is guided from the channel 54 into the groove via a radial transverse bore. The middle holder 8 has a circumferential groove in the outer wall 31 on the inner wall 30, i.e. on the inside of the bearing bore which forms the bearing for the innermost holder 6, near the base of this bearing bore. The groove is also referred to as an annular channel 60.Via this, the third medium is guided into two eccentric and axially parallel bores 62 and from there into the headspace to the holder 10. There, it finally reaches the outermost nozzle 16. This configuration of the fluid guide ensures that the second medium (here, the wall material), if it penetrates through the sealing gap 74 of the bearing area 18 into the annular channel 60, meets the third medium (hardener) in the annular channel 60. This leads to the sealing gap 74 being sealed by cross-linking the second medium (biomaterial) with the third medium (hardener), thus fulfilling the function of a reactive seal. This is particularly important for the second medium (here, the biomaterial) due to its higher viscosity compared to the support medium and hardener and the resulting higher pressures in the headspace 58.

[0084] However, this fluid guide limits the maximum displacement for extrusion operation to a few hundred micrometers to a few millimeters. More precisely, the displacement is limited to the area in which there is still sufficient contact sealing surface of the front bearing area 18 (interrupted by the circumferential groove in the axial direction in front of and behind the annular channel) in the middle holder 8. This depends on the width of the entire front bearing area 18 in the axial direction A, the width of the circumferential groove, the annular channel 60, and the material properties and tolerances of the sealing areas of the inner holders 6, 8.

[0085] In the illustrated embodiment, the channel 50 for the first medium has a constriction 76 with a diameter corresponding to an inner diameter 78 of the innermost nozzle 12, which is connected to the channel 50. The constriction 76, viewed here in cross-section along the central axis Z, is simply a constant, reduced inner diameter, so that a simple step is formed in the channel 50 as a transition to the constriction 76. In a variant not shown, however, a constriction 76 is formed by an inner diameter of the channel 50 that tapers continuously towards the front.

[0086] The innermost holder 6 further has a shape feature for an automated tool change, here for example a circumferential groove 80, in order to enable a form-fitting, easily detachable accommodation in a magazine.

[0087] The tool change assembly 40 serves as a holding device for the extrusion assembly 38 during operation and clamps the holders 6, 8, 10 such that they can be moved relative to one another in the axial direction A as needed and are otherwise fixed and centered as optimally as possible. For this purpose, the tool change assembly 40 has a clamping device 82, 84, 86 for each holder 6, 8, 10. Each clamping device 82, 84, 86 has a pull arm 88 and a push arm 90, which encompass a respective holder 6, 8, 10 on the circumference and are each tubular in shape. In the outer holders 8, 10, the push arm 90 is inserted into the pull arm 88; in the innermost holder 6, however, the pull arm 88 is inserted into the push arm 90. A respective outer holder 8, 10 then has a suitable circumferential contour, which is clamped between the pulling arm 88 and the pushing arm 90.However, for the innermost holder 6, this is the other way around; there, the pulling arm 88 pulls the holder 6 into the pushing arm 90. For this purpose, a groove 92 is formed behind the peripheral contour of the innermost holder 6 to allow the pulling arm 88 to engage. The pulling arm 88 and the pushing arm 90 of a respective clamping device 82, 84, 86 are mounted against one another by means of a bearing 94 and can be moved relative to one another in the axial direction A to clamp the respective holder 6, 8, 10. The pushing arm 90 is moved relative to the pulling arm 88 to clamp or release the respective holder 6, 8, 10, for example, using compressed air. The clamping is carried out with the clamping device 82, 84, 86 on the front side F here, whereas its bearing 94 is arranged between the middle and the rear side B.In the embodiment shown here, the circumferential contour for clamping is formed by a cone 96 of a respective holder 6, 8, 10 and the clamping device 82, 84, 86 has a corresponding inner cone 98. The inner cone 98 is formed on the respective tension arm 88 in the case of the outer holders 8, 10 and on the pressure arm 90 in the case of the innermost holder 6. Furthermore, a respective cone 96 of the outer holders 8, 10 has a flat surface 100 which extends in the radial direction R, is annular and serves as a stop for the pressure arm 90. An angle 102 of the cone 96 and the inner cone 98 relative to the central axis Z is selected such that, on the one hand, it does not have a self-locking effect, but on the other hand, also enables good centering.

[0088] The cone 96 of the innermost holder 6 is formed in the axial direction A at the rear B relative to the aforementioned groove 80 for the tool change. The cones 96 of the outer holders 8, 10 are inclined opposite to the cone 96 of the innermost holder 6, so that the innermost holder 6 and the outer holders 8, 10 are pressed in opposite directions by a respective internal pressure in the head spaces 58, 64, thereby clamping them in the tool change assembly 40 via the cones 96.

[0089] In addition, the tool change assembly 40 in the embodiment shown here includes three integrated, double-acting pneumatic cylinders for preloading the holders 6, 8, 10. These each have a pressure-side cylinder chamber 116 and a tension-side cylinder chamber 118. The intermediate pneumatic piston 120 with dynamic seal is connected to the associated tension arm 88 in the innermost holder 6 and to the respective pressure arm 90 in the outer holders 8, 10. By applying compressed air to the two cylinder chambers 116, 118, controlled e.g. via a 5 / 2-way pneumatic valve, a precisely axially acting force is generated and the holders 6, 8, 10 are thus preloaded.

[0090] During tool change operation, starting from the locked state as shown in Fig. 5a, the outer clamping devices 82, 84 are first unlocked by moving the associated pressure arms 90 and tension arms 88 apart, thereby releasing the outer holders 8, 10, as shown in Fig. 5b. The extrusion assembly 38 is then only fixed by the innermost clamping device 82. The extrusion device 2 now moves towards a tool magazine using the machine kinematics of the bioprinter and pushes the extrusion assembly 38 into the holding clamp of the tool magazine at the previously described groove 80. The last, innermost clamping device 82 is then also unlocked, as shown in Fig. 5c, so that the extrusion assembly 38 is completely released and is now held only by the holding clamp of the tool magazine.The tool change assembly 40 then moves away from the tool magazine in the radial direction R, thereby releasing the extrusion assembly 38. To lock an extrusion assembly 38 in the tool change assembly 40, the reverse procedure is followed.

[0091] As can be seen in Figs. 1, 2 and 3, the clamping devices 82, 84, 86 of the tool change assembly 40 in the area of ​​the extrusion assembly 38 each have a lateral recess 104 in order to enable a lateral entry of the extrusion assembly 38 and the media connections 56 into the tool change assembly 40 and thus also to enable a tool change.

[0092] The tension arms 88 are freely swinging in the present case and are fixed and positioned in the axial direction A by the drive unit 42. The relative displaceability of the holders 6, 8, 10 is also realized in this way. The drive unit 42 is connected to the tension arms 88 of at least the outer clamping devices 84, 86. Especially in the embodiment shown here with three holders 6, 8, 10 and three nozzles 12, 14, 16 for a support medium inside, a wall material in the middle and a hardener outside, a relative displacement of the innermost holder 6 to the outer holders 8, 10 is regularly carried out during operation, whereas a relative displacement of the outermost holder 10 to the middle holder 8 is required less frequently in comparison.Therefore, in the embodiment shown here, the drive unit 42 is designed as a linear axis with a low-pitch ball screw drive with a threaded spindle 106 as well as with a fixed nut 108 and a driven nut 110. The nuts 108, 110 are rotatably fixed and linearly guided by means of a profiled rail guide 112. Drive is provided, for example, via stepper motors 114 and belt drives (the associated belts not being shown here). The fixed nut 108 is connected to the middle bracket 8 via a suitable connection, whereas the driven nut 110 is connected to the outer bracket 10 via a suitable connection. In order to move the innermost bracket 6 relative to the other brackets 8, 10, only the threaded spindle 106 is driven. The relative positions of the other brackets 8, 10 to one another are maintained.In order to move only the outermost bracket 10 relative to the remaining brackets 6, 8, the driven nut 110 is moved, whereby the relative positions of the remaining brackets 6, 8 to one another are again maintained.

[0093] The entire extrusion device 2 is designed such that by adding additional, appropriate mounts to the extrusion assembly 38, additional nozzles can be added, coaxially positioned, moved, and operated. Accordingly, additional clamping devices are also added to the tool change assembly 40, and the drive unit 42 is further developed, e.g., with additional driven nuts, motors, and linear carriages. Such an expansion then enables, for example, the production of multilayer microstructures for the reproduction of more complex blood vessels.

[0094] List of reference symbols

[0095] 2 Extrusion device

[0096] 4 Hollow structure

[0097] 6 first / innermost / inner bracket

[0098] 8 second / inner / outer / middle bracket

[0099] 10 third / outermost / outer bracket

[0100] 12 first / innermost / inner nozzle

[0101] 14 second / inner / outer / middle nozzle

[0102] 16 third / outermost / outer nozzle

[0103] 18 front storage area

[0104] 20 front storage area

[0105] 22 rear storage area

[0106] 24 rear storage area

[0107] 26 Mouth

[0108] 28 Distance (between two mouths)

[0109] 30 inner wall (of a bracket), outer bearing surface (of a bearing)

[0110] 31 Outer wall (of a bracket), inner bearing surface (of a bearing)

[0111] 32 lumens

[0112] 34 wall

[0113] 36 Cell

[0114] 38 Extrusion assembly

[0115] 40 Tool change assembly

[0116] 42 drive unit

[0117] 44 Junction

[0118] 48 Holder (of a bracket), fit

[0119] 50 channels (for a first medium)

[0120] 52 channels (for a second medium)

[0121] 54 channels (for a third medium)

[0122] 56 Media connection

[0123] 58 Headroom (between innermost and middle bracket)

[0124] 60 ring canal

[0125] 62 Channel (axis-parallel holes from the annular chamber into the head space) 64 Head space (between the middle and outermost bracket)

[0126] 68 displacement path

[0127] 72 overhang

[0128] 74 Sealing gap

[0129] 76 bottleneck

[0130] 78 length (of one nozzle)

[0131] 80 groove (for tool change)

[0132] 82 first / innermost / inner clamping device

[0133] 84 second / inner / outer / middle clamping device

[0134] 86 third / outermost / outer clamping device

[0135] 88 Pull arm

[0136] 90 pressure arm

[0137] 92 groove (for pull arm)

[0138] 94 bearings (tension arm versus compression arm)

[0139] 96 cone

[0140] 98 inner cone

[0141] 100 plan area

[0142] 102 angles

[0143] 104 recess

[0144] 106 threaded spindle

[0145] 108 fixed nut

[0146] 110 driven nut

[0147] 112 Profile rail guide

[0148] 114 Stepper motor

[0149] 116 pressure-side cylinder chamber

[0150] 118 tension-side cylinder chamber

[0151] 120 pneumatic pistons

[0152] A axial direction

[0153] B back

[0154] F front

[0155] R radial direction

[0156] S gap Z central axis

Claims

Claims Extrusion device (2), for producing a hollow structure (4) by coaxial extrusion of several media, - wherein this has several holders (6, 8, 10), each for a nozzle (12, 14, 16) for extruding one of the media, - wherein the supports (6, 8, 10) extend in an axial direction (A) along a central axis (Z) and are arranged coaxially, for the coaxial arrangement of the nozzles (12, 14, 16) within one another, - wherein at least two of the holders (6, 8, 10) follow one another in a radial direction (R) and are mounted together in a radial direction (R) by means of a bearing, such that the at least two holders (6, 8, 10) are displaceable relative to each other in an axial direction (A) for adjusting the relative axial positions of the respective nozzles (12, 14, 16). Extrusion device (2) according to claim 1, wherein the multiple holders (6, 8, 10) are at least three holders (6, 8, 10), wherein the holders (6, 8, 10) are displaceable relative to each other in an axial direction (A) for adjusting the axial positions of the nozzles (12, 14, 16) relative to each other.Extrusion device (2) according to claim 2, wherein a first of the media is a support medium for filling a lumen (32) of the hollow structure (4), wherein a second of the media is a wall material for forming a wall (34) of the hollow structure (4), and wherein a third of the media is a hardener for curing the second medium upon combination with it. Extrusion device (2) according to any one of claims 1 to 3. wherein one of the supports (6, 8, 10) is an inner support (6, 8) and wherein another of the supports (6, 8, 10) is an outer support (8, 10), wherein the inner support (6, 8) is displaceable in axial direction (A) so far relative to the outer support (8, 10) that the nozzle (12, 14) of the inner support (6, 8) protrudes relative to the nozzle (14, 16) of the outer support (8, 10) for piercing an existing hollow structure (4) for forming a branch (44) by forming a hollow structure (4) onto the existing hollow structure (4).Extrusion device (2) according to one of claims 1 to 4, wherein the bearing serves to stabilize and guide the holders (6, 8, 10) and to align them coaxially when nested during assembly, wherein the bearing has at least one bearing area (18, 20, 22, 24) which is designed and arranged such that when nesting the holders (6, 8, 10) the bearing area (18, 20, 22, 24) always ensures guidance such that in the radial direction (R) a clearance of an inner of the nozzles (10, 12) does not exceed a predetermined gap dimension (S) to an outer of the nozzles (14, 16) in any area in order to avoid damage to the nozzles (12, 14, 16) when nested.Extrusion device (2) according to one of claims 1 to 5, wherein the bearing has two bearing areas (18, 20, 22, 24), namely a front bearing area (18, 20) and a rear bearing area (22, 24), wherein the front bearing areas (18, 20) and the rear bearing area (22, 24) are arranged one behind the other and spaced apart from each other in the axial direction (A) such that at any time during the extrusion both bearing areas (18, 20, 22, 24) bear on the material, in particular to ensure sufficient guidance and rigidity of the bearing and thus to guarantee a coaxial alignment of the nozzles (12, 14, 16) at any time. Extrusion device (2) according to any one of claims 1 to 6, wherein the bearing has at least one bearing area (18, 20) which is divided by an annular channel (60) for one of the media, such that another of the media, which enters the annular channel (60) through a sealing gap (74) of the bearing, is brought together with the medium in the annular channel (60) to seal the sealing gap (74). Extrusion device (2) according to any one of claims 1 to 7, wherein the supports (6, 8, 10) are rotatable about the central axis (Z) relative to each other to compensate for concentricity tolerances of the dies (12, 14, 16). Extrusion device (2) according to any one of claims 1 to 8, wherein each support (6, 8, 10) has a receptacle (48) for one of the dies (12, 14, 16), wherein each receptacle (48) is configured as a transverse press fit.Extrusion device (2) according to any one of claims 1 to 9, wherein the dies (12, 14, 16) are configured such that the hollow structure (4) is produced with an inner diameter of a maximum of 1 mm, preferably in the range of 10 pm to 200 pm. Extrusion device (2) according to any one of claims 1 to 10, wherein it comprises a drive unit (42) by means of which the holders (6, 8, 10) can be automatically displaced relative to one another. Extrusion device (2) according to any one of claims 1 to 11, wherein it comprises a tool change assembly (40) which has a clamping device (82, 84, 86) for each holder (6, 8, 10) for holding and fixing the respective holder (6, 8, 10). wherein each clamping device (82, 84, 86) has a pull arm (88) and a pressure arm (90) which circumferentially engage a respective holder (6, 8, 10).

13. Method for producing a hollow structure (4) by means of an extrusion device (2) according to any one of claims 1 to 12, wherein the at least two holders (6, 8, 10) are displaced in the axial direction (A) relative to each other to adjust the relative axial positions of the respective nozzles (12, 14, 16).

14. Use of an extrusion device (2) according to any one of claims 1 to 12 for biofabrication, in particular for the production of a hierarchical vascular system.

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