Patent Description:
<CIT> discloses a fluid mixing system including a container, such as a flexible bag, bounding a compartment. A flexible drive line is disposed within the compartment, the drive line having a first end rotatably connected to a first end of the container and an opposing second end rotatably connected to a second end of the container. At least one mixing element, such as an impeller, is coupled with the flexible drive line. Rotation of the drive line facilitates rotation of the impeller within the container. The impeller may comprise pivotable or foldable blades. By folding the blades (whereas the blade bends about location between the axis and the blade tip), the container can be more fully collapsed around the impeller while minimizing risk of damage to the container and to the blades, for instance during transportation. Each of the blades may catch the fluid and automatically move from a collapsed (folded) position to an expanded position (unfolded) for mixing the fluid.

However, a problem with the fluid mixing system of <CIT> is that in the collapsed state the foldable blades still occupy quite a lot of space around the drive line.

Furthermore, relatively complex mechanical systems are required to unfold the foldable blades to the expanded position in order to start agitation.

An object of the present disclosure is thus to provide an impeller system for use with a bioreactor, wherein in the collapsed state the blades are collapsed towards each other to occupy less space around the drive line.

A further object of the disclosure is to provide an impeller system for use with a bioreactor, wherein relatively less complex mechanical systems are required to transition the collapsed blades to an un-collapsed position in order to start agitation.

According to embodiments of the present disclosure, an impeller system for use with a bioreactor is provided, comprising:.

Due to the at least two impeller blades, such as three, four, five, six, or more blades, preferably all blades, not being positioned axisymmetrically around the drive shaft, such as being aligned along the longitudinal axis, in the collapsed state, much less space is occupied around the drive shaft in the collapsed state, allowing for easier transportation and a greatly reduced size of the impeller system when e.g. a bioreactor bag or a similar flexible container for bioreaction is used, i.e. when the flexible container for bioreaction is collapsed around the impeller system.

In the context of the present patent application, "aligned" means "substantially radially aligned", i.e. the angle formed between similar radially extending features of a first item (such as a blade) and a second item (such as an adjacently radially disposed blade) is less than <NUM> degrees from each other, more preferably less than <NUM> degrees from each other, and even more preferably less than <NUM> degrees from each other, and even more preferably less than <NUM>, degrees from each other, and even more preferably less than <NUM> degrees from each other about a common axis of rotation of the drive shaft, such as the longitudinal axis of the drive shaft, especially the portion of the drive shaft in which the blades are connected or otherwise engage the drive shaft.

Furthermore, the at least one of the at least two impeller blades transitions along the circumference of the drive shaft (e.g., along a circumferential arc) from the collapsed state to the un-collapsed state by rotating along a circumference of the drive shaft due to resistance from a liquid in the bioreactor when agitation is performed. Therein, at least one of the two (or more) impeller blades "automatically" and gradually transitions to its own individual/unique position along the circumference of the drive shaft in the final axisymmetric configuration of the impeller blades in the un-collapsed state, basically in a very natural way: the hydrodynamic forces exerted by the liquid on the at least one of the at least two impeller blades pushes the at least one of the impeller blades into its unique place in the final axisymmetric configuration of the impeller blades in the un-collapsed state, for instance by causing/allowing the at least one of the at least two impeller blades to slide (e.g., rotationally slide) along the circumference (or a circumferential arc) of the drive shaft. Thus, the use of complex mechanical systems to unfold the impeller blades can be avoided.

A further advantage of the above impeller system is that in the collapsed state, the at least two impeller blades are less likely to damage the flexible container (e.g., pliable bag) for bioreaction when the flexible container for bioreaction is collapsed around the impeller system, because the at least two impeller blades are aligned along the longitudinal axis, thereby distributing any pressure exerted on the inside of the (respective side of the) flexible container for bioreaction over multiple impeller blades, thus preventing puncturing or tearing of the flexible container for bioreaction.

Further general state of the art which is not considered to be of particular relevance to the present disclosure is disclosed in <CIT>, <CIT> and <CIT>: <CIT> discloses a mixing device as per the preamble of claim <NUM> for mixing beer, wine or other liquids in a barrel. <CIT> discloses a container with a flexible container wall, in particular a disposable bioreactor, with a container interior in which a mixer is arranged at one end of a mixer shaft which is passed through the container wall and is drivable from the outside, wherein the mixer shaft and/or mixer is/are designed such that it/they are foldable and such that it/they can be stabilized from the outside. <CIT> discloses a stirring device for homogenizing manure, with a drive shaft and agitator blades, which are mounted on the drive shaft so that they can be folded about pivot axes, the agitator blades being aligned parallel to the drive shaft when at a standstill and a position at an angle to the drive shaft when the drive shaft is rotating.

An embodiment relates to an aforementioned impeller system, wherein the at least two impeller blades are each independently connected to the drive shaft. Thus, the at least one individual impeller blade can move independently from the other impeller blades to the respective impeller blade's final position in the un-collapsed state, increasing reliability of the impeller system. Furthermore, the foregoing allows "tuning" of the impeller system by e.g. removing or adding impeller blades, which also facilitates manufacturing.

An embodiment of the present disclosure relates to an aforementioned impeller system, wherein at least one of the at least two impeller blades is independently attached to the drive shaft with a ring, configured for rotation around the drive shaft, wherein the ring is configured for rotating from a first orientation on the drive shaft in the collapsed state to a second, individual orientation on the drive shaft in the un-collapsed state, such that the at least two impeller blades are positioned axisymmetrically around the drive shaft. The use of such rotatable rings allows for a natural movement of the at least one of the at least two impeller blades to its final position in the un-collapsed state. Removal or addition of impeller blades is also further simplified.

An embodiment relates to an aforementioned impeller system, wherein one of the ring or a local circumference of the drive shaft at the axial location of the ring is provided with an engagement portion and the other of the ring or the local circumference is provided with an engagement member, wherein the engagement portion and the engagement member are configured to engage each other when the ring has reached the second orientation, thereby preventing rotation of the ring past the second orientation.

An embodiment relates to an aforementioned impeller system, wherein, in the collapsed state, the at least two impeller blades are adjacent to each other along the longitudinal axis. Thus, by spacing the at least two impeller blades closely together, such as by stacking them onto each other along the longitudinal axis, chances of local pressure points occurring further decrease, thus further preventing puncturing or tearing of the flexible container for bioreaction.

An embodiment relates to an aforementioned impeller system, wherein, in the collapsed state, the at least two impeller blades are adjacent to each other along the longitudinal axis in such a way, that contours of the at least two impeller blades are aligned or otherwise can be brought into approximation of each other, when viewed along the longitudinal axis. Thus, a compact "package" of impeller blades is achieved, wherein the at least two impellers are prevented from protruding with respect to each other in a direction perpendicular to the longitudinal axis due to the contours of the impeller blades being aligned in the longitudinal direction, thus further preventing local puncturing of the flexible container for bioreaction.

An embodiment relates to an aforementioned impeller system, wherein radially outer edges of the two or more impeller blades are rounded in a main plane of the impeller blade, allowing the bioreactor be smoothly collapsed over the impeller blades, for instance when transporting or storing the flexible container for bioreaction and the impeller system, further decreasing the risk of damage occurring to the flexible container for bioreaction.

An embodiment relates to an aforementioned impeller system, wherein the rounded, radially outer edges of the two or more impeller blades have a constant radius of curvature, to further facilitate smooth arrangement of the flexible container for bioreaction over the radially outer edges of the impeller blades in the collapsed state.

An embodiment relates to an aforementioned impeller system, wherein radially outer edges of the two or more impeller blades are rounded in a plane transversal to the main plane of the impeller blade and the radially outer edges. Thus, the impeller blades are less "sharp" to further prevent puncturing or cutting of the flexible container for bioreaction in the collapsed state.

An embodiment relates to an aforementioned impeller system, wherein the at least two impeller blades in the collapsed state are aligned along the longitudinal axis, providing for a compact impeller blade package.

An embodiment relates to an aforementioned impeller system, wherein the at least two impeller blades in the collapsed state establish a rotational angle with respect to each other about the longitudinal axis that is less than <NUM> degrees, more preferably less than <NUM> degrees, and even more preferably less than <NUM> degrees, most preferably around <NUM> degrees, such that the impeller blades are close together in the rotational direction in the collapsed state.

An embodiment relates to an aforementioned impeller system, wherein the at least two impeller blades are each independently connected to the drive shaft, allowing for optimal design and operational flexibility.

Another aspect of the disclosure concerns a flexible container for bioreaction, comprising an aforementioned impeller system, wherein the impeller system is arranged inside the flexible container for bioreaction.

An embodiment relates to an aforementioned flexible container for bioreaction, wherein the at least two impeller blades are in the collapsed state.

An embodiment relates to an aforementioned flexible container for bioreaction, wherein the inside of the flexible container for bioreaction is sterile to a sterility assurance level of at least <NUM>-<NUM> SAL.

An embodiment relates to an aforementioned flexible container for bioreaction, further comprising a sterility barrier encapsulating the flexible container, wherein the sterility barrier is optionally configured as a bag, pouch, or a tub with a sealed lid.

Another aspect of the disclosure concerns a bioreactor, comprising a drive motor and an aforementioned impeller system or an aforementioned flexible container for bioreaction, wherein the drive shaft is connected to the drive motor.

Another aspect of the disclosure concerns a method of using an aforementioned impeller system, comprising the steps of:.

Another aspect of the disclosure concerns a method of manufacturing an aforementioned impeller system, comprising the step of:.

An embodiment relates to an aforementioned method of manufacturing, wherein manufacturing the at least two impeller blades comprises 3D-printing at least one, such as two, of the at least two impeller blades. 3D-printing is any of various processes in which material is joined or solidified to create a three-dimensional object, with material being added together (such as liquid molecules or powder grains being fused together). 3D-printing is often used in both rapid prototyping and additive manufacturing (AM). Objects can be of almost any shape or geometry and typically are produced using digital model data from a 3D model or another electronic data source such as an Additive Manufacturing File (AMF) file (usually in sequential layers). There are many different technologies, like stereo-lithography (SLA) or fused deposit modeling (FDM). Thus, unlike material removed from a stock in the conventional machining process, 3D printing or AM builds a three-dimensional object from computer-aided design (CAD) model or AMF file, usually by successively adding material layer by layer.

An embodiment relates to an aforementioned method of manufacturing, wherein in the collapsed state the at least two impeller blades are aligned along the longitudinal axis.

The embodiments of the disclosure will be explained in more detail below, with reference to illustrative embodiments shown in the drawings.

<FIG> shows an example embodiment of a bioreactor <NUM>, comprising a drive motor <NUM> and an impeller system <NUM> according to an example embodiment of the disclosure, wherein the drive shaft <NUM> is connected to the drive motor <NUM>. The bioreactor <NUM> may be a single-use or multi-use bioreactor <NUM>. The bioreactor <NUM> may be configured for an operational/work volume of <NUM> - <NUM> liters, preferably <NUM> - <NUM> liters, more preferably <NUM> - <NUM> liters, such as <NUM> - <NUM> liters. A bioreactor <NUM> generally relates to a manufactured or engineered device or system that supports a biologically active environment. The bioreactor <NUM> may be cylindrical and may be made of glass and/or stainless steel. The bioreactor <NUM> may also relate to a device or system designed to grow cells or tissues in the context of cell culture.

The impeller system <NUM> is arranged inside a flexible container for bioreaction <NUM>. Outer surfaces of the flexible container for bioreaction <NUM>, such as a bioreactor bag <NUM>, are positioned against inner surfaces (i.e., inner sidewalls) of the bioreactor <NUM> to provide a proper fit, preferably without folds and the like. The flexible container for bioreaction <NUM> may be configured for single use. Such a single-use flexible container <NUM> has several advantages, in particular reducing assembly/disassembly, cleaning, sterilization and calibration demands. The impeller system <NUM> comprises the drive shaft <NUM>, which is configured for being rotated in a rotational direction R around a longitudinal axis X of the drive shaft <NUM> by the drive motor <NUM> of the bioreactor <NUM>. The drive shaft <NUM> may have a length of for instance <NUM> - <NUM>, such as <NUM> - <NUM>, for instance <NUM> - <NUM>, depending on the bioreactor <NUM> design. At least two impeller blades <NUM>, such as two, three, four, fix, six or even more, are connected to the drive shaft <NUM>, and are configured for being rotated along with the drive shaft <NUM> in the rotational direction R. The at least two impeller blades <NUM> are preferably arranged at a free end of the drive shaft <NUM>, although other arrangements are also conceivable (e.g., such as being spaced from the free end of the drive shaft <NUM>). The impeller blades <NUM> may have the form of a (flat) plate, although other shapes are also conceivable such as curved blades. The impeller blades <NUM> may also be arranged at an angle with respect to (a plane transversal to) the longitudinal axis X. The at least two impeller blades <NUM> are configured for transitioning from a collapsed state I, wherein the at least two impeller blades <NUM> are adjacent to each other or are otherwise capable brought into approximation of each other about the longitudinal axis X, to an un-collapsed state II, for performing agitation, wherein the at least two impeller blades are positioned rotationally away from each other axisymmetrically around the drive shaft <NUM>. If two impeller blades <NUM> are used, in the un-collapsed state the blades would be radially spaced about the axis X from each other by about <NUM> degrees, wherein if three impeller blades <NUM> are used, in the un-collapsed state the blades would be radially spaced about the axis X by about <NUM> degrees. <FIG> shows the impeller blades <NUM> in the un-collapsed state II. The at least one of the at least two impeller blades <NUM> transitions from the collapsed state I to the un-collapsed state II by rotating, i.e. moving, along a circumference <NUM> of the drive shaft <NUM> due to resistance from a liquid <NUM> in the bioreactor <NUM> when agitation is performed.

<FIG> shows an example embodiment of an impeller system <NUM> according to the disclosure, such as the impeller system <NUM> of <FIG>, with the impeller blades <NUM> in the collapsed state I. The at least two impeller blades <NUM> are in the collapsed state I, e.g. for being stored or transported. The at least two impeller blades <NUM> may each be independently connected to the drive shaft <NUM>, as will be more clearly explained with reference to <FIG>. In the collapsed state I, the at least two impeller blades <NUM> may be adjacent to each other <NUM> along the longitudinal axis X, forming a "package" of impeller blades <NUM>, preferably in such a way, that contours <NUM> of the at least two impeller blades <NUM> are aligned or otherwise can be brought adjacent to each other in a contacting or non-contacting manner, when viewed along the longitudinal axis X. By example, radially adjacent blades can establish an angle to each other with respect to the longitudinal axis X that is less than <NUM> degrees, more preferably less than <NUM> degrees or <NUM> degrees, more preferably less than <NUM> degrees, preferably less than <NUM> degrees, preferably less than <NUM> degrees, preferably less than <NUM> degrees, preferably less than <NUM> degrees, and if geometrically feasible can establish an angle to each other at or about <NUM> degrees, all the foregoing subject to geometric constraints such as but not limited to their respective blade thickness, shape, means of connecting to the drive shaft, and/or longitudinal spacing along the drive shaft <NUM>.

<FIG> shows an example embodiment of an impeller system <NUM> according to the disclosure, such as the impeller system <NUM> of <FIG> or <FIG>, with the impeller blades <NUM> in the un-collapsed state I. The impeller blades <NUM> are now axisymmetrically arranged around the drive shaft <NUM>, for performing agitation, and as shown using three blades, may establish an angle to each other with respect to the longitudinal axis X of about <NUM> degrees.

<FIG> shows an exploded view of an example embodiment of an impeller system <NUM> according to the disclosure, such as the impeller system <NUM> of <FIG>, <FIG>, with the impeller blades <NUM> in the un-collapsed state I. Radially outer edges <NUM> of the two or more impeller blades <NUM> are preferably rounded in a main plane <NUM> of the impeller blade <NUM>. The rounded, radially outer edges <NUM> of the two or more impeller blades <NUM> preferably have a constant radius of curvature r. The radius of curvature r could be <NUM> - <NUM>, such as <NUM> - <NUM>. The at least one of the at least two rotatable impeller blades <NUM> may be independently attached to the drive shaft <NUM> with a rotatable ring <NUM>, provided with an engagement portion <NUM>, such as a lower rotatable ring <NUM>, respectively, and an upper rotatable ring <NUM>, as shown in <FIG>.

The rotatable rings <NUM> may be configured for rotation around the drive shaft <NUM>, wherein the rotatable rings <NUM> are configured for rotating from a first orientation (i.e. a first angular position) on the drive shaft <NUM> in the collapsed state I to a second orientation (i.e. a second angular position) on the drive shaft <NUM> in the un-collapsed state II, such that the at least two rotatable impeller blades <NUM> are positioned axisymmetrically around the drive shaft <NUM>, with each of the impeller blades <NUM> having a unique axisymmetric position. As shown in <FIG>, the lower rotatable ring <NUM> may be provided with a lower circumferential recess <NUM>, whereas the upper rotatable ring <NUM> may be provided with an upper circumferential recess <NUM>. The local circumference <NUM> of the drive shaft <NUM> is provided with an engagement member <NUM> in the form of a notch, protrusion or the like. The circumferential length of the lower circumferential recess <NUM> differs from the circumferential length of the upper circumferential recess <NUM>.

Essentially, the rings <NUM> act with respect to the drive shaft <NUM> as a keyed slot mechanism. Keyed slots are typically designed with little to no "slop" to prevent rotation due to the similar dimension of the key width and the slot width. In the embodiment shown in <FIG>, however, relatively large keyway widths, i.e. the circumferential lengths of the lower and upper circumferential recesses <NUM>, <NUM>, are used to cause large degrees of "slop" to permit additional rotation, and the amounts of rotation permitted are different because the keyway equivalents of the lower and upper rings <NUM>, <NUM>, i.e. the lengths of the lower and upper circumferential recesses <NUM>, <NUM>, are different in size for each ring <NUM>. The "key" equivalent of the embodiment shown in <FIG> is essentially the engagement member <NUM>.

Each ring <NUM>, i.e. each of the lower ring <NUM> and the upper ring <NUM>, has a "keyway" (i.e. the respective circumferential lengths of the lower and upper circumferential recesses <NUM>, <NUM>) that is drastically larger than the key (engagement member <NUM>), such that when the second impeller blade <NUM> associated with the lower ring <NUM> - when counted upwards from the lower end of the impeller system <NUM> of <FIG> - rotates about the drive shaft <NUM> along the circumferential recess <NUM> and at the engagement portion <NUM> makes contact at one side of the engagement portion <NUM> with the engagement member <NUM>, it stops rotating, and when the third impeller blade <NUM> associated with the upper ring <NUM>, rotates about the drive shaft <NUM> along the upper circumferential recess <NUM> and the engagement portion <NUM> of the upper ring <NUM> makes contact with the same key, i.e. engagement member <NUM>, it also stops rotating.

The lower ring <NUM> has a keyway (circumferential recess <NUM> length) that is so large that it permits rotation to at or about <NUM> degrees, and the upper ring <NUM> has a keyway (circumferential recess <NUM> length) that is so large that it permits rotation to at or about <NUM> degrees, so that if three impeller blades <NUM> are used they are placed at or about <NUM> degrees out of phase from each other about the rotational axis X.

The ring <NUM>, such as the two rings <NUM> as shown in <FIG>, may be kept in their longitudinal position by using a lower end ring <NUM> and an upper end ring <NUM>. The rings <NUM> are then firmly "locked" (i.e. longitudinally) between the upper end ring <NUM> and the lower end ring <NUM>. As can be seen from <FIG>, the lower end ring <NUM> may be provided with an impeller blade <NUM> that is fixedly attached to the drive shaft <NUM>, e.g. being integrally formed therewith, i.e. unable to move with respect to the local circumference <NUM> of the drive shaft <NUM>. The other impeller blades <NUM> as shown in <FIG>, in contrast, are configured to rotate with respect to the drive shaft <NUM> due to the resistance of the liquid (i.e. in a direction opposite to the rotational direction R, as the skilled person will understand).

The radially outer edges <NUM> of the two or more impeller blades <NUM> are preferably rounded in a plane <NUM> transversal to the main plane <NUM> of the impeller blade and the radially outer edges <NUM>.

<FIG> show example embodiments of an impeller system <NUM> according to the disclosure, comprising a connection mechanism for connecting a (during use) lower drive shaft portion <NUM> of the drive shaft <NUM> to an upper drive shaft portion <NUM> of the drive shaft <NUM> (as more clearly shown in <FIG>). The two or more impeller blades <NUM> are connected to the lower drive shaft portion <NUM>. <FIG> shows a first variant of the connection mechanism, wherein one or more longitudinal guiding grooves <NUM>, such as one, two, three, four or more guiding grooves <NUM>, are provided in the lower drive shaft portion <NUM>, at an upper longitudinal end thereof. The guiding grooves <NUM> are configured for receiving one or more elongated guiding members <NUM>, such as shown in <FIG>. Thus, the torque of a drive motor connected to the upper drive shaft portion <NUM> can be properly transmitted to the lower drive shaft portion <NUM>. The first variant of the connection mechanism as shown in <FIG> comprises relatively short guiding grooves <NUM> compared to the second variant of the connection mechanism shown in <FIG> and <FIG>, showing relatively longer guiding grooves <NUM>.

The first variant, as shown in <FIG>, comprises one or more (radially) resilient locking members <NUM>, arranged below the relatively short guiding grooves <NUM>, for locking onto one or more corresponding protrusions (not shown) on the upper drive shaft portion <NUM>. The upper drive shaft portion <NUM> may be hollow, such as shown in <FIG>, for receiving the lower drive shaft portion <NUM>. The one or more protrusions may be arranged on an inside of a circumferential wall of such a hollow upper drive shaft portion <NUM>. To facilitate locking "behind" such protrusions, one or more radially outwardly extending connection edges <NUM> may be provided on a longitudinally upper end of the resilient locking members <NUM>.

The second variant, as shown in <FIG> and <FIG>, also comprises one or more (radially) resilient locking members <NUM> - although now arranged in between relatively longer guiding grooves <NUM>, in the rotational/circumferential direction R, for locking onto one or more corresponding protrusions (not shown) on the upper drive shaft portion <NUM>. The upper drive shaft portion <NUM> may be hollow, for receiving the lower drive shaft portion <NUM>, as mentioned in the foregoing, such as shown in <FIG>. The resilient locking members <NUM> are basically alternating with the guiding grooves <NUM> in the rotational/circumferential direction R in the second variant. The one or more protrusions may again be arranged on an inside of a circumferential wall of such a hollow upper drive shaft portion <NUM>. To facilitate locking behind the protrusions, one or more radially outwardly extending connection edges <NUM> may be provided on a longitudinally upper end of the resilient locking members <NUM>. The skilled person will understand that features of the first and second variants can be combined or mixed, if desired.

As mentioned previously, another aspect of the disclosure relates to a method of using an aforementioned impeller system <NUM>, comprising the steps of:.

Yet another aspect of the disclosure relates to a method of manufacturing an aforementioned impeller system <NUM>, comprising the step of:.

Manufacturing the at least two impeller blades <NUM> may comprise 3D-printing at least one of the at least two impeller blades <NUM>.

Claim 1:
Impeller system (<NUM>) for use with a bioreactor (<NUM>), comprising:
- a drive shaft (<NUM>) configured for being rotated in a rotational direction (R) around a longitudinal axis (X) of the drive shaft by a drive motor (<NUM>) of the bioreactor;
- at least two impeller blades (<NUM>) connected to the drive shaft, configured for being rotated along with the drive shaft when the drive shaft is rotated, wherein the at least two impeller blades are configured for transitioning from
a collapsed first state (I), wherein the at least two impeller blades are not positioned axisymmetrically around the drive shaft, to
an un-collapsed state (II), for performing agitation, wherein the at least two impeller blades are positioned axisymmetrically around the drive shaft,
characterized in that at least one of the at least two impeller blades transitions from the collapsed state to the un-collapsed state by rotating along a circumference (<NUM>) of the drive shaft due to resistance from a liquid (<NUM>) in the bioreactor when agitation is performed.