Bioreactor tray
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a tray configured to be provided oh a base station of
5 a bioreactor system, a bior~f!-Ctor system and a method for culturing cells in a
bioreactor system.
BACKGROUND OF THE INVENTION
Bioreactors are used for ,culturing cells. One type of bioreactor is a rocking bioreactor
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10 which will agitate the cell culture within the bioreactor bag by providing a rocking
motion to the bag. This is also referred to as a wave motion. In cell therapy cells are
retrieved from a patient or a donor and then prepared and grown in different steps
before they are provided to a patient as cell therapy. Incubators are often used for
growing low volumes of cell cultures and in a later stage of the cell culturing where
15 the volumes are larger bioreactors, such as a rocking bioreactor can be used.
Transferring of the cells from incubators to rocking bioreactors is both a risk for loss
of cells and a risk for contamination of the cells. Furthermore incubators need a lot of
space in cleanrooms which is expensive.
20 SUMMARY
It is an object of the present invention to provide an improved bi.oreactor system and
method for culturing cells.
It is also an object of the present invention to provide a method-for culturing cells
and a bioreactor system in which risk for contamination and loss of cells is decreased.
It is also an object of the present invention to provide a more effective and safe
method and system for culturing cells.
This is achieved in a tray, a bioreactor system and a method for culturing cells as
described in the independent patent claims.
s Hereby a rocking bioreactor can be used also for early cell expansion, i.e. cell cultures
with low volume. And furthermore the same bioreactor can be used for both small
culture volumes and larger culture volumes. In prior art bioreactors there are often
problems if low volume cell cultures are provided in a too large rocking bioreactor.
These problems are related to that cells can be destroyed by the rocking motion
10 when there is too little culture and cells could be lost due to condensation. With this
invention the size of the tray can be adapted for different volumes of cell culture
provided in the bioreactor bag and hereby the same bioreactor bag can be used for
first early cell expansion which is usually performed in incubators and then also for
later cell expansion. Hereby the cell culture need not be transferred from incubator
15 to bioreactor and risk of cell loss and contamination is decreased. Furthermore
clean room space is saved.
In one aspect of the invention a tray is provided, which tray is configured to be
provided on a base station of a bioreactor system, said tray comprising a bottom and
surrounding side walls and being configured to hold a bioreactor bag, said bottom
20 comprising at least two bottom parts, whereof one is a middle part of the bottom,
wherein at least one of the bottom parts is movable into at least a first and a second
position, wherein said first position provides the bottom parts substantially flush with
each other providing a substantially plane bottom of the tray and said second
position provides a bottom of the tray having a recessed middle part.
25 In one aspect of the invention a bioreactor system comprising a base station and a
tray as described above is provided.
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In a further aspect of the invention a method for culturing cells in a bioreactor system
is provided, wherein said method comprising the steps of:
determining a volume or weight of a cell culture provided in a bioreactor
bag which is positioned in a tray in the bioreactor system;
positioning at least one bottom part of a bottom of said tray comprising at
least two bottom pa'rts into one of at least a first position and a second
position in dependence of said determined volume or weight, said first
position providing the bottom parts substantially flush with each other
providing a substantially plane bottom of the tray and said second position
providing a bottom of the tray having a recessed middle part.
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In one embodiment of the invention the tray is configured to be provided on a base
station of a rocking bioreactor system.
In one embodiment of the invention the bottom comprises a first part being the
15 middle part and a second part surrounding said first part.
In one embodiment of the invention said first part is movable into the first and the
second positions.
In one embodiment of the invention the bottom parts each comprises at least one
heater. Hereby one or more of the bottom parts can be heated separately in
20 dependence of the position of the middle part of the bottom and/or in dependence
of a volume or weight of the content in the bioreactor bag.
In one embodiment of the invention the middle part comprises a temperature
sensor. Hereby the heaters can be controlled in dependence of a sensed temperature
in the bioreactor bag.
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In one embodiment of the invention the tray further comprises a positioning device
by which at least one of the bottom parts can be provided in the at least two
different positions.
In one embodiment of the invention said base station comprises a control device
5 connected to at least one heater in each bottom part of the tray and to the
positioning device of the tray;wherein said control device is arranged to control the
heaters in the tray in dependence of the position of the at least one bottom part
which is moved into at least two different positions by the positioning device.
In one embodiment of the invention said base station comprises a weight measuring
10 device configured for measuring the weight of a bioreactor bag provided in the tray
and said base station further' comprises a control device which is connected to at
least one heater in each bottom part of the tray and to the weight measuring device,
wherein said control device is arranged to control the heaters in dependence of a
weight of the bioreactor bag measured in the weight measuring device.
15 In one embodiment of the invention the control device further is connected to the
positioning device and arranged to control the positioning device to provide at least
one of the bottom parts of the tray in either the first position or the second position
in dependence of the measured weight.
In one embodiment of the invention the control device is further connected to a
20 temperature sensor provided in the middle part of the bottom of the tray and
wherein the control system is arranged to control the heaters in the tray in
dependence of the sensed temperature.
25
In one embodiment of the invention the method further comprises the step of:
- controlling one or more heaters provided in the tray in dependence of
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the position of the at least one bottom part which is positioned into at least
two different positions or in dependence of a measured weight of the
bioreactor bag.
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In one embodiment of the invention the method further comprises the step of
measuring a temperature in the bioreactor bag and controlling the heaters in the tray
in dependence of said measured temperature.
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BRIEF DESCRIPTION OF THE DRAWINGS
Figure la shows schematically a tray according to one embodiment of the invention
with a first part of the tray bottom provided in a first position.
Figure lb shows schematically the same tray as shown in Figure la with the first part
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10 of the tray bottom provided in a second position.
Figure 2a is a cross section side view of a bioreactor system according to one
embodiment of the invention with a first part of the tray bottom provided in a first
position.
Figure 2b is a cross section side view of the same bioreactor system as shown in
15 Figure 2a with a first part of the tray bottom provided in a second position.
Figure 3 is an exploded view of a tray according to one embodiment of the invention.
Figure 4a shows schematically a tray according to one embodiment of the invention.
Figure 4b is an exploded view of a tray according to one embodiment of the
invention.
20 , Figure 5 shows schematically components in a base station of a bioreactor system
according to one embodiment of the invention.
Figure 6 is a flow chart of a method for culturing cells according to one embodiment
of the invention.
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DETAILED DESCRIPTION OF EMBODIMENTS
The present invention relates to a bioreactor system and to a tray in said rocking
bioreactor system. It also relates to a method for culturing cells in a bioreactor
system. The bioreactor system can be a rocking bioreactor system, but also other
5 types of bioreactor systems where a tray is used to hold the bioreactor bag, such as
for example shaken reactors; should be covered by this patent application.
Figures 1a and 1b show schematically a tray according to one embodiment of the
invention.
Figures 2a and 2b show schematically a cross section side view of a bioreactor system
10 according to one embodiment of the invention .
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According to the invention a tray 1 which is arranged to be provided on a base station
3 of a rocking bioreactor system 5 is provided. The tray 1 comprises a bottom 7 and
surrounding side walls 9 and is arranged to hold a bioreactor bag 11. The bottom 7
comprises at least two bottom parts. In the embodiment shown in Figures 1-3 the
15 bottom comprises two bottom parts, a first part 7a and a second part 7b surrounding
the first part 7a. In another embodiment of the invention for example three separate
bottom parts could be provided. This is shown in Figures 4a and 4b. However,
common to these embodiments is that one of the bottom parts is a middle part of
the bottom. In the embodiment shown in Figures 1-3 the first part 7a is a middle part.
2.0 According to the invention at least one of the bottom parts is movable into at least a
first and a second position, wherein said first position provides the bottom parts
substantially flush with each other providing a substantially plane bottom 7 of the
tray and said second position provides a bottom 7 of the tray having a recessed
middle part. In the embodiment shown in Figures 1-3 the first part 7a, also called the
2.5 middle part 7a, is the bottom part which can be moved into at least a first and a
second position. In another embodiment it could as well be the one or more other
bottom parts, i.e. not the middle part, which is movable into at least two different
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positions. If one second part 7b surrounding the first part 7a is provided (as in Figures
1-3) this second part could be movable into the at least two different positions.
In the embodiment shown in Figures 1-3 the first part 7a of the bottom 7 can be
provided in two different positions wherein a first position is shown in Figure 1a and
5 2a and provides the first part 7a substantially flush with the second part 7b providing
a substantially plane bottom 7 of the tray 1. A second position of the first part 7a is
shown in Figure 1b and 2b and this is a position where the first part 7a is provided as
a recessed middle part of the bottom 7 of the tray. This recessed middle part will
house the most of the cell culture volume when the bioreactor bag 11 to be provided
10 in the tray 1 only comprises a small amount of cell culture. Hereby the cell culture will
be kept more together 11\(ithin the bioreactor bag during cultivation and during the
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rocking motion. This is better for the cells and will provide better possibilities for
temperature sensing and control of the cell culture. Without this recessed middle
part a low volume of cell culture would spread out too much within the bioreactor
15 and be more affected by overheating, condensation and also more damaged by the
rocking motion.
In one embodiment of the invention each bottom part comprises at least one heater.
In the embodiment shown in Figures 1-3, the first part 7a and the second part 7b
each comprises one heater. An exploded view of a tray according to one embodiment
20 of the invention is shown in Figure 3. In the embodiment shown in Figure 3 a first
heater 21a is shown provided to the first part 7a and a second heater 21b is shown
provided to the second part 7b. The first and second heaters 21a, 21b are each
connected to a control device 31 provided in the base station 3 of the bioreactor
system 5. The base station comprising the control device 31 is shown schematically in
25 Figure 5. The control device 31 can communicate with the first and second heaters
21a, 21b in the tray. This communication could be provided wir~lessly or through one
or more connection ports 22 between the base station and the tray. By having
separate heaters to each bottom part of the bottom of the tray the heating of the
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bioreactor can be provided in dependence on how much cell culture is provided in
the bioreactor bag. Hereby the temperature in the cell culture can be controlled
much better also for small volumes of cell culture.
In one embodiment of the invention the middle part of the bottom (the first part 7a
5 in the embodiment shown in Figures 1-3) comprises a temperature sensor 13. The
temperature sensor 13 is corrnected to the control device 31 in the base station via a
connection port 22 or wirelessly and the control of the first and second heaters 21a,
21b is provided in dependence of the sensed temperature.
The tray 1 comprises further a positioning device 15 by which at least one of the
10 bottom parts can be provided in the at least two different positions. In the
embodiment shown in Figure 1-3 the first part 7a of the bottom 7 can be provided in
the at least two different positions. The positioning device 15 is here shown to be an
oblong actuation knob which provides the first part 7a of the bottom of the tray in its
first position when the knob is provided in a vertical position. In the first position the
15 first and second parts of the bottom are provided substantially flush with each other.
The first part 7a of the bottom of the tray is provided in its second position, i.e. lower
than the second part 7b, when the knob is provided in a horizontal position. The knob
is hereby connected to a transferring means within the tray which can push the first
part 7a upwards to its first position. Another type of positioning device 15 can be
20 provided within the scope of this invention. Any device which can move at least one
of the bottom parts of the bottom 7 into it's at least two positions should be covered
by this invention. For example a motor or solenoid and automatic moving of the at
least one bottom part in dependence of for example measured weight of the
bioreactor bag is possible.
25 Figure 4a shows schematically a tray 1' according to another embodiment of the
invention. The tray 1' comprises a bottom 7' and surrounding side walls 9' and is
arranged to hold a bioreactor bag. In this embodiment the bottom 7' comprises three
separate bottom parts 8a, 8b, 8c. One of the three bottom parts is a middle part 8b
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and the other two are outer parts 8a and 8c and positioned one on each side of the
middle part 8b. Either the middle part 8b or the two outer parts 8a, 8c can be
provided in two different positions as described above. A first position provides the
bottom parts 8a,b,c substantially flush with each other providing a substantially
5 plane bottom 7' of the tray and a second position provides a bottom 7' of the tray
having a recessed middle part.~b. Heaters cannot be seen in this view but can be
provided one to each bottom part 8a, 8b, 8c. A temperature sensor 13' can be
provided to the middle part 8b. A positioning device (however not seen in this view)
is provided to the tray by whi.ch at least one of the bottom parts 8a,b,c can be
10 provided in the at least two different positions.
Figure 4b is an exploded vie"'( of a tray 1" according to another embodiment of the
invention. Also in this embodiment the tray bottom 7" is separated into three bottom
parts 8a', 8b', 8c'. However in the other direction compared to the embodiment
shown in Figure 4a. One of the three bottom parts is a middle part 8b' and the other
15 two are outer parts 8a' and 8c' and positioned one on each side of the middle part
8b'. Either the middle part 8b' or the two outer parts 8a', 8c' can be provided in two
different positions as described above. A first position provides the bottom parts
8a',b',c' substantially flush with each other providing a substantially plane bottom 7"
of the tray and a second position provides a bottom 7" of the tray having a recessed
20 middle part 8b'. Heaters 21a', 21b', 21c' can be seen in this exploded view one
provided to each bottom part 8a', 8b', 8c'. A temperature sensor 13" can be provided
to the middle part 8b'. A positioning device (however not seen in this view) is
provided to the tray by which at least one of the bottom parts 8a',b',c' can be
provided in the at least two different positions.
25 In Figure 5 a base station 3 is schematically shown. A control device 31 is provided in
the base station 3. The control device 31 is here shown to be connected to a
connection port 22 through which the control device 31 can communicate with the
first and second heaters 21a, 21b of the tray. This communication can also be
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provided through more than one connection port or wirelessly. The control device 31
is configured to control one or more of the heaters provided in the tray in
dependence of the position of the at least one movable bottom part of the tray or in
dependence of a measured weight of the bioreactor bag. Hereby the control device
5 31 is further connected to the positioning device 15, 15' in the tray either wirelessly
or via a connection port 22 and/or to a weight measuring device 33 provided in the
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base station 3. If the control device 31 is connected to both a weight measuring
device 33 and to the positioning device 15, 15' and the positioning device can be
controlled automatically it yvould be possible to control the position of at least one of
10 the bottom parts of the bottom 7, 7' of the tray 1, 1' automatically in dependence of
the weight of the bioreactor bag. The heaters are also controlled in dependence of
either the position of orie of the bottom parts or in dependence of the weight of the
bioreactor bag. Hereby temperature in the cell culture can be controlled with more
precision. The control device 31 is also connected to the temperature sensor 13, 13'
15 in the tray which will provide further possibilities for temperature control. The
heaters can be controlled in dependence of the sensed temperature.
Figure 6 is a flow chart of a method for culturing cells according to one embodiment
of the invention. The method steps are described in order below:
20 51: Determining a volume or weight of a cell culture provided in a bioreactor bag 11
which is positioned in a tray 1, 1' in the bioreactor system 5. This could be done
either manually by the operator making a judgement whether the volume in the
bioreactor bag is small or large or automatically by measuring the weight of the
bioreactor bag.
25 53: Positioning at least one bottom part of a bottom of said tray comprising at least
two bottom parts into one of at least a first position and a second position in
dependence of said determined volume or weight. Said first position providing the
bottom parts substantially flush with each other providing a substantially plane
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bottom of the tray and said second position providing a bottom of the tray having a
recessed middle part. In the embodiment shown in Figures 1-3 this step of the
method will be to positioning a first part 7a of a bottom 7 of said tray 1 in either a
first position or a second position in dependence of said determined volume or
5 weight. This positioning of at least one bottom part of the bottom 7 of the tray 1 can
also be done either manual.l.y through use of the positioning device 15, for example '
turning the knob as shown in the embodiment shown in Figures 1-3, or automatically
in dependence of the measured weight.
55: Controlling one or more' heaters 21a, 21b provided in the tray 1, 1' in dependence
10 of the position of the at least one bottom part which is positioned into at least two
different positions or in deP,endence of a measured weight of the bioreactor bag. A
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control device 31 in the base station 3 of the bioreactor system 5 is as described
above connected to the heaters 21a, 21b and to the positioning device 15 and
possibly also to a weight measuring device 33. The control device 31 can hereby turn
15 on the first heater 21a which is provided to the first part 7a of the bottom of the tray
when the first part 7a is provided in its second position and the control device 31 can
turn on both the first heater 21a and the second heater 21b when the first part 7a is
provided in its first position. Hereby a better control of the temperature in the cell
culture in the bioreactor bag can be provided.
20 57: Measuring a temperature in the bioreactor bag and controlling the heaters in the
tray in dependence of said measured temperature. Hereby even better temperature
control can be achieved.

CLAIMS
1. A tray {1; 1'; 1") configured to be provided on a base station {3) of a
bioreactor system {5), said tray {1; 1': 1") comprising a bottom {7; 7') and
surrounding side walls {9; 9') and being configured to hold a bioreactor bag
{11), said bottom {7; 7') comprising at least two bottom parts {7a, 7b; Sa,
Sb, Sc; Sa', Sb', Sci)', whereof one is a middle part {7a; Sb: Sb') of the
bottom, wherein at least one of the bottom parts {7a, 7b; Sa, Sb, Sc; Sa',
Sb', Sc') is movable into at least a first and a second position, wherein said
first position provides the bottom parts {7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc')
substantially flush with each other providing a substantially plane bottom
{7; 7') of the tray {1; 1'; 1") and said second position provides a bottom {7;
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7') of the tray having a recessed middle part {7a; Sb; Sb').
2. A tray according to claim 1, configured to be provided on a base station {3)
of a rocking bioreactor system {5).
3. A tray according to claim 1 or 2, wherein said bottom {7) comprises a first
part {7a) being the middle part and a second part {7b) surrounding said first
part {7a).
4. A tray according to any one of the preceding claims, wherein said middle
part {7a; Sb; Sb') is movable into the first and the second positions.
5. A tray according to any one of the preceding claims, wherein the bottom
parts {7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc') each comprises at least one heater
{21a, 21b; 21a', 21b', 21c').
6. A tray according to any one of the preceding claims, wherein the middle
part {7a; Sb; Sb') comprises a temperature sensor {13; 13'; 13").
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7. A tray according to any one of the preceding claims, wherein the tray (1; 1';
1") further comprises a positioning device (15) by which at least one of the
bottom parts (7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc') can be provided in the at least
two different positions.
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S. A bioreactor system comprising a base station (3) and a tray (1; 1'; 1")
according to any one of the claims 1-7.
10 9. A bioreactor system according to claim S, wherein said base station (3)
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comprises a control device (31) connected to at least one heater (21a,
21b .. ; 21a', 21b', He') in each bottom part {7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc')
of the tray (1; 1'; 1") and to the positioning device (15) of the tray, wherein
said control device (31) is arranged to control the heaters (21a, 21b; 21a',
21b', 21c') in the tray (1; 1'; 1") in dependence of the position of the at
least one bottom part (7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc') which is moved into
at least two different positions by the positioning device(15).
10. A bioreactor system according td claim S, wherein said base station (3)
comprises a weight measuring device (33) configured for measuring the
weight of a bioreactor bag (11) provided in the tray (1; 1'; 1") and said base
station (3) further comprises a control device (31) which is connected to at
least one heater (21a, 21b; 21a', 21b', 21c') in each bottom part (7a, 7b; Sa,
Sb, 8c; Sa', Sb', 8c') of the tray (1; 1'; 1") and to the weight measuring
device (33), wherein said control device {31) is arranged to control the
heaters (21a, 21b; 21a', 21b', 21c') in dependence of a weight of the
bioreactor bag measured in the weight measuring del(ice (33).
11. A bioreactor system according to claim 10, wherein the control device (31)
further is connected to the positioning device (15) and arranged to control
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the positioning device to provide at least one of the bottom parts (7a, 7b;
Sa, Sb, Sc; Sa', Sb', Sc') of the tray (1; 1'; 1") in either the first position or
the second position in dependence of the measured weight.
5 12. A bioreactor system according to any one of the claims S-11, wherein the
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control device (31) further is connected to a temperature sensor (13; 13';
13") provided in t:h'e middle part (7a, Sb; Sb') of the bottom (7; 7') of the
tray (1; 1'; 1") and wherein the control device (31) is arranged to control
the heaters (21a, 21b; 21a', 21b', 21c') in the tray (1; 1'; 1") in dependence
of the sensed temperature.
13.A method for culturing cells in a bioreactor system, said method comprising
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the steps of:
determining (51) a volume or weight of a cell culture provided in a
bioreactor bag (11) which is positioned in a tray {1; 1'; 1") in the bioreactor
system;
positioning (53) at least one bottom part of a bottom (7; 7') of said tray (1;
1'; 1") comprising at least two bottom parts (7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc')
into one of at least a first position and a second position in dependence of
said determined volume or weight, said first position providing the bottom
parts (7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc') substantially flush with each other
providing a substantially plane bottom (7; 7') of the tray (1; 1'; l")and said
second position providing a bottom (7; 7') of the tray (1; 1'; 1") having a
recessed middle part (7a; Sb; Sb').
14. A method according to claim 13, further comprising the step of:
- controlling (55) one or more heaters (21a, 21b; 21a'~ 21b', 21c') provided
in the tray (1; 1'; 1") in dependence of the position of the at least one
bottom part (7a, 7b; Sa, Sb, Sc; Sa', Sb', Sc') which is positioned into at
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least two different positions or in dependence of a measured weight of the
bioreactor bag.
15. A method according to claim 13 or 14, further comprising the step of
measuring (57) a temperature in the bioreactor bag (11) and controlling the
heaters (21a, 21b;. .2. 1a', 21b', 21c') in the tray (1; 1'; 1") in dependence of
said measured temperature .