Airlift Bioreactor

Abstract

An airlift bioreactor includes a vessel through which a culture medium can flow, a flow amplifier, and a sparger, both of which are disposed within the vessel. The flow amplifier accelerates a portion of the culture medium flowing through the flow amplifier. Then, a portion of the culture medium moves back into the vessel. The flow direction of the accelerated culture medium is different from the flow direction of the gas bubbles generated by the sparger. This allows the culture medium to have good recirculation within the vessel.

Description

[Technical Field]

[0001] The present invention relates to bioreactors, and in particular to airlift bioreactors. [Background technology]

[0002] Bioreactors are generally used to cultivate microorganisms, plant cells, and animal cells. Aeration-stirred bioreactors can be applied to microbial fermentation and plant cell cultivation. While airlift bioreactors are used to cultivate microorganisms, they are called airlift fermenters. In airlift fermenters, the aeration rate is generally 1 vvm (air volume / culture volume / minute). Because animal cell cultivation requires a low aeration rate, their aeration rate is usually as low as 0.05 vvm. At such a low aeration rate, the air and liquid flow rates are too low to create a stable circulation system. Therefore, the mass transfer rates of oxygen and nutrients are too low to achieve better cultivation efficiency. Therefore, animal cells are usually cultivated in stirred bioreactors.

[0003] An airlift bioreactor can be divided into four sections: the riser, downcomer, base, and gas separator. While airlift bioreactors are used for suspension cell culture, they can achieve a scale of 20,000 liters. While airlift bioreactors are used for microbial culture, they can even achieve a scale of 1,500,000 liters. However, culturing more viscous media in airlift bioreactors is not suitable due to their high energy dissipation rate and lower circulation rate. In animal cell culture processes, the air flow rate is too low to drive the more viscous culture media and create a suitable recirculation environment. The higher the liquid flow rate in the downcomer, the more gas bubbles are carried by the liquid and the more air retention occurs in the downcomer and riser.

[0004] Chinese Patent CN202297606U discloses a bioreactor suitable for the self-suspension culture of animal cells or suspension culture of microcarriers, which integrates stirring, aeration, and filtration and reduces shear-induced damage to cultured animal cells caused by the impeller and deep aeration process of a stirred bioreactor. Taiwan Patent M531483 discloses a biological reaction system that can improve the circulation efficiency of the culture liquid medium and has an arc-shaped inner bottom surface, a manifold located outside the column, and an aeration device connected to the column, thereby achieving airlift circulation and improving the growth efficiency of the cultured object. Summary of the Invention

[0005] To solve the above-mentioned problems, the present invention provides an airlift bioreactor suitable for a low aeration rate recirculation system, and uses an air sparger and a flow amplifier to generate power for driving gas bubbles and culture medium, thereby achieving the circulation efficiency of the airlift bioreactor.

[0006] To solve the above-mentioned problems, the present invention provides an airlift bioreactor including a flow amplifier that accelerates the flow of the culture medium so that the inner draft tube used to divide the circulating flow of the culture medium can be omitted, thereby making the airlift bioreactor flexible to use and easy to scale up, and thereby improving the efficiency of animal cell culture.

[0007] Provided herein is an airlift bioreactor comprising: a vessel having a first space through which a culture medium can flow; a flow amplifier disposed within the first space of the vessel and including an annulus, a fluid inlet disposed within the annulus, and a gap, wherein a portion of the culture medium enters the annulus through the fluid inlet and flows into the first space through the gap; and a sparger disposed within the first space of the vessel and generates a plurality of gas bubbles in the culture medium, wherein the flow direction of the gas bubbles differs from the flow direction of the portion of the culture medium that flows into the first space through the gap.

[0008] In one embodiment, the first end of the vessel is opposite the second end of the vessel, the flow amplifier is disposed near the first end, and the sparger is disposed near the second end.

[0009] In one embodiment, the airlift bioreactor further includes an inner draft tube disposed within the first space of the vessel, the culture medium flows through a second space provided by the inner draft tube, the flow amplifier annulus is disposed between the inner draft tube and the vessel, and the sparger is disposed within the second space of the inner draft tube.

[0010] In one embodiment, the airlift bioreactor further includes an inner draft tube disposed within the first volume of the vessel, the culture medium flows through a second volume provided by the inner draft tube, the flow amplifier annulus is disposed within the inner draft tube, and the sparger is disposed between the inner draft tube and the vessel.

[0011] In one embodiment, the annulus of the flow amplifier is closer to the sidewall of the vessel than the sparger.

[0012] In one embodiment, the sparger is closer to the sidewall of the vessel than the annulus of the flow amplifier.

[0013] In one embodiment, the sparger includes a plurality of annular tubes, a plurality of interconnecting channels interconnecting the air inlets, the plurality of interconnecting channels interconnecting the plurality of annular tubes, and a plurality of bubble via holes formed in the annular tubes.

[0014] In one embodiment, the annular tubes are concentrically arranged.

[0015] In one embodiment, the sparger is constructed from a metal or plastic material.

[0016] In one embodiment, a flow amplifier is used to accelerate a portion of the culture medium flowing therethrough. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a schematic perspective view of an assembled airlift bioreactor according to a first embodiment of the present invention.

[0018] [Figure 2] FIG. 1 is an exploded view schematically showing an airlift bioreactor according to a first embodiment of the present invention.

[0019] [Figure 3] FIG. 1 is a perspective top view schematically showing a sparger according to a first embodiment of the present invention.

[0020] [Figure 4] FIG. 1 is a perspective side view schematically showing a sparger according to a first embodiment of the present invention.

[0021] [Figure 5] 1 is a perspective top view schematically showing a flow amplifier according to a first embodiment of the present invention. FIG.

[0022] [Figure 6] 1 is a perspective side view schematically showing a flow amplifier according to a first embodiment of the present invention.

[0023] [Figure 7] 1 is a partial cross-sectional view schematically illustrating a flow amplifier according to a first embodiment of the present invention.

[0024] [Figure 8] FIG. 1 is a schematic perspective view of an assembled airlift bioreactor according to a second embodiment of the present invention.

[0025] [Figure 9]FIG. 10 is a schematic perspective view of an assembled airlift bioreactor according to a third embodiment of the present invention.

[0026] [Figure 10] FIG. 10 is a schematic perspective view of an assembled airlift bioreactor according to a fourth embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] FIG. 1 is a perspective view schematically illustrating an assembled airlift bioreactor according to a first embodiment of the present invention. FIG. 2 is an exploded view schematically illustrating the airlift bioreactor according to the first embodiment of the present invention. Referring to FIGS. 1 and 2, the airlift bioreactor 1 of the present invention includes a vessel 10, an inner draft tube 20, a sparger 30, and a flow amplifier 40. The vessel 10 provides a first space 11 for accommodating the inner draft tube 20, the sparger 30, and the flow amplifier 40, and a medium for culturing cells flows through the vessel 10. The liquid level 19 of the medium is higher than the flow amplifier 40. In the first embodiment, the inner draft tube 20 provides a second space 21 through which the culture medium can pass. The vessel 10 surrounds the inner draft tube 20 like a sleeve, and a portion of the first space 11 may be held between the sidewall of the vessel 10 and the sidewall of the inner draft tube 20, and the first space 11 is interconnected with the second space 21. The open first end 22 of the inner draft tube 20 is adjacent to the first end 12 of the vessel 10. The open second end 24 of the inner draft tube 20 is adjacent to the second end 14 of the vessel 10. A flow amplifier 40 is disposed on the inner draft tube 20 and adjacent to the open first end 22 of the inner draft tube 20. A sparger 30 is disposed between the vessel 10 and the inner draft tube 20 and adjacent to the open second end 24 of the inner draft tube 20. The first end is opposite the second end. The vessel 10 may include one or more interconnecting channels (not shown in the drawings) for connecting with external tubing and external devices (not shown in the drawings). A cover (not shown in the drawings) may be disposed at the first end 12 of the vessel 10 or may be designed with optional channels for connecting with external tubing and external devices. This allows the culture medium to flow back to the airlift bioreactor 1 through the external tubing and external devices connected to the vessel 10. For convenience of description, the first end will hereinafter be referred to as the top of the airlift bioreactor 1, and the second end will hereinafter be referred to as the bottom of the airlift bioreactor 1. To clearly illustrate the features of the present invention, the channels connecting the vessel 10 to the outside are simplified or omitted in the drawings. However, the present invention is not limited by the drawings.

[0028] FIG. 3 is a perspective top view schematically illustrating a sparger according to a first embodiment of the present invention. FIG. 4 is a perspective side view schematically illustrating a sparger according to a first embodiment of the present invention. Referring to FIGS. 1 to 4, by increasing the airflow area and reducing the size of gas bubbles, the sparger 30 can improve air / oxygen transfer and contribute to the driving force of the recirculation of the airlift bioreactor 1. The sparger 30 may include multiple hollow tubes 32 arranged concentrically. One or more interconnecting channels 34 may be disposed between the tubes 32 to interconnect the tubes 32 and stabilize the structure of the sparger 30. An air inlet 36 is disposed in one of the tubes 32 and is used to connect to an external air pumping device (not shown in the drawings) and to charge air from the air pumping device into the interconnected tubes 32. The charged air enters each tube 32 through the interconnecting channel 34. In one embodiment, the wall of each tube 32 has multiple bubble via holes 38. The air in the tube 32 diffuses through the bubble via holes 38 into the culture medium between the container 10 and the inner draft tube 20, generating an upward flow. The tube 32 can be made of metal, plastic, or other suitable material. The present invention does not limit the number of concentric ring tubes 32. The greater the number of concentric ring tubes 32, the greater the area available for the bubble via holes 38. The bubble via holes 38 can be distributed on the tube in a regular or irregular manner. For example, in a regular manner, the bubble via holes 38 can be distributed evenly along the circumference of the tube 32; in an irregular manner, the bubble via holes 38 can be distributed at different positions on the tube 32, and the density of the bubble via holes 38 is different in different tubes 32. Furthermore, the sizes of the bubble via holes 38 can be the same or different. Smaller bubble via holes 38 can generate smaller gas bubbles.

[0029] FIG. 5 is a perspective top view of a flow amplifier according to a first embodiment of the present invention. FIG. 6 is a perspective side view of a flow amplifier according to the first embodiment of the present invention. FIG. 7 is a cross-sectional view of a flow amplifier according to the first embodiment of the present invention. Referring to FIGS. 1, 2, and 5-7, a flow amplifier 40 includes a hollow annular body 42 and a fluid inlet 46 interconnected with a space 45 enclosed by the annular body 42. The height h of the space 45 can be adjusted according to requirements. An inner sidewall 44 of the annular body 42 has a gap 47 interconnected with the space 45 enclosed by the annular body 42. Furthermore, the inner sidewall 44 of the annular body 42 may be inclined and protrude toward the second space 21 of the inner draft tube 20, forming a longer path for the medium passing through the space 45 than the outer sidewall of the annular body 42, thereby forming a negative pressure region that can drive the medium above the flow amplifier 40 to flow downward. As shown in FIG. 7 , such a configuration of the annulus 42 allows the space 45 to be thicker adjacent the gap 47 than the area adjacent the closed end of the annulus 42. Next, the fluid inlet 46 allows the culture medium flowing back from the external tube (not shown) to enter the flow amplifier 40. Through the configuration of the space 45 surrounded by the annulus 45 and the gap 47, the flow amplifier 40 exerts a pushing force on the culture medium passing therethrough, creating a negative pressure region. The negative pressure region accelerates the intermediate flow 15 near the first end 12 and outside the inner draft tube 20, causing it to flow into the space 21 of the inner draft tube 20. Furthermore, the pushing force from the flow amplifier 40 accelerates the culture medium in the space 21 of the inner draft tube 20, creating a higher velocity downward flow 17 that reaches the bottom of the inner draft tube 20 and the vessel 10 (second end 14), which is advantageous for recirculation of the culture medium. The flow amplifier design allows the present invention to achieve an accelerating effect on more viscous culture media.

[0030] Figure 8 is a perspective view schematically illustrating an assembled airlift bioreactor according to a second embodiment of the present invention. Referring to Figures 1, 2, and 8, compared with the first embodiment shown in Figure 1, the sparger 30 of the airlift bioreactor 3 of the second embodiment is located within the inner draft tube 20 and near the open second end 24 of the inner draft tube 20; the flow amplifier 40 is located between the vessel 10 and the inner draft tube 20 and near the open first end 22 of the inner draft tube 20 and the first end 12 of the vessel 10; other components of the second embodiment are similar to those of the first embodiment and will not be repeated here. Thus, in the airlift bioreactor 3, an upward flow 13 is within the inner draft tube 10; an intermediate flow 15 flows from the interior of the inner draft tube 20 to the exterior of the inner draft tube 20; and a downward flow 17 is between the vessel 10 and the inner draft tube 20.

[0031] According to the above description, the airlift bioreactor of the present invention is provided with a sparger and a flow amplifier to establish a better, stable, and blind-spot-free circulation system. The culture medium circulates at a stable and uniform flow rate throughout the inner draft tube and all areas of the vessel. The sparger increases the airflow area in the airlift bioreactor, reduces the size of gas bubbles, thereby improving air / oxygen transfer and contributing to the recirculation driving force for the airlift bioreactor. The flow amplifier uses the difference in fluid flow to create a negative pressure area and increase the fluid flow rate.

[0032] FIG. 9 is a perspective view schematically illustrating an assembled airlift bioreactor according to a third embodiment of the present invention. See FIGS. 1, 2, 5, 7, 8, and 9. Compared to the first and second embodiments, the airlift bioreactor 2 of the third embodiment does not have an inner draft tube, and the height h of the annulus of the flow amplifier 50 is larger in the third embodiment. The relative sizes of the sparger 30 and the flow amplifier 50 may be specifically designed to differentiate the regions of upflow 13 and downflow 17 distributed within the vessel 10. When viewed from above, the projected area of ​​the sparger 30 being larger than the projected area of ​​the flow amplifier 50 may result in the upflow 13 being closer to the sidewall of the vessel 10 than the downflow 17. In other words, the ascending flow 13 of the culture medium surrounds the descending flow 17 in the first space 11 of the vessel 10; the intermediate flow 15 near the top (first end 12) flows from the sidewall of the vessel to the center of the vessel; and the intermediate flow 15 near the bottom (second end 14) flows from the center of the vessel to the sidewall of the vessel, allowing the culture medium to circulate without blind spots in the first space 11 of the vessel 10. Meanwhile, increasing the height h of the annulus of the flow amplifier 50 not only allows the space 45 of the flow amplifier 50 to accelerate the descending flow 17, but also forms a boundary between the descending flow 17 and the ascending flow 13 to prevent flow mixing. Therefore, the flow amplifier 50 can replace the inner draft tube of a conventional airlift bioreactor, simplifying the structure of the airlift bioreactor. Furthermore, omitting the inner draft tube allows the airlift bioreactor to be used flexibly and easily scaled up. Therefore, the simplified airlift bioreactor structure is more suitable for animal cell culture and other suspension cell cultures.

[0033] FIG. 10 is a perspective view schematically illustrating an assembled airlift bioreactor according to a fourth embodiment of the present invention. See FIGS. 1, 2, 5, 7, 8, 9, and 10. Compared to the third embodiment, the airlift bioreactor 4 of the fourth embodiment also does not have an inner draft tube. Viewed from above, the projected area of ​​the sparger 30 is smaller than that of the flow amplifier 50. The upward flow 13 is closer to the center of the vessel 10. In other words, the downward flow 17 of the culture medium surrounds the upward flow 13 in the first space 11 of the vessel 10; the intermediate flow 15 near the top flows from the center of the vessel to the sidewall of the vessel; and the intermediate flow 15 near the bottom flows from the sidewall of the vessel to the center of the vessel, thereby circulating the culture medium without blind spots in the first space 11 of the vessel 10. It should be noted that the airlift bioreactor 4 may include the flow amplifiers of the first and second embodiments, in which the annular bodies have different heights h. In embodiments without an internal draft tube, the position of the flow amplifier located within the vessel may be adjusted according to the culture medium level, as long as the culture medium level is higher than the flow amplifier. It is understood that the airlift bioreactor of the present invention is not limited to the use of spargers as described above, but can also be adapted to conventional bubble distribution components or devices. In embodiments without an internal draft tube, the amount of culture medium need not be limited by the height of a typical internal draft tube, resulting in increased flexibility in the design of the culture environment.

[0034] The described embodiments are merely intended to illustrate the technical ideas and features of the present invention, enabling those skilled in the art to understand, make, and use the present invention. However, these embodiments are not intended to limit the scope of the present invention. Any equivalent modifications or variations within the spirit of the present invention are also within the scope of the present invention.

Claims

1. a container having a first space through which a culture medium can flow; a flow amplifier disposed within the first space of the vessel, the flow amplifier including an annulus, a fluid inlet disposed within the annulus, and a gap, wherein a portion of the culture medium enters the annulus through the fluid inlet and flows through the gap into the first space; and a sparger disposed within the first space of the vessel and configured to generate a plurality of gas bubbles in the culture medium, wherein a flow direction of the plurality of gas bubbles is different from a flow direction of the portion of the culture medium flowing through the gap into the first space; An airlift bioreactor comprising:

2. 2. The airlift bioreactor of claim 1, wherein the first end of the vessel is opposite the second end of the vessel, the flow amplifier is located near the first end, and the sparger is located near the second end.

3. 3. The airlift bioreactor of claim 2, further comprising an inner draft tube disposed within the first space of the vessel, the culture medium flowing through a second space provided by the inner draft tube, the annulus of the flow amplifier disposed between the inner draft tube and the vessel, and the sparger disposed within the second space of the inner draft tube.

4. 3. The airlift bioreactor of claim 2, further comprising an inner draft tube disposed within the first volume of the vessel, wherein the culture medium flows through a second volume provided by the inner draft tube, the annulus of the flow amplifier disposed within the inner draft tube, and the sparger disposed between the inner draft tube and the vessel.

5. 3. The airlift bioreactor of claim 2, wherein the annulus of the flow amplifier is closer to the side wall of the vessel than the sparger.

6. 3. The airlift bioreactor of claim 2, wherein the sparger is closer to the sidewall of the vessel than the annulus of the flow amplifier.

7. 7. The airlift bioreactor of claim 1, wherein the sparger comprises a plurality of annular tubes, a plurality of interconnecting channels, and an air inlet interconnecting the plurality of interconnecting channels and the plurality of annular bodies; the plurality of interconnecting channels interconnect the plurality of annular tubes; and a plurality of bubble via holes formed on the plurality of annular tubes.

8. 8. The airlift bioreactor of claim 7, wherein the plurality of rings are arranged concentrically.

9. 8. The airlift bioreactor of claim 7, wherein the sparger is made of a metal or plastic material.

10. 7. The airlift bioreactor of claim 1, wherein the flow amplifier is used to accelerate the culture medium through the flow amplifier.

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