CN107988074A - The full suspension cell culture reactor of 6000L serum-frees - Google Patents
The full suspension cell culture reactor of 6000L serum-frees Download PDFInfo
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- CN107988074A CN107988074A CN201810074430.6A CN201810074430A CN107988074A CN 107988074 A CN107988074 A CN 107988074A CN 201810074430 A CN201810074430 A CN 201810074430A CN 107988074 A CN107988074 A CN 107988074A
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- cell culture
- serum
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- agitating
- tank body
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- 238000004113 cell culture Methods 0.000 title claims abstract description 38
- 239000000725 suspension Substances 0.000 title claims abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 43
- 239000001301 oxygen Substances 0.000 claims abstract description 43
- 239000003513 alkali Substances 0.000 claims abstract description 17
- 238000003860 storage Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 12
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 239000001569 carbon dioxide Substances 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- 238000003760 magnetic stirring Methods 0.000 claims description 2
- 239000013589 supplement Substances 0.000 claims description 2
- 239000007789 gas Substances 0.000 abstract description 23
- 238000005457 optimization Methods 0.000 abstract description 4
- 230000004083 survival effect Effects 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 3
- 238000012546 transfer Methods 0.000 abstract description 3
- 238000010008 shearing Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 13
- 238000004140 cleaning Methods 0.000 description 11
- 235000015097 nutrients Nutrition 0.000 description 11
- 238000013019 agitation Methods 0.000 description 7
- 238000010586 diagram Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000003833 cell viability Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 239000012930 cell culture fluid Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000007373 indentation Methods 0.000 description 3
- 238000011169 microbiological contamination Methods 0.000 description 3
- 230000001464 adherent effect Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940125644 antibody drug Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000000739 chaotic effect Effects 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- 241000743339 Agrostis Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001062009 Indigofera Species 0.000 description 1
- 241000580063 Ipomopsis rubra Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000005723 virus inoculator Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
- C12M27/02—Stirrer or mobile mixing elements
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
- C12M27/18—Flow directing inserts
- C12M27/20—Baffles; Ribs; Ribbons; Auger vanes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/06—Nozzles; Sprayers; Spargers; Diffusers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/26—Means for regulation, monitoring, measurement or control, e.g. flow regulation of pH
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
- C12M41/32—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of substances in solution
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Sustainable Development (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Clinical Laboratory Science (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
The present invention relates to the full suspension cell culture apparatus field of serum-free, in particular to a kind of full suspension cell culture reactor of 6000L serum-frees, including tank body；The tank interior is provided with microvesicle air-breather and agitating device；The tank skin of the tank body is internally provided with baffle；Lye injector head is provided with above the tank skin of the tank body, the lye injector head is connected by valve with storage alkali container；Top layer air inlet is additionally provided with above the tank skin of the tank body.Cell culture reactor provided by the present invention has carried out many optimization for the culture feature of big volume reactor, alkali system especially is mended to microvesicle aerating system, bioreactor and gas handling system is optimized, so that the reactor is very suitable for the full suspension cell culture of serum-free, it can realize that efficient oxygen transfer, cell and nutriment under low-shearing force uniformly mix, and pH in tank is effectively adjusted, cell survival rate is high.
Description
Technical field
The present invention relates to cell cultivation equipment field, in particular to a kind of full suspension cell culture of 6000L serum-frees
Reactor.
Background technology
Bioreactor is the core equipment of mass cell suspension culture, can effectively increase cell-unit volume
Culture density, is the mainstay of the large-scale production of such product.The biotechnologies such as the U.S., Switzerland, Germany power has established
The bioreactor research and development of comparatively perfect and industrialization technology system, can develop with production efficiency and product quality height, production
The advantages such as cost is low, and adapt to the commercialization bioreactor of different kind organism culture.In the world, for the culture production that suspends entirely
The bioreactor research of antibody is towards high-performance, extensive, intelligent direction development.The companies such as Abec, GEA GROUP are moved
The market scale of thing cell reactor (monomer) has reached more than 10 hundred million Euros.Switzerland dragon husky (Lonza), GlaxoSmithKline PLC (GSK)
All establish the zooblast reactor production line of ten thousand upgradings, the bioreactor utilization rate of bio-pharmaceutical industry one after another Deng company
Rise to more than 80%.
China has been that the largest production state of world's vaccine product and maximum use state, and with annual 15% rate delivery
Increase；In recent years, the development of antibody drug and the market demand also increase substantially.To improve production efficiency and product quality, effectively drop
Low production cost, changes the backwardness production technology with spinner culture cell, is badly in need of the zooblast of kilolitre level above production scale
Cultivation reactor.But bioreactor scale domestic at present, mostly in below 1000L, comprehensive performance and production efficiency are not
Height, technical merit have a long way to go compared with developed countries, and kilolitre level scale above bioreactor is manufactured almost by overseas enterprise
(Switzerland Bio, U.S. NBS, France PG etc.) is monopolized, and forms tight technical barrier, its scale amplifying technique and equipment centering
State's limitation outlet.Therefore, the research and development and industrialization of zooblast suspension cultivation reactor are carried out, to China's vaccine and antibody drug
Production has very important practical significance.
In view of this, it is special to propose the present invention.
The content of the invention
It is an object of the invention to provide a kind of full suspension cell culture reactor of 6000L serum-frees, to solve existing skill
Cell culture reactor volume used is universal (predominantly staying in below 3000L at present) less than normal in art, caused by low output, energy
Consume big height, labour demand, product quality heterogeneity, pollute the problems such as being difficult to control.
In order to realize the above-mentioned purpose of the present invention, spy uses following technical scheme：
The full suspension cell culture reactor of 6000L serum-frees provided by the present invention, including tank body；
The tank interior is provided with microvesicle air-breather and agitating device；
The tank skin of the tank body is internally provided with baffle；
Lye injector head is provided with above the tank skin of the tank body, the lye injector head is by valve with storing up alkali container phase
Even；
Top layer air inlet is additionally provided with above the tank skin of the tank body.
Compared with prior art, cell culture reactor provided by the present invention is directed to the culture feature of big volume reactor
Many optimization is carried out, especially to being that microvesicle aerating system, bioreactor benefit alkali system and gas handling system carry out
Optimization so that the reactor is very suitable for the culture of suspension cell, can realize efficient oxygen transfer under low-shearing force, cell and
Nutriment uniformly mixes, and effectively adjusts pH in tank, and cell survival rate is high.
Brief description of the drawings
, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution of the prior art
Embodiment or attached drawing needed to be used in the description of the prior art are briefly described, it should be apparent that, in describing below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
Put, other attached drawings can also be obtained according to these attached drawings.
Fig. 1 is shown by the structure for the full suspension cell culture reactor of 6000L serum-frees that one embodiment of the invention provides
It is intended to；
The schematic diagram for the benefit alkali system that Fig. 2 is provided by one embodiment of the invention；
The structure diagram for the microvesicle air-breather that Fig. 3 is provided by one embodiment of the invention；
The schematic diagram for the connecting rod that Fig. 4 is provided by one embodiment of the invention；
The schematic diagram that the microvesicle air-breather inlet port that Fig. 5 is provided by one embodiment of the invention amplifies；
The schematic diagram that the microvesicle air-breather notch end that Fig. 6 is provided by one embodiment of the invention is amplified；
The top view for the full suspension cell culture reactor of 6000L serum-frees that Fig. 7 is provided by one embodiment of the invention；
The knot for the full suspension cell culture chamber lid of 6000L serum-frees that Fig. 8 is provided by one embodiment of the invention
Structure schematic diagram；
The schematic diagram for amplifying culture systems step by step that Fig. 9 is provided by one embodiment of the invention.
Reference numeral：
Bioreactor tank body A；Agitation Tank B；Higher level's tank body C；
Microvesicle air-breather 1；Air admission hole 101；Micropore 102；Attachment device 103；Sticking department 1031；Protuberance 1032；Even
Extension bar 104；Plug 105；
Agitating device 2；Agitating shaft 201；Agitating paddle 202；
Power set 3；Baffle 4；
Lye injector head 5；Valve 501；
Top layer air inlet 6；Exhaust outlet 7；For air assembly 8；For carbon dioxide plant 9；Apparatus of oxygen supply 10；
Chuck temperature-controlling system 11；.
Mend alkali mouth 12；The malicious access port 13 of kind；Kind cell entry 14；First spare mouth 15；Culture medium adds mouth 16；CIP
17-1；CIP 17-2；Second spare mouth 18；Lamp mirror mouth 19；Gauge port 20；Mirror mouth 21 and manhole 22.
Embodiment
Technical scheme is clearly and completely described below in conjunction with the drawings and specific embodiments, but
Be it will be understood to those of skill in the art that following described embodiment is part of the embodiment of the present invention, it is rather than whole
Embodiment, is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.Based on the embodiments of the present invention, ability
Domain those of ordinary skill all other embodiments obtained without making creative work, belong to guarantor of the present invention
The scope of shield.The person that is not specified actual conditions in embodiment, the condition suggested according to normal condition or manufacturer carry out.Agents useful for same
It is the conventional products that can be obtained by commercially available purchase or production firm person is not specified in instrument.
In the description of the present invention, it is necessary to explanation, term " " center ", " on ", " under ", "left", "right", " vertical ",
The orientation or position relationship of the instruction such as " level ", " interior ", " outer " be based on orientation shown in the drawings or position relationship, merely to
Easy to describe the present invention and simplify description, rather than instruction or imply signified device or element must have specific orientation,
With specific azimuth configuration and operation, therefore it is not considered as limiting the invention.In addition, term " first ", " second ",
" the 3rd " is only used for description purpose, and it is not intended that instruction or hint relative importance.
In the description of the present invention, it is necessary to illustrate, unless otherwise clearly defined and limited, term " installation ", " phase
Even ", " connection " should be interpreted broadly, for example, it may be being fixedly connected or being detachably connected, or be integrally connected；Can
To be mechanical connection or be electrically connected；It can be directly connected, can also be indirectly connected by intermediary, Ke Yishi
Connection inside two elements.For the ordinary skill in the art, with concrete condition above-mentioned term can be understood at this
Concrete meaning in invention.
The present invention relates to a kind of full suspension cell culture reactor of 6000L serum-frees, as shown in Figure 1, including tank body A；
The tank body A is internally provided with microvesicle air-breather 1 and agitating device 2；
The tank skin of the tank body A is internally provided with baffle 4；
As shown in Fig. 2, being provided with lye injector head 5 above the tank skin of the tank body A, the lye injector head 5 passes through valve
Door 501 is connected with storage alkali container；
Top layer air inlet 6 is additionally provided with above the tank skin of the tank body A.
Preferably, the tank skin of the tank body A is long tubular, and tank base is arc-shaped outwards to arch upward.
Preferably, the bottom of the tank body A is provided with fluid distributing hole, and the leakage fluid dram is used to discharge and/or blowdown.
Preferably, the tank body A is additionally provided with temperature-controlling system；It is furthermore preferred that the temperature-controlling system is chuck temperature-controlling system
11。
It is thin that the several systems set separately below out of tank illustrate that 6000L serum-frees provided by the present invention suspend entirely respectively
The structure of born of the same parents' cultivation reactor.
Preferably, culture medium inlet and/or culture transferring mouth are provided with above the tank skin of the tank body A；
The culture medium inlet is connected with Agitation Tank B, and the culture transferring mouth is connected with higher level's tank body C.
As shown in figure 9, the cell culture process of the present invention is amplification technique step by step.During cell culture, preferably can from 5L →
25L → 125L → 600L → 1000L → 3000L → 6000L reactors are amplified step by step.
Thus higher level's tank body of 6000L reactors is preferably 3000L tank bodies.
It is needing it is noted that in the present invention, " the full suspension cell culture reactor of 6000L serum-frees " be only it is prominent this
Invention reactor is suitable for big volume culture cell, the particularly culture of suspension cell, but " 6000L " is not represented to reactor
Protection domain has restriction effect.In fact, the inventive concept of the present invention and content are suitable in the range of 600L~8000L volumes
Bioreactor, be preferably 3000L~6000L.
Lid is provided with the top of the cell culture reactor；Preferably, exhaust outlet 7 is provided with the lid；
Preferably, as shown in figure 8, the lid Shanghai is provided with the one or more under shed/device：
Mend the malicious access port 13 (being used for virus inoculation) of alkali mouth 12, kind, kind cell entry 14, the first spare mouth 15, culture medium
Add mouth 16, CIP 17-1 and CIP 17-2, the second spare mouth 18, lamp mirror mouth 19, gauge port 20, mirror mouth 21 and manhole
22。
CIP 17-1 and CIP 17-2 are a parts for CIP cleaning systems, and CIP cleaning systems are commonly called as cleaning system on the spot,
Also known as cleaning positioning or positioning cleaning (cleaning in place).Cleaning refers to not have to dismantle or mobile device on the spot, that is, adopts
With high temperature, the cleaning solution of high concentration, forceful action is subject to apparatus, the contact surface with product is cleaned up, for defending
Raw rank requires the cleaning of stringenter production equipment, purification.
One, microvesicle aerating systems
Microvesicle aerating system mainly includes microvesicle air-breather 1, agitating device 2 and baffle 4；Preferably, the tank body A
Inside it is additionally provided with dissolved oxygen amount detecting device；Preferably, the dissolved oxygen amount detecting device has two.
Double dissolved oxygen amount detecting devices ensure the accuracy of DO in tank by the way of 2 DO electrodes, even if an and dissolved oxygen
Amount detecting device, which goes wrong, needs the operating that equipment will not be influenced during maintenance.
Wherein, ventilate in the microvesicle air-breather 1 switching of body, agitating device 2 rotating speed can be by an electronics
Control device controls, which controls the operating of above device by reading dissolved oxygen amount detecting device and analyzing.
As shown in figure 3, the microvesicle air-breather 1 is with not closed circle ring jaggy；The microvesicle air-breather 1
Ring wall on be provided with an air inlet 101 and several equally distributed micropores 102；The ring body of the microvesicle air-breather
Inner hollow, the micropore 102 are communicated through ring wall with the hollow cavity of the ring body.
Carried out in the microvesicle air-breather 1 in use, being injected gas such as oxygen by the air admission hole 101, one
Under fixed air pressure, oxygen is full of whole microvesicle air-breather by the ring body of inner hollow, and is discharged by the micropore 102.The dress
Put simple in structure, thus micropore is not easy to plug, and is safeguarded also more convenient.The structure of annular increases gas distribution area, can be more equal
It is even that oxygen is released in cell culture fluid.
Preferably, a diameter of 0.05mm~0.2mm of the micropore 102.
For the holdup time using oxygen during the device in nutrient solution can be increased as much as possible, it is preferred that described micro-
The side of plane where hole 102 is distributed in the circular rings, so in use, can increase being set down where micropore 102
The advanced distance of oxygen floating.
According to ventilation demand needed for, the micropore 102 can according to S-shaped or it is Z-shaped arranged, may be set to be more
Row.In order to reduce technology difficulty, it is preferred that the micropore 102 is arranged along the ring wall into a row；It is furthermore preferred that the micropore
102 distance apart from 1 center of circle of microvesicle air-breather is equal.
Preferably, microvesicle air-breather as described above, the air inlet 101 are oppositely arranged with the notch, it is described into
Gas port 101 is fixed on bioreactor bottom by attachment device 103.
Preferably, microvesicle air-breather as described above, the air inlet 101 connect one by the attachment device 103
A hollow connecting rod 104 is fixed on bioreactor bottom；
Preferably, as shown in figure 4, the connecting rod 104 is the L-shaped structure of middle bent；It is furthermore preferred that the connecting rod
The angle of 104 middle bents is 120 °~160 °；It can also select 130 °~150 °, or 140 °.
The angle of 104 middle bent of connecting rod is 120 °~160 °, i.e., when one section is connected with the microvesicle air-breather,
The other end can horizontal plane upwarped in 20 °~60 ° angles, it is as agitating paddle lower section, and not with stirring by microvesicle air-breather that it, which is acted on,
Mixing paddle has scraping collision.104 opposite side of connecting rod and reactor can silk mouth nut be connected, convenient disassembly.
The microvesicle air-breather 1 is cleaned for convenience, it is preferred that the ring body of the microvesicle air-breather 1 can
Dismantle as two semi-rings；Cleaning way can be to be cleaned by ultrasonic.
In order to preferably simplify structure, it is preferred that the ring body dismounting of the microvesicle air-breather 1 is two semi-rings
Detachment point is arranged near the air inlet；It is furthermore preferred that as shown in figure 5, the attachment device 103 is three-way device, one end
Communicated with the connecting rod 104, in addition both ends are then communicated with two semi-rings respectively, and with least one activity in two semi-rings
Connection.Active connection place can be attached by a connector, as shown in figure 5, the connector is by sticking department 1031 and protrudes
Portion 1032 forms；The two can be connected by the form of lock, may be alternatively provided as magnetic connection.
Preferably, microvesicle air-breather as described above, the ring body end of 1 indentation, there of microvesicle air-breather are to beat
The structure opened；It is furthermore preferred that as shown in fig. 6, the ring body end set of the microvesicle air-breather indentation, there has dismountable block up
First 105.In an embodiment of the invention, the circle diameter of the microvesicle air-breather 1 is 570mm, the length of indentation, there
Spend has 2.5mm, 102 a diameter of 0.05mm~0.2mm of micropore for 80mm, 102 spacing of micropore.
As shown in Figure 1, the air inlet 101 of the microvesicle air-breather 1 is respectively by valve and apparatus of oxygen supply 10, for dioxy
Change carbon device 9 and be connected for air assembly 8；
Wherein, preferably above-mentioned gas are sterile compressed gas state when being stored in above-mentioned feeder.Oxygen and
Carbon dioxide is the common gas in cell culture.
Preferably, the agitating device 2 includes agitating shaft 201 and agitating paddle 202；
The agitating shaft 201 is perpendicular to horizontal plane and is fixed on tank bottom, and the agitating paddle 202 is arranged at the agitating shaft
On 201, the bottom of the agitating shaft 201 is connected with power set 3；
The microvesicle air-breather 1 is arranged at the underface of the agitating paddle 202, around the agitating shaft 201；It is preferred that
, the micropore 102 of the microvesicle air-breather 1 is set downward.
Preferably, the power set 3 are magnetic stirring apparatus.
Zooblast reactor is very stringent to sterility requirements, operation and the mechanically-sealing apparatus such as charging, sterilizing and inoculation
Deng may all bring microbiological contamination risk, once causing inside reactor microbiological contamination, huge economic loss is caused.The present invention develops pin
There is completely isolated magnetic drives stirring system to the bioreactor of 6000L animal cell cultures, its power transmission
The electromagnetic force of magnetic cylinder generation is fully relied on, has thoroughly prevented the microbiological contamination caused by sealing problem.
The microvesicle air-breather 1 is inserted in around the agitating shaft 201 by its notch.
Preferably, the agitating paddle 202 has three, and the first agitating paddle, second are from top to bottom followed successively by from the agitating shaft
Agitating paddle and the 3rd agitating paddle, the second agitating paddle agitated liquid are moved from top to bottom；The first and third stirring paddle stirring
Liquid moves from bottom to top.
By above-mentioned set-up mode, the oxygen discharged in microvesicle air-breather 1 can be confined between first and third agitating paddle
(it is considered that spiral liquid stream is formd between three agitating paddles), so that it is resident in nutrient solution to extend bubbles of oxygen
Time, increases the utilization rate of oxygen.
Preferably, the agitating paddle 202 is turbine type agitating paddle or pusher agitating paddle；
The blade of pusher agitating paddle has certain radian, enables to nutrient solution to form axial flowing, and mixing is stirred
It is more favourable with suspension effect.
It is furthermore preferred that the agitating paddle 202 is four leaf push type agitating paddles.
Preferably, the rake angle degree of the agitating paddle is 40 °~60 °；More preferably 50 °；Since each agitating paddle makes
The direction of motion of liquid stream is different, thus the preferably deflection of the deflection angle of second agitating paddle and first and third agitating paddle
Angle mirror symmetry.
Preferably, the ratio of the paddle footpath of the agitating paddle and tank diameter is 0.2~0.7, more preferably 0.3~0.5.
Preferably, the rotating speed of the agitating paddle is 30~70rpm.
Preferably, baffle 4 is additionally provided with inside the tank skin of the tank body A, the baffle 4 is perpendicular to horizontal plane；
It is furthermore preferred that the bottom of the baffle 4 is concordant with the 3rd agitating paddle, top is higher than the liquid level of cell culture fluid
Highly.
Preferably, the baffle 4 has 3~5, more preferably 4, and be uniformly distributed on the tank skin of the tank body；
Preferably, as shown in fig. 7, the baffle 4 deviate its with 30 ° of Grain lines where the tank body A tie points~
40 °, and each baffle yawing moment is consistent；
Preferably, the width of the baffle is 1/13~1/10 tank diameter.
It is furthermore preferred that each baffle yawing moment is consistent with the direction of rotation of agitating paddle；Such as the direction of rotation of agitating paddle is
Counterclockwise, then the yawing moment of the baffle 4 just as shown in fig. 7, being deflected in obtuse angle along current counterclockwise.
Due to second agitating paddle and first and third agitating paddle by the direction of motion of aqueous agitation on the contrary, nutrient solution
When being stirred liquid flow direction can than three agitating paddles equidirectional (upwards agitation) it is more chaotic, therefore, this agitation
Although mode can greatly increase dissolved oxygen amount, it is also easier to, because the chaotic impact of liquid stream forms turbulent flow, in turn result in thin at the same time
Born of the same parents crush death.Based on this reason, the present invention is provided with baffle 4, and its deflection angle is consistent with the direction of rotation of agitating paddle, gear
Plate 4 can play the role of water conservancy diversion, due to cell culture fluid bioreactor to close at tank skin flow velocity maximum, thus on tank skin
Baffle 4 can slow down flow rate of liquid, guiding liquid flow direction, and then effectively avoid the generation of turbulent flow herein.
For example, in one embodiment, bioreactor tank body is 6000L tank bodies, microvesicle air-breather used is Fig. 3
Shown in circular air-breather.As shown in Figure 1, bottom is provided with agitating device in tank, the agitating device includes stirring
Axis and agitating paddle, the agitating shaft is perpendicular to horizontal plane and is fixed on tank bottom, and the agitating paddle is arranged on the agitating shaft, institute
The bottom for stating agitating shaft is connected with power set；On agitating shaft set three agitating paddles, be followed successively by from down to up the first agitating paddle,
Second agitating paddle and the 3rd agitating paddle.Rotating speed is 40 turns/min, is to rotate counterclockwise.The second agitating paddle agitated liquid
Move from top to bottom；The first and third agitating paddle agitated liquid is moved from bottom to top.The rake angle degree of agitating paddle is 50 °,
The ratio of paddle footpath and tank diameter is 0.4.On tank skin set four baffles, the yawing moment of baffle be deviate counterclockwise its with it is described
35 ° of Grain lines where tank body tie point, the width of baffle is 1/12 tank diameter.This embodiment is arranged to experimental group, in this base
Comparative example is set on plinth；
Comparative example 1：Differed only in experimental group, remove baffle.
Comparative example 2：Differed only in experimental group, baffle is set perpendicular to tank body.
Comparative example 3：Differed only in experimental group, three agitating paddles stir nutrient solution upwards, and remove baffle.
Comparative example 4：Differed only in experimental group, which is conventional cylinder, and inside has porous
Net structure.
Cultivated cell is mdck cell, after being cultivated 5 days for 1,800,000/ml by cell culture density, detects following data：
Note：Cell survival rate=(total number of cells-dead cell number) ÷ total number of cells × 100%, platform phenol indigo plant decoration method meter
Calculate.
It was found from comparative example 1 and 2, baffle plate setting mode is incorrect or removes baffle, although flow of oxygen can be reduced,
More violent turbulent flow can be formed, causes Cell viability to be greatly lowered.From comparative example 3, three agitating paddles will culture
When liquid stirs upwards, it is resident and is shortened in nutrient solution due to oxygen, thus oxygen utilization rate declines, oxygen consumption total amount rises substantially；
It is uniformly dispersed in addition, the change of aqueous agitation mode is also unfavorable for oxygen, it is possible to cause the decline of local oxygen concentration, cause
Cell viability reduces.From comparative example 4, routine microvesicle air-breather of the prior art, since gas distribution is uneven, same meeting
Cell viability is reduced, and since the decline of oxygen dissolved efficiency causes the rise of flow of oxygen.Further, since the prior art is adopted
Conventional microvesicle air-breather not easy cleaning, can be blocked in the normal time using rear micropore, if increasing bleed pressure at this time,
Returning again causes the ventilation gas flow hole rate of outflow that does not block too fast, causes gas effciency to reduce, and is especially reacted in 6000L
During device culture cell, under the maximum mixing speed for not damaging cell microvesicle air inlet can only supply the dissolved oxygen of culture 0-20%
Amount, the dissolved oxygen amount for the 30-50% being unable to reach needed for cell growth.
In conclusion becoming larger with overall volume, cell cloth oxygen difficulty skyrockets.Due to always not used before the country
Large capacity bioreactor (6000L) cultivates the precedent of cell, thus lacks be directed to large capacity bioreactor in the prior art
The optimization and adjustment of equipment.Present invention applicant adapts to transformation stirring system by adjusting air-breather, it is achieved thereby that greatly
The uniform gas distribution of volume bioreactor, also reduces the dosage of oxygen, improves the survival rate of cell.
2nd, bioreactor mends alkali system
Mending alkali system mainly includes lye injector head 5, and agitating device 2 as described above and baffle 4.Preferably,
PH meter is additionally provided with the tank body A；Preferably, the pH meter has two.
Double pH meters ensure the accuracy of pH in tank by the way of 2 pH electrodes, even and if a pH meter go wrong need
The operating of equipment will not be influenced when overhauling.
Wherein, the opening and closing of the injection of lye injector head 5 and the control of emitted dose, the rotating speed of agitating device 2 can be by one
A electronic control unit control, the control device control the operating of above device by reading pH meter and analyzing.
As shown in Fig. 2, lye injector head 5 is spurted into lye in the culture medium of tank body with pulsed, it is fast in agitating device 2
Speed stirs and evenly mixs, can to avoid local pH it is excessive caused by cellular damage.
It is intermittent to open the valve 501 so that the lye when mend alkali operation using equipment as described above
5 pulsed of injector head sprays lye, while opens the agitating device 2 so that the lye of supplement mixes rapidly completely.
Preferably, the lye is the NaHCO of 0.8mol/L~1.2mol/L3Solution；The more preferably NaHCO of 1mol/L3
Solution.
Preferably, the valve 501 is opened once at interval of 4.5s~5.5s, opens 50ms~200ms every time；More preferably
, the valve 501 is opened once at interval of 5s, opens 100ms~150ms every time.
Preferably, when spraying lye, the fluid pressure in the lye injector head 5 is 0.08MPa~0.12MPa；It is more excellent
Choosing, the fluid pressure in the lye injector head 5 is 0.10MPa.
Preferably, when mend alkali operation, the rotating speed of the agitating device 2 is 30rpm~70rpm；It is furthermore preferred that institute
The rotating speed for stating agitating device 2 is 50rpm.
The switch time of concentration of lye, valve 501, the pressure in the rotating speed and lye injector head 5 of agitating device 2 (are matched somebody with somebody
The outlet diameter of injector head is closed, what is actually limited is the lye amount sprayed every time) it is the biology that applicant combines the present invention
Reactor tank mends what alkali device structure was especially set, to can quickly mix lye, to reduce its injury to cell.
In one embodiment, bioreactor tank body is 6000L tank bodies, cultivates floating type mdck cell.On tank skin
Side is provided with lye injector head, and lye injector head passes through valve and storage 1.0mol/L NaHCO3The container of solution is connected, valve
Opened once at interval of 5s, open 120ms every time.When spraying lye, the fluid pressure in the lye injector head is 1.0MPa,
The a diameter of 2mm of jet port of lye injector head.Bottom is provided with microvesicle air-breather and is used to lead to oxygen in tank, and bottom is also set in tank
Agitating device is equipped with, the agitating device includes agitating shaft and agitating paddle, and the agitating shaft is perpendicular to horizontal plane and is fixed on tank
Bottom, the agitating paddle are arranged on the agitating shaft, and the bottom of the agitating shaft is connected with power set；Three are set on agitating shaft
A agitating paddle, is followed successively by the first agitating paddle, the second agitating paddle and the 3rd agitating paddle, is to rotate clockwise from top to bottom；It is described
Second agitating paddle agitated liquid is moved from top to bottom；The first and third agitating paddle agitated liquid is moved from bottom to top.Agitating paddle
Rake angle degree is 50 °, and the ratio of paddle footpath and tank diameter is 0.4.When lye is added dropwise, rotating speed of agitator is 50 turns/min；Just
When often culture cell leads to oxygen, rotating speed of agitator is 40 turns/min.Four baffles are set on tank skin, and the yawing moment of baffle is suitable
Hour hands deviate itself and 35 ° of Grain lines where the tank body tie point, and the width of baffle is 1/12 tank diameter.This embodiment is set
For experimental group, comparative example is set on this basis；
Comparative example 1：Differed only in experimental group, remove baffle.
Comparative example 2：Lye injector head is removed, add alkaline methods replace with side wall of the prior art and formula is added dropwise；Agitating paddle
Rotating speed is always 40 turns/min.
Comparative example 3：Differed only in experimental group, baffle is set perpendicular to tank body.
Comparative example 4：Differed only in experimental group, three agitating paddles stir nutrient solution upwards, and remove baffle.
Cultivated by cell culture density for 1,800,000/ml with batch mdck cell 5 days, by adding alkali to maintain, pH is constant to be
6.8-7.2, detects following data：
It was found from comparative example 1 and 2, mode is added dropwise in different lye has large effect to Cell viability.It is adherent that drop is added dropwise
The mode added is also continuous, and it is excessive to often result in concentration of lye at dropwise addition, thus can cause more cell death.If accelerate
Rotating speed, then also result in the increase that mechanical damage causes cell mortality；Also can not in addition, dosage is added dropwise in adherent dropwise addition every time
Control, can not precisely adjust pH.It was found from comparative example 1 and 3, baffle plate setting mode is incorrect or removes baffle, although can reduce
Flow of oxygen, but more violent turbulent flow can be formed, cause Cell viability to be greatly lowered.From comparative example 4, three stirrings
When paddle stirs nutrient solution upwards, it is resident and is shortened in nutrient solution due to oxygen, thus oxygen utilization rate declines, oxygen consumption total amount
It is soaring obvious；It is uniformly dispersed in addition, the change of aqueous agitation mode is also unfavorable for oxygen, since the present invention is using the life of big volume
Thing reactor, the mixing difficulty of oxygen are consequently increased, it is possible to are caused the decline of local oxygen concentration, caused Cell viability to drop
It is low.
In conclusion lye additional way of the present invention by using pulsed, arrange in pairs or groups the agitating device that especially sets and
Baffle, can effectively less stirring when turbulent flow generation, quickly mix lye, so as to reduce because mechanical damage and local lye are dense
Cell death caused by spending height.In addition, surprisingly, unique agitating paddle rotation mode can also extend staying for oxygen
The time is stayed, so as to effectively reduce the consumption of oxygen.
3rd, gas handling system
Gas handling system mainly includes top layer gas handling system and deep layer gas handling system.As shown in Figure 1, deep layer gas handling system is main
Including for air assembly 8, microvesicle air-breather 1, exhaust outlet 7；Top layer gas handling system mainly include for air assembly 8, top layer into
Gas port 6, exhaust outlet 7.
The air that microvesicle air-breather 1 is passed through constitutes the deep layer gas handling system of cell culture reactor, the compressed air
The mode of being passed through can extend the flow path of air in the medium, increase the transfer amount of carbon dioxide and ammonia.
The method of the invention is also passed through compressed air on liquid phase top layer, can avoid lower compression air in flow process
Dissolving in the medium, increases the spilling of lower compression air.Preferably, top layer air inlet 6 be arranged on tank skin side be higher than with
40~60 centimeters air inlet of liquid level.In side into compressed air, top exhaust over there, makes compressed air in ullage institute
The distance walked is elongated, can carry out more carbon dioxide；It can ensure top layer air inlet not higher than 40~60 centimeters of liquid level
Directly nutrient solution is arrived in piping and druming, and then prevents and foam is produced in cell cultivation process.
Preferably, top layer air inlet and during deep layer air inlet, the pressure of compressed air is 0.02~0.06MPa, more preferably
0.04MPa, the compressed air are purified by two-stage air filter.
Gas handling system of the present invention combines top layer gas handling system and deep layer gas handling system, can effectively drive training
Ammonia and excessive carbon dioxide in nutrient solution, keep the culture environment stablized in cell cultivation process.
Finally it should be noted that：The above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Pipe is described in detail the present invention with reference to foregoing embodiments, but it will be understood by those of ordinary skill in the art that：Its
It can still modify to the technical solution described in foregoing embodiments, either to which part or all technical characteristic
Carry out equivalent substitution；And these modifications or replacement, the essence of appropriate technical solution is departed from various embodiments of the present invention skill
The scope of art scheme.
Claims (10)
1. a kind of full suspension cell culture reactor of 6000L serum-frees, it is characterised in that including tank body；
The tank interior is provided with microvesicle air-breather and agitating device；
The tank skin of the tank body is internally provided with baffle；
Lye injector head is provided with above the tank skin of the tank body, the lye injector head is connected by valve with storage alkali container；
Top layer air inlet is additionally provided with above the tank skin of the tank body.
2. the full suspension cell culture reactor of 6000L serum-frees according to claim 1, it is characterised in that the microvesicle
Air-breather is with not closed circle ring jaggy, is provided with an air inlet on ring wall and several are equally distributed micro-
Hole；The ring body inner hollow of the microvesicle air-breather, the micropore are communicated through ring wall with the hollow cavity of the ring body；
Preferably, the side of plane where the micropore is distributed in the circular rings；It is furthermore preferred that the micropore is along the ring
Wall is arranged into a row；It is furthermore preferred that distance of the micropore apart from the microvesicle air-breather center of circle is equal；
Preferably, the air inlet is oppositely arranged with the notch, and the air inlet is fixed on biological respinse by attachment device
Device bottom.
3. the full suspension cell culture reactor of 6000L serum-frees according to claim 2, it is characterised in that the air inlet
Mouth is connected by valve with apparatus of oxygen supply, for carbon dioxide plant and for air assembly respectively；
Preferably, it is described to be also connected for air assembly by valve with the top layer air inlet.
4. the full suspension cell culture reactor of 6000L serum-frees according to claim 1, it is characterised in that the stirring
Device includes agitating shaft and agitating paddle；
The agitating shaft is perpendicular to horizontal plane and is fixed on tank bottom, and the agitating paddle is arranged on the agitating shaft, the stirring
The bottom of axis is connected with power set；
Preferably, the underface that microvesicle air-breather is arranged at the agitating paddle is stated.
5. the full suspension cell culture reactor of 6000L serum-frees according to claim 4, it is characterised in that the stirring
Paddle has three, and the first agitating paddle, the second agitating paddle and the 3rd agitating paddle are from top to bottom followed successively by from the agitating shaft；Described
Two agitating paddle agitated liquids are moved from top to bottom；The first and third agitating paddle agitated liquid is moved from bottom to top；
Preferably, the agitating paddle is turbine type agitating paddle or pusher agitating paddle；
It is furthermore preferred that the agitating paddle is four leaf push type agitating paddles.
6. the full suspension cell culture reactor of 6000L serum-frees according to claim 4, it is characterised in that the stirring
The bottom of axis is connected with power set；
Preferably, the power set are magnetic stirring apparatus.
7. the full suspension cell culture reactor of 6000L serum-frees according to claim 1, it is characterised in that the baffle
There are 3~5, more preferably 4, and be uniformly distributed on the tank skin of the tank body；
Preferably, the baffle deviates itself and 30 °~40 ° of Grain lines where the tank body tie point, and each baffle deflects
Direction is consistent.
8. the full suspension cell culture reactor of 6000L serum-frees according to claim 1, it is characterised in that the 6000L
It is intermittent to open the valve when the full suspension cell culture reactor of serum-free mend alkali operation so that the lye injection
Head pulsed injection lye, while the agitating device is opened so that the rapid mixing of the lye of supplement is complete；
Preferably, the lye injector head front end endoporus aperture is 1mm~3mm；
Preferably, the lye is the NaHCO of 0.8mol/L~1.2mol/L3Solution；
Preferably, the valve is opened once at interval of 4.5s~5.5s, opens 50ms~200ms every time；
Preferably, when spraying lye, the fluid pressure in the lye injector head is 0.08MPa~0.12MPa；
Preferably, when mend alkali operation, the rotating speed of the agitating device is 30rpm~70rpm.
9. the full suspension cell culture reactor of 6000L serum-frees according to claim 1, it is characterised in that the tank body
Tank skin above be additionally provided with top layer air inlet, be provided with exhaust outlet on the lid at the top of the tank body.
10. the full suspension cell culture reactor of 6000L serum-frees according to claim 1, it is characterised in that the tank body
Inside it is additionally provided with pH meter and dissolved oxygen amount detecting device；
Preferably, the pH meter has two；
Preferably, the dissolved oxygen amount detecting device has two.
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| CN110241023A (en) * | 2019-06-20 | 2019-09-17 | 江南大学 | A kind of bioreactor and application for the extensive animal cell culture of high density |
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