CN106497783A - A kind of dynamic circulation cell culture apparatuses and cell culture processes - Google Patents
A kind of dynamic circulation cell culture apparatuses and cell culture processes Download PDFInfo
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Abstract
The present invention relates to technical field of cell culture, more particularly to a kind of dynamic circulation cell culture apparatuses and cell culture processes.Can be that the cell growth chamber sporadically supplements cell growth factor, improve cell culture efficiency.A kind of dynamic circulation cell culture apparatuses, including：Hollow fiber reactor, the hollow fiber reactor include culture fluid passage and cell growth chamber, cell growth factor delivery pump；The input of the cell growth factor delivery pump is used for being input into cell growth factor, the inlet communication in the outfan of the cell growth factor delivery pump and the cell growth chamber, the cell growth factor delivery pump are used for conveying cell growth factor to the cell growth chamber.
Description
Technical field
The present invention relates to technical field of cell culture, more particularly to a kind of dynamic circulation cell culture apparatuses and cell culture side
Method.
Background technology
T cell is formed by the differentiation of intrathymic lymphoid stem cell, is that quantity is most in lymphocyte, and function is most complicated
One class cell.It can be aided in or suppressed B cell to produce antibody, had silk point to specific antigen and rush with direct killing target cell
Split the responsing reaction of original and produce cell growth factor etc., the breast of ripe T cell through blood distribution to peripheral immune organ
Gland relies on area and settles down, and can carry out recirculation through lymphatic vessel, peripheral blood and tissue fluid etc., plays cellular immunization and immunomodulating etc.
Function.
Evolution about T cell and it achieve many progress in recent decades with the research of cancer.Particularly 21
The life Noah's ark plan that the beginning of the century mankind start for T cell evolution and it be even more with the research of cancer achieve breakthrough
Progress.Human body can naturally-produced T cell, but negligible amounts.Successful incubation T cell, and this cell is injected patient in a large number
In vivo, it is possibly realized with strengthening immune system.
Existing cell culture processes mainly have two classes：First kind method is to use Tissue Culture Dish, high-grade laminar flow
Cover and CO2 gas incubator carry out cell culture, and this kind of method is less efficient, it is impossible to meet clinical demand；Equations of The Second Kind method is
Cell is cultivated by hollow fiber reactor, referring to Fig. 1, the hollow fiber reactor 1 include hollow fiber conduit with
And the cylinder blanket (not shown) of the installation hollow fiber conduit, the inside of the hollow fiber conduit is used for being input into culture
Liquid (in figure shown in arrow a), is culture fluid passage 11, and the space between the outside of the hollow fiber conduit and the shell is used for
Inoculating cell, is cell growth chamber 12, by culture fluid is flowed through the hollow fiber conduit, and by the hollow fiber conduit
It is cells with nutrient that aperture enters the cell growth chamber 12, in the cell cultivation process in the cell growth chamber 12 constantly
Produce waste liquid and drain into outside, so constantly culture fluid, the large usage quantity of culture fluid is provided for cell culture, and will given up
The cell growth factor for being conducive to cell growth produced in cell cultivation process together can be discharged when discharging by liquid, cell culture
Environment is unstable, is unfavorable for cell growth.
Content of the invention
Embodiments of the invention provide a kind of dynamic circulation cell culture apparatuses and cell culture processes, can be the cell
Growth chamber sporadically supplements cell growth factor, improves cell culture efficiency.
For reaching above-mentioned purpose, embodiments of the invention are adopted the following technical scheme that：
On the one hand, the embodiment of the present invention provides a kind of dynamic circulation cell culture apparatuses, including：
Hollow fiber reactor, the hollow fiber reactor include culture fluid passage and cell growth chamber；
Cell growth factor delivery pump；The input of the cell growth factor delivery pump is used for being input into cell growth factor
Son, the inlet communication in the outfan of the cell growth factor delivery pump and the cell growth chamber, the cell growth factor
Delivery pump is used for conveying cell growth factor to the cell growth chamber.
Preferably, the incubator also includes cell growth factor storage tank, the outlet of the cell growth factor storage tank with
The input connection of the cytokine delivery pump, the bottom of the cell growth factor storage tank are provided with import, the cell
The entrance of somatomedin storage tank is provided with stop valve, and the stop valve is used for when closed by the cell growth factor storage tank
Interior cell growth factor is isolated from the outside.
Preferably, the incubator also includes pressure extended case and culture fluid delivery pump, in the pressure extended case filled with
Gas, the bottom of the pressure extended case are connected with the culture fluid passage or the cell growth chamber；
The input of the culture fluid delivery pump is used for being input into culture fluid, and outfan is connected with the import of the culture fluid passage
Logical, the culture fluid delivery pump is used for culture fluid to be flowed through in the form of impulse wave the culture fluid passage so that the culture
The positive and negative alternate of the pressure differential in liquid passage and the cell growth chamber, the pressure extended case are used for the change by gas volume
Change the pressure balance for causing the culture fluid passage and the cell growth chamber.
Preferably, the dynamic circulation cell culture apparatuses also include waste tank, waste liquid delivery pump and the first sampler, institute
The input of waste liquid delivery pump and the outlet of the culture fluid passage is stated, outfan is connected with the waste tank, described
The outlet of the collection terminal of the first sampler and the culture fluid passage, the first sampler are used for leading to flowing through the culture fluid
The culture fluid in road is sampled.
It is further preferred that the dynamic circulation cell culture apparatuses also include the second sampler, second sampler
Collection terminal is connected with the cell growth chamber, and second sampler is used for cell and culture fluid to the cell growth intracavity
It is sampled.
Optionally, the dynamic circulation cell culture apparatuses also include cellular collector, the import of the cellular collector with
Pipeline communication between the cell growth factor storage tank and the cell growth factor delivery pump, the cellular collector are used for
The cell collection in the cell growth chamber is got up in the cell growth factor delivery pump antiport.
It is further preferred that the dynamic circulation cell culture apparatuses also include controller, the controller respectively with described
Stop valve, culture fluid delivery pump, cell growth factor delivery pump, the electrical connection of waste liquid delivery pump, for controlling the stop valve, training
The opening and closing of nutrient solution delivery pump, cell growth factor delivery pump and waste liquid delivery pump, and control the culture fluid delivery pump
Culture fluid flows through in the form of impulse wave the culture fluid passage, control the cell growth factor delivery pump Positive work or
Person's antiport.
On the other hand, the embodiment of the present invention provides a kind of dynamic circulation cell culture processes, is applied to as above dynamic
State circulating cells incubator, including：
Cell growth factor is conveyed to the cell growth chamber by the cell growth factor delivery pump so that described thin
The cell growth factor content of intracellular growth intracavity is maintained in the first preset range.
Optionally, methods described also includes：Every the first Preset Time, by first sampler to flowing through the training
The culture fluid of nutrient solution passage is sampled detection, if Metabolites Concentration is more than or equal to the first preset value in the culture fluid,
Then the waste liquid delivery pump is controlled by the controller to open, the culture fluid for flowing through the culture fluid passage is drained into described useless
In liquid storage tank.
Further, methods described also includes：Every the second Preset Time, by second sampler to the cell
The cell and culture fluid of growth chamber is sampled and cell density therein is detected, if the cell density is more than or equal to the
Two preset values, then control the cell growth factor delivery pump antiport by the controller, by the cell growth chamber
In cell delivery into the cellular collector.
Optionally, described by the controller control cell growth factor delivery pump antiport, will be described thin
Cell delivery in intracellular growth chamber into the cellular collector after also include：The cell life is controlled by the controller
Long factor delivery pump Positive work, by the cellular collector to cell growth chamber inoculating cell.
A kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention and cell culture processes, in cell cultivation process
In, with cell growth, somatomedin constantly can be consumed, while with the continuous discharge of waste liquid, the cell growth chamber
Cell growth factor content can reduce, by arranging cell growth factor delivery pump, by the cell growth factor delivery pump
Cell growth factor can be conveyed to the cell growth chamber sporadically, keep the cell growth factor content to be maintained at one
In fixed scope such that it is able to improve cell culture effect.
Description of the drawings
A kind of structural representation of cell culture reactor that Fig. 1 is provided for prior art；
Fig. 2 is a kind of structural representation of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 3 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 4 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 5 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 6 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 7 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 8 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention；
Fig. 9 is the structural representation of another kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention.
Specific embodiment
Below in conjunction with the accompanying drawings to a kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention and cell culture processes
It is described in detail.
In describing the invention, it is to be understood that term " " center ", " on ", D score, "front", "rear", " left side ",
The orientation of instruction such as " right side ", " vertical ", " level ", " top ", " bottom ", " interior ", " outward " or position relationship are based on shown in the drawings
Orientation or position relationship, be for only for ease of description the present invention and simplify description, rather than indicate or hint indication device or
Therefore element must be not considered as limiting the invention with specific orientation, with specific azimuth configuration and operation.
Term " first ", " second " be only used for describe purpose, and it is not intended that indicate or hint relative importance or
The implicit quantity for indicating indicated technical characteristic.Thus, " first " is defined, the feature of " second " can be expressed or imply
Ground includes one or more this feature.
It should be noted that dynamic circulation cell culture apparatuses provided in an embodiment of the present invention are applied to the training of various cells
Support, the ambient parameter according to needed for the difference of cell category is only by changing various cell growths is for example, each in culture fluid
The concentration parameter of nutrient substance, cytokine concentrations parameter etc.；The embodiment of the present invention is particularly suited for suspension cell and adherent thin
The culture of born of the same parents.
On the one hand, the embodiment of the present invention provides a kind of dynamic circulation cell culture apparatuses, referring to Fig. 2, including：
Hollow fiber reactor 1, the hollow fiber reactor 1 include culture fluid passage 11 and cell growth chamber 12；
Cell growth factor delivery pump 02；The input of the cell growth factor delivery pump 02 is used for being input into cell growth
The factor, the inlet communication in the outfan of the cell growth factor delivery pump 02 and the cell growth chamber 12, the cell life
Long factor delivery pump 02 is used for conveying cell growth factor to the cell growth chamber 12.
A kind of dynamic circulation cell culture apparatuses provided in an embodiment of the present invention, in cell cultivation process, as cell is given birth to
Long, somatomedin constantly can be consumed, while with the continuous discharge of waste liquid, the cell growth factor in the cell growth chamber 12
Content can reduce, by arranging cell growth factor delivery pump 02, can be indefinite by the cell growth factor delivery pump 02
When ground convey cell growth factor to the cell growth chamber 12, keep the cell growth factor content to be maintained at certain model
In enclosing such that it is able to improve cell culture effect.
In one embodiment of the invention, referring to Fig. 3, the incubator also includes cell growth factor storage tank 3, the cell
The outlet of somatomedin storage tank 3 is connected with the input of the cytokine delivery pump 02, the cell growth factor storage tank 3
Bottom is provided with import, and the entrance of the cell growth factor storage tank 3 is provided with stop valve a, and the stop valve a is used for closing
The cell growth factor storage tank 3 is isolated from the outside when closing.
In embodiments of the present invention, by arranging stop valve a, extraneous antibacterial can be avoided from entering the cell growth factor
In storage tank 3.
, wherein it is desired to illustrate, as hollow fiber reactor generally includes container and is arranged in the container
At least one hollow fiber conduit, the inside of the hollow fiber conduit and the outside culture fluid passage 11 and described thin of being respectively
Intracellular growth chamber 12, for example, when the inside of the hollow fiber conduit is the culture fluid passage 11, then the hollow fiber conduit
Outside is the cell growth chamber 12, when the outside of the hollow fiber conduit is culture fluid passage 11, then the doughnut
The inside of pipe is the cell growth chamber 12.
Also, it should be noted when cultivating to suspension cell, suspension cell can be inoculated in cell life directly
In long chamber 12, cell is in suspended state, and when cultivating to attached cell, needs the surface in cell growth chamber 12 to carry out
Pretreatment, for example, when the inside of the hollow fiber conduit is cell growth chamber 12, then on the inwall of the hollow fiber conduit
One layer of albumen of laying so that cell can be attached to the inwall of the hollow fiber conduit and carry out adhere-wall culture.Vice versa.
In one embodiment of the invention, the incubator also includes pressure extended case 2 and culture fluid delivery pump 01, the pressure
Filled with gas, the bottom of the pressure extended case 2 and the culture fluid passage 11 or the cell growth chamber in power extension box 2
12 connections；
The input of the culture fluid delivery pump 01 is used for being input into culture fluid, and outfan is entered with the culture fluid passage 11
Mouth connection, the culture fluid delivery pump 01 are used for culture fluid to be flowed through in the form of impulse wave the culture fluid passage 11 so that
The positive and negative alternate of the pressure differential in the culture fluid passage 11 and the cell growth chamber 12, the pressure extended case 2 are used for leading to
The change for crossing gas volume causes the pressure balance in the culture fluid passage 11 and the cell growth chamber 12.
By arranging pressure extended case 2, and a certain amount of gas is filled with the pressure extended case 2, by the pressure
Extension box 2 is connected with the culture fluid passage 11 or cell growth chamber 12, and by the culture fluid delivery pump 01 with pulse
The form of ripple conveys culture fluid to the culture fluid passage 11 so that the culture fluid passage 11 and the cell growth chamber 12
The positive and negative alternate of pressure differential, when the culture fluid passage 11 and the cell growth chamber 12 pressure differential be timing, culture fluid
The culture fluid of passage 11 enters the cell growth chamber 12, and the gas volume in the pressure extended case 2 is compressed into the training
Nutrient solution passage 11 and the pressure balance in the cell growth chamber 12, when the culture fluid passage 11 and the cell growth chamber 12
When pressure differential is for bearing, the waste liquid in the cell growth chamber 12 enters the culture fluid passage 11, the gas in the pressure extended case 2
The increase of body volume is until the pressure balance in the culture fluid passage 11 and the cell growth chamber 12 such that it is able to realize culture fluid
Dynamic exchange with waste liquid；Culturing in vivo is simulated while being updated to the culture fluid in the cell growth chamber 12, is cell
Growth provides stable physiological environment, reduces the consumption of culture fluid.
Wherein, in addition it is also necessary to explanation, for different cell categories, culture fluid and waste liquid exchange capacity not yet
With, and need the pressure differential being applied between the culture fluid passage 11 and the cell growth chamber 12 would also vary from,
For example, the attached cell is compared with the suspension cell, as attached cell is attached on the tube wall of the hollow fiber conduit,
Stop can be produced to the exchange of culture fluid and waste liquid more or less, therefore, culture fluid passage when usual attached cell is cultivated
Pressure differential between 11 and the cell growth chamber 12 is slightly larger than pressure differential during suspension cell culture.
In another embodiment of the present invention, referring to Fig. 4, the dynamic circulation cell culture apparatuses also include cultivating liquid storage tank 4,
The outlet of the culture liquid storage tank 4 is connected with the input of the culture fluid delivery pump 01, the outlet of the culture fluid passage 11
Inlet communication with the culture liquid storage tank 4.
In embodiments of the present invention, by arranging culture liquid storage tank 4, culture fluid closed circuit can be formed, in culture fluid
During swapping with waste liquid, the waste liquid of discharge constantly can be taken back institute by the culture fluid for flowing through the culture fluid passage 11
Culture liquid storage tank 4 is stated, and for continuous feed flow, dynamic circulation utilization is carried out to culture fluid, reduce culture fluid and waste, and can protect
The nutrient substance for being conducive to cell growth in waste liquid is stayed, is conducive to cell culture.
In one embodiment of the invention, referring to Fig. 5, the dynamic circulation cell culture apparatuses also include waste tank 5, waste liquid
Delivery pump 03 and the first sampler 04, the outlet of the input of the waste liquid delivery pump 03 and the culture fluid passage 11,
Outfan is connected with the waste tank 5, the outlet of the collection terminal of first sampler 04 and the culture fluid passage 11 it
Between pipeline communication, the first sampler 04 is used for being sampled the culture fluid for flowing through the culture fluid passage 11.
The culture fluid flowed out by 04 pair of culture fluid passage 11 of the first sampler is sampled, can be to closed circuit
In the Metabolites Concentration of culture fluid detected in time such that it is able to according to testing result to the training in the closed circuit
Nutrient solution is processed in time, for example, when the Metabolites Concentration of the culture fluid detected in the closed circuit is higher, is unfavorable for cell
During growth, the waste liquid delivery pump 03 can be opened, so as to collect the culture fluid in the waste tank 5.
In another embodiment of the present invention, referring to Fig. 6, the dynamic circulation cell culture apparatuses also include the second sampler
05, the sampling end of second sampler 05 is connected with the cell growth chamber 12, and second sampler 05 is used for described
Cell and culture fluid in cell growth chamber 12 is sampled.
It is sampled by the cell and culture fluid in second sampler, 05 pair of cell growth chamber 12, can be to institute
The cell density for stating cell growth chamber 12 is detected such that it is able to determine continuation culture according to testing result or to cell
It is acquired, it is, of course, also possible to the Metabolites Concentration in the culture fluid in the cell growth chamber 12 is detected, and according to
Testing result is processed accordingly to which, for example：When in the culture fluid in the cell growth chamber, Metabolites Concentration is too high, no
During beneficial to cell growth, the pressure differential alternate for controlling the culture fluid passage 11 and the cell growth chamber 12 can be passed through
Frequency, promotes the exchange of waste liquid and culture fluid, so as to reduce the Metabolites Concentration in the cell growth chamber 12, exemplary
, the frequency of the positive and negative alternate of the pressure differential in the culture fluid passage 11 and the cell growth chamber 12 can pass through to control institute
State the pulse frequency of culture fluid delivery pump 01 to realize.
In one embodiment of the invention, referring to Fig. 7, the dynamic circulation cell culture apparatuses also include cellular collector 06,
Between the import of the cellular collector 06 and the cell growth factor storage tank 3 and the cell growth factor delivery pump 02
Pipeline communication, the cellular collector 06 are used for giving birth to the cell in 02 antiport of cell growth factor delivery pump
Cell collection in long chamber 12 gets up.
In embodiments of the present invention, carried out by the cell and culture fluid in 05 pair of cell growth chamber 12 of the second sampler
Sampling, after detecting its cell density, if the cell density reaches certain value, can pass through the cell growth factor
02 antiport of delivery pump, the cell collection in the cell growth chamber 12 is got up.
In one embodiment of the invention, referring to Fig. 8, the cell growth factor storage tank 3 and the cell growth factor are defeated
Send, the heater 6 is used for the cell growth factor to flowing through the pipeline
Heated.
By arranging heater 6, the temperature for entering the cell growth factor in the cell growth chamber 12 can be adjusted
Section, improves the activity of the cell growth factor, so as to improve cell culture effect.
In one embodiment of the invention, the dynamic circulation cell culture apparatuses also include controller (not shown), institute
State controller electric with the stop valve a, culture fluid delivery pump 01, cell growth factor delivery pump 02, waste liquid delivery pump 03 respectively
Connection, opens for controlling the stop valve a, culture fluid delivery pump 01, cell growth factor delivery pump 02, waste liquid delivery pump 03
Open and closing, and control the culture fluid delivery pump 01 culture fluid is conveyed to the culture fluid passage 11 in the form of impulse wave,
Control 02 Positive work of cell growth factor delivery pump or antiport.By arranging controller, cell can be trained
Foster whole process carries out Automated condtrol.
In one embodiment of the invention, referring to Fig. 9, the entrance of the culture liquid storage tank 4 is provided with the first valve b, institute
The top for stating culture liquid storage tank 4 is additionally provided with steam vent, the cell growth chamber 12 and the first valve b and the culture fluid
Pipeline between passage 11 is by being provided with the first pipeline communication, and first pipeline at the cell growth chamber 12
Air bleeding valve c, is additionally provided with the second valve d on the pipeline between the first valve b and the culture fluid passage 11, and described first
The outlet of pipeline is connected with the outfan side of the second valve d.
Waste gas can be produced in cell cultivation process, a part of waste gas can be entered in the pressure extended case 2, in addition one
Waste gas is divided smoothly to enter the culture fluid in air bleeding valve c unlatchings, the first valve b unlatchings, the second valve d when closing
In storage tank 4, waste gas can be drained into outside by steam vent by the culture liquid storage tank 4.
On the other hand, the embodiment of the present invention provides a kind of dynamic circulation cell culture processes, is applied to as above dynamic
State circulating cells incubator, including：
Cell growth factor is conveyed to the cell growth chamber by the cell growth factor delivery pump so that described thin
The cell growth factor content of intracellular growth intracavity is maintained in the first preset range.
A kind of dynamic circulation cell culture processes provided in an embodiment of the present invention, by arranging cell growth factor conveying
Pump, and the culture with cell, sporadically convey cell growth factor to the cell growth intracavity, are prevented from because of cell
Grow and cell growth factor and the continuous discharge of waste liquid is constantly consumed so that the cell growth factor in the cell growth chamber contains
Amount reduces so that the content of the cell growth factor is maintained in certain scope, it is possible to increase cell culture effect.
In another embodiment of the present invention, methods described also includes：By the culture fluid delivery pump by culture fluid with
The form of impulse wave flows through the culture fluid passage so that the positive and negative alternate of pressure differential inside and outside the hollow fiber conduit,
The pressure differential in the culture fluid passage and the cell growth chamber is timing, and the culture fluid of the culture fluid passage enters described thin
Intracellular growth chamber, the gas volume of the pressure extended case are compressed into the pressure in the culture fluid passage and the cell growth chamber
Balance；When the pressure differential in the culture fluid passage and the cell growth chamber is for bearing, the waste liquid in the cell growth chamber is entered
The culture fluid passage, the gas volume of the pressure extended case increase to the culture fluid passage and the cell growth chamber
Pressure balance.The exchange of the culture fluid and waste liquid, the consumption of less culture fluid can be promoted to prevent cell growth in waste liquid
The quick loss of favourable nutrient substance.
, wherein it is desired to illustrate, for different cell categories, the culture fluid passage and the cell growth chamber it
Between pressure differential demand different, for example, the attached cell compared with the suspension cell, as attached cell is attached to
On the tube wall of the hollow fiber conduit, more or less stop can be produced to the exchange of culture fluid and waste liquid, therefore, generally adherent thin
When born of the same parents cultivate, pressure differential between the culture fluid passage 11 and the cell growth chamber 12 is slightly larger than suspension cell culture
Pressure differential.
Wherein, pulse refers to the process of that a physical quantity rapidly returns back to its original state after being mutated in short duration.
The concrete form of the impulse wave is not limited, the impulse wave can be rectangular wave, can be sine wave, or its
The waveform of his shape.
In one embodiment of the invention, described culture fluid is flowed through in the form of impulse wave by culture fluid delivery pump described
Culture fluid passage is specifically included：
The culture fluid delivery pump is controlled with the first pre-set velocity and the second pre-set velocity alternately to the culture perfusion
Side conveys culture fluid.
In embodiments of the present invention, the culture flow velocity of the culture perfusion side is flowed through by control, can be to described
The pressure of culture perfusion side is controlled, and the pressure differential in the culture fluid passage and the cell growth chamber is with the shape of rectangular wave
Formula changes, and in the crest of the rectangular wave, the pressure of the culture fluid passage is more than institute to the speed of the culture fluid delivery pump
The pressure in cell growth chamber is stated, culture fluid enters the cell growth chamber up to pressure balance, then, the culture fluid delivery pump
Speed be transformed into rapidly the trough of the rectangular wave, the pressure of the pressure in the cell growth chamber more than the culture fluid passage
Power, waste liquid enters the culture fluid passage until pressure balance.
Wherein, the frequency of first pre-set velocity and the second pre-set velocity alternate is not limited, described first
The frequency of pre-set velocity and the second pre-set velocity alternate can be determined by the cell category being inoculated with, due to different cells
Species, during culture, the concentration of required nutrient substance difference, therefore, also has to the exchange frequency of culture fluid and waste liquid
Institute is different.
In one embodiment of the invention, methods described also includes：Every the first Preset Time, by first sampler
Detection is sampled to the culture fluid for flowing through the culture fluid passage, if Metabolites Concentration is more than or equal to the in the culture fluid
During one preset value, then the waste liquid delivery pump is controlled by the controller and opened, the culture of the culture fluid passage will be flowed through
Liquid is drained in the waste tank.
The cell is circulated by culture fluid culture during, with the growth of cell can produce substantial amounts of
Metabolite, by being sampled detection to the culture fluid that the culture fluid passage flows out, and when Metabolites Concentration is too high
Control closed circuit is closed, and the culture fluid is drained in waste tank, the environment of cell culture can be upgraded in time,
Improve the efficiency of cell culture.
In one embodiment of the invention, methods described also includes：Every the second Preset Time, by second sampler
The cell and culture fluid in the cell growth chamber are sampled cell density therein is detected, if the cell density
It is more than or equal to the second preset value, then the cell growth factor delivery pump antiport is controlled by the controller, will be described
Cell delivery in cell growth chamber is into the cellular collector.
In another embodiment of the present invention, described reverse by the controller control cell growth factor delivery pump
Operating, will also include after in the cell delivery in the cell growth chamber to the cellular collector：By the controller
The cell growth factor delivery pump Positive work is controlled, thin to cell growth chamber inoculation by the cellular collector
Born of the same parents.In embodiments of the present invention, inoculating cell can also be carried out to the cell growth chamber by the cellular collector, is promoted
The lasting culture of next wheel cells.
In one embodiment of the invention, methods described also includes：Every the 3rd Preset Time, control first valve and open
Open, exhaust valve opening and the second valve closing, the portion produced by the cell growth chamber is entered the culture fluid storage
In tank.
By by second valve closing, the portion that produce can the cell growth chamber smoothly drains into described
In culture liquid storage tank, and the steam vent by the culture fluid tank top drains into outside.
Certainly, methods described can also include：Every the 4th Preset Time, by second sampler to the cell
The culture fluid of growth chamber is sampled, and detects its cell growth factor content, if the cell growth factor content and first
Difference between the lower limit of preset range then controls the cell growth factor delivery pump and opens less than or equal to the first predetermined threshold value
Open, the cell growth factor that the second predetermined amount is conveyed by cell growth factor storage tank to the cell growth chamber so that described
Cell growth factor content is maintained in first preset range.
As cell growth constantly consumes the continuous exchange of cell growth factor and culture fluid and waste liquid, cell growth chamber
Cell growth factor content can reduce, by detecting to the cell growth factor content in the cell growth chamber, in institute
Infect by stop valve isolation is extraneous when stating cell growth factor content deficiency, steril cell is supplemented to the cell growth chamber and given birth to
The long factor, promotes cell to grow well.
The above, the only specific embodiment of the present invention, but protection scope of the present invention is not limited thereto, any
Those familiar with the art the invention discloses technical scope in, change or replacement can be readily occurred in, should all be contained
Cover within protection scope of the present invention.Therefore, protection scope of the present invention should be defined by the scope of the claims.
Claims (10)
1. a kind of dynamic circulation cell culture apparatuses, it is characterised in that include：
Hollow fiber reactor, the hollow fiber reactor include culture fluid passage and cell growth chamber；
Cell growth factor delivery pump；The input of the cell growth factor delivery pump is used for being input into cell growth factor, institute
State the outfan of cell growth factor delivery pump and the inlet communication in the cell growth chamber, the cell growth factor delivery pump
For conveying cell growth factor to the cell growth chamber.
2. dynamic circulation cell culture apparatuses according to claim 1, it is characterised in that
The incubator also includes cell growth factor storage tank, the outlet of the cell growth factor storage tank and the cytokine
The input connection of delivery pump, the bottom of the cell growth factor storage tank are provided with import, the cell growth factor storage tank
Entrance be provided with stop valve.
3. dynamic circulation cell culture apparatuses according to claim 2, it is characterised in that
The incubator also includes pressure extended case and culture fluid delivery pump, and the pressure extended case is interior filled with gas, the pressure
The bottom of power extension box is connected with the culture fluid passage or the cell growth chamber；
The input of the culture fluid delivery pump is used for being input into culture fluid, the inlet communication of outfan and the culture fluid passage,
The culture fluid delivery pump is used for culture fluid to be flowed through in the form of impulse wave the culture fluid passage, and the pressure extended case is used
In the pressure balance for causing the culture fluid passage and the cell growth chamber by the change of gas volume.
4. dynamic circulation cell culture apparatuses according to claim 3, it is characterised in that
The dynamic circulation cell culture apparatuses also include waste tank, waste liquid delivery pump and the first sampler, the waste liquid conveying
The outlet of the input of pump and the culture fluid passage, outfan are connected with the waste tank, first sampler
Collection terminal and the culture fluid passage outlet.
5. dynamic circulation cell culture apparatuses according to claim 1, it is characterised in that
The dynamic circulation cell culture apparatuses also include that the second sampler, the collection terminal of second sampler are given birth to the cell
Long chamber connection.
6. dynamic circulation cell culture apparatuses according to claim 4, it is characterised in that
The dynamic circulation cell culture apparatuses also include cellular collector, the import of the cellular collector and the cell growth
Pipeline communication between factor storage tank and the cell growth factor delivery pump, the cellular collector are used for giving birth in the cell
The cell collection in the cell growth chamber is got up during long factor delivery pump antiport.
7. dynamic circulation cell culture apparatuses according to claim 6, it is characterised in that
The dynamic circulation cell culture apparatuses also include controller, and the controller is conveyed with the stop valve, culture fluid respectively
Pump, cell growth factor delivery pump, the electrical connection of waste liquid delivery pump, for controlling the stop valve, culture fluid delivery pump, cell life
Long factor delivery pump and the opening and closing of waste liquid delivery pump, and the culture fluid delivery pump is controlled by culture fluid with impulse wave
Form flows through the culture fluid passage, controls the cell growth factor delivery pump Positive work or antiport.
8. a kind of dynamic circulation cell culture processes, the dynamic circulation cell culture being applied to described in any one of claim 1-7
Device, it is characterised in that include：
Cell growth factor is conveyed to the cell growth chamber by the cell growth factor delivery pump so that the cell life
The cell growth factor content of long intracavity is maintained in the first preset range.
9. dynamic circulation cell culture processes according to claim 8, it is characterised in that
Methods described also includes：Every the first Preset Time, by first sampler to flowing through the culture fluid passage
Culture fluid is sampled detection, if Metabolites Concentration is more than or equal to the first preset value in the culture fluid, by described
Controller control waste liquid delivery pump is opened, and the culture fluid for flowing through the culture fluid passage is drained in the waste tank.
10. dynamic circulation cell culture processes according to claim 8, it is characterised in that
Methods described also includes：Every the second Preset Time, by cell of second sampler to the cell growth chamber
It is sampled with culture fluid and cell density therein is detected, if the cell density is more than or equal to the second preset value,
The cell growth factor delivery pump antiport is controlled by the controller, by the cell delivery in the cell growth chamber
Into the cellular collector.
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| CN107058086A (en) * | 2017-05-26 | 2017-08-18 | 奥凯（苏州）生物技术有限公司 | A kind of method and system for preventing cell from blocking incubator |
| CN107189975A (en) * | 2017-05-26 | 2017-09-22 | 奥凯（苏州）生物技术有限公司 | A kind of cell collection method of closed cell expansion system |
| CN111592985A (en) * | 2020-04-28 | 2020-08-28 | 郑州伊美诺生物技术有限公司 | Continuous culture device and culture method for hybridoma cells |
| CN113817605A (en) * | 2021-09-18 | 2021-12-21 | 河南科技大学 | Dynamic cell culture device and single cell culture device |
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