CN108841727A - CAR-T automatic cell preparation system based on micro-fluidic chip - Google Patents
CAR-T automatic cell preparation system based on micro-fluidic chip Download PDFInfo
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- 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
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Abstract
The present invention relates to field of cell culture, in particular to the CAR-T automatic cell preparation system based on micro-fluidic chip, including micro-fluidic chip, culture bag, product bag, pass through piping connection between each component.Demand to technical staff can be reduced by producing preparation one with carrying out cell therapy product by using the automation scheme of this closed loop, it avoids in product preparation process because artificial participate in bring uncertainty risk, two can significantly reduce corresponding human cost and the toilet GMP cost, and then reduce the cost of entire cell therapy.
Description
Technical field
The present invention relates to field of cell culture, in particular to a kind of culture of CAR-T cell, and in particular to based on micro-fluidic
The CAR-T automatic cell preparation system of chip.
Background technique
Capture the dream that cancer is always biomedical worker.With oncology, immunology and molecular biology etc.
The fast development of related discipline, the appearance of immunotherapy of tumors, which allows, realizes that this target is possibly realized.The machine of immunotherapy of tumors
Reason is to lose the morbidity origin monitored to canceration from immunity of organism, is removed by remotivating or transferring human immune system
Or control tumour cell.The performance of current Chimeric antigen receptor T cell (CAR-T) immunization therapy in the prior art is robbed the most
Eye.This method by T cell in peripheral blood in patients in vitro by genetic engineering means expression can specific recognition tumour cell,
And patient is fed back after activating the reinforcement T cell function simultaneously, achieve the effect that high efficiency specifically kills tumour cell.The U.S.
FDA successively has approved 2 CAR-T cell products in Septembers, 2017 and December and enters clinical application, and therapeutic effect rouses oneself very much
The popular feeling, it may be said that CAR-T cell therapy has cured cancer, this is marvelous breakthrough in cancer research history.Domestic scholars are at this
Aspect has also carried out a large amount of explorations, achieves many progress.
But required cell therapy product is in the toilet for meeting GMP standard in CAR-T cell therapy at present
It carries out.In such a mode, to avoid cell cross contamination between different patients, it is necessary to one corresponding for each patient
Cell culture chamber and a Biohazard Safety Equipment.Its cost is high.Meanwhile there must be artificial intervention in such a mode.
By taking the preparation of CAR-T immunotherapy clinical prods as an example, in toilet, the equipment and device that whole preparation process is used are main
There are Biohazard Safety Equipment, centrifuge, Magneto separate frame and cell incubator etc., the reagent and consumptive material used are even more to have more than 10, operation
Member needs accurately to handle each step, and needs to carry out sample multiple transfer, and this mode efficiency is very low, and undoubtedly can
Greatly increase the cost of cell therapy and pollution and uncertainty in product preparation process.
But the emphasis of research and hot spot are concentrated on the special of CAR-T cell by scholar and insider mostly at present
Property target spot find and its in the research of the orientation treatments such as solid tumor.The automation preparation system research side of CAR-T cell
Ignore to by scholar, at present still in the blank phase, this is constraining the development of CAR-T cell therapy technology and popularization is answered to a certain degree
With.
Summary of the invention
Goal of the invention of the invention is to provide a kind of CAR-T automatic cell preparation system, so as to realize that CAR-T is thin
It is prepared by the automation of born of the same parents.And guarantee to can be realized the asepsis ring of the sorting of former blood sample, whole flow process during the preparation process
Border and Chimeric antigen receptor transformation and CAR-T cell effectively can be carried out to T cell and expanded, including between each process
Integration and linking.
In order to achieve the above-mentioned object of the invention, CAR-T automatic cell preparation system is disclosed in the present invention, the system packet
Micro-fluidic chip is included, the micro-fluidic chip is provided with sample introduction end, products export end, also sets up or be not provided with non-product
Mouth end；It further include culture bag, the culture bag includes inlet and liquid outlet, the products export end of micro-fluidic chip and culture bag
Inlet by the first pipeline connection, be additionally provided with adding mouth on first pipeline, be additionally provided on first pipeline
Branch is the 4th pipeline, the 4th pipeline separates by the products export end of the micro-fluidic chip of the first pipeline, and culture bag into
It is imported in the first pipeline at liquid mouth, filter device, the non-product outlet of the micro-fluidic chip is provided on the 4th pipeline
End is connected at waste collection by the first waste-solution line, and the culture bag is placed in culture storehouse, and the culture storehouse includes culture
Warehouse offers entrance and pipe outlet on the culture warehouse, further includes having bin gate structure, the bin gate structure opens up
On culture warehouse, it being provided with concussion platform in the culture storehouse, further includes product bag, the product bag is equipped with the first sack,
The liquid outlet of culture bag and the first sack of product bag are additionally provided with magnetic field on the second pipeline by the second pipeline connection；The
It is connected with multiple sample-adding pipelines or multiple sample-adding pipelines at the adding mouth of one pipeline respectively with the first piping connection, is formed more
A adding mouth；
Herein be arranged three sample-adding pipelines, respectively slow virus suspension sample-adding pipeline, micro- suspension containing magnetic beads be loaded pipeline with
And cell culture fluid is loaded pipeline, further includes：
First valve, first valve are set on blood sample sample feeding pipe；
Second valve, second valve are set on cell culture fluid sample-adding pipeline；
Third valve, the third valve are set on slow virus suspension sample-adding pipeline；
4th valve, the 4th valve are set on micro- suspension containing magnetic beads sample-adding pipeline；
5th valve, the 5th valve are set on the first waste-solution line；
7th valve, the 7th valve are set on the first pipeline, and are located at the inlet of culture bag；
8th valve, the 8th valve are set on the second pipeline, and are located at the first sack of product bag；
9th valve, the 9th valve are set on the second pipeline, and are located at the liquid outlet of culture bag；
11st valve, the 11st valve are set on the second pipeline, and are located at magnetic field front end；
13rd valve, the 13rd valve are set at the products export end of micro-fluidic chip；
14th valve, the 14th valve are set to the filter device front end of the 4th pipeline；
15th valve, the 15th valve are set to the filter device rear end of the 4th pipeline；
16th valve, the 16th valve are set on the first pipeline, positioned at the branch mouth rear end of the 4th pipeline；
17th valve, the 17th valve are set on the pipeline that sample tap is connected with detecting instrument.
It further include having peristaltic pump, the peristaltic pump is set on the first pipeline, the second pipeline and/or third pipeline；
It further include having MCU, each valve is controlled by MCU；
It further include having man-machine interactive system, which connect with MCU.
Former blood sample is entered in micro-fluidic chip by the sample introduction end of micro-fluidic chip, and completes cell by micro-fluidic chip
Sorting, the T cell after sorting are flowed out by products export end, and by the 4th tube runs to culture bag, in the 4th pipeline, point
Cell after choosing is filtered by filter device, and enters culture bag by the inlet of culture bag, passes through what is be arranged on the first pipeline
Slow virus suspension is added into culture bag for adding mouth, after slow virus suspension is mixed well with T cell cell liquid, then by adding
Micro- suspension containing magnetic beads are added in sample mouth, when the mixed liquor of micro- suspension containing magnetic beads and slow virus suspension and T cell cell liquid after mixing, then
It is secondary that cell culture fluid (interior factor-containing) is added into culture bag by adding mouth, to complete T cell in culture bag
The proliferation of transformation and CAR-T cell；After CAR-T increment, is flowed out by the liquid outlet of culture bag, flowed in the second pipeline, and
Dynamic magnetic bead is completed in the magnetic field part of the second pipeline and is detached from step, then proceedes to flow to product bag, via the bag of product bag
Mouth flows into product bag, to complete sorting, transformation, proliferation and the harvest in the preparation of CAR-T cell.
The present invention can substitute GMP by medical disposable materials such as disposable pipeline, micro-fluidic chip, cell culture bags
Cleaning ambient creation, thus more inexpensive, facilitation sorting, transformation and the proliferation for realizing CAR-T cell.In the present invention
In, using the cooperation of peristaltic pump and valve, the liquid flowloop of a closure is created in links, both can guarantee liquid
The directed flow of body, and can guarantee the miniaturization of whole device system.It is worth noting that the model of valve, quantity and pipe
The specific form of road system is not limited to diagram and associated description.
In the transformation of T cell and the breeding of CAR-T cell, necessary condition of culture can be related to, these culture items
The realization of part is realized by the temperature, humidity, gas concentration lwevel that are arranged in culture storehouse.We only need cell culture bags
Culture apparatus appropriate is put into as can be realized in culture storehouse.These condition of culture and meet the culture apparatus of condition according to existing
The technical operation of some CAR-T cell transformation and proliferation.Or we can through the invention disclosed in culture storehouse, and lead to
The existing realization device such as heating, humidification, carbon-dioxide generator is crossed, the necessary environment of cell culture and condition are provided.
It cultivates in storehouse in the present invention and is additionally provided with concussion platform, thus after culture bag is placed on earthquake platform, shake
The effect swung is to mix suspension, such as guarantees culture solution diffusion uniformly, and it is uniform to guarantee that magnetic bead is spread.
Here magnetic field can be solid magnetic field and be also possible to electromagnetic field.Gu magnetic field is realized by the way that solid magnet is arranged, electromagnetism
It is realized by setting electromagnetism coiling field.It as needed, can be by adjusting stock magnet size position or electromagnetism coiling
Circle number and magnetic field size is adjusted by size of current.
Artificial participation can be reduced to the greatest extent by carrying out automation control to system by embedded MCU, to avoid
Artificially participate in the pollution that may cause and other potential uncertain problems.Man-machine interactive system and main key can be to
User provides observation and manually-operated interface to be suitable for the artificial experiment demand of user.
As a preferred mode, it is further disclosed in the present invention on the second pipeline and is additionally provided with sample tap.
The sample tap can carry out Process Character detection, benefit to the product in culture bag in the breeding of CAR-T cell
Product is detected with detection means such as flow cytometer detection systems either microplate reader detection system.Here the target component detected
Including but not limited to cell Proliferation number.
Further preferred mode is that the second sack is offered on product bag, and the second sack passes through third piping connection
It further include having the tenth valve to sample tap, the tenth valve is set on third pipeline, and is located at the second of product bag
At sack.
So as to which final products are carried out with online quality testing.
Further preferred mode is that sample introduction needle is provided at sample tap, so as to directly connect with detecting instrument.Subtract
Intermediate transfer link is sampled less, is avoided pollution.
Further preferred mode is that rinse mouth is additionally provided on the second pipeline, and the rinse mouth is arranged in the second pipeline
Magnetic field front end, be connected with flushing pipeline on the rinse mouth, and be also connected with second on the second pipeline of magnetic field rear end
The other end of waste-solution line, second waste-solution line is connected at waste collection；It further include having the 6th valve, the 6th valve
Door is set on the second waste-solution line, the position at waste collection.
Further preferred mode be further include having syringe pump sampling system, including push rod, injection tube, the injection tube
Front end exit at and micro-fluidic chip sample introduction end connect.
Former blood sample enters micro-fluidic chip by the front end exit of injection tube by the promotion of push rod.
Preferably, it is also provided with sample feeding mouth on the barrel of the injection tube, is connected with blood sample sample feeding pipe thereon.
More preferably mode is folded upward at the front end exit of the injection tube, and " n " font bending is formed.
Due to using such a bending, so when former blood is flowed out by injection tube originally, will not due to injection tube and injection-tube it
Between relative altitude difference and overflow.
It is that oscillation blending device is additionally provided at product bag as another preferred technical solution.Preferably, it can adopt
Use shaking table system.There can certainly be oscillation blending device using other.So that the transfection of CAR-T, transformation, proliferation
It is carried out in earthquake, is more conducive to the preparation of CAR-T cell.
It is worth noting that we can merge a part of part pipeline sometimes according to the needs of actual use
Come, shares identical one section or several sections of pipelines.So that structure is more compact.
Flowing velocity of the liquid in pipeline can be increased using peristaltic pump, improve the work effect of automation preparation system
Rate.And peristaltic pump has speed-regulating function, using the adjustable CAR-T cell liquid of peristaltic pump by the speed in magnetic field, to control
De- magnetic bead effect.
It is the quantity being directly arranged by magnet block there are also another mode for adjusting magnetic field, or by adjusting electricity
In magnet by electric current adjust magnetic field size.
When using solid magnet, mainly by magnet size, movement pipeline device or mobile solid magnet arrangement come real
The regulation in existing magnetic field；It is main that magnetic field is realized by electromagnetism coiling size and the on-off size of electric current when using electromagnet
Regulation.
Both peristaltic pump and the big minor adjustment in magnetic field are applied alone or are used cooperatively, so that Effective Regulation CAR-T cell liquid passes through
Rate of applied magnetic field controls de- magnetic bead effect.
A preferred technical solution is, in the magnetic field of the second pipeline, to be provided with silica gel cylindrical pipe as magnetic bead
Detachment system.Here a part of silica gel cylindrical pipe as the second pipeline.
Further open to illustrate, the arrangement mode of micro-fluidic chip array separation system can be superposition in the present invention
Formula, it is also possible to parallel arranged mode.Superposing type mentioned here refers to the public identical sample introduction end of all chips and production
Product or non-product outlet end.Juxtaposition mentioned here refers to that different chips have different sample introduction end and outlet end,
Pass through pipeline outside array for each sample introduction end, each products export end, each non-product outlet end connection.
Micro-fluidic chip can choose the micro-fluidic chip based on Dien stream principle, or be based on certainty laterally offset
The micro-fluidic chip of principle.It is worth noting that can choose this two kinds of micro-fluidic chips in the present invention, but be not restricted to that
This two kinds of micro-fluidic chips.
More preferably technical solution is, after system includes MCU control system, syringe pump sampling system is used
OEM type.To which the syringe pump sampling system can be unified to be controlled by MCU.
Also, in the present invention, we disclose the culture storehouse for CAR-T automatic cell preparation system, the trainings
Supporting storehouse includes culture storehouse warehouse, offers entrance and pipe outlet on the warehouse of the culture storehouse, further includes having bin gate structure,
The bin gate structure is provided on culture storehouse warehouse.
Preferably, door corresponds on two corresponding side walls for being opened in culture storehouse warehouse or door is opened in culture
The top of the warehouse.
It is worth noting that the design for cultivating storehouse is not limited to the structure, major function is to guarantee basic culture
While environment, cell culture bags can be reasonably disposed, and concussion mixing can be carried out to main process.
Each pipeline can select medical sterile pipes, for example medical grade silicone pipe.
Micro-fluidic chip, cell culture bags, sterile pipes are all made of medical disposable material, avoid cross-infection.
The aseptic for realizing whole preparation process using closed sterile pipes system consumptive material in the present invention, without investment
Great number cost establishes GMP control system.Micro-fluidic chip, product bag, culture bag are connected by the pipeline being completely closed and are given up
The devices such as liquid processing, by sorting, transformation, proliferation, de- magnetic bead, product collecting processes in the state of not contacted with external environment
It completes, to guarantee the aseptic of entire preparation flow, prevents contact stain.
The automated production preparation of cell therapy product may be implemented in technical solution disclosed by the invention.Specifically it is exactly
By in main module integrated to one automation equipment such as cell sorting, culture, observation, automation equipment as one
In the space that not will receive external interference, under the premise of meeting GMP standard, cell therapy product is carried out by automation equipment
Prepared by production, in overall process, it is only necessary to simple artificial assistance, or even completely disengage artificial.Using the automatic of this closed loop
Change scheme, which produces preparation one with carrying out cell therapy product, can reduce demand to technical staff, avoid product preparation process
In because artificial participate in bring uncertainty risk, two can significantly reduce corresponding human cost and the toilet GMP at
This, and then in addition to this cost for reducing entire cell therapy can also promote the standardization of cell therapy using this scheme
Process, pushes the formation of related industry chain, so that cell therapy be made to be easier from laboratory to clinical transition.
Detailed description of the invention
Fig. 1 is the CAR-T automatic cell preparation system schematic diagram based on microfluidic chip technology.
Fig. 2 is syringe pump sampling system schematic diagram.
Fig. 3 is a kind of partial structure diagram for cultivating storehouse.
Fig. 4 is the partial structure diagram in another culture storehouse.
Specific embodiment
In order to better understand the present invention, we in conjunction with specific embodiments further explain the present invention below
It states.
Embodiment 1
CAR-T automatic cell preparation system as shown in Figure 1, including micro-fluidic chip 1, the micro-fluidic chip setting
There is sample introduction end, connect herein with syringe pump sampling system 2 in the present embodiment, former blood sample is by the promotion of push rod, by injecting
The front end exit of cylinder enters micro-fluidic chip, and micro-fluidic chip further includes having products export end 101, being additionally provided with non-product outlet
End 102；It further include culture bag 3, the culture bag includes inlet 301 and liquid outlet 302, the products export end of micro-fluidic chip
101 are connected to the inlet 301 of culture bag by the first pipeline 401, are additionally provided with adding mouth, adding mouth on first pipeline
Three sample-adding pipelines are separately connected, respectively slow virus suspension is loaded pipeline 403, micro- suspension containing magnetic beads are loaded pipeline 404 and thin
The non-product outlet end of micro-fluidic chip described in born of the same parents' culture solution sample-adding pipeline 402 is connected to waste liquid by the first waste-solution line 405
5 at collection, as shown in Figure 1, it is the 4th pipeline 410, the 4th pipeline that branch is additionally provided on first pipeline 401
410 are separated by the products export end of the micro-fluidic chip of the first pipeline 401, and the first pipeline is imported at the inlet of culture bag
In 401, it is provided with filter device 12 on the 4th pipeline 410, further includes product bag 6, the product bag is equipped with the first sack
601, the liquid outlet 302 of culture bag is connected to the first sack 601 of product bag by the second pipeline 406, on the second pipeline 406
It is additionally provided with magnetic field.We have seen that, magnetic field is formed by solid magnet 7 in the present embodiment according to Fig. 1.
The culture bag 3 is placed in culture storehouse 13, and the culture storehouse includes culture warehouse 131, is opened on the culture warehouse
It further include having bin gate structure 134, the bin gate structure is provided with culture warehouse equipped with entrance 132 and pipe outlet 133
On, it is provided with concussion platform in the culture storehouse,.
As shown in Figure 3 and Figure 4, door can have both modes, and a kind of mode is that door correspondence is opened in training
In the two side walls for supporting warehouse, as shown in Figure 3, it is provided in left side and front side two side walls respectively, the second way is storehouse
Door is opened in culture the top of the warehouse, as shown in Figure 4.
Former blood sample is entered in micro-fluidic chip by the sample introduction end of micro-fluidic chip, and completes cell by micro-fluidic chip
Sorting, the T cell after sorting are flowed out by products export end, and by the first tube runs to culture bag, by the feed liquor of culture bag
Mouth enters culture bag, passes through the adding mouth being arranged on the first pipeline, slow virus suspension is added into culture bag, when slow virus suspension
After mixing well with T cell cell liquid, then micro- suspension containing magnetic beads are added by adding mouth, when micro- suspension containing magnetic beads and slow virus suspension and
Cell culture fluid is added into culture bag after mixing, again by adding mouth and (includes cell for the mixed liquor of T cell cell liquid
The factor), to complete the transformation of T cell and the proliferation of CAR-T cell in culture bag；After CAR-T increment, by culture bag
Liquid outlet outflow, flowed in the second pipeline, and the magnetic field part of the second pipeline complete dynamic magnetic bead be detached from step, then after
It is continuous to flow to product bag, it is flowed into product bag via the sack of product bag, to complete the sorting in the preparation of CAR-T cell, change
It makes, be proliferated and harvest.
In the present embodiment, it is preferred that be additionally provided with sample tap on the second pipeline 406, the sample tap and 8 phase of detecting instrument
Even.
The sample tap can carry out Process Character detection, benefit to the product in culture bag in the breeding of CAR-T cell
Product is detected with detection means such as flow cytometer detection systems either microplate reader detection system.Here the target component detected
Including but not limited to cell Proliferation number.
As shown in Figure 1, it is preferred in this embodiment, the second sack 602, the second sack 602 are offered on product bag 6
Sample tap is connected to by third pipeline 407.
So as to which final products are carried out with online quality testing.
It can also be provided with sample introduction needle, at sample tap preferably in the present embodiment so as to directly connect with detecting instrument
It connects.Intermediate transfer link is down-sampled, is avoided pollution.
Further preferred mode is that rinse mouth is additionally provided on the second pipeline 406, and the rinse mouth setting is in the second pipe
The magnetic field front end on road is connected with flushing pipeline 408 on the rinse mouth, and is also connected on the second pipeline of magnetic field rear end
Second waste-solution line 409, the other end of second waste-solution line 409 are connected to 5 at waste collection.
As shown in Figure 2, syringe pump sampling system 2, including push rod 201, injection tube 202, the front end of the injection tube
Exit and the sample introduction end of micro-fluidic chip connect.
Preferably, it is also provided with sample feeding mouth on the barrel of the injection tube, is connected with blood sample sample feeding pipe thereon.
As shown in Fig. 2, being folded upward at the front end exit of injection tube, " n " font bending is formed.
It includes valve that we are further open in this example, preferably electromagnetic valve.The valve is set to respectively
The front end or rear end of a pipeline and/or component.In conjunction with Fig. 1, in this example valve can according to any one following or
The multiple modes of person are arranged, and a liquid inductor is provided at each valve, is not marked still further.
First valve 801, first valve are set on blood sample sample feeding pipe；
Second valve 802, second valve are set on cell culture fluid sample-adding pipeline；
Third valve 803, the third valve are set on slow virus suspension sample-adding pipeline；
4th valve 804, the 4th valve are set on micro- suspension containing magnetic beads sample-adding pipeline；
5th valve 805, the 5th valve are set on the first waste-solution line；
6th valve 806, the 6th valve are set on the second waste-solution line, the position at waste collection；
7th valve 807, the 7th valve are set on the first pipeline, and are located at the inlet of culture bag；
8th valve 808, the 8th valve are set on the second pipeline, and are located at the first sack of product bag
Place；
9th valve 809, the 9th valve are set on the second pipeline, and are located at the liquid outlet of culture bag；
Tenth valve 810, the tenth valve are set on third pipeline, and are located at the second sack of product bag
Place；
11st valve 811, the 11st valve are set on the second pipeline, and are located at magnetic field front end；
12nd valve 812, the 12nd valve are set in flushing pipeline；
13rd valve 813, the 13rd valve are set at the products export end 101 of micro-fluidic chip, when point
At the end of choosing, the 13rd valve is opened, to realize the transfer of T cell, after completing transfer, which is closed, and avoids other
In the process, liquid flow enters in micro-fluidic chip；
14th valve 814, the 14th valve are set to the filter device front end of the 4th pipeline；
15th valve 815, the 15th valve are set to the filter device rear end of the 4th pipeline；
16th valve 816, the 16th valve is set on the first pipeline, after the branch mouth of the 4th pipeline
End.
17th valve 817, the 17th valve are set on the pipeline that sample tap is connected with detecting instrument 8.
It should be noted that the design position of practical valve should be as close to the position of bifurcation mouth, to be substantially reduced not
Possible stagnant liquid problem is shifted with process liquids.
As shown, in the present embodiment further including having peristaltic pump 9.
Partially there is the pipeline of coincidence to be merged in the present embodiment, to share identical one section or several sections pipe
Road, structure are more compact.
As shown in Figure 1, it is provided with silica gel cylindrical pipe 9 and is used as magnetic bead detachment system.Here silica gel cylindrical tube
The a part of road as the second pipeline.
More preferably scheme be further include having MCU10.Intelligentized control method is realized using Embedded controller.
More preferably mode further includes having man-machine interactive system 11.Operator is controlled whole by man-machine interactive system
A automation preparation system.
Specific operating process is as follows：
Prepare by pretreated former blood sample, the cell culture fluid for being mixed with cell factor, slow virus suspension, micro- magnetic bead
Suspension etc..Here the processing of former blood sample is done according to the sample introduction requirement of micro-fluidic chip.Usually by former hemodilution, have
When can add erythrocyte splitting process.Disposable closed conduit system consumptive material, basic culture environment detection are installed.Then by
One valve opening, remaining valve are closed, and the former blood sample in A enters syringe pump system；Then by the 13rd valve, the tenth
Four valves, the 15th valve, the 5th valve, the 7th valve opening, remaining valve close, syringe pump sampling system drive sample into
Enter micro-fluidic array separation system, waste liquid is entered at waste collection by non-product outlet end, and the T cell product being sorted is then
Entered in culture bag by products export end via filter device.After T cell sorted product enters corresponding region, start T cell
Transformation, CAR-T generation step.By third valve, the 7th valve and the 16th valve opening, remaining valve is closed, in peristaltic pump
Driving under, by C slow virus suspension injection culture bag in, mix rocking equipment starting, slow virus and T cell suspension are abundant
It mixes, then by the 4th valve, the 7th valve and the 16th valve opening, remaining valve is closed, will under the driving of peristaltic pump
In micro- suspension containing magnetic beads injection culture bag in D, rocking equipment starting is mixed, keeps micro- suspension containing magnetic beads and cell suspension and slow virus outstanding
The mixed liquor of liquid mixes well.Then, into CAT-T cell Proliferation incubation.At regular intervals, by the second valve,
Seven valves and the 16th valve opening, remaining valve is closed, and under the driving of peristaltic pump, the cell culture fluid in B (is included thin
Intracellular cytokine) injection cell culture area in product transfer cell culture bags.Rocking equipment starting is mixed, cell culture fluid and thin is made
Born of the same parents' suspension mixes well.During the cultivation process, at regular intervals, procedure quality detection is carried out, concrete mode is by the 9th valve
Door and the 17th valve opening, the sample fraction being introduced into culture bag under peristaltic pump driving enter detecting instrument and carry out process
Detect quality control.After the completion of proliferation, the 8th valve, the 9th valve, the 11st valve, the 16th valve opening are being wriggled
Under the driving of pump, the CAR-T cell products suspension in culture bag is passed through at a slow speed controllable magnetic place, dynamic magnetic bead is completed and is detached from
Afterwards, into final products bag.By the 6th valve, the 12nd valve and the 16th valve opening, remaining valve is closed, and peristaltic pump is led
Draw the flushing liquor in E and enter pipeline, and the magnetic bead of field region is poured at waste collection.
Quality testing is carried out to final products, concrete mode is by the tenth valve and the 17th valve opening, remaining valve
It closes, the sample fraction being introduced into final products bag under peristaltic pump driving enters process detection quality control module.
Product bag is unloaded, as includes the product of CAR-T cell.
The foregoing is a specific embodiment of the present invention.It should be pointed out that for those skilled in the art
For, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also considered as
Protection scope of the present invention.
Claims (10)
1.CAR-T automatic cell integration preparation system, it is characterised in that：The system includes micro-fluidic chip, the miniflow
Control chip is provided with sample introduction end, products export end, also sets up or be not provided with non-product outlet end；It further include culture bag, institute
Stating culture bag includes inlet and liquid outlet, and the products export end of micro-fluidic chip and the inlet of culture bag pass through the first pipeline
It is connected to, is additionally provided with adding mouth on first pipeline, it is the 4th pipeline, the 4th pipe that branch is additionally provided on first pipeline
The products export end for routing the micro-fluidic chip of the first pipeline separates, and imports in the first pipeline at the inlet of culture bag,
Filter device is provided on 4th pipeline, the non-product outlet end of the micro-fluidic chip is connected by the first waste-solution line
To waste collection, the culture bag is placed in culture storehouse, and the culture storehouse includes cultivating storehouse warehouse, on the warehouse of the culture storehouse
Entrance and pipe outlet are offered, further includes having bin gate structure, the bin gate structure is provided on culture storehouse warehouse, described
Concussion platform is provided in culture storehouse, product bag is placed in concussion platform, and the product bag is equipped with the first sack, and culture bag goes out liquid
First sack of mouth and product bag passes through the second pipeline connection, is additionally provided with magnetic field on the second pipeline；Further include,
First valve, first valve are set on blood sample sample feeding pipe；
Second valve, second valve are set on cell culture fluid sample-adding pipeline；
Third valve, the third valve are set on slow virus suspension sample-adding pipeline；
4th valve, the 4th valve are set on micro- suspension containing magnetic beads sample-adding pipeline；
5th valve, the 5th valve are set on the first waste-solution line；
7th valve, the 7th valve are set on the first pipeline, and are located at the inlet of culture bag；
8th valve, the 8th valve are set on the second pipeline, and are located at the first sack of product bag；
9th valve, the 9th valve are set on the second pipeline, and are located at the liquid outlet of culture bag；
11st valve, the 11st valve are set on the second pipeline, and are located at magnetic field front end；
13rd valve, the 13rd valve are set at the products export end of micro-fluidic chip；
14th valve, the 14th valve are set to the filter device front end of the 4th pipeline；
15th valve, the 15th valve are set to the filter device rear end of the 4th pipeline；
16th valve, the 16th valve are set on the first pipeline, positioned at the branch mouth rear end of the 4th pipeline.
It further include having peristaltic pump, the peristaltic pump is set on the first pipeline, the second pipeline and/or third pipeline；
It further include having MCU, each valve is controlled by MCU；
It further include having man-machine interactive system, which connect with MCU.
2. CAR-T automatic cell preparation system according to claim 1, it is characterised in that：It is also set on the second pipeline
It is equipped with sample tap, further includes having the 17th valve, the 17th valve is set on the pipeline for leading to quality detection module.
3. CAR-T automatic cell preparation system according to claim 2, it is characterised in that：Is offered on product bag
Two sacks, the second sack, to sample tap, further include having the tenth valve, the tenth valve is set to by third piping connection
On third pipeline, and it is located at the second sack of product bag.
4. CAR-T automatic cell preparation system according to claim 2, it is characterised in that：Be provided at sample tap into
Sample needle.
5. CAR-T automatic cell preparation system according to claim 1, it is characterised in that：It is also set up on second pipeline
There is rinse mouth, the magnetic field front end of the second pipeline is arranged in the rinse mouth, it is connected with flushing pipeline on the rinse mouth, and
It is also connected with the second waste-solution line on second pipeline of magnetic field rear end, the other end of second waste-solution line is connected to waste collection
Place；
It further include having the 6th valve, the 6th valve is set on the second waste-solution line, the position at waste collection.
6. CAR-T automatic cell preparation system according to claim 1, it is characterised in that：Further include have syringe pump into
Sample system, including push rod, injection tube, at the front end exit of the injection tube and sample introduction end of micro-fluidic chip connect.
7. CAR-T automatic cell preparation system according to claim 6, it is characterised in that：The barrel of the injection tube
On be also provided with sample feeding mouth, be connected with blood sample sample feeding pipe thereon.
8. CAR-T automatic cell preparation system according to claim 7, it is characterised in that：The front end of the injection tube
Exit is folded upward at, and forms " n " font bending.
9. being used for the culture storehouse of CAR-T automatic cell preparation system, it is characterised in that：The culture storehouse includes culture Cang Cang
Body offers entrance and pipe outlet on the warehouse of the culture storehouse, further includes having door, and the door is provided with culture storehouse
On warehouse.
10. the culture storehouse according to claim 9 for CAR-T automatic cell preparation system, it is characterised in that：Door
On corresponding two corresponding side walls for being opened in culture storehouse warehouse or door is opened in culture the top of the warehouse.
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| CN108841727B (en) | 2022-03-04 |
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Effective date of registration: 20240123 Address after: No. 8 Dongtaifeng Road, Shipai, Bacheng Town, Kunshan City, Suzhou City, Jiangsu Province, 215000 Patentee after: Suzhou Zhongjian Haozhi Pharmaceutical Technology Co.,Ltd. Country or region after: China Address before: 211189 No. 2, Four Pailou, Xuanwu District, Nanjing City, Jiangsu Province Patentee before: SOUTHEAST University Country or region before: China |