CN1446924A - Biomimetic biological reaction device of cells utilized for screening medication - Google Patents
Biomimetic biological reaction device of cells utilized for screening medication Download PDFInfo
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- CN1446924A CN1446924A CN 03109125 CN03109125A CN1446924A CN 1446924 A CN1446924 A CN 1446924A CN 03109125 CN03109125 CN 03109125 CN 03109125 A CN03109125 A CN 03109125A CN 1446924 A CN1446924 A CN 1446924A
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- 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
- C12M29/18—External loop; Means for reintroduction of fermented biomass or liquid percolate
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- 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
- C12M41/48—Automatic or computerized control
Abstract
A bionic cell bioreactor for screening medicines is composed of square bottle for reproducing cells, culture liquid bottle, buffer bottle, waste liquid bottle, sampling valve, computer, creep pump, electronic valve and connection pipeline. It can periodically exchange the nutritive liquid in square bottle, continuously apply medicine, culturing cells by high density, easily sample and analyze, and simulate the blood flow in blood vessel and creep of intestine.
Description
Technical field
The present invention relates to a kind of artificial cell biological reaction apparatus that is used for drug screening, belong to bioengineering field.
Background technology
Carrying out drug screening by the square vase culturing cell is one of general drug screening means.Tradition square vase culturing cell carries out external drug screening process, need add the aseptic technique of medicine again when cell inoculation or through behind the cell cultures certain hour.The former causes the false positive phenomenon easily, and latter's program is lengthy and tedious, and workload is big, the pollution rate height.In addition, the cell in-vitro growth environment that traditional square vase provided is not easy control, changes with the cultivation process usually; This in addition training method can not be replenished cell growth desired nutritional material at any time, so these means often cause result of study false positive and false-negative pseudo-phenomenon as a result to occur.The tradition training method also exists sampling analysis process complexity, defective that pollution rate is high.The tradition training method is difficult to accomplish successive administration, control drug treating time etc.
Summary of the invention
Purpose of the present invention and task provide a kind of artificial cell biological reaction apparatus that is used for drug screening, cause false positive phenomenon and program lengthy and tedious easily to overcome traditional square vase culturing cell, and workload is big, the high defective of pollution rate; Can guarantee the periodic replacement cell culture fluid, the screened sample of arbitrary period adding in cell culture period prolongs cell culture period, also can realize the automatic management of culturing process simultaneously.The present invention is achieved through the following technical solutions:
A kind of artificial cell biological reaction apparatus that is used for drug screening, it is characterized in that: this device comprises a cell proliferation square vase, nutrient solution storage bottle and surge flask, the bottle cap of described cell proliferation square vase are provided with can be for liquid and the gas admission port, is provided with and the tangent outlet of bottle wall in its bottom; On the bottle cap of described nutrient solution storage bottle, be respectively equipped with the pneumatic outlet and the gas inlet of band strainer, be respectively equipped with the pneumatic outlet and the thief hole of band strainer on the surge flask bottle cap, nutrient solution storage bottle and surge flask are communicated with the import of cell proliferation square vase by peristaltic pump, valve and corresponding pipeline respectively; Described cell proliferation square vase outlet at bottom is communicated with surge flask by peristaltic pump and pipeline.
On the basis of such scheme, on the pipeline of the inlet of described cell proliferation square vase or outlet, be provided with one or a sampling valve that is used to add medicinal fluid is set respectively, the arbitrary period that can be implemented in cell culture period adds screened sample.
Biological reaction apparatus provided by the invention also comprises a waste liquid bottle, and this waste liquid bottle is communicated with surge flask by pipeline, and the pneumatic outlet of band strainer is installed on its bottle cap; When nutrient solution consumption is big, when perhaps in working cycle, needing to empty surge flask, the liquid in the surge flask can be imported in the waste liquid bottle and preserve.
In order to realize the automatic management of culturing process, this device also comprises a computer that contains software control procedure, and this computer links to each other with magnetic valve with peristaltic pump in the described device by a blocks of data interface card.
In order to realize screening sample and nutrient solution pre-mixing, can in system, settle a magnetic stirring apparatus, surge flask is placed on the magnetic stirring apparatus.
The present invention cultivates square vase with tradition and compares, have the following advantages and the high-lighting effect: 1. this device is owing to be provided with nutrient solution storage bottle and surge flask, make nutrient solution add the propagation square vase from the nutrient solution storage bottle, nutrient solution in the propagation square vase enters surge flask and preserves, can guarantee the cell nutrient solution regular update in the square vase, realize that various cells reach high-density culture, prolong cell culture period, and can be easily from the surge flask sampling analysis; Also can in cell cultivation process, the switching by valve realize that the nutrient solution of surge flask enters the cultivation square vase once more, realizes the regular circulation of nutrient solution.2. is connected in the stream of cultivating square vase and surge flask and can adds screening thing fluidic sampling valve, the arbitrary period that can be implemented in cell culture period adds screened sample, makes soup enter the cultivation square vase and cell carries out common cultivation; Also can in cell cultivation process, repeatedly add screened sample, accomplish successive administration, control drug treating time etc.3. can medicine and co-culture of cells after certain period with medicine and cellular segregation, in system, add other screening samples after emptying surge flask, realize the research of the different time effect of multiple medicines thing.4. cultivate flow rate of liquid that square vase the flows through velocity of blood flow in can simulated blood vessel, the effect situation of research medicine pair cell by regulation and control.In addition, can be by the intestines peristalsis frequency control medicine residence time, the drug effect situation under the simulation intestinal movement state.5. can realize the automatic management of culturing process.
Description of drawings
Fig. 1 is the structural representation of the biological reaction apparatus of being made up of " nutrient solution storage bottle-cell proliferation square vase-surge flask " provided by the invention.
Fig. 2 is the structural representation of cell proliferation square vase among Fig. 1.
Fig. 3 is the structural representation that the biological reaction apparatus of application of sample valve is housed.
Fig. 4 is the structural representation that the biological reaction apparatus of waste liquid bottle is housed.
Fig. 5 is the structural representation that the biological reaction apparatus that detects Controlling System is housed.
Fig. 6 is the circuit catenation principle figure of computer and power element.
Fig. 7 is the FB(flow block) of control software.
Fig. 8 utilizes device shown in Figure 5 to cultivate Hela cell growth condition (institute's hours of marking is the operational cycle to discharge opeing in the legend).
Fig. 9 utilizes device shown in Figure 5 to cultivate Sh-Sy5y cell growth condition (institute's hours of marking is the operational cycle to discharge opeing in the legend).
Figure 10 utilizes cytosis the inhibiting rate 18 hour after of device research Norcantharidin shown in Figure 1 to growing 72 hours.
Figure 11 utilizes cytosis the inhibiting rate 42 hour after of device research Norcantharidin shown in Figure 1 to growing 72 hours.
Figure 12 utilizes the changing conditions of device research sophorine shown in Figure 1 after cell proliferation square vase and Hela cytosis.
Figure 13 utilizes the changing conditions of device research sophorine shown in Figure 1 after cell proliferation square vase and Sy5y cytosis.
Figure 14 utilizes the changing conditions of device research sophorine shown in Figure 1 after cell proliferation square vase and HepG2 cytosis.
Embodiment
The present invention is further illustrated below in conjunction with drawings and Examples.
The artificial cell biological reaction apparatus (as shown in Figure 1) that is used for drug screening provided by the invention, mainly by nutrient solution storage bottle 11, cell proliferation square vase 2 and surge flask 12 are formed.Described nutrient solution storage bottle is equipped with gas duct 4, and peristaltic pump 51 and strainer 71 are installed on the gas duct 4, and inserts 11 bottom; Pneumatic outlet also is housed on the bottleneck of nutrient solution storage bottle 11, communicates with atmosphere by strainer 72.The bottleneck of described surge flask 12 is equipped with pneumatic outlet respectively and can supplies the thief hole 10 of sampling analysis, and pneumatic outlet communicates with atmosphere through filter 73; Thief hole 10 can be with the nutrient solution sampling analysis in the surge flask 12 by peristaltic pump 55.The structure of cell proliferation square vase is equipped with liquids and gases admission port 21 as shown in Figure 2 on its bottle cap, be provided with and the tangent outlet 22 of bottle wall in its bottom.The import of cell proliferation square vase 2 is through threeway 100, and respectively through magnetic valve 61, peristaltic pump 52 links to each other with nutrient solution storage bottle 11; Link to each other with surge flask 12 with peristaltic pump 53 through magnetic valve 66.The outlet 22 of cell proliferation square vase links to each other with surge flask 12 through peristaltic pump 54.
The air that contains 5% carbonic acid gas is pumped into by peristaltic pump 51, after filtering through filter 71, enters in 11 the nutrient solution, makes nutrient solution saturated by gas; By peristaltic pump 52 nutrient solution is sent into cell proliferation square vase 2 along the direction of arrow, at this moment, magnetic valve 61 is opened, and 66 close.When needing to change the nutrient solution in 2, peristaltic pump 54 and 52 is opened simultaneously, and the nutrient solution in the cell proliferation square vase 2 is taken away by 54 and entered surge flask 12, and the nutrient solution in the nutrient solution storage bottle 11 enters cell proliferation square vase 2 by peristaltic pump 52, and nutrient solution is replenished.This function can realize the cell culture fluid periodic replacement, has prolonged cell culture period, can realize the high-density culture of cell simultaneously.Screened sample is disposable adding cell proliferation square vase 2 in inoculation, or in the training period bottle cap is opened adding.
Shown in Figure 3 is a kind of artificial cell biological reaction apparatus that can the drug screening of online adding screening sample in cell cultivation process promptly is provided with the sampling valve 3 that can inject for sample between cell proliferation square vase 2 and surge flask 12.In cell cultivation process, can add screening sample by sampling valve, the cell of being brought in cell proliferation square vase and the square vase by the liquid circulation in the stream carries out common cultivation.Sampling valve 3 can be arranged between the outlet 22 and surge flask 12 of cell proliferation square vase, screening sample carries out entering cell proliferation square vase 2 after the pre-mixing in surge flask 12, surge flask is placed can realize screening sample and nutrient solution thorough mixing (as the parts 9 of Fig. 5) on the magnetic stirring apparatus 9; Also sampling valve 3 can be arranged between threeway 100 and the cell proliferation square vase 2, the screening thing directly enters cell proliferation square vase 2.Can repeatedly add screening sample at different time by sampling valve 3; Perhaps a sampling valve is being set respectively between threeway 100 and the cell proliferation square vase 2 and between the outlet 22 of cell proliferation square vase and the surge flask 12, can satisfying above-mentioned pre-mixing or premixed two kinds of functions of needs not so simultaneously.
Fig. 4 is the structural representation that the biological reaction apparatus of waste liquid bottle is housed, this device is a kind of artificial cell biological reaction apparatus that carries out the different multiple pharmaceutically-active drug screenings of period of same cell, and it is to be provided with a waste liquid bottle 13 on the basis of Fig. 3 again.Described waste liquid bottle 13 is connected by peristaltic pump 56 with surge flask 12, and bottleneck is provided with pneumatic outlet, communicates with atmosphere by strainer 74.After first kind of drug effect of screening finishes, the culturing mixt in the surge flask 12 is transferred to waste liquid bottle 13 under the effect of peristaltic pump 56, and uses the fresh medium cleaning system, add second kind of screening sample from sampling valve 3 again.
For the operational process to above-mentioned reaction unit carries out automatic management, this device also comprises a computer 8 (as shown in Figure 5) that contains software control procedure, and this computer links to each other with magnetic valve (power element) with peristaltic pump in the described device by a blocks of data interface card 201.Fig. 6 is the schematic circuit that computer is connected with power element.By A/D, D/A, the data interface card 201 that I/O forms is by resistance 204, and triode 202 links to each other with rly. 203.The action of rly. control power element 205.Data interface card directly is plugged on the computer motherboard.
Fig. 7 is the FB(flow block) of computer control software.After the user selects " stream pattern ", the operating parameters in per step of input in " flow process sequence " hurdle.Wherein first of every row classify the stream that to carry out number as.After clicking the " RUN " key, program begins to carry out the operation in first row, and behind the first step EO, current operation line number adds one.If when stream number is zero in the current action row, the equal executed of all operations is described, EP (end of program).If when stream is number non-vanishing in the current action row, carries out this line operate, and repeat above step.After the user selects " pump operated pattern ", the pump that selection will be operated, and set the on off state of valve and the waiting time t1 of pump, working time t2, pitch time t3, travelling speed and number of run.After the operation beginning, program picks up counting, and behind the wait t1, the time variable control pump brings into operation with the speed of setting, and be t2 working time.Behind the end of run, number of run adds 1.If number of run is less than the number of run of setting, then timing once more, the waiting time changes t3 into.After time arrived, pump brought into operation once more, and repeated above step.Can be by the intestines peristalsis frequency control medicine residence time, the drug effect situation under the simulation intestinal movement state, screening of medicaments realizes the automatic management of culturing process.
Embodiment 1 (cell cultures)
Utilize device shown in Figure 5, at first with system component, comprise that air feed path, nutrient solution storage bottle, cell proliferation square vase, surge flask and waste liquid bottle are connected by the flow process requirement and check resistance to air loss after, place the universal method sterilization routinely of high pressure steam pot.After sterilization is cooled to and is not higher than 37 ℃, will be in advance in the aseptic technique platform the nutrient solution 500ml of filtration sterilization pack in the nutrient solution storage bottle, and in the cell proliferation square vase, insert cell, inoculum density about 5 * 10
4Individual/ml, the initial about 20ml of liquid measure in the bottle.After this, place temperature to be set in 37 ℃ water bath the cell proliferation square vase, start cell proliferation square vase airing system, after static state is kept 12 hours,, grow for cell according to the square vase timing of research needs on cell proliferation or continuously to row's nutrient solution.Fig. 8 and Fig. 9 are the cultivation results to Hela cell and Sh-Sy5y cell.
Embodiment 2 (action effect of cell in Norcantharidin (Nc) the on cell proliferation square vase)
Utilize device shown in Figure 5, the drug level of used Nc is 10 μ g/ml, and used cell is SH-SY5Y.The mode of action of cell is the period effects mode in the Nc on cell proliferation square vase.Observe after 72 hours, experimental result as shown in figure 10, data are the empirical average value 4 times.X-coordinate cell proliferation square vase CPB8 among the figure, cell proliferation square vase CPB12, cell proliferation square vase CPB24 and cell proliferation square vase ∞ represent every 8 hours, 12 hours, and 24 hours and the operation that was administered once in ∞ hour.Wherein, ∞ hour is to be pitch time endless, and actual is exactly the mode of action in the common square vase, does not then need to test on the cell proliferation square vase in actual experiment, substitutes with porous plate to get final product.
Represent 18 hours result of drug effect by Figure 10, this shows that than other operating frequency, the cell in the porous plate after the identical time, shows more significant susceptibility to drug effect under same concentrations Nc effect.Cell in the porous plate then has been in decline phase at this moment, and the cellular control unit under other frequency still is in the excellent activity state.Obviously, why the cell in the porous plate shows bigger susceptibility to medicine, is that promptly the weak of self causes because its cell itself has been in bad active condition.With respect to the cell in the cell proliferation square vase, this significant drug susceptibility is false positive.There are some researches show, under fixed concentration, the inhibiting rate of Nc pair cell in time growth and increase.Figure 11 represents 42 hours result of drug effect, this shows, cell meets this trend in the cell proliferation square vase, and the cell in the porous plate has shown variation tendency in contrast to this.This be because, the cell in the porous plate enters the paracme after growth in 72 hours, activity begins to descend, from the method for calculation of inhibiting rate, this can cause inhibiting rate not rise counter falling.And cell still is in stationary phase through 72 hours its cytoactives of growth back in the cell proliferation square vase, and excellent activity is arranged, can reveal naturally and meet " inhibiting rate in time growth and increase " rule.This shows to have had false negative again by the result that obtains in the porous plate.
Above-mentioned studies show that, cell proliferation square vase not only can effectively avoid occurring in the drug efficacy study pseudo-result's phenomenon, but also can be used for investigating for a long time the research of drug effect.
Embodiment 3 (sophorine (Sp) is to the dynamic action of viable cell)
Utilize device shown in Figure 5, sophorine (Sp) for the experiment medicine, with Sy5y, Hela and HepG2 are subject, in the experiment in the Sp on cell proliferation square vase mode of action of cell be Circulation.Than common square vase, this mode is that the cell proliferation square vase is peculiar.With the static action of cell in the Sp on cell proliferation square vase with to the exercising result of cell in the common square vase is contrast, and experimental result such as Figure 12 are shown in 13 and 14.Its common law is, in the static action process of common square vase and cell proliferation square vase, and in the starting stage of cell proliferation square vase recurrent state, Sp all reduces with that its concentration of a kind of cytosis, and identical with downtrending under the operational condition at equivalent environment, but fall off rate and amplitude increase successively.In the cell proliferation square vase, no matter Sp and cell are in Circulation or its fall off rate of static action and amplitude all greater than common square vase, it is former in being that cell in the cell proliferation square vase is Duoed than the quantity in the common square vase and activity stabilized, has shown the ability of stronger metabolism Sp.Meanwhile also can see, than cell proliferation square vase static cultivation, Sp in the fall off rate of cell proliferation square vase recurrent state starting stage and amplitude again obviously greater than the former, obviously, cyclical operation makes cell strengthen Sp absorption or metabolic ability, and the intensity of variation that shows as Sp increases.From this angle, the cyclical operation of cell proliferation square vase has been played and has been amplified the effect that medicine changes.
In addition, in the Circulation of Sp and Sy5y and HepG2 cell, bounce-back (referring to Figure 13 and 14) has appearred in the concentration of Sp, and do not resemble with the Hela cytosis in the lasting reduction phenomenon (referring to Figure 12) that shown.When Sp concentration rebounds, find that all the phenomena of mortality have appearred in Sy5y and HepG2 cell, this phenomenon should be the common result of Sp and Circulation.
Claims (5)
1. artificial cell biological reaction apparatus that is used for drug screening, it is characterized in that: this device mainly comprises a cell proliferation square vase (2), nutrient solution storage bottle (11) and surge flask (12), the bottle cap of described cell proliferation square vase is provided with can be for liquid and gas admission port (21), is provided with and the tangent outlet (22) of bottle wall in its bottom; On the bottle cap of described nutrient solution storage bottle (11), be respectively equipped with the pneumatic outlet and the gas inlet of band strainer, be respectively equipped with the pneumatic outlet and the thief hole (10) of band strainer on surge flask (12) bottle cap, nutrient solution storage bottle and surge flask are communicated with the import (21) of cell proliferation square vase (2) by peristaltic pump, valve and corresponding pipeline respectively; Described cell proliferation square vase outlet at bottom (22) is communicated with surge flask (12) by peristaltic pump (54) and pipeline.
2. according to the described artificial cell biological reaction apparatus of claim 1, it is characterized in that: on the pipeline of the inlet of described cell proliferation square vase (2) or outlet, be provided with one or a sampling valve (3) that is used to add medicinal fluid is set respectively.
3. according to claim 1 or 2 described artificial cell reaction units, it is characterized in that: this device also comprises a waste liquid bottle (13), and this waste liquid bottle is communicated with surge flask by pipeline, and the pneumatic outlet of band strainer is installed on its bottle cap.
4. according to according to the described artificial cell reaction unit of claim 3, it is characterized in that: this device also comprises a computer (8) that contains software control procedure, and this computer links to each other with magnetic valve with peristaltic pump in the described device by a blocks of data interface card (201).
5. according to the described reaction unit of claim 1, it is characterized in that: a magnetic stirring apparatus (9) is set in described surge flask bottom.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102588270A (en) * | 2011-01-13 | 2012-07-18 | 帕尔公司 | Peristaltic pumps and filtration assembly systems for use therewith |
| CN104833783A (en) * | 2015-05-11 | 2015-08-12 | 王超 | Device for detecting irritation degree of drug to cell |
| CN104937093A (en) * | 2013-01-23 | 2015-09-23 | 哈美顿博纳图斯股份公司 | Cell culturing system for cultivating adherent cells and liquid supply interface comprising a cell culture container |
| CN105087380A (en) * | 2015-07-31 | 2015-11-25 | 南方医科大学珠江医院 | System for massively culturing animal cells |
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- 2003-04-04 CN CN 03109125 patent/CN1212406C/en not_active Expired - Fee Related
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| CN102588270A (en) * | 2011-01-13 | 2012-07-18 | 帕尔公司 | Peristaltic pumps and filtration assembly systems for use therewith |
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| CN104937093A (en) * | 2013-01-23 | 2015-09-23 | 哈美顿博纳图斯股份公司 | Cell culturing system for cultivating adherent cells and liquid supply interface comprising a cell culture container |
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| US10093893B2 (en) | 2013-01-23 | 2018-10-09 | Hamilton Bonaduz Ag | Cell culturing system for cultivating adherent cells and liquid supply interface comprising a cell culture container |
| CN104833783A (en) * | 2015-05-11 | 2015-08-12 | 王超 | Device for detecting irritation degree of drug to cell |
| CN104833783B (en) * | 2015-05-11 | 2016-08-24 | 王超 | Medicine irritation cell degree verifying attachment |
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| CN105087380A (en) * | 2015-07-31 | 2015-11-25 | 南方医科大学珠江医院 | System for massively culturing animal cells |
| CN107603878A (en) * | 2017-09-05 | 2018-01-19 | 广东省第二人民医院 | Cell culture apparatus and its method under a kind of in-vitro simulated pressing environment |
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