CN1316414C - Program controlled feedback feeding-system for culturing cell - Google Patents
Program controlled feedback feeding-system for culturing cell Download PDFInfo
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- CN1316414C CN1316414C CNB200510041968XA CN200510041968A CN1316414C CN 1316414 C CN1316414 C CN 1316414C CN B200510041968X A CNB200510041968X A CN B200510041968XA CN 200510041968 A CN200510041968 A CN 200510041968A CN 1316414 C CN1316414 C CN 1316414C
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Abstract
The present invention discloses a program controlled feedback feeding system for cell culture, which is based on a PID feedback control principle. A measurement signal of a biochemistry analyzer is introduced by a communication interface of a computer, the measurement signal after the data treatment of the computer is output by a corresponding interface, the action of an added peristaltic pump of nutrient material flows is regulated by various feedback control algorithms predetermined by program controlled software, and the adding speed rate of nutrient materials flowing into a biological reactor is controlled in real time. Therefore, the closed-loop cooperation automatic measurement and control of the biochemistry analyzer, the peristaltic pump and the biological reactor is achieved, and the concentration of the nutrient materials in the biological reactor can be in accurate feedback control. The program controlled feedback feeding system for cell culture has the characteristics of high stability, high control accuracy, specific process control index, strong operability, wide application range, etc., and the program controlled feedback feeding system for cell culture is suitable for the scale production and the technological process research of the biologically technical products of animal cell expression.
Description
Technical field
The present invention relates to a kind of Control System of Microcomputer, further relate to Control System of Microcomputer based on nutriment concentration in the Biochemical Analyzer FEEDBACK CONTROL bio-reactor.
Background technology
Animal cell large-scale is cultivated has become one of most important gordian technique of field of biological pharmacy, and with going deep into of its research and developing rapidly of progress promotion biotechnology industry.
It is the culture process that occupies the main flow advantage in the current animal cell culture technology that stream adds culture process, also is the focus of animal cell large-scale culture studies in recent years
[1]The company of selecting to use stream to add technology (Fed-batch) in the protein production of scale has, as the Genentech of the U.S., IDEC, MedImmune, Merck etc.That this technology has is simple to operate, productive rate is high, easy amplification advantages such as (more than 10000 liters).The gordian technique that stream adds in the culture process is that basal medium and stream add the design that concentrates nutrient medium.Thanked to good will utilization stechiometry (Xie LZ) in 1996, demand according to the zooblast growth, the nutrient solution that concentrates is quantitatively added in design, the concentration stabilize of accurately controlling glucose, glutaminase maintain reduced levels (＜0.1mmol/L), to change the cellular metabolism mode
[2]. hybridoma stream adds cultivation cycle and surpasses 550 hours, and general stream adds technology lactic acid specific production rate and reduced 4 times, and the ammonia specific production rate has reduced 10 times, and cell density reaches 5 * 10
7/ ml, the viable cell density of peak value is greater than 1.5 * 10
7/ ml, the antibody cumulative concentration reaches 2.4g/L
[3]
But add in the research and application process of technology at stream, the accurate control of nutrients being kept concentration and stream rate of acceleration thereof is the principal element that influences process optimization always.Though at present the animal cell culture of producing with bio-reactor routine be equipped with some simple feed supplement pump control programs, consumption is the characteristics of nonlinearities change to nutrients far can not to adapt to zooblast
[4]In addition, generally can not be general between the product of each bio-reactor and checkout equipment producer, each instrument in the existing laboratory is generally and works alone, once in a while can many collaborative work, also be manually to intervene or identical producer series of products are prerequisite with artificial.Therefore, maintain reduced levels with the control nutrient concentrations, in change cellular metabolism mode, thereby the method that improves culture efficiency has been subjected to restriction significantly in actual applications.
At present, in the bioprocess automation control area, based on feedforward, the feedback principle of classics, new technology continues to bring out, as fuzzy control, neural network etc.
[5]But wherein, be easily understood because of it, do not need condition precedents such as accurate system model in the use, thereby control method still so far for being most widely used with the controller of PID (proportional-integral-differential) feedback mode control design and practicability.In cell cultivation process, the nutriment concentration in the bio-reactor can be regarded the big inertia object with pure lag system as, is very suitable for the thereof using PID principle and carries out feedback regulation, uses different algorithms, as Smith estimate, integration separation, Da Lin algorithm
[6,7,8]Deng can on the basis of stable control, further improving sensitivity of control system and accuracy, incubation is controlled played effect well.But in application process, must set up hardware system system that matches with culture device and the general switching software of writing based on specific control algolithm, the PID control principle effectively can be applied to produce.
Patent related to the present invention and document mainly concentrate on the following aspects: the 1) improvement of feedback control algorithm; 2) automatic feeding device; 3) Biochemical Analyzer; 4) peristaltic pump etc.Wherein, feedback control algorithm mostly is the optimization and the improvement of mathematical model, does not relate to the composition and the application of particular hardware equipment
[9,10,11,12]The automatic feeding device mostly is and utilizes the interior PH of cultivation tank body, oxyty or weight to carry out the automatic feeding operation, does not carry out direct FEEDBACK CONTROL at nutrient concentrations itself
[13,14,15]And Biochemical Analyzer and peristaltic pump mainly are based on different detection principles and physical construction is carried out patent protection
[16,17,18], only use principle inner and structure-irrelevant in the present invention with it as assembly.
Below be some pertinent literatures that the inventor provides:
[1]Wei-Shou Hu，John G Aunins.Large-scale mammalian cell culture.Current Opinionin Biotechnology，1997，8：148-153。
[2]Xie L Z，Wang D I.Integrated approaches to the design of media and feeding strategiesfor fed-batch cultures of animal cells.Trends Biotechnol，1997，15(3)：109-113。
[3]Xie L Z，Wang D I.High cell density and high monoclonal antibody productionmedium design and rational control in a bioreactor.Biorechnol Bioeng，1996，51：725-729。
[4]D.Ramkrishna.On modeling of bioreactors for control.Journal of ProcessControl，2003，13：581-589。
[5]Lee J.，Lee S.Y.，Sunwon P.，etc.Control of fed-batch fermentiations.BiotechnologyAdvances，1999，17：29-48。
[6]MATAUSEK M R，MICIC A D.A modified Smith predictor for controlling a processwith an integrator and long dead-time[J].IEEE Trans Automat Contr，1996，41(8)：1199-1203。
[7]MATAUSEK M R，MICIC A D.On the modified Smith predictor for controlling aProcess with an integrator and long dead-time[J].IEEE Trans Automat Contr，1999，44(8)：1603-1606。
[8] Li Zhengjun. computer control system. Beijing: China Machine Press's first published in 2005,172-178 page or leaf.
[9] Toshiba Corporation. have the process control of improved feedforward feedback combination. number of patent application: 88103947.0.
[10] Toshiba Corporation. feed back control system. number of patent application: 92103988.3
[11] Woodward Governor Co.. be used for estimating method and apparatus with the non-linear interference of Control and Feedback control system. number of patent application: 97125234.3.
[12] Samsung Electronics Co., Ltd. feedback control system and method. number of patent application: 200410046529.3.
[13] Institute of Microorganism, Academia Sinica. be used for the method for mushroom liquid submerged fermentation control. number of patent application: 00109088.7.
[14] Xiamen University. stream feeds back dilution and control device automatically. number of patent application: 200310123856.X.
[15] Guoqiang Biochemical Engineering Equipment Co., Ltd., Shanghai. be used for the automatically controlled fermentor device that process optimization and data are amplified. number of patent application: 00127307.8.
[16]Hitachi，Ltd.(Tokyo，JP).Biochemical analyzer and attenuated total reflection prismcell used in said analyzer.United States Patent：5,362,445。
[17] BeiJing HangTianWanXin Science Co., Ltd. automatic clinical chemistry analyzer. number of patent application: 03266090.1.
[18] Societe Des Produits Nestle S.A. peristaltic pump. application (patent) number: 98804300.9.
The present invention has used classical PID control theory on principle, but all carrying out system optimization aspect system's formation and the hardware configuration according to the characteristics of animal cell culture, present proven technique such as computing machine, Biochemical Analyzer and peristaltic pump are combined, to satisfy the demand of animal cell large-scale High Density Cultivation, there is no the patent and the bibliographical information of set of equipments both at home and abroad.
Summary of the invention
At the problems referred to above, the object of the present invention is to provide a kind of program controlled feedback feeding-system for culturing cell, this system is a kind of based on the Biochemical Analyzer monitor signal, with nutriment concentration in the PID principle FEEDBACK CONTROL bio-reactor, and be applicable to the computer control system of multiple bio-reactor.
To achieve these goals, the technical solution adopted in the present invention is, a kind of program controlled feedback feeding-system for culturing cell, it is characterized in that, this system constitutes closed loop by Biochemical Analyzer, bio-reactor, peristaltic pump group and computer control system, nutrient solution signal by computer control system monitoring Biochemical Analyzer makes bio-reactor, peristaltic pump group and Biochemical Analyzer collaborative work with feedback control principle, the nutriment concentration in the control bio-reactor.
Described computer control system is a kind of based on the Biochemical Analyzer monitor signal, the computer control system of nutriment concentration in the FEEDBACK CONTROL bio-reactor, it includes digital control virtual instrument, digital I/O card and signal condition and driving circuit, in the digital control virtual instrument interface modular converter is arranged, be connected with Biochemical Analyzer with digital I/O card respectively by serial communication interface, numeral I/O card is connected with driving circuit with signal condition, special-purpose cellular incubation is arranged with feeding back the feed supplement Control Software in the digital control virtual instrument;
After specific nutrition substrate concentration in the bio-reactor is regularly detected by Biochemical Analyzer, measuring-signal is sent into interface modular converter by serial ports, modular converter is sent into program-controlled computer through the communication expansion card and is read by general switching software, calculate the nutrients amount that should add in the bio-reactor according to the PID feedback control principle again, its digital control amount is by voltage output card output simulation controlled quentity controlled variable after being converted to the peristaltic pump amount of spin, send drive current by sqignal conditioning and driving circuit, the work of control peristaltic pump group.
Other characteristics of the present invention are, described bio-reactor is used for animal cell culture, and a plurality of interfaces are arranged on the tank body, can be in cell cultivation process in sampling is emitted or outside liquid added jar, provide the cell growth required nutriment to nutrient solution in the jar.
Described Biochemical Analyzer is used for specific nutrition substrate concentration in the periodic monitor bio-reactor, and can reads its measured value, input database by outside general switching software behind the supporting respective detection film;
Described peristaltic pump group is made of a plurality of peristaltic pumps, and each peristaltic pump connects a concentrated nutrition liquid container, is used for follow procedure setting stream in bio-reactor and adds concentrated nutriment.
Described interface modular converter is used for that the cell effect concentration that Biochemical Analyzer is monitored is converted in good time sampled data and sends into program-controlled computer;
Described signal condition and driving circuit are used for the analog quantity of voltage output card output is carried out conversion of signals, drive the peristaltic pump running.
The present invention is based on the PID feedback control principle, communication interface by computing machine is introduced the Biochemical Analyzer measuring-signal, handle and the corresponding interface output by computer data, utilize the default various feedback control algolithm of general switching software to regulate the nutrition logistics and add the action of using peristaltic pump, control stream is added to nutraceutical interpolation speed in the bio-reactor in real time, thereby realize the closed loop synergistic autocontrol of Biochemical Analyzer, peristaltic pump and bio-reactor, the nutriment concentration in the bio-reactor is carried out accurate FEEDBACK CONTROL.
System of the present invention can cooperate all kinds bio-reactor, two kinds of nutriment concentration in the incubation are accurately controlled simultaneously, and per hour sampling is an example with the glutamine once automatically, range of control is 0.05～2mmol/L, and control accuracy is ± 0.02mmol/L.Show through test: this system can finish the FEEDBACK CONTROL of nutrient concentrations by requirement is set, and has reached the control accuracy and the effect of expection.
Description of drawings
Fig. 1 is a system construction drawing of the present invention;
Fig. 2 is the modulate circuit schematic diagram;
Fig. 3～Figure 13 is a computer control of the present invention interface synoptic diagram.
The present invention is described in further detail below in conjunction with embodiment that accompanying drawing and inventor provide.
Embodiment
(1) feedback control system constitutes
Referring to Fig. 1, feedback control system of the present invention comprises: Biochemical Analyzer, 485/232 interface modular converter, communication port expansion card, computing machine and special-purpose Control Software, voltage output card, signal condition and driving circuit, peristaltic pump group and bio-reactor constitute.
(2) be applied to the ultimate principle of feedback control system
The PID feedback control principle
Current automatic control technology all is based on the notion of feedback.The key element of feedback theory comprises three parts: measure, compare and carry out.Measure the variable of being concerned about, compare with expectation value, with the response of this error correction regulation and control system.This key theoretical and that use control automatically is, make correct measurement and comparison after, correcting system how better.
The conduct of PID (proportional-integral-differential) controller is existing more than 50 year history of controller of practicability the earliest, remains most widely used industrial control unit (ICU) now.The PID controller is easily understood, and does not need condition precedents such as accurate system model in the use, thereby becomes the controller that is most widely used.
The PID controller is made up of ratio unit (P), integral unit (I) and differentiation element (D).Its input e (t) with the pass of output u (t) is:
Therefore its transport function is:
It because of many uses, use flexibly, existing tandem product only needs to set three parameters (Kp, Ki and Kd) and gets final product in the use.Under many circumstances, might not need whole three unit, can get one to two unit wherein, but ratio control unit be absolutely necessary.
At first, PID applied range.Though a lot of industrial processs be non-linear or the time become, by becoming substantially linear and dynamic perfromance time invariant system to its simplification, PID is with regard to may command like this.
Secondly, pid parameter is more easily adjusted.Just, pid parameter Kp, Ki and Kd can in time adjust according to the dynamic perfromance of process.If the dynamic perfromance of process changes, for example may cause that system dynamic characteristic changes by the variation of load, pid parameter just can be adjusted again.
(3) realization of feedback control system function
1. overall system design thought and principle of work
Program control feeding-system research and development program element based on the Biochemical Analyzer feedback is to optimize animal cell large-scale culture technique platform, the important measures that improve the process control automation degree.
The overall design philosophy of native system is:
Communication interface by computing machine, introduce Biochemical Analyzer feedback measuring-signal, by the special software deal with data, pass through output interface, the utilization computer software realizes that powerful control algolithm is controlled the peristaltic pump adjusting flexibly, thereby realize the closed loop synergistic autocontrol of Biochemical Analyzer, peristaltic pump and bio-reactor, make that nutrient concentrations is able to accurate control in the incubation, improve culture efficiency.
The hardware General layout Plan as shown in Figure 1, wherein digital control virtual instrument is a common computer, control output is by the adjusting of a plurality of peristaltic pumps of control behind special digital I/O card and signal condition and the driving circuit, the feedback signal of computing machine is imported via serial ports of computers by each collection capacity of fractional analysis instrument, thereby constitutes closed-loop control system.
SDK (Software Development Kit) is LabView6.1.
Nutriment concentration can be regarded the big inertia object with pure lag system as in the controlling object bio-reactor of native system.Existing feedback is a conventional PID control, sample rate be 1 hour once.Because the existence of pure lag system, the consequence that low sampling rate is brought is the inertia time constant that has strengthened object, and it is elongated to make concentration reach the adjusting time of expecting stable state, influences cellular incubation.But taking so, slow sample rate is because the solution concentration change procedure is slower, concentration has bigger hysteresis to change the time when nutriment consumes, if raising sample rate, must improve the controlled quentity controlled variable output frequency, promptly the speed of Kong Zhi speed and object variation is asynchronous, thereby make concentration overshoot excessive, be difficult to reach stable state.But do not change sample rate, it is very long again that concentration is controlled the adjusting time that reaches stable state, and the inertia of regulating once is also very big, thereby the overshoot error is bigger.At above-mentioned contradiction, used following some control strategy among the design to improve control accuracy:
1. take pid control algorithm with the Smith prediction device
Known to above-mentioned, because the influence of the retardation time of concentration-response makes present control method can not improve sample rate, thus influence control effect.The effect of Smith prediction device is just at pure lag compensation control algolithm that retardation time, problem proposed.Its ultimate principle is with introducing Smith prediction device in parallel with object, makes the equivalent object after the compensation not comprise pure hysteresis characteristic, thereby can reach better control effect with general pid algorithm.For native system, when being equivalent to peristaltic pump output controlled quentity controlled variable exactly, the concentration in the bio-reactor changes immediately, without any time-delay, thereby can sample immediately, has also just accelerated sample rate, can reach good effect with conventional PID control.
2. improving the common pid algorithm is integral separation PID controling algorithm
In order to improve the accuracy of concentration control, avoid the integration saturated phenomenon (to refer to that the retentive control amount is in the flow range of pump, avoid unusual control), among the design the common pid algorithm is improved to Integration Separation PID Control, promptly limit deviation in certain thresholding, during the deviation of super thresholding, do not introduce long-pending effect, avoid integration saturated, thereby improved the output characteristics of system.
In addition, provide a kind of control algolithm incessantly in the native system design, the user can select appropriate algorithm according to particular requirement, wishes that as the user controlled device reaches stable state faster, and when being indifferent to overshoot, the minimum that can take this software to provide is clapped control.And the comparison of various control algorithm effect is provided, estimate the comparison of pid algorithm as Da Lin algorithm and Smith, relatively the waiting of common pid and Integration Separation PID Control.By multiple algorithm controls, the user can obtain different concentration change environment, improves the efficient of cell culture experiments greatly.
2. The hardware design
2.1 hardware is formed
Native system hardware is formed structure as shown in Figure 1, by computing machine, and digital I/O card and signal condition and driving circuit, and Biochemical Analyzer, peristaltic pump is formed, and each peristaltic pump connects a concentrated nutrition liquid container, is used for follow procedure setting stream in bio-reactor and adds concentrated nutriment.The controlling object of computing machine is a nutriment concentration in the bio-reactor.
Computing machine
Computing machine is the existing common computer in laboratory, and the special tool control computer is adopted in suggestion during follow-up study certainly, to obtain more reliable and more stable control effect.Computing machine is finished following function:
(1) be the serial communication card of expansion, the aanalogvoltage output card provides PCI slot;
(2) system master running software platform;
(3) bio-reactor AFS running software platform;
(4) routine office work;
(5) self serial ports 1 can directly connect usefulness as Biochemical Analyzer, convenient debugging.
Native system has been expanded the two boards card, and wherein data communication card is PCI-1612, and function is the serial ports quantity of expansion ordinary PC and the level standard of serial ports.Because the central controlled needs of laboratory computer, this TV station computer is not only as the main control computer of this system, but also as UPS, the control computer of AFS, the latter has just used up two serial ports.For this reason, expanded a communication card PCI-1612 in the native system in addition, this card can add four serial ports in addition.In addition, because Biochemical Analyzer and computing machine need carry out telecommunication not in a room, the serial ports level of this card expansion is RS485, can support the communication distance of 1.2km.The software operation of communication card is mainly drive installation, the common serial ports read-write of Windows.Address card line preface is as shown in the table:
Table 1 address card connecting line preface
| Used terminal on the card | The distributing cabinet terminal | The terminal line preface | Distributing cabinet line preface | ||||
| P1 | Communication A/ communication B | 1 DATA- | 2 DATA- | 5GND | 2 DATA- | 3 DATA- | 5GND |
The data output card is a voltage output card, and model is PCI-1723, and function is exported with the form of voltage for the controlled quentity controlled variable that primary control program is obtained, and drives rotating speed and the amount of spin of modulate circuit with the control peristaltic pump.This output card has 8 voltage output channels, can independently control 8 peristaltic pumps.8 digital channels can be used for promptly stopping the operation of peristaltic pump.The software operation of this analog output card mainly is drive installation, driving function call the software and hardware pattern configurations.The lead-out terminal of output card is fixed in the conditioning case, its connecting line preface such as following table:
The method of attachment of table 2 output card
| The pin sequence number | Connect |
| VO | |
| 67 | Meet conditioning plate voltage input channel Vin1 |
| 66 | Meet conditioning plate simulation ground GND |
| 33 | Meet conditioning plate voltage |
| 32 | Meet conditioning plate simulation ground GND |
| 62 | Meet conditioning plate voltage input channel Vin3 |
| 61 | Meet conditioning plate |
| 28 | Meet conditioning plate voltage input channel Vin4 |
| 27 | Meet conditioning plate simulation ground GND |
| DIO | |
| 47 | Meet conditioning plate digital quantity input channel Din1 |
| 13 | Meet conditioning plate digital quantity |
| 46 | Meet conditioning plate digital quantity |
| 12 | Meet conditioning plate digital quantity input channel Din4 |
| 39 | Meet digitally DGND of conditioning plate |
| 5 | Meet digitally DGND of conditioning plate |
Signal process box
Signal process box is mainly by cabinet, power supply, and conditioning plate is formed.
Cabinet is the size custom-made according to the size of modulate circuit and power supply, its power supply lead wire, and interface, pilot lamp, switch, communication seat groove, the output slot all passes through specialized designs, meets industrial standard.Cabinet panel table composed as follows:
| Front panel | Power light.5V delivery outlet by power supply connects LED and the realization of 1k current-limiting resistance. | The modulate circuit running indicator, indication modulate circuit state | The switch groove, power switch, 220V switch | Structural representation |
| Rear panel | Output card terminal lead groove | Four road DB9 delivery outlets | Three core power supply lead wire grooves |
Power supply is 100W four outputting standard Switching Power Supplies, and voltage output is stable, and waveform is level and smooth, has better guaranteed the precision of modulate circuit.The 15V of power supply exports to the conditioning plate power supply.
The complete autonomous Design of conditioning plate, basic circuit principle are voltage, the Control of Voltage transistor switching circuit.Wherein voltage is imported the 0-10 signal, output 4-20mA circuit, meet the control signal requirement of peristaltic pump, and current signal can realize that remote transmission is unattenuated, reached the target of accurate control pump rotating speed, and physical circuit is seen modulate circuit schematic diagram in the appendix.The voltage cut-out circuit can produce switching signal by digital quantity delivery outlet (DIO) the level control of output card, is used for the emergency stop of peristaltic pump.Certainly this function and voltage are exported the equivalence that makes zero, and physical circuit is seen Fig. 2 in the appendix.
This modulate circuit can receive 4 road input control signals, and 4 tunnel output control signals can independently be controlled the operation of four peristaltic pumps.As the more pumps of need, only need add conditioning plate in addition and get final product.
Distributing cabinet, distributing frame, signal and transmission line
Distributing cabinet and coil holder choose for meeting communication industry standard distributing cabinet and special-purpose patch bay, make current drive signal and signal of communication can easily more relocate preface be connected.
Signal and transmission line have been chosen and have been surpassed 5 class netting twines, made things convenient for the making of terminal and easy to connect, and twisted pair construction also can better be anti-interference, and transmission quality is higher.
The distributing cabinet role is a signal converting, so the line preface essence at its two ends still is 1 pair 1,2 pair 2, but in order to strengthen antijamming capability, the spy has kept twisted-pair feeder to link to each other in twos on the actual line of using as far as possible.
The communication interface modular converter
The communication interface modular converter is 485 to change 232 usefulness, and the signal that comes from card is 485 level, becomes 232 compatible with the Biochemical Analyzer interface after conversion.Power supply has used the independent charge power supply of 12V, and 232 ports are the DB9 interface, are connected with Biochemical Analyzer through adapter, and adapter line preface is as shown in the table.485 ports have only DATA-and two pins of DATA+, respectively with distribution in the DATA-(being 2 pins of network interface) that comes, DATA+ (being 3 pins of network interface) links to each other.
| 2-3 | 3-2 | 5-7 | 4+6+1 is short | 20+5 |
Biochemical Analyzer
Model is YSI-2700, carries serial line interface and has guaranteed the hardware feasibility that is connected with PC, after increasing some necessary adapters and working out perfect communication protocol, can guarantee communication normally.As the feedback signal source of native system, nutriment concentration in the real-time monitoring bio reactor.
Peristaltic pump
Peristaltic pump is blue lattice BT300 type pump, and DB9 is provided external control structure, the input of 4-20mA standard industry control signal, and the output of 0-300r/m rotating speed, the input of STOP switching signal is used for emergency stop.
2.2 system hardware operation steps
1) opens the Biochemical Analyzer power supply, correctly set on request, order wire is correctly connected;
2) on peristaltic pump, clip the feed supplement pipeline, open the peristaltic pump power supply, correctly set traffic direction, gauge tap is got to " external control " shelves, correctly connect the external control line;
3) to the main control computer chamber, correctly connect order wire and output line, open computer power earlier, open conditioning case power supply again, then enter the main control software interface, experimentize by software operation step proper operation main control software;
4) experiment finishes, withdraw from main control software after, please close conditioning case power supply earlier, close computer power again, be Biochemical Analyzer and peristaltic pump power supply then, finish operations.
3. software section design
3.1 service requirement
The above type of PIII800, the above internal memory of 128M, the above free hard disk space of 50M, Windows 9x, WindowsXP, Windows NT4.0 or the Chinese operating system of highest version more.
Start: from explorer select profeed.exe or start menu, input profeed.exe in service place catalogue profeed, by starting profeed.exe behind the enter key, insert boot disk (if boot disk is arranged) through prompting, program will be activated, and main interface as shown in Figure 3 occur.
3.2 operation interface and setting
Click the operation button and this program master interface (Fig. 3) promptly occurs, fluid-velocity survey, parameter setting, actual measurement demonstration, these four buttons of historical query are arranged topmost.
3.2.1 fluid-velocity survey
Click the fluid-velocity survey button, enter fluid-velocity survey subroutine interface (Fig. 4).
" liquid capacity " and " rotating speed " two arranged at the subroutine interface.
" liquid capacity " refers to the capacity in the make-up solution of selecting in advance for the flow velocity of testing this solution per minute.Unit is ml.
" rotating speed " refers to peristaltic pump per minute rotating speed.For example be set at 10, refer to that promptly rotating speed is per minute l0 circle.
After hardware system connected, click and begin to measure, observe the container at make-up solution place, after all being exhausted, click and finish to measure.
At this moment another one shows that column unit speed flow can demonstrate the solution magnitude of recruitment through this test per minute after calculating.
Click is returned, and will turn back to the master routine interface, and the data of measurement are returned in the lump.
3.2.2 parameter setting
Click " parameter setting " button, enter parameter main interface (Fig. 5) is set, be provided with: " communications parameter setting ", " state parameter setting ", " pid parameter setting ", " database setting " and " setting completed for parameter " 5 OptionButtons on the right at interface.
1) communications parameter setting:
Click " communications parameter setting " button, the entry communication parameter is provided with interface (Fig. 6), sets each parameter of communication.
Buffer size: buffer size (200)
Port number: port numbers (4)
Band rate: baud rate (9600)
Data bits: data bit (8)
Stop bits: position of rest (1)
Sample time: sampling interval chronomere: second (3600)
Annotate: be the default value of this program in the bracket.
2) state parameter setting
Click state parameter button is set, getting the hang of is provided with interface (Fig. 7).It is two row that this interface is divided into, and first classifies various Status Names as, and second classifies various status values as, and state parameter will work in the control to solution concentration.
3) pid parameter setting
Click pid parameter button is set, enter pid parameter interface (Fig. 8) is set.
Mainly contain following column:
First project upper limit: first kind of mxm. that solution concentration allows surpasses this mathematical program and will provide caution.
First project lower limit: first kind of minimum that solution concentration allows is lower than this mathematical program and will provides caution.
Second project upper limit: second kind of mxm. that solution concentration allows surpasses this mathematical program and will provide caution.
Second project lower limit: second kind of minimum that solution concentration allows is lower than this mathematical program and will provides caution.
Annotate: the unit unification is: g/L
First project objective concentration: first kind of concentration value that solution will be controlled in this experiment, PID will regulate the volume that stream adds solution according to this numerical value.
Second project objective concentration: second kind of concentration value that solution will be controlled in this experiment, PID will regulate the volume that stream adds solution according to this numerical value.
Flow velocity is set: set when time fluid infusion flow velocity of experiment.Two options are arranged, and first is set for fluid-velocity survey, and second is manually to set.Manual setting is set can be under the immovable prerequisite of experiment condition, skips the measurement of rate of flow step during start-up system once more, continues to continue to use setting value last time, for the user of service provides convenience.
Retort volume: the total measurement (volume) of solution in inferior culture bioreactors.
Pid parameter: first is a scale-up factor, and second is integral coefficient, and the 3rd is differential coefficient; Program will be carried out the PID FEEDBACK CONTROL according to the coefficient of setting.
4) database setting
Notebook data storehouse system is the ACCESS of Microsoft, needs to be provided with odbc data source behind the installation system.Concrete grammar is as follows: click " my computer ", click " control panel ", click " management tool ", click " ODBC " icon wherein again.Click " user DSN ", select " Ms Access Database ", click " interpolation " again, " creating the new data source " dialog box occurs, select " Microsoft Access Drive " option, click " finishing ", occur dialog box is installed, click " selection ", choosing for preserving experimental result data designated storehouse, click OK is finished the data source setting again.Notice that this step is carried out 1 time and got final product after system installs.
Click data lab setting button enters database interface (Fig. 9) is set.
Click " database is set " option, a dialog box will occur: whether reset tables of data.Click "Yes", will create a new tables of data, click "No", will from drop-down menu, select a tables of data to preserve the data of experiment this time for this experiment.
5) setting completed for parameter
After parameter sets, click " setting completed for parameter ", will return main interface, wait for that the user begins executive routine.
3.2.3 working procedure
1) begin and in real time the monitoring
Setting completed, all experiment conditions are clicked " beginning to measure " after being ready to when all parameters, and watchdog routine will begin to start, and program enters real-time monitoring interface (Figure 10).
What 1# concentration currency illustrated is first kind of concentration that solution is current measuring;
What 2# concentration currency illustrated is second kind of concentration that solution is current measuring;
What trend map showed is corresponding solution concentration tendency, can very find out the control effect of whole experiment clearly.
The pilot lamp of downside correspondence represents whether current concentration is normal, and is bright as green light within allowed band, otherwise red light is bright, and shows out-of-limit type simultaneously.
2) the inquiry of historical data.
Click " browsing data " button, enter the inquiry of historical data interface.
Click " data base querying " button earlier, at this moment, program will be called in internal memory to the data in the database that configures for inquiry.
Click " graphic presentation " button, can show " time-concentration " curve (Figure 11) of this experimental data in the interface, drag the cross in the figure, will show the concentration of corresponding time of mouse position.In the display box below, maximum, the time of Cmin appearance and the mean concentration of various solution will be demonstrated.
Click " form demonstration " button, can show the report form (Figure 12) of this experimental data in the interface, make things convenient for the user of service to inquire about the concrete data of each time point, and carry out cross-reference.
After experiment finishes, click " form setting " button, insert experimenter's title and report name, click report printing, will generate the form of this test automatically, see Figure 13.
After experiment finished, click " finished to measure " and quits a program.
Claims (6)
1. program controlled feedback feeding-system for culturing cell, it is characterized in that, this system constitutes closed loop by Biochemical Analyzer, bio-reactor, peristaltic pump group and computer control system, specific nutrition substrate concentration measured signal by computer control system monitoring Biochemical Analyzer, in bio-reactor, flow the speed of Ensure Liquid material by feedback control principle control peristaltic pump group, make bio-reactor, peristaltic pump group and Biochemical Analyzer collaborative work, setting range is stablized, accurately is controlled to the nutrient concentrations in the bio-reactor;
Described computer control system is a kind of based on the Biochemical Analyzer monitor signal, the computer control system of nutriment concentration in the FEEDBACK CONTROL bio-reactor, it includes digital control virtual instrument, digital I/O card and signal condition and driving circuit, in the digital control virtual instrument interface modular converter is arranged, be connected with Biochemical Analyzer with digital I/O card respectively by serial communication interface, numeral I/O card is connected with driving circuit with signal condition, special-purpose cellular incubation is housed with feeding back the feed supplement Control Software in the digital control virtual instrument;
After specific nutrition substrate concentration in the bio-reactor is regularly detected by Biochemical Analyzer, measuring-signal is sent into interface modular converter by serial ports, modular converter is sent into program-controlled computer through the communication expansion card and is read by general switching software, calculate the nutrients amount that should add in the bio-reactor according to the PID feedback control principle again, its digital control amount is by voltage output card output simulation controlled quentity controlled variable, by signal condition and the work of driving circuit control peristaltic pump group after being converted to the peristaltic pump amount of spin.
2. the system as claimed in claim 1 is characterized in that, described bio-reactor is used for animal cell culture, and a plurality of interfaces are arranged on the tank body, can be in the jar in cell cultivation process to nutrient solution sampling emit; Or, provide the cell growth required nutriment with in the outside liquid adding jar.
3. the system as claimed in claim 1 is characterized in that, described Biochemical Analyzer is used for specific nutrition substrate concentration in the periodic monitor bio-reactor behind the supporting respective detection film, and reads its measured value, input database by outside general switching software.
4. the system as claimed in claim 1 is characterized in that, described peristaltic pump group is made of a plurality of peristaltic pumps, and each peristaltic pump connects a concentrated nutrition liquid container, is used for follow procedure setting stream in bio-reactor and adds concentrated nutriment.
5. the system as claimed in claim 1 is characterized in that, described interface modular converter is used for that the specific nutrition material concentration that Biochemical Analyzer is monitored is converted to the real-time sampling data and sends into program-controlled computer.
6. the system as claimed in claim 1 is characterized in that, described signal condition and driving circuit are used for the analog quantity of voltage output card output is carried out conversion of signals, drive the peristaltic pump running.
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| CNB200510041968XA CN1316414C (en) | 2005-04-18 | 2005-04-18 | Program controlled feedback feeding-system for culturing cell |
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| CN1316414C true CN1316414C (en) | 2007-05-16 |
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| CN102399688B (en) * | 2011-09-18 | 2013-01-16 | 淮北市三和诺生物工程有限责任公司 | Methanol flowing feeding on-line disinfection method and automatic control system |
| CN109761344A (en) * | 2019-03-26 | 2019-05-17 | 中冶华天南京电气工程技术有限公司 | A kind of surface aeration Dissolved Oxygen Control Method |
| CN116855370A (en) * | 2023-07-19 | 2023-10-10 | 安及义实业（上海）有限公司 | Automatic feeding device and method for bioreactor or fermentation tank |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1260486A (en) * | 1999-02-23 | 2000-07-19 | 王劲松 | Detecting method and apparatus for yeast concentration (measuring bioconcentration) |
| CN2486557Y (en) * | 2001-01-19 | 2002-04-17 | 中国科学院化学研究所 | Cell cultivator |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1260486A (en) * | 1999-02-23 | 2000-07-19 | 王劲松 | Detecting method and apparatus for yeast concentration (measuring bioconcentration) |
| CN2486557Y (en) * | 2001-01-19 | 2002-04-17 | 中国科学院化学研究所 | Cell cultivator |
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Assignee: Jiangsu Pacific Meinuoke Biopharmaceutical Co., Ltd. Assignor: Chen Zhinan Contract fulfillment period: 2009.3.10 to 2015.3.10 contract change Contract record no.: 2009320000517 Denomination of invention: Program controlled feedback feeding-system for culturing cell Granted publication date: 20070516 License type: Exclusive license Record date: 2009.3.27 |
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Effective date of registration: 20160216 Address after: 710032 Changle West Road, Shaanxi, China, No. 169, No. Patentee after: The Fourth Military Medical University of the Chinese People's Liberation Army Address before: 710032 Changle West Road, Shaanxi, China, No. 17, No. Patentee before: Chen Zhinan |