CN102199536A - Apparatus and method for monitoring cell quantity or cell proportion during dynamic stem cell differentiation - Google Patents
Apparatus and method for monitoring cell quantity or cell proportion during dynamic stem cell differentiation Download PDFInfo
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- CN102199536A CN102199536A CN2010101306641A CN201010130664A CN102199536A CN 102199536 A CN102199536 A CN 102199536A CN 2010101306641 A CN2010101306641 A CN 2010101306641A CN 201010130664 A CN201010130664 A CN 201010130664A CN 102199536 A CN102199536 A CN 102199536A
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Abstract
The invention discloses an apparatus and a method for monitoring cell quantities or cell proportions during dynamic stem cell differentiation. The invention relates to the field of bioengineering, and especially relates to apparatuses and methods for the on-line or off-line monitoring of cell numbers or other relative information of dynamic cellular differentiation during the cultivation, amplification, and differentiation processes of stem cells. The apparatus comprises: an upstream cell culture solution supplying system or an upstream differentiation solution supplying system; upstream physiological and biochemical index detecting head chambers; detecting heads or connecting heads arranged in the upstream detecting head chambers with an aseptic and sealed condition; cell cultivating apparatuses, downstream physiological and biochemical index detecting head chambers; detecting heads or connecting heads arranged in the downstream detecting head chambers with an aseptic and sealed condition; a fluid speed controlling aseptic pusher; a downstream waste liquid or obtained solution system; and speed-controlling liquid-conveying tubing systems for connecting the above components. According to the method, on-line or off-line monitoring is carried out upon the gas/liquid phase of upstream/downstream cell cultivating system, for monitoring nutrients, metabolites, production concentrations, total quantities, or quantity differences of target cells. Quantities or other relative information of functioning cells or functioning precursor cells differentiated during stem cell differentiation processes can be dynamically obtained.
Description
Technical field
The present invention relates to a kind of apparatus and method of bioengineering field, specifically is the apparatus and method that a kind of stem cell is cultivated online or relevant informations such as dynamic noble cells quantity of off-line monitoring or quantitative proportion in amplification and the atomization.
Background technology
At present, along with the in-depth to stem-cell research, the evidence that more and more stem cells have multidirectional differentiation potential be it is found that, for example mesenchymal stem cells MSCs can be divided into scleroblast, adipocyte, chondrocyte, neurocyte etc., these results of study provide foundation for clinical application.But, people in most cases can only carry out discrete, non-dynamic, the evaluation of formula as a result to the phenomenon of differentiation of stem cells at present, and can not be to stem cell in atomization, the functioning cell quantity that is differentiated or its quantitative proportion carry out dynamic, instant, quantitative online or off-line monitoring and control.
Find by prior art documents, people such as Mark F.Pittenger are at " Science " April1999, " Multilineage Potential of Adult HumanMesenchymal Stem Cells " (the polyphyly differentiation potential of adult human marrow mesenchymal stem cell) literary composition report of delivering on the Vol.284.143-147, adult's mesenchymal stem cells MSCs has the polyphyly differentiation function, can be divided into scleroblast, adipocyte, muscle cell etc.The polyphyly differentiation potential of document proof adult bone marrow stem cell, but correlative study as other reports, can only identify the kind of its noble cells, and the quantity or the quantitative proportion of the functioning cell that stem cell is differentiated in atomization can not quantitatively be described.This development that from now on stem cell biological reactor is cultivated the commercial processes of preparation and directional induction differentiation has brought a blind area undoubtedly, and this present invention's problem of being intended to solve and blank of filling up just.
Summary of the invention
The present invention is directed to present shortage relevant informations such as the quantity of the cell that differentiated in the differentiation of stem cells process or quantitative proportion are carried out the method for quantitative, dynamic online or off-line monitoring, provide a kind of based on apparatus and method biochemical basis, simple and rapid, online or relevant informations such as off-line dynamic quantitative monitoring noble cells number and ratio thereof.
In the present invention, have distinctive according to the difference in functionality cell to certain nutrition or certain metabolite, the per unit cell count specific consumption rate of different values or than the principle of metabolic rate, it is distinctive that perhaps the difference in functionality cell may produce having of certain certain material that comprises the specific cells factor, the per unit cell count of different values is than the principle that produces speed, in the expansion of stem cells culturing process, when the stem cell total quantity is in stable state and does not begin the directional induction differentiation phase as yet, the nutrition specific consumption rate of cell or metabolite are substantially invariable than the ratio production rate that cumulative percentage or cell produce thing, promptly the closed continous pouring of cell culture apparatus on, reach the intravital target cell nutrition of gas phase or the metabolite concentration of cell cultures body in the liquid phase body of downstream cell cultures body or produce the thing difference and remain unchanged; But after stem cell directional is induced the differentiation beginning, the part stem cell begins to be divided into another functioning cell or function precursor cell, the whole apparent nutrition specific consumption rate of above-mentioned whole cell or metabolite just can change than production rate than metabolic rate or generation thing, according to or off-line monitoring arrive, on the closed continous pouring of cell culture apparatus, the gas of downstream cell cultures body, above-mentioned target nutrition or metabolite or the concentration of generation thing or the variation of total amount difference in the liquid phase body, and then by from or online monitoring control and/or computer system, dynamically obtain the quantity of the functioning cell that differentiated in the differentiation of stem cells process or function precursor cell or quantitative proportion in interior relevant information.
Compared with prior art, the invention has the beneficial effects as follows: have and stem cell is cultivated information such as the quantity of the cell that is differentiated in the atomization or quantitative proportion carry out quantitative, dynamic online or off-line monitoring function, provide a kind of based on apparatus and method biochemical basis, simple and rapid, online or information such as off-line dynamic quantitative monitoring noble cells number and ratio thereof.Realized that stem cell cultivates controlledization of atomization, can monitoring, for the stem cell clinical application, formulate statutory standards such as correlative GTP or GMP strong foundation is provided.
Description of drawings
Fig. 1 is the basic structure synoptic diagram of apparatus of the present invention;
Fig. 2 is the structural representation that apparatus of the present invention of the detection of a plurality of reason biochemical indicator or connecting joint and a plurality of cell culture apparatus of series-parallel connection are installed.
Embodiment
Core of the present invention is: the present invention has distinctive according to the difference in functionality cell to certain nutrition or certain metabolite, the per unit cell count specific consumption rate of different values or than the principle of metabolic rate, it is distinctive that perhaps the difference in functionality cell may produce having of certain certain material that comprises the specific cells factor, the per unit cell count of different values is than the principle that produces speed, in the differentiation of stem cells process, the quantity of the functioning cell that stem cell differentiated or the variation of quantitative proportion will cause the metabolism amount of above-mentioned target substance or the variation of generation, promptly the closed continous pouring of cell culture apparatus on, target nutrition or metabolite or generation substrate concentration difference or total amount difference change in the downstream; And the quantitative information of the quantity of the specific function cell that just can calculate in the differentiation of stem cells process immediately to be differentiated to the online or offline inspection of this concentration difference or total amount difference or quantitative proportion etc.
In the expansion of stem cells culturing process, when the stem cell total quantity is in stable state and does not begin the directional induction differentiation phase as yet, the nutrition specific consumption rate of cell or metabolite are substantially invariable than the ratio production rate that cumulative percentage or cell produce thing, promptly in the liquid phase body of the upstream and downstream cell cultures body of the closed continous pouring of cell culture apparatus the intravital target cell nutrition of gas phase or the metabolite concentration of (for example in the transport pipe in the cell mixture) and cell cultures body or produce the thing difference and remain unchanged; But after stem cell directional is induced the differentiation beginning, the part stem cell begins to be divided into another functioning cell or function precursor cell, and the whole apparent nutrition specific consumption rate of above-mentioned whole cell or metabolite just can change than production rate than metabolic rate or generation thing.According to or off-line monitoring to, above-mentioned target nutrition or metabolite or produce the concentration of thing or the variation of total amount difference in the gas, liquid body of the upstream and downstream cell cultures body of the closed continous pouring of cell culture apparatus, and then by from or online computer and supervisory system, the quantitative information of the functioning cell that calculates in the differentiation of stem cells process immediately to be differentiated or the quantity of function precursor cell or quantitative proportion etc.
The present invention is by realizing that with lower device and technical scheme the dynamic quantitative that the present invention relates to is monitored the method for differentiation of stem cells quantity or ratio, and realizes the perfusion culture bioreactor device system that this method and technology is related.This system comprise upstream cell culture fluid or differentiation liquid supply system 1, upstream reason biochemical indicator detecting head storehouse 3 and sterile seal be installed on wherein detection or connecting joint 4 (for example: survey or connecting joint 4 can be applicable to dissolved oxygen detecting head or the glucose detecting head or the lactic acid detecting head of liquid phase; The connection of GC-MS gas chromatography mass spectrometer device that perhaps is applied to gas phase is oral), detection or connecting joint quantity that above-mentioned reason biochemical indicator detecting head storehouse and sterile seal are installed on wherein may be greater than one, it is a plurality of reason biochemical indicator detecting heads storehouse 31,32 and corresponding detection or connecting joint 41,42, (it is by one or more bio-reactors for cell culture apparatus 5, the T bottle, rolling bottle, strings such as culture bag, compose in parallel), downstream reason biochemical indicator detecting head storehouse 6 and sterile seal be installed on wherein detection or connecting joint 7 (for example: dissolved oxygen detecting head or glucose detecting head or lactic acid detecting head or gas chromatography mass spectrometer joint; And can comprise more than a detecting head storehouse 61,62 and corresponding detection or connecting joint 71,72), fluid control speed aseptic pusher 8 (for example peristaltic pump), the downstream is useless or results liquid system 9, the liquid conducting pipes system 2 with fluid control aseptic pushers of speed and control speed is formed by connecting therebetween.Upstream and downstream reasons biochemical indicator detecting head or joint all through pipeline or data electric wire with monitor control system and/or computer 10 and be connected, with instant processing with obtain institute's monitoring data.
Its mode of connection is: upstream cell culture fluid or differentiation liquid supply system 1 are by controlled fast fluid pipeline 2 (as silicone tube), and (detection or connecting joint 4 sterile seals are installed in the gauge head storehouse 3 through reason biochemical indicator detecting head storehouse, upstream 3; Gauge head storehouse 3 can comprise a plurality of detecting heads storehouse 31,32 etc. and a plurality of detections or connecting joint 41,42 etc.), be connected to cell culture apparatus 5 inlets; Cell culture apparatus 5 outlets connect controlled fast fluid pipeline 2 (as silicone tube), and (detection or connecting joint 7 sterile seals are installed in the gauge head storehouse 6 through reason biochemical indicator detecting head storehouse, downstream 6; Can comprise a plurality of detecting heads storehouse 61,62 etc. and a plurality of detections or connecting joint 71,72 etc.), be connected to the useless or results liquid system 9 in downstream; The aseptic pusher 8 of fluid control speed can be connected on before the cell culture apparatus 5 or after fluid pipeline 2 on, mix the aseptic closed Continuous Flow of liquid through described whole apparatus system to promote and to control fast nutrient solution or differentiation liquid or cell.Reason biochemical indicator detecting head storehouse, downstream 6 must be as far as possible near connected cell culture apparatus 5, to improve the accuracy of detection data.If desired, a plurality of cell culture apparatus 51,52,53 etc. can also or after the series connection be connected between the detecting head storehouse 3 and 6 of upstream and downstream, in the hope of cultivating different cells, perhaps cultivate same cell but desire increases the cell quantity of total system and increases institute's detection of a target substrate concentration value or concentration difference (detectable signal of amplification target thing).
Described controlled fast liquid flow conduits is installed sealed, sterile, the nontoxic pipeline that Sliding Control valve or clip come nutrient solution flow velocity in the control tube, for example cell cultures silicone tube for cooperating.
Described reason biochemical indicator detecting head or connecting joint can be monitored target compound concentration or amount or active probe or connecting joint in the liquid phase of cell cultures body or the gas phase, for example are applied to monitor dissolved oxygen detecting head or the glucose detecting head or the lactic acid detecting head of target compound in the liquid phase; The connection of GC-MS gas chromatography mass spectrometer device that perhaps is applied to target compound in the gas phase is oral.Detecting head or connecting joint can be aseptic, hermetically in the resonable biochemical indicator detecting head of the plug-in mounting storehouse.
Described reason biochemical indicator detecting head storehouse is the device that salable dress is plugged target compound concentration in the liquid phase of stating monitoring cell cultures body or the gas phase or amount or active probe or connecting joint, and reason biochemical indicator detecting head storehouse is the sealed, sterile connection with being connected of probe or connecting joint.
Described cell culture apparatus is the aggregation system that upstream and downstream is made up of reusable or disposable one or more cell culture apparatus such as the various cell biological reactors of liquid inlet, liquid exit, cell cultures wave device, cell factories, cell cultures T bottle, cell cultures rolling bottle, cell cultures culture bag respectively; It can be single a kind of, also can be that the various kinds of cell culture apparatus combines by series and parallel.
The aseptic pusher of described fluid control speed is the aseptic propelling nutrient solution mobile device of various controlled speed, for example cell cultures peristaltic pump.
When the inventive method and device work, cell culture fluid or differentiation liquid or cell mix the aseptic closed Continuous Flow of liquid through described apparatus system, and upstream and downstream reason biochemical indicator detection or connecting joint 4,7 are (for example: the dissolved oxygen detecting head or glucose detecting head or the lactic acid detecting head that are applied to liquid phase; The connection of GC-MS gas chromatography mass spectrometer device that perhaps is applied to gas phase is oral), can dynamically, immediately detect concentration or total amount or activity or its difference or its variation of target cell nutrition or the cell metabolite or the cell generation thing of one or more selected detections, and then by monitoring control system and/or computer system 10, off-line or relevant information such as the quantity of the quantitative Analysis cell that goes out in the differentiation of stem cells process to be differentiated or quantitative proportion online.
The concrete operation method of a kind of embodiment of the present invention is as follows:
The first step. use various cell cultures to cut pistol with connection plug, bolt, plug etc. and silicone tube hot melt, cooperate aseptic breather filter (for example filter in 0.2 micron hole), Sliding Control valve or clip etc., with 3,4,5,6,7,8,9,10 of apparatus of the present invention, liquid conducting pipes system 2 by apparatus of the present invention connects into work system according to the order of sequence;
Second goes on foot. and after checking that by air pressure stopping property is qualified, whole apparatus system is carried out the high-temperature steam sterilization, be sterile state in the assurance system;
The 3rd step. prepare the aseptic attitude upstream cell culture fluid or the differentiation liquid supply system 1 of link cost contrive equipment by modes such as sterile filtrations;
The 4th step. with upstream of the present invention cell culture fluid or differentiation liquid supply system 1,, be connected with total system after the sterilization by the liquid conducting pipes system 2 of apparatus of the present invention, complete to reach, be the system that can start operating conditions;
The 5th step. according to the kind and the character of the cell culture apparatus 5 of apparatus of the present invention, select to use carbon dioxide cell incubator; Perhaps use functions such as temperature control that cell culture apparatus 5 self possesses, control dissolved oxygen, control potential of hydrogen;
The 6th step. start the fluid control speed aseptic pusher 8 (for example cell cultures peristaltic pump) of apparatus of the present invention, after total system was cleaned in the perfusion of use clean water, the perfusion cell culture fluid left standstill 1-3 day, to monitor aseptic attitude;
The 7th step. start the fluid control speed aseptic pusher 8 (for example cell cultures peristaltic pump) of apparatus of the present invention, pour into fresh cell culture fluid, inoculating cell in the cell culture apparatus 5 of apparatus of the present invention, beginning static (non-perfusion) is cultivated;
The 8th step. according to cell growth state, start the perfusion cultured continuously.Regulate cell cultures peristaltic pump speed to satisfy the demand of cell growth and target compound upstream and downstream reason biochemical indicator detectivity;
The 9th step. according to cell growth state, start the differentiation of stem cells perfusion, begin to induce atomization;
The tenth step. start detection or connecting joint 4, reason biochemical indicator detecting head storehouse 6, downstream and the sterile seal that the reason biochemical indicator detecting head storehouse 3, upstream of apparatus of the present invention and sterile seal be installed on wherein and be installed on wherein detection or connecting joint 7, upstream and downstream reason biochemical indicator monitoring control system and/or computer 10, begin that stem cell is cultivated information such as the quantity of the cell that is differentiated in the atomization or quantitative proportion and carry out quantitative, dynamic online or off-line monitoring.
Claims (8)
1. device of monitoring dynamic noble cells quantity of stem cell or ratio, be used for cultivating and atomization is online or off-line monitoring noble cells number or noble cells are counted the associated dynamic information of ratio stem cell, it is characterized in that, comprise: upstream cell culture fluid or differentiation liquid supply system, reason biochemical indicator detecting head storehouse, upstream and sterile seal are installed on detection or connecting joint wherein, cell culture apparatus, reason biochemical indicator detecting head storehouse, downstream and sterile seal are installed on detection or connecting joint wherein, the aseptic pusher of fluid control speed, useless or the results liquid system in downstream, fast liquid conducting pipes system is formed by connecting and keep liquid-flow by the aseptic pusher of fluid control speed with controlling therebetween, on, downstream reason biochemical indicator detecting head or joint are connected with monitoring control system and/or computer through pipeline or data electric wire respectively, described supervisory system and/or computer, last in order to regularly to pass through, downstream reason biochemical indicator detecting head or joint detect the closed continous pouring of cell culture apparatus on, target nutrition or metabolite or produce the substrate concentration difference or the total amount difference value of changing in the downstream just can calculate the quantity that comprises the specific function cell that differentiated in the differentiation of stem cells process or the quantitative information of quantitative proportion immediately to the online or offline inspection of this concentration difference or total amount difference again.
2. device according to claim 1 is characterized in that, described upstream and downstream reason biochemical indicator surveys or connecting joint comprises dissolved oxygen detecting head or glucose detecting head or the lactic acid detecting head that is applied to liquid phase; Perhaps be applied to the oral various devices at specific objective monitoring thing of connection of the GC-MS gas chromatography mass spectrometer device of gas phase, detection or connecting joint quantity that above-mentioned reason biochemical indicator detecting head storehouse and sterile seal are installed on wherein are one or more.
3. device according to claim 1, it is characterized in that the aggregation system that described cell culture apparatus is made up of the reusable or disposable one or more cell culture apparatus that comprises various cell biological reactors, cell cultures wave device, cell factories, cell cultures T bottle, cell cultures rolling bottle, cell cultures culture bag; It is that single one or more cell culture apparatus combine by series and parallel, increase institute's detection of a target substrate concentration value or concentration difference, the i.e. detectable signal of amplification target thing by increasing the series and parallel cell culture apparatus with the cell quantity that increases total system.
4. device according to claim 1, it is characterized in that, described cell culture apparatus is provided with the entrance and exit of upstream and downstream culturing mixt, cell cultures and related detection target nutrition, metabolite, the generation thing of differentiation are closed in the interior liquid and gas of continous pouring system, can not leak loss and cause the monitoring error, the target monitoring material of especially cultivating in the body gas phase can all be collected to monitoring device through sealing-duct.
5. device according to claim 1 is characterized in that, the aseptic pusher of described fluid control speed is the liquid asepsis conveying thrust unit that comprises peristaltic pump, can regulate the controlled liq velocity of flow.
6. method of monitoring dynamic noble cells quantity of stem cell or ratio, be used for obtaining stem cell is cultivated and atomization or off-line monitoring noble cells number or noble cells count ratio in interior associated dynamic information, it is characterized in that, may further comprise the steps: have distinctive to certain nutrition or certain metabolite according to the difference in functionality cell, the per unit cell count specific consumption rate of different values or than the principle of metabolic rate, it is distinctive that perhaps the difference in functionality cell may produce having of certain certain material that comprises the specific cells factor, the per unit cell count of different values is than the principle that produces speed, in the expansion of stem cells culturing process, when the stem cell total quantity is in stable state and does not begin the directional induction differentiation phase as yet, the nutrition specific consumption rate of cell or metabolite are substantially invariable than the ratio production rate of cumulative percentage or cell generation thing, but after stem cell directional is induced the differentiation beginning, the part stem cell begins to be divided into another functioning cell or function precursor cell, the whole apparent nutrition specific consumption rate of above-mentioned whole cell or metabolite just can change than production rate than metabolic rate or generation thing, according to or off-line monitoring arrive, on the closed continous pouring of cell culture apparatus, the gas of downstream cell cultures body, above-mentioned target nutrition or metabolite or the concentration of generation thing or the variation of total amount difference in the liquid phase body, and then by from or online monitoring control and/or computer system, dynamically obtain the quantity of the functioning cell that differentiated in the differentiation of stem cells process or function precursor cell or quantitative proportion in interior relevant information.
7. method as claimed in claim 6 is characterized in that, also comprises:
One device is provided, described device comprises upstream cell culture fluid or differentiation liquid supply system, reason biochemical indicator detecting head storehouse, upstream and sterile seal are installed on detection or connecting joint wherein, cell culture apparatus, reason biochemical indicator detecting head storehouse, downstream and sterile seal are installed on detection or connecting joint wherein, the aseptic pusher of fluid control speed, useless or the results liquid system in downstream, fast liquid conducting pipes system is formed by connecting and keep liquid-flow by the aseptic pusher of fluid control speed with controlling therebetween, on, downstream reason biochemical indicator detecting head or joint are connected with monitoring control system and/or computer through pipeline or data electric wire respectively;
Monitoring control system and/or computer detect in the gas, liquid body of upstream and downstream cell cultures body of the closed continous pouring of cell culture apparatus above-mentioned target nutrition or metabolite or produce the concentration of thing or the variation of total amount difference by those detecting heads, and then obtain the quantity of the functioning cell that differentiated in the differentiation of stem cells process or function precursor cell or quantitative proportion in interior relevant information.
8. method as claimed in claim 7 is characterized in that, also comprises:
The target monitoring material of cultivating in the body gas phase body is all collected to monitoring device through sealing-duct.
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| CN2010101306641A CN102199536A (en) | 2010-03-23 | 2010-03-23 | Apparatus and method for monitoring cell quantity or cell proportion during dynamic stem cell differentiation |
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| CN2010101306641A CN102199536A (en) | 2010-03-23 | 2010-03-23 | Apparatus and method for monitoring cell quantity or cell proportion during dynamic stem cell differentiation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103031250A (en) * | 2012-10-17 | 2013-04-10 | 浙江赛尚医药科技有限公司 | Cell culture pipeline device and automatic cell culture system |
| CN109401970A (en) * | 2018-12-19 | 2019-03-01 | 南京比瑞生物科技有限公司 | A kind of multi-functional T bottles of full-automatic, totally-enclosed expansion of stem cells, induction Differentiation System |
| CN111855509A (en) * | 2020-07-27 | 2020-10-30 | 淄博市中心医院 | Cell monitoring system based on bone marrow cell differentiation |
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| CN111855509A (en) * | 2020-07-27 | 2020-10-30 | 淄博市中心医院 | Cell monitoring system based on bone marrow cell differentiation |
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Application publication date: 20110928 |