CN100544684C - The artificial liver microcapsule suspension type fluidized bed type bioreactor - Google Patents
The artificial liver microcapsule suspension type fluidized bed type bioreactor Download PDFInfo
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- CN100544684C CN100544684C CNB2007100702790A CN200710070279A CN100544684C CN 100544684 C CN100544684 C CN 100544684C CN B2007100702790 A CNB2007100702790 A CN B2007100702790A CN 200710070279 A CN200710070279 A CN 200710070279A CN 100544684 C CN100544684 C CN 100544684C
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Abstract
The invention belongs to medical biotechnology field, be the artificial liver microcapsule suspension type fluidized bed type bioreactor.Reactor is the big infundibulate in footpath, little top, footpath, the end, last cervical region has cell screen cloth 8, lower bottom part has cell screen cloth 7, liquid outlet 2 places are provided with cellular filter 11, between liquid-inlet 1 and the cell screen cloth 7, a buffering loculus district 12 is respectively arranged between cellular filter 11 and the cell screen cloth 8, hold microencapsulated hepatocyte 9 between cell screen cloth 8 and the cell screen cloth 7; The external membrane oxygenator 14 of liquid-inlet, liquid outlet is external to be used to adsorb immune macromolecular immunoadsorption device 15.Bioreactor for artificial liver provided by the invention is owing to be designed to infundibulate, and the container bottom footpath is little, and the footpath, top is big, the movement locus of impact flow is demulcent parabola, meet the hydrodynamics characteristics, effectively avoid perfusion dead space and invalid perfusion, can effectively bring into play bioartificial liver's therapeutical effect.
Description
Technical field
The invention belongs to field of biomedicine technology, relate to a kind of armarium, a kind of core apparatus---artificial liver microcapsule suspension type fluidized bed type bioreactor for biotype or mixed biology artificial liver treatment.
Background technology
Bioreactor is the core apparatus of biotype and hybrid artificial liver support system, be not only the place that exogenous hepatocyte and patient blood or blood plasma carry out mass exchange, also provide comparatively ideal growing environment for hepatocyte, generally to meet following basic demand as bioreactor for artificial liver: middle micromolecule transmitted in both directions, and the macromolecular substances immunity deadens a guarantee hepatocyte activity and a constant volume.
At present, what wherein application at present was maximum is hollow-fiber bioreactor, but it is inhomogeneous that the shortcoming of hollow-fiber bioreactor is a cell distribution, cell adhesion is poor, hepatocyte can be gathered into bigger agglomerate in actual applications, both influence its growth metabolism function, easily caused the obstruction of semipermeable membrane again, be unfavorable for mass exchange.In order to overcome this shortcoming, hepatocyte is wrapped in the microcapsule of permeability, constituted the hepatocyte of microencapsulation, put in the reaction vessel, also directly carry out perfusion with this with blood plasma/cultivation, made up microcapsule-type suspension type biological reactor artificial liver support system, for the artificial liver treatment provides new trial, the result shows that microcapsule suspension type bioreactor can show its special advantages aspect the raising mass exchange efficient, this efficacy exertion to bioreactor is particularly important, the microencapsulated hepatocyte bioreactor is to take to solidify the design of bed formula bioreactor at first, only be fit to the meiofauna experiment, but after amplifying application limitation is just arranged, be because direct path has caused the hepatocyte low perfusion state of a large amount of microencapsulation, influence the inside and outside mass exchange of microcapsule membrane, and material absorbing, transform function of detoxification, and under the high shear of perfusate, the easier damage of fixed microencapsulated hepatocyte.So adopting the fluidized bed type bioreactor to be more suitable for microencapsulated hepatocyte plays a role in this bioartificial liver system.But traditional bioartificial liver's fluidized bed reactor adopts column type, also has the perfusion dead space under general flow velocity, even the problem of invalid perfusion and border effect, has influenced Supporting Therapy's effect of bioartificial liver.
Summary of the invention
The object of the present invention is to provide a kind of microcapsule suspension type fluidized bed type bioreactor that is applicable to biological artificial liver, avoid the perfusion dead space, easy and simple to handle, cost is low, and effect is stronger.
Artificial liver microcapsule suspension type fluidized bed type bioreactor of the present invention, comprise liquid-inlet 1, liquid outlet 2, microcapsule and preflush inlet 3 and sample tap 5, reactor is the big infundibulate 13 in footpath, little top, footpath, the end, the last cervical region of infundibulate reactor has cell screen cloth 8, lower bottom part has cell screen cloth 7, liquid outlet 2 places are provided with cellular filter 11, between liquid-inlet 1 and the cell screen cloth 7, a buffering loculus district 12 is respectively arranged between cellular filter 11 and the cell screen cloth 8, hold microencapsulated hepatocyte 9 between cell screen cloth 8 and the cell screen cloth 7; Liquid-inlet 1 external membrane oxygenator 14, liquid outlet 2 is external to be used to adsorb immune macromolecular immunoadsorption device 15.
The diameter of above-mentioned cell screen cloth 7 is 20-40mm, and mesh size 200-300 order, the diameter of cell screen cloth 8 are 60-80mm, mesh size 600-700 order, and the aperture of cellular filter 11 is 1-5um.
Microcapsule and preflush inlet 3 are arranged on 20mm-40mm place, cell screen cloth 8 below, and preparation valve 4; Sample tap 5 is arranged on cell screen cloth 7 above 20mm-30mm places, preparation valve 6.
The present invention program is further described below:
The artificial liver that is used for of the present invention comprises liquid entrance 1,2, microcapsule inlet 3 and sample tap 5 with novel microcapsule-type fluidized bed type bioreactor, and container appearances is infundibulate 13, meets the hydrodynamics characteristics.The container bottom footpath is little, the footpath, top is big, filler neck, hopper base have the cell screen cloth 7,8 in different apertures, microencapsulated hepatocyte for circulating between the last lower screen cloth, upper and lower side connects outlet and inlet respectively, and there is cellular filter 11 in the exit, and there is membrane oxygenator 14 the inlet upstream, there is the immune macromolecular immunoadsorption device 15 of absorption in the outlet downstream, between inlet and outlet and the cell screen cloth a relative relief area 12 is arranged respectively.Chamber housing microencapsulated hepatocyte and reactor activity composition that infundibulate housing 13 constitutes.The cell screen cloth 7 of filler neck, its diameter 20-40mm, mesh size 200-300 order, the cell screen cloth 8 of hopper base, its cell screen cloth 60-80mm, mesh size 600-700 order, the cellular filter net 11 of hopper outlet, aperture 1-5um.Near the about 20mm-40mm of hopper base cell screen cloth place microcapsule/preflush inlet 3 is arranged, use for inoculation microcapsule and pre-flushing, and inlet has standby valve-off 4, near filler neck screen cloth 20mm-30mm sample tap 5 is being arranged, sampling usefulness for microcapsule and liquid in the artificial liver therapeutic process has standby valve-off 6 too.Artificial liver of the present invention needs important auxiliary device with the microcapsule suspension type fluidized bed type reactor, one is at the membrane oxygenator 14 near the reactor upstream, one is the immunoadsorption device 15 near reactor downstream, and they and reactor body constitute complete artificial liver microcapsule suspension type fluidized bed type reactor assembly.
Artificial liver provided by the present invention is designed to infundibulate with novel microcapsule-type fluidized bed type bioreactor, and the container bottom footpath is little, and the footpath, top is big, the impact flow track is demulcent parabola, meet the hydrodynamics characteristics, effectively avoid perfusion dead space and invalid perfusion, effect is stronger.
The cell screen cloth 7,8 that different apertures are arranged near filler neck, hopper base, microencapsulated hepatocyte 9 for circulating between the last lower screen cloth, upper and lower side connects outlet and inlet respectively, there is membrane oxygenator 14 the inlet upstream, there is an immune macromolecular immunoadsorption device 15 of absorption in the outlet downstream, between inlet and outlet and the cell screen cloth a relative relief area 12 is arranged respectively.
Funnel-shaped container of the present invention can and dwindle according to clinical specific requirement amplification, and the import and export of funnel-shaped container are at the two ends up and down of container, and close container top has the inlet 3 of microcapsule and preflush, near the bottom sample tap 5 is arranged.
Description of drawings
Fig. 1 is the perspective view of artificial liver with the microcapsule suspension type fluidized bed type bioreactor main body.
Fig. 2 is the artificial liver external system supplymentary schematic representation of apparatus of microcapsule suspension type fluidized bed type bioreactor.
The specific embodiment
The present embodiment artificial liver is an infundibulate with microcapsule suspension type fluidized bed type reactor profile, plastics or lucite shell, and size dimension is: long 20cm, funnel top footpath 6cm, footpath, end 3cm, volume is 800ml.Can amplify as required or dwindle during actual fabrication, formulate needed size.
As Fig. 1, shown in Figure 2: 1 is blood/plasma/or culture fluid inlet, enter in the fluidized bed reactor container for blood/plasma/culture fluid, carry out mass exchange with microencapsulated hepatocyte therein, 2 confession blood/plasma/or the culture fluid outlet, 3 for entering the mouth towards liquid/microencapsulated hepatocyte in advance, inject hepatocyte suspension and pour by this inlet in advance towards liquid, 4 is valve, close after the microencapsulated hepatocyte inoculation, 5 is sample tap, for taking a sample in the artificial liver therapeutic process, 6 is the sample tap valve-off, 7 is the cell screen cloth in footpath at the bottom of the hopper reactor, the liquid that flows into through this screen cloth makes the continuous shuttling movement of microencapsulated hepatocyte by fluidization, be convenient to mass exchange, 8 is the big cell screen cloth in microcapsule infundibulate reactor top footpath, from then on liquid after the microencapsulated hepatocyte fluidization flowed out, pass through and stop microencapsulated hepatocyte, 9 is the hepatocyte of microencapsulation, contain hepatocellular microcapsule for external by what generator for microcapsules was made, average diameter 400-500um, under the fluidization of liquid, constantly circulation, carry out mass exchange, 10 is lucite or cabinet, 11 is cellular filter, be for preventing that cell or cell debris from entering the immunoreation that blood flow produces body, 12 is reactor liquid stream relief area, make in order to keep hemodynamic stablizing, 13 is whole infundibulate fluidized bed reactor schematic appearance, and 14 is oxygenator, make that to carry in the oxygen supply fluidized bed reactor microencapsulated hepatocyte behind blood plasma/culture fluid oxygenate required, 15 is the immunoadsorption device, adsorbs the immune macromolecular substances (IgG that a small amount of microcapsule spills, IgM and complement series), prevent to enter body generation immunoreation.
This example is the fluidization that prevents from easily to gather after microcapsule from depositing agglomerating employing liquid, be convenient to the material friendshipization, for solving traditional invalid perfusion of cylindricality development of evil in febrile disease bed bioreactor and low perfusion situation, adopted funnel-shaped design, the microencapsulated hepatocyte that external making is in advance also cultivated becomes the many cells congeries, be seeded in the fluidized bed reactor, part is brought into play hepatocellular alternative functions.
The comparing advantage with fluidized bed reactor in the past and be of this infundibulate fluidized bed reactor:
The present invention is a kind of hydromechanical microcapsule suspension type fluidized bed type reactor that meets. Because microencapsulated hepatocyte is easy to sink Amass, and be easy to adhere to each other, be difficult to separately, more outstanding when using especially on a large scale the liver cell micro-capsule, Must take the method for liquid stream fluidisation, the direct perfusion of traditional fixed bed reactors, shearing force is big, exist low perfusion state or There is relative perfusion dead space, is conducive to the iterative cycles motion of micro-capsule with the reactor of fluidized bed type, reduce shearing force, more sharp In material exchange. Traditional fluidized bed reactor adopts column type, also has perfusion dead space and edge effect under general flow velocity, Adopt the funnel shaped fluidized bed reactor more to meet the hydrodynamics of micro-capsule according to hydromechanical characteristics, do at fluid like this Do the parabola shuttling movement with lower more favourable micro-capsule, optimized the fluid effect of microencapsulated hepatocyte, more favourable material is handed over Change. There is buffering area at this funnel type reactor two ends, and liquid stream is relatively steady in the artificial liver process, are keeping fluid dynamic Learn and stablize the advantage that the aspect can show uniqueness.
This bioartificial liver's micro-capsule fluidized bed reactor system is that artificial liver has been opened up new way, and function is comparatively comprehensive, operation Convenient, it is comparatively reasonable to design, and has good application prospect.
Claims (4)
1, the artificial liver microcapsule suspension type fluidized bed type bioreactor, comprise liquid-inlet (1), liquid outlet (2), microcapsule and preflush inlet (3) and sample tap (5), it is characterized in that: reactor is the big infundibulate (13) in footpath, little top, footpath, the end, the last cervical region of infundibulate reactor has the first cell screen cloth (8), lower bottom part has the second cell screen cloth (7), liquid outlet (2) locates to be provided with cellular filter (11), between the liquid-inlet (1) and the second cell screen cloth (7), a buffering little alveolus (12) is respectively arranged between the cellular filter (11) and the first cell screen cloth (8), hold microencapsulated hepatocyte (9) between the first cell screen cloth (8) and the second cell screen cloth (7); The external membrane oxygenator of liquid-inlet (1) (14), liquid outlet (2) is external to be used to adsorb immune macromolecular immunoadsorption device (15).
2, artificial liver microcapsule suspension type fluidized bed type bioreactor according to claim 1, it is characterized in that: the diameter of the described second cell screen cloth (7) is 20-40mm, mesh size 200-300 order, the diameter of the described first cell screen cloth (8) is 60-80mm, mesh size 600-700 order, the aperture of described cellular filter (11) is 1-5um.
3, artificial liver microcapsule suspension type fluidized bed type bioreactor according to claim 1 is characterized in that: microcapsule and preflush inlet (3) are arranged on 20mm-40mm place, the first cell screen cloth (8) below, and prepare first valve (4); Sample tap (5) is arranged on the above 20mm-30mm of the second cell screen cloth (7) place, prepares second valve (6).
4, artificial liver microcapsule suspension type fluidized bed type bioreactor according to claim 1 is characterized in that: the spatial altitude that cushions little alveolus (12) is 15mm-20mm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100702790A CN100544684C (en) | 2007-08-13 | 2007-08-13 | The artificial liver microcapsule suspension type fluidized bed type bioreactor |
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| CNB2007100702790A CN100544684C (en) | 2007-08-13 | 2007-08-13 | The artificial liver microcapsule suspension type fluidized bed type bioreactor |
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| CN101129276A CN101129276A (en) | 2008-02-27 |
| CN100544684C true CN100544684C (en) | 2009-09-30 |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7160719B2 (en) | 2002-06-07 | 2007-01-09 | Mayo Foundation For Medical Education And Research | Bioartificial liver system |
| EP2405957B1 (en) | 2009-03-13 | 2020-12-23 | Mayo Foundation For Medical Education And Research | Bioartificial liver |
| CN102091360B (en) * | 2011-01-18 | 2012-08-29 | 南方医科大学珠江医院 | Reciprocally turning perfusion bioreactor for biological artificial liver and processing method thereof |
| CN102210892B (en) * | 2011-05-05 | 2012-12-19 | 浙江大学 | Integrated microcapsule suspension fluidized bed bioreactor |
| CN103566421B (en) * | 2012-07-18 | 2016-08-03 | 中国科学院大连化学物理研究所 | A kind of artificial liver is with magnetic field fluidized bed load microcapsule reactor |
| CN103170021A (en) * | 2013-04-11 | 2013-06-26 | 浙江大学 | Deflector-type micro-capsule suspension type fluidized bed bioreactor for artificial liver |
| CN109456891A (en) * | 2018-12-05 | 2019-03-12 | 中国人民解放军第四军医大学 | A kind of efficient plasma exchange system of bionical tissue engineering epidermis diaphragm |
| CN109966579B (en) * | 2019-05-24 | 2019-08-23 | 上海赛立维生物科技有限公司 | Biological reaction apparatus and bio-reaction system |
| CN110205245B (en) * | 2019-06-14 | 2022-07-08 | 科先医疗科技(苏州)有限公司 | Cell reactor for biological artificial liver support system |
| CN114432583B (en) * | 2022-04-11 | 2022-07-08 | 杭州谷禾信息技术有限公司 | Microecological transplanting device for vagina |
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Assignee: Weihai Weigao Life Science & Technology Co., Ltd. Assignor: Zhejiang University Contract record no.: 2012330000164 Denomination of invention: Microcapsule suspension type fluidized bed type bioreactor for artificial liver Granted publication date: 20090930 License type: Exclusive License Open date: 20080227 Record date: 20120411 |