CN101129276A - Microcapsule Suspension Fluidized Bed Bioreactor for Artificial Liver - Google Patents
Microcapsule Suspension Fluidized Bed Bioreactor for Artificial Liver Download PDFInfo
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- CN101129276A CN101129276A CNA2007100702790A CN200710070279A CN101129276A CN 101129276 A CN101129276 A CN 101129276A CN A2007100702790 A CNA2007100702790 A CN A2007100702790A CN 200710070279 A CN200710070279 A CN 200710070279A CN 101129276 A CN101129276 A CN 101129276A
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- cell
- fluidized bed
- cell screen
- artificial liver
- microcapsule
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 37
- 210000004185 liver Anatomy 0.000 title claims abstract description 32
- 239000000725 suspension Substances 0.000 title claims abstract description 18
- 210000004027 cell Anatomy 0.000 claims abstract description 45
- 210000003494 hepatocyte Anatomy 0.000 claims abstract description 28
- 239000007788 liquid Substances 0.000 claims abstract description 24
- 239000012528 membrane Substances 0.000 claims abstract description 8
- 229920002521 macromolecule Polymers 0.000 claims abstract description 4
- 238000005070 sampling Methods 0.000 claims description 3
- 239000011148 porous material Substances 0.000 claims 2
- 230000010412 perfusion Effects 0.000 abstract description 15
- 239000012530 fluid Substances 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000004744 fabric Substances 0.000 description 24
- 230000000694 effects Effects 0.000 description 8
- 230000001413 cellular effect Effects 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 238000005243 fluidization Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000012531 culture fluid Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 229920005479 Lucite® Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000012510 hollow fiber Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 208000015220 Febrile disease Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- External Artificial Organs (AREA)
Abstract
本发明属于医学生物技术领域，为人工肝用微囊悬浮型流化床式生物反应器。反应器呈底径小顶径大的漏斗形，上颈部有细胞筛网8，下底部有细胞筛网7，液体出口2处设置细胞滤器11，液体进口1与细胞筛网7之间，细胞滤器11与细胞筛网8之间各有一个缓冲小腔区12，细胞筛网8和细胞筛网7之间容纳微囊化肝细胞9；液体进口外接膜氧合器14，液体出口外接用于吸附免疫大分子的免疫吸附器15。本发明提供的人工肝用生物反应器由于设计为漏斗形，容器底径小，顶径大，流动冲击的运动轨迹为缓和的抛物线，符合流体力学特点，有效避免灌流死腔及无效灌流，能有效发挥生物人工肝的治疗作用。
The invention belongs to the field of medical biotechnology, and is a microcapsule suspension type fluidized bed bioreactor for an artificial liver. The reactor is funnel-shaped with a small bottom diameter and a large top diameter. There is a cell screen 8 on the upper neck, and a cell screen 7 on the lower bottom. A cell filter 11 is set at the liquid outlet 2. Between the liquid inlet 1 and the cell screen 7, There is a small buffer cavity area 12 between the cell filter 11 and the cell screen 8, and the microencapsulated hepatocytes 9 are accommodated between the cell screen 8 and the cell screen 7; the liquid inlet is externally connected to the membrane oxygenator 14, and the liquid outlet is externally connected to Immunosorber 15 for adsorbing immune macromolecules. The artificial liver bioreactor provided by the present invention is designed to be funnel-shaped, the bottom diameter of the container is small, the top diameter is large, and the trajectory of the flow impact is a gentle parabola, which conforms to the characteristics of fluid mechanics, effectively avoids perfusion dead space and ineffective perfusion, and can Effectively exert the therapeutic effect of bioartificial liver.
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)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100702790A CN100544684C (en) | 2007-08-13 | 2007-08-13 | Microcapsule Suspension Fluidized Bed Bioreactor for Artificial Liver |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100702790A CN100544684C (en) | 2007-08-13 | 2007-08-13 | Microcapsule Suspension Fluidized Bed Bioreactor for Artificial Liver |
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| CN101129276A true CN101129276A (en) | 2008-02-27 |
| CN100544684C CN100544684C (en) | 2009-09-30 |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102091360A (en) * | 2011-01-18 | 2011-06-15 | 南方医科大学珠江医院 | Reciprocally turning perfusion bioreactor for biological artificial liver and processing method thereof |
| CN102210892A (en) * | 2011-05-05 | 2011-10-12 | 浙江大学 | Integrated microcapsule suspension fluidized bed bioreactor |
| CN102421467A (en) * | 2009-03-13 | 2012-04-18 | 梅约医学教育与研究基金会 | Bioartificial liver |
| CN103170021A (en) * | 2013-04-11 | 2013-06-26 | 浙江大学 | Deflector-type micro-capsule suspension type fluidized bed bioreactor for artificial liver |
| CN103566421A (en) * | 2012-07-18 | 2014-02-12 | 中国科学院大连化学物理研究所 | Magnetic-field fluidized bed micro-capsule-loaded artificial liver reactor |
| US8785117B2 (en) | 2002-06-07 | 2014-07-22 | Mayo Foundation For Medical Education And Research | Method for treating blood or plasma using hepatocyte spheroids |
| 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 |
| CN109966579A (en) * | 2019-05-24 | 2019-07-05 | 上海赛立维生物科技有限公司 | Bioreactors and Bioreaction Systems |
| CN110205245A (en) * | 2019-06-14 | 2019-09-06 | 科先医疗科技(苏州)有限公司 | A kind of cell reactor for Biotype artificial liver |
| CN113073053A (en) * | 2021-03-30 | 2021-07-06 | 弗元(上海)生物科技有限公司 | Cell culture reactor |
| CN114432583A (en) * | 2022-04-11 | 2022-05-06 | 杭州谷禾信息技术有限公司 | Microecological transplantation device for vagina |
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2007
- 2007-08-13 CN CNB2007100702790A patent/CN100544684C/en active Active
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8785117B2 (en) | 2002-06-07 | 2014-07-22 | Mayo Foundation For Medical Education And Research | Method for treating blood or plasma using hepatocyte spheroids |
| US9650609B2 (en) | 2002-06-07 | 2017-05-16 | Mayo Foundation For Medical Education And Research | Bioartificial liver system |
| EP2405957A4 (en) * | 2009-03-13 | 2017-07-12 | Mayo Foundation For Medical Education And Research | Bioartificial liver |
| CN102421467A (en) * | 2009-03-13 | 2012-04-18 | 梅约医学教育与研究基金会 | Bioartificial liver |
| US10792410B2 (en) | 2009-03-13 | 2020-10-06 | Mayo Foundation For Medical Education And Research | Bioartificial liver |
| US10130748B2 (en) | 2009-03-13 | 2018-11-20 | Mayo Foundation For Medical Education And Research | Bioartificial liver |
| CN102091360A (en) * | 2011-01-18 | 2011-06-15 | 南方医科大学珠江医院 | Reciprocally turning perfusion bioreactor for biological artificial liver and processing method thereof |
| CN102210892A (en) * | 2011-05-05 | 2011-10-12 | 浙江大学 | Integrated microcapsule suspension fluidized bed bioreactor |
| CN102210892B (en) * | 2011-05-05 | 2012-12-19 | 浙江大学 | Integrated microcapsule suspension fluidized bed bioreactor |
| CN103566421A (en) * | 2012-07-18 | 2014-02-12 | 中国科学院大连化学物理研究所 | Magnetic-field fluidized bed micro-capsule-loaded artificial liver reactor |
| 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 |
| CN109456891B (en) * | 2018-12-05 | 2024-08-16 | 中国人民解放军第四军医大学 | Efficient plasma replacement system for bionic tissue engineering epidermis membrane |
| CN109966579A (en) * | 2019-05-24 | 2019-07-05 | 上海赛立维生物科技有限公司 | Bioreactors and Bioreaction Systems |
| US12102743B2 (en) | 2019-05-24 | 2024-10-01 | Shanghai Celliver Biotechnology Co., Ltd. | Bioreactor and biological reaction system |
| CN110205245A (en) * | 2019-06-14 | 2019-09-06 | 科先医疗科技(苏州)有限公司 | A kind of cell reactor for Biotype artificial liver |
| 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 |
| CN113073053A (en) * | 2021-03-30 | 2021-07-06 | 弗元(上海)生物科技有限公司 | Cell culture reactor |
| CN114432583A (en) * | 2022-04-11 | 2022-05-06 | 杭州谷禾信息技术有限公司 | Microecological transplantation device for vagina |
| 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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| CN100544684C (en) | 2009-09-30 |
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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 |