CN1257262C - Perfusion bioreactor system constructed in vitro with bilayer active skin - Google Patents
Perfusion bioreactor system constructed in vitro with bilayer active skin Download PDFInfo
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- 230000010412 perfusion Effects 0.000 title claims abstract description 31
- 238000000338 in vitro Methods 0.000 title claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 139
- 239000000463 material Substances 0.000 claims abstract description 8
- 238000010276 construction Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract 2
- 238000003860 storage Methods 0.000 claims description 26
- 230000002572 peristaltic effect Effects 0.000 claims description 16
- 239000007789 gas Substances 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims 2
- 210000003491 skin Anatomy 0.000 abstract description 39
- 238000011081 inoculation Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 210000002615 epidermis Anatomy 0.000 abstract description 3
- 210000004207 dermis Anatomy 0.000 abstract 1
- 239000001963 growth medium Substances 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- 230000008520 organization Effects 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 239000002131 composite material Substances 0.000 description 4
- 230000002500 effect on skin Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 108010001781 Apligraf Proteins 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 108010002823 integra artificial skin Proteins 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
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- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/10—Perfusion
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/58—Reaction vessels connected in series or in parallel
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/26—Means for regulation, monitoring, measurement or control, e.g. flow regulation of pH
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
- C12M41/32—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of substances in solution
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Abstract
一种双层活性皮肤体外构建的灌注式生物反应器系统，包括加液装置、灌注式生物反应器、收液装置、液体回流装置和供气装置；加液装置与灌注式生物反应器的液体进口相连接，收液装置与灌注式生物反应器的液体出口相连接，用于收集反应器中培养后的培养基，液体回流装置通过管线分别与加液装置和收液装置相连通，供气装置通过管线与灌注式生物反应器的气体入口相连通；将用于皮肤构建的支架材料或细胞材料复合物平放在灌注式生物反应器内多孔支撑板上，本发明的反应器系统结构简单、易于放大，可进行湿热灭菌，能长时间维持无菌环境，能很好地模拟体内生长环境，实现从接种到真皮构建到表皮构建的整个双层活性皮肤体外构建过程。
A perfusion bioreactor system constructed in vitro with double-layer active skin, including a liquid addition device, a perfusion bioreactor, a liquid collection device, a liquid return device, and an air supply device; the liquid addition device and the perfusion bioreactor The inlet is connected, and the liquid collection device is connected with the liquid outlet of the perfusion bioreactor, which is used to collect the culture medium in the reactor. The liquid return device is connected with the liquid addition device and the liquid collection device through pipelines, and the gas supply The device is connected to the gas inlet of the perfusion bioreactor through pipelines; the scaffold material or cell material compound used for skin construction is placed flat on the porous support plate in the perfusion bioreactor, and the reactor system of the present invention has a simple structure , Easy to scale up, can be sterilized by moist heat, can maintain a sterile environment for a long time, can well simulate the growth environment in vivo, and realize the entire in vitro construction process of double-layer active skin from inoculation to dermis construction to epidermis construction.
Description
Technical field
The present invention relates to a kind of bio-reactor, relate in particular to the filling type bioreactor of external structure double-layer active skin in a kind of medical science and the organizational engineering.
Background technology
Skin is the tissue of human body maximum, the about 1.5-2.0m of its surface-area
2As one barrier of outermost of human body, skin also is the easiest tissue that sustains damage.Annual nearly 60000-80000 burn patient need carry out dermatoplasty.
The present auto-skin grafting that adopts, allogeneic skin graft, dermatoheteroplasty exist for problems such as district's deficiency, immunological rejection and pathophoresiss.New vitality has been injected in the dermatoplasty that appears as of organization engineering skin.
The research of organization engineering skin starts from nineteen seventies, has developed various Graftskins with clinical value so far, can be divided into epiderm substitute, dermal substitute and composite skin surrogate by forming.There are shortcomings such as thin and frangible, not wear-resisting, that contraction is bigger in epiderm substitute owing to lacking skin corium, and clinical application is restricted; There is not the dermal substitute of epidermal area to exist moisture easily to evaporate shortcomings such as easy infection.The ideal skin substitute products should be able to be repaired the corium and the epidermal area that are lacked simultaneously, because not only cutaneous function of these two kinds of compositions and profile, and can influence each other, promote differentiation each other.The Apligraf that U.S. Organogenesis company produces is first kind of organization engineering skin that contains epidermis and corium simultaneously.
The final purpose that organization engineering skin makes up is that to carry out dermatoplasty be that burn patient or some other skin injury (the acute skin corrupted that causes as wound or operation, chronic ulcer etc.) patient provides temporary transient or nonvolatil Graftskin.Yet a typical burn patient needs 3000-5000cm usually
2Graftskin, for can scale operation Graftskin to satisfy clinical demand, exploitation is applicable to that the bioreactor system of external structure artificial skin is organization engineering skin move towards application from the laboratory the only way which must be passed.
Apligraf (William HE, Eaglastein MD, and Vincent Falanga, MD.Tissue engineeringand the development of Apligraf, a human skin equivalent.Clinical Therapeutics, 1997,19 (5): production 894-905.) is to adopt traditional static cultivation, with inoblast be laid on culture dish not of uniform size after collagen gel mixes, cultivate and connect keratinocyte on the surface after 4-6 days, use liquid-gas interface after submerged culture 2 days instead and cultivate.This manual preparation mode complicated operation is difficult for amplifying, and can't simulate intravital growing environment, and organizes homogeneity, production repeatability and quality stability to be difficult to guarantee, the bio-reactor that therefore is used for the skin histology structure is more in recent years come out one after another.
Halberstadt (Halberstadt CR, Hardin R, Bezverkov K, et al.The in vitro growthof a three-dimensional human dermal replacement using a single-pass perfusion system, Biotechnol Bioeng, 1994,43:740-746.) wait the people to design and develop a kind of unidirectional perfusion culture system of sealing, be used to produce the dermal tissue surrogate.This system adopts the dynamically mode of inoculation, but the culture systems complex structure, and does not realize the structure of epidermal area.Prenosil and Villeneuve (PrenosilJE, Villeneuve PE.Automated production of cultured epidermal autograpts and sub-confluentepiderlmal autografts in a computer controlled bioreactor.Biotechnol Bioeng, 1998,59:679-683.) having developed the cover epiderm substitute reactor assembly of control automatically, this system still can't realize the production of composite skin.
Kermer (Michael Kremer, Ekkehard Lang, Alfred Berger.Organotypical engineeringof differentiated composited-skin equivalents of human keratinocytes in a collagen-GAGmatrix (INTEGRA Artificial Skin) in a perfusion culture system.Langenbeck ' s Arch Surg, 2001,386:357-363.) etc. the filling system of human MINUCELLS and MINUTISSUE exploitation be used for the external structure of composite skin, yet they directly with the Integra artificial skin as skin corium, omit corium and made up this step, and this device for casting liquid-gas interface of structurally failing to support, therefore can't really finish the external structure of composite skin.People such as Cao Yilin are at Chinese utility model patent (application number: the new-type bioreactor that has disclosed a kind of organization engineering skin external structure 02266979.5), this reactor is complex structure not only, and little for the improvement effect of timbering material inside cell micro-environment.
Summary of the invention
The technical issues that need to address of the present invention are the pouring type bioreactor systems that disclose a kind of double-layer active skin external structure, with overcome complex structure that prior art exists, can't analogue body in growing environment, be difficult for the shortcoming of amplifying, satisfy the demand of clinical application.
Technical conceive of the present invention is such:
By regulating the liquid level of substratum, in same reactor, carry out submerged culture or the liquid-gas interface cultivation, to satisfy preparation technology's requirement of double-layer active skin; By monitoring to culturing process, determine nutrition wear rate and metabolism generating rate, in time reflect cell growing state in bio-reactor, to determine suitable irrigation rate and to carry out perfusion culture, thereby the optimization culture environment satisfies normal growth of cell and secretion extracellular protein; Realize the multiple spot inoculation by liquid distributor in the cell inoculation process, cell is more evenly distributed in biomaterial, the artificial skin of preparing is more near the histological structure and the physiological function of natural skin; Bio-reactor of the present invention has the amplification characteristic of simple, not only can amplify the size of single reactor, increase the area of the artificial skin of preparation, also can be by a plurality of reactor parallel connections, realize the increase of product amount, therefore, can be from truly realizing external scale operation artificial skin.
The pouring type bioreactor system of double-layer active skin external structure of the present invention comprises at least: liquid-adding device, filling type bioreactor, receipts liquid device, liquid reflux device and air feeder;
Said filling type bioreactor comprises: the closed container that is provided with loam cake; Be arranged on the porous support plate that in the closed container closed container is divided into last chamber and following chamber; Be arranged on the fit sealing spare of porous support plate top near the closed container inwall; The timbering material or the cell material mixture that are used for the skin structure lie in porous support plate, and fix by fit sealing spare, and porous support plate can provide liquid-gas interface when epidermal area made up; Last chamber is provided with liquid inlet and liquid exit, and following chamber is provided with liquid inlet and liquid exit, on be covered with liquid inlet, gas inlet and pneumatic outlet, loam cake below is provided with liquid distributor, is used to the substratum that distributes and enter from the liquid inlet of loam cake 1.
Said liquid-adding device is connected with the liquid-inlet of filling type bioreactor, be used for fresh culture is imported filling type bioreactor, said receipts liquid device is connected with the liquid exit of filling type bioreactor, be used for collecting the reacted substratum of reactor, said liquid reflux device is connected with liquid-adding device and receipts liquid device respectively by pipeline, and said air feeder is connected with the gas inlet of filling type bioreactor by pipeline;
System of the present invention uses like this:
The timbering material or the cell material mixture that will be used for the skin structure lie in porous support plate in the filling type bioreactor, and fix by fit sealing spare, fresh culture is sent into filling type bioreactor by liquid-adding device, realize the inoculation of cell multiple spot by liquid distributor, in reactor, carry out submerged culture or the liquid-gas interface cultivation, to satisfy preparation technology's requirement of double-layer active skin, enter the receipts liquid device by the filling type bioreactor liquid exit then, the air air feeder is sent into filling type bioreactor, to satisfy the needed oxygen of reaction and to regulate pH, liquid reflux device can be sent the reacted substratum of receiving the liquid device collection back to liquid-adding device, to reuse.
Reactor assembly of the present invention is simple in structure, be easy to amplify, can carry out moist heat sterilization, can keep gnotobasis for a long time, growing environment in the analogue body is realized being building up to the whole double-layer active skin external structure process that epidermis makes up from being inoculated into corium well.
Description of drawings
Fig. 1 is that the pouring type bioreactor system one-piece construction of double-layer active skin external structure is formed synoptic diagram.
Fig. 2 is the structural representation of filling type bioreactor main body.
Embodiment
Referring to Fig. 1 and Fig. 2, the pouring type bioreactor system of double-layer active skin external structure of the present invention comprises at least: liquid-adding device, filling type bioreactor, receipts liquid device, liquid reflux device and air feeder;
Said filling type bioreactor comprises: the closed container 2 that is provided with loam cake 1; Be arranged on the porous support plate 5 that in the closed container 2 closed container 2 is divided into last chamber 3 and following chamber 4, be arranged on the fit sealing spare 6 of porous support plate 5 tops near closed container 2 inwalls; The timbering material or the cell material mixture 7 that are used for the skin structure lie in porous support plate 5, and fixing by fit sealing spare 6, and porous support plate 5 can provide liquid-gas interface when epidermal area made up; Last chamber 3 is provided with liquid inlet 8 and liquid exit 9, following chamber is provided with liquid inlet 8 and liquid exit 9, loam cake 1 is provided with liquid inlet 8, gas inlet 10 and pneumatic outlet 11, and loam cake 1 below is provided with liquid distributor 101, is used to the substratum that distributes and enter from the liquid inlet 8 of loam cake 1.
Said liquid-adding device is connected with the liquid inlet 8 of filling type bioreactor, said receipts liquid device is connected with the liquid exit 9 of filling type bioreactor, said liquid reflux device is connected with liquid-adding device and receipts liquid device respectively by pipeline, and said air feeder is connected with the gas inlet 10 of filling type bioreactor by pipeline;
As seen from Figure 1:
Said liquid-adding device comprises liquid feeding peristaltic pump 12 and coupled liquid feeding liquid storage bottle 13, liquid feeding liquid storage bottle 13 is connected with the liquid inlet 8 of filling type bioreactor by pipeline, because said bio-reactor has three liquid inlets 8, select the liquid inlet 8 of loam cake 1 during inoculation for use, perfusion culture may be selected the liquid inlet 8 of avris, therefore be preferably between liquid feeding peristaltic pump 12 and the pipeline that each liquid inlet 8 of filling type bioreactor links to each other by-pass valve control 26 is set, entering the mouth from which with controlled liq 8 enters;
Said receipts liquid device comprises: receive liquid peristaltic pump 14, receive liquid liquid storage bottle 15, receive hydraulic control valve 16 and receive liquid bottle 17, the import of receiving liquid peristaltic pump 14 is connected with the liquid exit 9 of filling type bioreactor, the outlet of receiving liquid peristaltic pump 14 is connected with the inlet of receiving liquid liquid storage bottle 15, the outlet of receiving liquid liquid storage bottle 15 is connected with receipts liquid bottle 17 by liquid storage peristaltic pump 25, receiving hydraulic control valve 16 is arranged on the pipeline of receiving between liquid liquid storage bottle 15 and the liquid storage peristaltic pump 25, be used for control and receive liquid measure, be provided with by-pass valve control 26 between each outlet of bio-reactor and the receipts liquid peristaltic pump 14.
Said liquid reflux device comprises by reflux pipeline 19 and is arranged on the recycle control valve of receiving between liquid liquid storage bottle 15 and the liquid feeding liquid storage bottle 13 18;
Said air feeder comprises interconnective successively pneumatic pump 20, air flowmeter 21 and air filter 22, and air filter 22 is connected with filling type bioreactor;
Said proofing unit comprises and is inserted in liquid feeding liquid storage bottle 13, receives the dissolved oxygen electrode 23 in the liquid liquid storage bottle 15 and receives pH electrode 24 in the liquid liquid storage bottle 15, dissolved oxygen electrode 23 is connected with the pH determinator with dissolved-oxygen content analyser respectively with pH electrode 24, to detect and to control the oxyty and the pH of substratum in liquid feeding liquid storage bottle 13, the receipts liquid liquid storage bottle 15.
As seen from Figure 1, a plurality of said filling type bioreactors can be connected in parallel, to satisfy the needs that enlarge turnout.
Claims (9)
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100166516A CN1257262C (en) | 2004-03-01 | 2004-03-01 | Perfusion bioreactor system constructed in vitro with bilayer active skin |
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| CNB2004100166516A CN1257262C (en) | 2004-03-01 | 2004-03-01 | Perfusion bioreactor system constructed in vitro with bilayer active skin |
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| CN1560225A CN1560225A (en) | 2005-01-05 |
| CN1257262C true CN1257262C (en) | 2006-05-24 |
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Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101402917B (en) * | 2008-11-25 | 2011-07-06 | 中国人民解放军第三军医大学第三附属医院 | Bioreactor for producing tissue engineering products |
| CN102071137B (en) * | 2009-11-19 | 2014-10-22 | 上海坤巨科技发展有限公司 | Device and method for preparing stem cells through continuous perfusion bioreactor/tank (bag) system |
| CN102199536A (en) * | 2010-03-23 | 2011-09-28 | 上海坤巨科技发展有限公司 | Apparatus and method for monitoring cell quantity or cell proportion during dynamic stem cell differentiation |
| CN102199535A (en) * | 2010-03-23 | 2011-09-28 | 上海坤巨科技发展有限公司 | Device and method for noninvasive continuous monitoring of quantity or concentration of dynamic cells |
| CN102296029B (en) * | 2010-06-28 | 2013-01-30 | 裴国献 | Perfusion Bioreactor System |
| CN102618442A (en) * | 2012-04-06 | 2012-08-01 | 中国人民解放军第四军医大学 | Artificial skin culture device and using method thereof |
| CN103266182B (en) * | 2013-05-30 | 2015-04-15 | 中山大学 | Method and device for regulating tower plate type perfusion bioreactor |
| CN103290145B (en) * | 2013-06-03 | 2015-09-23 | 中山大学 | A kind of filling type bioreactor experimental technique and using appts thereof |
| WO2015059799A1 (en) * | 2013-10-24 | 2015-04-30 | 株式会社日立製作所 | Automated culture device |
| EP3147349B1 (en) * | 2014-05-22 | 2019-07-10 | The Third Affiliated Hospital of Third Military Medical University | Bioreactor for three-dimensional tissue perfusion culture |
| CN103966095B (en) * | 2014-05-22 | 2016-01-20 | 中国人民解放军第三军医大学第三附属医院 | A kind of bio-reactor being applicable to three-dimensional tissue's Cell infusion and cultivating |
| CN105176815B (en) * | 2015-10-20 | 2017-03-22 | 哈尔滨工业大学 | Gas-liquid interface perfusion bioreactor for artificial skin tissue culture and preparation method and application method of gas-liquid interface perfusion bioreactor |
| CN105524832B (en) | 2016-02-26 | 2018-03-30 | 广州洁特生物过滤股份有限公司 | Cell culture apparatus and method |
| EP3681365A4 (en) * | 2017-09-11 | 2021-06-16 | 3D Biotek, LLC | Large-scale bioreactor |
| CN112933298B (en) * | 2021-04-01 | 2023-11-17 | 领博生物科技(杭州)有限公司 | Biological material preparation device and biological material preparation system |
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