CN101549179A - Perforated brick type filling support type reactor used in artificial liver - Google Patents
Perforated brick type filling support type reactor used in artificial liver Download PDFInfo
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- CN101549179A CN101549179A CNA2009100981232A CN200910098123A CN101549179A CN 101549179 A CN101549179 A CN 101549179A CN A2009100981232 A CNA2009100981232 A CN A2009100981232A CN 200910098123 A CN200910098123 A CN 200910098123A CN 101549179 A CN101549179 A CN 101549179A
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Abstract
本发明涉及医疗设备，旨在提供一种人工肝用多孔砖式填充支架型反应器。该反应器包括反应器外壳；反应器外壳内部由两个密布网格的隔离板分为三个舱：自下而上为氧合舱、填充支架舱、免疫阻隔舱。本发明采用独特的多孔砖式固定床作为反应器内部主体，通过固定床中互不相通的细长孔柱分割反应器内部成微型独立单元，将反应器内腔化整为零，减小了无效腔、死腔、液流阻力，使反应器内部液流均匀。既解决支架型反应器缺乏免疫隔离、氧供不充分的问题，又弥补中空纤维型反应器细胞生长空间不足，细胞黏附性差，缺乏三维立体生长环境，易堵塞半透膜的缺陷。兼具氧合、免疫阻隔、三维立体培养功能，综合性能强大，而制作工艺简单、成本低、易于放大。
The invention relates to medical equipment and aims to provide a porous brick-type filled bracket type reactor for an artificial liver. The reactor includes a reactor shell; the interior of the reactor shell is divided into three compartments by two dense grid-covered isolation plates: an oxygenation compartment, a filling bracket compartment, and an immune barrier compartment from bottom to top. The present invention adopts a unique porous brick-type fixed bed as the internal body of the reactor, divides the interior of the reactor into miniature independent units through the elongated pore columns that are not connected to each other in the fixed bed, and divides the inner cavity of the reactor into parts, reducing the The dead space, dead space and liquid flow resistance make the liquid flow inside the reactor uniform. It not only solves the problems of lack of immune isolation and insufficient oxygen supply in scaffold-type reactors, but also makes up for the lack of cell growth space in hollow-fiber reactors, poor cell adhesion, lack of three-dimensional growth environment, and easy to block the defects of semi-permeable membranes. It has the functions of oxygenation, immune barrier, and three-dimensional culture, and has strong comprehensive performance. The production process is simple, low-cost, and easy to scale up.
Description
Technical field
The present invention relates to a kind of armarium, is core apparatus---the perforated brick type filling support type reactor used in artificial liver of a kind of biotype or hybrid artificial liver treatment.
Background technology
Artificial liver Supporting Therapy as one of effective treatment means of hepatitis gravis, liver failure patient by universally acknowledged.It comprises abiotic type, biotype, hybrid artificial liver three major types, and wherein back two classes are main International Development directions.Bioreactor (being reactor) is the core apparatus of biotype and hybrid artificial liver treatment just, and the place of mass exchange both is provided for exogenous hepatocyte and blood samples of patients or blood plasma, for hepatocyte provides suitable growing environment, has a extensive future again.Ideal bioreactor for artificial liver should meet following basic demand: 1, competent hepatic cell growth space, and support a liver failure patient to need 10% normal liver quality approximately, amount to hepatocyte number about 15,000,000,000.2, excellent biological compatibility can guarantee hepatocellular activity and function.3, medium and small material transmitted in both directions, the macromolecular substances immunity intercepts.
Bioreactor mainly contains four types so far: hollow fiber type, dull and stereotyped monolayer culture type, filling fluidized-bed type/support rack type and cell parcel/floating type.What clinical practice at present was maximum is the hollow fiber type reactor, it has concurrently, and immunity is isolated and the effect of oxygenate, cell is subjected to shearing force little, but has following shortcoming: 1, traditional hollow fiber reactor cell growing space deficiency, skewness, cell adhesion are poor; 2, can only provide two dimension to cultivate, can not provide 3 D stereo to cultivate; 3, semipermeable membrane barrier or collagen layer can influence the material exchange efficiency; 4, cell is grown in fiber surface so easily stop up fiber holes.And dull and stereotyped monolayer culture type since body surface area than little, amplify difficulty, cell parcel/floating type is because the stability of suspension cell is not good, the mass exchange of parcel cell is influenced, the Recent study report seldom.Using another also more type of reactor aspect zoopery and cell culture, is to irritate fluidized-bed type/support rack type reactor.It has the following advantages: 1, hepatocyte directly contacts with blood plasma or blood, helps mass exchange; 2, the introducing of biologic bracket material makes the cell growing space increase; 3, biological support can adhere to substrate and 3 D stereo growing environment for hepatocyte provides; Hepatocyte must adhere to and could survive and keep function as a kind of adherent growth type cell, and the 3 D stereo growing environment helps the generation of hepatocyte spheroplast, helps the performance of cell function and keeps for a long time.But there is following shortcoming in it: 1, exist to lack immune isolated potential safety hazard; 2, the oxygen of cell is for insufficient; 3, the central area of whole reactor support and edge zone easily produce dead space, dead space; 4, the resistance by a large amount of supports is big, and required perfusion intensity is big, causes cell to be subjected to shearing force big, is difficult to amplify.
How comprehensively the advantage of variety classes reactor is maximized favourable factors and minimized unfavourable ones, and overcomes one's shortcomings, and becomes recently the focus of research both at home and abroad.In recent years, biologic bracket material research has had considerable progress, emerging nano material, inside to be the macromolecule polymer material emerge in multitude of modifications such as natural material such as the alginic acid-chitosan of the netted connectivity structure of 3 D stereo and galactose, heparin and has been widely used in cell culture.The considerable progress of biologic bracket material is the development of novel reactor, has created huge opportunity.Existing in the world good comprehensive properties reactor, often complex structure, processing technology require high, cost is high.The development combination property is good, structure is simple with processing technology, the relative low new-type bioreactor of cost, for vast developing country and third world countries, has special important practical sense.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of oxygenate, immune isolation features of having concurrently is provided, perfusion is evenly abundant, and dead space, dead space are improved the perforated brick type filling support type reactor used in artificial liver that cost of manufacture is low, practical.
The present invention is achieved by the following technical solutions:
A kind of perforated brick type filling support type reactor used in artificial liver is provided, comprises shell of reactor; Described shell of reactor inside is divided into three cabins by the division board of two densely covered grids: from bottom to top for oxygenate cabin, filling bracket cabin, immunity intercept the cabin, between oxygenate cabin and the filling bracket cabin, establish the division board of being with grid between filling bracket cabin and the immunity obstruct cabin;
Lateral arrangement has the doughnut of permeable watertight in the described oxygenate cabin, and bilge portion establishes the liquid inlet; Doughnut inside is the gas passage, and its two ends connect gas access and gas outlet respectively;
Described filling bracket cabin is a fixed bed that is thick with the transparent organic glass of elongated hole post, fills three-dimensional porous crack biological support bead in the post of fixed bed hole; The all adjacent division board of the bottom surface of fixed bed and end face, the length of side of grid spills to prevent the support bead less than the little bulb diameter of support on the division board;
Described immunity intercepts the cabin and is made up of shell, doughnut and sealed card flap three parts; The sidewall in immunity obstruct cabin is established liquid outlet and is linked to each other with the space of doughnut outside, and the sealed card flap of the bilge links to each other with the division board at top, filling bracket cabin; Doughnut is the doughnut of vertically arranging and having permeable and immune iris action, and its inner chamber lower ending opening is communicated with upper end closed with the filling bracket cabin.
As a kind of improvement, described oxygenate cabin and filling bracket cabin interconnect as a whole, and it is individual member that immunity intercepts the cabin.
As a kind of improvement, the diameter of described support bead is 2mm, and the diameter of fixed bed hole post is 3mm, only allows single the inserting of three-dimensional porous crack biological support bead.
As a kind of improvement, the support bead of described filling is following any one: alginic acid-chitosan stent bead, polyvinyl resin support bead, polyurethane foam support bead or polycaprolactone support bead, support bead inside is three-dimensional netted connectivity structure.
As a kind of improvement, the bottom surface in described filling bracket cabin is connected with division board is fixed, and the division board of its end face links to each other with the sealed card flap that immunity intercepts the cabin.
As a kind of improvement, the shell of described reactor is transparent cuboid shell.
As a kind of improvement, the doughnut in described oxygenate cabin is the polypropylene hollow fiber of permeable watertight, perhaps the polysulfone hollow fibre of silicon-coating rubber; The doughnut that described immunity intercepts the cabin is that aperture 0.2 μ m, molecular retention amount are polysulfone hollow fibre or the polyether sulfone doughnut of 50～100kD.
Beneficial effect of the present invention:
Traditional filling fluidized-bed type/support rack type inside reactor is generally the integral body that a liquid stream communicates, and exists to form problems such as dead space, dead space, liquid stream is inhomogeneous, liquid flowing resistance is big easily.Type filling bracket reactor of the present invention, adopt unique porous brick formula fixed bed as the inside reactor main body, purpose is that cutting apart inside reactor by elongated hole post not connected in the fixed bed becomes miniature separate unit, the reactor inner chamber is broken the whole up into parts, thereby dead space, dead space have been reduced, reduced liquid flowing resistance, made the inside reactor liquid stream even.Simultaneously, the present invention utilizes the ingenious combination of filling bracket and doughnut, both solved the support rack type reactor and lacked immunity isolation, oxygen for inadequate problem, remedied hollow fiber type reactor cell growing space deficiency again, cell adhesion is poor, lack the 3 D stereo growing environment, easily stop up the defective of semipermeable membrane.The present invention has functions such as oxygenate, immunity obstruct, 3 D stereo cultivation concurrently, and combination property is powerful, and processing technology is simple, cost is low, be easy to amplification.
Description of drawings
Fig. 1 is a perforated brick type filling support type reactor used in artificial liver longitudinal cross-section structural representation;
Fig. 2 is the lateral cross section structural representation in the oxygenate cabin of perforated brick type filling support type reactor used in artificial liver;
Fig. 3 is the lateral cross section structural representation in the filling bracket cabin of perforated brick type filling support type reactor used in artificial liver;
Fig. 4 is the lateral cross section structural representation that the immunity of perforated brick type filling support type reactor used in artificial liver intercepts the cabin;
Fig. 5 uses sketch map for biological artificial liver support system.
Reference numeral: porous brick formula fixed bed 1, support bead 2, doughnut 3, doughnut 4, division board 5, sealed card flap 6, shell of reactor 7, liquid inlet 8, liquid outlet 9, gas access 10, gas outlet 11, patient or laboratory animal 12, plasma separator 13, extracorporeal circulation pool 14.
The specific embodiment
The perforated brick type filling support type reactor used in artificial liver of present embodiment, the shell of reactor 7 that comprises the cuboid transparent organic glass, division board 5 by two densely covered grids in the shell of reactor 7 is divided into three cabins, is from bottom to top, and oxygenate cabin, filling bracket cabin, immunity intercept the cabin.Oxygenate cabin and filling bracket cabin are an integral body, and it is individual member that immunity intercepts the cabin, links to each other with aforementioned integral body by sealed card flap 6.
Lateral arrangement has the doughnut 3 of permeable watertight in the oxygenate cabin, and bilge portion establishes liquid inlet 8.The inside of doughnut 3 is the gas passage, and two ends connect gas access 10 and gas outlet 11 respectively.The doughnut 3 in oxygenate cabin is the polypropylene hollow fiber of permeable watertight, perhaps the polysulfone hollow fibre of silicon-coating rubber.
The main body in filling bracket cabin is unique porous brick formula fixed bed 1, promptly is thick with the transparent organic glass fixed bed of elongated hole post, is filled with three-dimensional porous crack biological support bead 2 in the porous brick formula fixed bed 1 hole post.The diameter 2mm of support bead 2.The slightly larger in diameter of porous brick formula fixed bed 1 hole post is 3mm in the diameter of support bead 2, only allows single support bead 2 to insert.The material of support bead 2 can be a natural material, as alginic acid-chitosan stent, also can be macromolecular compound, as polyvinyl resin, polyurethane foam, polycaprolactone, the inside of support bead 2 is three-dimensional netted connectivity structure, and hepatocyte is the 3 D stereo growth in its appearance and inside.
The all adjacent division board 5 of the bottom surface of porous brick formula fixed bed 1 and end face, the length of side of grid spills to prevent support bead 2 less than the diameter of support bead 2 on the division board 5.The division board 5 of bottom surface is fixed, and 5 of the division boards of end face link to each other with sealed card flap 6, can open to pack into or to pour out support bead 2.
Immunity intercepts the cabin and is made up of shell, the doughnut 4 with immune iris action, sealed card flap 6 three parts.Doughnut 4 is for arranging vertically and have permeable and immune iris action that the inner chamber lower ending opening of doughnut 4 is communicated with upper end closed with the filling bracket cabin.The cabin sidewall is established liquid outlet 9, links to each other with the space of doughnut 4 outsides.The doughnut 4 that immunity intercepts the cabin is that aperture 0.2 μ m, molecular retention amount are polysulfone hollow fibre or the polyether sulfone doughnut of 50～100kD.
Occupation mode is as follows:
After the blood lead body of patient or laboratory animal 12 is outer, at first be separated into cell composition and blood plasma components through blood plasma separator 13.Wherein blood plasma components enters extracorporeal circulation pool 14, and the liquid inlet 8 from reactor oxygenate bilge portion enters the oxygenate cabin from bottom to top then.Oxygen and carbon dioxide gas mixture enter the inner chamber of the doughnut 3 in oxygenate cabin by gas access 10, flow out to the gas outlet 11 of offside.Blood plasma passes through the exocoel of oxygenate cabin doughnut, plays the effect of oxygenate.Grid by division board 5 enters the filling bracket cabin then, evenly pass the porous crack support bead 2 of filling, after hepatocyte on the bead (hepatocyte for inoculate in advance and cultivate) fully contacts, the grid of the division board 5 at process top, filling bracket cabin enters the inner chamber that immunity intercepts the doughnut 4 in cabin.The macromole immune material is intercepted in the blood plasma, and the middle small-molecule substance therefrom fiber holes of hollow fiber 4 spills into exocoel, returns circulatory pool 14 by liquid outlet 9 outflow reactors again.After repeatedly circulating, the cell composition in blood feeds back in the body again.
Hepatocyte can be selected former generation people, porcine hepatocyte or hepatic cell line etc. for use, and summary inoculation and incubation step are as follows:
1, opens reactor sealed card flap 6, in the elongated hole post of porous brick formula fixed bed 1, pour porous crack biological support bead 2 into, cover sealed card flap 6, immunity is intercepted the cabin be linked to be an integral body with oxygenate cabin, filling bracket cabin.
2, reactor comprises that its inner porous crack biological support bead 2 sterilizes together.
3, be mixed with the hepatocyte suspension of suitable concn with culture fluid.
4, from the liquid inlet 8 of oxygenate bilge portion with in the hepatocyte suspension injecting reactor, till the liquid outlet 9 that liquid component intercepts the cabin sidewall from immunity to the cell suspension overflows.Hepatocyte attaches to porous crack biological support bead 2, attaches firmly after about 24 hours.
5, the liquid outlet 9 from immunity obstruct cabin sidewall pours into fresh culture, and through filling bracket cabin and oxygenate cabin, 8 flow out from the liquid inlet, wash away not adherent hepatocyte.
6, shown in pressing this reactor and extracorporeal circulation pool 14 etc. in Fig. 5 frame of broken lines, be linked to be the liver cell culture peripheral passage, fresh culture medium respectively from the liquid inlet 8 and liquid outlet 9 flow into and outflow reactors, for hepatocyte provides nutrient and takes away metabolite.
7, after the suitable time of cultivation, can be combined into the Biotype artificial rami hepatici by Fig. 5 connection and hold system.
The scale of the perforated brick type filling support type reactor used in artificial liver among the present invention can or be dwindled according to the practical application amplification.
At last, it is also to be noted that what more than announce only is specific embodiments of the invention.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (7)
1, a kind of perforated brick type filling support type reactor used in artificial liver, comprise shell of reactor, it is characterized in that described shell of reactor inside is divided into three cabins by the division board of two densely covered grids: intercept the cabin for oxygenate cabin, filling bracket cabin, immunity from bottom to top;
Lateral arrangement has the doughnut of permeable watertight in the described oxygenate cabin, and bilge portion establishes the liquid inlet; Doughnut inside is the gas passage, and its two ends connect gas access and gas outlet respectively;
Described filling bracket cabin is a fixed bed that is thick with the transparent organic glass of elongated hole post, fills three-dimensional porous crack biological support bead in the post of fixed bed hole; The all adjacent division board of the bottom surface of fixed bed and end face, the length of side of grid spills to prevent the support bead less than the little bulb diameter of support on the division board;
Described immunity intercepts the cabin and is made up of shell, doughnut and sealed card flap three parts; The sidewall in immunity obstruct cabin is established liquid outlet and is linked to each other with the space of doughnut outside, and the sealed card flap of the bilge links to each other with the division board at top, filling bracket cabin; Doughnut is the doughnut of vertically arranging and having permeable and immune iris action, and its inner chamber lower ending opening is communicated with upper end closed with the filling bracket cabin.
2, perforated brick type filling support type reactor used in artificial liver according to claim 1 is characterized in that, described oxygenate cabin and filling bracket cabin interconnect as a whole, and it is individual member that immunity intercepts the cabin.
3, perforated brick type filling support type reactor used in artificial liver according to claim 1 is characterized in that, the diameter of described support bead is 2mm, and the diameter of fixed bed hole post is 3mm, only allows single the inserting of three-dimensional porous crack biological support bead.
4, perforated brick type filling support type reactor used in artificial liver according to claim 1, it is characterized in that, the support bead inside of described filling is three-dimensional netted connectivity structure, is following any one: alginic acid-chitosan stent bead, polyvinyl resin support bead, polyurethane foam support bead or polycaprolactone support bead.
5, perforated brick type filling support type reactor used in artificial liver according to claim 1 is characterized in that, the bottom surface in described filling bracket cabin is connected with division board is fixed, and the division board of its end face links to each other with the sealed card flap that immunity intercepts the cabin.
6, perforated brick type filling support type reactor used in artificial liver according to claim 1 is characterized in that, the shell of described reactor is transparent cuboid shell.
According to described any one perforated brick type filling support type reactor used in artificial liver of claim 1 to 6, it is characterized in that 7, the doughnut in described oxygenate cabin is the polypropylene hollow fiber of permeable watertight, perhaps the polysulfone hollow fibre of silicon-coating rubber; The doughnut that described immunity intercepts the cabin is that aperture 0.2 μ m, molecular retention amount are polysulfone hollow fibre or the polyether sulfone doughnut of 50～100kD.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102639688A (en) * | 2009-10-12 | 2012-08-15 | 泰尔茂比司特公司 | Method of assembling a hollow fiber bioreactor |
| CN105999448A (en) * | 2016-07-29 | 2016-10-12 | 武汉仝干医疗科技股份有限公司 | Four-in-one plush linear artificial liver reactor |
| CN106139289A (en) * | 2016-07-29 | 2016-11-23 | 武汉仝干医疗科技股份有限公司 | Semipermeable membrane layering integrated biological reactor |
| CN106267399A (en) * | 2016-07-29 | 2017-01-04 | 武汉仝干医疗科技股份有限公司 | Four-in-one formula bioreactor of artificial liver |
| WO2018018792A1 (en) * | 2016-07-29 | 2018-02-01 | 武汉仝干医疗科技股份有限公司 | Four-in-one on-line monitoring and constant-temperature heating integrated system of plush type for bioartificial liver |
| CN108588006A (en) * | 2018-05-10 | 2018-09-28 | 华东理工大学 | A kind of biological support and its preparation method and application for liver cell dimensional culture |
| CN109689124A (en) * | 2016-09-06 | 2019-04-26 | 甘布罗伦迪亚股份公司 | Liver 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 |
| CN110903978A (en) * | 2019-12-26 | 2020-03-24 | 南京比瑞生物科技有限公司 | Micro-channel carrier structure for large-scale culture of stem cells and immune cells |
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Assignee: Weihai Weigao Life Science & Technology Co., Ltd. Assignor: Zhejiang University Contract record no.: 2012330000164 Denomination of invention: Perforated brick type filling support type reactor used in artificial liver Granted publication date: 20110914 License type: Exclusive License Open date: 20091007 Record date: 20120411 |