CN101837151A - Two-way filling type bioreactor control system and method - Google Patents
Two-way filling type bioreactor control system and method Download PDFInfo
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- CN101837151A CN101837151A CN201010130358A CN201010130358A CN101837151A CN 101837151 A CN101837151 A CN 101837151A CN 201010130358 A CN201010130358 A CN 201010130358A CN 201010130358 A CN201010130358 A CN 201010130358A CN 101837151 A CN101837151 A CN 101837151A
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Abstract
The invention discloses a two-way filling type bioreactor control system and method. One main improvement is in the bioreactor; a ligating part is used to tightly bind a filtration membrane in the bioreactor with a spindle to perform ligating so that a gap between the filtration membrane and the spindle is divided into a plurality of gap areas which are not communicated; and the other improvement is to provide a flow direction controller used for automatically switching the flow direction of a second fluid passing through the bioreactor. The invention comprehensively solves the problems of non-uniform filling, dead space, blockage and low exchange rate of the existing bioreactor.
Description
[technical field]
The present invention relates to field of biomedicine technology, relate in particular to a kind of two-way filling type bioreactor control system and method.
[background technology]
Liver failure is the whole performance in latter stage of various hepatopathys, and conditions of patients is critical, case fatality rate height, prognosis extreme difference.Liver transplantation is the most effectively Therapeutic Method of generally acknowledging at present, but owing to reasons such as donor shortage, technical difficulty height, has greatly limited extensively carrying out of liver transplantation operation.Appearance based on the treatment meanss such as bioartificial liver of In vitro culture hepatocyte, be expected to once make the renal failure treatment produce revolutionary variation as artificial kidney, for the modern treatment of liver failure provides effective means, yet, appropriate design new-type bioreactor how, realizing external hepatocellular long-term large-scale culture, be still the bottleneck problem of present strong restrictions bioartificial liver's development, also is the important topic that needs to be resolved hurrily at present.
Bioreactor is bioartificial liver's core, and its performance is directly connected to the support effect of artificial liver.Research at present and numerous bioreactors of using mainly are divided into following several types, though existing part biological bioreactor of artificial liver has entered clinical experiment, do not have a kind of ideal bioreactor can fully satisfy the clinical application needs at present yet:
1, hollow fiber bioreactor: be a class reactor of studying at present and being most widely used.Its advantage is that foreign protein can be isolated, and prevents simultaneously in the human body at the lethal effect of the antigenic preexisting antibody of heterogenous cell to the loading cell.Thereby relatively more suitable heterogenous cell class (as porcine hepatocyte) bioreactor.Still there is following problem in this reactor at present: (1) volume is limited, and the cell useful load is little, and culture fluid and hepatocyte exchange area are limited, is unfavorable for external scale amplification; (2) side opening of semipermeable membrane is easily stopped up by cell mass, influences exchange efficiency, also is unfavorable for that the permanently effective of hepatocellular function and vigor keep; Therefore hollow fiber bioreactor is not best bioartificial liver's bioreactor.
2, flat plate bioreactors: such reactor is that hepatocyte is directly planted on flat board, its advantage is that cell distribution is even, the microenvironment unanimity, but surface to volume ratio descends, the reactor cell is a monolayer culture, can not permanently effective survival and keep function with active, and be difficult for amplifying, can't reach clinical requirement.
3, microcapsule suspension bioreactor: this bioreactor is that hepatocyte is wrapped up with a kind of semipermeable membrane material, make porous microcapsule, carry out perfusion cultures then. its advantage is that all cells has identical microenvironment, the space that a large amount of cell culture are arranged, reducing immunoreactive generation. shortcoming is because the existence of semipermeable membrane and the mutual gathering between hepatocyte cause the exchange of the inside and outside matter energy of capsule limited.In addition, Hoshiba[11] etc. research also show that hepatocyte is an anchorage-dependent cell, as lose attaching to timbering material, can inspire cell generation apoptosis.Therefore, this class bioreactor also is not that hepatocellular optimum selection is cultivated in external scale.
4, stirring type bioreactor is that a class is developed early and widely used perfusion bed/support bioreactor in research and production.This reactor is to make cell and timbering material reach suspended state by stirring, on the tank body top pick off is housed also, but parameters such as the temperature of continuous monitoring culture, pH, pO2, glucose consumption, its great advantage be can cultivate various types of zooblasts, culture process amplifies easily, but this bioreactor also has a fly in the ointment, be that mechanical agitation can produce certain shearing force, pair cell causes the damage of going up largely easily, thereby has limited its further utilization.
In view of analysis, be necessary to use for reference some prior aries and be optimized present all kinds bioreactor mentality of designing.
See also disclosed US5989913 patent application on November 23rd, 1999, its disclosed a kind of incubator, this incubator comprises: tubular vessel, have first and second end walls and place a cylindrical wall between these two end walls, one inlet, an outlet, and first and second filters, described first and second filters have a plurality of openings, this opening allow fluid medium and cellular metabolism waste material by and stop cell and cell cluster to pass through; One culturing room, by described cylindrical wall, first and second end walls, and described first and second filters define jointly, and this culturing room has a penetrating fore and aft axis; One device is used for rotating this tubular vessel around the fore and aft axis of level; One pump is used to keep liquid culture medium arteries and veins stream by this culturing room.
Design and be applied to the rotating and culturing system (RCCS) of microgravity life science at present by NASA (NASA), through nearly twenties years correlational study, success applies in a plurality of field of tissue engineering technology such as rabbit corneal cell, Skeletal Muscle Cell, osteoblast widely.Up-to-date member's rotary pouring microgravity bioreactor (RCMW) in its series of products, have and aforementioned US5989913 patent application corresponding structure, can horizontally rotate by culture vessel and reach the microcarrier that makes in the container and cell and overcome gravity and reach suspended state, and realize the two-way circulation of oxygen in the container, nutrient substance and metabolite by external peristaltic pump.But the applicant finds that in the process of in earlier stage using this bioreactor still there are bottleneck problems such as nutrition supply deficiency, perfusion heterogeneity and easy obstruction at present in this reactor, mainly shows:
At first, it is low to cultivate the interior two-way mass exchange efficient of vessel: all coated by filter membrane owing to cultivate the outlet and the inlet of the fore and aft axis of vessel inside, cause a part of culture medium pass behind the filter membrane with the outer culturing room of film in culture medium carry out the exchange of nutrient and oxygen, realize " effectively circulation "; Another part culture medium is a passage with the gap between filter membrane and this fore and aft axis then, directly flows out and cultivates outside the vessel, can not finish the function of nutrient and oxygen exchange, can cause cultivating the cell tissue nutrition supply deficiency in the vessel, becomes " invalid circulation ".
Secondly, perfusion heterogeneity in the culture vessel, there is dead space: in the RCMW circulation pattern, the permeability that increases filter membrane helps to improve the filter membrane outer circulation, reduces " invalid circulation ", but because the fluid pressure of culture vessel central authorities (pivot center place) is lower than the fluid pressure of its periphery, make the culture medium flow velocity of culture vessel central authorities and change speed very fast, container periphery culture medium flow velocity and replacing speed are slower, cause the perfusion heterogeneity in the container, form dead space in the culture vessel periphery.
Moreover in the RCMW circulation pattern, because liquid circulation flows to singlely in the culture vessel, (outlet is 4 small side holes) concentrated in the little and position of culture fluid discharge area, thereby causes cell and microcarrier in the exit position blocking problem.
[summary of the invention]
Primary and foremost purpose of the present invention is to provide a kind of exchange efficiency and uniformity coefficient can strengthen two kinds of fluids that participate in reaction and exchange the time, and insufficient two-way filling type bioreactor control systems such as dead space that exists when overcoming exchange and obstruction;
Another object of the present invention is to provide the described control system of a kind of and last purpose corresponding two-way filling type bioreactor control method.
For realizing this purpose, the present invention adopts following technical scheme:
A kind of two-way filling type bioreactor control system comprises:
Bioreactor, it comprises cylindrical shell, mandrel and filter membrane, cylindrical shell forms reative cell and reacts to offer first fluid that has fused first material and second fluid that has fused second material, mandrel traverses drum shaft to setting, the mandrel two ends respectively form a path, this filter membrane coats this mandrel, to stop first material, to allow second material to pass through, is formed with the slit between filter membrane and the mandrel;
Motor is used to drive described bioreactor around its mandrel rotation;
Storage bottle is used to store second fluid that has fused second material;
Kinetic pump, second fluid that is used for keeping storage bottle enters reative cell after another path is got back to storage bottle to constitute closed circuit through a path of bioreactor;
This control system also comprises and flows to controller, is used to switch the flow direction of described closed circuit;
In this bioreactor, at least one place of filter membrane is directly flowed out through this slit to stop second fluid described slit is split up into mutual disconnected a plurality of crack district by the ligation of ligation part institute.
This storage bottle is connected with at least one oxygenator, oxygenator is connected with kinetic pump, kinetic pump with flow to that controller is connected flows to controller so that second fluid enters, flowing to controller also directly is communicated with storage bottle, controller also is communicated with respectively with two passages of bioreactor so that second fluid refluxes through behind this bioreactor so that second fluid reflux to storage bottle, flows to.The described controller that flows to comprises two automatically controlled three-way valve of directed ends and two automatically controlled three-way valve of commutation end, each three-way valve all has two mouthful vertical mouths with downstream, two of the automatically controlled three-way valve of each directed ends downstream mouth mouthful be communicated with downstream with each one of two automatically controlled three-way valve of commutation end respectively, vertical mouthful of the automatically controlled three-way valve of first directed ends is connected with kinetic pump, vertical mouthful of the automatically controlled three-way valve of second directed ends is connected with storage bottle, and vertical mouthful of two automatically controlled three-way valve of commutation end is connected with a path of bioreactor respectively.
This ligation part is circular, directly with filter membrane and mandrel banding mutually.This ligation part is positioned at axially central authorities' setting of mandrel.Between at least one pairing filter membrane in crack district and the mandrel, be arranged with net sheet tube, net sheet tube is provided with some mesh.
This control system also comprises an oxygenator for the second fluid oxygen supply in the closed circuit.This oxygenator comprises a cylindrical shell, cylindrical shell has a wall and two headwalls reach by they defined synthetic chambeies, synthetic intracavity is provided with the group of fibers of being made up of side by side many doughnuts, the both sides of the longitudinally of this group of fibers and synthetic chamber cementation are to form the liquid stream chamber of passing through for second fluid between cementation position, two places, the hollow cavity of each doughnut forms the airflow chamber that oxygen supply gas passes through jointly, cylindrical shell is provided with air inlet and the gas outlet that is communicated with this airflow chamber, and is provided with inlet and the liquid outlet that is communicated with this liquid stream chamber.The cross section at described inlet and liquid outlet place is provided with buffer board and enters the liquid stream chamber so that second fluid presents with the non-rectilinear path.
The cylindrical shell of described bioreactor is provided with sample tap and application of sample mouth.
Any path of described bioreactor all has from biological reactor outboard shafts to the mouth that gos deep into mandrel with stretch out the mouth of the inboard reative cell of bioreactor from the mandrel inner radial.
A kind of two-way filling type bioreactor control method, it is applicable to described two-way filling type bioreactor control system, comprises the steps:
Fused the first fluid of first material for the pre-splendid attire of the reative cell of bioreactor;
Fused second fluid of second material for the storage bottle splendid attire;
The following parallel step of carrying out simultaneously:
With kinetic pump power is provided so that in the described storage bottle second fluid enter its reative cell through a path of bioreactor, in reative cell, react with first fluid, another path through bioreactor refluxes again, forms closed circuit;
Provide power that bioreactor is rotated so that the evenly fully reaction of the first fluid in its reative cell and second fluid around its mandrel with motor;
Preset and flow to controller with the second fluidic flow direction in the constant duration switching closed circuit;
In closed circuit that oxygen is fused mutually with second fluid with oxygenator.
Compared with prior art, the present invention possesses following advantage:
At first, the present invention is by improving the internal structure of bioreactor, make slit between inside reactor filter membrane and the mandrel by ligation, second fluid can directly not escaped to exit passageway through this slit after entry enters reactor, and can behind reative cell, flow out through exit passageway more earlier, so just, stopped the phenomenon of " invalid circulation ", can enhancing reactor in exchange efficiency between first fluid and second fluid.
Secondly, by control system and the control method that proposes in conjunction with the present invention, utilize dexterously and flow to controller the second fluidic flow direction in the closed circuit is switched, realize the function of two-way filling, simple in structure, be convenient to realize, make the present invention can further guarantee two kinds of fluidic abundant exchanges in the reative cell, can only not accumulate in an end of reative cell.
Moreover, by further providing the net sheet that places between filter membrane and mandrel tube for bioreactor, and the outlet before a plurality of mesh that form on the net sheet tube to be second fluids the enter exit passageway, disperse to enter exit passageway with entering exit passageway second fluid before through a plurality of outlets, like this, first material and the first fluid thereof relatively large at the diameter of this side of reative cell can only not accumulate in an exit, so just can not cause of the obstruction of first material, guarantee the operate as normal of bioreactor, control system at the exit passageway place.
In addition, improved the oxygenator of structure, make flow through wherein oxygen can be fully and second fluid in the closed circuit fuse, and can control effectively to the oxygen-supplying amount that enters this kind oxygenator in conjunction with corresponding control approach, undoubtedly, the quantitative management of realizing bioreactor, control system there be bigger benefiting.
[description of drawings]
Fig. 1 is the sectional side elevation of bioreactor of the present invention, and its internal structure is shown;
Fig. 2 is the structural representation that the inner crack of bioreactor shown in Figure 1 district increases net sheet tube;
Fig. 3 a, Fig. 3 b, Fig. 3 c and Fig. 3 d are the sketch map when net sheet tube launches among Fig. 2, so that its different mesh that form to be shown;
Fig. 4 is the structural representation of the bioreactor, control system of one embodiment of the present of invention, and it adopts two kinds of oxygenators simultaneously;
Fig. 5 is the structural representation of the bioreactor, control system of one embodiment of the present of invention, and it only adopts a kind of oxygenator among Fig. 4;
Fig. 6 is the structural representation of the bioreactor, control system of one embodiment of the present of invention, and it adopts and is different from another kind of oxygenator embodiment illustrated in fig. 4;
Fig. 7 is the structural representation of the bioreactor, control system of one embodiment of the present of invention, its with the difference of Fig. 6 only be in the closed circuit second fluidic flow to different;
Fig. 8 is the sectional side elevation of the oxygenator of one embodiment of the present of invention, and its internal structure is shown;
Fig. 9 is the internal structure principle schematic that flows to controller of one embodiment of the present of invention.
[specific embodiment]
The present invention is further illustrated below in conjunction with drawings and Examples:
Biochemical reaction can take place between the first fluid that the present invention is alleged and second fluid, carry out in two kinds of fluids of biochemical reaction at needs, after biochemical reaction takes place with two of fluid in one of fluid, one of them can become object, and this object is the object of the purpose that reaches certain preparation or treatment.The biochemical reaction that is carried out, saying is because second (class) material that first (class) material that first fluid fused or existed and second fluid fuse or exist reacts each other more specifically.For example, the cell culture stage when the simulation bioartificial liver, earlier in bioreactor perfusion fused treat cultured cell culture medium as first fluid, first material wherein is cell, make the culture medium that has fused nutrient (aminoacid, glucose etc.) and oxygen pass through this bioreactor again as second fluid, so that the cell for the treatment of in the bioreactor is cultivated, nutrient wherein and oxygen are second (class) material.Routine again, treatment stage when the simulation bioartificial liver, dabbling first fluid is the health blood that comprises healthy cell in bioreactor, healthy cell becomes first (class) material herein, second fluid by this bioreactor then is a blood samples of patients, metabolic waste in the blood samples of patients and toxin become second (class) material at this moment, when fusing with first fluid, metabolic waste and toxin are all engulfed by the healthy blood cell, and effusive second fluid will become healthy relatively blood from bioreactor.More than two examples, disclose two kinds of biochemical reactions that bioreactor of the present invention inside is carried out jointly, all be to utilize celelular mechanism to implement.In like manner, those skilled in the art should know, and bioreactor of the present invention also can be applied to the occasion of other biochemical reaction.
By above two examples as can be seen, the first fluid of the present invention and second fluid generally are of identical composition, for example aforesaid culture medium, and second fluid can change to some extent through the composition before and after the bioreactor, show that mainly second material (nutrient and/or oxygen) can biochemical reaction take place with first material (cell) in the reative cell and causes second amount of substance to become or disappear, and exchange also may take place in total part wherein such as culture medium between the first fluid and second fluid.When second fluid initially provides, its second material only comprises some nutrients, and when dissolved in oxygen in this second fluid after, then its second material just comprises nutrient and oxygen simultaneously, when second fluid when biological reactor stream goes out, part second material wherein falls sharply even disappears.As seen, as kinematic concepts, the variation of composition should not influence the understanding to difference of the present invention " fluid ".
To serve as main being described with aforementioned first example below the present invention, also be, taked to fuse treat cultured cell culture medium as first fluid, the culture medium of having taked to comprise nutrient and oxygen is as second fluid, thus, reative cell in the following bioreactor also can be referred to as culturing room, so that its name more meets those skilled in the art's custom.
Please consult Fig. 4 to Fig. 7 earlier, disclosed the structure of two-way filling type bioreactor control system of the present invention among each figure, this control system comprises bioreactor 50, motor 56, flows to controller 55, kinetic pump 54, oxygenator 52,53 and storage bottle 51, these parts are common to constitute a closed circuit.Below disclose in detail each ingredient of bioreactor, control system.
See also Fig. 1, described bioreactor 50, integral body is tubular, and it comprises cylindrical shell 1, mandrel 3 and filter membrane 2.
Mandrel 3 traverses the end walls 11 of cylindrical shell 1,12 are provided with, except that being provided with of entry 31 and exit passageway 32, the mandrel 3 of present embodiment is solid material substantially, the axis of mandrel 3 preferably with the dead in line of cylindrical shell 1, mandrel 3 two ends form respectively for the culture medium (second fluid) that has fused nutrient and oxygen and enter the entry 31 of this reative cell 10 and for participating in reacted culture medium (second fluid) autoreaction chamber 10 effusive exit passageways 32.This entry 31 is in the circle centre position perforate of first end wall 11 and axially go deep into mandrel 3 inside, pass mandrel 3 to be communicated to this reative cell 10 in mandrel 3 inner radial then, for this reason, adapt to the setting of this entry 31, first end wall, 11 outsides are formed with the outer side entrance 310 that culture medium that a confession carries nutrient and oxygen enters, and mandrel 3 one lateral column faces are formed with one or more interior side entrances 313 that enter reative cell 10.In like manner, this exit passageway 32 is in position, the center of circle perforate of second end wall 12 and axially go deep into mandrel 3 inside, pass mandrel 3 to be communicated to this reative cell 10 in mandrel 3 inner radial then, for this reason, adapt to the setting of this exit passageway 32, second end wall, 12 outsides are formed with one for participating in the outer side outlet 320 that reacted culture medium is back to storage bottle 51, and mandrel 3 opposite side cylinders then are formed with one or more for participating in the interior side outlet 323 that reacted culture medium flows out reative cell 10.Obviously, the particular location and the distance of the interior side entrance 313 of entry 31 and the interior side outlet 323 of exit passageway 32 have determined the motion range of most of fluid in reative cell 10 in most cases.
This filter membrane 2 is tubular because of the cylinder that is coated on this mandrel 3, filter membrane 2 surfaces are formed with the moderate a plurality of miniature aperture (not shown) in aperture, so that stop aforementioned first fluid especially first material pass through, and allow aforesaid second fluid especially second material pass through, particularly, because the diameter of cell is big than nutrient and oxygen molecule,, can realize this function so the aperture size of filter membrane 2 is arranged on less than first material size in the size range greater than the second material size.Filter membrane 2 is because its structure is lax relatively, the character softness, so with easy formation slit 20 between the mandrel 3.So, after second fluid enters from entry 31, a part can see through filter membrane 2 and enter reative cell 10, escape into the interior side outlet 323 of exit passageway 32 through this slit 20 for fear of second fluidic another part, directly flow out reative cell 10 through exit passageway 32 then, so as shown in Figure 1, center at filter membrane 2 longitudinallies, adopt 400 pairs of filter membranes of a ligation part, 2 formed tubulars to carry out ligation, thus, filter membrane 2 is at ligation position and mandrel 3 banding and fitting tightly mutually, and described slit 20 just is divided into disconnected two cracks district 201 mutually, 203, because of 201,203 in two cracks district is not communicated with each other, so after second fluid enters reative cell 10, to all enter and participate in the reative cell 10 flowing out again after the reaction, so can make the exchange rate enhancing of itself and first fluid.
This ligation part 400 is designed to circular, and its radial width is not required, and its cross section can be positive circle, but it preferably has certain elasticity, so that the user regulates ligation site.Certainly, ligation part 400 radially being enlarged along it, make it in the form of sheets, not stop the circulation of fluid-mixings in the reative cell 10, so also is feasible.In a typical application, the elastic tape that can adopt elastomeric material to make directly uses as ligation part 400.In addition, in some not shown embodiment, it is feasible suitably adjusting the ligation site of ligation part 400 on filter membrane 2, for example it is provided with by entry 31 or exit passageway 32, all can avoid " invalid circulation " phenomenon.
Notice shown in Figure 1, filter membrane section between the interior side entrance 313 of entry 31 and first end wall 11, and the filter membrane section between the interior side outlet 323 of exit passageway 32 and second end wall 12, also easily form between this two places filter membrane section and the mandrel 3 and accommodate fluidic dead space, in order to stop dead space herein, adopt ligation part 401,402 to carry out ligation, can overcome at this two place.A kind of interchangeable mode is with the interior side outlet 323 close corresponding end walls 11 or 12 settings of the interior side entrance 313 of entry 31 and exit passageway 32, so just can not have the problem that needs the two ends ligation.
Note the ligation part 401 at filter membrane 2 two ends, 402 with the difference of intermediary ligation part 400 are, the ligation part 401 at filter membrane 2 two ends, 402 outside reative cell 10 fluid movement ranges, be to be provided with for the dead space that prevents both sides between filter membrane 2 and the mandrel 3, the ligation part 400 at filter membrane 2 middle parts then places the motion range of fluid in reative cell 10, is in order to stop second fluid directly to be escaped through the slit 20 of 3 of filter membrane 2 and mandrels.And in theory, as long as the interior side entrance 313 and the distance between first end wall 11 of entry 31 are enough little, and fastening between this side filter membrane 2 and the mandrel 3 by 11 of first end walls; In like manner, as long as the interior side outlet 323 and the distance between second end wall 12 of exit passageway 32 are enough little, and fastening between this side filter membrane 2 and the mandrel 3 by 12 of second end walls, in this case, described two ends ligation part 401,402 needn't be set then.
In addition,, one sample tap 14 and an application of sample mouth 15 are set respectively, with the tight respectively lid of plug part 140,150, only just open the plug part when needed and used at ordinary times in cylindrical shell 1 post jamb 13 any positions for the ease of sampling and application of sample from reative cell 10.
As further improvement to bioreactor, please in conjunction with Fig. 2, two cracks districts 201 that form jointly by slit between filter membrane 2 and the mandrel 3 20 that are divided into two by a ligation part 400, in 203, especially refer to be provided with a net sheet tube 28 in the occupied crack district 201 of side outlet in it 323 by exit passageway 32.This net sheet tube 28 is adapted to the shape of mandrel 3 and is tubular, be provided with a plurality of mesh 280 around its tubular post jamb 13, this mesh 280 can freely design, consult shown in Fig. 3 a to 3d, its both arrange can rule also can be irregular, its shape can be rectangle, square (Fig. 3 a), rhombus (Fig. 3 b), circular (Fig. 3 c), triangle, mixing shape arbitrary shapes such as (Fig. 3 d).The setting of mesh 280, make and participate in reacted second fluid, it is passing after filter membrane 2 enters this crack district 201, could enter exit passageway 32 through interior side outlet 323 after at first need passing this net sheet tube 28, because net sheet tube 28 cylinders are provided with a plurality of mesh 280, so second fluid that passes after the filter membrane 2 can disperse to enter exit passageway 32 through a plurality of mesh 280 of net sheet tube 28, like this, filter membrane 2 surfaces form a plurality of invisible " inlets " undoubtedly, make the fluid-mixing that carries in the reative cell 10 can not gather in certain, and can be relatively dispersedly at whole filter membrane 2 surface currents to crack district 201, pass net sheet tube 28 and enter exit passageway 32 again, so, just, can avoid the gather caused blockage problem of reative cell 10 inner cells at interior side outlet 323 pairing filter membranes 2 places of exit passageway 32.
In conjunction with Fig. 4 to Fig. 7, motor 56 of the present invention is mainly used in the described bioreactor 50 of driving and is rotated around its axis, because the axis of mandrel 3 overlaps substantially with the axis of the barrier part 1 of bioreactor 50, axis rotation mandrel 3 around mandrel 3 promptly turns whole barrier part 1 in fact, thereby realizes the rotation of whole bioreactor 50.Rotation direction can be unidirectional also can be two-way, the rotation direction of motor 56 does not influence enforcement of the present invention.
In two-way filling type bioreactor control system, storage bottle 51 is communicated with respectively to form closed circuit with the outer side entrance 310 and the outer side outlet 320 of bioreactor 50 by pipeline, so need in this closed circuit, to utilize a kinetic pump 54 to drive the circulation of second fluid in this loop of storage bottle 51, carry sufficient amount of oxygen in order to make in the storage bottle 51 culture medium, also need in conjunction with at least one oxygenator 52,53 provide the oxygen composition in the source (not shown) to fuse in second fluid in this loop the natural air or oxygen, in addition, also be required to be this loop outfit and flow to controller 55.
Please in conjunction with Fig. 5 and Fig. 9, the controller 55 that flows to of the present invention is by forming in conjunction with a plurality of three-way valve (not shown), it has two inputs and two outfans, by adopting electronics or manual form, the switchings that can make two inputs flowing in the controller 55 and two outfans realize flowing to, this switching are by the annexation realization of the different three-way valve of reasonable direction.The described controller 55 that flows to comprises two automatically controlled three-way valve 71 of directed ends, 72 and two automatically controlled three-way valve 73 of commutation end, 74, each three-way valve all has two mouths 701 downstream, 702 vertical mouthfuls 703 with one, two of the automatically controlled three-way valve 71 of first directed ends downstream mouthfuls 701,702 hold automatically controlled three-way valve 73 with two commutations respectively, mouthful connection downstream of each of 74, vertical mouthful 703 of the automatically controlled three-way valve 71 of first directed ends can directly be communicated with kinetic pump 54, two of the automatically controlled three-way valve 72 of second directed ends downstream mouth also respectively with two automatically controlled three-way valve 73 of commutation end, mouthful connection downstream of each of 74, vertical mouthful of the automatically controlled three-way valve 72 of second directed ends can directly be communicated with storage bottle 51, the first commutation end and the second automatically controlled three-way valve 73 that commutates and hold, being connected between 74 vertical mouthful and the bioreactor 50,, do not need the strictness appointment owing to can constantly switch by the control that flows to 55 pairs of automatically controlled three-way valve of controller.In fact, owing to flow to the realization of controller 55, bioreactor 50 has become no longer strict with flowing to controller 55 each end connected relation physically, but depends on the switching voluntarily that flows to controller.
Control system of the present invention is used this kind bioreactor 50, realize with following structure and mode: its at first in storage bottle 51 splendid attire fused the culture medium solution of nutrient as second fluid, in bioreactor 50 splendid attire comprised treat cultured cell culture medium solution as first fluid, with the structure shown in Fig. 4 to 7, by two pipelines that draw from storage bottle 51, one of pipeline elder generation and at least one oxygenator 52,53 connections are synthetic to carry out oxygen herein, again by oxygenator 52,53 are connected with kinetic pump 54 promotes that to apply herein second fluid carries out circulation power, then, finish being communicated with of one of this pipeline with the vertical mouth of the automatically controlled three-way valve 71 of first directed ends that flows to controller 55 by kinetic pump 54, and, the vertical mouth that flows to the automatically controlled three-way valve 72 of second directed ends of controller 55 directly is connected with two of pipeline, to flow to 55 liang of automatically controlled three-way valve 73 of commutation end of controller again, 74 are connected with outer side outlet 320 with the outer side entrance 310 of bioreactor 50 respectively, can finish the physical connection of The whole control system.After flowing to the parameter of the default flow direction that automaticallyes switch in the controller 55, closed circuit flows to and just can be switched by self-timing, but does not need manual intervention just to switch on constant duration ground.This shows that for the bioreactor 50 of first embodiment, its exit passageway 32 is relative with entry 31, both are interchangeable each other, decide on flowing to the flow direction that controller 55 determined.
During work, with a direction shown in Figure 6 is example, under the driving of kinetic pump 54, the culture medium of having carried nutrient is from storage bottle 51, arrive one of by the road oxygenator 52,53 mix with oxygen, subsequently from oxygenator 52,53 culture medium that fused nutrient and oxygen of coming out enter through kinetic pump 54 and flow to controller 55, second fluid communication that flows to controller ultromotivity pump in 55 future 54 is to the outer side entrance 310 of the entry 31 in bioreactor left side, second fluid enters reative cell 10 then and carries out biochemical reaction with first fluid, after cell in the first fluid has absorbed nutrient and oxygen in second fluid, the outer side outlet 320 of the exit passageway 32 on second fluid right side in figure is back to and flows to controller 55, flows to controller 55 then with its conducting another pipeline to storage bottle 51, finishes a circulation.Wherein, oxygenator 52,53 is the work that participates in real time with kinetic pump 54, flows to controller 55 and then sets according to the user and regularly flow to switching, and the relative closed circuit of this three's work is parallel to carry out.
As shown in Figure 7, after flowing to inner flow direction of controller 55 automatic switchovers, can be switched in the outer side entrance 310 of the entry 31 on right side to the figure through second fluid that kinetic pump 54 enters, at last can be in figure the outer side outlet 320 of exit passageway 32 in left side enter and flow to controller 55, again by flow to controller 55 will participate in reacted second fluid flow guiding extremely aforementioned another pipeline be back to storage bottle 51 and finish circulation.
Introduction by above-mentioned work process further discloses, and the exit passageway 32 and the entry 31 of bioreactor 50 can exchange, and just different names occurs based on its function, are path in essence, all has inboard mouthful and lateral port.As for bioreactor 50 inside, because ligation part 400 is positioned at the place, middle part of the longitudinally of its mandrel 3, so to the effect that two-way filling played that forms in the reative cell 10 is consistent, more excellent part is, two-way filling makes reative cell 10 both sides can not cause the cell density inequality as unidirectional perfusion, and can make that the 10 interior two kinds of fluidic exchanges of entire reaction chamber are more even.
Notice and used two oxygenators 52 and 53 among Fig. 4 that one of them 53 is independent improvement the of the present invention, can more be applicable among the present invention.
See also Fig. 8, oxygenator 53 comprises a cylindrical shell 6, this cylindrical shell 6 has a wall 60 and two headwalls 61,62, described two headwalls 61,62 are the lid that is provided with female thread, tube wall 60 axis direction two ends outer walls have then formed external screw thread, thus, and two headwalls 61,62 just can distinguish the two ends of screw lock at tube wall 60, form closely to connect.Certainly, as the facility on not considering to install, dismantle, safeguard, in not shown embodiment, also can with at least one headwall 61 or 62 and tube wall 60 one-body molded.
Described two headwalls 61,62 and the tube wall 60 between, defined a synthetic chamber 63 in cylindrical shell 6 inside, should be provided with the group of fibers 620 of trooping side by side and making in the synthetic chamber 63 by many doughnuts, every doughnut in the group of fibers 620 all is parallel to the axis setting of cylindrical shell 6 with its longitudinally, so can be understood as the longitudinally of group of fibers 620 and axially paralleling of cylindrical shell 6.There is the gap between doughnut and the doughnut.The chamber wall in the synthetic chamber 63 of the both sides of the axis direction of group of fibers 620 and this cylindrical shell 6 seals with the viscose glue cementation, locate 64 places, cementation position 620 liang of group of fibers, between each doughnut also by cementation in the hope of the integral sealing of group of fibers 620 outsides at this place, the gap has been by just having constituted a liquid stream chamber 632 that belongs to these synthetic chamber 63 parts between fiber between the cementation position, two places 64 and fiber, and the hollow cavity of each doughnut just constitutes the airflow chamber 631 that belongs to these synthetic chamber 63 another part jointly.As everyone knows, doughnut in a tubular form, the relative gas of fiber tube wall has penetrance, liquid then has sealing relatively, when so gas can pass through at the hollow cavity of each fiber, part gas can penetrate the fiber tube wall, and liquid then can not penetrate the fiber tube wall and enter its hollow cavity.
But the airflow chamber 631 and the liquid stream chamber 632 that are made of jointly group of fibers 620 and cylindrical shell 6 have the architectural feature that non-overlapping copies staggers mutually.In the cross section visual angle of cylindrical shell 6, liquid stream chamber 632 surrounds airflow chamber 631 basically and is provided with, or being provided with for surrounding a plurality of more tiny airflow chamber of looking.
As previously mentioned, airflow chamber 631 is used for by oxygen, and liquid stream chamber 632 is used for by culture fluid (second fluid).Make fluid liquid stream chamber 632 in, to circulate because of half permeation of group of fibers 620 between airflow chamber 631 and the liquid stream chamber 632 and can not pass the doughnut tube wall and enter airflow chamber 631, and the oxygen of airflow chamber 631 can penetrate the doughnut tube wall and enters liquid stream chamber 632 and fuse mutually with culture fluid.Therefore, in liquid stream chamber 632, gas and fluid have carried out biochemical reaction, and because of cylindrical shell 6 air-tightness own are good, gas can not leak into cylindrical shell 6 outsides.
For oxygen being provided for airflow chamber 631, a described headwall 61 is provided with air inlet 616, another headwall 12 is provided with gas outlet 626, air inlet 616 all is connected with this airflow chamber 631 with gas outlet 626, but between the respective end of headwall 61 and group of fibers 620, and between the respective end of headwall 62 and group of fibers 620, also be formed with one the buffering crack, after this buffering crack supplied gas enters wherein again every trade advance.Because of air inlet 616 and gas outlet 626 are distance with the lengthwise span of cylindrical shell 6, so have the abundant exercise range to flow out this airflow chamber 631 after oxygen enters airflow chamber 631, again because of having the gap between each doughnut, be equivalent to the contact area that has increased airflow chamber 631 and liquid stream chamber 632, oxygen has time enough and contact area to pass group of fibers 620 to fuse mutually with fluid in the liquid stream chamber 632 is more abundant during this period.
For culture fluid being provided for liquid stream chamber 632, in conjunction with liquid stream chamber 632 basic construction featuress of surrounding airflow chamber 631, at a distance of the position inlet 606 and a liquid outlet 608 are set respectively at any two places of the outer wall of tube wall 60, inlet 606 and liquid outlet 608 all are connected with liquid stream chamber 632, after the fluid that enters by inlet 606 just can enter liquid stream chamber 632 and mixes with oxygen, flow out through liquid outlet 608 again.
The design of inlet 606 and liquid outlet 608 makes it present a straight line path separately; enter and from liquid outlet 608 effusive fluids from inlet 606; generally be to drive by kinetic pump (not shown); therefore; unmanageable flow velocity can bring certain influence to nutrient in the culture medium and soft group of fibers 620; particularly when flow velocity is higher; relative group of fibers 620; it is bigger to enter fluidic momentum along linear passages; can cause group of fibers 620 distortion or destruction; for fear of this kind situation; in inlet 606 and liquid outlet 608; the buffer board 69 of cushioning effect together is set; change the non-rectilinear path into the linear passages with inlet 606 and liquid outlet 608, fluid changes into along buffer board 69 peripheries and enters liquid stream chamber 632 after impacting this buffer board 69; the fluidic impulsive force that enters liquid stream chamber 632 this moment is just alleviated greatly, effectively group of fibers 620 has been implemented protection.
For the ease of producing, described buffer board 69 is set at inlet 606 and liquid outlet 608 and tube wall 60 intersections, and around the circumferential of tube wall 60 circlewise, further, can also appropriate change tube wall 60 with ring-type buffer board 69 between the space with expansion fluid throughput.
Those skilled in that art can predict, and described airflow chamber 631 can exchange with liquid stream chamber 632, therefore, should regard it as not unconventional the spirit and scope of the present invention.
In the phenolsulfonphthalein test that the applicant carried out, control system of the present invention demonstrates than prior art and exchanges effect more uniformly, but because of the formed picture of phenolsulfonphthalein test process is a photochrome, do not meet Patent Law about the regulation of accompanying drawing and diagram is not provided, those skilled in that art can test voluntarily with verify this type of according to the present invention predictable result.
In sum, bioreactor of the present invention and control system thereof and method, be particularly suited for the bioartificial liver application scenario, problems such as perfusion inequality, dead space, obstruction and exchange rate that the prior biological reactor exists are low have comprehensively been solved, then the multiple control system that is made of different bioreactors is provided, for the biochemical reaction field provides better supplementary instrument.
Above embodiment only in order to the explanation the present invention and and unrestricted technical scheme described in the invention; Therefore, although this description has been described in detail the present invention with reference to each above-mentioned embodiment,, those of ordinary skill in the art should be appreciated that still and can make amendment or be equal to replacement the present invention; And all do not break away from the technical scheme and the improvement thereof of the spirit and scope of the present invention, and it all should be encompassed in the middle of the claim scope of the present invention.
Claims (13)
1. two-way filling type bioreactor control system comprises:
Bioreactor, it comprises cylindrical shell, mandrel and filter membrane, cylindrical shell forms reative cell and reacts to offer first fluid that has fused first material and second fluid that has fused second material, mandrel traverses drum shaft to setting, the mandrel two ends respectively form a path, this filter membrane coats this mandrel, to stop first material, to allow second material to pass through, is formed with the slit between filter membrane and the mandrel;
Motor is used to drive described bioreactor around its mandrel rotation;
Storage bottle is used to store second fluid that has fused second material;
Kinetic pump, second fluid that is used for keeping storage bottle enters reative cell after another path is got back to storage bottle to constitute closed circuit through a path of bioreactor;
It is characterized in that:
This control system also comprises and flows to controller, is used to switch the flow direction of described closed circuit;
In this bioreactor, at least one place of filter membrane is directly flowed out through this slit to stop second fluid described slit is split up into mutual disconnected a plurality of crack district by the ligation of ligation part institute.
2. two-way filling type bioreactor control system according to claim 1, it is characterized in that, this storage bottle is connected with at least one oxygenator, oxygenator is connected with kinetic pump, kinetic pump with flow to that controller is connected flows to controller so that second fluid enters, flowing to controller also directly is communicated with storage bottle, controller also is communicated with respectively with two passages of bioreactor so that second fluid refluxes through behind this bioreactor so that second fluid reflux to storage bottle, flows to.
3. two-way filling type bioreactor control system according to claim 2, it is characterized in that, the described controller that flows to comprises two automatically controlled three-way valve of directed ends and two automatically controlled three-way valve of commutation end, each three-way valve all has two mouthful vertical mouths with downstream, two of the automatically controlled three-way valve of each directed ends downstream mouth mouthful be communicated with downstream with each one of two automatically controlled three-way valve of commutation end respectively, vertical mouthful of the automatically controlled three-way valve of first directed ends is connected with kinetic pump, vertical mouthful of the automatically controlled three-way valve of second directed ends is connected with storage bottle, and vertical mouthful of two automatically controlled three-way valve of commutation end is connected with a path of bioreactor respectively.
4. according to any described two-way filling type bioreactor control system in the claim 1 to 3, it is characterized in that: this ligation part is circular, directly with filter membrane and mandrel banding mutually.
5. two-way filling type bioreactor control system according to claim 4 is characterized in that: this ligation part is positioned at axially central authorities' setting of mandrel.
6. according to any described two-way filling type bioreactor control system in the claim 1 to 3, it is characterized in that: between at least one pairing filter membrane in crack district and the mandrel, be arranged with net sheet tube, net sheet tube is provided with some mesh.
7. according to any described two-way filling type bioreactor control system in the claim 1 to 3, it is characterized in that this control system also comprises an oxygenator for the second fluid oxygen supply in the closed circuit.
8. two-way filling type bioreactor control system according to claim 7, it is characterized in that, this oxygenator comprises a cylindrical shell, cylindrical shell has a wall and two headwalls reach by they defined synthetic chambeies, synthetic intracavity is provided with the group of fibers of being made up of side by side many doughnuts, the both sides of the longitudinally of this group of fibers and synthetic chamber cementation are to form the liquid stream chamber of passing through for second fluid between cementation position, two places, the hollow cavity of each doughnut forms the airflow chamber that oxygen supply gas passes through jointly, cylindrical shell is provided with air inlet and the gas outlet that is communicated with this airflow chamber, and is provided with inlet and the liquid outlet that is communicated with this liquid stream chamber.
9. two-way filling type bioreactor control system according to claim 8 is characterized in that, the cross section at described inlet and liquid outlet place is provided with buffer board and enters the liquid stream chamber so that second fluid presents with the non-rectilinear path.
10. according to any described two-way filling type bioreactor control system in the claim 1 to 3, it is characterized in that: described cylindrical shell is provided with sample tap and application of sample mouth.
11. according to any described two-way filling type bioreactor control system in the claim 1 to 3, it is characterized in that: any path of described bioreactor all has from biological reactor outboard shafts to the mouth that gos deep into mandrel with stretch out the mouth of the inboard reative cell of bioreactor from the mandrel inner radial.
12. a two-way filling type bioreactor control method, it is applicable to any described two-way filling type bioreactor control system in the claim 1 to 11, it is characterized in that it comprises the steps:
Fused the first fluid of first material for the pre-splendid attire of the reative cell of bioreactor;
Fused second fluid of second material for the storage bottle splendid attire;
The following parallel step of carrying out simultaneously:
With kinetic pump power is provided so that in the described storage bottle second fluid enter its reative cell through a path of bioreactor, in reative cell, react with first fluid, another path through bioreactor refluxes again, forms closed circuit;
Provide power that bioreactor is rotated so that the evenly fully reaction of the first fluid in its reative cell and second fluid around its mandrel with motor;
Preset and flow to controller with the second fluidic flow direction in the constant duration switching closed circuit.
13. two-way filling type bioreactor control method according to claim 12 is characterized in that, it also comprises another parallel step: in closed circuit that oxygen is fused mutually with second fluid with oxygenator.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113220A1 (en) * | 2010-03-19 | 2011-09-22 | 南方医科大学珠江医院 | Bioreactor, control system and method thereof |
| CN107635597A (en) * | 2015-05-12 | 2018-01-26 | 索林集团意大利有限责任公司 | With for reducing the restriction element of gas exchanges or the blood gas exchanger of multiple restriction elements |
| CN109804059A (en) * | 2016-08-03 | 2019-05-24 | 诺斯威克公园医学研究所有限公司 | Bioreactor and the method for handling biomaterial |
| US10814056B2 (en) | 2014-11-12 | 2020-10-27 | Sorin Group Italia S.R.L. | Elastic protection tube for a hollow fiber blood processing apparatus |
| US11160912B2 (en) | 2010-08-19 | 2021-11-02 | Sorin Group Italia S.R.L. | Blood processing unit with modified flow path |
| US11471577B2 (en) | 2014-02-28 | 2022-10-18 | Sorin Group S.r.l. | System for providing an integrated arterial filter into an oxygenator, minimizing added priming volume |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0909565A1 (en) * | 1997-10-16 | 1999-04-21 | B. BRAUN CAREX S.p.A. | Use of a non-ionic adsorbent resin combined with the system known as bioartificial liver |
| US5989913A (en) * | 1998-07-02 | 1999-11-23 | Charles Daniel Anderson | Culture vessel for growing or culturing cells, cellular aggregates, tissues and organoids and methods for using the same |
| CN2761164Y (en) * | 2004-12-30 | 2006-03-01 | 中国科学院电工研究所 | Biological reactor |
| CN101087873A (en) * | 2004-12-27 | 2007-12-12 | 弗雷森纽斯医疗护理德国有限责任公司 | Reactor and reactor unit with hollow fibers |
| CN101336290A (en) * | 2005-12-30 | 2008-12-31 | 药物模式有限责任公司 | Bioreactor for cell and tissue culture |
| CN201643113U (en) * | 2010-03-19 | 2010-11-24 | 南方医科大学珠江医院 | Control system for two-way perfusion type bioreactor |
-
2010
- 2010-03-19 CN CN2010101303588A patent/CN101837151B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0909565A1 (en) * | 1997-10-16 | 1999-04-21 | B. BRAUN CAREX S.p.A. | Use of a non-ionic adsorbent resin combined with the system known as bioartificial liver |
| US5989913A (en) * | 1998-07-02 | 1999-11-23 | Charles Daniel Anderson | Culture vessel for growing or culturing cells, cellular aggregates, tissues and organoids and methods for using the same |
| CN101087873A (en) * | 2004-12-27 | 2007-12-12 | 弗雷森纽斯医疗护理德国有限责任公司 | Reactor and reactor unit with hollow fibers |
| CN2761164Y (en) * | 2004-12-30 | 2006-03-01 | 中国科学院电工研究所 | Biological reactor |
| CN101336290A (en) * | 2005-12-30 | 2008-12-31 | 药物模式有限责任公司 | Bioreactor for cell and tissue culture |
| CN201643113U (en) * | 2010-03-19 | 2010-11-24 | 南方医科大学珠江医院 | Control system for two-way perfusion type bioreactor |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113220A1 (en) * | 2010-03-19 | 2011-09-22 | 南方医科大学珠江医院 | Bioreactor, control system and method thereof |
| US11160912B2 (en) | 2010-08-19 | 2021-11-02 | Sorin Group Italia S.R.L. | Blood processing unit with modified flow path |
| US11471577B2 (en) | 2014-02-28 | 2022-10-18 | Sorin Group S.r.l. | System for providing an integrated arterial filter into an oxygenator, minimizing added priming volume |
| US10814056B2 (en) | 2014-11-12 | 2020-10-27 | Sorin Group Italia S.R.L. | Elastic protection tube for a hollow fiber blood processing apparatus |
| CN107635597A (en) * | 2015-05-12 | 2018-01-26 | 索林集团意大利有限责任公司 | With for reducing the restriction element of gas exchanges or the blood gas exchanger of multiple restriction elements |
| US10661004B2 (en) | 2015-05-12 | 2020-05-26 | Sorin Group Italia S.R.L. | Blood gas exchanger with restriction element or elements to reduce gas exchange |
| CN109804059A (en) * | 2016-08-03 | 2019-05-24 | 诺斯威克公园医学研究所有限公司 | Bioreactor and the method for handling biomaterial |
| US11473048B2 (en) | 2016-08-03 | 2022-10-18 | Videregen Limited | Bioreactors and methods for processing biological material |
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|---|---|
| CN101837151B (en) | 2012-07-04 |
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