CN106267399B - Four-in-one formula bioreactor of artificial liver - Google Patents
Four-in-one formula bioreactor of artificial liver Download PDFInfo
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- CN106267399B CN106267399B CN201610607440.2A CN201610607440A CN106267399B CN 106267399 B CN106267399 B CN 106267399B CN 201610607440 A CN201610607440 A CN 201610607440A CN 106267399 B CN106267399 B CN 106267399B
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- oxygenator
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- cavity
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- 210000004185 liver Anatomy 0.000 title claims abstract description 30
- 210000002381 plasma Anatomy 0.000 claims abstract description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000005192 partition Methods 0.000 claims abstract description 24
- 210000004027 cell Anatomy 0.000 claims abstract description 23
- 210000004369 blood Anatomy 0.000 claims abstract description 22
- 239000008280 blood Substances 0.000 claims abstract description 22
- 229920005749 polyurethane resin Polymers 0.000 claims description 37
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 30
- 239000012530 fluid Substances 0.000 claims description 28
- 230000037452 priming Effects 0.000 claims description 28
- 239000012528 membrane Substances 0.000 claims description 25
- 239000000835 fiber Substances 0.000 claims description 22
- 239000012510 hollow fiber Substances 0.000 claims description 21
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 17
- 239000001569 carbon dioxide Substances 0.000 claims description 17
- 239000011148 porous material Substances 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 235000015097 nutrients Nutrition 0.000 claims description 13
- 210000003494 hepatocyte Anatomy 0.000 claims description 12
- 238000001802 infusion Methods 0.000 claims description 7
- -1 polyethylene Polymers 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 6
- 239000004698 Polyethylene Substances 0.000 claims description 5
- 229920000573 polyethylene Polymers 0.000 claims description 5
- 239000004695 Polyether sulfone Substances 0.000 claims description 4
- 229920006393 polyether sulfone Polymers 0.000 claims description 4
- 229920002635 polyurethane Polymers 0.000 claims description 3
- 239000004814 polyurethane Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- RZXDTJIXPSCHCI-UHFFFAOYSA-N hexa-1,5-diene-2,5-diol Chemical compound OC(=C)CCC(O)=C RZXDTJIXPSCHCI-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 230000004060 metabolic process Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000012856 packing Methods 0.000 abstract 1
- 229960004424 carbon dioxide Drugs 0.000 description 14
- 239000000243 solution Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 230000035764 nutrition Effects 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 235000012489 doughnuts Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 238000013310 pig model Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1698—Blood oxygenators with or without heat-exchangers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3601—Extra-corporeal circuits in which the blood fluid passes more than once through the treatment unit
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3621—Extra-corporeal blood circuits
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3687—Chemical treatment
- A61M1/3689—Chemical treatment by biological cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/0021—Special media to be introduced, removed or treated removed from and reintroduced into the body, e.g. after treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0413—Blood
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/33—Controlling, regulating or measuring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/36—General characteristics of the apparatus related to heating or cooling
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2210/00—Anatomical parts of the body
- A61M2210/12—Blood circulatory system
Abstract
The invention discloses four-in-one formula bioreactor of artificial liver, the three-in-one bioreactor including constant temperature water tank and portion disposed within；The three-in-one bioreactor includes cavity and the first partition and second partition that are arranged in the cavity；The cavity is divided into three separate spaces from left to right by first partition and second partition, is followed successively by plasma separator, oxygenator and reactor；The constant temperature water tank includes water tank shell and the hot water inlet on water tank shell and hot water outlet.The beneficial effects of the invention are as follows：After blood enters plasma separator, blood plasma sequentially enters oxygenator and reactor, reduces unnecessary pipeline；It can be provided for cell suitable for metabolism environment, ensure cell activity；Effective cell packing volume is improved, ensures that cell cross direction profiles are uniform.
Description
Technical field
The invention belongs to bioartificial liver's technical field more particularly to a kind of four-in-one formula bioreactor of artificial liver.
Background technology
Biological artificial liver support system is in vitro using having the function of the cell of liver metabolism, to hepatic failure patients blood
It is purified, realizes the function that Vitro hepatic ramus splanchnicus is held, for liver regeneration or liver transplant waited for win the quality time, there is weight
Want clinical value.In biological artificial liver support system, bioreactor provides abundance as core apparatus for cell mass
Oxygen, appropriate nutriment and suitable pH environment, enable cell to play its bioactivity to greatest extent, high to realize
The liver function expression of effect provides safeguard.
At present, the biological artificial liver support system for having been used for clinical test or treatment mainly includes plasma separator, oxygen coupling
Clutch and bioreactor three parts.After patient blood export is external, blood plasma and haemocyte are detached through plasma separator first；
The blood plasma isolated enters bioreactor after the enough oxygen of oxygen coupler load；In the bioreactor cell mass using blood plasma as
Basic nutrition carries out metabolism and exchange；Blood plasma after removal biotoxin detaches blood cells with plasma separator again and mixes
It closes, is fed back to patient's body, realize external artificial liver function.Plasma separator, oxygen coupler and bioreactor three
It is higher to be divided into this, operation is cumbersome, needs to be advanced optimized.Also, common bioreactor is reacted for hollow fiber type at present
Device, fibre pipe arrangement is close in the reactor, and volume is smaller between fibre pipe, and centre is not easy to be loaded into cell, easily causes thin
Born of the same parents are unevenly distributed, and lead to the reduction of system detoxifying properties.Meanwhile existing bioreactor is increased just with heat booster at present
Temperature can not carry out constant temperature to bioartificial liver's reactor and uniformly heat, and heating is unstable, influences bioartificial liver's reactor
Efficiency.
Ideal bioreactor of artificial liver should have following characteristics：It can provide suitable for metabolism environment, ensure thin for cell
Cytoactive；Sufficient amount cell can be loaded, filling cell distribution is uniform, and cell can come into full contact with carry out mass exchange with blood plasma；
Heated at constant temperature can be carried out to reactor and thermal-stable is uniform, system structure is succinct, simple operation.
Invention content
Present invention aim to overcome plasma separator in existing biological artificial liver support system, oxygen coupler,
The defects of four departmental costs such as bioreactor and incubator are higher, operation is cumbersome, complicated, provides a kind of realization blood
It starches separation, oxygen coupling, bioreactor and incubator four-in-one and realizes that pH regulation and control, cell fill uniform, mass exchange simultaneously
Fully, the four-in-one formula bioreactor of artificial liver easy to operate of heated at constant temperature is carried out to reactor.
To achieve the above object, the four-in-one formula bioreactor of artificial liver designed by the present invention, including constant temperature water tank and
The three-in-one bioreactor in portion disposed within；
The three-in-one bioreactor includes cavity and the first partition and second partition that are arranged in the cavity；The
The cavity is divided into three separate spaces from left to right by one partition board and second partition, is followed successively by plasma separator, oxygen closes
Device and reactor；
The plasma separator is connected the two inner cavity from outside by device room connecting tube with the oxygenator, the device room
Connecting tube is equipped with separation and pumps；The reactor and the oxygenator are by the intercommunicating pore that is opened up on second partition by the two inner cavity
Connection；
Left side cavity upper end at the plasma separator is equipped with blood/priming fluid entrance, and lower end is equipped with haemocyte
Outlet, to be set on the doughnut of the inside of the plasma separator between the blood/priming fluid entrance and haemocyte outlet
Shu Liantong；
The cavity upper end of middle section at the oxygenator is equipped with oxygen/carbon dioxide entrance, the oxygenator
Be internally provided with the permeable fiber membrane tube being connected with the oxygen/carbon dioxide entrance；
Right side cavity at the reactor is equipped with nutrient solution/hepatocyte suspension entrance, nutrient solution/liver cell
Suspension outlet and blood plasma/priming fluid outlet, the intercommunicating pore and blood plasma/priming fluid export the inside to be set on the reactor
Hollow fiber film tube connection；
The constant temperature water tank includes water tank shell and the hot water inlet on the water tank shell and hot water outlet；The water tank
Shell wraps the three-in-one bioreactor, is further opened on the water tank shell multiple for each on three-in-one bioreactor
The hole that a entrance is pierced by, and on the three-in-one bioreactor each entrance be nozzle, nozzle outer wall with it is described
The inner wall sealing connection of hole.
Further, the inlet end of device room connecting tube is located at the side wall lower ends of the plasma separator, liquid outlet
End is positioned at the lower end of the oxygenator；The intercommunicating pore is located at the upper end of second partition.
Still further, it is additionally provided with along its cross-sectional direction to obstruct the close of blood plasma/priming fluid inside the oxygenator
Supporting plate is sealed, the sealed support plate is located at the top of intercommunicating pore；Multiple apertures are offered on the sealed support plate, it is described
The upper end of gas fiber membrane tube is fastened in aperture, and the space formed by sealed support plate and oxygenator inner cavity top, with oxygen
Gas/carbon dioxide entrance is connected.
The advantageous effect of above-mentioned further scheme is：Permeable fiber membrane tube is fixed on by oxygenator by sealed support plate
It is interior, it can both ensure that oxygen/carbon dioxide entrance was connected with permeable fiber membrane tube, gas is not obstructed, and can play barrier blood
The effect of slurry/priming fluid.
Preferably, two are additionally provided with along its cross-sectional direction inside the plasma separator for obstructing cell and liquid leads to
The polyurethane resin supporting plate crossed, two polyurethane resin supporting plates are located at plasma separator upper and lower ends and divide with blood plasma respectively
It keeps at a distance from device end inner cavity, offers multiple through-holes on the polyurethane resin supporting plate, the two of the hollow fiber bundle
End is arranged in respectively in the through-hole of different polyurethane resin supporting plates, and the inlet end of device room connecting tube is located at two poly- ammonia
Between ester resin scaffold plate.Setting polyurethane resin supporting plate can realize hollow fiber bundle in plasma separator inner homogeneous point
It the purpose of cloth rather than blood/priming fluid entrance and haemocyte is all filled in into the end of hollow fiber bundle exports.
Further, the inside reactor is additionally provided with two for obstructing cell and liquid passes through along its cross-sectional direction
Polyurethane resin rack plate, two polyurethane resin rack plates respectively be located at reactor upper and lower ends and in reactor end
Chamber is kept at a distance, and multiple through-holes are offered on polyurethane resin rack plate, and the both ends of the hollow fiber film tube are arranged in respectively
In the through-hole of different polyurethane resin rack plates, the intercommunicating pore is located at the top of polyurethane resin rack plate, and nutrient solution/liver is thin
Born of the same parents' suspension inlet and nutrient solution/hepatocyte suspension outlet are located between two polyurethane resin rack plates.Polyurethane is set
Resin scaffold piece can realize hollow fiber film tube in the equally distributed purpose of inside reactor.
Optionally, the left side cavity at the plasma separator is gone back between two polyurethane resin supporting plates
Equipped with the spare sample-adding entrance of plasma separator and the outlet of plasma separator sample-adding connected with plasma separator inner cavity；The oxygen closes
The lower end of device is equipped with the outlet of oxygenator sample-adding；The inlet end of device room connecting tube connects with the outlet of plasma separator sample-adding
It is logical；The outlet end of device room connecting tube is loaded outlet with the oxygenator.
Further, it is additionally provided with the Micropump spare interface communicated therewith in the oxygenator sample-adding outlet.For feeding Portugal
The nutriments such as grape sugar.
Be preferably located at the middle section at the oxygenator the cavity upper end be additionally provided with oxygenator it is spare be loaded into
Mouthful, the spare sample-adding entrance of oxygenator is connected with the space below the sealed support plate；At the oxygenator
The lower end of the cavity of middle section is equipped with the infusion sample-adding entrance for infusion medicine-feeding.
Preferably, the permeable fiber membrane tube complications setting, the upper end are connected with the oxygen/carbon dioxide entrance, under
It holds as blind end.
Further, the blood plasma/priming fluid outlet is equipped with polyethersulfone filter film, polyethylene filter membrane or polyethylene ethylene
Alcohol filter membrane, film thickness are 100 μm ± 25 μm, and membrane aperture is 0.5 μm ± 0.1 μm.
The beneficial effects of the invention are as follows：
1st, it is one by the way that traditional plasma separator, oxygenator, heater and standard biologic reactor are closed four, makes biology
Artificial Liver Support System structure is more succinct, simple operation；
2nd, after blood enters plasma separator, oxygenator and reaction are sequentially entered by the blood plasma that hollow fiber bundle is isolated
Device reduces unnecessary pipeline；
3rd, the inside complications in oxygenator are provided with permeable fiber film, enough oxygen are provided for reactor, simultaneously
Carbon dioxide is participated in permeable fiber film timely and appropriate discovery and realizes that pH is adjusted, and maintains pH environment relatively stable in bioreactor, energy
It is provided for cell suitable for metabolism environment, ensures cell activity；
4th, by the effect of constant temperature water tank, constant temperature water tank coats three-in-one bioreactor setting so that three-in-one biology
Cell in reactor can carry out constant temperature water bath heating, and homogeneous heating, thermal-stable is good, and save space so that system
It is simple in structure.
Description of the drawings
Fig. 1 is the structure diagram of four-in-one formula bioreactor of artificial liver of the present invention.
Fig. 2 is the schematic cross-sectional view of Fig. 1.
Fig. 3 is the schematic cross-sectional view of three-in-one bioreactor in Fig. 2.
In figure, three-in-one bioreactor 1, plasma separator 1.1, blood/priming fluid entrance 1.1.1, haemocyte outlet
1.1.2, the spare sample-adding entrance 1.1.3 of plasma separator, plasma separator sample-adding outlet 1.1.4, oxygenator 1.2, oxygen/dioxy
Change carbon entrance 1.2.1, infusion are loaded the spare sample-adding entrance 1.2.3 of entrance 1.2.2, oxygenator, oxygenator sample-adding exports 1.2.4,
Reactor 1.3, nutrient solution/hepatocyte suspension entrance 1.3.1, nutrient solution/hepatocyte suspension outlet 1.3.2, blood plasma/preliminary filling
Liquid outlet 1.3.3, cavity 1.4, first partition 1.5, second partition 1.6, constant temperature water tank 2, water tank shell 2.1, hole 2.1.1, heat
Water inlet 2.2, hollow fiber bundle 3, permeable fiber membrane tube 4, hollow fiber film tube 5, device room connecting tube 6, connects hot water outlet 2.3
Through-hole 7, polyurethane resin supporting plate 8, polyurethane resin rack plate 9, polyethersulfone filter film 10, sealed support plate 11, separation pump
12nd, Micropump spare interface 13.
Specific embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in further detail.
Four-in-one formula bioreactor of artificial liver as shown in Figure 1, Figure 2, Figure 3 shows, including constant temperature water tank 2 and portion disposed within
Three-in-one bioreactor 1；
Three-in-one bioreactor 1 includes cavity 1.4 and the first partition 1.5 and second partition that are arranged in cavity 1.4
1.6；Cavity 1.4 is divided into three separate spaces from left to right by first partition 1.5 and second partition 1.6, is followed successively by blood plasma
Separator 1.1, oxygenator 1.2 and reactor 1.3；
Plasma separator 1.1 is connected the two inner cavity from outside by device room connecting tube 6 with oxygenator 1.2, the connection of device room
Pipe 6 is equipped with separation pump 12；Reactor 1.3 will be in the two by the intercommunicating pore 7 opened up on second partition 1.6 with oxygenator 1.2
Chamber connects；
1.4 upper end of left side cavity at plasma separator 1.1 is equipped with blood/priming fluid entrance 1.1.1, and lower end is equipped with
Haemocyte exports 1.1.2, to be set on plasma separator 1.1 between blood/priming fluid entrance 1.1.1 and haemocyte outlet 1.1.2
The hollow fiber bundle 3 of inside connect；
1.4 upper end of cavity of middle section at oxygenator 1.2 is equipped with oxygen/carbon dioxide entrance 1.2.1, and oxygen closes
Device 1.2 is internally provided with the permeable fiber membrane tube 4 being connected with oxygen/carbon dioxide entrance 1.2.1；
Right side cavity 1.4 at reactor 1.3 is equipped with nutrient solution/hepatocyte suspension entrance 1.3.1, nutrition
Liquid/hepatocyte suspension outlet 1.3.2 and blood plasma/priming fluid outlet 1.3.3, intercommunicating pore 7 and blood plasma/priming fluid outlet 1.3.3
It is connected with the hollow fiber film tube 5 for being set on the inside of reactor 1.3；
Constant temperature water tank 2 includes water tank shell 2.1 and the hot water inlet 2.2 on water tank shell 2.1 and hot water outlet 2.3；Water
Case shell 2.1 wraps three-in-one bioreactor 1, is further opened on water tank shell 2.1 multiple for three-in-one bioreactor 1
The hole 2.1.1 that each entrance is pierced by, and on three-in-one bioreactor 1 each entrance be nozzle, nozzle outer wall with
The inner wall sealing connection of hole 2.1.1.
The inlet end of device room connecting tube 6 is located at the side wall lower ends of plasma separator 1.1, and outlet end is located at oxygenator
1.2 lower end；Intercommunicating pore 7 is located at the upper end of second partition 1.6.
The sealed support plate 11 for obstructing blood plasma/priming fluid is additionally provided with along its cross-sectional direction inside oxygenator 1.2, it is close
Envelope supporting plate 11 is located at the top of intercommunicating pore 7；Multiple apertures, the upper end of permeable fiber membrane tube 4 are offered on sealed support plate 11
It is fastened in aperture, and the space formed by sealed support plate 11 and 1.2 inner cavity top of oxygenator, with oxygen/carbon dioxide
Entrance 1.2.1 is connected.Permeable fiber membrane tube is fixed in oxygenator by sealed support plate, can both ensure oxygen/bis-
Carbonoxide entrance is connected with permeable fiber membrane tube, and gas is not obstructed, and can play the role of barrier blood plasma/priming fluid.
Inside plasma separator 1.1 along its cross-sectional direction be additionally provided with two for obstruct cell and liquid by poly- ammonia
Ester resin scaffold plate 8, two polyurethane resin supporting plates 8 are located at 1.1 upper and lower ends of plasma separator and are detached with blood plasma respectively
1.1 end inner cavity of device is kept at a distance, and multiple through-holes, the both ends difference of hollow fiber bundle 3 are offered on polyurethane resin supporting plate 8
It is arranged in the through-hole of different polyurethane resin supporting plates 8, the inlet end of device room connecting tube 6 is located at two polyurethane resin branch
Between frame plate 8.Setting polyurethane resin supporting plate can realize the mesh that hollow fiber bundle is distributed in plasma separator inner homogeneous
Rather than blood/priming fluid entrance and haemocyte all filled in into the end of hollow fiber bundle export.
Inside reactor 1.3 along its cross-sectional direction be additionally provided with two for obstruct cell and liquid by polyurethane tree
Fat rack plate 9, two polyurethane resin rack plates 9 respectively be located at 1.3 upper and lower ends of reactor and with 1.3 end inner cavity of reactor
It keeps at a distance, multiple through-holes is offered on polyurethane resin rack plate 9, the both ends of hollow fiber film tube 5 are arranged in difference respectively
In the through-hole of polyurethane resin rack plate 9, intercommunicating pore 7 is located at the top of polyurethane resin rack plate 9, and nutrient solution/liver cell is hanged
Supernatant liquid entrance 1.3.1 and nutrient solution/hepatocyte suspension outlet 1.3.2 are located between two polyurethane resin rack plates 9.Setting
Polyurethane resin rack plate can realize hollow fiber film tube in the equally distributed purpose of inside reactor.
Left side cavity 1.4 at plasma separator 1.1 is additionally provided between two polyurethane resin supporting plates 8 and blood
Starch the spare sample-adding entrance 1.1.3 of plasma separator of 1.1 inner cavity of separator connection and plasma separator sample-adding outlet 1.1.4；Oxygen
The lower end of clutch 1.2 is equipped with oxygenator sample-adding outlet 1.2.4；The inlet end of device room connecting tube 6 is loaded out with plasma separator
Mouth 1.1.4 connections；The outlet end of device room connecting tube 6 is loaded outlet 1.2.4 with oxygenator and connects.
It is spare that the Micropump communicated therewith for feeding the nutriments such as glucose is additionally provided on oxygenator sample-adding outlet 1.2.4
Interface 13.
1.4 upper end of cavity of middle section at oxygenator 1.2 is additionally provided with the spare sample-adding entrance 1.2.3 of oxygenator,
The spare sample-adding entrance 1.2.3 of oxygenator is connected with the space of 11 lower section of sealed support plate；Middle part at oxygenator 1.2
The lower end of the cavity 1.4 divided is equipped with the infusion sample-adding entrance 1.2.2 for infusion medicine-feeding.
The tortuous setting of permeable fiber membrane tube 4, shape can be helical form, snakelike shape or other curved shapes, the upper end with
Oxygen/carbon dioxide entrance 1.2.1 is connected, and lower end is blind end.
Blood plasma/priming fluid outlet 1.3.3 is equipped with polyethersulfone filter film 10, polyethylene filter membrane or poly ethylene vinyl alcohol filtering
Film, film thickness are 100 μm ± 25 μm, and membrane aperture is 0.5 μm ± 0.1 μm.
In use, be first turned on oxygen/carbon dioxide entrance 1.2.1, then open blood/priming fluid entrance 1.1.1 and
Blood plasma/priming fluid outlet 1.3.3, and pass through blood/priming fluid entrance 1.1.1 saline injections with the three-in-one biology of pre-flush
Reactor 1；Blood/priming fluid entrance 1.1.1 is turned off, will aseptically carry liver cell microcarrier suspension from nutrition
Liquid/hepatocyte suspension entrance 1.3.1 injection reactors 1.3, makes entire reactor 1.3 be full of microcarrier cell suspension；Then
The blood of acute hepatic failure pig model is introduced into plasma separator 1.1 from blood/priming fluid entrance 1.1.1, blood is by hollow
After fibre bundle 3, haemocyte and part blood plasma are from haemocyte outlet 1.1.2 discharges, and remaining blood plasma is under the action of separation pump 12
Oxygenator 1.2 inner cavity is entered by device room connecting tube 6, and passes through intercommunicating pore 7 and enters 1.3 inner cavity of reactor, finally through blood plasma/pre-
Filling liquid outlet 1.3.3 discharge reactors 1.3；The haemocyte and part blood plasma and blood plasma/priming fluid of haemocyte outlet 1.1.2 discharges
It is fed back in pig body after the blood plasma mixing of outlet 1.3.3 discharges, forms a treatment circulation circuit.Over the course for the treatment of, oxygen/
Carbon dioxide entrance 1.2.1 is filled with gas to 1.2 inner cavity of oxygenator, and gas enters permeable fiber from 4 upper end of permeable fiber membrane tube
In membrane tube 4, since permeable fiber membrane tube 4 is placed in 1.2 inner cavity of oxygenator, so as to ensure certain dissolved oxygen, pH (carbon dioxide tune
Section) in the case of, the circulation treatment of blood plasma can be maintained to terminate treatment, Kaplan-Meier existence point up to dozens of hour
Analysis shows that this treatment can significantly extend the time-to-live of animal subject.
Claims (10)
1. a kind of four-in-one formula bioreactor of artificial liver, it is characterised in that：Include the three of constant temperature water tank (2) and portion disposed within
Unify bioreactor (1)；
The three-in-one bioreactor (1) includes cavity (1.4) and the first partition being arranged in the cavity (1.4)
(1.5) and second partition (1.6)；First partition (1.5) and second partition (1.6) by the cavity (1.4) be divided into from a left side to
Three right separate spaces, are followed successively by plasma separator (1.1), oxygenator (1.2) and reactor (1.3)；
The plasma separator (1.1) is connected the two inner cavity from outside by device room connecting tube (6) with the oxygenator (1.2)
Logical, device room connecting tube (6) is equipped with separation pump (12)；The reactor (1.3) passes through second with the oxygenator (1.2)
The intercommunicating pore (7) opened up on partition board (1.6) connects the two inner cavity；
Left side cavity (1.4) upper end at the plasma separator (1.1) is equipped with blood/priming fluid entrance (1.1.1), under
End is equipped with haemocyte and exports (1.1.2), and the blood/priming fluid entrance (1.1.1) and haemocyte export between (1.1.2) to set
Hollow fiber bundle (3) in the inside of the plasma separator (1.1) connects；
Cavity (1.4) upper end of middle section at the oxygenator (1.2) is equipped with oxygen/carbon dioxide entrance
(1.2.1), the oxygenator (1.2) are internally provided with the ventilative fibre being connected with the oxygen/carbon dioxide entrance (1.2.1)
Tie up membrane tube (4)；
Right side cavity (1.4) at the reactor (1.3) be equipped with nutrient solution/hepatocyte suspension entrance (1.3.1),
Nutrient solution/hepatocyte suspension outlet (1.3.2) and blood plasma/priming fluid outlet (1.3.3), the intercommunicating pore (7) and blood plasma/pre-
Filling liquid exports (1.3.3) to be set on the connection of the hollow fiber film tube (5) of the inside of the reactor (1.3)；
Hot water inlet (2.2) and heat of the constant temperature water tank (2) including water tank shell (2.1) and on the water tank shell (2.1)
Water out (2.3)；The water tank shell (2.1) wraps the three-in-one bioreactor (1), is gone back on the water tank shell (2.1)
Offer multiple holes (2.1.1) being pierced by for each entrance on three-in-one bioreactor (1), and the three-in-one life
Each entrance is nozzle on object reactor (1), and nozzle outer wall is connect with the inner wall sealing of described hole (2.1.1).
2. four-in-one formula bioreactor of artificial liver according to claim 1, it is characterised in that：Device room connecting tube
(6) inlet end is located at the side wall lower ends of the plasma separator (1.1), and outlet end is located at the oxygenator (1.2)
Lower end；The intercommunicating pore (7) is positioned at the upper end of second partition (1.6).
3. four-in-one formula bioreactor of artificial liver according to claim 2, it is characterised in that：The oxygenator (1.2)
Inside is additionally provided with the sealed support plate (11) for obstructing blood plasma/priming fluid, the sealed support plate along its cross-sectional direction
(11) positioned at the top of intercommunicating pore (7)；Multiple apertures, the permeable fiber membrane tube are offered on the sealed support plate (11)
(4) upper end is fastened in aperture, and the space and oxygen for passing through sealed support plate (11) and the formation of oxygenator (1.2) inner cavity top
Gas/carbon dioxide entrance (1.2.1) is connected.
4. the four-in-one formula bioreactor of artificial liver according to Claims 2 or 3, it is characterised in that：The blood plasma separation
Device (1.1) it is internal along its cross-sectional direction be additionally provided with two for obstruct cell and liquid by polyurethane resin supporting plate
(8), two polyurethane resin supporting plates (8) respectively be located at plasma separator (1.1) upper and lower ends and with plasma separator (1.1)
End inner cavity is kept at a distance, and multiple through-holes are offered on the polyurethane resin supporting plate (8), the hollow fiber bundle (3)
Both ends are arranged in respectively in the through-hole of different polyurethane resin supporting plates (8), and the inlet end of device room connecting tube (6) is located at
Between two polyurethane resin supporting plates (8).
5. the four-in-one formula bioreactor of artificial liver according to Claims 2 or 3, it is characterised in that：The reactor
(1.3) it is internal along its cross-sectional direction be additionally provided with two for obstruct cell and liquid by polyurethane resin rack plate (9),
Two polyurethane resin rack plates (9) are located at reactor (1.3) upper and lower ends and are kept with reactor (1.3) end inner cavity respectively
Distance offers multiple through-holes on polyurethane resin rack plate (9), and the both ends of the hollow fiber film tube (5) are arranged in respectively
In the through-hole of different polyurethane resin rack plates (9), the intercommunicating pore (7) is positioned at the top of polyurethane resin rack plate (9), battalion
Nutrient solution/hepatocyte suspension entrance (1.3.1) and nutrient solution/hepatocyte suspension outlet (1.3.2) are positioned at two polyurethane trees
Between fat rack plate (9).
6. four-in-one formula bioreactor of artificial liver according to claim 4, it is characterised in that：It is detached positioned at the blood plasma
Left side cavity (1.4) at device (1.1) is additionally provided between two polyurethane resin supporting plates (8) and plasma separator
(1.1) the spare sample-adding entrance (1.1.3) of the plasma separator of inner cavity connection and plasma separator sample-adding outlet (1.1.4)；It is described
The lower end of oxygenator (1.2) is equipped with oxygenator sample-adding outlet (1.2.4)；The inlet end of device room connecting tube (6) with it is described
Plasma separator sample-adding outlet (1.1.4) connection；The outlet end of device room connecting tube (6) is exported with oxygenator sample-adding
(1.2.4) is connected.
7. four-in-one formula bioreactor of artificial liver according to claim 6, it is characterised in that：The oxygenator is loaded out
The Micropump spare interface (13) communicated therewith is additionally provided on mouth (1.2.4).
8. four-in-one formula bioreactor of artificial liver according to claim 3, it is characterised in that：Positioned at the oxygenator
(1.2) cavity (1.4) upper end of the middle section at is additionally provided with the spare sample-adding entrance (1.2.3) of oxygenator, and the oxygen closes
The spare sample-adding entrance (1.2.3) of device is connected with the space below the sealed support plate (11)；Positioned at the oxygenator (1.2)
The lower end of the cavity (1.4) of the middle section at place is equipped with the infusion sample-adding entrance (1.2.2) for infusion medicine-feeding.
9. four-in-one formula bioreactor of artificial liver according to claim 1, it is characterised in that：The permeable fiber membrane tube
(4) tortuous setting, the upper end are connected with the oxygen/carbon dioxide entrance (1.2.1), and lower end is blind end.
10. four-in-one formula bioreactor of artificial liver according to claim 1, it is characterised in that：Blood plasma/the priming fluid
(1.3.3) is exported equipped with polyethersulfone filter film (10), polyethylene filter membrane or poly ethylene vinyl alcohol filter membrane, film thickness is 100 μ
M ± 25 μm, membrane aperture are 0.5 μm ± 0.1 μm.
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| US5976870A (en) * | 1994-11-09 | 1999-11-02 | Park; Sung-Su | Artificial liver composed of a liver-slice culture apparatus |
| CN2514001Y (en) * | 2001-10-26 | 2002-10-02 | 邹立军 | Biological reactor |
| CN1383898A (en) * | 2001-04-28 | 2002-12-11 | 细胞生物技术有限公司 | Composite artificial liver supporting system and its usage |
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| CN101549179A (en) * | 2009-04-30 | 2009-10-07 | 浙江大学 | Perforated brick type filling support type reactor used in artificial liver |
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|---|---|---|---|---|
| US6979308B1 (en) * | 1999-06-03 | 2005-12-27 | University Of North Carolina At Chapel Hill | Bioreactor design and process for engineering tissue from cells |
| ITMI20060490A1 (en) * | 2006-03-17 | 2007-09-18 | Eurosets Srl | INTEGRATED DEVICE FOR BLOOD RE-HEALING AND OXYGENATION IN EXTRACORPOREAL CIRCUIT |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5976870A (en) * | 1994-11-09 | 1999-11-02 | Park; Sung-Su | Artificial liver composed of a liver-slice culture apparatus |
| CN1383898A (en) * | 2001-04-28 | 2002-12-11 | 细胞生物技术有限公司 | Composite artificial liver supporting system and its usage |
| CN2514001Y (en) * | 2001-10-26 | 2002-10-02 | 邹立军 | Biological reactor |
| CN1633950A (en) * | 2004-12-24 | 2005-07-06 | 浙江大学 | Bioreactor for artificial liver |
| CN101549179A (en) * | 2009-04-30 | 2009-10-07 | 浙江大学 | Perforated brick type filling support type reactor used in artificial liver |
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Address after: 4th floor, podium building, Gongtou Building, No. 433-505 Chunhui Road, Lingxi Town, Cangnan County, Wenzhou City, Zhejiang Province, 325000 Patentee after: Zhejiang Tonggan Medical Technology Co.,Ltd. Country or region after: China Address before: No. 818, Gaoxin Avenue, Donghu high tech Development Zone, Wuhan, Hubei 430206 Patentee before: WUHAN TOGO MEDITECH Co.,Ltd. Country or region before: China |