CN104147651B - Whole blood perfusion bioartificial liver system - Google Patents
Whole blood perfusion bioartificial liver system Download PDFInfo
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- CN104147651B CN104147651B CN201410376523.6A CN201410376523A CN104147651B CN 104147651 B CN104147651 B CN 104147651B CN 201410376523 A CN201410376523 A CN 201410376523A CN 104147651 B CN104147651 B CN 104147651B
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- 210000004369 blood Anatomy 0.000 claims description 61
- 239000008280 blood Substances 0.000 claims description 61
- 210000004027 cell Anatomy 0.000 claims description 54
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- 210000003494 hepatocyte Anatomy 0.000 claims description 11
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 5
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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
Abstract
A kind of whole blood perfusion bioartificial liver system, including blood circulation, bioreactor circulation, cell renewal system three part, three parts are communicated by pipeline, bioreactor circulation includes the bioartificial liver's reactor group being made up of one or more bioartificial liver's reactors, in bioartificial liver's reactor external space, filling has L 02 cell, makes therapeutic effect and safety more preferable；Cell renewal system is used for updating L 02 cell, the present invention over the course for the treatment of can treatment cell in timely replacement reactor, ensure continual and steady curative effect, and without the therapy discontinued for replacing bioartificial liver's reactor, shorten treatment time, whole system can use manual operation or PLC to carry out Automatic Control, eliminate medical personnel and sample detection work frequently, it is achieved monitor in real time, highly effective and safe, there is preferable practicality, be suitable to industrialization and produce.
Description
Technical field
The present invention relates to bioartificial liver's technical field, biological in particular to a kind of whole blood perfusion
Bioartificial liver system.
Background technology
China is the country that hepatopathy is the most serious in the world, and annual liver failure neopathy number exceedes
1000000, the most about 500,000 hepatic failure patients are dead because can not get effectively treating.Cure
Chance only one, i.e. liver transplantation, but due to liver source difficulty, the waiting time is long, or
Having no chance to obtain for liver, therefore most humans does not has chance for survival at all at all.Cause
This, be badly in need of bioartificial liver system and maintain patients ' lives, waits liver transplantation chance, or patient self
The chance that liver recovers.
But owing to traditional artificial liver (i.e. physics artificial liver) cost is high, most patient
All cannot undertake, curative effect is very limited, it is impossible to significantly reduce the mortality rate of liver failure,
Therefore clinical practice is restricted.In recent years, active Hepatocyte or quasi-liver cell are joined people
To improve curative effect in work liver system, it has also become world's research and development focus, this with hepatocyte filling
Artificial liver based on reactor is referred to as bioartificial liver (bio-artificial liver, BAL),
Numerous studies prove that its curative effect is substantially better than physics artificial liver, can significantly reduce liver failure
Case fatality rate, hence it is evident that extend life cycle, self liver for acute hepatic failure sufferer recovers
Wait that liver transplantation creates condition with chronic liver failure sufferer.
Existing bioartificial liver system structure is similar, with bioartificial liver's reactor is
Core, this reactor, mainly based on hollow fiber reactor, fills a certain amount of liver in it
Cell or quasi-liver cell are (such as human liver cell, immortalized hepatocyte, hepatoma cell line, Hepar Sus domestica
Cell etc.).All there are two broad aspect serious problems and limit clinical practice in these technology
Probability: one is that above-mentioned cell source is respectively arranged with significant deficiency, such as the former two or cell derived difficulty
Or cannot rise in value on a large scale, thus cannot popularization and application；The latter two liver functions and poor stability
(carcinogenic or transfected animal is viral), limits clinical practice.Two is bioartificial liver system's structure
Unreasonable, because in use for some time, the cell in reactor is affected by toxin can be by
Step death, bioreactor purifies the efficiency of blood and extends with the working time and reduce, for protecting
Hold curative effect, need to change the reactor of fresh cells at set intervals.Bioartificial liver
Reactor cost is high, and seance may be replaced multiple bioartificial liver's reactor, control
Treat costly；If be changed without or few replacing, it is difficult to ensure that curative effect；Need during replacement to close
System, add the waiting time of patient, treatment time extend, and replace time, completely by
Manual operation adds the risk of systemic contamination.
Summary of the invention
The purpose of the present invention includes two aspects, on the one hand is to overcome existing bioartificial liver to be
The cost of system configuration aspects is high, have the defects such as pollution and security risk, it is provided that a kind of safety,
Whole blood perfusion bioartificial liver system reliably, it is achieved treatment free of discontinuities；On the other hand coordinate
Filling has bioartificial liver's reactor of L-02 cell to use, and overcomes existing cell source curative effect
Low, the defect of poor stability, L-02 cell has that liver function is good, increment power is strong, safe
Advantage, for the whole blood perfusion bioartificial liver system of the present invention, it is achieved in cell and structure
On thorough improvement, better efficacy, make impaired liver more have an opportunity regeneration, or to liver
The patient of nonfunction provides more effectively support, until the donor device for transplanting can be found
Official.
For achieving the above object, the whole blood perfusion bioartificial liver system designed by the present invention,
Circulate including blood recovery, bioreactor circulates, cell renewal system three part, three
Divide and communicated by pipeline；
Described blood circulation includes blood input port, blood pump and the blood recovery that order is connected
Mouthful；
The circulation of described bioreactor includes bioartificial liver's reactor group, described bio-artificial
Liver reactor group includes bioartificial liver's reactor of multiple parallel connection；Bioartificial liver's reactor
It is provided with plasma inlet, plasma outlet port, cell entry and discard solution discharge port；Bioartificial liver
The plasma inlet of reactor is connected with blood input port by stop valve respectively, and plasma outlet port is equal
It is connected with blood recovery mouth；The discard solution discharge port of bioartificial liver's reactor is connectable to waste liquid
Storage tank；
Described cell renewal system includes cell eluting flow container, cell suspension flow container, thermostatted water
Bath cabinet and infusion pump, described cell eluting flow container and cell suspension flow container pass through a three-way valve
Being connected with the input of infusion pump, described transfusion delivery side of pump passes through control valve respectively with each
The cell entry of individual bioartificial liver's reactor is connected；Described cell suspension flow container is placed in constant temperature
In water bath.
Preferably, described whole blood perfusion bioartificial liver system also includes referring to for detecting biochemistry
Target biochemical instruments, before the plasma inlet of described bioartificial liver's reactor and plasma outlet port it
After be provided with the first detection mouth, second detection mouth, described first detection mouth, second detection mouth with
The test side of biochemical instruments is connected.
Preferably, heparin pump, described blood it are additionally provided with at described blood input port or at blood pump
It is provided with force (forcing) pump between liquid input port and the first detection mouth of biochemical instruments.Force (forcing) pump is used for ensureing
The properly functioning pressure of bioartificial liver's reactor.
Preferably, it is provided with between the first detection mouth of described blood input port and biochemical instruments and heats
Device and/or glucose pump.It is respectively used to the blood plasma temperature ensureing to enter bioartificial liver's reactor
Spend and increase sugar for blood plasma.
Preferably, it is additionally provided with increasing between described blood input port and the first detection mouth of biochemical instruments
Oxygen instrument.
Preferably, being additionally provided with booster pump at described blood recovery mouth, described bioartificial liver is anti-
Answer and at the plasma outlet port of device, be additionally provided with acceleration pump.This booster pump can make blood return by supercharging
Defeated, in the case of being not provided with booster pump, then need to ensure the blood plasma of bioartificial liver's reactor
Outlet and blood recovery mouth have certain altitude poor, and gravity could be utilized to make blood recovery.
Preferably, the plasma inlet of described bioartificial liver's reactor be provided with temperature inductor and
Pressure inductor, is additionally provided with temperature inductor at plasma outlet port.
Preferably, it is provided with discharge valve at the discard solution discharge port of described bioartificial liver's reactor.
Preferably, the foreign hepatocytes in described bioartificial liver's reactor is that L-02 is thin
Born of the same parents.
Preferably, described whole blood perfusion bioartificial liver system also includes for controlling biological people
Valve in work liver system, pump and each can the programmable logic controller (PLC) of automatically controlled instrument.Increase
Programmable logic controller (PLC) realizes full-automation and processes.
Preferably, bioartificial liver's reactor is non-woven fabrics reactor, the micro-load of Bacterial cellulose
Reactor according, Bacterial cellulose reactor, hollow fiber reactor, microcarrier reactor,
These are only that citing is not in order to limit the present invention.
Prior art does not have any bioartificial liver system can be applied to face
Bed, the present inventor studies discovery this is because human liver cell source is extremely limited, and
And human liver cell survival period is short, can not vitro propagation, therefore can not extensively apply；And other is each
Plant alternative cell and limit application because there being various major defect.The L-02 that the present invention uses
Cell has that normal liver cell key character albumen and enzyme, liver function be good, multiplication capacity pole
By force, safety is good.It is a kind of superior and unique that these characteristic indications L-02 cell
Bioartificial liver's cell source, more excellent than any one of at present both at home and abroad research and development cell source
More.L-02 cell not only has good liver function, the breeding of fabulous immortalization In vitro culture
Ability, easily can cultivate, not find to cause through multinomial zoopery checking in a large amount of industrialization
Carcinous.
Present configuration improve beneficial effect: use cell renewal system be in systems
The bioartificial liver's reactor run carries out hepatocyte in time and supplements replacement, it is not necessary to change biology
Artificial liver reactor and intermittent treatment, shorten treatment time, and whole system can use PLC
(programmable logic controller (PLC)) carries out Automatic Control, eliminates medical personnel frequently
Sampling detection work, it is achieved monitor in real time, highly effective and safe, coordinate and there is good liver function
L-02 cell line uses, and has preferable practicality, is suitable to industrialization and produces.
Accompanying drawing explanation
Fig. 1 is the structural representation of whole blood perfusion bioartificial liver system of the present invention.
Fig. 2 is the structure for amplifying schematic diagram of bioartificial liver's reactor group in Fig. 1.
In figure, blood input port 1, blood pump 2, force (forcing) pump 3, bioartificial liver's reactor
Group 4, bioartificial liver's reactor 5, plasma inlet 5.1, plasma outlet port 5.2, cell enter
Mouth 5.3, discard solution discharge port 5.4, constant water bath box 6, acceleration pump 7, booster pump 8, blood
Liquid feeds back mouth 9, heat booster 10, glucose pump 11, oxygen supplement instrument 12, cell eluting flow container
13, cell suspension flow container 14, first detect mouth 15, second detect mouth 16, biochemical instruments 17,
Temperature inductor 18, infusion pump 19, pressure inductor 20, three-way valve 21, heparin pump 22,
Stop valve A1, stop valve A2, stop valve An, control valve B1, control valve B2, control
Valve Bn, discharge valve C1, discharge valve C2, discharge valve Cn.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention is described in further detail.
As shown in Figure 1, 2, the whole blood perfusion bioartificial liver system of present invention design, blood
Liquid feeds back circulation, bioreactor circulation, cell renewal system three part, and three parts are passed through
Pipeline communicates；
Blood circulation include order be connected blood input port 1, heparin pump 22, blood pump 2,
Booster pump 8 and blood recovery mouth 9；Booster pump 8 it is provided with, in order to return at blood recovery mouth
Blood transfusion liquid.
Bioreactor circulation include with blood input port 1 order be connected glucose pump 11,
Force (forcing) pump 3, heat booster 10, automatic aerator 12, automatic biochemical analyzer 17, bioartificial liver are anti-
Answer device group 4；
Bioartificial liver's reactor group 4 includes bioartificial liver's reaction of one or more parallel connection
Device 5；Foreign hepatocytes in bioartificial liver's reactor 5 is L-02 cell.
Bioartificial liver's reactor 5 is provided with plasma inlet 5.1, plasma outlet port 5.2, cell
Entrance 5.3 and discard solution discharge port 5.4；The plasma inlet of two bioartificial liver's reactors 5
5.1 respectively by stop valve A1, stop valve A2 ... stop valve An and blood input port
1 is connected, and plasma outlet port 5.2 is all connected with blood recovery mouth 9；Bioartificial liver's reactor
The plasma outlet port of group 4 is additionally provided with acceleration pump 7 after converging.
Cell renewal system includes cell eluting flow container 13, cell suspension flow container 14, constant temperature
Water bath 6 and infusion pump 19, cell suspension flow container 14 is placed in constant water bath box 6, carefully
Born of the same parents' eluting flow container 13 and cell suspension flow container 14 are by a three-way valve 21 and infusion pump 19
Input be connected, the outfan of infusion pump 19 is respectively by control valve B1, control valve
Cell entry 5.3 phase of B2 ... control valve Bn and each bioartificial liver's reactor 5
Even, it is provided with discharge valve C1, drainage at the discard solution discharge port 5.4 of bioartificial liver's reactor 5
Valve C2 ... discharge valve Cn, each discharge valve can be connected output liquid extremely by pipeline
Waste liquid collection vessel.
Whole blood perfusion bioartificial liver system also includes the biochemical instruments for detecting biochemical indicator
17, be provided with before the plasma inlet of bioartificial liver's reactor 5 5.1 first detection mouth 15,
Being provided with the second detection mouth 16 after plasma outlet port 5.2, the first detection mouth 15, second detects mouth
16 are connected with the test side of biochemical instruments 17.
It is provided with heat booster between blood input port 1 and the first detection mouth 15 of biochemical instruments 17
10, force (forcing) pump 3, glucose pump 11, oxygen supplement instrument 12.
The plasma inlet 5.1 of bioartificial liver's reactor 5 is provided with temperature inductor 18 and pressure
Induction apparatus 20, is additionally provided with temperature inductor 18 at plasma outlet port 5.2.
Whole blood perfusion bioartificial liver system also includes for controlling in bioartificial liver system
Valve, pump and each can the programmable logic controller (PLC) (not shown) of automatically controlled instrument, at this
In embodiment programmable logic controller (PLC) respectively with stop valve, control valve, discharge valve, blood
Pump 2, booster pump 8, heat booster 10, glucose pump 11, oxygen supplement instrument 12, biochemical instruments 17,
Temperature inductor 18, infusion pump 19, pressure inductor 20, three-way valve 21, heparin pump 22
Electrical connection, to control said apparatus.
The embodiment of the present invention passes through two bioartificial liver's reactors 5 in parallel to facilitate explanation
The work process of bioartificial liver's reactor group 4, the quantity of bioartificial liver's reactor 5 can
To adjust according to actual needs.
When using above-mentioned whole blood perfusion bioartificial liver system, scale can be used commonly to train
The L-02 cell that nutrient solution method is cultivated, gathers in the crops competent cell, and activity rate is more than 98%.So
After in biological cabinet sterile working, appropriate hepatocyte is fed into and remaines in bioartificial liver
In reactor 5 and cell fluid reservoir 14, enclose entrance, by bioartificial liver's reactor 5,
Cell fluid reservoir 14 is sealed in sterile bag, sets to 0～4 DEG C of preservations are stand-by.Fill before the treatment
During machine take out bioartificial liver's reactor 5, cell suspension flow container 14, sterile working and by figure
Show order installation, connect patient artery blood entrance and venous re-transfusion mouth, be for preparing treatments for.
Treatment starts, after the blood lead body of patient or laboratory animal is outer, by blood input port
1 enters whole blood perfusion bioartificial liver system, and blood enters in bioartificial liver's reactor group
Removing toxic substances, after having detoxified in blood recovery mouth 9 is back to patient or laboratory animal body, these rank
During Duan Yunhang, stop valve A1, stop valve A2 ... stop valve An open, control valve B1,
Control valve B2 ... control valve Bn is closed, infusion pump 19 power-off.
During treatment is carried out, biochemical instruments 17 utilize and be positioned at bioartificial liver's reactor group 4 two ends
The first detection mouth 15, second detect mouth 16 and monitor respectively and pass in and out bioartificial liver's reactor group
The biochemical indicators such as the blood plasma bilirubin of 4, ammonia, creatinine, blood urea nitrogen, liver enzyme, albumin
Change, when find bioartificial liver's reactor group 4 efficiency decline, it is judged that bioartificial liver
When the interior L-02 cell as foreign hepatocytes of reactor 5 occurs consuming downright bad, by compiling
First journey logic controller reduces blood pump 2, the speed of booster pump 8, to reduce the stream of blood
Speed, controls one or more stop valve and closes, to carry out part biological artificial liver reactor 5
In hepatocellular replacement, such as, stop valve A1 close, coupled bioartificial liver is anti-
Answering device 5 to stop supply blood plasma, control valve B1 and discharge valve C1 open, three-way valve 21 the most only with
Cell eluent bin 13 communicates, and infusion pump 19 is started working, by cell eluting flow container 13
In cell eluent such as normal saline pump into this bioartificial liver's reactor 5 and carry out inside it
Rinse, make the hepatocyte of death come off and discharged by discard solution discharge port 5.4；Then, three-way valve 21
Disconnect the connection with cell eluting flow container 13, communicate with cell suspension flow container 14, by infusion pump
Cell fresh in cell suspension flow container 14 is pumped in bioartificial liver's reactor 5 by 19, complete
Become supplementary, the replacement of cell, after, close discharge valve C1, control valve B1, transfusion
Pump 19 power-off, opening stop valve A1, make bioartificial liver's reactor 5 that interruption is detoxified again
Come into operation.
According still further to same sequential control other biological artificial liver reactor 5 stop valve, control
Valve, discharge valve complete supplementary, the replacement of cell in other biological artificial liver reactor 5, it
After by normal for the rate recovery of blood pump 2, booster pump 8.This process can be by manually
Completing or utilize programmable logic controller (PLC) or manual operation to control, it is advantageous in that nothing
The treatment of hepatopathy patients need to be interrupted, it is not necessary to change bioartificial liver's reactor, saved cost
And the time, during particularly when use programmable logic controller (PLC) to control, can monitor in real time
Circulating plasma temperature, pressure change, and are heated by heat booster 10, glucose pump 11 supplements Portugal
Grape sugar, oxygen supplement instrument 12 oxygen supplement, the automatic sample detecting of biochemical instruments 3, transmission data are reported to the police, real
What in whole monitoring, sample detecting, bioartificial liver's reactor, hepatocyte was replaced is whole
Automatization is carried out, and saves substantial amounts of medical treatment manpower.
Claims (8)
1. a whole blood perfusion bioartificial liver system, it is characterised in that: include blood recovery
Circulation, bioreactor circulation, cell renewal system three part, three parts are communicated by pipeline；
The circulation of described blood recovery includes blood input port (1), the blood pump (2) being sequentially connected
With blood recovery mouth (9)；
The circulation of described bioreactor includes bioartificial liver's reactor group (4), described biological people
Work liver reactor group (4) includes bioartificial liver's reactor (5) of multiple parallel connection；Biological people
Work liver reactor (5) is provided with whole blood inlet (5.1), whole blood outlet (5.2), cell entry
And discard solution discharge port (5.4) (5.3)；The whole blood inlet (5.1) of bioartificial liver's reactor (5)
It is connected, entirely with blood input port (1) by stop valve (A1, A2 ... An) respectively
Blood outlet (5.2) is all connected with blood recovery mouth (9)；Described bioartificial liver's reactor (5)
Interior foreign hepatocytes is L-02 cell；
Described cell renewal system include cell eluting flow container (13), cell suspension flow container (14),
Constant water bath box (6) and infusion pump (19), described cell eluting flow container (13) and cell are mixed
Suspension tank (14) is connected with the input of infusion pump (19) by a three-way valve (21),
The outfan of described infusion pump (19) respectively by control valve (B1, B2 ... Bn) with
The cell entry (5.3) of each bioartificial liver's reactor (5) is connected；Described cell suspension
Flow container (14) is placed in constant water bath box (6)；
Described whole blood perfusion bioartificial liver system also includes the biochemistry for detecting biochemical indicator
Instrument (17), is provided with before the whole blood inlet (5.1) of described bioartificial liver's reactor (5)
First detection mouth (15), is provided with the second detection mouth (16), institute after whole blood outlet (5.2)
State the first detection mouth (15), the second detection mouth (16) and test side phase of biochemical instruments (17)
Even.
Whole blood perfusion bioartificial liver system the most according to claim 1, it is characterised in that:
Described blood input port (1) place or blood pump (2) place are additionally provided with heparin pump (22), described
It is provided with pressurization between blood input port (1) and the first detection mouth (15) of biochemical instruments (17)
Pump (3).
Whole blood perfusion bioartificial liver system the most according to claim 1, it is characterised in that:
It is provided with between described blood input port (1) and the first detection mouth (15) of biochemical instruments (17)
Heat booster (10) and/or glucose pump (11).
Whole blood perfusion bioartificial liver system the most according to claim 1, it is characterised in that:
Also set between described blood input port (1) and the first detection mouth (15) of biochemical instruments (17)
There is oxygen supplement instrument (12).
Whole blood perfusion bioartificial liver system the most according to claim 1, it is characterised in that:
Described blood recovery mouth (9) place is additionally provided with booster pump (8), described bioartificial liver's reactor
(5) whole blood outlet (5.2) place is additionally provided with acceleration pump (7).
Whole blood perfusion bioartificial liver system the most according to claim 1, it is characterised in that:
The whole blood inlet (5.1) of described bioartificial liver's reactor (5) is provided with temperature inductor (18)
With pressure inductor (20), whole blood outlet (5.2) place is additionally provided with temperature inductor (18).
Whole blood perfusion bioartificial liver system the most according to claim 1, it is characterised in that:
Discard solution discharge port (5.4) place of described bioartificial liver's reactor (5) be provided with discharge valve (C1,
C2、……Cn)。
8. according to whole blood perfusion bioartificial liver system described in any one of claim 1～7, its
It is characterised by: described whole blood perfusion bioartificial liver system also includes for controlling bioartificial liver
In system, each can the programmable logic controller (PLC) of automatically controlled instrument.
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| CN104958795B (en) * | 2015-06-23 | 2017-03-29 | 四川大学华西医院 | Whole blood perfusion bioartificial liver system |
| CN106075625A (en) * | 2016-08-26 | 2016-11-09 | 合肥市力维生物科技有限公司 | A kind of Biotype artificial liver |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AUPP108597A0 (en) * | 1997-12-22 | 1998-01-22 | Sheil, A G R Prof. | Liver support system |
| CN1178706C (en) * | 2001-04-28 | 2004-12-08 | 细胞生物技术有限公司 | Composite artificial liver supporting system and its usage |
| CN2624926Y (en) * | 2003-06-24 | 2004-07-14 | 中国人民解放军第三军医大学 | Shedding biologic artificial liver supporting device |
| US7338461B2 (en) * | 2004-02-02 | 2008-03-04 | The General Hospital Corporation | Modified organ support devices |
| CN2761164Y (en) * | 2004-12-30 | 2006-03-01 | 中国科学院电工研究所 | Biological reactor |
| US20110190680A1 (en) * | 2008-09-29 | 2011-08-04 | Yoram Vodovotz | Self-Regulating Device for Modulating Inflammation |
| CN103877631A (en) * | 2014-03-06 | 2014-06-25 | 浙江大学 | Bioartificial liver system |
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