CN1178706C - Composite artificial liver supporting system and its usage - Google Patents
Composite artificial liver supporting system and its usage Download PDFInfo
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- CN1178706C CN1178706C CNB011156708A CN01115670A CN1178706C CN 1178706 C CN1178706 C CN 1178706C CN B011156708 A CNB011156708 A CN B011156708A CN 01115670 A CN01115670 A CN 01115670A CN 1178706 C CN1178706 C CN 1178706C
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
- A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
- A61M1/3489—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents by biological cells, e.g. bioreactor
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61M1/369—Temperature treatment
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- 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
- A61M2202/0415—Plasma
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Abstract
The present invention relates to a composite type artificial liver supporting system and a use method thereof. A composite type artificial liver supporting system comprises a blood / blood plasma exchange (or adsorption) device for removing toxic substances and harmful substances in the blood / blood plasma and a biological artificial liver device. The blood / blood plasma exchange (or adsorption) device comprises a blood plasma separating device for separating the blood plasma of patients and discharging the separated blood plasma, a health blood plasma introducing device for a pump, a valve and a pipeline, and a constant temperature device for causing the blood / blood plasma exchange (adsorption) device to be below human body temperature. The biological artificial liver device comprises a bioreactor composed of a culture device and a matter exchanger, a blood / blood plasma constant current device, a culture solution constant current device and a constant temperature device. The method of the present invention comprises the following steps: (1) the detoxication of blood / blood plasma for patients; the cultivation of exogenous liver cells; (2) the liver function actions such as synthesis, metabolism, substance exchange, etc. by using the exogenous liver cells.
Description
Technical field
The present invention relates to a kind of composite artificial liver supporting system, in more detail, relating to a kind of being used for can substitute acute hepatic failure (acute liver failure in the long term, ALF) patient's liver function, support severe liver failure patient to wait for liver transplantation, perhaps make the liver failure patient recover hepatic tissue of self and its regeneration and compensation gradually, thereby improve ALF patient's survival rate and the composite artificial liver supporting system of time-to-live.In addition, the invention still further relates to the using method of above-mentioned composite artificial liver supporting system, this using method can improve the therapeutic effect of said system greatly.
Background technology
Acute hepatic failure is common critical illness, and mortality rate is up to 70～90%.For this disease, the treatment means of using roughly has following several at present.
1. the secular clinical experience of Drug therapy proves, for the acute hepatic failure patient, because patient's liver has been lost regeneration and compensation, Drug therapy is difficult to fundamentally make the hepatic tissue restore funcitons, so can not obtain desirable therapeutic.
2. it is to dialyse by blood/plasma that abiotic type artificial liver support system is treated this Therapeutic Method, or adopt activated carbon and ion exchange resin to carry out means such as blood/plasma perfusion or displacement, remove toxicant and chemical substances such as aromatic amino acid, phenol in the blood, to alleviate the burden of liver, the expectation patient recovers self hepatocellular compensation gradually.This Therapeutic Method has better therapeutic effect for the lighter patient of liver organization degree of injury, but for the serious patient of liver organization degree of injury, just can not make its liver organization restore funcitons, the effect of treatment is undesirable, can not obviously improve patient's survival rate.
3. to hold this Therapeutic Method of system (BALSS) treatment be to cultivate a kind of exogenous hepatocyte in bioreactor to the Biotype artificial rami hepatici, liver failure patient's blood/plasma is circulated by this bioreactor, in in the cyclic process of blood/plasma, being undertaken by a kind of semipermeable membrane, micromolecular mass exchange, carry out such as functions such as synthetic, detoxifcation and biotransformations, for the liver failure patient provides the support of hepatic tissue function with exogenous hepatocyte.Studies show that this BALSS can keep liver failure patient survival within a certain period of time, for liver failure patient's further treatment (for example, liver transplantation) gains time.
Yet, because the mass exchange of ALF blood/plasma in the bioreactor of BALSS needs a large amount of exogenous hepatocyte, functions such as, detoxifcation synthetic and biotransformation to finish, so, obtain and cultivate a large amount of exogenous hepatocyte for a long time, be the key of BALSS technology.
In application number was 94192400.9 Chinese invention patent prospectus, a kind of " artificial liver device and be used for blood and the method for blood plasma purging in vitro " disclosed.Artificial liver device in this application is exactly that a kind of Biotype artificial rami hepatici is held system, the effect of this device is to make patient's blood/plasma by being applied in the boundling fiber pipe made from semipermeable membrane in culture fluid and the exogenous hepatocellular bioreactor is housed, make soluble protein, glucose and toxicant etc. in the blood/plasma, seeing through semipermeable membrane is diffused in the culture fluid, detoxify and metabolism by exogenous hepatocyte, finish liver function.
Though the Biotype artificial rami hepatici in the above-mentioned patent disclosure description is held the liver function that system can support the liver failure patient in theory within a certain period of time, it also exists following shortcoming.
At first, in order to keep the exogenous hepatocellular activity in the bioreactor, this device need oxygen supply in bioreactor.Therefore, it needs the facility of a series of oxygen supplys, oxygen generator for example, and the oxygen supply pump, valve and pipeline or the like, but also need the control device of a whole set of control oxygen pressure.This just makes that the formation of bioreactor is complicated, thereby can improve its manufacturing cost, the reliability when reducing its this device and using.The more important thing is, be oxygen content in the atmosphere and the oxygen partial pressure in the atmosphere for the dividing potential drop of optimum oxygen content of hepatocyte and oxygen in the culture fluid in the bioreactor, oxygen content is too high or too low, and the dividing potential drop of oxygen is too high or too low, all is unfavorable for hepatocellular survival.With the oxygen supply in culture fluid of oxygen supply pump, sterilization not only bad for device, also be difficult to make the oxygen content in the culture fluid to remain on the degree that is suitable for the hepatocyte survival, thereby, unfavorable son is kept hepatocellular survival, as a result, just can not give full play to the usefulness of bioreactor, the effect of treatment is reduced.
Secondly, this device is simple Biotype artificial liver device basically, and the method that it is implemented is functions such as synthetic, the metabolism that compensates that patient's liver loses by means of exogenous hepatocyte and biotransformation.Yet, when existing a large amount of toxicants maybe can not pass through the macromolecular material of semipermeable membrane in patient's the blood/plasma, it is powerless that this device just seems, also can make the very fast devitalization of the exogenous hepatocyte of cultivating among the BALSS, therefore, can not obtain the obvious treatment effect in a short time, thereby patient's opportunity is saved in forfeiture.
And, the more important thing is, in above-mentioned patent application, only enumerated time that the test animal hepatocyte survives and some test datas of reaction effect in bioreactor, do not enumerate the actual clinical effect that these apparatus and method is applied in the treatment liver failure on the human body.In medicine technology field, it is very big in laboratory animal liver cell being tested and the patient is carried out the gap of clinical treatment between the two, from laboratory tests to the clinical practice, also need to do a large amount of intermediate experiments and carry out performing creative labour in the middle of this.
Yet, in No. 94192400.9 applications for a patent for invention, describe Biotype artificial liver device in detail, and many ins and outs of using this when device, these details are for those skilled in the art, have reference value, therefore, can be used as the application's immediate list of references.
Summary of the invention
Because existing problem in the prior art, the purpose of this invention is to provide a kind of composite artificial liver supporting system, the complete function of this system, high efficiency, wherein be used to cultivate the oxygen content of exogenous hepatocellular culture fluid and the most suitable hepatocellular growth of dividing potential drop of oxygen, thereby can carry out highdensity cultivation, when being used for the treatment of various types of acute and chronic liver failure disease, can improving cure rate greatly and prolong patient's time-to-live.In addition, the formation of the bioreactor in this system is simple and usefulness is high, thereby can reduce the manufacturing cost of this system.
Another object of the present invention provides a kind of method of using above-mentioned composite artificial liver supporting system, uses this composite artificial liver supporting system according to method of the present invention, can give full play to the effect of system of the present invention, improves therapeutic effect.
For achieving the above object, composite artificial liver supporting system of the present invention can be made up of following each several part:
A is used for removing the blood/plasma displacement and/or the adsorbent equipment of the harmful substance of the toxicant of blood/plasma and aromatic amino acid, phenol and so on, and this device comprises following each several part:
A. be used to separate patient's blood plasma and will separate after the plasma separating unit of blood plasma discharge;
B. the healthy blood plasma gatherer that comprises pump, valve and pipeline;
The constant temperature that above-mentioned blood/plasma displacement and/or adsorbent equipment are under the human body temperature is adorned
Put;
B Biotype artificial liver device, this device comprises following each several part:
A. bioreactor, this reactor comprises following each several part:
(1) mass exchange device is useful on the import and the outlet that allow patient's blood/plasma come in and go out in this mass exchange device; Be used to allow and contain import and the outlet that exogenous hepatocellular culture fluid is come in and gone out; And the boundling fiber pipe of making by semipermeable membrane, this boundling fiber pipe be used for above-mentioned patient's blood/plasma with contain exogenous hepatocellular culture fluid and keep apart, but between can carry out in, micromolecular mass exchange;
(2) one are used for introducing and the active exogenous hepatocellular incubator of cultivation, and a permeability cell that holds culture medium is arranged in this incubator, and the atmosphere porous around this permeability cell is by this root permeability cell; On this permeability cell, have one with the above-mentioned substance exchanger in contain the exogenous hepatocellular culture fluid import that contains that exogenous hepatocellular culture fluid outlet is communicated with; One be communicated with culture fluid import in the above-mentioned substance exchanger contain exogenous hepatocellular culture fluid outlet;
B. one is used to make patient's blood/plasma to carry out circulation blood/plasma constant-current device between above-mentioned substance exchanger and human recycle system;
C. one is used to make and contains exogenous hepatocellular culture fluid carry out circulation culture fluid constant-current device between above-mentioned substance exchanger and incubator; And
D. one is used to make this bioreactor to remain on thermostat under the human body temperature.
Should be noted that especially, permeability cell in the above-mentioned incubator has special performances, because it can make culture fluid be contained in this root pipe, do not make its seepage, big impervious around allowing again is by this root pipe, with used up oxygen in the additional culture fluid, and the dividing potential drop of the oxygen in the atmosphere that is replenished and content are suitable for the growth and the survival of cell most.Like this, just do not need to be provided with the various parts of pump, valve and so on for supply oxygen, not only simplified equipment, reduced manufacturing expense, and the exogenous hepatocellular density that has improved exogenous hepatocellular activity greatly and cultivated at culture fluid, thereby help improving the usefulness of equipment, can improve the effect of treatment greatly.
The method of the above-mentioned composite artificial liver supporting system of use of the present invention is made up of following each step:
1. the blood/plasma that makes the patient in composite artificial liver supporting system of the present invention the blood/plasma displacement and/or adsorbent equipment in replace and/or adsorb so that dispose part toxicant and detrimental substance in patient's the blood/plasma;
2. the culture fluid import by the incubator in the Biotype artificial liver device of the present invention adds and contains exogenous hepatocellular culture fluid, at human body temperature (37 ℃) and atmospheric pressure and contain the exogenous hepatocyte of cultivation under the oxygen condition;
3. with the blood/plasma constant-current device in the Biotype artificial liver device of the present invention, by the blood/plasma import in the above-mentioned bioreactor, blood/plasma through the patient after displacement and/or the absorption, import in the mass exchange device of above-mentioned bioreactor, simultaneously, with the culture fluid constant-current device in the Biotype artificial liver device of the present invention, the fresh exogenous hepatocellular culture fluid of sufficient amount will be contained in the incubator, by the culture fluid import in the above-mentioned bioreactor, in the input bioreactor, in making that above-mentioned patient's blood/plasma and above-mentioned culture fluid are undertaken by the boundling fiber pipe of being made by semipermeable membrane, the small-molecule substance exchange, finish synthetic, metabolism, liver functions such as biotransformation, then, the culture fluid of having finished liver function through mass exchange is exported by the culture fluid in the bioreactor, be transported in the incubator with the culture fluid constant-current device, blood/plasma through the patient after the mass exchange then exports by the blood/plasma in the bioreactor, with the blood/plasma constant-current device it is sent back in the blood circulation of human body.
In the method for the invention, displacement or absorption in blood/plasma displacement and/or adsorbent equipment, have been carried out owing at first make patient's blood/plasma, part toxicant and harmful substance have been removed, and then in Biotype artificial liver device, finish synthetic with exogenous hepatocyte, liver function such as metabolism and biotransformation, so, on the one hand, can alleviate the hepatic coma state that ALF patient causes because of poisonous substance rapidly, reduce the neural damage of patient, on the other hand, also therefore improved the task performance of bioreactor, making exogenous hepatocyte can finish it more effectively synthesizes, metabolism and biotransformation etc. " own job " are worked, thereby have improved the therapeutic effect of composite artificial liver supporting system of the present invention greatly.
In addition, as mentioned above, because the incubator in the Biotype artificial liver device of the present invention is made by permeability cell, the residing environment of exogenous hepatocyte of Pei Yanging is near the environment among the normal human therein, so the exogenous hepatocellular density of cultivating can be very big, activity is also very high, and the hepatocellular active time of being cultivated can surpass 8 hours, thereby improved the curative effect of Therapeutic Method of the present invention greatly.In the clinical treatment case of the application that is described below composite artificial liver supporting system of the present invention and method, will introduce curative effect of the present invention in detail.
In addition, in first step of the inventive method, can decide the displacement of adopting blood/plasma according to the concrete condition of contained toxicant and harmful substance in patient's the different state of an illness and the cause of disease and the blood, or the absorption of blood/plasma, perhaps both dual-purposes.
Description of drawings
Fig. 1 is the sketch map of an exemplary embodiments of composite artificial liver supporting system of the present invention;
Fig. 2 is a using method of using composite artificial liver supporting system of the present invention when carrying out clinical treatment, the flow chart of each treatment step.
The specific embodiment
Below, describe the embodiment of composite artificial liver supporting system of the present invention in detail and adopt method of the present invention to carry out the case of clinical treatment with reference to accompanying drawing.In the accompanying drawing:
See also Fig. 1, Fig. 1 represents composite artificial liver supporting system of the present invention.Among Fig. 1, label 10 displacement of expression blood/plasma and/or adsorbent equipments.Label 11 is the blood plasma that is used to separate the patient, and the plasma separating unit that discharges of the blood plasma after will separating.Label 16 is the outlets that are used to discharge the blood plasma after the separation.Label 12 is the devices that import healthy blood plasma, and this device comprises low-lift pump commonly used, valve and pipeline, is used in the blood plasma input blood/plasma displacement and/or adsorbent equipment with health.Label 16 is that the blood plasma with the patient after separating is discharged to the outlet that the segregation apparatus outside is gone.Label 15 is a kind of three-way valve, changes the position of this valve, can make with the pipeline of human vas connection or with blood/plasma displacement and/or adsorbent equipment to link to each other, and perhaps links to each other with Biotype artificial liver device.Label 13 is displacement and/or adsorber, when as displacer, the healthy blood plasma that imports herein with human body in the other biological liquid mixing, when as adsorber, the toxicant in the adsorbable blood/plasma of adsorbent wherein (for example activated carbon, the activated carbon that coat is arranged, affinity column, ion exchange resin or the like).Certainly, if desired, also can make it both play immixture with healthy blood plasma, also play the toxicant in the absorption blood.
According to the requirement of the state of an illness, also can not use above-mentioned three-way valve 15, and adopt pipe joint, in the different step of treatment, be connected with blood/plasma displacement apparatus or Biotype artificial liver device respectively.
The included scope of dotted line of label 14 indications is to make the blood/plasma displacement apparatus be in the working range of the thermostat under the human body temperature (37 ℃), adopts glass or adiabator that it is surrounded.This thermostat generally is the packaged air-conditioner of controlling automatically, and when ambient temperature was lower than 37 ℃, it made the device temperature inside be elevated to 37 ℃, otherwise, then make the device temperature inside be reduced to 37 ℃.
Displacement of above-described blood/plasma and/or adsorbent equipment device commonly used when being the various hematopathy of treatment, when using in the present invention, its effect is also substantially the same.
Label 20 expressions Biotype artificial liver device of the present invention.Label 21 wherein is mass exchange devices, is used for carrying out between patient's blood/plasma and exogenous hepatocyte such as reactions such as synthetic, detoxifcation and biotransformations the patient being carried out the liver function support.Label 211 is a kind of boundling fiber pipes, this boundling fiber pipe is made by semipermeable membrane, behind the mass exchange of packing into device 21 inside, patient's blood/plasma enters the interior tube chamber of this boundling fiber pipe 211 by import 212, contain exogenous hepatocellular culture fluid then by import 214, enter in the mass exchange device, be in the outer lumen of boundling fiber pipe 211, thus both can by semipermeable membrane carry out various biological respinses and in, micromolecular mass exchange.Flow out the material exchanger through the blood/plasma after biological respinse and the mass exchange by going out 213, flow back in patient's body, the exogenous hepatocellular culture fluid that contains through biological respinse and mass exchange then flows out the material exchanger by outlet 215, gets back in the incubator.
Incubator of label 22 expressions is used for introducing and cultivating exogenous hepatocyte, makes that hepatocyte can reach desired density in culture fluid and activity (is generally 1.5 * 10
10Individual hepatocyte, motility rate is greater than 80%).Permeability cell of label 221 expressions contains exogenous hepatocellular culture fluid and flows in this root permeability cell, then is surrounding air around the permeability cell.Porous is not by permeability cell for culture fluid, but permeability cell ambient air porous enters the inside of permeability cell by permeability cell, in order to cultivate exogenous hepatocyte.Because hepatocyte is under the optimized atmospheric pressure, and airborne oxygen content is suitable for hepatocellular existence, so this incubator does not only need a whole set of apparatus of oxygen supply and pressure-regulating device to come to the hepatocyte oxygen supply.So not only simplified the formation of device, and improved hepatocellular density and activity greatly, cultivating the hepatocellular time with high activity under high density can surpass 8 hours, thereby has improved the task performance of package unit.
The hepatocellular culture fluid that contains from culture fluid outlet 223 outputs enters in the mass exchange device through the culture fluid import 214 in the exchanger; Through the culture fluid after the mass exchange, flow out from the culture fluid outlet 215 of exchanger, in the permeability cell 221 in the 222 inflow incubators of the culture fluid import in the incubator.Label 26 is the hepatocyte sources that are used for supplemented with exogenous hepatocyte and culture fluid in incubator.
Label 23 expressions are used to make patient's blood/plasma to carry out circulation blood/plasma constant-current device between mass exchange device and human recycle system.This constant-current device comprises the parts such as low-lift pump, valve, pressure-regulating device and flow regulator that are contained on the circulation duct, flows so that blood/plasma is under in check pressure and the flow velocity.
Label 24 expression is used to make and contains exogenous hepatocellular culture fluid carry out circulation culture fluid constant-current device between mass exchange device and incubator.This device also comprises the parts such as low-lift pump, valve, pressure-regulating device and flow regulator that are contained on the circulation duct, flows so that culture fluid is under in check pressure and the flow velocity.
Label 25 expression makes bioreactor remain on thermostat under the human body temperature.The included scope of dotted line of label 25 indications is that thermostat makes bioreactor be in working range under the human body temperature.The same with the thermostat of blood/plasma, it also is a kind of packaged air-conditioner that can control automatically.
More than these two kinds of constant-current devices and thermostat all be device commonly used in the armarium of blood purification.In disclosed No. 94192400.9 description, more detailed description is arranged.Just here do not describe in detail.
See also Fig. 2, Fig. 2 is the flow chart of the using method of using composite artificial liver supporting system of the present invention each step when carrying out clinical treatment.
In the step S1 of Fig. 2, utilize blood/plasma of the present invention displacement and/or adsorbent equipment blood samples of patients/blood plasma is replaced and/or to adsorb, so that remove part toxicant and detrimental substance in blood samples of patients/blood plasma.When carrying out the displacement of blood/plasma, the useless blood plasma of separating from patient's blood be excluded, add fresh healthy blood plasma.When adsorbing, can use adsorbing materials such as activated carbon, affinity column or ion exchange resin.Perhaps,, also can both replace, also adsorb according to patient's the state of an illness.The treatment time of this step was generally about 2 hours.
In the step S2 of Fig. 2, incubator in Biotype artificial liver device of the present invention adds and contains exogenous hepatocellular culture fluid, and at human body temperature and atmospheric pressure and contain and cultivate exogenous hepatocyte under the oxygen condition.The exogenous hepatocellular total amount of being cultivated should reach 1.5 * 10
10More than individual, competent cell wherein should be higher than 80%.Employed incubator is made of permeability cell etc. among the present invention, and as mentioned above, this permeability cell can provide best living environment for exogenous hepatocyte.Should contain nutrient substance and the additional composition that to keep the hepatocyte vigor in the culture fluid used in the present invention.This culture fluid is that the technology of the present invention field is known, can buy on the market.And, according to the needs of the hepatocyte kind of being cultivated, can also add other the nutrient substance that replenishes.Employed exogenous hepatocyte among the present invention mainly is a porcine hepatocyte.Certainly, also can use the hepatocyte of other animals, but, be good with porcine hepatocyte according to inventor's experience.
In the step S3-1 of Fig. 2, utilize the blood/plasma constant-current device in the Biotype artificial liver device of the present invention, will be through displacement and/or the patient's of adsorbing blood/plasma, import tube chamber in the boundling fiber pipe made from semipermeable membrane of mass exchange device in the above-mentioned Biotype artificial liver device, and the various parts by connecting pipe and constant-current device, make between its tube chamber and patient's in the boundling fiber pipe of mass exchange device the human body and circulate with suitable flow velocity.
In the step S3-2 of Fig. 2, utilize the culture fluid constant-current device in the Biotype artificial liver device of the present invention, make and circulate with suitable flow velocity between the boundling fiber pipe outer lumen that contains hepatocellular culture fluid tube chamber and mass exchange device in the permeability cell of above-mentioned incubator of in step S2, cultivating.
On the basis of the step S3-1 of Fig. 2 and S3-2, promptly, all carry out on the basis of normal circulation under the control at constant-current device in blood/plasma and culture fluid, in the step 4 of Fig. 2, the blood/plasma that flows through the patient of tube chamber in the boundling fiber pipe just see through tube wall carry out with exogenous hepatocyte in the culture fluid that flows through boundling fiber pipe outer lumen in, micromolecular mass exchange, liver functions such as, metabolism synthetic to finish and biotransformation promptly, are finished the function of treatment disease.
Below, introduce the process of using the method that composite artificial liver supporting system of the present invention treats in detail by several clinical cases, and the effect that adopts this method treatment to be obtained.
Case 1
Female patient 50 years old, is suffered from obstructive jaundice, hilar cholangiocarcinoma and has been shifted to leftlobe of liver.Once implemented the excision of hilar bile duct carcinectomy regulating liver-QI lobus sinister.Postoperative first day, oliguria, anuria, abdominal distention, symptom such as drowsiness appear in the patient; Hematological results is: ALT 3724U/L, AST 4053U/L, TB 412 μ mol/L, DB 257 μ mol/L, Cr 652 μ mol/L, BUN 41 μ mol/L.Be diagnosed as acute hepatorenal syndrome.Through twice blood filtration treatment, patient still blood ammonia raises, and is drowsiness, is hepatic encephalopathy.
On January 25th, 2000, after the hepatectomy the 7th day, treat with composite artificial liver supporting system of the present invention and using method.The process of treatment is as follows:
At first patient's blood plasma is carried out 2 hours adsorbing therapy with the displacement of the blood/plasma in the composite artificial liver supporting system of the present invention (absorption) device, make patient's blood ammonia drop to 98 μ mol/L, and ALT, AST, TB, DB, BUN and Cr etc. also slightly reduce from 134 μ mol/L.
Then, in the incubator in composite artificial liver supporting system of the present invention, the motility rate that adds acquisition after separating adds up to 1.5 * 10 greater than 80%
10Fresh Chinese experimental use the miniature pig hepatocyte, under 37 ℃ constant temperature, cultivate with culture fluid, and make between the permeability cell of its incubator in bioreactor of the present invention and the boundling fiber pipe space outerpace in the mass exchange device by the culture fluid constant-current device among the present invention and to circulate.
Simultaneously by means of the blood constant-current device among the present invention, the blood that makes the patient circulates between the inner chamber of the vein of the blood circulation of its human body and the boundling fiber pipe in the bioreactor of the present invention.
In the middle of treatment, patient's blood pressure, heart rate and breathing are steady, do not tell discomfort.After with above-mentioned steps treatment 4 hours, the various indexs of patient's blood are detected.The result who detects: blood ammonia obviously reduces, and is reduced to 45 μ mol/L from 98 μ mol/L, and ALT, TB, DB, BUN reduce, and AST, Cr raise.
After the treatment first day, patient's mind recover clear-headed, and blood ammonia is in normal level, and ALT slightly raises, and AST is then than the obvious reduction in the therapeutic process, but DB obviously raises, still oliguria.After the treatment second day carried out blood filtration with blood/plasma displacement (absorption) device of the present invention once more and treated.Treatment back the 3rd day, patient's liver function are near normal level, but renal function is still depleted.Back patient requires to stop treatment because of economic cause.
In above-mentioned therapeutic process, also per hour from the incubator of composite artificial liver supporting system, take out hepatocyte, measure the sum and the survival rate of exogenous porcine hepatocyte with the blue staining of Placenta Hominis.Measurement result is, when ading up to 1.5 * 10
10The time, survival rate is all greater than 80% within 6 hours.
This case shows, adopts the blood plasma adsorbent equipment to adsorb earlier, and reuse Biotype artificial liver device is treated blood plasma, can prevent to occur in the blood circulation conduit blood coagulation, and can reduce the toxicant in the liver failure blood samples of patients.Adopt porcine hepatocyte patient's blood plasma to be treated, can obviously reduce patient's blood ammonia, indexs such as TB, DB, help to improve hepatic encephalopathy patient's mind as exogenous hepatocyte.
Case 2
The male patient, 32 years old.Suffer from the chronic heavy type hepatitis B, hepatic insufficiency.Before once crossed Drug therapy and 8 plasmapheresiss (each 2500-3000ml), but patient's liver function continues deterioration, jaundice is deepened, and ascites increases, and the urine amount is few, impaired renal function, lethargy.The result that has a blood test, blood ammonia is normal, and the enzyme subcutaneous ulcer is separated, coagulation disorders.
On August 25th, 2000 was that method is treated with composite artificial liver supporting system of the present invention, and therapeutic process is as follows:
At first patient's blood plasma is carried out 2 hours adsorbing therapy, but the TB in the blood samples of patients, DB etc. there is not obviously improvement with the blood/plasma in the composite artificial liver supporting system of the present invention displacement (absorption) device.
Subsequently, treat with the Biotype artificial liver device in the composite artificial liver supporting system of the present invention.Used exogenous hepatocellular motility rate is identical with case 1 with density.After treatment in 2 hours, the TB in patient's blood plasma, DB, AST slightly reduce, and CH raises before the treatment.After treatment in 4 hours, ALT, AST promptly are reduced to normal level, and TB, DB further reduce; CH, Alb raise before the treatment.In the process for the treatment of with Biotype artificial liver device, patient's blood pressure, heart rate and breathing are steady, and mind transfers to clear-headedly by drowsiness, and initiatively talk requires drinking-water, feed, does not tell discomfort.After the treatment, the patient just can walk out therapeutic room voluntarily, and safety is returned the ward.
Treated back first day, the urine amount increases 3000ml, and AST, TB, DB slightly raise.In first day to the 7th day after the treatment, patient's private prosecution spirit is clearly better, and abdominal distention alleviates, and appetite takes a turn for the better, and can descend ground movable.But arrive the 20th day after the treatment, TB, DB further raise, and CH, Alb are lower than normal value, illustrate that the patient still is in chronic liver function and loses the compensatory phase.Afterwards, continued to treat with medicine, keep 5 months after, the patient leaves hospital because of economic problems.
This case shows, to the compensatory patient of chronic liver function forfeiture, adopts composite artificial liver supporting system of the present invention and method to treat, and also can temporarily obviously reduce TB, DB level in the blood plasma, obtains quite significantly curative effect.But because patient's liver regeneration and reserve capabillity are too poor, the effect of treatment can only be kept the relatively shorter time.As need long term maintenance therapeutic effect, as long as the economic condition permission can repeat to treat with method of the present invention.
Case 3
Female patient, 43 years old.Suffer from acute severe viral hepatitis, symptom is a fulminant hepatic failure, hepatic encephalopathy, hepatic coma IV degree.Treating with method of the present invention preceding 9 days, poor appetite has appearred, yellowish urine was treated preceding 2 days, occur drowsiness, obnubilation, exhale should, condyle clonic spasm (+), liver dullness circle dwindles.The blood examination result, ALT, AST, TB, DB, ALP obviously raise, and PTA obviously reduces.Treat the previous day, hepatic coma IV degree, 39 ℃ of body temperature.B ultrasonic is reported as the diffusivity hepatic injury., adopt various protecting the liver therebetween, support, infection, hormone, dehydration or the like treatment there is no effect, and once carries out once little rescue.
11 o'clock on the 11st January of calendar year 2001 begins, and treats with composite artificial liver support system of the present invention and using method thereof.
At first carry out plasmapheresis, totally 3.5 liters.Check blood samples of patients, ALT, AST, TB, DB, ALP obviously reduce.Treat since 14: 40 with the Biotype artificial liver device of composite artificial liver supporting system of the present invention.Used exogenous hepatocellular motility rate is identical with case 1 with density.After treating 4 hours, check blood samples of patients, ALT, ALP, TP obviously reduce, and TB, DB slightly reduce, and AST obviously raises.
Treat back first day (January 12), the patient transfers light coma to.Blood examination result: PTA obviously raise (21.56%).
Treat back second day (January 13), the patient transfers to drowsiness, thinks feed, and that exhales can answer, and can answer simple problem, and cognitive power and orientation force have recovery slightly.Do not see condyle clonic spasm.Have a blood test, ALT, AST, ALP obviously reduce before the treatment, and PTA is elevated to 29.63%.
On the 3rd day (January 14) after the treatment, patient's consciousness transfers to clear, can take food.
On the 4th day (January 15) after the treatment, the patient tells hunger, and mind is clear, computing power, and it is normal that orientation force is recovered.Infection control is good.
On the 6th day (January 17) after the treatment, the patient recovers normally substantially, and the result that has a blood test is elevated to 49.9% for PTA.
On the 8th day (January 18) after the treatment, the patient leaves hospital.
After three weeks the patient is followed up a case by regular visits to, find that patient's ordinary circumstance is good, can carry out light physical labor, check liver function, near normal.
This case shows that composite artificial liver supporting system of the present invention and using method thereof have excellent curative for acute fulminant hepatic failure patient and hepatic encephalopathy patient, can make patient's mind recover clear-headed very soon.This mainly is because alternative by detoxifcation and temporary transient liver function, for the time has been won in the regeneration and the reparation of the compensatory and liver of the liver function of patient's depletion, thereby has saved patient's life.The temporary transient rising of AST level that takes place in when treatment according to analysis, may be that dead exogenous porcine hepatocyte has discharged AST and causes.
In sum, can see by these cases, composite artificial liver supporting system of the present invention and using method thereof, because it combines the state-of-the-art technology of blood purification, the displacement or the absorption of advanced row blood/plasma, reduced the toxicant in the blood samples of patients, and then treat with Biotype artificial liver device, help the survival of exogenous hepatocyte (in the present invention adopt be porcine hepatocyte) and bring into play the effect of its alternative liver function better, and adopted the container of permeability cell as exogenous hepatocellular incubator, can increase substantially and cultivate exogenous hepatocellular density and time-to-live, so, no matter for the patient of acute or chronic liver failure, all has outstanding therapeutic effect, it is after detoxifying to blood/plasma, can utilize exogenous hepatocyte that the liver function of human body is carried out substantial support, make the synthetic of the good liver of the temporary transient acquisition of patient, functions such as metabolism, for the acute hepatopathy patient, can win opportunity for patient's self liver regeneration; For chronic hepatitis patients,, also can gain time for its transplanting of waiting for liver though patient's liver itself can't be regenerated.
Claims (4)
1. composite artificial liver supporting system, it has and is used for removing the toxicant of blood/plasma and blood/plasma displacement and/or the adsorbent equipment and the Biotype artificial liver device of harmful substance,
Above-mentioned blood/plasma displacement and/or adsorbent equipment comprise following each several part:
A. be used to separate patient's blood plasma and will separate after the plasma separating unit of blood plasma discharge;
B. the healthy blood plasma gatherer that comprises pump, valve and pipeline;
It is characterized in that,
Displacement of above-mentioned blood/plasma and/or adsorbent equipment also have makes above-mentioned blood/plasma displacement and/or adsorbent equipment be in thermostat under the human body temperature;
Above-mentioned Biotype artificial liver device comprises following each several part:
A. bioreactor, this reactor comprises following each several part:
(1) mass exchange device is useful on the import and the outlet that allow patient's blood/plasma come in and go out in this mass exchange device; Be used to allow and contain import and the outlet that exogenous hepatocellular culture fluid is come in and gone out; And the boundling fiber pipe of making by semipermeable membrane, this boundling fiber pipe be used for above-mentioned patient's blood/plasma with contain exogenous hepatocellular culture fluid and keep apart, but between can carry out in, micromolecular mass exchange;
(2) one are used for introducing and the active exogenous hepatocellular incubator of cultivation, and a permeability cell that holds culture medium is arranged in this incubator, and the atmosphere porous around this permeability cell is by this root permeability cell; On this permeability cell, have one with the above-mentioned substance exchanger in contain the exogenous hepatocellular culture fluid import that contains that exogenous hepatocellular culture fluid outlet is communicated with; One be communicated with culture fluid import in the above-mentioned substance exchanger contain exogenous hepatocellular culture fluid outlet;
B. one is used to make patient's blood/plasma to carry out circulation blood/plasma constant-current device between above-mentioned substance exchanger and human recycle system;
C. one is used to make and contains exogenous hepatocellular culture fluid carry out circulation culture fluid constant-current device between above-mentioned substance exchanger and incubator; And
D. one is used to make this bioreactor to remain on thermostat under the human body temperature.
2. composite artificial liver supporting system as claimed in claim 1 is characterized in that, above-mentioned blood/plasma constant-current device comprises low-lift pump, valve, pressure-regulating device and the flow regulator that is contained on the circulation duct.
3. composite artificial liver supporting system as claimed in claim 1 is characterized in that, above-mentioned culture fluid constant-current device comprises low-lift pump, valve, pressure-regulating device and the flow regulator that is contained on the circulation duct.
4. composite artificial liver supporting system as claimed in claim 1, it is characterized in that, the thermostat of displacement of above-mentioned blood/plasma and/or adsorbent equipment, and the thermostat of above-mentioned bioreactor all is a kind of small-sized, can control the air-conditioner of the temperature that sets automatically.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011156708A CN1178706C (en) | 2001-04-28 | 2001-04-28 | Composite artificial liver supporting system and its usage |
| PCT/CN2002/000287 WO2002087661A1 (en) | 2001-04-28 | 2002-04-24 | A compound artificial liver system and the method for using the said system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011156708A CN1178706C (en) | 2001-04-28 | 2001-04-28 | Composite artificial liver supporting system and its usage |
Publications (2)
| Publication Number | Publication Date |
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| CN1383898A CN1383898A (en) | 2002-12-11 |
| CN1178706C true CN1178706C (en) | 2004-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011156708A Expired - Lifetime CN1178706C (en) | 2001-04-28 | 2001-04-28 | Composite artificial liver supporting system and its usage |
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| Country | Link |
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| CN (1) | CN1178706C (en) |
| WO (1) | WO2002087661A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100335142C (en) * | 2004-12-24 | 2007-09-05 | 浙江大学 | Apparatus adapted for artificial liver |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100337698C (en) * | 2003-06-24 | 2007-09-19 | 中国人民解放军第三军医大学 | In vitro biologic artificial liver supporting device |
| CN104147651B (en) * | 2014-08-01 | 2016-09-28 | 武汉仝干医疗科技股份有限公司 | Whole blood perfusion bioartificial liver system |
| CN104958795B (en) * | 2015-06-23 | 2017-03-29 | 四川大学华西医院 | Whole blood perfusion bioartificial liver system |
| CN106267399B (en) * | 2016-07-29 | 2018-07-06 | 武汉仝干医疗科技股份有限公司 | Four-in-one formula bioreactor of artificial liver |
| CN106139289B (en) * | 2016-07-29 | 2018-06-19 | 武汉仝干医疗科技股份有限公司 | Semi-permeable membrane is layered integrated biological reactor |
| CN108211032B (en) * | 2018-02-01 | 2023-11-17 | 南方医科大学珠江医院 | Combined bioartificial liver support system |
| CN115537375B (en) * | 2022-10-21 | 2023-10-03 | 兰州大学第一医院 | Preparation method of biological artificial liver treatment serum for liver fibrosis treatment |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5270192A (en) * | 1991-02-07 | 1993-12-14 | Monsanto Company | Biological artificial liver |
| AU7959494A (en) * | 1992-09-11 | 1996-04-19 | Xenogenex, Inc. | Artificial liver apparatus and method |
| US5866420A (en) * | 1993-10-08 | 1999-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Artificial liver device |
| FR2718643B1 (en) * | 1994-04-13 | 1996-06-14 | Fondation Transplantation | Extra-corporeal hepatodialyser using the liver taken from a living being. |
| CN2426361Y (en) * | 2000-06-29 | 2001-04-11 | 重庆西南医院 | Mixed biologic artificial liver supporting device |
-
2001
- 2001-04-28 CN CNB011156708A patent/CN1178706C/en not_active Expired - Lifetime
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2002
- 2002-04-24 WO PCT/CN2002/000287 patent/WO2002087661A1/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100335142C (en) * | 2004-12-24 | 2007-09-05 | 浙江大学 | Apparatus adapted for artificial liver |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1383898A (en) | 2002-12-11 |
| WO2002087661A1 (en) | 2002-11-07 |
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