JP2003250882A - Artificial organ system using new perfusion method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new artificial organ system which can perfuse a sufficient amount of blood for blood purifying treatment of patients suffering a hepatic insufficiency. <P>SOLUTION: In the artificial organ system for a blood purifying treatment which comprises a patient side blood circulation circuit containing a blood component separation part to be directly connected to patients and a blood circulation circuit on the organ functioning side containing a reservoir for storing perfused blood, as organ function alternative part or a blood circuit part having organ functions, the blood separated by a blood component separation part in the patient side blood circulation circuit flows into the reservoir in the blood circulation circuit on the organ functioning side. The perfused blood shunted at a shunt part for return blood provided on the downstream of the organ functioning alternative part and on the upper stream of the reservoir or on the downstream of the organ functioning alternative part in the blood circulation circuit on the organ functioning side and on the upstream of the reservoir, when the blood circulation circuit having organ functions on the organ functioning side has the organ functioning alternative part or at an arbitrary point in the circuit when the blood circulation circuit itself on the organ functioning side has organ functions converges at the converging part for the return blood as provided on the downstream of the blood component separation part in the patient side blood circulation circuit. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an artificial organ system for purifying blood by perfusing a part of a blood component of a patient with a circuit including an organ function substituting portion or a circuit having an organ function.

[0002]

2. Description of the Related Art The liver and kidney are central organs of metabolism in the body and play an important role in maintaining homeostasis in the body. For this reason, this homeostasis is once destroyed, and over a long period of time, it causes liver failure and renal failure, respectively, resulting in a serious life threat.

As a therapeutic method for severe liver failure, progress in therapeutic methods using artificial liver is expected. Currently, the artificial liver, which is the development target, is not a completely implantable type like an artificial blood vessel, but rather, it is waiting for the support of liver function in patients with fulminant hepatitis and postoperative liver failure and the appearance of donors for liver transplantation. It is an extracorporeal type that is used for perfusion therapy as an alternative bridge for liver function during the period. The mainstream of its development is the hybrid type and whole liver type artificial liver.

The whole liver type artificial liver is of a type that uses whole liver derived from a non-human xenogeneic organism (xenogeneic whole liver).
A method of whole blood direct perfusion therapy using surgically isolated xenogeneic whole liver was started by the isolated pig whole liver in 1965 by Eisemann et al. [Eisemann B., et al: Ann Surg 162: 329 (19
65)], Abouna, Neuhaus et al. Furthermore, Ozawa et al. Of Kyoto University developed a cross-perfusion treatment method using porcine liver and baboon liver, and clinically applied it to 16 patients with liver failure. However, due to factors such as a heterogeneous immune reaction, perfusion could be continued for only a few hours, and no significant prolongation of survival was observed.

On the other hand, since it was established that a method for separating and culturing hepatocytes using a collagenase solution was established and that hepatocytes were cultivated under optimum conditions in an engineering device, good liver function was exhibited, Hybrid artificial livers incorporating cell-containing bioreactors have been developed and have been clinically applied one after another in the 1990s. Rozg
a et al. described a hollow fiber bioreactor using dextran microcarriers [Rozga J., et a
l.:Ann Surg 217: 502 (1993)], and Gerlach et al. [Gerlach] a three-dimensional capillary network bioreactor.
J., et al .: Transplantation 58: 984 (1994)] respectively. Both have immobilized porcine hepatocytes, and have been clinically applied to more than 40 patients and Gerlach et al. To 8 patients, respectively. In addition, the research group of the present inventor has developed a non-woven fabric-filled bioreactor in which pig hepatocytes are immobilized on a collagen-coated polyester non-woven fabric. However, it is not clear whether the hybrid type also had a certain effect in clinical application.

On the other hand, as a method for treating renal failure, artificial kidneys and kidney transplants can be mentioned. About the world at the end of 1995
700,000 people are receiving artificial kidney treatment by hemodialysis. In Japan, the number of patients treated with artificial kidney reached 176,000 at the end of 1997, and the number of patients treated with artificial kidney per capita is the highest in the world. Although it has the effect of removing metabolites such as urea and toxic substances from blood, it does not have the re-absorption ability that corresponds to the function of renal tubular tubules and results in the elimination of useful proteins. Another problem is the reabsorption of useful substances. Also, like liver transplants, kidney transplants suffer from a shortage of donors. Under such circumstances, it has been desired to develop an extracorporeal perfusion treatment method for an artificial kidney that can better replace the renal function.

Rozga et al., Or G, which have been clinically applied so far
In the hybrid artificial liver system of erlach et al., plasma separated by a plasma separator passes from a bioreactor from whole blood flowing from a patient into an extracorporeal perfusion system. The major problem is that only 20 to 30% of the total blood flow is perfused into the bioreactor, and the perfusion efficiency is low, and plasma has an oxygen-dissolving capacity that is less than one-tenth that of whole blood. It does not have oxygen supply to hepatocytes because it does not have it. Along with this, the activity of hepatocytes in the liver function replacement part is reduced, and the liver function is insufficiently exerted. In order to overcome these drawbacks, it is necessary to directly perfuse whole blood into the hepatic function replacement site in order to improve perfusion efficiency and oxygen supply, thereby satisfactorily replacing and assisting liver function in patients with hepatic failure. There is a need for an artificial liver system that can.

The present inventors have conducted research based on the above-mentioned problems, and as a result, in an artificial liver system or artificial kidney system for extracorporeal perfusion, in addition to an organ function replacement part (liver function replacement part or kidney function replacement part), By installing the white blood cell removing portion and / or the immunoglobulin removing portion, and further the blood component separating portion, whole blood is allowed to pass through the organ function substituting portion without causing a heterogeneous immune reaction. Succeeded in improving efficiency and oxygen supply to the organ function replacement part, preventing reduction of immunocompetent cells such as white blood cells and saving equipment required for white blood cell removing part and / or immunoglobulin removing part Prior to the completion of the artificial organ system for direct perfusion therapy, a patent application was filed first (Patent application 2000-80131, new artificial liver system, 2000).
(Filed on March 22,) (PCT International Patent Application No. PCT / JP01 / 02233),
New artificial organ system, filed on March 21, 2001).

[0009]

DISCLOSURE OF THE INVENTION The present invention is directed to a novel artificial organ system capable of perfusing a sufficient amount of blood to a heterogeneous organ and plasma separated from whole blood of a patient, which is then perfused with human whole blood. An object of the present invention is to provide a novel artificial organ system that allows the combined blood to flow into the circuit of the storage device and pass through the organ storage device, and then separates plasma again and returns the blood to the patient.

The present invention further includes whole human blood alone, or
A suspension of hepatocytes in human whole blood is circulated in a circuit consisting of a reservoir (blood reservoir), a dialyzer (dialyzer), a plasma separation unit, etc. An object of the present invention is to provide a therapeutic system for purifying blood by exchanging plasma between two plasma separators in between.

[0011]

Means for Solving the Problems The present inventors have conducted research on a perfusion method for extracorporeal perfusion therapy for artificial organs, and it is desirable that the perfusion method for extracorporeal perfusion therapy for artificial organs have the following conditions. I found that. 1. The ability to directly perfuse whole blood into a heterologous organ. 2. To be able to secure the flow rate and flow rate of whole blood required to perfuse a different organ. 3. The ability to prevent foreign viruses from entering the patient's body.

As a result of further research, the present inventors have found that
We have further improved the artificial organ system for whole blood direct perfusion therapy, which we have already applied for a patent, and developed a system that can perfuse a different amount of blood into a different organ. On the other hand, plasma is separated from the whole blood of the patient, and this is allowed to flow into the circuit of the organ storing device in which human whole blood is perfused. We newly developed an artificial organ system that returns blood to and named it repetitive plasma separation perfusion method.

In addition, when the whole blood of a pig as an organ function substitute part in an artificial liver was compared with an immobilization type bioreactor for immobilizing hepatocytes on a non-woven fabric by using the direct whole blood perfusion method, the following results were obtained. I got the result. That is, 1. The metabolic synthesis ability of both is the same. 2. Bilirubin, a waste product of red blood cells, can be used as bile in the whole liver. 3. In the immobilized bioreactor, it takes about 1 day to excise the pig liver, separate and purify hepatocytes, and immobilize it on the non-woven fabric to complete the bioreactor. The system can be completed in a short time. 4. In the immobilized bioreactor, it is considered that 1/3 to 1/2 of the original liver is lost during the process of separating, purifying and immobilizing hepatocytes, but in whole liver, hepatocytes are lost. I will not be told. 5. In the immobilized bioreactor, it is possible that contaminants may be mixed in during the process of separating, purifying, and immobilizing hepatocytes, or that they may be cultivated during immobilization. For the reasons described above, which are unlikely to grow in culture, we came to the conclusion that whole liver is more practical and clinically suited as a liver function replacement site. Therefore, the present inventors newly developed a whole liver storage device and filed a patent application (patent application 2001-401200, new organ storage system, filed on December 28, 2001).

From the perspective of performance and medical ethics regarding the research and development up to this point, the method of performing the repeated separation plasma perfusion method using a system incorporating a whole liver storage device is the most excellent and practical. It was considered to be a suitable artificial liver perfusion method. However, in vitro management of whole liver still has the following drawbacks. That is, 1. Surgery should be more advanced and time consuming than hepatocyte isolation. 2. It is very complicated and difficult to manage the operation of the system, such as placement of the liver, monitoring the pressure of inflow and outflow of the liver, oxygen supply, heat retention, operation of pulsatile pump, recovery of exudate leaking from the surface of the liver, and therefore it is very difficult to manage the system. It is considered unlikely that it will spread to other medical fields.

Therefore, as a result of earnest research, the present inventors have found that
Hepatocytes are separated from the liver by collagenase or the like, and a suspension of this in human whole blood is circulated in a circuit composed of a blood reservoir (reservoir), a dialyzer (dialyzer), and a plasma separator, By performing repeated separated plasma perfusion in which plasma is exchanged through two plasma separators between this circuit and a blood circuit that directly connects to the patient, the liver function is exerted and a dialyzer is used in combination. We also devised an artificial organ system that also has renal functions such as water removal and excretion of toxic substances.

The characteristics of this method are as follows. 1. Since hepatocytes are suspended in whole blood, hepatocytes can obtain sufficient oxygen supply. 2. When heterologous hepatocytes are used, it is possible to prevent the virus from flowing into the patient's body. 3. There is no loss of time for immobilization as in non-woven fabric immobilized bioreactors. 4. Compared to the case of perfusing the whole liver as it is, surgery is easier and requires less time, and even if it takes time to separate and purify hepatocytes, it takes about an additional hour to set up compared to the case of whole liver. is there. 5. The operation management of the system is not complicated and difficult like the whole liver. The perfusate has a defined flow rate in a closed circuit and does not leak partially. Also, there is no risk of losing heat retention that tends to go unnoticed in the whole liver. 6. It can be performed with a console (integrated perfusion device), a reservoir that incorporates an oxygen supply fiber and a heat-retaining band, and does not require the large-scale console that is required in the case of an immobilized bioreactor or a whole liver device, and saves space. Absent. 7. Since the separated hepatocytes can be carried in a reservoir, it can be performed even in a community hospital. 8. At first glance, it's the same as hemodialysis, so not only patients,
It is considered that there is little psychological resistance to paramedical such as nurses and medical technologists.

On the other hand, even when human whole blood is used alone without mixing hepatocytes in place of the above-mentioned mixed solution in which hepatocytes are suspended in human whole blood, hepatic-deficient plasma is transferred to the human whole blood circulation circuit. By confluence, the nitrogen compound in the plasma of liver failure is diluted or removed by a dialyzer, so that the effect as a sufficient blood purification treatment is recognized. This method can replace the continuous hemodiafiltration that has been performed as a conventional blood purification therapy for patients with severe liver failure.

In the artificial liver system of the present invention, both the metabolic function and the synthetic function of the liver can be sufficiently exerted, and by using a dialysis machine together, water removal and toxic substances possessed by the kidney It can also have functions such as excretion of. First, as a metabolic function, ammonia is directly excreted from the dialyzer in the system or is metabolized to urea nitrogen by hepatocytes. Urea nitrogen is also excreted from the dialyzer or returned to the patient's body and then excreted outside the patient's kidneys. As a synthetic function, albumin and coagulation proteins produced by hepatocytes are concentrated by dewatering and then separated by a plasma separator and returned to the patient's body. This is plasma exchange using raw hepatocytes. Can be called treatment. Further, in the system of the present invention, as described below, by injecting a liquid such as sterilized maintenance infusion solution into the hollow fiber outer cavity of the plasma separator, and removing the water corresponding to the amount from the dialyzer, the acute renal failure is currently occurring. Hemodiafiltration (CHDF), which is widely used as a blood purification therapy for severe liver failure
You can also do

That is, the present invention is (1) an artificial organ system including two blood circulation circuits of a patient side blood circulation circuit and an organ function side blood circulation circuit, the patient side blood circulation circuit being directly connected to the patient. In the blood flow path, a blood component separation section and a blood return confluence section are included in this order, and the organ function side blood circulation circuit has a reservoir for storing perfused blood in the blood flow path, a dialyzer, An artificial organ system including a blood flow diversion part in this order, wherein the blood component separated by the blood component separation part in the patient-side blood circulation circuit is the organ function-side blood circulation circuit. Flow into the reservoir in the blood circulation circuit in the organ function side, and the blood component diverted in the blood flow diversion portion in the blood circulation circuit of the organ is transferred to the blood circulation circuit of the patient side in the blood flow junction of the patient side blood circulation circuit. Is combined in an artificial organ system for blood purification therapy by blood return to the patient,

(2) The artificial organ system of (1) in which water removal and dissolved substances are removed by ultrafiltration in a dialyzer in the blood circulation circuit on the organ function side, (3) the blood component separation part is a whole blood Is a blood component separation device (1) or (2), characterized in that the blood is separated into blood containing white blood cells in a concentrated manner and blood from which white blood cells have been removed, (4)
(3) an artificial organ system comprising an organ function replacement part at a position downstream of the dialyzer and upstream of the blood flow diversion part in the organ function side blood circulation circuit; and (5) the organ function replacement part, (4) artificial organ system, which is a bioreactor containing animal whole liver, animal whole kidney, or animal hepatocytes inside,

(6) A leukocyte-removing portion and / or an immunoglobulin-removing portion is included in a position in the blood circulation circuit on the organ function side, downstream of the reservoir or dialyzer and upstream of the organ function substitute portion (4) or (5) Artificial organ system, (7) Patient's whole blood is separated by a blood component separation device in the blood circulation circuit of the patient into blood from which white blood cells have been removed and blood containing white blood cells in a concentrated manner, thereby enriching white blood cells. The blood contained in is returned to the patient, and the blood from which white blood cells have been removed is allowed to flow into the organ function-side blood circulation circuit, into the reservoir in which human whole blood is stored, and then at least in the organ function-side blood circulation circuit. Pass through a dialyzer and / or organ function replacement,
Further, after that, a part of the blood is diverted in the blood flow diversion part, and the blood purification circuit is performed by merging with the blood circulation circuit on the patient side to return blood to the patient. (3) to (6) Organ system,

(8) The blood component separating section in the patient-side blood circulation circuit is a plasma separator, and the blood return diversion section in the organ function-side blood circulation circuit is a plasma separator (1) or ( (2) Artificial organ system of (2), (9) A liquid such as a sterilized maintenance infusion solution flows into the hollow fiber outer space of the first plasma separation section, and is mixed with plasma separated in the plasma separation section (8) (10) The artificial organ system according to (8) or (9), wherein the semipermeable membrane of the second plasma separation part has a pore size that does not allow passage of viruses (11) In the blood circulation circuit on the organ function side (8) to (1) at a position downstream of the dialyzer and upstream of the blood flow diversion part, which comprises an organ function replacement part.
0) any artificial organ system,

(12) The organ function replacement part is the whole liver of the animal,
The artificial organ system of (11), which is a bioreactor containing animal whole kidney or animal hepatocytes inside, (1
3) The artificial whole organ system according to any one of (8) to (10), wherein the mixed solution of human whole blood and animal hepatocytes circulates in the organ function side blood circulation circuit so that the circuit itself has organ function. (14) The artificial organ system according to (13), wherein the hepatocyte is derived from human, pig, or cow.

(15) The artificial organ system according to (12) or (14), which comprises an immunoglobulin-removing portion, and (16) plasma from the patient's whole blood by the first plasma separator in the patient's blood circulation circuit. At least in the organ function side blood circulation circuit, and then the plasma is allowed to flow into a reservoir in the blood circuit of the organ function side where human whole blood or a mixture of human whole blood and hepatocytes is stored. The blood is passed through the dialyzer and / or the organ function substitute portion in the circuit, and thereafter, the plasma is separated in the second plasma separator, and the plasma is joined to the patient-side blood circulation circuit in the return blood joining portion, The artificial organ system according to any one of (8) to (15), wherein blood purification treatment is performed by returning blood.

Furthermore, the present invention provides (17) a blood circulation circuit on the patient side, which is directly connected to a patient and includes a blood component separation unit,
And an organ function-side blood circulation circuit having an organ function replacement portion or a blood circuit portion having an organ function, the organ function-side blood circulation circuit including a reservoir for storing perfused blood, comprising: When the blood separated by the blood component separation unit flows into the reservoir in the organ function side blood circulation circuit, and the organ function side blood circulation circuit having an organ function substitute unit or organ function has an organ function substitute unit For returning blood, provided in the organ function side blood circulation circuit downstream of the organ function substitute portion and upstream of the reservoir, at an arbitrary point in the circuit when the organ function side blood circulation circuit itself has an organ function. Blood purification treatment by merging the perfused blood that has been diverted in the diverting section in the blood-return merging section in the blood circulation circuit on the patient side, which is provided downstream of the blood component separating section. Artificial organ system to perform, (18)
The blood component separation unit is an artificial organ system according to (17), which is a blood component separation device characterized by dividing whole blood into blood containing white blood cells in a concentrated manner and blood having white blood cells removed.

(19) The whole blood of a patient is separated into blood from which white blood cells have been removed and blood containing a large amount of white blood cells by a blood component separation device in the blood circulation circuit on the patient side, and blood containing a large amount of white blood cells to the patient. After the blood has been removed and the white blood cells have been removed, the blood is allowed to flow into the organ function-side blood circulation circuit, a reservoir in which human whole blood is stored, and then at least the organ function-side blood circulation circuit passes through the organ function replacement part. After that, part of the blood is diverted in the blood flow diversion part, and then merged with the patient side blood circulation circuit to return blood to the patient, and the blood flow volume perfusing the organ function side blood circulation circuit is increased. By maintaining it, blood perfusion to the organ function replacement part is increased (1
(8) The artificial organ system, (20) The leukocyte-removing part and / or the immunoglobulin-removing part are installed downstream of the reservoir in the blood circulation circuit on the organ function side and upstream of the organ function substitute part (19). system,

(21) The artificial blood vessel according to (17), wherein the blood component separating section in the patient side blood circulation circuit is a plasma separator, and the blood return diversion section in the organ function side blood circulating circuit is a plasma separator. Organ system, (22) Plasma is separated from the whole blood of the patient by the first plasma separator in the blood circulation circuit on the patient side, and this plasma is stored in human whole blood in the blood circulation circuit on the organ function side. After flowing into the reservoir, it passes through at least the immunoglobulin removal part in the organ function side blood circulation circuit and the organ function substitution part, and then is installed in the blood flow diversion part in the organ function side blood circulation circuit. In the second plasma separator, the plasma is separated and the plasma is
An artificial organ system according to (21), which performs blood purification treatment by merging with the patient-side blood circulation circuit and returning blood to the patient at the blood-return confluence section in the patient-side blood circulation circuit,

(23) Plasma is separated from whole blood of a patient by a first plasma separator in a blood circulation circuit on the patient side, and this plasma includes a reservoir, a dialyzer, and a second plasma separator, and , Human whole blood or a mixed solution of human whole blood and hepatocytes circulates so that the circuit itself merges with an organ function side blood circulation circuit having organ function, while the plasma separated in the second plasma separation unit (21) An artificial organ system for performing blood purification treatment by merging blood with a patient-side blood circulation circuit in the blood return confluence section and returning blood to the patient. (24) Water removal by ultrafiltration in a dialyzer. And the artificial organ system of (23), in which dissolved substances are removed,
(25) The artificial organ system according to (24), wherein liquid such as sterilized maintenance infusion flows into the hollow fiber outer space of the first plasma separation unit and is mixed with the plasma separated in the plasma separation unit. )
The hepatocytes are of human origin (23) to (25)
One of the artificial organ systems,

(27) The artificial organ system according to any one of (23) to (25), wherein the hepatocytes are of porcine or bovine origin, (28) an immunoglobulin-removing portion (2)
(7) The artificial organ system, (29) The artificial organ system according to (22) or (28), wherein the semipermeable membrane of the second plasma separation part has a pore size that does not allow passage of viruses.
Plasma is separated from the whole blood of the patient by the first plasma separation unit, and the plasma is separated from at least the reservoir, the dialyzer, and
A second plasma separator is included, which joins a circuit in which whole human blood or a mixed solution of human whole blood and hepatocytes circulates, while a second plasma separator separates plasma from the combined blood. An artificial organ system that provides treatment by returning blood to the patient

(31) Removal of dissolved water and removal of dissolved substances by ultrafiltration in a dialyzer (30) Artificial organ system (32) Maintenance of sterilization in the hollow fiber outer cavity of the first plasma separator (30) An artificial organ system in which a fluid such as an infusion flows in and is mixed with plasma separated in the instep, (33) An artificial organ system according to any one of (30) to (32), wherein the hepatocytes are of human origin. An organ system, (34) an artificial organ system according to any one of (30) to (32), wherein the hepatocytes are of porcine or bovine origin, (35) an organ function replacement part,
An artificial organ system including a reservoir for storing perfused blood, wherein perfusion blood shunted downstream of an organ replacement portion in a blood perfusion main circuit that circulates a patient, a reservoir, and an organ function replacement portion in this order is a collateral. An artificial organ system that rejoins the main blood perfusion circuit in a reservoir in the main blood perfusion circuit through the tract,

(36) Reservoir for storing blood which includes an organ function replacement portion and is returned to the patient after the patient blood or the patient blood from which a part of blood components have been separated and removed passes through the organ replacement portion. An artificial organ system including a blood perfusion main circuit including a blood perfusion side subpath connected to a reservoir of the main circuit, wherein a part of blood components separated and removed from the main circuit is returned to a patient, (35) Artificial organ system, (37) Leukocyte removal part and / or immunoglobulin removal, wherein blood flowing through the organ passes through an organ replacement part and is then partly diverted to a collateral passage to join the main circuit in the reservoir. (36) The artificial organ system according to (36), further including a part, (38) Further including a blood component separation part, (37)
(39) The artificial organ system according to (38), wherein the blood component separation unit divides whole blood into blood containing white blood cells in a concentrated manner and blood from which white blood cells have been removed.

(40) Blood rich in white blood cells separated in the blood component separating portion returns to the patient by returning to the main circuit of blood perfusion without passing through any of the white blood cell removing portion, immunoglobulin removing portion and organ replacement portion. (39) The artificial organ system of (39), (41) The whole blood of a patient is separated by a blood component separation device into blood from which white blood cells have been removed and blood containing white blood cells in a rich manner. Blood that has been returned to the patient and has its white blood cells removed is passed through at least the white blood cell removal portion, immunoglobulin removal portion, and organ replacement portion, and then returned to the patient, and the perfusion of blood to the organ replacement portion is performed. (40) is provided with a reservoir for storing blood in the perfusion circuit so that a part of the blood that has passed through the organ replacement part is diverted to the collateral passage connected to the reservoir. Further includes two plasma separating unit, the plasma separating unit separates the plasma from the blood blood or a portion of the blood component flowing through the blood perfusion main circuit is removed, (35) or (36) of the artificial organ system,

(43) Blood from the patient flows into the first plasma separation section, and the blood separated from the plasma in the first plasma separation section is returned to the patient without passing through the organ replacement section, Plasma separated by the plasma separation unit enters the blood perfusion main circuit, and merges with blood from the blood perfusion side accessory path or blood from which some blood components have been removed in the reservoir in the blood perfusion main circuit to replace the organ. Through the part, the blood from the organ replacement part or the blood from which some blood components have been removed flows into the second plasma separation part,
The blood separated from the plasma in the second plasma separation section or the blood from which a part of the blood components has been removed is diverted to the blood perfusion side subpathway, enters the reservoir, and is separated in the second plasma separation section. (42) The artificial organ system, wherein plasma is returned to the patient,

(44) Plasma is separated from the whole blood of the patient, blood separated from the plasma is returned to the patient, and the separated plasma is perfused with human whole blood including at least an immunoglobulin removing portion and an organ replacement portion. An artificial organ system for performing blood purification treatment by confluent with a circuit, and after the combined blood has passed through the organ replacement part, plasma is separated again and the separated plasma is returned to the patient to perform blood purification treatment. (42) The artificial organ system according to (42), and the hollow fiber in the second plasma separation section, wherein the separated blood joins the circuit in which human whole blood is perfused through the collateral path. The semipermeable membrane of is impermeable to virus (43) or (44)
Is the artificial organ system of. Hereinafter, the present invention will be described in detail.

[0035]

BEST MODE FOR CARRYING OUT THE INVENTION 1. Artificial Organ System of the Present Invention The artificial organ system of the present invention includes an artificial organ system for whole blood direct perfusion (DHP) treatment, repetitive plasma separation perfusion (RSP).
P) Includes artificial organ system for treatment. "Whole blood direct perfusion method" is a method in which whole blood from a patient is processed by perfusion, and "Plasma separation perfusion method" separates plasma from blood from a patient using a plasma separator and processes it. Say the method.

Here, the "artificial organ system" means a device for substituting or assisting the function of a patient's organ,
There are a device (artificial liver system) for substituting or assisting a liver function of a patient such as liver failure, a device (artificial kidney system) for substituting or assisting a renal function of a patient such as renal failure. The "organ function replacement part" means a part other than an organ in the living body, which exerts the function of the organ in the living body, and the "liver function replacement part" is detoxification of harmful substances such as ammonia. , Protein synthesis, glycogen degradation / synthesis,
It refers to the part that exerts the functions performed by the liver in the body, such as the synthesis of bile. The “renal function replacement part” refers to a part that performs the function performed by the kidney, such as generation and excretion of urine and reabsorption of a substance useful for the human body from urine.

The "blood circuit having an organ function" means a circuit which does not have the organ function substitute portion as described above in the circuit but can exert an organ function in the whole circuit. By providing a dialyzer in the circuit, the circuit can exert the function of the liver or the kidney, and further by mixing the hepatocytes with the blood flowing in the circuit, the function of the liver can be better exerted. .

Blood refers to a liquid that circulates in the vascular system in a living body, and includes solid components such as white blood cells, red blood cells and platelets and plasma which is a liquid component. As used herein, "blood"
Is sometimes referred to as "whole blood" that is blood separated from a living body containing all of these solid and liquid components, and some or all of the solid and liquid components may be referred to as "whole blood". It may also be referred to as “removed blood”, which is “blood from which some blood components have been removed”.

The "main blood perfusion circuit" means a circuit of blood that circulates through a patient, a reservoir and an organ function substitute part or a dialyzer in this order or a part of blood components is removed. The term “” means a flow path of blood that is once branched from the main blood perfusion circuit and then rejoins into the main blood perfusion circuit or blood from which some blood components have been removed.

The artificial organ system of the present invention is a blood circulation circuit on the patient side that is directly connected to a patient and that includes a blood component separation section, and a blood circuit section that has an organ function replacement section or an organ function and that supplies perfused blood. It is an artificial organ system including an organ function side blood circulation circuit including a reservoir for storing, and an artificial organ system in which whole blood or plasma is exchanged between both circuits. Here, the patient-side blood circulation circuit refers to a blood circulation circuit that is directly connected to the patient, and the organ function-side blood circulation circuit is blood that includes an organ replacement portion or that can perform organ functions as a whole circuit. A circulation circuit.

FIG. 1 is a diagram showing the concept of the artificial organ system of the present invention. In FIG. 1, two blood component separation parts are shown, but the one shown by the dotted line is necessary for repeated plasma separation perfusion, but not necessary for whole blood direct perfusion.

An artificial organ system for whole blood direct perfusion therapy is illustrated in FIG. As shown in FIG. 2, the whole blood flow channel part 2, the blood coagulation inhibitor injection part 3, the white blood cell separation blood component separation part 4, the red blood cell / platelet / plasma rich blood flow path part 5, the white blood cell rich blood flow path part 6, White blood cell removal unit 7, immunoglobulin removal unit 8, oxygen supply unit 9, warming unit 10, on-off valve 11, organ function replacement unit 12, organ leakage liquid collection unit 13, processed blood branch unit 14, collateral passage 15, It includes a reservoir 16, a reservoir inflow passage 17, a reservoir outflow passage 18, a separated leukocyte-rich blood confluence portion 19, a treated blood flow passage portion 20, a pump 21, and may further include a dialyzer, an oxygen cylinder, a dissolved oxygen measuring portion, and the like. .. For example, when a dialyzer is provided, it may be provided downstream of the reservoir in the blood circulation circuit on the organ function side.

In addition, the artificial organ system illustrated in FIG. 2 is connected directly to a patient and is a blood circulation circuit on the patient side including a blood component separation portion, and a blood circuit portion having an organ function replacement portion or organ function and perfusion. When regarded as an artificial organ system composed of an organ function side blood circulation circuit including a reservoir for storing blood, the artificial organ system includes a patient 1 to a whole blood confluence unit 2, a white blood cell separation blood component separation unit 4,
Leukocyte-rich blood flow path section 6, separated leukocyte-rich blood merging section 1
9. A blood circulation circuit on the patient side that returns to the patient 1 through 9 and the treated blood flow path section 20, and a reservoir 16 to a reservoir outflow path 18, an immunoglobulin removing section 8, an oxygen supply section 9, a heating section 10, an opening / closing valve 11, It is composed of an organ function side blood circulation circuit that returns to the reservoir 16 through the organ function substitute unit 12, the treated blood branch unit 14, and the collateral passage 15. The inflow of plasma from the patient-side blood circulation circuit to the organ-function-side blood circulation circuit is performed through the blood component separation unit 4, the leukocyte removal unit 7, the reservoir inflow passage 17, and the flow path reaching the reservoir 16. The inflow of whole blood or plasma from the functional blood circulation circuit to the patient blood circulation circuit is performed through the flow path reaching the separated leukocyte-rich blood confluence portion 19 from the treated blood branch portion 14, and between both circuits. Exchange of whole blood or plasma takes place. In this case, the treated blood branching unit 14 is a blood flow dividing unit that divides the blood that is returned to the patient after circulating in the organ function side circulation circuit, and the separated leukocyte-rich blood confluence unit 19 is used for returning blood. It is a blood return confluence part where the blood returned from the flow dividing part and the blood separated in the blood component separation part 4 in the patient side blood circulation circuit and returned to the patient join. The blood merged at the blood return merging portion is returned to the patient through the treated blood flow path portion 20.

An artificial organ system for repeated plasma separation perfusion therapy is illustrated in FIG. As shown in FIG. 3, the whole blood flow path part 2, the blood coagulation inhibitor injecting part 3, the plasma separating part (A) 22 as the blood component separating part, the plasma separating whole blood flow path part 24,
Plasma channel part (A) 26, immunoglobulin removal part 8, oxygen supply part 9, heating part 10, opening / closing valve 11, organ function replacement part 1
2, organ leakage solution collection unit 13, plasma separation unit (B) 23 as a blood component separation unit, collateral passage 15, reservoir 16, reservoir inflow passage 17, reservoir outflow passage 18, plasma flow passage portion (B) 27, Whole blood plasma confluence section 25, treated blood flow path section 2
0, the pump 21, and may further include a dialyzer, an oxygen cylinder, a dissolved oxygen measuring unit, a leukocyte removing unit, and the like. For example, when a dialyzer is provided, it may be provided downstream of the reservoir in the blood circulation circuit on the organ function side.

Further, the artificial organ system illustrated in FIG. 3 is used as a blood circulation circuit for a patient, which is directly connected to a patient and includes a blood component separation section, and a blood circuit section having an organ function replacement section or an organ function. When considered as an artificial organ system consisting of an organ function side blood circulation circuit including a reservoir for storing blood, the artificial organ system includes the whole blood flow path section 2 from the patient 1, the plasma separation section (A) 22, A patient-side blood circulation circuit that returns to the patient 1 through the plasma-separated whole blood flow channel section 24, the whole blood plasma merging section 25, the treated blood flow channel section 20, the reservoir 16 to the reservoir outflow channel 18, the immunoglobulin removing section 8, Oxygen supply unit 9, heating unit 10, on-off valve 11,
Organ function replacement part 12, plasma separation part (B) 23, collateral path 1
It consists of a blood circulation circuit on the organ function side that returns to the reservoir 16 through 5. The inflow of plasma from the blood circulation circuit on the patient side to the blood circulation circuit on the organ function side is performed through a flow path from the plasma separation section (A) 22 to the reservoir inflow path 17 to reach the reservoir 16, and The inflow of whole blood or plasma from the circulation circuit to the patient-side blood circulation circuit passes through the flow path from the plasma separation section (B) 23 through the plasma flow path section (B) 27 to the whole blood plasma confluence section 25. The whole blood or plasma is exchanged between the two circuits. In this case, the plasma separation unit (B) 23 also serves as a blood return diversion unit that diverts blood that is returned to the patient after circulating in the organ function side circulation circuit,
Further, in the whole blood plasma confluence section 25, the blood returned from the blood flow return section and the blood returned to the patient separated by the plasma separation section (A) 22 in the patient side blood circulation circuit join together. It is a confluence part for blood return. The blood merged at the blood return merging portion is returned to the patient through the treated blood flow path portion 20.

An artificial organ system including a blood circuit having an organ function is illustrated in FIG. The artificial organ system shown in FIG. 4 is also a repetitive plasma separation perfusion night system, but differs from the artificial organ system of FIG. 3 in the presence or absence of an organ function replacement unit. As shown in FIG. 4, the whole blood flow path part 2, the blood coagulation inhibitor injection part 3, and the plasma separation part (A) as the blood component separation part
22, plasma-separated whole blood channel part 24, plasma channel part (A) 2
6, immunoglobulin removal unit 8, oxygen supply unit 9, heating unit 1
0, on-off valve 11, plasma separating part (B) 23 as a blood component separating part, collateral passage 15, reservoir 16, reservoir inflow passage 17, reservoir outflow passage 18, plasma passage portion (B)
27, whole blood plasma confluence section 25, treated blood flow path section 20, pump 21, dialyzer 28, and may further include an oxygen cylinder, a dissolved oxygen measurement section, a leukocyte removal section and the like.

In addition, the artificial organ system illustrated in FIG. 4 is connected to a patient directly, and is connected to a patient side blood circulation circuit including a blood component separation section, and a blood circuit section having an organ function replacement section or an organ function and perfused. When considered as an artificial organ system consisting of an organ function side blood circulation circuit including a reservoir for storing blood, the artificial organ system includes the whole blood flow path section 2 from the patient 1, the plasma separation section (A) 22, A blood circulation circuit on the patient side that returns to the patient 1 through the plasma-separated whole blood flow path section 24, the whole blood plasma merging section 25, the treated blood flow path section 20, the reservoir 16 to the reservoir outflow path 18, the oxygen supply section 9, and the like. Warm part 10, dialyzer 28, plasma separation part (B) 23,
It is composed of an organ function side blood circulation circuit that returns to the reservoir 16 through the collateral passage 15. The plasma inflow from the blood circulation circuit on the patient side to the blood circulation circuit on the organ function side is performed by the plasma separation unit (A) 2
2 through the reservoir inflow path 17 to the reservoir 16 and the inflow of whole blood or plasma from the organ function side blood circulation circuit to the patient side blood circulation circuit is performed by the plasma separation unit (B) 23. From the whole blood to the plasma merging portion 25, and whole blood or plasma is exchanged between both circuits. In this case, the plasma separation part (B) 23
The whole blood plasma confluence part 25 also serves as a blood return flow dividing part for dividing the blood returned to the patient after circulating the organ function side circulation circuit, and the blood returning from the blood flow dividing part It is a blood return confluence part where the blood separated by the plasma separation part (A) 22 in the patient side blood circulation circuit and returned to the patient joins.
The blood merged at the blood return merging portion is returned to the patient through the treated blood flow path portion 20.

In the present invention, any of the above-mentioned functional parts can be omitted or a functional part other than the above can be added depending on the system, and each functional part exerts its function. As long as it is provided in any part of the circuit or flow path. (1) Whole Blood Flow Path 2 The whole blood flow path is a conduit through which blood from a patient flows in the artificial organ system. The conduit preferably has a structure connectable to an injection needle, a catheter or the like. For example, an infusion tube (made by Terumo Co., Ltd.), a master flex / silicon tube (made by Coal Palmer Co., Ltd.) or the like can be used as the whole blood flow path part.

(2) Blood coagulation inhibitor injection part 3 The blood coagulation inhibitor injection part injects a blood coagulation inhibitor such as heparin, fragmin (daltevaline sodium), fusan (nafamostat mesylate) into the blood flow path. It is a part. Administration of the blood coagulation inhibitor, heparin, fragmin is 10 to 20 units / kg / hour, fusan is dissolved in glucose solution etc. alone or in combination so that the administration rate is 20 to 50 mg / hour, Can be injected into the stream.

(3) White blood cell separation blood component separation unit 4 The blood component separation unit converts whole blood into white blood cells, red blood cells, platelets,
An apparatus that separates blood plasma or the like and separates it or separates it into separate circuits, and at the same time, as a blood pump, a device that allows a blood component to flow in a certain direction and at a constant flow rate in a blood flow path. When the system includes an organ function replacement part, the flow rate of the blood pump is preferably such that the organ function replacement part is not damaged and blood is sufficiently processed. Further, when hepatocytes circulate in a part of the flow path in the system, a flow rate at which the hepatocytes are not damaged and the blood is sufficiently treated is preferable. For example, the blood flow rate is 30-200 mL / min, preferably 50-150 mL / min.
Min, most preferably 80-120 m1 / min. As a blood component separation unit, a centrifugal blood component separation device (Fresenius
(Made by Hemocare), a membrane-type blood component separator, etc. can be used. Of the blood component separation unit, the device portion that separates white blood cells from whole blood is called the white blood cell separation blood component separation unit.
The plasma separation part (A) 22 and the plasma separation part (B) 23 described later are
It is used to separate plasma from whole blood, and the plasma separation part is also a kind of blood component separation part. Therefore, in the present invention, the term “blood component separation unit” includes both white blood cell separation blood component separation unit and plasma separation unit.

(4) Red Blood Cell / Platelet / Plasma Concentrated Blood Flow Channel Section 5 The red blood cell / platelet / plasma concentrated blood flow channel section is a red blood cell derived from whole blood separated by the blood component separation section in (3) above.
It is a conduit through which blood rich in platelets and plasma flows. As the flow path part, an infusion tube (made by Terumo), a master flex / silicon tube (made by Coal Palmer)
Etc. can be used.

(5) Leukocyte-enriched blood channel section 6 The leukocyte-enriched blood channel section is a channel through which the leukocyte-enriched blood derived from whole blood separated by the blood component separation section in (3) above flows. . Infusion tube as the flow path
(Made by Terumo), Masterflex Silicon Tube
(Manufactured by Cole Palmer) or the like can be used. Is leukocyte-rich blood returned to the blood perfusion main circuit after merging?
Alternatively, the blood is directly returned to the patient without joining the main blood perfusion circuit.

(6) Leukocyte removal unit 7 The leukocyte removal unit is a device that allows red blood cells in blood to pass and selectively capture white blood cells. The leukocyte removal unit includes a filter made of a polymer material as a removal medium, and the selective removal of leukocytes by the filter is performed by filtration, that is, a physical trap due to a difference in size between leukocytes and other solid components in blood, And selective adsorption of leukocytes to the removal medium. Examples of the filter include a fibrous medium such as a nonwoven fabric and a porous body having a uniform average pore diameter. Polymer materials that compose the filter include polyester, polyurethane, polystyrene,
Examples include, but are not limited to, polyacrylonitrile, polyamide, polyvinyl alcohol, polysulfone, cellulose, cellulose acetate and the like. These materials can be manufactured by a manufacturing method known in the art. As the white blood cell removing section, a cell sober (Ce11) using a polyester non-woven fabric as a white blood cell removing medium is used.
sorba, manufactured by Asahi Medical Co., Ltd., etc. can be used.

The average pore size of the filter is preferably 2 to 200 μm, more preferably 3 to 100 μm. Here, the “average pore size” is a diameter obtained by cutting a porous filter having continuous pores in a direction perpendicular to the blood flow direction and measuring the diameter of each of the pores dispersed in the entire cross section. When referring to the relationship between the number of pores and the number of pores, it means the diameter converted into a circle for the most numerous pores. In addition,
The "diameter converted to a circle" is set in the meaning of correcting the pores because the pores have various shapes and the diameters are also different. The circle when the number of pores in the normal distribution curve in the graph in which the diameter of the circle is the horizontal axis and the number of pores is the vertical axis when converted to a circle having the same area as the cross-sectional area is the peak The diameter of

The leukocyte removal efficiency can be improved as follows. That is, when a fibrous medium such as a non-woven fabric is used as a filter, leukocyte removal efficiency can be improved by increasing the packing density of the fibrous medium and by using a fiber laminate having a small average fiber diameter. Further, when a porous material having a uniform average pore size is used as the filter, the leukocyte removal efficiency can be improved by making the average pore size smaller.

When blood is passed through the filter, blood cells may be adsorbed on the surface of the filter and the filter may be clogged to increase the pressure loss. In such a case, it is possible to use a filter in which the average pore size of the filter decreases substantially continuously or stepwise from the blood inlet side to the blood outlet side. In particular,
The average pore size on the blood inlet side is preferably 10 to 300 μm, more preferably 20 to 200 μm, and most preferably 25 to 100 μm. The average pore size on the blood outlet side is preferably 1 to 30.
μm, more preferably 2-20 μm, most preferably 3-15 μm
m. Furthermore, in order to increase the leukocyte-removing ability of the filter material, the surface of the filter material can be coated with a surface modifier such as collagen.

(7) Immunoglobulin removing section 8 The immunoglobulin removing section means immunoglobulin in blood,
It is a device that can selectively remove immune factors such as complement and cytokine. For example, a column filled with a removal medium in which an immunoglobulin-binding ligand is immobilized on a suitable carrier can be used. Here, the “immunoglobulin-binding ligand” refers to a substance capable of specifically binding not only immunoglobulin but also various immune factors such as complement and cytokine. Specific examples of the immunoglobulin-binding ligand include tryptophan and protein
Examples include A, protein G, anti-immunoglobulin antibody, anti-cytokine antibody, and phenylalanine. The carrier is not particularly limited as long as it has excellent stability and does not elute the material substance from the carrier, and can easily and highly efficiently fix the immunoglobulin-binding ligand to the surface of the carrier, and specifically, , Polyvinyl alcohol, polyurethane, polyvinyl chloride, polystyrene, polyacetal,
Polycarbonate, modified polyphenylene oxide, polybutylene terephthalate, polyethylene terephthalate, diallyl phthalate, polyimide, polyamideimide, polymethylpentene, polyethersulfone, polyacrylate, polyetheresterketone, polytetrafluoroethylene, polyethylene, polypropylene, polyvinylacetal, bis Examples thereof include spherical or bead-shaped porous carriers made of polymer materials such as coarse, ethylene vinyl alcohol, cellulose, cellulose acetate, and polymethylmethacrylate. Immobilization of the immunoglobulin-binding ligand on the carrier can be carried out by a covalent bonding method via a functional group. In addition, a plurality of types of immunoglobulin-binding ligands may be simultaneously immobilized on the carrier. Further, when the carrier to which the above-mentioned immunoglobulin-binding ligand is bound is packed in a column, not only one kind of ligand-immobilized carrier but also a plurality of kinds of ligand-immobilized carrier can be mixed and packed. is there.

Further, as the immunoglobulin removing portion,
Imsorba TR350 (Imuusorba TR350, manufactured by Asahi Medical)
It is also possible to use a commercially available product such as. Further, a filter such as an F filter (manufactured by Asahi Medical Co., Ltd.) can be installed at the blood outlet of the immunoglobulin removing section in order to suppress the outflow of the carrier.

(8) Oxygen Supply Unit 9 The oxygen supply unit is a device capable of supplying oxygen to blood and increasing the concentration of dissolved oxygen in blood. For example, an oxygen supplier used for cell culture or the like, an oxygen supplier used in an artificial lung, and the like can be mentioned. The oxygen supply amount from the oxygen supply unit can be adjusted by controlling the oxygen supply amount from the oxygen pump to the oxygen supply unit based on the feedback data from the dissolved oxygen measurement unit that monitors the dissolved oxygen concentration in blood. Specifically, as the oxygen supply unit, a hollow fiber type oxygen supply device (manufactured by YMA Kagaku Co., Ltd.), a Capiox (manufactured by Terumo Co., Ltd.) or the like can be used.

(9) Heating unit 10 The heating unit is a part for maintaining a constant temperature at a part or all of the blood flowing in the artificial liver system and / or each functional part in the artificial liver system. .. The maintenance temperature is preferably 35.0 to 37.5 ° C, more preferably 35.5 to 37.5.
7.O ° C, most preferably 36.O-36.5 ° C. The installation site of the heating unit may be between the oxygen supply unit and the organ function replacement unit or the dialyzer as shown in FIGS. 2 and 3, but the installation site can be changed as necessary. Further, the heating unit may be integrated with the oxygen supply unit. A warmer coil (manufactured by Yako Shoji Co., Ltd.) or the like can be used as the heating unit. Further, as a unit in which the oxygen supply unit and the heating unit are integrated, a Capiox (made by Terumo Corp.) and the like can be mentioned.

(10) On-off valve 11 In the artificial organ system including the organ function substituting portion of the present invention, when whole liver or whole kidney is used as an organ, the blood flow is sufficiently spread to the peripheral tissues of the liver or kidney. Requires dilation of peripheral blood vessels in the liver, which is why
The pulsatile pump should be sufficient to create a pressure difference between systole and diastole, that is, pulse pressure. Such blood flow is called "pulsatile flow". It can be used as a pulsatile pump by combining an on-off valve and a steady flow pump. An on-off valve is installed in the flow path to generate pulse pressure. The pulse pressure is generated by opening and closing the on-off valve while circulating the blood with the steady flow pump.

In order to generate pulse pressure, a so-called artificial heart device equipped with an artificial valve, an elastic sac, and a pneumatic drive device may be used instead of the steady flow pump and the on-off valve.
The former pump has an on-off valve installed at any position of the flow path of blood circulation, preferably upstream of the liver, and while delivering liquid at a constant speed with a steady flow pump, at regular time intervals or by pressure changes. The on-off valve is opened and closed to create pulse pressure. The latter pump expands and contracts an elastic sac inside the blood pump by alternately generating positive pressure and negative pressure by using a pneumatic drive device to create a pulsatile flow. This is also used in clinical medicine as an implantable complete artificial heart, and its blood pump unit includes a diaphragm type, a sack type, and a cylindrical type. The flow rate of blood delivered by the pulsatile pump is, for the liver, 30 to 1000 mL / min, preferably 100 to 500 mL / min,
Particularly preferably, it is 150 to 300 mL / min. The pulse pressure generated by the pulsatile pump is 10 to 100 mmHg, preferably 20 to 8
It is 0 mmHg, particularly preferably 40 to 60 mmHg. Furthermore, the timing of pulsation is 0.5 to 10 seconds, preferably 1 to 5 seconds, which is the time of one contraction and one expansion.

Although the positions of the on-off valve and the heart pump device in the circuit are not limited, it is desirable to install them on the upstream side of the organ considering that the pulse pressure is directly transmitted to the organ. Also,
The position of the steady flow pump is also not limited. For example, if the position is set to that shown in FIG. 2 or 3, blood will flow smoothly through the circuit.

(11) Organ Function Substituting Unit 12 The organ function substituting unit is properly used according to its purpose.
That is, for the purpose of substituting for liver function, raw liver can be used, or a bioreactor in which hepatocytes are immobilized can be used. When the purpose is to substitute for renal function, whole kidney is used. When the whole liver or the whole kidney is used, the whole liver or the whole kidney is stored in an appropriate organ storage part and constitutes an organ function replacement part.

When the live liver is used as an organ function substitute, the live liver may be one extracted from mammals such as humans, pigs, cows, monkeys and baboons. When a human-derived live liver is used, a liver derived from a brain death patient is mainly used instead of a living body-derived liver. Incorporation of the isolated liver into the artificial liver system consists of a blood inlet on the portal side,
This can be done by connecting the inferior vena cava side as a blood outlet. At this time, the organ may be stored in an appropriate storage device for use.

When a bioreactor with hepatocytes immobilized is used as an organ function substitute, a nonwoven fabric-filled bioreactor or hollow fiber bioreactor [Shatford, RA, et al .: J. Surg. Res 53 : 549 (199
2)], Microcarrier type bioreactor [Shnyra,
A: Artif Organs 15: 189 (1991)], Hepatocyte floating bioreactor [Sakai, Y: Ce11 transp1ant. 8: 531 (1999)]
Etc. can be used.

As the hepatocytes, hepatocytes derived from mammals such as humans, pigs, cows, monkeys and baboons can be used. When human-derived hepatocytes are used, hepatocytes isolated from living liver are not used, but those established mainly as a culture strain are used. In the case of blood perfusion using a hepatocyte-immobilized bioreactor, blood directly contacts the hepatocytes to carry out substance exchange, and thus exhibits excellent performance not seen in a whole liver type artificial liver. That is, compared to whole liver type artificial liver, the hybrid type artificial liver has a more direct substance exchange by removing the sinusoidal structure of hepatocytes and directly contacting with external fluid. Separation eliminates vascular endothelial cells and Kuffer cells, which are a type of macrophage, to reduce the heterogeneous immune response, and the size can be varied by adjusting the amount of hepatocytes as necessary. It has advantages such as nathan.

On the other hand, when the whole kidney is used as an organ function substitute part, the whole kidney can be obtained by removing the mammals such as humans, pigs, cows, monkeys and baboons by the following surgical method. . When a human-derived whole kidney is used, a kidney derived from a brain death patient is mainly used instead of a living body-derived kidney. That is, one is the “bilateral renal en block enucleation method”, in which bilateral kidneys, bilateral renal arteries and adjacent abdominal aorta, and bilateral renal veins and adjacent inferior vena cava are abdominal aortic stump and inferior vena cava It is a method of en bloc extraction so that there is no leakage of blood except at the edges. The other is the "single nephrectomy method", in which one side of each bilateral kidney is removed separately by cutting off the renal artery and renal vein at the root branching from the abdominal aorta and inferior vena cava. Is the way to do it.

In the "bilateral renal en bloc excision method", one of the two abdominal aortic stumps was ligated and the other end was used as a blood inlet, in order to incorporate the excised kidney into the artificial kidney system.
Of the two inferior vena cava stumps at two locations, one end is ligated and the other end is connected as a blood outlet. In the "single nephrectomy method", the renal artery and the renal vein are respectively connected to the blood inlet and the blood inlet. Connect as a blood outlet. The ureter is cut off near the bladder and attached to the kidney, and is removed to serve as a urine outlet.

Further, in the artificial organ system including the blood circuit having the organ function shown in FIG. 4, the organ function substitute portion is not required, and the blood flowing through the organ function side blood circulation circuit is mixed with hepatocytes and is small in size. The molecular waste may be removed with a dialyzer. That is, the reservoir 16 passes from the reservoir 16 through the reservoir outflow passage 18, the oxygen supply unit 9, the heating unit 10, the dialyzer 28, the plasma separation unit (B) 23, and the collateral passage 15.
Organ function side blood circulation circuit has organ function. Further, only the blood may flow through the organ function side blood circulation circuit, and the small molecule waste products in the blood may be removed by a dialyzer. In this case, the organ function side blood circulation circuit also has the organ function.

(12) Organ Leakage Collecting Section 13 When whole liver or whole kidney is used as the organ function substitute section, it is desirable to collect the leaked solution from the organ surface and return it to the perfusion circuit. For example, a container part may be provided in the organ function substituting part for the leaked liquid, and the container part may be stored in the container part and returned to the circuit by a pump. The collected leaked liquid may be returned to any place in the circuit, and examples thereof include a reservoir immediately downstream of the organ function substitute portion and a reservoir in the main perfusion circuit.

(13) Processed blood branching part (returning flow dividing part) 14 In the processed blood branching part, a part of the blood processed by the organ function substitute part goes from the main blood perfusion circuit to the patient to the reservoir. This is the part that diverts to the collateral road. An appropriate valve or stopcock may be provided in this portion, or a pump or the like for controlling the flow rate may be provided. This part is also a blood return diversion part where the blood returned to the patient after having circulated in the organ function side circulation circuit is diverted. In the artificial organ system of FIG. 2, which includes the organ function replacement part, the part is provided downstream of the organ function replacement part and upstream of the reservoir.

(14) Side auxiliary path 15 The side auxiliary path is a circuit for sending a part of the blood branched in the treated blood branching section or a part of the blood separated in the plasma separating section to the reservoir of the main circuit. Infusion tube as the collateral path
(Made by Terumo), Masterflex Silicon Tube
(Manufactured by Cole Palmer) or the like can be used.

(15) Reservoir 16 The reservoir is a part for storing blood in order to supply sufficient blood to the organ function replacement part when the organ function replacement part is present, and is provided in the main circuit. . The reservoir is necessary because the patient blood alone cannot supply sufficient blood to the organ in the organ storage device. The capacity of the reservoir is 1.5 to 3 L, and about 1 to 2 L of blood when the organ function replacement part replaces the liver and about 0.5 to 1 L when the organ function replacement part replaces the kidney during system operation. Store blood.

In the LCAP whole blood perfusion system shown in FIG. 2, a reservoir may be provided in the circuit in which blood is perfused, and the blood that has been diverted after passing through the organ in the organ storage portion and the patient is discharged from the patient. It is desirable that the blood that has passed through the blood component separation unit and the leukocyte removal unit flows in and mixes, and then flows out of the reservoir again and flows into the organ in the organ storage unit.

In the repetitive plasma separation / perfusion system shown in FIG. 3, a reservoir may be provided in the circuit for blood perfusion, and the plasma is separated by the plasma separation unit after passing through the organ of the organ storage unit in the reservoir. It is desirable that the blood and the plasma that has flowed out of the patient and that has been separated by the plasma separation unit flow in and mix, and then flow out of the reservoir again and flow into the organ of the organ storage unit.

In the artificial organ system including the blood circuit having the organ function shown in FIG. 4, the reservoir portion contains whole blood or a mixed solution of whole blood and hepatocytes. The whole blood or a mixed solution of whole blood and hepatocytes circulates in the reservoir, the dialyzer, the plasma separation unit (B), and the collateral passage to return to the reservoir unit. The blood in the reservoir may be stirred by a stirrer or the like so that the inflowing blood is well mixed.

(16) Reservoir inflow passage 17 The reservoir inflow passage is a passage through which blood flows into the reservoir in the main blood perfusion circuit. As the inflow path, an infusion tube (manufactured by Terumo Corp.), a Masterflex silicon tube (manufactured by Cole Palmer), or the like can be used.

(17) Reservoir outflow passage 18 Blood flowing in the blood perfusion main circuit mixed in the reservoir or blood from which some blood components have been removed, and blood which has been diverted after passing through the organ function replacement portion or dialyzer. Alternatively, it is a flow path through which blood from which some blood components have been removed flows out of the reservoir.

(18) Separated leukocyte-rich blood confluence part (returning blood confluence part) 19 The confluence part is the treated blood flowing out of the organ function substitute part or the dialyzer and the leukocyte-rich blood part separated in the blood component separation part. Is a part where the and are joined, and is provided downstream of the blood component separating part in the blood circulation circuit on the patient side. If the separated leukocyte-enriched blood is directly returned to the patient without merging into the main blood perfusion circuit, this merging portion may be omitted. This part is
It is also a blood return confluence part where the blood returned from the blood flow return part and the blood separated in the patient-side blood circulation circuit and returned to the patient join together.

(19) Processed blood flow path section 20 The processed blood flow path section is a conduit for sending the processed blood combined in (18) above to the patient. The conduit preferably has a structure connectable to an injection needle, a catheter or the like. For example, as a treated blood flow path part, an infusion tube (made by Terumo), a master flex / silicon tube (made by Coal Palmer)
Etc. can be used.

(20) Pump 21 The pump smoothly circulates the blood in the main blood perfusion circuit and the collateral passage, is provided at at least one position in the circuit, and near the branching portion and the merging portion as necessary. Is further provided. For example, if it is installed at the position shown in FIG. 2, FIG. 3 or FIG. 4, blood will flow through the circuit smoothly.

(21) Plasma Separation Units 22 and 23 The plasma separation unit is a type of blood component separation unit, and is a plasma separator for separating plasma from blood. As described above, in the present specification, the term “blood component separation unit” also includes “plasma separation unit”.

The plasma separating section is a column containing hollow fibers, and the hollow fibers are semipermeable membranes that do not allow passage of molecules having a molecular weight of 150,000 to 250,000 or more, and plasma is separated from blood. In this case, not all of the plasma in the blood is separated, but for example 25% to 35% of the blood plasma is separated. The proportion of plasma to be separated can be appropriately set depending on the pore size of the hollow fiber of the plasma separation unit, the flow rate of blood flowing in the circuit, and the like.

As a plasma separating part, plasma flow, cascade flow (manufactured by Asahi Medical Co., Ltd.), and hollow fiber for artificial kidney, such as APS-E, APS-S, PAN-SF,
AM-BCX, AM-BCF, AM-BCP, AM-PC (Made by Asahi Medical)
Etc. can be used.

Examples of the polymer material constituting the hollow fiber include polyethylene, cellulose diacetate, polysulfone, polyacrylonitrile, polyester, cupraammonium rayon and the like, but are not limited thereto. These materials can be manufactured by a manufacturing method known in the art. The average pore size of the filter is preferably 0.3 μm or less. here,
The “average pore size” is in accordance with the definition described in the leukocyte removal part.

In the artificial organ system of the present invention, it is desirable that the virus of the animal organ does not flow into the patient's body, but the virus is almost spherical in most cases and its diameter is 25 to 100 nm. . In particular, the porcin retrovirus (porcin), which is most problematic when using porcine organs
e endogenous retrovirus: PERV) is about 100 nm in diameter. It is considered that none of the hollow fiber membranes used in the plasma separation part exemplified above pass these.

The plasma separation unit is used in the artificial plasma system including the repeated plasma separation perfusion method shown in FIG. 3 and the blood circuit having the organ function shown in FIG. 3 or 4
As shown in Fig. 2, it is provided in two parts in the circuit. One (plasma separation part (A)) separates blood from the patient, the separated plasma goes to the reservoir in the main circuit, and the other (plasma separation part). Part (B) separates blood from the organ function replacement part or dialyzer. Blood from the organ function replacement part or dialyzer is split into plasma and plasma-separated whole blood in the plasma separation part (B), and the plasma passes through the plasma flow path part (B) and the plasma separation part (A).
The plasma is combined with the separated whole blood at the plasma confluence part and returned to the patient. In addition, the plasma-separated whole blood separated in the plasma separation unit (B) is diverted into the collateral circuit connected to the reservoir and returns to the main circuit before returning to the patient. In the present specification, the plasma separation part (A) is referred to as a first plasma separation part,
The plasma separation part (B) is also referred to as a second plasma separation part.

In the artificial organ system including the circuit having an organ function shown in FIG. 4, since water is removed by the dialyzer, the removed water can be supplied into the circuit as needed. For example, an external fluid inflow portion may be provided in the plasma separation unit (A) in FIG. 4 and a sterilized dialysate, a maintenance infusion solution, or the like may be supplied to the external cavity of the hollow fiber.

The artificial organ system of the present invention is connected to a patient directly, and a blood circulation circuit on the patient side including a blood component separation unit,
And a blood circuit part having an organ function replacement part or an organ function, and an artificial organ system consisting of an organ function side blood circulation circuit including a reservoir for storing perfused blood, flow through the patient side blood circulation circuit Blood is separated in the plasma separation unit (A), and the separated plasma flows toward the reservoir and joins the blood circulation circuit on the organ function side. Further, the blood flowing in the organ function side blood circulation circuit is split into plasma and plasma separated whole blood in the plasma separation section (B), and the plasma joins the patient side blood circulation circuit through the plasma flow path section (B). , Plasma-separated whole blood circulates in the blood circulation circuit on the organ function side.

The plasma separating section (B) also serves as a blood flow dividing section for dividing the blood returned to the patient after circulating in the organ function side circulation circuit. The plasma separation part (B) is provided downstream of the organ function replacement part and upstream of the reservoir when the artificial organ system includes the organ function replacement part, and when the organ function side blood circulation circuit itself has the organ function, It is provided at an arbitrary position in the functional blood circulation circuit.

(22) Plasma-separated whole blood flow passage part 24 The plasma-separated whole blood flow passage part flows the whole blood separated from the plasma in the plasma separation part (A) in the repeated plasma separation perfusion method shown in FIG. It is a flow path. As the plasma-separated whole blood flow path, an infusion tube (manufactured by Terumo Corp.), a master flex / silicon tube (manufactured by Cole Palmer), or the like can be used.

(23) Whole blood plasma merging section 25 (also serving as a blood flow dividing section) The whole blood plasma merging section includes the repeated plasma separation perfusion method shown in FIG. 3 and the blood circuit having an organ function shown in FIG. In the artificial organ system, this is a part provided downstream of the plasma separation part (A) where the plasma separated in the plasma separation part (B) and the whole blood separated in the plasma separation part (A) join together. .
This part is also a blood return diversion part where the blood returned to the patient after having circulated in the organ function side circulation circuit is diverted.

(24) Plasma Flow Channel (A) 26 The plasma flow channel (A) is a flow channel for plasma separated by the plasma separation unit (A) in the repeated plasma separation and perfusion method shown in FIG. For plasma, a transfusion tube (manufactured by Terumo Corp.), a Masterflex silicon tube (manufactured by Cole Palmer), or the like can be used as the plasma flow path toward the organ function alternative portion.

(25) Plasma Flow Channel (B) 27 The plasma flow channel (B) is a flow channel for plasma separated by the plasma separation unit (B) in the repeated plasma separation and perfusion method shown in FIG. , Plasma goes to the patient. As the plasma channel, an infusion tube (made by Terumo Corp.), a master flex / silicon tube (made by Cole Palmer), or the like can be used.

(26) Dialyzer 28 A dialyzer is used for separating and removing small molecule dissolved substances (waste products) from blood circulating in a reservoir by ultrafiltration and further removing water. Hollow fiber type, coil type,
There is a laminated type, and any dialyzer can be used, but a hollow fiber type dialyzer is preferable from the viewpoint of easy availability. Hollow fiber type dialyzer is made of semi-permeable membrane with very thin tube-shaped fibers (hollow fiber) with an inner diameter of about 200 microns bundled in a plastic cylinder in the order of several thousand to tens of thousands. Flow through the hollow fiber, and dialysate flows outside the hollow fiber to separate small molecule substances. As a dialyzer, APS-E, AM-BCF, AM
-PC (manufactured by Asahi Medical Co., Ltd.) or the like can be used.
The dialysis machine is connected to a dialysis machine having a pump to carry out liquid delivery and the like. Since the water content in the blood is also separated in the dialyzer, the volume of blood passing through the dialyzer is reduced. Therefore, it is necessary to return the dialysate into the blood circuit by the amount of the reduced water. The returning position may be any position as long as it can supply the water reduced by the dialyzer to the circuit circulating through the reservoir, the dialyzer, and the collateral passage. For example, as shown in FIG. 4, if the plasma separating unit (A) supplies the water. good. As the dialysate, a known dialysate or a known maintenance infusion may be used, and examples thereof include Kinderley, Subrad A and B (Fuso Yakuhin), AK Solita (Shimizu-Takeda Yakuhin) and the like.

(27) Hepatocytes In one embodiment of the present invention, hepatocytes are mixed with blood circulating in the blood circulation circuit on the organ function side and used as an artificial organ system. Hepatocytes suspended in blood exert liver function in the state of hepatocytes, and decompose waste products and the like in blood. Decomposed waste is separated in the dialyzer and removed from the artificial organ system. In this respect, when hepatocytes are mixed with blood, it can be said that the entire circuit in which the mixed blood circulates substitutes the liver function. As the hepatocytes, those derived from mammals such as humans, pigs, cows and dogs may be used. Since the composition of hepatocytes in blood does not mix into the blood circuit that flows through the patient due to the action of the plasma separation part (B), hepatocytes of different origin such as pig, cow, dog, etc. may also be used. it can. Hepatocytes can be obtained by treating the liver with an enzyme such as collagenase and isolating the cells. In addition, hepatocytes having the function of hepatocytes differentiated and proliferated from established hepatocytes, hematopoietic stem cells, or embryonic stem cells (ES cells) may be used. Hepatocyte concentration to be mixed is 1 × 10 ⁶ to 1 × 10 ⁸ cells / m 2.
L, preferably 5 × 10 ^{6 to} 5 × 10 ⁷ cells / mL.

When a dialyzer is present in the organ function side blood circulation circuit (artificial organ system including the blood circuit having the organ function of FIG. 4), hepatocytes can be mixed with blood. Even if they have it, mixing of hepatocytes is not essential, and although it is not possible to detoxify and decompose toxic substances, it is possible to remove a considerable part of waste products with a dialyzer, so it is useful as an artificial organ system without hepatocytes. Is.

(28) Channel connecting the blood circulation circuit on the patient side and the blood circulation circuit on the organ function side The artificial organ system of the present invention is directly connected to the patient, and the blood circulation circuit on the patient side including the blood component separation part, and When considered as an artificial organ system consisting of an organ function side blood circulation circuit including a reservoir for storing perfused blood, which is a blood circuit part having an organ function replacement part or organ function,
A part is required for exchanging whole blood or plasma between both circuits. In the artificial organ system shown in FIG. 2, the portion from the white blood cell separation blood component separation unit 4 to the white blood cell removal unit 7 and the reservoir inflow path 17 to reach the reservoir 16 flows from the patient side blood circulation circuit to the organ function side blood circulation circuit. Is a flow path through which the blood flows from the treated blood branching section 14 to the separated leukocyte-rich blood confluence section 19 from the organ function side blood circulation circuit to the patient side blood circulation circuit. Further, in the artificial organ system of FIG. 3, the flow of blood from the plasma separation part (A) 22 through the reservoir inflow path 17 to the reservoir 16 flows from the patient side blood circulation circuit to the organ function side blood circulation circuit. The road,
The part from the plasma separation part (B) 23 through the plasma channel part (B) 27 to the whole blood plasma confluence part 25 is a channel through which blood flows from the organ function side blood circulation circuit to the patient side blood circulation circuit. . Further, in the artificial organ system including the blood circuit having the organ function shown in FIG. 4, the portion from the plasma separation unit (A) 22 through the reservoir inflow path 17 to the reservoir 16 extends from the patient side blood circulation circuit to the organ function side blood. It is a flow path through which blood flows to the circulation circuit, and a part from the plasma separation section (B) 23 to the whole blood plasma confluence section 25 is a flow path through which blood flows from the organ function side blood circulation circuit to the patient side blood circulation circuit. is there.

(29) Other functional parts When an organ function replacement part is included, a fine particle removal part or the like can be further installed downstream of the organ function replacement part, if necessary. By disposing the fine particle removing unit, it is possible to remove the lost cells, hepatocyte debris, fine particles and the like derived from the organ function replacement unit. Specifically, a filter of hollow fiber type, flat membrane type or the like can be used as the fine particle removing section.

The dissolved oxygen measuring unit is a device for monitoring the dissolved oxygen amount of blood flowing in the flow path. The dissolved oxygen value obtained by the dissolved oxygen measuring section is sent to an oxygen cylinder,
The oxygen supply amount from the oxygen cylinder to the oxygen supply unit is appropriately controlled. As a dissolved oxygen measuring unit, a dissolved oxygen meter OX
300S (Toko Kagaku), dissolved oxygen controller HDO-200
(Manufactured by Toko Chemical Co., Ltd.) can be used.

2. Blood purification treatment using the artificial organ perfusion system by the artificial organ system of the present invention, artificial organ perfusion treatment by the artificial organ system of the present invention,
This will be described with reference to FIGS. 2, 3 and 4. In the present description, the flow rate of blood flowing through each part or blood from which a part of blood components has been removed is shown, but this is an example, and may be appropriately changed depending on the condition of the patient or the condition of the organ function replacement part. The content of the blood component in each split stream is also an example, and this may change.

1) Treatment Using Whole Blood Direct Perfusion System (FIG. 2) First, the artificial organ system of the present invention is connected to a patient 1 with liver failure or renal failure. Here, examples of the connection site include the cephalic vein and groin femoral vein of the patient. Blood from the patient has a flow rate of 50-150 mL / min, more preferably 70-1
It passes through the whole blood flow path at 20 mL / min, receives the blood coagulation inhibitor from the blood coagulation inhibitor injection part, enters the leukocyte separation blood component separation part LCAP, and red blood cell / platelet / plasma rich blood and leukocyte rich blood. Can be divided into Then, the red blood cell / platelet / plasma rich blood flow path portion and the white blood cell rich blood flow path portion are respectively branched, and the red blood cell / platelet / plasma concentrated blood is sent to the white blood cell removing portion. At this time, red blood cells, platelets, and plasma rich blood are 50 to 90% of the whole blood. The flow rate is 50-150 mL /
min, and more preferably 70 to 120 mL / min. On the other hand, leukocyte-enriched blood is 10 to 50% of whole blood in leukocytes and platelets.
%, And the flow rate can be 10-150 mL / min. In the functional portion, white blood cells remaining in red blood cells, platelets, and plasma-enriched blood are adsorbed and removed. The blood discharged from the leukocyte removal unit merges with human blood that contains the optimum amount of red blood cells and plasma and does not contain leukocytes, which is sent through the collateral route in the reservoir, and then passes through the reservoir outflow route to the immunoglobulin removal unit. Sent to. After merging, the flow rate of blood flowing out of the reservoir is 150 to 450 mL / min, and more preferably 20
0 to 320 mL / min. The total flow velocity of the blood flowing into the reservoir after passing through the blood component separation part and the blood flowing into the reservoir after being split into the posterior collateral passage after passing through the organ function substitution part is
It must be equal to the flow rate of blood flow out of the reservoir. The immunoglobulin removing unit removes immune factors such as immunoglobulin and complement in red blood cells, platelets, and plasma-enriched blood. The blood flowing out from the immunoglobulin removing section is sent to the oxygen supply section, and oxygen is supplied so as to have a desired dissolved oxygen concentration. The blood that has left the oxygen supply unit is sent to the heating unit and heated to a desired temperature. The blood that has exited the heating section is sent to an organ function replacement section [liver function replacement section (liver) or kidney function replacement section (kidney)]. In the liver function alternative part, detoxification of harmful substances in blood, protein synthesis, glycogen decomposition / synthesis, bile synthesis and the like are performed. In the liver, bile is synthesized and excreted from the common bile duct. Urine is produced and excreted in the renal function replacement part. Red blood cell / platelet / plasma-rich blood that has left the liver function replacement part or the kidney function replacement part, after passing through the dissolved oxygen measurement part, is the amount of blood flowing out of the reservoir minus the amount of blood flowing out of the patient and flowing into the reservoir. Divide the same amount of blood into the reservoir. The flow rate of blood diverted to the reservoir is 10
It is 0 to 300 mL / min, more preferably 130 to 200 mL / min. Further, it joins with the white blood cell-rich blood and is returned to the patient's body again through the processing blood flow path. The blood flow rate after diverting and before merging with leukocyte-rich blood is 50 to 150 mL / min, and more preferably 70 to 120 mL / min. The blood flow rate after confluence should be equal to the blood flow rate derived from the patient, specifically 50-150 mL / min, more preferably 70-120 mL / min. The measured value of dissolved oxygen obtained in the dissolved oxygen measuring section is sent to an oxygen cylinder to determine the amount of oxygen introduced from the oxygen cylinder to the oxygen supply section.

The artificial organ system of the present invention is connected to a patient directly, and a blood circulation circuit on the patient side including a blood component separation unit,
And an organ function side blood circulation section having an organ function and an organ function side blood circulation circuit including a reservoir for storing perfused blood, the artificial organ system shown in FIG. In, the blood from the patient is separated into erythrocyte / platelet / plasma-enriched blood and leukocyte-enriched blood in the leukocyte-separating blood component separation section in the patient-side blood circulation circuit, and erythrocyte / platelet / plasma-enriched blood is circulated on the organ function side. The reservoir in the circuit joins the blood circulation circuit on the organ function side, and the white blood cell-rich blood is returned to the patient through the blood circulation circuit on the patient side. The blood flowing through the organ function side blood circulation circuit is processed through the organ function substitution part to remove waste products, and a part is separated at the processed blood branch part (returning flow dividing part), resulting in the separation of white blood cells with concentrated white blood cells. The blood is merged into the blood circulation circuit on the patient side at the section (returning blood merging section), and the blood is returned to the patient.

2) Treatment Method Using Repeated Plasma Separation and Perfusion System (FIG. 3) First, the artificial liver system of the present invention is connected to a patient with liver failure or renal failure. Here, examples of the connection site include the cephalic vein and groin femoral vein of the patient. Blood from the patient has a flow rate of 50-150 mL / min, more preferably 70
The blood coagulation inhibitor is added from the blood coagulation inhibitor injection part through the whole blood flow path part at about 120 mL / min, and flows into the plasma separation part (A). The plasma separation part here is a column for blood purification therapy containing a large number of hollow fibers, and the pore diameter of the semipermeable membrane used for the hollow fibers is a membrane that does not allow passage of molecules having a molecular weight of 150,000 to 250,000 or more. . Blood that flows in from the patient passes through the hollow fiber lumen, and plasma leaches from the semipermeable membrane into the outer space and is transported to the artificial organ system. At this time, the plasma separation part (A) from the patient
20-35% of the blood flowing into the blood is separated as plasma. Therefore, the plasma flow rate is 15-50 mL / m
in, more preferably 30 to 40 mL / min. When the blood flow rate from the patient to the plasma separation unit (A) is 100 mL / min and the plasma separation rate is 30%, the plasma flow rate is 30 mL / min, and the remaining 70% blood flow rate after plasma separation Is 70 mL / min.

As shown in FIG. 3, the artificial organ system comprises a reservoir, a constant flow pump, a white blood cell removing section, an immunoglobulin removing section, an oxygen supplier, a warmer, a pulsating pump mechanism, an organ storing device and the like. In the treatment of patients with human liver or renal failure, the artificial organ system is preliminarily filled with human whole blood excluding white blood cells or a mixed blood of human concentrated red blood cells and fresh frozen plasma as a priming solution (initial filling solution). be satisfied. In such a case, the leukocyte removal unit is not necessary, and the leukocyte removal unit is necessary only when the priming solution is one in which leukocytes have not been removed, such as fresh blood (whole blood). Liver-deficient plasma or renal-deficiency plasma separated in the plasma separation part (A) is combined with human whole blood that is diverted through the artificial organ function replacement part in the reservoir in the main circuit, and then the organ function is passed through the reservoir outflow channel. Head to the replacement section. At this time, the flow rate of blood flowing out of the reservoir is 150 to 350 mL / min,
More preferably, it is 200 to 320 mL / min. Plasma separation unit
Plasma that flows into the reservoir through (A) and the plasma separation unit
The flow velocity of blood passing through (B) and flowing into the reservoir through the collateral path must be equal to the flow velocity of blood flowing out of the reservoir. Then, this blood mixture of liver-deficient plasma or renal-deficient plasma and human whole blood or a blood from which some blood components have been removed is carried to an immunoglobulin removal section, where immune factors such as immunoglobulin and complement in blood are contained. Are removed. The blood flowing out from the immunoglobulin removing section is sent to the oxygen supply section, and oxygen is supplied so as to have a desired dissolved oxygen concentration. The blood that has left the oxygen supply unit is sent to the heating unit and heated to a desired temperature. The blood that has exited the heating section is sent to the organ function replacement section. In the organ function substitute part, metabolism of liver failure substances in blood, detoxification of harmful substances, protein synthesis, glycogen decomposition / synthesis, bile synthesis and the like are performed, and bilirubin is excreted as bile from the common bile duct. The blood that has left the organ function replacement part passes through the dissolved oxygen measuring part,
It flows into the plasma separation part (B).

The measured value of dissolved oxygen obtained in the dissolved oxygen measuring section is sent to an oxygen cylinder, and the amount of oxygen introduced from the oxygen cylinder to the oxygen supply section is determined. In the plasma separation part (B), plasma is separated from the patient blood depleted in liver failure substances such as ammonia and bilirubin, and the remaining whole blood returns to the reservoir. The plasma separated by the plasma separation unit (B) is combined with the plasma-separated whole blood carried from the plasma separation unit (A) at the blood confluence unit, and returned to the patient.
After plasma is separated in the plasma separation unit (B), the flow rate of blood flowing into the reservoir is from the flow rate of blood flowing out of the reservoir and perfusing the main circuit to the reservoir from the plasma separation unit (A). It should be equal to the flow rate minus the plasma flow rate, specifically 100-300 mL / min, more preferably 130-200 mL / min. The flow rate of plasma separated in the plasma separation section (B) should be equal to the flow rate of plasma separated in the plasma separation section (A), specifically, a flow rate of 15-50
mL / min, more preferably 30-40 mL / min. The flow rate of plasma is about 30 mL / min, 70 mL / min from the plasma separation part (A)
It merges with blood at a flow rate of min and returns to the patient's body at a flow rate of 100 mL / min.

In this perfusion treatment method, albumin and the like pass through the semipermeable membrane, but the amount thereof is much smaller than that in the whole blood direct perfusion treatment method. Further, since a heterologous virus carried from a non-human animal, for example, a liver of a pig, cannot pass through the semipermeable membrane of the plasma separation part, the virus can be prevented from flowing into the patient's body. Therefore,
As the artificial liver perfusion method, the repeated plasma separation perfusion method is
It is considered that this method has fewer side effects on patients than the whole blood direct perfusion treatment method.

The artificial organ system of the present invention is connected to a patient directly, and a blood circulation circuit on the patient side including a blood component separation unit,
And an organ function substitute portion or a blood circuit portion having an organ function and an organ function side blood circulation circuit including a reservoir for storing perfused blood, the artificial organ system shown in FIG. In, the blood from the patient is separated in the plasma separation part (A) in the blood circulation circuit on the patient side, the separated plasma joins the blood circulation circuit on the organ function side in the reservoir, and the blood from which plasma has been separated and removed is the patient Blood is returned to the patient through the side circulation circuit. Blood flowing through the blood circulation circuit on the organ function side is processed through the organ function substitute section to remove waste products and the plasma separation section (B).
The separated plasma is merged into the blood circulation circuit on the patient side at the whole blood plasma merging portion (returning blood merging portion) and returned to the patient.

3) Perfusion Method Using Artificial Organ System Including Blood Circuit Having Organ Function (FIG. 4) First, the artificial liver system of the present invention is connected to a patient with liver failure or renal failure. Here, examples of the connection site include the cephalic vein and groin femoral vein of the patient. Blood from the patient has a flow rate of 50-150 mL / min, more preferably 70
The blood coagulation inhibitor is added from the blood coagulation inhibitor injection part through the whole blood flow path part at about 120 mL / min, and flows into the plasma separation part (A). The plasma separation part here is a column for blood purification therapy containing a large number of hollow fibers, and the pore diameter of the semipermeable membrane used for the hollow fibers is a membrane that does not allow passage of molecules having a molecular weight of 150,000 to 250,000 or more. . Blood that flows in from the patient passes through the hollow fiber lumen, and plasma leaches from the semipermeable membrane into the outer space and is transported to the artificial organ system. At this time, the plasma separation part (A) from the patient
20-35% of the blood flowing into the blood is separated as plasma. Therefore, the plasma flow rate is 15-50 mL / m
in, more preferably 30 to 40 mL / min. When the blood flow rate from the patient to the plasma separation unit (A) is 100 mL / min and the plasma separation rate is 30%, the plasma flow rate is 30 mL / min, and the remaining 70% blood flow rate after plasma separation Is 70 mL / min.

As shown in FIG. 4, the artificial organ system comprises a reservoir, a constant flow pump, a white blood cell removing section, an immunoglobulin removing section, an oxygen supplier, a warmer, a dialyzer and the like. In the treatment of patients with human liver or renal failure, the artificial organ system is preliminarily filled with human whole blood excluding white blood cells or a mixed blood of human concentrated red blood cells and fresh frozen plasma as a priming solution (initial filling solution). be satisfied. In such cases, the white blood cell depletion part is not necessary, and the priming solution does not require fresh blood (whole blood).
The white blood cell removing unit is necessary only when the white blood cells have not been removed, as in the above. Although the leukocyte removal unit is not shown in FIG. 3, it may be installed upstream of the immunoglobulin removal unit, for example. In addition, reservoir, dialyzer,
If necessary, hepatocytes are mixed in the blood circulating in the collateral passage. The hepatic failure plasma or renal failure plasma separated in the plasma separation section (A) goes through the immunoglobulin removal section and further through the reservoir in the main circuit to the dialyzer. In the immunoglobulin removing portion, immune factors such as immunoglobulin and complement in blood are removed. At this time, the flow rate of blood flowing out from the reservoir is 150 to 350 mL / min, and more preferably 200 to 320 mL / min. The flow rate of the blood flowing into the reservoir through the plasma separation unit (A) and the blood flow passing through the plasma separation unit (B) and the collateral passage into the reservoir is equal to the flow speed of the blood flow flowing out of the reservoir. Must be equal. The blood flowing out from the reservoir is sent to the oxygen supply unit, and oxygen is supplied so as to have a desired dissolved oxygen concentration. The blood that has left the oxygen supply unit is sent to the heating unit and heated to a desired temperature. The blood that has left the heating section is sent to the dialyzer. In the dialyzer, the dialysate circulates across the blood circulation flow path through a semipermeable membrane, and removes small molecular weight toxic substances in blood. At this time, when hepatocytes are mixed in the blood circulating through the reservoir, dialyzer and collateral passage, the liver cells act to metabolize liver failure substances in the blood, detoxify harmful substances, etc. Synthesis, decomposition / synthesis of glycogen, synthesis of bile, etc. are performed, and unnecessary toxic substances having a small molecular weight produced at this time are removed by the dialyzer. The blood that has left the dialyzer flows into the plasma separation unit (B). If necessary, a dissolved oxygen measuring unit may be installed in the flow path that circulates through the reservoir, the dialyzer, and the collateral passage. The measured value of dissolved oxygen obtained in the dissolved oxygen measuring section is sent to an oxygen cylinder, and the amount of oxygen introduced from the oxygen cylinder to the oxygen supply section is determined. In the plasma separation part (B), plasma is separated from the patient blood depleted in liver failure substances such as ammonia and bilirubin, and the remaining whole blood returns to the reservoir. The plasma separated by the plasma separation unit (B) is combined with the plasma-separated whole blood carried from the plasma separation unit (A) at the blood confluence unit, and returned to the patient. After plasma is separated in the plasma separation unit (B), the flow rate of blood flowing into the reservoir is such that the flow rate of blood flowing out of the reservoir and perfusing the main circuit flows from the plasma separation unit (A) into the reservoir. Should be equal to the plasma flow rate minus the flow rate, specifically 100
~ 300 mL / min, more preferably 130-200 mL / min. The flow rate of plasma separated in the plasma separation section (B) should be equal to the flow rate of plasma separated in the plasma separation section (A), specifically, a flow rate of 15 to 50 mL / min, more preferably, 30-40 mL / min. The flow rate of plasma is about 30 mL / min, merges with blood at a flow rate of 70 mL / min from the plasma separation part (A), and returns to the patient body at a flow rate of 100 mL / min. Further, in the artificial organ system shown in FIG. 4, water in the blood in the flow path circulating through the reservoir, the dialyzer and the collateral passage is removed by the dialyzer. This removed water must be returned to the flow path circulating through the reservoir, dialyzer and collateral path,
For example, in the plasma separation unit (A), the maintenance infusion or the like may be supplied at the same flow rate as the removal flow rate of the removed water. The flow rate at this time is, for example, 50 mL / m
In, the liquid flowing out from the dialyzer is 100 mL / min., and the liquid flowing in from the outside in the plasma separation part (A) is 50 mL / min.

The artificial organ system of the present invention comprises a blood circulation circuit on the patient side, which is directly connected to the patient and includes a blood component separation unit,
And an organ function substitute portion or a blood circuit portion having an organ function and an organ function side blood circulation circuit including a reservoir for storing perfused blood, the artificial organ system shown in FIG. In, the blood from the patient is separated in the plasma separation part (A) in the blood circulation circuit on the patient side, the separated plasma joins the blood circulation circuit on the organ function side in the reservoir, and the blood from which plasma has been separated and removed is the patient Blood is returned to the patient through the side circulation circuit. Blood flowing through the organ function side blood circulation circuit is treated with hepatocytes mixed with blood and a dialyzer to remove waste products, and is separated in the plasma separation part (B). The separated plasma is the whole blood plasma confluence part. The blood is joined to the patient's blood circulation circuit at the (returning blood merging section) and returned to the patient.

3. Performance Evaluation of Artificial Organ System of the Present Invention (1) Performance Evaluation of Artificial Liver System The performance evaluation of the artificial liver system was carried out by using animals for liver failure model as follows to examine whether GOT / GPT activity increased or not. To evaluate by intracranial pressure of the body, blood ammonia concentration, bile production, color of liver tissue after perfusion, presence or absence of blood coagulation, flexibility of liver tissue, survival time of liver failure model animal and presence of side effects etc. You can

Preparation of Liver Failure Model As a liver failure model animal, a dog (eg, shepherd dog) or the like can be used. For example, a canine liver failure model can be prepared as follows. First, after general anesthesia, the skull is punctured and an intracranial pressure measurement catheter is inserted and left in the ventricle, and a perfusion catheter is inserted and left in the external jugular vein. An anastomosis of the portal vein-inferior aorta is performed. On the liver side of the anastomosis, the portal vein is ligated and cut off, and a tape is wrapped around the hepatic artery and the common bile duct so that it can be remotely tightened. 5 in that state
Observe the passage of time and wait until the blood ammonia concentration rises. The perfusion treatment is started 5 hours later, but immediately before that, the arteries in the hilum of the liver and the common bile duct are ligated with the above tape for 2 hours to put the dog's liver in a completely ischemic state and opened 2 hours later. This surgery and manual manipulation can put the dog in a liver failure state.

Presence / absence of perfusion obstruction Whether or not the artificial liver system used can be perfused without causing hyperacute rejection by examining whether or not perfusion can continue without obstruction. Can be evaluated. In the case of the conventional whole liver type artificial liver, the blood flowing into the liver causes a hyperacute rejection reaction against vascular endothelial cells,
As a result, obstruction of passage of the perfusion circuit may occur. Also,
Even in the case of a hybrid artificial liver, the inflowing blood can cause hyperacute rejection of hepatocytes.

It can be assessed that the artificial liver system used is able to perform a good perfusion without hyperacute rejection if the perfusion is continued without obstruction, and the perfusion is within 1 hour after the start of the perfusion. In particular, if it becomes impossible to perfuse, the artificial liver system used can be evaluated as unsuitable for blood perfusion.

Presence / absence of GOT / GPT activity increase Enzymes such as GOT (glutamate oxaloacetate transaminase) and GPT (glutamate pyruvate transaminase) flow out from hepatocytes into blood when hepatocytes are destroyed. Therefore, GO in blood from the liver
By examining the T and GPT values, it is possible to examine whether hepatocyte necrosis or destruction has occurred in the liver. That is, GOT in blood from the liver and / or
If an increase in GPT value with time is observed, it can be evaluated that liver cell death has occurred in the liver, and that liver function of the liver during storage or in the artificial liver system decreases over time. If it is not observed, death of hepatocytes does not occur, and it can be evaluated that liver function in the preserved liver or artificial liver system is maintained.

Subject's Intracranial Pressure and Blood Ammonia Concentration The subject's intracranial pressure and blood ammonia concentration are elevated during liver failure. Therefore, if these values do not increase, it can be evaluated that the artificial liver system used is exhibiting good liver function of the subject.

Bile production, color of liver tissue after liver perfusion, presence / absence of blood coagulation, flexibility of liver tissue In the liver of the whole liver type artificial liver system, bile production from the common bile duct was examined to determine the function of the liver. You can evaluate whether you are doing. Without bile production, the liver is considered non-functional.

Further, the system can be disassembled after the end of perfusion, and the presence or absence of blood coagulation, the color of the liver, and the softness of the liver can be examined to make more detailed evaluation. For example, if blood coagulation was not observed, and the liver was reddish brown and kept soft at the time of extraction, the liver preservation device or whole liver type artificial liver system used did not cause blood coagulation and could not be preserved or perfused. It can be evaluated as well done. Conversely, part or all of the liver surface turns black purple,
If the patient was in a firm and tense state, it is estimated that perfusion was not performed well due to blood coagulation due to a heterogeneous immune reaction or the like inside the whole liver type artificial liver system used.

The artificial liver system of the present invention can be maintained over a period of good perfusion use without obstruction of passage. In addition, no increase in GOT / GPT activity was observed, and the liver function of hepatocytes was maintained during the period of use as it was at the beginning. In addition, intracranial pressure is reduced and elevated blood ammonia is suppressed in subjects with liver failure. In particular, in the artificial liver system of the present invention, the hyperacute rejection reaction of vascular endothelial cells to blood, which has conventionally occurred in the whole liver type artificial liver, does not occur, so that it is possible to suppress the obstruction of passage of the perfusion circuit. It is possible to extend the perfusable time as compared with the conventional artificial liver system. Furthermore, the blood component separation device separates the leukocyte concentrate in the first portion of the circuit and directly returns the blood to the patient's body, whereby it is possible to prevent a marked decrease in the white blood cells from the patient's body. In addition, by removing leukocytes from the blood perfused through the liver function replacement part as much as possible, the immunoadsorption removal device can be saved. Due to these advantages, the artificial liver system of the present invention can be used in clinical settings.
You can expect better clinical results than before. The artificial liver system of the present invention provides good perfusion efficiency. The term "perfusion efficiency" refers to the value of the ratio of the blood volume processed by the liver function replacement part to the blood volume that flows into the artificial liver system, expressed as a percentage. That is, the perfusion efficiency represents the rate at which blood from a patient with liver failure is sent to the liver function replacement site. Therefore, the higher this value, the more likely the blood from a patient is to undergo sufficient liver function treatment. It means that you can do it.

(2) Performance Evaluation of Artificial Kidney System The performance of the artificial kidney system was evaluated using the animal for renal failure model, as follows, urinary excretion from the kidney, creatinine clearance of the kidney, and of the subject. It can be evaluated by blood creatinine and urea nitrogen concentrations, color of renal tissue after perfusion, presence / absence of blood coagulation, flexibility of renal tissue, and presence / absence of side effects in renal failure model animals.

Preparation of Renal Failure Model As a renal failure model animal, a dog (eg, shepherd dog) or the like can be used. For example, a canine renal failure model can be prepared as follows. First, after general anesthesia, insert a perfusion catheter into the external jugular vein,
Detain. Wrap the tape around the left and right renal arteries and the renal veins so that they can be tightened remotely. Immediately before the start of perfusion therapy, the left and right renal arteries and renal veins are ligated for 2 hours with the above tape to leave the dog's kidney in a state of complete ischemia and released 2 hours later. This surgery and manipulative procedure can put the dog in a renal failure condition.

Urinary Excretion from the Kidney By examining the urinary excretion from the kidney, it can be assessed whether the kidney is functioning. Without urine output, the kidney is considered non-functional.

The blood creatinine and urea nitrogen levels in subjects have normal blood creatinine and urea nitrogen levels of 1.2 or less and 5-10, respectively, but in renal failure patients these values are elevated. There is. Therefore,
If the increase is observed, it can be evaluated that the renal function decreases over time, and if the increase is not observed, it can be evaluated that the renal function is maintained.

Presence or absence of blood coagulation after perfusion, color and flexibility of renal tissue, and presence or absence of side effects in a model animal of renal failure. Further, the system was decomposed after the completion of perfusion, presence or absence of blood coagulation, color of kidney and renal By examining the softness, more detailed evaluation can be performed. For example, blood coagulation is not found inside the kidney, the kidney keeps a bright red color,
Moreover, if the softness at the time of extraction was maintained, it can be evaluated that the artificial kidney system used did not cause blood coagulation and that perfusion was performed well. On the contrary, if the color of part or the whole of the kidney surface is dark brown and it is in a hard and tense state, inside the artificial kidney system used,
It is estimated that perfusion was not performed well due to blood coagulation due to heterogeneous immune reaction.

The artificial kidney system of the present invention can be maintained over a period of good perfusion use without obstruction of passage. In particular, in the artificial kidney system of the present invention, since hyperacute rejection of vascular endothelial cells does not occur, the resulting obstruction of passage of the perfusion circuit can be suppressed, and the perfusion treatment can be continued for a long time. Furthermore, the blood component separation device separates the leukocyte concentrate in the first portion of the circuit and directly returns the blood to the patient's body, whereby it is possible to prevent a marked decrease in the white blood cells from the patient's body. In addition, by removing leukocytes from the blood that perfuses the kidneys as much as possible, it is possible to save the immunoadsorption removal device. Due to such advantages, the artificial kidney system of the present invention can be expected to have better clinical results in clinical practice than ever before.

[0128]

EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited to these. [Example 1] Whole blood direct perfusion treatment for a liver-free dog liver failure model using a whole liver type artificial liver system using pig liver Using a whole liver type artificial liver system, a liver-free dog liver failure model (Subject) was subjected to whole blood direct perfusion therapy. First, a dog (type: Shepherd dog) having a body weight of 25 to 30 kg was subjected to induction anesthesia by injecting ketamine and phenobarbital, and placed under general ventilator control by endotracheal intubation for general anesthesia. A catheter for perfusion was inserted and left in the external jugular vein. After anastomosis of the portal vein-inferior aorta, the portal vein, hepatic artery, and common bile duct were ligated and cut off at the hepatic hilum, and then the liver parenchyma was cut off at the leading edge of the inferior vena cava, and a total hepatectomy was performed, and no liver was removed. A canine liver failure model was created.

On the other hand, a liver storing device using whole pig liver was manufactured as follows and used as a liver function substitute part.
Firstly, a catheter was inserted into the portal vein of a pig (type: Sangen hybrid) having a body weight of 25 to 30 kg, and thereby about 3000 mL of heparin-added physiological saline was perfused into the liver to remove blood. The artery was ligated and cut off, the common bile duct was cut off, a bile duct tube was inserted, and the inferior vena cava was cut off above and below the liver attachment site, and the entire liver including the inferior vena cava was removed. A blood perfusion tube was inserted into the inferior vena cava, and the portal vein was used as the blood inflow side and the inferior vena cava was used as the blood outflow side.

Furthermore, another dog was subjected to laparotomy under general anesthesia, and a blood sampling catheter was inserted into the inferior vena cava.
1.0 to 1.5 L of whole blood was collected and stored in a 2 L reservoir bottle.

Further, the whole liver type artificial liver system was constructed as follows. As shown in Fig. 2, the blood component separation device (LCAP), the leukocyte adsorption / removal device, the immunoglobulin removal device, the oxygen supply and warmer Capiox (made by Terumo Corp.), and the excised whole pig liver were passed through the portal vein side. The inlet and the inferior vena cava side were used as outlets, which were sequentially connected to form a main circuit. Furthermore, by incorporating the blood storage reservoir as a collateral passage, the whole liver type artificial liver system of the present invention was constructed. However, since the blood in the collateral path contains white blood cells, the junction to the main circuit is
Before the leukocyte adsorption / removal device. The blood component separator (LCAP) is a continuous centrifuge Fresenius.
AS.TEC204 (Fresenius), as leukocyte adsorption / removal device, Cellsorba using polyester nonwoven fabric as leukocyte removal medium (Cellsorba, manufactured by Asahi Medical Co., Ltd.), as immunoglobulin removal device, polyvinyl alcohol gel with tryptophan bound as a ligand A packed column, Imsorbor TR350 (Immusorba TR350, manufactured by Asahi Medical) was used (perfusion treatment group: 1 subject).

[0132] Four hours after the operation for producing a dog without liver, a perfusion catheter of a canine liver failure model was connected to the system,
Perfusion therapy was started. The flow rate of blood derived from a dog is
50 mL / min, the blood flow rate in the blood reservoir and collateral flow path is 150 mL / min, the flow rate of the blood that joins them into the pig liver is 200 mL / min, and the perfusion time is 3 hours. there were. After completion, the dogs were followed up on mechanical ventilation.

In the perfusion treatment group, the perfusion treatment was continued without any obstacles. By blood component separation device (LCAP)
Of the total blood volume flowing from the subject into the system, 15-20% of the flow rate and about 50-70% of the white blood cell volume are separated as white blood cell concentrate, while 80-85% of the white blood cell flow rate and the white blood cell volume are separated. Approximately 30 to 50% was perfused as a red blood cell, platelet, and plasma concentrate to the liver function replacement site. As a result, the white blood cell count in the systemic blood of dogs was not reduced at all. In addition, one leukocyte removal device and one immunoglobulin removal device were required for each of the three hours of perfusion treatment, and when they were disassembled after the end of the experiment, no blood coagulation was attached to these adsorption columns. No increase in enzyme activity such as GOT / GPT was observed, indicating that hepatocyte necrosis or destruction did not occur.

On the other hand, as a control group, a liver failure dog liver failure model group (the number of subjects was 5) was prepared. In the control group, the circulating ammonia level in dogs continued to rise. In the perfusion treatment group, the elevation of ammonia level was suppressed. The ammonia level in the blood of the perfusion circuit was 246.0 immediately before flowing into the whole liver, whereas it was 126.0 immediately after flowing out of the whole liver, showing a marked decrease, indicating that the whole liver had sufficient ammonia. It was clear that it was removed. From the common bile duct, bile excretion of 10 to 20 mL per hour was constantly observed.
The effect of these treatments is that white blood cells, platelets, white blood cells, immunoglobulins, complement, etc. remaining in the plasma concentrated liquid are adsorbed and removed by the leukocyte removal device and immunoglobulin removal device, and rejection reaction does not occur inside pig liver. Therefore, it was considered that the pig liver was able to exhibit good liver function. When the system was disassembled after the completion of perfusion, blood coagulation did not occur at all inside the liver, and the pig liver was reddish brown and kept normal softness.

The survival time of the liver-free dog liver failure model was 19 to 25 hours after the end of surgery in the control group, but was prolonged to 36 hours in the perfusion treatment group. This indicates that the artificial liver system replaced the liver function for the extended time.

From the above results, by using the artificial liver system of the present invention in which the leukocyte removing device and the immunoglobulin removing device are installed in front of the whole liver, the heterologous immune reaction and the liver in the liver function substitute part in the artificial liver system are used. Can assist and replace liver function in hepatic failure subjects without inducing shock in deficient subjects, and by placing a blood component separation device in the first part of the circuit, reduce white blood cells in the patient It was found that perfusion therapy can be performed without saving the leukocyte depletion device and immunoglobulin depletion device, and as a result, has a significant life prolonging effect in liver failure subjects.

Example 2 Repeated Plasma Separation and Perfusion Treatment for Liver Failure Model of Liver Failure in Liver Failure Dogs with Whole Liver Type Artificial Liver System Using Pig Liver Using the whole liver type artificial liver system, Repeated plasma separation perfusion therapy was performed on a liver failure model (subject). First, a dog (type: Shepard dog) having a body weight of 25 to 30 kg was subjected to induction anesthesia by injecting ketamine and phenobarbital, and placed under general mechanical anesthesia under ventilation control by endotracheal intubation. A catheter for perfusion was inserted and left in the external jugular vein. Portal vein-inferior aorta anastomosis, ligating and disconnecting portal vein, hepatic artery, and common bile duct at the hilum of the liver, then dissecting the liver parenchyma at the anterior margin of the inferior vena cava, and performing a total hepatectomy to remove the liver A canine liver failure model was created.

In the same manner as in Example 1, the whole pig liver of a pig (type: Sangen hybrid) having a body weight of 25 to 30 kg was removed, and a blood inflow tube was inserted into the portal vein and a blood outflow tube was inserted into the inferior vena cava. did. A bile outflow tube was inserted into the common bile duct.

Furthermore, an artificial liver system was constructed as follows. The artificial liver system was, as shown in FIG. 3, a plasma separation unit (A), a leukocyte adsorption / removal device, an immunoglobulin removal device, an oxygen supply and warmer Capiox (made by Terumo Corp.), a pulsating on-off valve, a reservoir, and excision. The whole liver of the pig was used as the main circuit by sequentially connecting the plasma separation unit (B) with the portal vein side as the inlet and the inferior vena cava side as the outlet. A whole liver type artificial liver system of the present invention was constructed by storing 1.5 L of whole blood collected from another dog in a reservoir and incorporating this as a collateral route. However, since the blood in the collateral path contains leukocytes, the leukocyte adsorption / removal device was incorporated in the main circuit as described above, and the confluence part to the main circuit was in front of the leukocyte adsorption / removal device. The leukocyte adsorption / removal device is a cellsorber (Cellsorb
a, manufactured by Asahi Medical Co., Ltd.) As an immunoglobulin removing apparatus, Imsorber TR350 (I of polyvinyl alcohol gel packed column bound with tryptophan as a ligand)
mmusorba TR350, manufactured by Asahi Medical Co., Ltd.) was used. The circuit of the subject's liver failure model was connected to the fiber lumen line of the plasma separation part (A), and the artificial liver system line was connected to the fiber separation space line of the plasma separation part (A) (perfusion treatment group. : Number of subjects 1).

Four hours after the operation for making a dog without liver, perfusion treatment of a canine liver failure model by the system was started. The blood flow rate, which was derived from the liver failure model of liver in canine, and which flows through the fiber lumen of the plasma separation part, was 50 mL / min.
The flow rate of the plasma separated in (A) is 17 mL / min, the flow rate of blood in the blood reservoir and the collateral passage is 150 mL / min, and the flow rate of the blood that joins them and flows into pig liver is 167 mL / m
The plasma flow rate, which was in, and was separated again in the plasma separation unit (B) was set to 17 mL / min. The perfusion time was 3 hours. After completion, the dogs were followed up on mechanical ventilation.

In the perfusion treatment group, the perfusion treatment was continued without any obstacles. When dismantled after the end of the experiment, blood coagulation did not adhere to these adsorption columns at all. No increase in enzyme activity such as GOT / GPT was observed, indicating that hepatocyte necrosis or destruction did not occur.

In the perfusion treatment group, the elevation of ammonia level was suppressed. Ammonia level in the perfusion circuit blood was 504.3 in the part immediately before flowing into the whole liver, whereas it was markedly decreased to 179.5 in the part immediately after flowing out from the whole liver, showing that ammonia was sufficiently supplied in the whole liver. It was clear that it was removed. As a result, the ammonia value in the circuit of the subject liver failure model was 557.9 in the part immediately before flowing into the plasma separation part (A), whereas in the part immediately after the plasma merged from the plasma separation part (B). It showed a marked decrease of 234.2. From the common bile duct, bile excretion of 10 to 20 mL per hour was constantly observed. When the system was disassembled after the completion of perfusion, blood coagulation did not occur at all inside the liver, and the pig liver was reddish brown and kept normal softness.

This was compared with a control group (number of subjects: 5) of a liver failure model of liver failure in dogs. The survival time in the liver-free dog liver failure model was 19 to 25 hours after surgery in the control group, but was extended to 32 hours in the perfusion treatment group. This indicates that the artificial liver system replaced the liver function for the extended time.

From the above results, by using the artificial liver system of the present invention, it is possible to assist or replace the liver function in a liver failure subject, and as a result, a significant life-prolonging effect is obtained in the liver failure subject. I found it to bring.

Example 3 Repeated Plasma Separation and Perfusion Treatment without Live Liver Tissue By the method of using repeated plasma separation and perfusion itself as a blood purification therapy system without using live liver tissue, ammonia was added as follows. For purification of added pig whole blood
An in vitro experiment was conducted.

First, a pig weighing about 20 kg was anesthetized by injecting ketamine and phenobarbital, and placed under general ventilator control by endotracheal intubation for general anesthesia. An intravascular indwelling catheter was inserted into the portal vein, and heparin-added physiological saline was injected. An intravascular indwelling catheter was inserted into the distal side of the portal vein and the inflow portion of the renal vein of the inferior vena cava, and 2 L of blood was removed through the catheter.

Further, a blood purification therapy system was constructed as follows. As shown in the figure, the blood purification therapy system consists of a plasma separation unit (A), a reservoir (referred to as a system reservoir), an oxygen supply and warmer Capiox (Terumo), a dialyzer (dialyzer), and a plasma separation unit. (B) were sequentially connected. 2 L of whole blood collected from another pig was stored in a reservoir, which was assumed to be blood in the patient's body (called a subject reservoir), and ammonia was added to this.
It was added at a concentration of 1 mmol / L. The circuit of the subject reservoir was connected to the fiber lumen line of the plasma separation part (A) and the artificial liver system line was connected to the fiber separation space line of the plasma separation part (A).

[0148] The flow rate of blood drawn from the subject's reservoir and flowing through the fiber lumen of the plasma separation part was 100 mL / mi.
n, The flow rate of plasma separated in the plasma separation unit (A) is 30 mL / mi
n, The flow rate of blood flowing from the system reservoir to the dialyzer (dialyzer) was set to 180 mL / min.
In the dialyzer, the dialysate flowing through the fiber outer lumen is
Using a Kinderley solution (Fuso Yakuhin) used in general dialysis treatment, perfusion was performed at 200 mL / min, and water was removed by ultrafiltration at 100 mL / h. The plasma flow rate separated again in the plasma separation unit (B) was set to 30 mL / min. Plasma separation part (B)
The flow rate of blood from the system to the system reservoir is 14
It was 8.3 mL / min. About 10 minutes after starting the perfusion of the subject side circuit consisting of the subject reservoir and the plasma separation part (A), the time point when the ammonia concentration in the subject side circuit becomes uniform is 0 minutes, and the plasma separation is started, Then, a perfusion experiment was performed for 2 hours.

The ammonia levels in the plasma separated in the plasma separation section (A) are 0,1339.2, 60 minutes 930.4, 120 minutes, 659.5, while the ammonia levels in the plasma separated in the plasma separation section (B) are Ammonia level showed remarkable decrease at 0 minutes 584.3, 60 minutes 503.8, and 120 minutes 410.7. The ammonia value of blood in the system reservoir is 0 minutes 647.0, 60 minutes 561.1, 120 minutes 421.5, while the blood ammonia value after passing through the dialyzer is 0 minutes 596.9, 60 minutes 546.8. , 120 minutes 387.5, and it was found that some amount of ammonia was removed in the dialyzer. However, the main cause of the decrease in ammonia was thought to be the dilution of the system reservoir with whole blood. As a result, the ammonia level in the subject reservoir was 0 minutes 1478.
4, 60 minutes 723.9, 120 minutes 455.5, showing a marked decrease.

From the above results, it is possible to assist or substitute a part of the liver function in a liver failure subject by the method of using the repeated plasma separation perfusion itself as a blood purification therapy system without using the live liver tissue. all right.

Example 4 Allogeneic Repeated Plasma Separation and Perfusion Treatment by Porcine Hepatocyte Perfusion Type Artificial Organ System Using the porcine hepatocyte perfusion type artificial organ system, an ischemic porcine liver failure model (subject) was prepared as follows. He underwent homologous repeated plasma separation perfusion therapy. This is a simulated experiment assuming that repeated plasma separation and perfusion therapy will be performed on a patient with liver failure by the human hepatocyte perfusion artificial organ system.

First, a pig weighing about 25 kg was anesthetized by injecting ketamine and phenobarbital, and placed under general ventilator control by endotracheal intubation for general anesthesia. A catheter for perfusion was inserted and left in the external jugular vein. An anastomotic porcine liver failure model was prepared by performing an anastomosis of the portal vein-inferior aorta and ligating and disconnecting the portal vein, the hepatic artery, and the common bile duct at the hilum of the liver.

An intravascular indwelling catheter was inserted into the portal vein of a pig (type: Sangen hybrid) weighing 20 kg, and heparin-added physiological saline was infused. An intravascular indwelling catheter was inserted into the distal side of the portal vein and the inflow portion of the renal vein of the inferior vena cava, and 2 L of blood was removed through the catheter. This whole blood was stored in the system reservoir. Then, the whole liver was removed, and the portal vein was used as the inlet and the inferior vena cava was used as the outlet, and EDTA and EGTA-added Ha were added.
The nk's solution and the collagenase solution were perfused over the whole pig liver for 30 minutes to separate hepatocytes. The porcine hepatocytes thus obtained were washed and purified using a maintenance infusion solution or the like, and the concentrated porcine hepatocyte lysate finally obtained was mixed with the autologous blood previously stored in the system reservoir.

Further, an artificial organ system was constructed as follows. In the artificial organ system, as shown in Fig. 4, the plasma separation unit (A), the system reservoir, the oxygen supply and warmer Capiox (Terumo), the dialyzer (dialyzer), and the plasma separation unit (B) are sequentially connected. did. The circuit of the subject liver failure model was connected to the fiber lumen line of the plasma separation part (A), and the artificial system line was connected to the fiber separation space line of the plasma separation part (A).

Immediately after the completion of the operation for making pigs with hepatic failure, perfusion treatment of a porcine liver failure model by the system was started. The flow rate of blood derived from a liver failure pig (subject) and flowing through the fiber lumen of the plasma separation unit was 50 mL / min, and the flow rate of plasma separated in the plasma separation unit (A) was 15 mL / min. The flow rate of blood flowing from the system reservoir to the dialyzer was set to 100 mL / min. In the dialyzer, the dialysate flowing through the outer cavity of the fiber was perfused at 100 mL / min with a Kinderley solution (Fuso Yakuhin) used in general dialysis treatment. Further, in the dialyzer, the amount of water increased by mixing the porcine hepatocyte liquid was removed by ultrafiltration. The plasma flow rate separated again in the plasma separation unit (B) was set to 15 mL / min. The flow rate of blood flowing from the plasma separation unit (B) into the system reservoir was 85 mL / min. The perfusion time was 3 hours.

The mixture of porcine hepatocytes and whole blood was smoothly perfused by continuous infusion of 1000 units of heparin as an anticoagulant into the circuit per hour, and the perfusion treatment was continued without any obstacle. When dismantled after the end of the experiment, blood coagulation and hepatocytes did not adhere to the plasma separation part, dialyzer, etc. at all. No significant increase in enzyme activity such as GOT / GPT was observed, indicating that hepatocyte necrosis or destruction did not occur.

For metabolism of ammonia, see the plasma separation section.
The value in plasma separated in (A) is the value 1 hour after the start of perfusion149.
7, 2 hours value is 189.6, 3 hours value is 158.0, whereas the ammonia value in plasma separated in the plasma separation part (B) is 1 hour value 96.5, 2 hours value 121.4, 3 hours value after the start of perfusion. It showed a decrease of 113.1. As a result, the ammonia level in the subject's reservoir was 153.0 immediately after the start of perfusion, the 1-hour value was 73.2, and the 2-hour value was 88.
The value was 94.8 for a few hours, showing a decrease immediately after the start of perfusion, and the increase was suppressed.

Regarding the metabolism of urea nitrogen (BUN), the values in the plasma separated in the plasma separation part (A) were 1 hour 17.6, 2 hours 16.3, and 3 hours 15.1 after the start of perfusion. On the other hand, the ammonia level in the plasma separated in the plasma separation section (B) showed a decrease of 1 hour after the start of perfusion 10.9, 2 hours after 14.4, and 3 hours after 14.8. Urea nitrogen levels in the subject's reservoir were 19.7 immediately after the start of perfusion, 1 hr 17.8, 2 hr 15.6, and 3 hr 14.3.
, Showed a persistent decrease.

From the above results, it is possible to assist or replace the liver function in a liver failure subject by using the same kind of artificial organ system of the present invention, and as a result, significantly prolong the life of the liver failure subject. It turned out to be effective.

Example 5 Heterogeneous Repeated Plasma Separation and Perfusion Treatment by Porcine Hepatocyte Perfusion-Type Artificial Liver System Using the pig hepatocyte-perfusion-type artificial liver system, the liver failure model of hepatitis-free dog (subject) was performed as follows. Heterogeneous repeated plasma separation perfusion therapy was performed on the. This is a simulation experiment on the assumption that heterologous repeated plasma separation perfusion therapy is performed on a liver failure patient by the porcine hepatocyte perfusion artificial liver system.

First, a dog (type: Shepard dog) having a body weight of about 25 kg was induced anesthesia by injecting ketamine and phenobarbital, and placed under the artificial ventilation control by endotracheal intubation for general anesthesia. A catheter for perfusion was inserted and left in the external jugular vein. After anastomosis of the portal vein-inferior aorta, the portal vein, hepatic artery, and common bile duct were ligated and cut off at the hilum of the liver, and the liver parenchyma was cut off at the anterior margin of the inferior vena cava, and total hepatectomy was performed. A canine liver failure model was created.

On the other hand, 2 L of whole blood was exsanguinated from another dog under general anesthesia, and this was adsorbed on a leukocyte adsorption / removal device (Cellsorb).
a, manufactured by Asahi Medical Co., Ltd.), and an immunoglobulin removing device (Immusorba TR350, manufactured by Asahi Medical Co., Ltd.) to sequentially pass white blood cells, immunoglobulins, and
After removing complement, blood was collected in the system reservoir.

In the same manner as in Example 4, an intravascular indwelling catheter was inserted into the portal vein of a pig (kind: Sangen hybrid) weighing about 20 kg, and heparin-added physiological saline was injected. Whole liver was removed, hepatocytes were separated in the same manner as in Example 4, washed and purified using a maintenance infusion solution, etc., and then porcine hepatocyte fluid was stored in the system reservoir to obtain leukocytes previously stored in the system reservoir, Mixed with immunoglobulin, complement-free whole dog blood.

Furthermore, an artificial organ system was constructed as follows. As shown in FIG. 4, the artificial organ system includes a plasma separation unit (A), an immunoglobulin removing device, a system reservoir, an oxygen supply and warmer Capiox (made by Terumo Corp.), a dialyzer (dialyzer), and a plasma separation unit ( B) were connected in sequence. In addition, as an immunoglobulin removing device, an immunosorber TR350 (Immusorba TR3) of a polyvinyl alcohol gel packed column to which tryptophan was bound as a ligand was used.
50, manufactured by Asahi Medical Co., Ltd.) was used. The circuit of the subject's liver failure model is connected to the fiber lumen line of the plasma separation part (A), and the artificial organ system line is connected to the plasma separation part (A).
Connected to the fiber extraluminal line.

[0165] Four hours after the operation for producing a dog without liver, perfusion treatment of a canine liver failure model by the system was started. The blood flow rate, which was derived from the liver failure model of liver in canine, and which flows through the fiber lumen of the plasma separation part, was 50 mL / min.
The flow rate of plasma separated in (A) is 15 mL / min,
The flow rate of blood flowing from the reservoir to the dialyzer (dialyzer) was set to 100 mL / min. In the dialyzer, the dialysate flowing through the outer cavity of the fiber was perfused at 100 mL / min with a Kinderley solution (Fuso Yakuhin) used in general dialysis treatment. Further, in the dialyzer, the amount of water increased by mixing the porcine hepatocyte liquid was removed by ultrafiltration. The plasma flow rate separated again in the plasma separation unit (B) was set to 15 mL / min. The flow rate of blood flowing from the plasma separation unit (B) into the system reservoir was 85 mL / min. The perfusion time was 3 hours.

The mixed solution of porcine hepatocytes and whole dog blood was smoothly perfused by continuous infusion of 1000 units of heparin as an anticoagulant into the circuit per hour, and the perfusion treatment was continued without any obstacle. When dismantled after the end of the experiment, blood coagulation and hepatocytes did not adhere to the plasma separation part, dialyzer, etc. at all. No significant increase in enzyme activity such as GOT / GPT was observed, indicating that hepatocyte necrosis or destruction did not occur.

For metabolism of ammonia, see the plasma separation section.
The value in plasma separated in (A) is 513.
5, 2 hours value 480.3, 3 hours value 347.6, while the ammonia level in the plasma separated in the plasma separation section (B) is 1 hour value 232.3, 2 hours value 71.6, 3 hours value after the start of perfusion It was a significant decrease of 66.4. As a result, the ammonia level in the subject's reservoir was 436.7 immediately after the start of perfusion, the 1-hour value was 400.0, and the 2-hour value was 414.
The rise was suppressed with a value of 462.9 for 0 and 3 hours.

From the above results, it is possible to assist or substitute the liver function in a liver failure subject by using the heterogeneous artificial organ system of the present invention, and as a result, the life extension of the liver failure subject is significantly prolonged. It turned out to be effective.

[0169]

EFFECTS OF THE INVENTION As shown in Example 1, whole blood can be directly perfused to a different organ by the artificial organ system for whole blood direct perfusion treatment of the present invention, and the whole blood required for perfusing the different organ can be obtained. The flow velocity and flow rate can be secured, and a sufficient amount of blood can be perfused into a different organ.

Furthermore, as shown in Example 2, plasma was separated from the whole blood of a patient by the artificial organ system for repeated plasma separation and perfusion treatment of the present invention, and the plasma was separated from the whole blood of a patient and stored in an organ storage device perfused with human whole blood. After flowing into the circuit and the combined blood passes through the organ storage device, plasma can be separated again and returned to the patient, and the flow rate and flow rate of whole blood required to perfuse different organs can be determined. It can be ensured, and the inflow of heterologous virus into the patient's body can be prevented.

Furthermore, the artificial organ system including the blood circuit having the organ function shown in Examples 3 to 5 can exert the following effects. 1. Since hepatocytes are suspended in whole blood, hepatocytes can obtain sufficient oxygen supply. 2. When heterologous hepatocytes are used, it is possible to prevent the virus from flowing into the patient's body. 3. There is no loss of time for immobilization as in non-woven fabric immobilized bioreactors. 4. Compared to the case of perfusing the whole liver as it is, surgery is easier and requires less time, and even if it takes time to separate and purify hepatocytes, it takes about an additional hour to set up compared to the case of whole liver. is there. 5. The operation management of the system is not complicated and difficult like the whole liver. The perfusate has a defined flow rate in a closed circuit and does not leak partially. Also, there is no risk of losing heat retention that tends to go unnoticed in the whole liver. 6. It can be performed with a console (integrated perfusion device), a reservoir that incorporates an oxygen supply fiber and a heat-retaining band, and does not require the large-scale console that is required in the case of an immobilized bioreactor or a whole liver device, and saves space. Absent. 7. Since the separated hepatocytes can be carried in a reservoir, it can be performed even in a community hospital. 8. At first glance, it's the same as hemodialysis, so not only patients,
It is considered that there is little psychological resistance to paramedical such as nurses and medical technologists.

[Brief description of drawings]

FIG. 1 is a conceptual diagram of an artificial organ system of the present invention.

FIG. 2 is a diagram showing a whole blood direct perfusion system of the present invention.

FIG. 3 is a diagram showing the repeated plasma separation and perfusion system of the present invention.

FIG. 4 is a view showing an artificial organ system including a blood circuit having an organ function of the present invention.

[Code]

1, patient 2, whole blood flow path 3, blood coagulation inhibitor injection part 4, white blood cell separation blood component separation unit 5. Red blood cell / platelet / plasma rich blood flow path 6. Leukocyte-rich blood channel 7, white blood cell removal section 8. Immunoglobulin removal section 9, oxygen supply unit 10, heating section 11, on-off valve 12, organ function replacement unit 13. Organ leakage collection unit 14, processing blood branch 15, collateral road 16, reservoir 17, reservoir inflow path 18, reservoir outflow path 19, separation leukocyte-rich blood junction 20, processing blood flow path 21, pump 22, plasma separation unit (A) 23, Plasma Separation Section (B) 24, plasma separation whole blood flow path 25, whole blood plasma junction 26, plasma channel (A) 27, plasma channel (B) 28, dialyzer

Claims (16)

[Claims] 1. An artificial organ system including two blood circulation circuits of a patient side blood circulation circuit and an organ function side blood circulation circuit, wherein the patient side blood circulation circuit is directly connected to the patient,
In the blood flow path, the blood component separation part, the return blood merging part,
The organ function-side blood circulation circuit includes a reservoir for storing perfused blood, a dialyzer, and a blood return diversion unit in this order in the blood flow path. In the artificial organ system, the blood component separated by the blood component separation unit in the patient-side blood circulation circuit flows into the reservoir in the organ-function-side blood circulation circuit, while in the organ-function-side blood circulation circuit The blood component diverted in the blood return diversion part is joined to the patient blood circulation circuit in the patient blood circulation circuit in the patient blood circulation circuit, and blood purification treatment is performed by returning blood to the patient. Organ system. 2. The artificial organ system according to claim 1, wherein water removal and dissolved substances are removed by ultrafiltration in a dialyzer in the blood circulation circuit on the organ function side. 3. The artificial organ according to claim 1, wherein the blood component separation unit divides whole blood into blood containing white blood cells in a concentrated manner and blood having white blood cells removed therefrom. system. 4. The artificial organ system according to claim 3, comprising an organ function substitute portion at a position downstream of the dialyzer and upstream of the blood return diversion portion in the organ function side blood circulation circuit. 5. The artificial organ system according to claim 4, wherein the organ function replacement part is a whole animal liver, whole animal kidney, or a bioreactor containing animal hepatocytes inside. 6. The leukocyte-removing portion and / or the immunoglobulin-removing portion is included in a position in the organ function side blood circulation circuit downstream of the reservoir or dialyzer and upstream of the organ function replacement portion. The described artificial organ system. 7. The whole blood of a patient is separated by a blood component separation device in the blood circulation circuit of the patient into blood from which white blood cells have been removed and blood containing a large amount of white blood cells. After returning blood and removing white blood cells, the blood is allowed to flow into a reservoir in the blood circulation circuit of the organ function side where human whole blood is stored, and at least a dialyzer and / or organ in the blood circulation circuit of the organ function side 7. The blood purification treatment is performed by passing through the function substituting unit, and then further diverting a part thereof in the blood return diversion unit and further joining the blood into the patient side blood circulation circuit to return blood to the patient. The artificial organ system according to any one of 1. 8. The blood component separation unit in the patient-side blood circulation circuit is a plasma separator, and the blood return diversion unit in the organ function-side blood circulation circuit is a plasma separator. Artificial organ system. 9. The artificial organ system according to claim 8, wherein a liquid such as a sterilized maintenance infusion solution flows into the hollow fiber outer space of the first plasma separation unit and is mixed with the plasma separated in the plasma separation unit. . 10. The artificial organ system according to claim 8, wherein the semipermeable membrane of the second plasma separation part has a pore size that does not allow passage of viruses. 11. The organ function substituting portion is included at a position downstream of the dialyzer and upstream of the blood return diversion portion in the organ function side blood circulation circuit, according to any one of claims 8 to 10. Artificial organ system. 12. The artificial organ system according to claim 11, wherein the organ function substitute portion is a whole animal liver, whole animal kidney, or a bioreactor containing therein animal hepatocytes. 13. The mixed solution of human whole blood and animal hepatocytes circulates in the blood circulation circuit on the organ function side so that the circuit itself has an organ function. Artificial organ system. 14. The artificial organ system according to claim 13, wherein the hepatocytes are of human, porcine, or bovine origin. 15. The artificial organ system according to claim 12, which comprises an immunoglobulin removing unit. 16. Plasma is separated from whole blood of a patient by a first plasma separator in the blood circulation circuit on the patient side, and the plasma is separated from human whole blood in the blood circulation circuit on the organ function side, or
After flowing into a reservoir in which a mixed solution of human whole blood and hepatocytes is stored, it is passed through at least a dialyzer and / or an organ function substitute portion in a blood circulation circuit on the organ function side, and then, a second plasma 16. The blood purifying treatment is performed by separating plasma in a separator, merging the plasma with a blood circulation circuit on the patient side at a blood return confluence section, and returning the blood to the patient to perform blood purification treatment. Artificial organ system.