WO2001070302A1 - Nouveau systeme d'organe artificiel - Google Patents

Nouveau systeme d'organe artificiel Download PDF

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Publication number
WO2001070302A1
WO2001070302A1 PCT/JP2001/002233 JP0102233W WO0170302A1 WO 2001070302 A1 WO2001070302 A1 WO 2001070302A1 JP 0102233 W JP0102233 W JP 0102233W WO 0170302 A1 WO0170302 A1 WO 0170302A1
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blood
liver
artificial organ
organ system
artificial
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PCT/JP2001/002233
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English (en)
Japanese (ja)
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Katsutoshi Naruse
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Katsutoshi Naruse
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Priority to AU2001242738A priority Critical patent/AU2001242738A1/en
Publication of WO2001070302A1 publication Critical patent/WO2001070302A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3623—Means for actively controlling temperature of blood

Definitions

  • the present invention relates to an artificial organ system comprising a leukocyte removal unit and a immunoglobulin removal unit, and a liver function replacement unit or a kidney function replacement unit.
  • liver and kidney are central organs of metabolism in the living body and play an important role in maintaining the homeostasis of the living body. For this reason, once this homeostasis is broken, and over a long period of time, it causes liver failure and renal failure, respectively, leading to a serious life crisis.
  • liver transplantation has a high mortality rate of 80 to 90%, and effective treatment is desired.
  • Treatments for such severe liver failure include liver transplantation, plasma exchange, and treatment with artificial liver.
  • Liver transplantation has already been established as a treatment for hepatic failure, including fulminant hepatitis.
  • more than 1,000 cases have been performed so far, and the five-year survival rate has reached nearly 80%.
  • the first brain-dead liver transplant was performed in Japan, and cases have been steadily repeated since then.
  • the shortage of donors is so severe that it cannot meet the growing demand for transplant waiting patients.
  • Plasmapheresis which separates plasma from the patient's blood and replaces it with fresh frozen plasma, can be expected to have a sufficient effect.However, the huge amount of fresh frozen plasma is used, so the medical cost is high. Is a problem. Under such circumstances, progress in treatment using artificial liver is expected.
  • the artificial liver which is the target of development, is not a completely implantable type such as an artificial blood vessel, but rather until the emergence of donors for liver function assistance and liver transplantation in patients with fulminant hepatitis or postoperative liver failure Of liver function during waiting period It is an extracorporeal type used for perfusion treatment as an alternative bridge. Specifically, it is classified into three types: adsorption removal type, whole liver type and hybrid type.
  • the adsorptive removal type artificial liver replaces part of the liver function by removing harmful substances from the blood using an adsorbent. Ammonia adsorption and removal equipment using a cation exchange resin developed by Schechter et al.
  • the whole liver-type artificial liver is a type that uses a whole liver derived from a heterologous organism other than human (xenogeneic whole liver).
  • a pioneer in perfusion therapy using xenogeneic whole liver was conducted by Kimoto and Hori et al. In 1958 at the University of Tokyo School of Medicine Second Surgery, the predecessor of the University of Tokyo School of Medicine, where the present inventors belong.
  • a crossover perfusion therapy performed [Kimoto S., et al .: Trans Am Soc Art if Intern Organs 5: 102 (1959)] 0
  • cross-perfusion is performed in a chamber filled with dialysate, and the dialysate is further perfused into an adsorption removal device.
  • This method detoxifies toxic substances using a dog liver and an adsorption removal device, and was clinically applied to four patients with hepatic failure and improved encephalopathy.
  • Direct whole blood perfusion therapy using xenogeneic whole livers removed by surgery has been started by Eisemann et al. In 1965 using isolated livers [Eisemann B., et al: Ann Surg 162: 329. (1965)], Abouna, Neuhaus, Schoen, et al.
  • Ozawa et al. Of Kyoto University developed a cross-port therapy using Buyu liver and baboon liver and applied it clinically to 16 patients with liver failure.
  • perfusion can only last for a few hours, and the survival time is significantly increased. I was not able to admit.
  • hepatocyte isolation and culturing method using collagenase solution has been established, and it has been shown that hepatocytes exhibit good liver function when cultured under optimal conditions in engineering equipment.
  • Hybrid artificial livers incorporating bioreactors have been developed, and have been clinically applied one after another in the 1990s.
  • Rozga et al. Described a hollow fiber bioreactor using dextran and microcarriers [Rozga J., et al. Ann Surg 217: 502 (1993)], and Gerlach et al. Described a three-dimensional capillary network. Work-type oliactors have been developed [Gerlach J., et al.
  • FIG. 1 shows a hybrid artificial liver system that incorporates a holo-fiber bioreactor developed by Rozga et al. That is currently being clinically applied.
  • blood from a patient is first sent to a plasma separator 2 by a pump 1.
  • the plasma separated by the plasma separator 2 is temporarily stored in a plasma transmission reservoir 3, heated in a water bath 4, and sent to an activated carbon column 5.
  • the activated carbon column 5 removes medium molecular weight substances such as pyrilvin present in plasma.
  • the plasma exiting the activated carbon column 5 is sent to a hollow fiber bioreactor 6 in which hepatocytes are immobilized.
  • liver function treatments such as ammonia decomposition and urea synthesis are performed.
  • the plasma exiting the hollow fiber bioreactor 6 is stored again in the plasma transmission reservoir 3 and returned to the patient's body.
  • the major problem with this system is that only about 20-30% of the whole blood flow is perfused into the bioreactor, the perfusion efficiency is low, and the plasma is less than 1/10 of whole blood. Insufficient oxygen supply to hepatocytes because they have only oxygen-dissolving ability. As a result, the activity of hepatocytes in the hepatic function replacement site decreases, and hepatic function is insufficiently exhibited.
  • renal failure treatments include artificial kidneys and kidney transplants.
  • Chronic glomerulonephritis is the most common source of renal failure, but diabetic nephropathy has been increasing in recent years.
  • Hemodialysis has grown dramatically as the center of artificial kidney therapy since ⁇ ⁇ ⁇ and others used it to successfully rescue patients with acute renal failure in 1945.
  • As of the end of 1995 about 700,000 people worldwide had received artificial kidney treatment.
  • the number of patients treated with artificial kidney reached 176,000 as of the end of 1997, and the number of patients treated with artificial kidney per population is the largest in the world.
  • kidney transplantation can restore both the secretion of toxic substances in the glomerulus and the reabsorption of renal tubules, and once engrafted, does not require constant treatment as in hemodialysis.
  • Immunosuppressants have to be taken for a long time thereafter, and are currently the most ideal treatment for renal failure.
  • the total number of cases per year peaked at 838 cases in 1989 (573 living kidneys and 265 kidney donations) and has been steadily decreasing since then.
  • 658 cases (509 living kidneys and 149 kidney donations) ).
  • kidney transplantation suffers from a shortage of donors. Under the above circumstances, it is desired to develop an extracorporeal perfusion therapy for artificial kidneys that can better substitute for renal function. Disclosure of the invention
  • the present invention has an improved perfusion efficiency and oxygen supply ability to an organ replacement part, and is capable of replacing or assisting a subject's hepatic function and Z or renal function for a longer period of time as compared with a conventional artificial organ system.
  • the purpose is to provide an organ system.
  • the present inventors have conducted intensive studies based on the above-mentioned problems, and as a result, in an extracorporeal perfusion artificial liver system or artificial kidney system, in addition to the organ replacement part (liver function replacement part or kidney function replacement part), leukocyte removal was performed. And / or an immunoglobulin removal section, and a blood component separation section, to allow whole blood to pass through the organ replacement section without causing a heterogeneous immune reaction, thereby increasing the perfusion time, In addition to improving perfusion efficiency and oxygen supply to the organ replacement unit, we succeeded in preventing the reduction of immunocompetent cells such as leukocytes and saving the equipment necessary for the leukocyte removal unit and / or immunoglobulin removal unit. Of the present invention We have completed an artificial organ system for whole blood direct perfusion therapy.
  • the present invention is an artificial organ system comprising a leukocyte removal part and / or an immunoglobulin removal part, and a liver function replacement part or a kidney function replacement part.
  • the artificial organ system can further include a blood component separation unit.
  • the blood component separation section may be characterized by dividing whole blood into blood containing rich white blood cells and other blood components. For example, as the blood component separation section, centrifugal blood And a component separation device.
  • the leukocyte removal unit may be characterized by capturing leukocytes and passing erythrocytes.
  • the leukocyte removing section include a filter containing a filter (for example, a nonwoven fabric) made of a polymer material (for example, polyester, polyurethane, polystyrene, polyacrylamide, or polysulfone) as a removing medium.
  • the immunoglobulin-removing section comprises a carrier (for example, polyvinyl alcohol, polyurethane, urethane, etc.) on which immunoglobulin-binding ligands (for example, triptophan, protein A, protein G, phenylalanine) are immobilized as a removal medium.
  • a carrier for example, polyvinyl alcohol, polyurethane, urethane, etc.
  • immunoglobulin-binding ligands for example, triptophan, protein A, protein G, phenylalanine
  • the liver function replacement part is a bioreactor containing a liver derived from a mammal (eg, a human, a baboon, a monkey, a bush, a mosquito), or a hepatocyte derived from a mammal (eg, a nonwoven fabric-filled bioreactor)
  • a mammal eg, a human, a baboon, a monkey, a bush, a mosquito
  • a hepatocyte derived from a mammal eg, a nonwoven fabric-filled bioreactor
  • the renal function replacement part may be a kidney derived from a mammal (eg, a human, a baboon, a monkey, a bush, a horse).
  • a mammal eg, a human, a baboon, a monkey, a bush, a horse.
  • the artificial organ system of the present invention is different from the conventional perfusion type artificial organ system, and includes a leukocyte removing section and / or an immunoglobulin removing section in addition to the organ replacement section (liver function replacement section or kidney function replacement section).
  • a person characterized by being This is an artificial organ system that includes a blood component separation unit.
  • “artificial organ system” refers to a device (artificial liver system) for substituting or assisting the liver function of a patient such as liver failure or a device for substituting or supporting the kidney function of a patient such as renal failure. (Artificial kidney system).
  • Liver function replacement part refers to a part that performs the functions of the liver, such as detoxification of harmful substances such as ammonia, protein synthesis, glycogen decomposition / synthesis, and bile synthesis.
  • Renal function replacement part refers to the part that performs the functions of the kidney, such as the production and excretion of urine and the reabsorption of substances useful to the human body from urine.
  • Bood component separation part refers to a part that separates whole blood into white blood cells, red blood cells, platelets, plasma, etc., and separates them or separates them into separate circuits.
  • the “leukocyte removal section” is a part that passes red blood cells and removes white blood cells such as neutrophils, eosinophils, basophils, monocytes, macrophages, and lymphocytes involved in cell-mediated immunity from the blood.
  • white blood cells such as neutrophils, eosinophils, basophils, monocytes, macrophages, and lymphocytes involved in cell-mediated immunity from the blood.
  • Immunoglobulin-removing section refers to a section that removes immune factors involved in humoral immunity, such as immunoglobulin, site-in, and complement, from blood.
  • the provision of the leukocyte removal section and / or the immunoglobulin removal section in the artificial organ system makes it possible to avoid the heterogeneous immune reaction conventionally observed in the organ replacement section.
  • the whole liver-type artificial liver or hybrid-type human liver or the artificial kidney of the present invention exhibits better functions than conventional ones, and can be perfused for a longer time.
  • the “whole liver artificial liver” refers to an artificial liver system that uses a whole mammal-derived liver (hereinafter, also referred to as a whole liver) as a viscera replacement part.
  • “Hybrid artificial liver” refers to an artificial liver system that uses a bioreactor containing mammalian hepatocytes as an organ replacement unit.
  • Artificial kidney refers to an artificial kidney system that uses whole mammal-derived kidney as an organ replacement unit.
  • the artificial organ system of the present invention can be constructed as follows. 1. The artificial organ system of the present invention
  • the artificial organ system of the present invention comprises a whole blood flow path section 8, a blood coagulation inhibitor injecting section 9, a blood component separation section 10, a red blood cell / platelet / plasma-rich blood flow path section 11, a white blood cell.
  • any of the above-described functional parts can be omitted, or functional parts other than those described above can be added as necessary.
  • the whole blood channel is a channel through which blood from the patient flows in the artificial organ system.
  • the conduit preferably has a structure connectable to an injection needle, a catheter, or the like.
  • a tube for infusion manufactured by Terumo Corporation
  • a mass tubing-flex® silicon tube manufactured by Coal Perm Co., Ltd.
  • the blood coagulation inhibitor injection part is a part that injects blood coagulation inhibitors, such as heparin, fragmin (dalteparin sodium), and fusane (nafamositic mesylate), into the blood channel.
  • blood coagulation inhibitors such as heparin, fragmin (dalteparin sodium), and fusane (nafamositic mesylate).
  • the blood coagulation inhibitors are heparin, fragmin, glucose is used alone or in combination so that the administration rate is 10 to 20 units / kg / hour, and fusan is 20 to 50 nig / hour. It can be dissolved in liquids and injected into the bloodstream.
  • the blood component separation unit separates whole blood into white blood cells, red blood cells, platelets, plasma, etc., and separates them or separates them into separate circuits, and at the same time, as a blood pump, converts the blood components into the blood flow path.
  • the blood flow rate is SOSOO HI IZ min, preferably 50-: L 50 ml Z min, most preferably 80-120 ml min.
  • a centrifugal blood component separator Frresenius Hemocare
  • a membrane blood component separator or the like can be used as the blood component separator.
  • the erythrocyte / platelet / plasma-rich blood flow path is a conduit through which red blood cells, platelets and plasma-rich blood derived from whole blood, separated by the blood component separation section (3), flow.
  • an infusion tube manufactured by Terumo Corporation
  • a master flex silicon tube manufactured by Coal Palmer
  • the leukocyte-rich blood flow path is a conduit through which the leukocyte-rich blood derived from whole blood, which is separated by the blood component separation section in (3) above, flows.
  • an infusion tube manufactured by Terumo Corporation
  • a masterflex silicon tube manufactured by Coal Palmer
  • the leukocyte removal unit is a device that allows red blood cells in blood to pass through and selectively captures white blood cells.
  • the leukocyte removal section 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, i.e., a physical difference due to a size difference between leukocytes and other blood solid components. This is achieved by selective trapping and selective adsorption of leukocytes to the removal medium.
  • the filler include a fibrous medium such as a nonwoven fabric and a porous body having a uniform average pore diameter.
  • the polymeric materials that make up the filter include, but are not limited to, polyester, polyurethane, polystyrene, polyacrylonitrile, polyamide, polyvinyl alcohol, polysulfone, cellulose, and cellulose acetate. Not. These materials can be manufactured by a manufacturing method known in the art. Polyester non-woven fabric is used as the leukocyte removal part. Cellsorber (Cellsorba, manufactured by Asahi Medical Co., Ltd.) or the like as a blood cell removal medium can be used.
  • the average pore size of the filter is preferably 2 to 200 mm, more preferably 3 to 100 m.
  • the “average pore size” means that a porous filter having continuous pores is cut in the direction perpendicular to the blood flow direction, and the diameter of each of the pores dispersed throughout the cross section is measured. When the relationship between the diameter and the number of pores is examined, the diameter of the largest number of pores is converted to a circle.
  • the “diameter converted into a circle” is set in a sense that the pores have various shapes and have various diameters, and are set in a sense to correct the pores.
  • the diameter of the circle When converted into a circle with the same area as the cross-sectional area of the pores, the diameter of the circle is the horizontal axis, and the number of pores in the graph created with the number of pores on the vertical axis is the peak. The diameter of the circle at that time.
  • Leukocyte removal efficiency can be improved as follows. That is, when a fibrous medium such as a nonwoven fabric is used as a filter, the leukocyte removal efficiency can be increased by increasing the packing density of the fibrous medium and using a fiber laminate having a small average fiber diameter. When a porous material having a uniform average pore size is used as a filter, the leukocyte removal efficiency can be increased by making the average pore size smaller.
  • the 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 can be used.
  • the average pore size on the blood inlet side is preferably 10 to 300 x m, more preferably 20 to 200 mm, and most preferably 25 to 100 m.
  • the average pore size on the blood outlet side is preferably 1 to 30 m, more preferably 2 to 20 mm, and most preferably 3 to 15 // m.
  • the surface of the filter material can be coated with a surface modifier such as collagen. You.
  • the immunoglobulin removing unit is a device that can selectively remove immune factors such as immunoglobulin, complement, and site force in blood.
  • a column in which a removal medium in which an immunoglobulin-binding ligand is immobilized on a suitable carrier is packed in a column can be used.
  • immunoglobulin-binding ligand refers to a substance that can specifically bind not only to immunoglobulin but also to various immune factors such as complement and cytokine.
  • Specific examples of the immunoglobulin-binding ligand include tryptophan, protein 8, protein G, anti-immunoglobulin antibody, anti-cytopotency antibody, phenylalanine, and the like.
  • the carrier is not particularly limited as long as it has excellent stability and can easily and efficiently immobilize the immunoglobulin-binding ligand on the surface of the carrier without eluting the material substance from the carrier.
  • the immunoglobulin-binding ligand can be immobilized on a carrier by a covalent bonding method via a functional group. Note that a plurality of immunoglobulin-binding ligands may be simultaneously immobilized on the carrier. Furthermore, when the column is packed with a carrier to which the immunoglobulin-binding ligand has been bound, not only one type of ligand-immobilized carrier but also a mixture of multiple types of ligand-immobilized carriers can be used. Filling is also possible.
  • Imsorva TR350 Imsorva TR350 (Immu sorba Commercial products such as TR350 and Asahi Medical Co., Ltd.) can also be used.
  • a filter such as an F filter (manufactured by Asahi Medical Co., Ltd.) can be provided at the blood outlet of the immunoglobulin removing section to suppress the outflow of the carrier.
  • the oxygen supply unit is a device that can supply oxygen to blood and increase the concentration of dissolved oxygen in blood.
  • an oxygen supplier used in cell culture and the like, an oxygen supplier used in an artificial lung, and the like can be mentioned.
  • the amount of oxygen supplied from the oxygen supply unit can be adjusted by controlling the amount of oxygen supplied from the oxygen pump to the oxygen supply unit based on feedback data from the dissolved oxygen measurement unit that monitors the dissolved oxygen concentration in blood.
  • a hollow fiber type 1 oxygen supply device manufactured by YMA Kagaku Co., Ltd.
  • a capiox Capiox, manufactured by Terumo Corporation
  • the heating section is a section for maintaining a part or all of the blood flowing in the artificial liver system and / or each functional part in the artificial liver system at a constant temperature.
  • the maintenance temperature is preferably from 35.0 to 37.5: 1, more preferably from 35.5 to 37.0, most preferably from 36.0 to 36.5 ° C.
  • the location of the heating section can be between the oxygen supply section and the organ replacement section as shown in Figures 2 to 4, but the location can be changed if necessary.
  • the heating unit may be integrated with the oxygen supply unit.
  • a warmer coil manufactured by Yakko Shoji Co., Ltd.
  • the oxygen supply section and the heating section are formed in a body, there is a capiox (manufactured by Terumo Corporation).
  • the organ replacement unit is used properly according to its purpose. That is, when the purpose is to substitute liver function, the whole liver can be used as shown in FIG. 2, or a bioreactor in which hepatocytes are immobilized can be used as shown in FIG. If the purpose is to replace renal function, as shown in Fig. 4, Is used.
  • the whole liver When the whole liver is used as an organ replacement part, the whole liver can be used from mammals such as human, bush, squirrel, monkey, and baboon. When using whole livers derived from humans, use livers mainly from brain death patients instead of living body-derived livers. Incorporation of the isolated liver into the artificial liver system can be performed by connecting the portal vein side as a blood inlet and the inferior vena cava side as a blood outlet.
  • a bioreactor in which hepatocytes are immobilized is used as an organ replacement part, a nonwoven-filled bioreactor, a hollow fiber-type bioreactor [Shatford, RA, et al .: J. Surg. Res 53: 549 (1992)], Microcarrier-type bioreactor [Shnyra, A: Artif Organs 15: 189 (1991)], Hepatocyte floating bioreactor [Sakai , Y: Cell transplant. 8: 531 (1999)].
  • a nonwoven-filled type biolique can be manufactured as follows. First, a polyester nonwoven fabric with a fiber diameter of 0.001 to 0.1 mm and a pore size of 0.05 to 0.5 mm is cut to an appropriate size, washed thoroughly in carbon tetrachloride, and further washed with ethanol and water. Next, the nonwoven fabric is immersed in a collagen solution and then dried to form a collagen coat. The collagen-coated polyester non-woven fabric is spirally wound and packed in a cylindrical column (for example, made of polycarbonate). The lid with the inlet and outlet is closed and sterilized with ethinoxide gas.
  • FIG. 5 shows the structure of the bioreactor.
  • the blood that has flowed into the center is once dispersed radially outward, and then re-centers through a nonwoven fabric (NWF: non-woven fabric in Fig. 5) on which hepatocytes are immobilized and flows out.
  • NWF non-woven fabric in Fig. 5
  • the perfused blood can be prevented from turbulent flow or stasis in the bioreactor.
  • the immobilization of hepatocytes to the sterilized nonwoven fabric-filled column can be performed as follows. You That is, first, heparin-supplemented saline was added to the mammalian liver via the portal vein.
  • the blood is removed, the liver is removed, and the Hanku's solution containing EDTA / EGTA, collagenase solution and the like are similarly perfused to separate the liver cells.
  • the obtained hepatocytes are suspended in a medium (for example, William's Eagle medium) supplemented with fetal calf serum, insulin, dexamethasone and an antibiotic.
  • the hepatocyte suspension is put into a reservoir bottle equipped with a dissolved oxygen valve and oxygen supply device, and this is connected to a non-woven packed column and a mouthpiece pump with a silicon tube, and the closed circuit of invitro Create Then, the suspension is perfused at a flow rate of 100 to 150 ml / min for about 3 to 30 hours, so that hepatocytes are trapped in a nonwoven-filled force ram, thereby producing a nonwoven-filled bioreactor.
  • hepatocytes hepatocytes derived from mammals such as a human, a bush, a sea lion, a monkey, and a baboon can be used.
  • human-derived hepatocytes hepatocytes established mainly as culture strains are used instead of hepatocytes isolated from living liver.
  • the blood directly contacts the hepatocytes and exchanges substances, thus exhibiting superior performance not found in a whole liver-type artificial liver.
  • the hybrid type artificial liver is capable of performing a more direct substance exchange by directly contacting the external fluid with the hepatic parenchymal cells being removed from the sinusoidal structure, as compared to the whole liver type artificial liver.
  • Hepatocyte isolation removes vascular endothelial cells and cuffer cells, which are a type of macrophage, so that xenoimmune reactions are reduced.If necessary, the size of hepatocytes can be adjusted by adjusting the amount of hepatocytes. It has advantages such as being able to
  • kidneys mainly from brain death patients are used instead of kidneys derived from living bodies.
  • One method is the bilateral renal en bloc extirpation method, in which the bilateral kidney, bilateral renal artery and adjacent abdominal aorta, and the bilateral renal vein and adjacent inferior vena cava are abdominal aorta. In this method, blood is leaked except for the stump and inferior vena cava so that there is no leakage of blood (en bloc).
  • the other is the unilateral nephrectomy method, in which each side of the bilateral kidney is separated separately by separating the renal artery and renal vein at the root branching off the abdominal aorta and inferior vena cava. It is a method of extracting. Incorporation of the resected kidney into the artificial kidney system is based on the bilateral renal en bloc excision method, in which two ends of the abdominal aorta are ligated at one end, the other end is used as a blood inlet, and two This can be performed by ligating one end of the stump of the vena cava and connecting the other end as a blood outlet.
  • the renal artery and the renal vein are connected as a blood inlet and a blood outlet, respectively.
  • the ureter should be removed near the bladder and attached to the kidney, and removed as a urine outlet.
  • the dissolved oxygen measurement unit is a device that monitors the amount of dissolved oxygen in the blood flowing in the flow channel.
  • the dissolved oxygen value obtained by the dissolved oxygen measurement unit is sent to the oxygen cylinder, and the oxygen supply from the oxygen cylinder to the oxygen supply unit is appropriately controlled.
  • a dissolved oxygen meter 0X300 S manufactured by Toko Chemical Co., Ltd.
  • a dissolved oxygen controller HD0-200 manufactured by Toko Chemical Co., Ltd.
  • the junction is where the processed blood that has flowed out of the organ replacement unit and the leukocyte-rich blood separated in the blood component separation unit join.
  • the treated blood flow path is a conduit for sending the treated blood joined in (12) to the patient. It is preferable that the conduit has a structure connectable to a syringe needle, a catheter, or the like.
  • a tube for orbital fluid manufactured by Terumo Corporation
  • a mass Yuichi Flex 'silicon tube manufactured by Coal Palmer
  • a particle removal unit downstream of the organ replacement unit can do.
  • a particle removing section it is possible to remove shed cells, hepatocyte debris, fine particles and the like from the organ replacement section.
  • a filter of a hollow fiber type, a flat membrane type, or the like can be used as the fine particle removing section.
  • the artificial organ system of the present invention is connected to a liver failure patient or a kidney failure patient 7.
  • the connection site includes the cephalic vein and the radial femoral vein of the patient.
  • Blood from the patient passes through the whole blood flow path section 8, receives the addition of a blood coagulation inhibitor from the blood coagulation inhibitor injection section 9, and enters the blood component separation section 10, where it is converted into red blood cells, platelets, and plasma-rich blood. It is divided into leukocyte-rich blood.
  • the red blood cells, platelets, and plasma-rich blood channel section 11 are diverted to the white blood cell-rich blood channel section 12, and the red blood cells, platelets, and plasma-rich blood section are sent to the leukocyte removal section 13.
  • leukocytes remaining in red blood cells, platelets, and plasma-enriched blood are adsorbed and removed.
  • the blood that has flowed out of the leukocyte removal unit 13 is sent to the immunoglobulin removal unit 14.
  • immune factors such as immune globulin and complement in red blood cells, platelets, and plasma-rich blood are removed.
  • the blood that has flowed out of the immunoglobulin removal unit 14 is sent to the oxygen supply unit 15 where oxygen is supplied so as to have a desired dissolved oxygen concentration.
  • the blood that has flowed out of the oxygen supply unit 15 is sent to a heating unit 16 where it is heated to a desired temperature.
  • the blood that has flowed out of the heating section is replaced by an organ replacement section [liver function replacement section (whole liver) 17; liver function replacement section (hepatocyte immobilization bioreactor) 18 or renal function replacement section (whole kidney) 1 9].
  • the liver function replacement unit 17 or 18 performs detoxification of harmful substances in blood, protein synthesis, glycogen decomposition synthesis, bile synthesis, and the like. In the case of whole liver 17, the synthesized bile is excreted from the common bile duct. In the renal function replacement unit 19, urine is produced and excreted.
  • Red blood cells, platelets, and plasma-enriched blood leaving the liver function replacement part 17 or 18 or the renal function replacement part 19 are dissolved.
  • the measured value of dissolved oxygen obtained in the dissolved oxygen measuring section 20 is sent to the oxygen cylinder 21 to determine the amount of oxygen introduced from the oxygen cylinder 21 to the oxygen supply section 15. .
  • the performance of the artificial liver system was evaluated using animals for hepatic insufficiency model as follows: presence or absence of perfusion passage, presence or absence of increased G0T / GPT activity, intracranial pressure of subject, blood ammonia concentration, bile It can be evaluated by the color of the liver tissue after production and perfusion, the presence or absence of blood coagulation, the flexibility of the liver tissue, and the survival time of the liver failure model animal and the presence or absence of side effects.
  • Dogs can be used as animals for liver failure models.
  • a dog liver failure model can be prepared as follows. First, after general anesthesia, the skull is punctured, a catheter for measuring intracranial pressure is inserted and placed in the ventricle, and a perfusion catheter is inserted and placed in the external jugular vein. An anastomosis of the portal and inferior aorta is performed. On the hepatic side, the portal vein is ligated and separated, and a tape is wound around the hepatic artery and the common bile duct so that it can be remotely tightened. In this state, observe the progress for 5 hours and wait for the blood ammonia level to rise.
  • Perfusion therapy is started 5 hours later, but immediately before, the dog's liver is placed in complete ischemia by ligating the artery and common bile duct at the hilar port with the tape for 2 hours, and released 2 hours later. .
  • the dog can be brought into a state of hepatic insufficiency by this operation and operation.
  • the artificial liver system used can be perfused without hyperacute rejection.
  • the liver Blood entering the viscera can cause hyperacute rejection of vascular endothelial cells, resulting in impaired passage through the perfusion circuit.
  • the inflowing blood can cause a hyperacute rejection reaction against hepatocytes. If the port flow is continued without obstruction, the used artificial liver system can be evaluated as being able to perform perfusion without causing hyperacute rejection, and the perfusion can be performed within 1 hour after the start of perfusion. If perfusion is not possible, the artificial liver system used can be evaluated as unsuitable for blood perfusion.
  • GOT glutamic acid oxa mouth acetic acid transaminase
  • GPT glutamate pyruvate transaminase
  • the GOT and Z or GPT values in the blood from the liver function replacement part increase over time, the death of hepatocytes occurs in the liver function replacement part, and the liver in the human liver system Function can be assessed as decreasing over time, and if no increase is observed, it can be assessed that hepatocytes do not die and liver function in the artificial liver system is maintained.
  • Subjects have increased intracranial pressure and blood ammonia levels during liver failure. Therefore, if these values do not increase, it can be evaluated that the artificial liver system used is satisfactorily exhibiting the liver function of the subject.
  • liver artificial liver system determines whether the liver is functioning. If the liver is functioning can be evaluated by examining bile production from the common bile duct. Without bile production, the liver may not be functioning.
  • the system is disassembled to check for blood coagulation, liver color and More detailed evaluation can be made by examining the softness of the liver and liver. For example, if no blood coagulation was observed, the liver was reddish-brown and the initial softness was maintained, the whole liver-type artificial liver system used did not cause blood coagulation, and the perfusion was good. Can be evaluated. Conversely, if part or the whole of the liver surface turns black-purple and becomes firm and tight, blood coagulation occurs due to a heterogeneous immune reaction and the like inside the whole liver-type artificial liver system used, and the perfusion is reduced. It is evaluated that it was not performed well.
  • the artificial liver system of the present invention can be maintained throughout the period of good perfusion without causing passage obstruction.
  • the blood component separator separates the leukocyte concentrate at the beginning of the circuit and returns it directly to the patient, thereby preventing a significant decrease in leukocytes from the patient. Can be. Further, by removing leukocytes as much as possible from the blood perfusing the liver function replacement part, the immunoadsorption removal device can be saved. Due to these advantages, the artificial liver system of the present invention can be expected to provide better clinical results than ever before in clinical settings. In the artificial liver system of the present invention, whole blood is processed without separating plasma components, and the perfusion efficiency of the conventional hybrid artificial liver was 30% or less. According to the liver system, it is 100%.
  • Perfusion efficiency refers to the percentage of the amount of blood processed by the liver function replacement unit to the amount of blood flowing into the artificial liver system.
  • the port flow efficiency indicates the rate at which blood from a liver failure patient is sent to the liver function replacement unit. Therefore, the higher this value is, the more the blood from the patient undergoes sufficient liver function processing. It means that you can receive it.
  • the performance of the artificial kidney system was evaluated using the animal model for renal failure as follows: urine output from the renal function replacement unit, creatinine clearance in the renal function replacement unit, and blood in the subject. It can be evaluated based on creatinine and urea nitrogen concentrations, color of renal tissue after perfusion, presence or absence of blood coagulation, flexibility of renal tissue, and presence or absence of side effects in renal failure model animals.
  • Dogs can be used as animals for renal failure model.
  • a canine renal failure model can be prepared as follows. First, after general anesthesia, a perfusion force table is inserted into the external venous vein and placed there. Turn the tape around the right and left renal arteries and the renal vein so that it can be tightened remotely. Immediately before starting the perfusion treatment, the left and right renal arteries and renal veins are ligated with the above-mentioned tape for 2 hours to place the dog's kidney in a completely ischemic state, and released 2 hours later. The dog can be brought into a renal failure state by this operation and the manual operation.
  • Normal values of blood creatinine and urea nitrogen are less than 1.2 and 5 to 10, respectively, and these values are elevated in patients with renal failure. Therefore, if an increase is observed, it can be evaluated that renal function in the artificial kidney system decreases over time in the renal function replacement unit, and if no increase is observed, liver function in the artificial kidney system is maintained It can be evaluated that it is done.
  • the artificial kidney system of the present invention can be maintained throughout the period of good perfusion without causing any obstruction.
  • the blood component separation device prevents significant reduction of leukocytes from the patient by separating the leukocyte concentrate at the beginning of the circuit and returning it directly to the patient.
  • an immunoadsorption removal device can be saved. From such an advantage, the artificial kidney system of the present invention can expect better clinical results than ever before in clinical practice.
  • FIG. 1 is a diagram showing a conventional hybrid artificial liver system.
  • FIG. 2 is a diagram showing the whole liver artificial liver system of the present invention.
  • FIG. 3 is a diagram showing a hybrid artificial liver system of the present invention.
  • FIG. 4 is a diagram showing an artificial kidney system of the present invention.
  • FIG. 5 is a diagram showing the structure of a non-woven fabric-filled bioreactor. BEST MODE FOR CARRYING OUT THE INVENTION
  • the present invention will be described specifically with reference to Examples, but the scope of the present invention is not limited thereto.
  • Example 1 Whole blood direct perfusion in a canine liver failure model using a whole liver type artificial liver system
  • a whole liver artificial liver system whole blood was directly perfused on a dog liver failure model (subject) as follows.
  • dogs type: Husky or Shepherd dogs
  • dogs weighing 25 to 30 kg are anesthetized by injecting ketamine and phenovalpital, and placed under human respiratory control by endotracheal intubation.
  • Anesthetized After perforating the canine skull, a catheter for measuring intracranial pressure was inserted and placed in the ventricle, and a perfusion catheter was inserted and placed in the external venous vein.
  • An anastomosis of the portal and inferior aorta is performed.On the hepatic side, the portal vein is ligated and separated, and a tape is wound around the hepatic artery and the common bile duct so that it can be remotely tightened. The time course was observed.
  • an artificial liver system using pig whole liver was constructed as follows. First, a catheter was inserted into the portal vein of a bush (type: Sangen hybrid) weighing 10 to 15 kg, whereby approximately 2000 ml of saline containing heparin was perfused into the liver to remove blood. Thereafter, the artery was ligated and dissected, the common bile duct was dissected, a bile duct tube was inserted, and the entire liver was removed. Then, as shown in Fig.
  • a catheter was inserted into the portal vein of a bush (type: Sangen hybrid) weighing 10 to 15 kg, whereby approximately 2000 ml of saline containing heparin was perfused into the liver to remove blood. Thereafter, the artery was ligated and dissected, the common bile duct was dissected, a bile duct tube was inserted, and the entire liver was removed. Then, as shown in Fig.
  • the blood component separation device, leukocyte adsorption and removal device, immunoglobulin removal device, oxygen supply and heating device Capiox (manufactured by Terumo Corporation), and the excised whole liver were removed from the inferior vena cava
  • the whole liver-type artificial liver system of the present invention was constructed by sequentially connecting the side as an inlet and the portal side as an outlet.
  • a continuous centrifugal separator, Fresenius AS. TEC 204 (Fresenius) is used as a blood component separator, and a cell sober (Cellsorba, Asahi) using a polyester non-woven fabric as a leukocyte removal medium is used as a leukocyte adsorption and removal device.
  • the hepatic artery and the common bile duct at the hilar portion of the dog liver failure model were clamped with the tape to put the dog liver in a completely ischemic state.
  • a perfusion catheter for a dog hepatic failure model was connected to the system, and the Nanfuru therapy was started.
  • the hepatic artery and common bile duct clamps were released after 2 hours.
  • the perfusion treatment was performed for 3 hours, and after completion, the dog was extubated from the endotracheal intubation tube, housed in a dog cage, and followed up.
  • the perfusion treatment continued without any obstacles.
  • the blood component separator separates 15-20% of the total blood flow from the subject into the system as a flow rate and about 50-70% of the white blood cell amount as a leukocyte concentrate, while About 80% to 85% and about 30% to 50% of the amount of white blood cells were perfused into the liver function replacement part as red blood cells, platelets, and plasma concentrate.
  • the white blood cell count in the circulating canine blood did not decrease at all.
  • only one leukocyte depletion device and one immunoglobulin depletion device were required after perfusion treatment for 3 hours, and when the experiment was disassembled, blood coagulation did not adhere to these adsorption columns at all.
  • the blood component separation device group is the same as the perfusion treatment group.
  • the pig liver began to turn patchy to dark brown, and after 2-3 hours, the whole liver became dark brown and the blood pressure of the dog decreased, resulting in a decrease in blood pressure. It has become difficult to continue.
  • the ammonia level in the perfusion circuit blood was almost unchanged, with 242 just before flowing into the whole liver and 224 just after flowing out of the whole liver. Bile excretion from the common bile duct was slight in the first hour, but not thereafter.
  • perfusion therapy can be performed smoothly as in the case of the perfusion therapy group.
  • reduction of intracranial pressure, suppression of increase in ammonia level in canine systemic blood, and significant decrease of ammonia level in perfusion circuit blood were observed.
  • the ammonia level in the perfusion circuit blood was 434.7 ⁇ 44.4 just before flowing into the whole liver, and 255. 7 ⁇ 16.9 (mean soil standard deviation) just after flowing out of the whole liver.
  • the leukocyte removal device and immunoglobulin removal device must be replaced every hour to one and a half hours. If the port flow is continued without replacement for a longer time, blood coagulation occurs in the entire system. Was. The dogs lived between 24 and 5 days after the end of surgery (mean 72.0 hours).
  • the artificial liver system of the present invention in which a leukocyte removal device and an immunoglobulin removal device were installed in front of the whole liver, it was possible to test for heterogeneous immune reactions and liver failure in the liver function replacement part in the artificial liver system. It can assist and replace liver function in subjects with hepatic failure without inducing shock in the body, and by installing a blood component separation device at the beginning of the circuit, the patient can receive white blood cells. Perfusion therapy without the need for leukocyte depletion and immunoglobulin depletion without reducing blood loss, and as a result, a significant prolongation of life in hepatic failure subjects .
  • Example 2 Direct whole blood perfusion for a dog liver failure model using a hybrid artificial liver system
  • a hybrid artificial liver system centered on a bioreactor Built a system.
  • a nonwoven-filled bioreactor with immobilized liver cells was prepared. That is, a polyester non-woven fabric having a fiber diameter of 0.06 mm and a pore size of 0.1 mm was cut into a size of 140 ⁇ 1500 ⁇ 2 mni, washed with carbon tetrachloride for a while, then washed with 100% ethanol and water. And rinsed several times.
  • the polyester nonwoven fabric was collagen-coated by dipping it in a 0.03% type I sheep tail / collagen solution and drying it.
  • the obtained collagen-coated non-woven fabric was spirally wound and packed in a cylindrical column made of polycarbonate having a capacity of 350 ml, and a lid with an inlet and an outlet was attached thereto and sterilized with ethylene oxide gas.
  • a catheter was inserted into the portal vein of a bush (type: hybrid of sungen) weighing 15 to 20 kg, whereby about 2000 ml of saline containing heparin was perfused into the liver to remove blood, and then the whole liver was removed. Removed.
  • the liver liver cells were isolated by sequentially perfusing the Hank's solution and collagenase solution with EDTA / EGTA for 30 minutes in the portal portal vein.
  • a blood component separation device a leukocyte adsorption and removal device, an immunoglobulin removal device, an oxygen supply and heating device Cap iox (manufactured by Terumo Corporation) and the nonwoven fabric-filled bioreactor are sequentially used.
  • an eight-bridged artificial liver system of the present invention was constructed.
  • a continuous centrifugal separator Fresenius AS. TEC204 (Fresenius) is used as a blood component separator, and a cellsorber (Cellsorba, manufactured by Asahi Medical) using a polyester nonwoven fabric as a leukocyte removal medium is used as a leukocyte adsorption and removal device.
  • a polyvinyl alcohol gel-filled column immobilizer TR350 (Immu sorba TR350, manufactured by Asahi Medical Co., Ltd.) to which tributofan was bound as a ligand was used.
  • a canine liver failure model was prepared in the same manner as in Example 1. Five hours after the end of the operation, the hepatic artery and the common bile duct in the hepatic hilum of the canine liver failure model were clamped with tape to put the canine liver in a completely ischemic state. Next, a perfusion catheter of a canine liver failure model was connected to the system, and perfusion treatment was started. Hepatic artery and common bile duct clamps were released after 2 hours. The perfusion treatment was performed for 3 hours. After completion, the dog was extubated from the endotracheal intubation tube, housed in a dog cage, and followed up.
  • the experiment consisted of a hybrid in which a blood component separation device, a leukocyte adsorption and removal device, an immunoglobulin removal device, an oxygen supply / warming device Capiox (manufactured by Terumo Corporation), and the nonwoven fabric-filled bioreactor were connected in series.
  • Group with perfusion treatment using an artificial liver system (perfusion treatment group: 2 subjects), without blood component separation device, but with perfusion by a system that connects a leukocyte removal device and an immunoglobulin removal device (Immunodepletion device group: 7 subjects) and a group perfused by a system without any blood component separator, leukocyte depletion device and immunoglobulin depletion device (control group: 4 subjects) I went.
  • the experimental significance was that in the case of a whole liver artificial liver system Since it is the same and has already been studied for all liver types, it has been omitted.
  • the perfusion treatment continued without any obstacles.
  • the inflow of blood from the patient by the blood component separator was performed with the same flow rate and leukocyte distribution as in the case of the whole liver type artificial liver system.
  • the leukocyte count in the circulating canine blood did not decrease at all, and only one leukocyte depletion device and one immunoglobulin depletion device were required after a 3-hour port flow treatment.
  • Intracranial pressure is reduced and canine circulating blood The rise in daunting value was suppressed.
  • the ammonia level in the blood of the perfusion circuit was 353.3 ⁇ 44.6 just before flowing into the bioreactor and 114.3 ⁇ 51.2 just after flowing out of the bioreactor (average soil standard).
  • perfusion therapy can be performed smoothly as in the case of the perfusion therapy group.
  • reduction of intracranial pressure, suppression of increase in ammonia level in canine systemic blood, and significant decrease of ammonia level in perfusion circuit blood were observed.
  • No increase in the activity of enzymes such as G0T / GPT was observed.
  • the white blood cell count in the canine circulating blood showed a slight, though not significant, decrease after the end of perfusion.
  • the leukocyte depletion device and immunoglobulin depletion device had to be replaced every hour, and if perfusion was continued without replacement for a longer time, blood coagulation occurred in the entire system.
  • the dogs lived between 20 and 5 days after surgery (mean 74.6 hours).
  • the leukocyte removal device and immunoglobulin removal device were By using the eight-artificial artificial liver system of the present invention installed in front of the orifice, it is possible to induce a heterogeneous immune response in the liver function replacement part in the artificial liver system and a shock in the liver failure subject. Assists and replaces liver function in subjects with liver failure, and installs a blood component separation device at the beginning of the circuit to eliminate leukocytes without reducing leukocytes in patients It was found that the perfusion treatment can be performed while saving the device and the immunoglobulin removal device, and as a result, it was found that the hepatic insufficiency had a significant prolonging effect on the subject.
  • a dog weighing 25 to 30 kg (type: Husky dog or Shepherd dog) is subjected to induction anesthesia by injecting ketamine and phenobarbital and placed under ventilator management by endotracheal intubation. And under general anesthesia.
  • a port catheter was inserted and placed in the external jugular vein.
  • a tape was wound around the right and left renal arteries and the renal vein so that it could be tightened remotely.
  • the left and right renal arteries and renal veins were ligated with the above-mentioned tape for 2 hours to place the dog kidney in a completely ischemic state, and opened 2 hours later.
  • an artificial kidney system using porcine whole kidney was constructed as follows. First, general anesthesia of bushu (type: hybrid of sungen) weighing 10 to 15 kg and laparotomy is performed. The bilateral kidney, bilateral renal artery and adjacent abdominal aorta, and bilateral renal vein and adjacent inferior vena cava are detached from the surrounding tissue, the ureter is cut off near the bladder, and the abdominal aorta and inferior vena cava are renal artery, respectively. Ligation and dissection are performed above and below the bifurcation of the renal vein, and a lump is removed (above-mentioned bilateral kidney en bloc removal method).
  • a catheter is inserted into the upper end of the abdominal aorta, and approximately 1 000 ml of heparinized saline is perfused into the bilateral kidneys to remove blood. Insert a catheter at the upper end of the inferior vena cava. Incorporation of an isolated kidney into an artificial kidney system This is done by connecting the upper end of the aortic aorta as the blood inlet and the upper end of the inferior vena cava as the blood outlet. Insert a ureteral catheter into the ureter stump to serve as a urine outlet. Then, as shown in Fig.
  • the blood component separation device leukocyte adsorption and removal device, immunoglobulin removal device, oxygen supply and heating device Capiox (manufactured by Terumo), and the excised Buney kidney were removed from the aortic side.
  • a continuous centrifugal separator Fresenius AS. TE C 204
  • the canine kidney was placed in complete ischemia by clamping with the above tape in a canine renal failure model.
  • a perfusion catheter of a canine renal failure model was connected to the system, and perfusion treatment was started.
  • the clamp was released after 2 hours.
  • the perfusion treatment was performed for 3 hours, and after completion, the dog was extubated from the endotracheal intubation tube, housed in a dog cage, and followed up.
  • the experiment was carried out by an artificial kidney system in which a blood component separator, a leukocyte adsorption and removal device, an immunoglobulin removal device, an oxygen supply and heating device Capiox (manufactured by Terumo Corporation), and a bushu kidney were sequentially connected.
  • the comparison was made between treated dogs and dogs perfused with a system without any blood component separator, leukocyte depletor and immunoglobulin depletor (one subject each).
  • the blood component separator separates 15% of the total blood volume from the patient into the system as a flow rate and about 50% of the white blood cell volume as a white blood cell concentrate, while the blood flow rate is 85% and the white blood cells are separated. Approximately 50% of the volume was perfused into the renal replacement area as erythrocytes, platelets, and plasma concentrate. As a result, the white blood cell count in canine circulating blood did not decrease at all. In addition, only one leukocyte removal device and one immunoglobulin removal device were required during the 3-hour perfusion treatment, and when the experiment was terminated, blood coagulation did not adhere to these adsorption columns at all.
  • control group 1 subject
  • the blood pressure of the dog drops 2 hours after the start of perfusion, and blood flow is reduced. Perfusion was stopped because it became difficult. From the ureter, 30 mL of normal urine excretion was observed for the first hour, but blood urine was reduced for the next hour to 20 mL. Buyu kidney was ⁇ red and firm and tight, suggesting that blood coagulation occurred due to hyperacute rejection.
  • the artificial kidney system of the present invention in which the leukocyte removal device and the immunoglobulin removal device were installed in front of the whole kidney, It can assist and replace renal function in renal failure subjects without inducing a heterogeneous immune response in the renal function replacement part of the kidney system or shock in renal failure subjects, and separate blood components
  • the device By placing the device in the first part of the circuit, it is possible to perform the perfusion treatment with a reduced leukocyte and immunoglobulin depletion device without causing leukopenia in the subject with renal failure; and As a result, it was found that a significant life-prolonging effect was exerted on subjects with renal failure.
  • an artificial organ system capable of replacing or assisting the organ function of a subject better and for a longer period than conventional artificial organ systems.

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  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
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  • Anesthesiology (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

On décrit un système d'organe artificiel constitué d'une partie qui élimine les leucocytes et/ou d'une partie qui élimine les immunoglobulines et d'une partie qui se substitue à la fonction hépatique ou d'une partie qui se substitue à la fonction rénale. Ce système présente une efficacité de perfusion élevée, peut fournir de l'oxygène à un niveau élevé et peut remplacer et/ou supporter la fonction hépatique et/ou la fonction rénale d'un sujet sur une longue période comparativement aux systèmes d'organes artificiels actuels.
PCT/JP2001/002233 2000-03-22 2001-03-21 Nouveau systeme d'organe artificiel WO2001070302A1 (fr)

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Cited By (4)

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JP2005514127A (ja) * 2001-12-21 2005-05-19 レナルテック インターナショナル， エルエルシー． 選択的吸着デバイスおよび選択的吸着システム
JP2014514936A (ja) * 2011-02-28 2014-06-26 ポール・コーポレーション 体液からのイムノグロブリンおよび白血球の除去
CN110478548A (zh) * 2019-07-31 2019-11-22 南方医科大学珠江医院 生物人工肝系统
KR20210044206A (ko) * 2018-06-27 2021-04-22 더 제네바 파운데이션 단일 기관 및 다기관 기능 부전의 이동식 치료를 위한 착용 가능한 모듈형 체외 생명 유지 장치

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WO1991018087A1 (fr) * 1990-05-16 1991-11-28 Baylor College Of Medicine Lignee cellulaire hepatique humaine permanente et son utilisation dans un dispositif d'aide hepatique (dah)
WO1993016171A1 (fr) * 1992-02-07 1993-08-19 Monsanto Company Foie artificiel biologique
WO1996009876A1 (fr) * 1992-09-11 1996-04-04 Xenogenex, Inc. Foie artificiel et son fonctionnement

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JPS61255666A (ja) * 1985-05-09 1986-11-13 工業技術院長 代謝補助装置
WO1991018087A1 (fr) * 1990-05-16 1991-11-28 Baylor College Of Medicine Lignee cellulaire hepatique humaine permanente et son utilisation dans un dispositif d'aide hepatique (dah)
WO1993016171A1 (fr) * 1992-02-07 1993-08-19 Monsanto Company Foie artificiel biologique
WO1996009876A1 (fr) * 1992-09-11 1996-04-04 Xenogenex, Inc. Foie artificiel et son fonctionnement

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005514127A (ja) * 2001-12-21 2005-05-19 レナルテック インターナショナル， エルエルシー． 選択的吸着デバイスおよび選択的吸着システム
JP4787468B2 (ja) * 2001-12-21 2011-10-05 レナルテック インターナショナル， エルエルシー． 選択的吸着デバイスおよび選択的吸着システム
JP2014514936A (ja) * 2011-02-28 2014-06-26 ポール・コーポレーション 体液からのイムノグロブリンおよび白血球の除去
KR20210044206A (ko) * 2018-06-27 2021-04-22 더 제네바 파운데이션 단일 기관 및 다기관 기능 부전의 이동식 치료를 위한 착용 가능한 모듈형 체외 생명 유지 장치
JP2021529612A (ja) * 2018-06-27 2021-11-04 ザ ジェニーヴァ ファウンデーション 単一および多臓器不全の移動式治療のための装着可能モジュール式体外生命維持デバイス
JP7474715B2 (ja) 2018-06-27 2024-04-25 ザ ジェニーヴァ ファウンデーション 単一および多臓器不全の移動式治療のための装着可能モジュール式体外生命維持デバイス
KR102674168B1 (ko) 2018-06-27 2024-06-12 더 제네바 파운데이션 단일 기관 및 다기관 기능 부전의 이동식 치료를 위한 착용 가능한 모듈형 체외 생명 유지 장치
CN110478548A (zh) * 2019-07-31 2019-11-22 南方医科大学珠江医院 生物人工肝系统

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