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WO1999032171A1 - Systeme d'assistance hepatique par biodialyse - Google Patents

Systeme d'assistance hepatique par biodialyse Download PDF

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Publication number
WO1999032171A1
WO1999032171A1 PCT/AU1998/001065 AU9801065W WO9932171A1 WO 1999032171 A1 WO1999032171 A1 WO 1999032171A1 AU 9801065 W AU9801065 W AU 9801065W WO 9932171 A1 WO9932171 A1 WO 9932171A1
Authority
WO
WIPO (PCT)
Prior art keywords
bioreactor
patient
blood
cartridge
support system
Prior art date
Application number
PCT/AU1998/001065
Other languages
English (en)
Inventor
Ainslie Glenister Ross Sheil
Junhong Sun
Lisheng Wang
Original Assignee
The University Of Sydney
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Sydney filed Critical The University Of Sydney
Priority to AU16529/99A priority Critical patent/AU1652999A/en
Publication of WO1999032171A1 publication Critical patent/WO1999032171A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • 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
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3482—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate by filtrating the filtrate using another cross-flow filter, e.g. a membrane filter
    • 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
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A61M1/3489—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents by biological cells, e.g. bioreactor

Definitions

  • This invention concerns a liver support system.
  • it concerns a bioartificial liver support system which operates by liver biodialysis, or blood filtrate or plasma biomodulation.
  • hepatocytes in contact with semi-permeable membranes, usually in the form of hollow fibres or flat plates.
  • semi-permeable membranes usually in the form of hollow fibres or flat plates.
  • the patient's blood, plasma or serum passes or is pumped to place it in contact with the other side of the membrane.
  • the pore size of the membrane determines the transport of molecules between the patient's blood and the hepatocytes.
  • Such bioartificial liver support systems have a number of significant disadvantages.
  • the hepatocytes attached to the outside of the semi- permeable membrane are in inferior culture conditions and are limited in number. Their presence inhibits the free transfer of molecules across the membrane.
  • close contact between the patient's blood, plasma or serum, and the hepatocytes facilitates allo- or xeno-reactions which adversely affect the hepatocytes.
  • the pore size of a semi-permeable membrane is sufficiently large to allow passage from the blood of important large-molecule toxic metabolites, it will also be sufficiently large to allow passage back into the patient's blood stream of toxic metabolites, infective agents including feared viruses and cells or cell debris. These effects add danger to the treatment. As a result treatment is often limited to 6-8 hour intermittent periods each day or second day, which are inadequate. Fresh hepatocytes must be provided for repeat treatments and the logistics of providing this are severe.
  • the invention is an artificial liver support system, including:
  • a bioreactor in which hepatocytes are maintained in culture An exchange barrier having two sides.
  • a first circuit which is arranged to carry fluid from the bioreactor to a first side of the exchange barrier and back.
  • a second circuit which is arranged to carry blood from a patient to the second side of the exchange barrier and back.
  • Such a system separates the patient's blood stream from the hepatocytes, which diminishes the opportunity for allo- or xeno-reactions and increases the safety of the system.
  • the bioreactor may have an associated computerised control system.
  • the bioreactor may also include a containment vessel maintained at constant temperature in a water bath or otherwise.
  • a temperature probe may report the temperature of the containment vessel to the computer system to allow feedback control of the temperature.
  • a gas exchanger may receive fluid from the bioreactor, and inject oxygen, carbon dioxide, nitrogen and air in doses measured by the computer system.
  • a dissolved oxygen probe may provide a measure of dissolved oxygen to the computer system to allow feedback control of the gases.
  • a pH probe may provide a measure of pH to the computer system to allow feedback control of pH by adjustment of carbon dioxide flow.
  • disorders of the patient's pH and blood gas concentrations which are common in fulminant hepatic failure, may also be influenced by manipulation of the system.
  • primary animal or human hepatocytes or animal or human hepatocyte-derived cell lines may be attached to a polyester or other suitable matrix and bathed in fluid which could be plasma, serum, blood filtrate or other culture medium. Ports may be provided for connection to the first circuit , and for monitoring, sampling, variation and removal of the contents of the bioreactor.
  • the bioreactor may culture the hepatocytes in large and sometimes life sustaining numbers in culture conditions which permit cell survival and function for an interval which may be several hours to several days or weeks.
  • hepatocytes provide improved detoxification of the patient's blood, plasma or serum and improved synthesis of needed substances. Furthermore, since the cells remain in good condition, there is greatly reduced cell death and disintegration, with resulting diminished release of dangerous products. Dead hepatocytes, their breakdown products and cell debris are able to settle to the bottom of the bioreactor from where they may be easily cleared.
  • the continued viability and function of the cells allow prolonged use of the equipment in patient treatment up to and including continuous treatment for hours, days or weeks without replacement of the hepatocytes.
  • the overall effect is to improve the logistics and efficacy of treatment.
  • Fluid from the bioreactor may be pumped through the first circuit to circulate in a reverse direction through the extra-fibre compartment of a dialysis cartridge, and is then returned to the bioreactor.
  • Blood may pass or be pumped through the second circuit from the patient in the forward direction through the hollow fibres of the dialysis cartridge, and is then returned to the patient.
  • a subsidiary circuit may be incorporated into the system.
  • Detoxified filtrate from the bioreactor may be directed through a second dialysis cartridge, and filtrate from the second cartridge may then pass on to the first cartridge or be returned to the patient.
  • the use of subsidiary circuits permits viruses and other infective agents to be continuously cleared from the patient's circulation. Also, infective agents from the bioreactor may be prevented from accessing the patient's circulation.
  • the semi-permeable membrane pore sizes of the second cartridge may be smaller than those of the first cartridge. The smaller pores may prevent access of large molecule toxic or infective agents to the patient, and allow enhanced metabolism of the toxic molecules from the patient's blood because of recirculation through the bioreactor.
  • the larger pore sizes of the first cartridge may allow passage of large molecule toxic products from the patient's blood.
  • Plasma proteins and coagulation factors may be administered separately by intravenous infusion.
  • a third dialysis cartridge may be added to receive the modulated filtrate emerging from the second cartridge and filter it again before passing it to the first cartridge.
  • blood from the patient may circulate through a dialysis cartridge or an apherisis system.
  • Blood filtrate may be pumped from the dialysis cartridge, or apherisis system, to the bioreactor.
  • Detoxified fluid containing hepatocyte-synthesised molecules may be returned directly to the patient from the bioreactor after traversing an in-line millipore bacterial filter.
  • Such a system may also be enhanced by returning the detoxified filtrate from the bioreactor through a subsidiary dialysis cartridge.
  • a charcoal filter may be included on the outflow line from the dialysis cartridge or apherisis system to the bioreactor.
  • the equipment can be used in much the same way as that for artificial kidney treatment for patients with renal failure, or that for patients requiring plasmapheresis, and has the same alarms and protective devices. This greatly facilitates usage as medical and paramedical personnel are fully familiar with artificial kidney and plasmapheresis treatments.
  • Anticoagulation may be no more than is required for haemodialysis or plasmapheresis and in many patients may not be necessary.
  • the cartridge or the disposable items of the apherisis system can be replaced without interference with the hepatocytes.
  • Haemodialysis can be incorporated into the system for patients with concurrent renal failure, a frequent complication of fulminant hepatic failure.
  • the invention is a method of processing blood, including the steps of:
  • FIG. 1 is a schematic diagram of a liver biodialysis system embodying the present invention
  • FIG. 2 is a schematic diagram of an enhanced version of the liver biodialysis system of Figure 1;
  • FIG. 3 is a schematic diagram of a further enhanced version of the liver biodialysis system of Figures 1 and 2;
  • FIG 4 is a schematic diagram of a blood filtrate or plasma biomodulation system embodying the present invention
  • Figure 5 is a schematic diagram of an alternative blood filtrate or plasma biomodulation system embodying the present invention.
  • Figure 6 is a schematic diagram of an enhanced version of the blood filtrate or plasma biomodulation system of Figure 4.
  • liver support system 1 includes a bioreactor 2 having a computerised control system indicated generally at 3. Fluid from the bioreactor 2 is pumped through a circuit indicated generally at 4 to circulate in a reverse direction through the extra-fibre compartment of a dialysis cartridge 5. A second circuit indicated generally at 6 passes or pumps blood from the patient through the hollow fibres of the dialysis cartridge 5.
  • the bioreactor includes a containment vessel 7 maintained at constant temperature in a water bath 8.
  • a temperature probe 9 reports temperature to a computer system 10a to allow feedback control of the temperature of the water bath.
  • a gas exchanger 10b receives fluid from the bioreactor 2 via line 11, and injects oxygen, carbon dioxide, nitrogen and air from bottles 12, 13, 14 and 15 respectively, via line 16, in doses measured by computer system 10a and 10b. Fluid from the gas exchanger 10b is returned to the top of the bioreactor by line 17.
  • a dissolved oxygen probe 18 provides a measure of dissolved oxygen to the computer system 10a
  • a pH probe 19 provides a measure of pH to the computer system 10a to allow feedback control of these variables.
  • primary human or animal hepatocytes or animal hepatocyte-derived cell lines are attached to polyester discs or other suitable matrix and bathed in appropriate fluid.
  • Ports are provided for connection to circulation systems, and for monitoring, sampling, variation and removal of the contents of the bioreactor 2.
  • fluid is pumped by pump 22 from the bioreactor via line 23 to the dialysis cartridge 5.
  • Line 23 may incorporate a blood transfusion filter.
  • the fluid flows through the extra-fibre compartments of the cartridge, and returns from the cartridge to the bioreactor via line 25, helped, if needed, by pump 24.
  • blood from the patient 26 is drawn along line 27 and, if required, mixed with anti-coagulant from pump 28, before passing, or being pumped by pump 29 into the dialysis cartridge 5.
  • the patient's blood circulates through the hollow fibres of the dialysis cartridge, dialysing across a semi-permeable membrane against the fluid from the bioreactor which is circulating in the opposite direction. Blood is then returned to the patient along line 30.
  • the directions of the circulations from the patient and from the bioreactor through the dialysis cartridge may be reversed without consequence to the objectives.
  • hepatocytes metabolise the toxic fulminant hepatic failure metabolites and the detoxified fluid returns to the extra-fibre compartments of the dialysis cartridge for further exposure across the semi-permeable membrane to the patient's blood.
  • the hepatocytes in the bioreactor as well as detoxifying, also synthesise molecules such as proteins, enzymes, carrier molecules and coagulation factors. As a result these molecules are at increased concentration in the circulating bioreactor fluid, and therefore pass across the semi-permeable membrane in the cartridge into the patient's blood.
  • a subsidiary circuit 31 can be incorporated into the liver biodialysis system as shown in Figure 2.
  • detoxified fluid from the bioreactor 2 is directed through the hollow fibres of dialysis cartridge 34 and recirculates to the bioreactor via line 35.
  • Filtrate from the extra-fibre compartment of cartridge 34 passes to the extra- fibre compartment of dialysis cartridge 5 along line 36 where it dialyses against the patient's blood before returning to the bioreactor along line 25.
  • the subsidiary circuit 31 acts as a safety device preventing access of large molecule toxic or infective agents to the patient from the bioreactor, or such as might occur in the event of rupture of fibres of cartridge 5. It also allows enhanced metabolism of the toxic molecules from the patient's blood because of recirculation through the bioreactor.
  • cartridge 34 has a pore size less than that of cartridge 5, selective removal of molecules from the patient's blood occurs with trapping in the bioreactor subsidiary circuit 31.
  • the dialysis cartridge 5 has large pore sizes which allow passage of large molecules
  • dialysis cartridge 34 semi-permeable membrane has small pore sizes which prevent the passage of large-molecules
  • large-molecule toxic products and infective agents with sizes greater then the semi-permeable membrane pore sizes of cartridge 34 are continuously removed from the patient's plasma and returned to the bioreactor. Together with cells, cell debris and infective agents from the bioreactor the noxious agents are trapped in the subsidiary circuit and prevented from passing to the patient. Again, the detoxification of the blood is greatly enhanced because of recirculation through the bioreactor.
  • a third dialysis cartridge 37 can be added to the circuit, as shown in Figure 3.
  • modulated filtrate emerges in the extra-fibre compartment of the dialysis cartridge 34 having passed through the pores of the semi-permeable membrane hollow fibres.
  • the filtrate passes to dialysis cartridge 37 along line 36, passing through the semi-permeable membrane before continuing to dialysis cartridge 5 via line 38.
  • the third cartridge 37 acts as a safety filter for large molecule toxic metabolites, cell debris and infective agents in case of fibre rupture in cartridge 34.
  • blood from the patient circulates through a dialysis cartridge 5.
  • Blood filtrate or plasma is pumped from the dialysis cartridge to the bioreactor.
  • Detoxified filtrate or plasma containing hepatocyte-synthesised molecules returns to the patient along return line 23 and 30, the return line being guarded by an in-line millipore bacterial filter 39.
  • a similar arrangement is shown in Figure 5 in which blood circulates through an apherisis system 40.
  • the system of Figure 4 is enhanced by returning the detoxified filtrate from the bioreactor through the hollow fibres of a subsidiary dialysis cartridge 34 from which it recirculates to the bioreactor allowing continued detoxification of metabolites in the bioreactor. Filtrate from the secondary circuit returns to the patient.
  • the hepatocytes may be of human or animal origin or animal or human hepatocyte-derived cell lines.
  • the polyester matrix within the bioreactor may comprise other forms as well as the discs described.
  • the hepatocytes in the bioreactor may be bathed in plasma, serum, blood filtrate or other fluid which circulates from the bioreactor and exchanges with the blood of the patient.
  • a charcoal filter may be included on the outflow line from the dialysis cartridge or apherisis system to the bioreactor.

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  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Anesthesiology (AREA)
  • Hematology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • External Artificial Organs (AREA)

Abstract

L'invention concerne un système d'assistance hépatique. En particulier, l'invention concerne un système artificiel d'assistance hépatique qui fonctionne par biodialyse hépatique, par filtrat sanguin ou par biomodulation plasmatique. L'invention comprend un bioréacteur dans lequel est pratiquée une culture d'hépatocytes; une barrière d'échange présentant deux côtés; un premier circuit disposé de manière à amener un fluide du bioréacteur à un premier côté de la barrière d'échange et inversement; et un second circuit disposé de manière à amener le sang d'un patient à un second côté de la barrière d'échange et inversement.
PCT/AU1998/001065 1997-12-22 1998-12-22 Systeme d'assistance hepatique par biodialyse WO1999032171A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16529/99A AU1652999A (en) 1997-12-22 1998-12-22 A biodialysis system for liver support

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP1085A AUPP108597A0 (en) 1997-12-22 1997-12-22 Liver support system
AUPP1085 1997-12-22

Publications (1)

Publication Number Publication Date
WO1999032171A1 true WO1999032171A1 (fr) 1999-07-01

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Application Number Title Priority Date Filing Date
PCT/AU1998/001065 WO1999032171A1 (fr) 1997-12-22 1998-12-22 Systeme d'assistance hepatique par biodialyse

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AU (1) AUPP108597A0 (fr)
WO (1) WO1999032171A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058496A1 (fr) 2000-02-11 2001-08-16 Allied Therapeutics Limited Systeme destine au traitement extracorporel de sang
US7160719B2 (en) 2002-06-07 2007-01-09 Mayo Foundation For Medical Education And Research Bioartificial liver system
CN100335142C (zh) * 2004-12-24 2007-09-05 浙江大学 适用于人工肝的装置
CN102421467A (zh) * 2009-03-13 2012-04-18 梅约医学教育与研究基金会 生物人工肝
WO2012171182A1 (fr) * 2011-06-14 2012-12-20 Hangzhou Everlong Biotechnics, Co., Ltd. Système dirigé sur cible, à fonctionnalité magnétique pour la détoxification de patients
EP2578081A3 (fr) * 2006-10-11 2013-04-24 The General Hospital Corporation Compositions, procédés et dispositifs pour le traitement des maladies hépatiques
CN104147651A (zh) * 2014-08-01 2014-11-19 周平 全血灌流生物人工肝系统
CN108030968B (zh) * 2018-01-15 2023-12-26 上海赛立维生物科技有限公司 一种用于生物人工肝支持系统的储液池

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016171A1 (fr) * 1992-02-07 1993-08-19 Monsanto Company Foie artificiel biologique
US5328614A (en) * 1979-05-21 1994-07-12 Matsumura Kenneth N Methods and apparati for removing protein-bound molecules from body fluids
WO1996009876A1 (fr) * 1992-09-11 1996-04-04 Xenogenex, Inc. Foie artificiel et son fonctionnement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5328614A (en) * 1979-05-21 1994-07-12 Matsumura Kenneth N Methods and apparati for removing protein-bound molecules from body fluids
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

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058496A1 (fr) 2000-02-11 2001-08-16 Allied Therapeutics Limited Systeme destine au traitement extracorporel de sang
US9650609B2 (en) 2002-06-07 2017-05-16 Mayo Foundation For Medical Education And Research Bioartificial liver system
US7160719B2 (en) 2002-06-07 2007-01-09 Mayo Foundation For Medical Education And Research Bioartificial liver system
US8785117B2 (en) 2002-06-07 2014-07-22 Mayo Foundation For Medical Education And Research Method for treating blood or plasma using hepatocyte spheroids
CN100335142C (zh) * 2004-12-24 2007-09-05 浙江大学 适用于人工肝的装置
US10363276B2 (en) 2006-10-11 2019-07-30 The General Hospital Corporation Compositions, methods, and devices for treating disease
EP2578081A3 (fr) * 2006-10-11 2013-04-24 The General Hospital Corporation Compositions, procédés et dispositifs pour le traitement des maladies hépatiques
CN102421467A (zh) * 2009-03-13 2012-04-18 梅约医学教育与研究基金会 生物人工肝
US10130748B2 (en) 2009-03-13 2018-11-20 Mayo Foundation For Medical Education And Research Bioartificial liver
US10792410B2 (en) 2009-03-13 2020-10-06 Mayo Foundation For Medical Education And Research Bioartificial liver
WO2012171182A1 (fr) * 2011-06-14 2012-12-20 Hangzhou Everlong Biotechnics, Co., Ltd. Système dirigé sur cible, à fonctionnalité magnétique pour la détoxification de patients
CN104147651A (zh) * 2014-08-01 2014-11-19 周平 全血灌流生物人工肝系统
CN108030968B (zh) * 2018-01-15 2023-12-26 上海赛立维生物科技有限公司 一种用于生物人工肝支持系统的储液池

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