US20070062877A1 - Dialysis device - Google Patents

Dialysis device Download PDF

Info

Publication number
US20070062877A1
US20070062877A1 US11/533,734 US53373406A US2007062877A1 US 20070062877 A1 US20070062877 A1 US 20070062877A1 US 53373406 A US53373406 A US 53373406A US 2007062877 A1 US2007062877 A1 US 2007062877A1
Authority
US
United States
Prior art keywords
protein
liver
soy protein
layer
compartment
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US11/533,734
Inventor
Potito Paolis
Saleh Slehmoghaddam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to US11/533,734 priority Critical patent/US20070062877A1/en
Publication of US20070062877A1 publication Critical patent/US20070062877A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01DSEPARATION
    • B01D61/00Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/24Dialysis ; Membrane extraction
    • B01D61/28Apparatus therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/022Artificial gland structures using bioreactors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1694Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes with recirculating dialysing liquid
    • A61M1/1696Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes with recirculating dialysing liquid with dialysate regeneration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A61M1/3489Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents by biological cells, e.g. bioreactor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M2209/00Ancillary equipment
    • A61M2209/08Supports for equipment
    • A61M2209/088Supports for equipment on the body
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01DSEPARATION
    • B01D2319/00Membrane assemblies within one housing
    • B01D2319/06Use of membranes of different materials or properties within one module

Definitions

  • This invention relates to dialysis. More specifically, the invention relates to a device for treating a patient with liver failure and with minor modification can be used to treat a patient with kidney failure.
  • liver transplantation is the favored treatment for serious liver disease or liver failure.
  • the number of suitable liver donors varies and is not always sufficient to meet the demand for liver transplant operations.
  • U.S. Pat. No. 5,866,420 issued Feb. 2, 1999 to Talbot et al. describes continuous cultures of pluripotent parenchymal hepatocytes.
  • the cells are useful in an artificial liver device which may be utilized as temporary liver support for mitigating the pathological effects of liver failure.
  • the use of cultures of cells of a different genotype, such as pig hepatocytes raises the prospect of inter-species disease transfer and the emergence of diseases not previously seen in man.
  • a latent virus integrated into the DNA of a pig cell may not show up in a viral screen. Handling and processing cell cultures is complicated and would add to the cost of the treating a liver failure patient.
  • the '420 patent does not teach or suggest, for example, using soybean protein to treat blood from a patient with liver disease.
  • U.S. Pat. No. 6,653,105 issued Nov. 25, 2003 to Triglia et al. describes a serum-free C3A clonal cell line of possible use in a bio-artificial liver device.
  • the '105 cell line is a liver cell line similar to the cell line described in U.S. Pat. No. 5,290,684.
  • the cell line exhibits liver-specific activity and may therefore be of use in a bio-artificial liver device to treat a patient having or suspected of having a liver condition, liver related disorder or compromised liver function resulting either from disease or trauma (e.g. Fulminate hepatic failure (FHF), awaiting liver transplant or following liver rejection and awaiting liver retransplant).
  • FHF Fulminate hepatic failure
  • vascular filter is composed of: a reinforced membrane unit composed of: a thin filter membrane, and fibers of reinforcement material embedded in the membrane to strengthen the filter and securely attach the fibers to the membrane.
  • the method of fabricating comprises the steps of: providing a mold that can be melted, dissolved, or deformed without damaging membrane material; covering the mold with an intermediate material that is easily separated from the membrane material; covering the intermediate material with the membrane material; placing the fibers in contact with the membrane material that covers the intermediate material; covering the fibers with additional membrane material to form the membrane with embedded fibers; removing the mold by melting, dissolving, or deforming the mold; and removing the intermediate material from the membrane.
  • the '943 device and method does not teach or suggest, for example, using soybean protein in the treatment of a patient with actual or suspected liver disease.
  • U.S. Pat. No. 6,294,380 issued Sep. 25, 2001 to Qiang et al. describes a blood perfusion device used for bioartificial liver support.
  • Human hepatocyte lines established from normal regenerating liver tissue and modulated in toxin-challenging conditions are provided. These functional hepatocytes exhibit extraordinarily enhanced detoxification functions, which are characterized by the elevated glutathione content and glutathione S-transferase activity.
  • a bioreactor is constructed with the functional hepatocytes for bioartificial liver support system, which includes perfusion inlets and perfusion outlets, a containment vessel, a centrifugal pump and macroporous microcarriers where the functional hepatocytes are grown. Relying on human hepatocyte lines to treat a liver patient's blood is complicated and requires a high level of specialist skill.
  • U.S. Pat. No. 3,972,818 issued Aug. 3, 1976 to Bokros describes a device for treating human blood prior to its return to a living human body.
  • the blood filter employs a bed of fibers between about 1 and 100 microns in diameter, the outer surface of which is formed of impermeable carbon.
  • Suitable fibrous substrates may be coated with vapor-deposited pyrolytic carbon, and the fibers may be supported between similarly coated upper and lower screens.
  • the '818 device does not teach or suggest the subject matter of the present invention.
  • a liver dialysis apparatus for treating a patient with liver and/or kidney disease.
  • a liver dialysis apparatus comprises an artificial liver.
  • the artificial liver comprises a blood compartment, a vegetable protein compartment, and a clear dialysis compartment.
  • the liver dialysis apparatus comprises cartridge made up of at least one layer of vegetable protein.
  • a dialysate regeneration device is provided which comprises at least one layer of vegetable protein.
  • the vegetable protein is preferably a soy protein.
  • the soy protein may be unmodified soy protein with urease enzyme activity, modified soy protein with or without urease activity, alone or in combination.
  • FIG. 1 is an environmental perspective view of a mobile liver dialysis device integrated into the design of a belt according to the present invention.
  • FIG. 2 is an environmental perspective view of a compact sized liver dialysis device according to the present invention.
  • FIG. 3A is a schematic representation of a liver dialysis device according to the present invention.
  • FIG. 3B shows a partially cut-away view of an artificial liver according to one aspect of the present invention.
  • FIG. 3C is a schematic representation of an artificial liver that comprises more than one blood compartment.
  • FIG. 4A is a schematic representation of a dialysis system that employs an unconventional dialysate regeneration cartridge according to the present invention.
  • FIG. 4B shows a partially cut away view of a dialyzer of conventional design.
  • the present invention is particularly directed to a device that comprises at least one layer of vegetable protein for removing toxic agents from the blood of a patient with a dysfunctional liver and/or dysfunctional kidney.
  • the vegetable protein may be substantially unmodified or chemically modified with or without urease enzyme activity.
  • the vegetable protein is preferably a legume protein derived from the seeds of leguminous plants such as soybean, cottonseed, peanut, tung nut, castor bean, and linseed, alone or in combination.
  • the protein is substantially unmodified soy protein containing active urease enzyme.
  • the protein is chemically modified soy protein substantially free of urease enzyme activity.
  • the soy protein is chemically modified soy protein with added urease enzyme activity.
  • Soybean is known to be a very healthy legume that contains a high amount of healthy protein that is not normally toxic to man and is necessarily substantially free of animal or liver related disease agents such as the causative agent of hepatitis. Soy protein offers a far safer alternative to animal or human albumin that could harbor undesirable disease agents.
  • Vegetable protein such as soy protein is made up of amino acids linked together to form a three dimensional structure. At least some of the vegetable protein amino acids are hydrophilic such as the serine and threonine amino acids. At least some of the vegetable protein amino acids are hydrophobic such as phenylalanine, leucine and isoleucine. Other amino acids may be charged such as aspartate and lysine, which at physiological pH are respectively negatively and positively charged. (The ionic states of amino acid side chains as a function of pH are found, for example, on page 14 in Chemical Modification Of Proteins (Authors: Gary E. Means and Robert E. Feeney, publisher: San Francisco, Holden-Day [1971], ISBN: 0-81625-561-X, Library of Congress Catalog Card Number: 74-140785).
  • the vegetable amino acids are able to bind to molecules by means of a variety of non-covalent intermolecular binding interactions including hydrogen bonding and other electrostatic interactions, hydrophobic bonding, and non-polar Van der Waal interactions.
  • an amino acid with a side-chain that exhibits a net negative charge has a strong affinity for a liver toxic molecule with a positive charge.
  • a vegetable amino acid with a side chain having a positive charge at a specific pH e.g., lysine
  • Amino acids with non-polar aliphatic side chains such as leucine, isoleucine and valine would tend to non-covalently bind to hydrophobic molecules or hydrophobic parts of molecules.
  • a vegetable protein molecule comprises of numerous residues, i.e. amino acid side-chains, which are available for binding to toxic molecules.
  • the soy protein can be chemically modified in vitro to modify the binding properties of specific side-chains; disulfide bond breaking agents, such as the reducing agent ammoniumthioglycolate (ATG), may be used to break —S—S— bonds to help denature the soy protein molecules to expose internal amino acids for binding to toxic molecules.
  • disulfide bond breaking agents such as the reducing agent ammoniumthioglycolate (ATG)
  • AGT ammoniumthioglycolate
  • Other methods of altering the shape of soy protein are well known and include alkaline hydrolysis, which also breaks the protein backbone at random points to produce variable length soy polypeptides.
  • the amount of hydrolysis should be limited.
  • SDS polyacrylamide gel electrophoresis (SDS-PAGE) along with appropriate molecular weight markers can be used to check the size distribution of the hydrolyzed Soy protein.
  • Unsuitable polypeptide lengths can be selectively discarded using established techniques such as dialysis based on, for example, permeable membranes with molecular weight cut-offs of around 10,000 Daltons to remove the unwanted lower molecular Soy molecules.
  • the molecular weight of the unwanted polypeptides can vary according to the molecular weight cut-offs of the permeable membranes used in the invention. For example, if the membranes have a 5,000 Dalton cut-off, the unsuitable molecular weight range would be less than about 5,000 Daltons. Thus, the invention is not restricted to making use of peptides of greater than 10,000 Daltons, but may make use of lower molecular weight peptides based on the cut-off of the membranes used in the dialysis apparatus according to the invention.
  • the vegetable protein may be further chemically modified using a variety of known techniques and reagents.
  • the terms “chemically modified” or “chemical modification” are used herein to encompass any treatment, such as hydrolysis, carboxylation, oxidation, precipitation or additional separation, which occurs after the vegetable protein material is extracted.
  • the field of chemical modification of proteins is well known in the art and is reviewed, for example, in: (1) Gary E. Means and Robert E.
  • Isolated unmodified soy protein may be prepared by selecting dehulled soybeans that are cracked and flaked for extraction of oil by means of solvent. The oil extraction process and subsequent removal of solvent from the flakes are carried out without undesirable alteration of the protein present in the flakes.
  • To isolate the unmodified protein 1 part of substantially oil-free flakes is slurried with 10 to 20 parts of water and a small amount of alkali is added to increase the solubility of the soy protein. The solution containing the extracted protein is then usually separated from the flake residue by means of shaker screens.
  • the screened solution is subjected to filtration or centrifugation to remove flake fines, and the protein is precipitated from the solution, in the isoelectric range of the protein (usually in the pH range of about 4.0 to 4.5), by means of acid.
  • the protein curds obtained are dewatered and dried to provide unmodified soy protein.
  • the unmodified soy protein curd can be dried to produce a granulated dried protein of greater than 95% purity.
  • this soy isolate which has not otherwise been heated or chemically modified in some fashion, will contain a significant amount of urease enzyme activity, which is an inherent component of uncooked or unmodified soy protein.
  • Urease enzyme activity can also be maintained in soy protein that has been modified by adding urease to the modified protein.
  • the soy protein may be oxidized and provided with urease activity by carrying out the following steps: (1) forming a slurry of a urease containing unmodified soy protein with a proteinaceous solids content of 10 to 30% by weight; (2) adding to the slurry a sufficient amount of urea to react with the urease therein to produce ammonia sufficient to increase the pH of the slurry to a value above about pH 8.0; (3) adding an oxidizing agent to the slurry in an amount and for a time sufficient to improve the rheological properties by lowering the viscosity of the protein material; and (4) adding urease enzyme back into the oxidized (i.e., modified) slurry to provide a modified soy protein slurry with urease activity; and (5) gently drying the modified urease containing soy protein slurry for later incorporation into a liver or kidney dialysis device
  • the modified soy protein is intended to treat a patient with abnormal liver function and normal kidney function, the modified soy protein need not contain urease activity; therefore, step (4) may be skipped, i.e. urease enzyme need not be added to the modified soy protein.
  • the types of soy protein may be mixed, e.g. modified with unmodified soy protein.
  • the soy protein component may vary in form: unmodified urease containing soy protein, modified soy protein lacking urease activity, modified soy protein with urease activity, alone or in combination. It will be understood that the handling and processing of the soy protein should be undertaken to meet the appropriate legal standards, including but not limited to: use of a clean facility, and practicing where possible aseptic technique to avoid contaminating the soy protein with undesirable matter.
  • FIG. 1 shows one embodiment of the present invention.
  • a liver dialysis device 100 (represented by the alpha-numeric label “ 100 a ”) is shown integrated into a belt 120 that can be worn by a patient 140 with liver disease or suspected liver disease.
  • Visible in the belt 120 is an artificial liver 160 , a regeneration device 180 that purifies the dialysis liquid (dialysate), and a power supply 200 .
  • Tubes 220 and 240 provide appropriate arterial and venous access between the artificial liver 160 and the patient 140 .
  • the extracorporeal transport of the patient's blood through tubes 220 and 240 may be assisted by a blood pump 380 (see FIG. 3A ); the blood flow rate should be at least about 250 milliliters per minute (ml/min), and preferably in the range between about 250 ml/min and about 500 ml/min.
  • FIG. 2 shows another embodiment of the present invention. Specifically, a liver dialysis device 100 (represented by the alpha-numeric label “ 100 b ”) is shown integrated into a housing 260 . The device 100 b is shown positioned next to a liver patient 140 .
  • FIG. 3A is a schematic representation of a liver dialyzer device 100 (represented by the alpha-numeric label “ 100 c ”).
  • An artificial liver 160 is shown comprising at least one blood compartment 280 , a soy protein compartment 300 , and a clear dialysis compartment 320 .
  • a first selectively permeable membrane 340 separates compartments 280 and 300 .
  • a second selectively permeable membrane 360 separates compartments 300 and 320 .
  • the membranes 340 and 360 may be in any suitable form, for instance in that of flat or tubular film (see FIG. 3B ), or it may comprise a large number of hollow fibers.
  • the blood compartment 280 is connected to the circulatory system of a patient 140 by means of tubes 220 and 240 . If necessary, the extracorporeal transport of the blood may be assisted by a blood pump 380 .
  • the blood pump 380 may be integrated into the design of, for example, the artificial liver 160 .
  • Dialysis liquid flows through compartment 320 and circulates through a dialysis circuit 400 by means of a dialysate pump 420 .
  • Dialysate enters compartment 300 from compartment 320 thereby allowing an interchange across membrane 340 .
  • the molecular weight of the protein molecules inside compartment 300 are such that they are unable to penetrate membranes 340 or 360 , but smaller molecules that don't bind to the protein are able to transfer across membrane 340 and into circuit 400 for selective removal by the dialysate regeneration device 180 .
  • FIG. 3C shows an artificial liver 160 (shown as 160 a ), wherein the tube 220 directs patient blood to more than one blood compartment 280 (shown as 280 a , 280 b , and 280 c ). Since volume increases by the cube and surface area by the square the ratio of surface area to volume ratio is more favorable as volume decreases. Thus, the rate of exchange across membrane 340 improves with lower cross section area of the at least one blood compartment 280 . However, the cross section area of the at least one blood compartment 280 should be sufficient not to obstruct the flow of blood through blood compartment 280 .
  • dialysate pump 420 may be integrated into the design of the regeneration device 180 .
  • the location of the flow meter 500 may also vary without detracting from the spirit of the present invention.
  • the term “clear” as used in “clear dialysis compartment 320 ” is intended to mean “substantially clear of soy protein”; the membrane 360 serves to allow the interchange of dialysate between the compartments 300 and 320 while preventing transfer of soy protein molecules from soy protein compartment 300 into clear dialysate compartment 320 ; incidentally, membrane 340 prevents transfer of soy protein molecules from soy protein compartment 300 into blood compartment 280 .
  • Toxic molecules from the blood compartment 280 transfer into the soy protein compartment 300 for absorption by the soy protein held therein, toxic molecules not absorbed are free to transfer across membrane 360 into the clear dialysate compartment 320 which forms part of the dialysate circuit 400 .
  • the membrane 340 is rated to be impermeable to blood cells, including white and red blood cells, but is permeable to electrolytes and molecules up to about 10,000 Daltons.
  • the membrane 360 is preferably permeable to electrolytes and molecules up to about 10,000 Daltons; however, the molecular weight cut-offs of the membranes 340 and 360 can be dissimilar. Also, the membranes 340 and 360 may be dissimilar and may separately take the form of a flat or tubular film, or hollow fibers. Waste products not absorbed by the soy protein in compartment 300 are transferred across the membrane 360 into the clear dialysate compartment 320 .
  • the soy protein may be unmodified soy protein with urease activity, modified protein with urease activity, and modified protein absent urease activity, alone or in combination. It is preferred that if the patient 140 is not suffering from kidney failure (i.e. liver failure absent kidney failure) the soy protein is modified protein absent urease activity.
  • dialysis circuit 400 comprises a regeneration device 180 adapted to purify the dialysate (dialysis liquid) from the waste products it has taken up from compartment 300 . More specifically, the device 180 converts used dialysate back into “fresh” or reconstituted dialysate.
  • the regeneration device 180 may consist of several layers connected in series or in parallel, which each serve to eliminate one or more waste products.
  • the cartridge may be of conventional design such as the REDYTM purification cartridge as used in the REDYTM dialysis system.
  • the REDYTM purification cartridge comprises five layers through which used dialysate passes: (i) a purification layer comprising of activated charcoal; (ii) an enzyme layer comprising of urease; (iii) a cation exchange layer comprising of zirconium oxide; (iv) and anion exchange layer comprising of hydrated zirconium oxide; and (v) an absorbent layer comprising again of activated charcoal.
  • a purification layer comprising of activated charcoal
  • an enzyme layer comprising of urease
  • a cation exchange layer comprising of zirconium oxide
  • anion exchange layer comprising of hydrated zirconium oxide
  • an absorbent layer comprising again of activated charcoal.
  • the regeneration device 180 may comprise a layer of vegetable protein such as soy protein (unmodified, modified with or without urease enzyme activity, alone or in combination); the layer of vegetable protein may replace or act as a partial substitute for the activated charcoal layer normally found in conventional dialysate regeneration cartridges such as that used in the REDYTM dialysis system.
  • the layers in device 180 may be in series or in parallel.
  • the regeneration device 180 need not have a layer comprising of urease enzyme.
  • the vegetable protein is unmodified vegetable protein with urease activity and/or modified protein with added urease activity there is no requirement for a separate layer of urease activity in device 180 .
  • the regeneration device 180 may comprise of four layers: (i) a purification layer comprising of activated charcoal; (ii) a cation exchange layer comprising of zirconium oxide; (iii) and anion exchange layer comprising of hydrated zirconium oxide; and (iv) an absorbent layer comprising again of activated charcoal.
  • the charcoal layers are left out or diminished in device 180 ; for example, the regeneration device 180 may be made of just three layers: (i) a cation exchange layer comprising of zirconium oxide; (ii) an anion exchange layer comprising of hydrated zirconium oxide; and (iii) a layer comprising activated charcoal.
  • ammonia scavenger may be incorporated into device 180 , e.g. as a separate layer comprising of ammonia scavenger or mixed with another layer in device 180 .
  • Any suitable ammonia scavenger may be used such as a particulate magnesium phosphate product as described in U.S. Pat. No. 4,650,587 (issued Mar.
  • a dialysate pump 420 in the dialysis circuit 400 there are: a dialysate pump 420 , an optional vessel 440 to hold reconstituted dialysate, dialysate temperature probe 460 , a dialysate heater 480 , and a flow meter 500 .
  • the order of devices in the circuit 400 may vary; additionally, the devices may be integrated into single functional members, e.g., the temperature probe 460 and heater 480 might be integrated and operated under the control of a dedicated temperature controller.
  • the terms “reconstituted dialysate” and “fresh dialysate” are regarded as equivalent terms.
  • the devices 420 , 460 , 480 , 500 are monitored and/or operated by a controller 520 adapted to perform logic operations based on a control algorithm.
  • the controller 520 monitors and controls the function of the pump 420 (in response to data received from, for example, the flow meter 500 ), and heater 480 is switched on or off (in response to data received from the temperature probe 460 ).
  • a power supply 200 is connected to all parts that require power such as, for example, the controller 520 and dialysate pump 420 .
  • FIG. 4A is a schematic representation of a further embodiment of the present invention 100 d employing a novel dialysate regeneration cartridge 180 a ; the cartridge 180 a comprises at least one layer of vegetable protein such as soy protein.
  • the dialysate regeneration cartridge 180 a is used in conjunction with a dialyzer of conventional design (represented by the alpha-numeral “ 160 b ”).
  • the conventional dialyzer 160 b operates much in the same way as an artificial kidney as described in column 6, lines 44-56 in U.S. Pat. No. 4,213,859 (issued Jul. 22, 1980 to Smakman et al); the '859 patent is hereby incorporated by reference in its entirety.
  • FIG. 4B shows a partially cut away view of dialyzer 160 b .
  • Dialyzer 160 b has a blood compartment 280 and a clearance or dialysis compartment 320 separated by a selectively permeable membrane 365 .
  • the membrane 365 may be in any desirable form, for instance in that of flat or tubular film, or it may be a large number of hollow fibers.
  • Dialysis liquid flows through compartment 300 and circulates through the dialysis circuit 400 as shown in FIG. 4A .
  • the dialysate regeneration device 180 a comprises at least one layer of vegetable protein.
  • the vegetable protein may be unmodified or modified soy protein with or without urease enzyme activity.
  • the layer of vegetable protein may replace or complement a charcoal layer as found in the REDYTM purification cartridge.
  • the dialysate regeneration cartridge 180 a may comprise of the following layers: (i) a layer of vegetable protein; (ii) a cation exchange layer comprising of zirconium oxide; (iii) and anion exchange layer comprising of hydrated zirconium oxide; and (iv) a layer comprising of activated charcoal.
  • the composition of the layer of vegetable protein in cartridge 180 a may vary.
  • Cartridge 180 a may comprise a layer of modified or unmodified soy protein with or without urease enzyme activity.
  • the layer of vegetable protein may be made of a combination of modified and unmodified soy protein with or without urease enzyme activity.
  • the order of layers with respect to dialysate flow may vary, though it is preferable to have a purification layer downstream of the cation and anion exchange layers, e.g. a layer of activated charcoal downstream of the ion exchange layers.
  • Dialysate regeneration device 180 a enables a conventional dialyzer 160 b to be used to treat a patient 140 with liver and/or kidney disease.

Abstract

A dialysis apparatus for treating a patient with liver and/or kidney disease. In one embodiment a liver dialysis apparatus comprises an artificial liver. The artificial liver comprises a blood compartment, a vegetable protein compartment, and a clear dialysis compartment. In another embodiment the liver dialysis apparatus comprises cartridge made up of at least one layer of vegetable protein. In a further embodiment of the invention a dialysate regeneration device is provided which comprises at least one layer of vegetable protein. The vegetable protein is preferably a soy protein. The soy protein may be unmodified soy protein with urease enzyme activity, modified soy protein with or without urease activity, alone or in combination.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application is a divisional patent application of patent application Ser. No. 10/793,792 filed on Mar. 8, 2004.
  • STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • Not Applicable.
  • FIELD OF THE INVENTION
  • This invention relates to dialysis. More specifically, the invention relates to a device for treating a patient with liver failure and with minor modification can be used to treat a patient with kidney failure.
  • BACKGROUND OF THE INVENTION
  • Treatment options for liver disease are limited. Liver transplantation is the favored treatment for serious liver disease or liver failure. However, the number of suitable liver donors varies and is not always sufficient to meet the demand for liver transplant operations. Thus, there is a need for a way to treat patients with liver failure.
  • A review of the prior art follows.
  • The topic of artificial livers is discussed in a world wide web (www) article entitled “Artificial Liver” at URL: http://www.organtx.org/bioart/liver.htm. The article notes that a healthy liver is able to get toxic particles out of the blood by separating them from a sticky carrier protein called albumin. Thus, if the liver fails the toxins stay in the blood and harm nerves, increase pressure in the brain, and damage other important systems. Despite years of research, no machine has been able to remove toxins without harming liver failure patients. One system described is the albumin dialysis system, where albumin is combined with hollow fibers to remove toxins from the blood of a patient with liver problems. Albumin is an animal protein that requires extraction from animals. Animals are known to be source of animal diseases that can harm man. Thus, there is a need for a non-animal sticky protein that can act as an absorbent to remove toxins from the blood of a patient with liver disease.
  • U.S. Pat. No. 5,866,420 issued Feb. 2, 1999 to Talbot et al., describes continuous cultures of pluripotent parenchymal hepatocytes. In combination with feeder cells and, optionally, adult pig hepatocytes and macrophages, the cells are useful in an artificial liver device which may be utilized as temporary liver support for mitigating the pathological effects of liver failure. The use of cultures of cells of a different genotype, such as pig hepatocytes, raises the prospect of inter-species disease transfer and the emergence of diseases not previously seen in man. A latent virus integrated into the DNA of a pig cell may not show up in a viral screen. Handling and processing cell cultures is complicated and would add to the cost of the treating a liver failure patient. In addition, the '420 patent does not teach or suggest, for example, using soybean protein to treat blood from a patient with liver disease.
  • U.S. Pat. No. 6,653,105 issued Nov. 25, 2003 to Triglia et al., describes a serum-free C3A clonal cell line of possible use in a bio-artificial liver device. The '105 cell line is a liver cell line similar to the cell line described in U.S. Pat. No. 5,290,684. The cell line exhibits liver-specific activity and may therefore be of use in a bio-artificial liver device to treat a patient having or suspected of having a liver condition, liver related disorder or compromised liver function resulting either from disease or trauma (e.g. Fulminate hepatic failure (FHF), awaiting liver transplant or following liver rejection and awaiting liver retransplant). Maintaining the viability of the serum-free C3A clonal cell line is complicated and requires a high level of specialist skill not generally found in a liver failure unit in a general hospital. Therefore, there is a need for a device to treat patients with a liver condition, or suspected liver condition, that does not rely on maintaining a viable line of liver cells in an artificial environment.
  • U.S. Pub. No. 20030153943 published Aug. 14, 2003 to Michael et al., describes a medical device, such as a vascular filter, and a method of making the same. The vascular filter is composed of: a reinforced membrane unit composed of: a thin filter membrane, and fibers of reinforcement material embedded in the membrane to strengthen the filter and securely attach the fibers to the membrane. The method of fabricating comprises the steps of: providing a mold that can be melted, dissolved, or deformed without damaging membrane material; covering the mold with an intermediate material that is easily separated from the membrane material; covering the intermediate material with the membrane material; placing the fibers in contact with the membrane material that covers the intermediate material; covering the fibers with additional membrane material to form the membrane with embedded fibers; removing the mold by melting, dissolving, or deforming the mold; and removing the intermediate material from the membrane. The '943 device and method does not teach or suggest, for example, using soybean protein in the treatment of a patient with actual or suspected liver disease.
  • U.S. Pat. No. 6,294,380 issued Sep. 25, 2001 to Qiang et al., describes a blood perfusion device used for bioartificial liver support. Human hepatocyte lines established from normal regenerating liver tissue and modulated in toxin-challenging conditions are provided. These functional hepatocytes exhibit extraordinarily enhanced detoxification functions, which are characterized by the elevated glutathione content and glutathione S-transferase activity. A bioreactor is constructed with the functional hepatocytes for bioartificial liver support system, which includes perfusion inlets and perfusion outlets, a containment vessel, a centrifugal pump and macroporous microcarriers where the functional hepatocytes are grown. Relying on human hepatocyte lines to treat a liver patient's blood is complicated and requires a high level of specialist skill.
  • U.S. Pat. No. 3,972,818 issued Aug. 3, 1976 to Bokros, describes a device for treating human blood prior to its return to a living human body. The blood filter employs a bed of fibers between about 1 and 100 microns in diameter, the outer surface of which is formed of impermeable carbon. Suitable fibrous substrates may be coated with vapor-deposited pyrolytic carbon, and the fibers may be supported between similarly coated upper and lower screens. The '818 device does not teach or suggest the subject matter of the present invention.
  • None of the above inventions and patents, taken either singly or in combination, is seen to describe the present invention as claimed.
  • SUMMARY OF THE INVENTION
  • The invention is directed to a dialysis apparatus for treating a patient with liver and/or kidney disease. In one embodiment a liver dialysis apparatus comprises an artificial liver. The artificial liver comprises a blood compartment, a vegetable protein compartment, and a clear dialysis compartment. In another embodiment the liver dialysis apparatus comprises cartridge made up of at least one layer of vegetable protein. In a further embodiment of the invention a dialysate regeneration device is provided which comprises at least one layer of vegetable protein. The vegetable protein is preferably a soy protein. The soy protein may be unmodified soy protein with urease enzyme activity, modified soy protein with or without urease activity, alone or in combination.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is an environmental perspective view of a mobile liver dialysis device integrated into the design of a belt according to the present invention.
  • FIG. 2 is an environmental perspective view of a compact sized liver dialysis device according to the present invention.
  • FIG. 3A is a schematic representation of a liver dialysis device according to the present invention.
  • FIG. 3B shows a partially cut-away view of an artificial liver according to one aspect of the present invention.
  • FIG. 3C is a schematic representation of an artificial liver that comprises more than one blood compartment.
  • FIG. 4A is a schematic representation of a dialysis system that employs an unconventional dialysate regeneration cartridge according to the present invention.
  • FIG. 4B shows a partially cut away view of a dialyzer of conventional design.
  • Similar reference characters denote corresponding features consistently throughout the attached drawings.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • Specific structural and functional details disclosed hereby are not to be interpreted as limiting, but merely as providing a proper basis for the claims and as a representative basis for teaching one of ordinary skill in the art how to practice the invention.
  • The present invention is particularly directed to a device that comprises at least one layer of vegetable protein for removing toxic agents from the blood of a patient with a dysfunctional liver and/or dysfunctional kidney. The vegetable protein may be substantially unmodified or chemically modified with or without urease enzyme activity. The vegetable protein is preferably a legume protein derived from the seeds of leguminous plants such as soybean, cottonseed, peanut, tung nut, castor bean, and linseed, alone or in combination.
  • In one embodiment of the invention, the protein is substantially unmodified soy protein containing active urease enzyme. In another embodiment of the invention, the protein is chemically modified soy protein substantially free of urease enzyme activity. In a still further embodiment of the invention, the soy protein is chemically modified soy protein with added urease enzyme activity.
  • Soybean is known to be a very healthy legume that contains a high amount of healthy protein that is not normally toxic to man and is necessarily substantially free of animal or liver related disease agents such as the causative agent of hepatitis. Soy protein offers a far safer alternative to animal or human albumin that could harbor undesirable disease agents.
  • Vegetable protein such as soy protein is made up of amino acids linked together to form a three dimensional structure. At least some of the vegetable protein amino acids are hydrophilic such as the serine and threonine amino acids. At least some of the vegetable protein amino acids are hydrophobic such as phenylalanine, leucine and isoleucine. Other amino acids may be charged such as aspartate and lysine, which at physiological pH are respectively negatively and positively charged. (The ionic states of amino acid side chains as a function of pH are found, for example, on page 14 in Chemical Modification Of Proteins (Authors: Gary E. Means and Robert E. Feeney, publisher: San Francisco, Holden-Day [1971], ISBN: 0-81625-561-X, Library of Congress Catalog Card Number: 74-140785).
  • The vegetable amino acids are able to bind to molecules by means of a variety of non-covalent intermolecular binding interactions including hydrogen bonding and other electrostatic interactions, hydrophobic bonding, and non-polar Van der Waal interactions. For example, an amino acid with a side-chain that exhibits a net negative charge has a strong affinity for a liver toxic molecule with a positive charge. Conversely, a vegetable amino acid with a side chain having a positive charge at a specific pH (e.g., lysine) would bind to a liver toxic molecule with a negative charge. Amino acids with non-polar aliphatic side chains such as leucine, isoleucine and valine would tend to non-covalently bind to hydrophobic molecules or hydrophobic parts of molecules. Thus, a vegetable protein molecule comprises of numerous residues, i.e. amino acid side-chains, which are available for binding to toxic molecules.
  • To render more of the amino-acid side chains of the soy protein molecules available to bind to toxic molecules, the soy protein can be chemically modified in vitro to modify the binding properties of specific side-chains; disulfide bond breaking agents, such as the reducing agent ammoniumthioglycolate (ATG), may be used to break —S—S— bonds to help denature the soy protein molecules to expose internal amino acids for binding to toxic molecules. Other methods of altering the shape of soy protein are well known and include alkaline hydrolysis, which also breaks the protein backbone at random points to produce variable length soy polypeptides.
  • Since it is important that the dialysate is not contaminated with low molecular weight soy polypeptides (for example, under 10,000 Daltons) the amount of hydrolysis should be limited. SDS polyacrylamide gel electrophoresis (SDS-PAGE) along with appropriate molecular weight markers can be used to check the size distribution of the hydrolyzed Soy protein. Unsuitable polypeptide lengths can be selectively discarded using established techniques such as dialysis based on, for example, permeable membranes with molecular weight cut-offs of around 10,000 Daltons to remove the unwanted lower molecular Soy molecules.
  • It will be understood that the molecular weight of the unwanted polypeptides can vary according to the molecular weight cut-offs of the permeable membranes used in the invention. For example, if the membranes have a 5,000 Dalton cut-off, the unsuitable molecular weight range would be less than about 5,000 Daltons. Thus, the invention is not restricted to making use of peptides of greater than 10,000 Daltons, but may make use of lower molecular weight peptides based on the cut-off of the membranes used in the dialysis apparatus according to the invention.
  • In addition to breaking —S—S— bonds, the vegetable protein may be further chemically modified using a variety of known techniques and reagents. The terms “chemically modified” or “chemical modification” are used herein to encompass any treatment, such as hydrolysis, carboxylation, oxidation, precipitation or additional separation, which occurs after the vegetable protein material is extracted. The field of chemical modification of proteins is well known in the art and is reviewed, for example, in: (1) Gary E. Means and Robert E. Feeney in Chemical Modification Of Proteins (publisher: San Francisco, Holden-Day (1971), ISBN: 0-81625-561-X, Library of Congress Catalog Card Number: 74-140785); (2) Nashef et al., Effects of Alkali on Proteins, Disulfides and Their Products, J. Agric. Food Chem., Vol. 25, No. 2, (1977), pp 245-251; and (3) McKinney and Uhing, Carboxymethylated Soybean Protein, J. Amer. Oil Chem. Soc., Vol. 36, No. 2, (1959), pp 49-51. The Means and Feeney, Nashef, and McKinney references are hereby incorporated by reference in their entirety.
  • Isolated unmodified soy protein may be prepared by selecting dehulled soybeans that are cracked and flaked for extraction of oil by means of solvent. The oil extraction process and subsequent removal of solvent from the flakes are carried out without undesirable alteration of the protein present in the flakes. To isolate the unmodified protein, 1 part of substantially oil-free flakes is slurried with 10 to 20 parts of water and a small amount of alkali is added to increase the solubility of the soy protein. The solution containing the extracted protein is then usually separated from the flake residue by means of shaker screens. The screened solution is subjected to filtration or centrifugation to remove flake fines, and the protein is precipitated from the solution, in the isoelectric range of the protein (usually in the pH range of about 4.0 to 4.5), by means of acid. The protein curds obtained are dewatered and dried to provide unmodified soy protein. Specifically, after the isoelectric precipitation step the unmodified soy protein curd can be dried to produce a granulated dried protein of greater than 95% purity. Typically, this soy isolate, which has not otherwise been heated or chemically modified in some fashion, will contain a significant amount of urease enzyme activity, which is an inherent component of uncooked or unmodified soy protein. The natural urease activity enables the soy protein to convert urea into ammonia, and may be used in the invention as described below. For further information see, for example, U.S. Pat. No. 4,352,692 (issued Oct. 5, 1982 to Krinski et al); the '692 patent is hereby incorporated by reference in its entirety. In addition, the manufacture and chemistry of isolated soy protein is discussed in chapters five and six of the TAPPI Monograph Series-No. 9 (PROTEIN and SYNTHETIC ADHESIVES for Paper Coating, TAPPI Monograph Series-No. 9, (1952), pp 84-108); chapters five and six are herein incorporated by reference in their entirety.
  • Urease enzyme activity can also be maintained in soy protein that has been modified by adding urease to the modified protein. For example, the soy protein may be oxidized and provided with urease activity by carrying out the following steps: (1) forming a slurry of a urease containing unmodified soy protein with a proteinaceous solids content of 10 to 30% by weight; (2) adding to the slurry a sufficient amount of urea to react with the urease therein to produce ammonia sufficient to increase the pH of the slurry to a value above about pH 8.0; (3) adding an oxidizing agent to the slurry in an amount and for a time sufficient to improve the rheological properties by lowering the viscosity of the protein material; and (4) adding urease enzyme back into the oxidized (i.e., modified) slurry to provide a modified soy protein slurry with urease activity; and (5) gently drying the modified urease containing soy protein slurry for later incorporation into a liver or kidney dialysis device of the present invention. If the modified soy protein is intended to treat a patient with abnormal liver function and normal kidney function, the modified soy protein need not contain urease activity; therefore, step (4) may be skipped, i.e. urease enzyme need not be added to the modified soy protein. In addition, the types of soy protein may be mixed, e.g. modified with unmodified soy protein. Thus, it should be clear that the soy protein component may vary in form: unmodified urease containing soy protein, modified soy protein lacking urease activity, modified soy protein with urease activity, alone or in combination. It will be understood that the handling and processing of the soy protein should be undertaken to meet the appropriate legal standards, including but not limited to: use of a clean facility, and practicing where possible aseptic technique to avoid contaminating the soy protein with undesirable matter.
  • Referring now to the figures.
  • FIG. 1 shows one embodiment of the present invention. Specifically, a liver dialysis device 100 (represented by the alpha-numeric label “100 a”) is shown integrated into a belt 120 that can be worn by a patient 140 with liver disease or suspected liver disease. Visible in the belt 120 is an artificial liver 160, a regeneration device 180 that purifies the dialysis liquid (dialysate), and a power supply 200. Tubes 220 and 240 provide appropriate arterial and venous access between the artificial liver 160 and the patient 140. If necessary, the extracorporeal transport of the patient's blood through tubes 220 and 240 may be assisted by a blood pump 380 (see FIG. 3A); the blood flow rate should be at least about 250 milliliters per minute (ml/min), and preferably in the range between about 250 ml/min and about 500 ml/min.
  • FIG. 2 shows another embodiment of the present invention. Specifically, a liver dialysis device 100 (represented by the alpha-numeric label “100 b”) is shown integrated into a housing 260. The device 100 b is shown positioned next to a liver patient 140.
  • FIG. 3A is a schematic representation of a liver dialyzer device 100 (represented by the alpha-numeric label “100 c”). An artificial liver 160 is shown comprising at least one blood compartment 280, a soy protein compartment 300, and a clear dialysis compartment 320. A first selectively permeable membrane 340 separates compartments 280 and 300. A second selectively permeable membrane 360 separates compartments 300 and 320. The membranes 340 and 360 may be in any suitable form, for instance in that of flat or tubular film (see FIG. 3B), or it may comprise a large number of hollow fibers. The blood compartment 280 is connected to the circulatory system of a patient 140 by means of tubes 220 and 240. If necessary, the extracorporeal transport of the blood may be assisted by a blood pump 380. The blood pump 380 may be integrated into the design of, for example, the artificial liver 160.
  • Dialysis liquid flows through compartment 320 and circulates through a dialysis circuit 400 by means of a dialysate pump 420. Dialysate enters compartment 300 from compartment 320 thereby allowing an interchange across membrane 340. The molecular weight of the protein molecules inside compartment 300 are such that they are unable to penetrate membranes 340 or 360, but smaller molecules that don't bind to the protein are able to transfer across membrane 340 and into circuit 400 for selective removal by the dialysate regeneration device 180.
  • It should be understood that the exact arrangement and layout of the artificial liver 160 might vary. For example, FIG. 3C shows an artificial liver 160 (shown as 160 a), wherein the tube 220 directs patient blood to more than one blood compartment 280 (shown as 280 a, 280 b, and 280 c). Since volume increases by the cube and surface area by the square the ratio of surface area to volume ratio is more favorable as volume decreases. Thus, the rate of exchange across membrane 340 improves with lower cross section area of the at least one blood compartment 280. However, the cross section area of the at least one blood compartment 280 should be sufficient not to obstruct the flow of blood through blood compartment 280.
  • It will be understood that the order and arrangement of the various functional members in the dialysis circuit 400 may vary. For example, the dialysate pump 420 may be integrated into the design of the regeneration device 180. The location of the flow meter 500 may also vary without detracting from the spirit of the present invention.
  • It should be understood that the term “clear” as used in “clear dialysis compartment 320” is intended to mean “substantially clear of soy protein”; the membrane 360 serves to allow the interchange of dialysate between the compartments 300 and 320 while preventing transfer of soy protein molecules from soy protein compartment 300 into clear dialysate compartment 320; incidentally, membrane 340 prevents transfer of soy protein molecules from soy protein compartment 300 into blood compartment 280. Toxic molecules from the blood compartment 280 transfer into the soy protein compartment 300 for absorption by the soy protein held therein, toxic molecules not absorbed are free to transfer across membrane 360 into the clear dialysate compartment 320 which forms part of the dialysate circuit 400.
  • The membrane 340 is rated to be impermeable to blood cells, including white and red blood cells, but is permeable to electrolytes and molecules up to about 10,000 Daltons. The membrane 360 is preferably permeable to electrolytes and molecules up to about 10,000 Daltons; however, the molecular weight cut-offs of the membranes 340 and 360 can be dissimilar. Also, the membranes 340 and 360 may be dissimilar and may separately take the form of a flat or tubular film, or hollow fibers. Waste products not absorbed by the soy protein in compartment 300 are transferred across the membrane 360 into the clear dialysate compartment 320. The soy protein may be unmodified soy protein with urease activity, modified protein with urease activity, and modified protein absent urease activity, alone or in combination. It is preferred that if the patient 140 is not suffering from kidney failure (i.e. liver failure absent kidney failure) the soy protein is modified protein absent urease activity.
  • Still referring to FIG. 3A, dialysis circuit 400 comprises a regeneration device 180 adapted to purify the dialysate (dialysis liquid) from the waste products it has taken up from compartment 300. More specifically, the device 180 converts used dialysate back into “fresh” or reconstituted dialysate. The regeneration device 180 may consist of several layers connected in series or in parallel, which each serve to eliminate one or more waste products. The cartridge may be of conventional design such as the REDY™ purification cartridge as used in the REDY™ dialysis system. The REDY™ purification cartridge comprises five layers through which used dialysate passes: (i) a purification layer comprising of activated charcoal; (ii) an enzyme layer comprising of urease; (iii) a cation exchange layer comprising of zirconium oxide; (iv) and anion exchange layer comprising of hydrated zirconium oxide; and (v) an absorbent layer comprising again of activated charcoal. Organon Teknika Corporation of Oklahoma City, Okla., USA, supplies the REDY™ dialysis system. Alternatively, the regeneration device 180 may comprise a layer of vegetable protein such as soy protein (unmodified, modified with or without urease enzyme activity, alone or in combination); the layer of vegetable protein may replace or act as a partial substitute for the activated charcoal layer normally found in conventional dialysate regeneration cartridges such as that used in the REDY™ dialysis system. The layers in device 180 may be in series or in parallel.
  • When urease enzyme activity is present in the vegetable protein in compartment 300 the regeneration device 180 need not have a layer comprising of urease enzyme. Specifically, when the vegetable protein is unmodified vegetable protein with urease activity and/or modified protein with added urease activity there is no requirement for a separate layer of urease activity in device 180. For example, the regeneration device 180 may comprise of four layers: (i) a purification layer comprising of activated charcoal; (ii) a cation exchange layer comprising of zirconium oxide; (iii) and anion exchange layer comprising of hydrated zirconium oxide; and (iv) an absorbent layer comprising again of activated charcoal. Preferably the charcoal layers are left out or diminished in device 180; for example, the regeneration device 180 may be made of just three layers: (i) a cation exchange layer comprising of zirconium oxide; (ii) an anion exchange layer comprising of hydrated zirconium oxide; and (iii) a layer comprising activated charcoal.
  • Where ammonia remains a problem due to urease activity an ammonia scavenger may be incorporated into device 180, e.g. as a separate layer comprising of ammonia scavenger or mixed with another layer in device 180. Any suitable ammonia scavenger may be used such as a particulate magnesium phosphate product as described in U.S. Pat. No. 4,650,587 (issued Mar. 17, 1987 to Polak et al) with the general formula (Mg)x(H)y (PO4)z, wherein when “z” has an assigned value of 1, “x” has a value greater than 1, and about 1.1 to about 1.3, and “y” has a value less than 1 and about 0.4 to about 0.8; the '587 reference is hereby incorporated by reference in its entirety.
  • Still referring to FIG. 3A, in the dialysis circuit 400 there are: a dialysate pump 420, an optional vessel 440 to hold reconstituted dialysate, dialysate temperature probe 460, a dialysate heater 480, and a flow meter 500. It should be understood that the order of devices in the circuit 400 may vary; additionally, the devices may be integrated into single functional members, e.g., the temperature probe 460 and heater 480 might be integrated and operated under the control of a dedicated temperature controller. The terms “reconstituted dialysate” and “fresh dialysate” are regarded as equivalent terms.
  • The devices 420, 460, 480, 500 are monitored and/or operated by a controller 520 adapted to perform logic operations based on a control algorithm. For example, the controller 520 monitors and controls the function of the pump 420 (in response to data received from, for example, the flow meter 500), and heater 480 is switched on or off (in response to data received from the temperature probe 460). A power supply 200 is connected to all parts that require power such as, for example, the controller 520 and dialysate pump 420.
  • FIG. 4A is a schematic representation of a further embodiment of the present invention 100 d employing a novel dialysate regeneration cartridge 180 a; the cartridge 180 a comprises at least one layer of vegetable protein such as soy protein. The dialysate regeneration cartridge 180 a is used in conjunction with a dialyzer of conventional design (represented by the alpha-numeral “160 b”). The conventional dialyzer 160 b operates much in the same way as an artificial kidney as described in column 6, lines 44-56 in U.S. Pat. No. 4,213,859 (issued Jul. 22, 1980 to Smakman et al); the '859 patent is hereby incorporated by reference in its entirety.
  • FIG. 4B shows a partially cut away view of dialyzer 160 b. Dialyzer 160 b has a blood compartment 280 and a clearance or dialysis compartment 320 separated by a selectively permeable membrane 365. The membrane 365 may be in any desirable form, for instance in that of flat or tubular film, or it may be a large number of hollow fibers. Dialysis liquid flows through compartment 300 and circulates through the dialysis circuit 400 as shown in FIG. 4A.
  • The dialysate regeneration device 180 a comprises at least one layer of vegetable protein. The vegetable protein may be unmodified or modified soy protein with or without urease enzyme activity. The layer of vegetable protein may replace or complement a charcoal layer as found in the REDY™ purification cartridge. For example, the dialysate regeneration cartridge 180 a may comprise of the following layers: (i) a layer of vegetable protein; (ii) a cation exchange layer comprising of zirconium oxide; (iii) and anion exchange layer comprising of hydrated zirconium oxide; and (iv) a layer comprising of activated charcoal.
  • The composition of the layer of vegetable protein in cartridge 180 a may vary. Cartridge 180 a may comprise a layer of modified or unmodified soy protein with or without urease enzyme activity. The layer of vegetable protein may be made of a combination of modified and unmodified soy protein with or without urease enzyme activity. The order of layers with respect to dialysate flow may vary, though it is preferable to have a purification layer downstream of the cation and anion exchange layers, e.g. a layer of activated charcoal downstream of the ion exchange layers. Dialysate regeneration device 180 a enables a conventional dialyzer 160 b to be used to treat a patient 140 with liver and/or kidney disease.
  • It is to be understood that the present invention is not limited to the embodiments described above, but encompasses any and all embodiments within the scope of the following claims.

Claims (6)

1. A dialysate regeneration device, comprising:
at least one cation exchange layer;
at least one anion exchange layer; and
at least one absorbent layer, wherein the at least one absorbent layer comprises a vegetable protein.
2. The dialysate regeneration device according to claim 1 further comprising a layer of activated charcoal.
3. The dialysate regeneration device according to claim 1, wherein the vegetable protein is essentially unmodified soy protein with urease activity.
4. The dialysate regeneration device according to claim 1, wherein the vegetable protein is essentially unmodified soy protein with urease activity, and wherein the dialysate regeneration device further comprises an ammonia scavenger compound.
5. The dialysate regeneration device according to claim 1, wherein the vegetable protein is modified soy protein lacking urease enzyme activity.
6. The dialysate regeneration device according to claim 1, wherein the vegetable protein is modified soy protein in combination with active urease enzyme capable of converting urea into ammonia.
US11/533,734 2004-03-08 2006-09-20 Dialysis device Abandoned US20070062877A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/533,734 US20070062877A1 (en) 2004-03-08 2006-09-20 Dialysis device

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/793,792 US7128836B2 (en) 2004-03-08 2004-03-08 Dialysis device
US11/533,734 US20070062877A1 (en) 2004-03-08 2006-09-20 Dialysis device

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/793,792 Division US7128836B2 (en) 2004-03-08 2004-03-08 Dialysis device

Publications (1)

Publication Number Publication Date
US20070062877A1 true US20070062877A1 (en) 2007-03-22

Family

ID=34912124

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/793,792 Expired - Fee Related US7128836B2 (en) 2004-03-08 2004-03-08 Dialysis device
US11/533,734 Abandoned US20070062877A1 (en) 2004-03-08 2006-09-20 Dialysis device

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/793,792 Expired - Fee Related US7128836B2 (en) 2004-03-08 2004-03-08 Dialysis device

Country Status (1)

Country Link
US (2) US7128836B2 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160719B2 (en) * 2002-06-07 2007-01-09 Mayo Foundation For Medical Education And Research Bioartificial liver system
US7135156B2 (en) * 2003-03-28 2006-11-14 Baxter International Inc. Method for processing a zirconium oxide composition in crystalline form
US8029454B2 (en) 2003-11-05 2011-10-04 Baxter International Inc. High convection home hemodialysis/hemofiltration and sorbent system
US8038639B2 (en) 2004-11-04 2011-10-18 Baxter International Inc. Medical fluid system with flexible sheeting disposable unit
US8114276B2 (en) 2007-10-24 2012-02-14 Baxter International Inc. Personal hemodialysis system
EP2331688B1 (en) 2008-09-30 2018-01-17 Fresenius Medical Care Holdings, Inc. Covalently immobilized enzyme and method to make the same
CN102421467B (en) 2009-03-13 2015-04-22 梅约医学教育与研究基金会 Bioartificial liver
CN104958795B (en) * 2015-06-23 2017-03-29 四川大学华西医院 Whole blood perfusion bioartificial liver system
WO2017116515A1 (en) 2015-12-31 2017-07-06 Baxter International Inc. Methods and apparatuses using urea permselective diffusion through charged membranes

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2848342A (en) * 1958-08-19 Protein compositions
US4213859A (en) * 1977-04-12 1980-07-22 Akzo N.V. Dialysis with ion exchange extraction of phosphates
US4460555A (en) * 1983-08-25 1984-07-17 Organon Teknika Corporation Ammonia scavenger
US4581141A (en) * 1978-02-27 1986-04-08 Purdue Research Foundation Dialysis material and method for removing uremic substances
US4650587A (en) * 1982-09-09 1987-03-17 Akzona Incorporated Ammonia scavenger
US4661246A (en) * 1984-10-01 1987-04-28 Ash Medical Systems, Inc. Dialysis instrument with dialysate side pump for moving body fluids
US4950224A (en) * 1988-08-05 1990-08-21 Healthdyne, Inc. Apparatus and method for in vivo plasma separation
US6579460B1 (en) * 2001-03-13 2003-06-17 Uop Llc Process and composition for removing toxins from bodily fluids
US6878283B2 (en) * 2001-11-28 2005-04-12 Renal Solutions, Inc. Filter cartridge assemblies and methods for filtering fluids
US7033498B2 (en) * 2000-11-28 2006-04-25 Renal Solutions, Inc. Cartridges useful in cleaning dialysis solutions
US7241272B2 (en) * 2001-11-13 2007-07-10 Baxter International Inc. Method and composition for removing uremic toxins in dialysis processes

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3701433A (en) * 1970-11-10 1972-10-31 Pall Corp Filter for use in the filtration of blood
US3716372A (en) * 1970-11-16 1973-02-13 Paolis P De Process for manufacture of soy concentrates, soy isolates and related products
GB1391049A (en) * 1972-08-21 1975-04-16 Cargill Inc Treatment of vegetable protein
US3901808A (en) * 1974-02-25 1975-08-26 Gen Atomic Co Blood filter
US4038194A (en) * 1974-04-19 1977-07-26 Johnson & Johnson Blood filter unit
US3972818A (en) * 1974-08-22 1976-08-03 General Atomic Company Blood filter using glassy carbon fibers
US4289623A (en) * 1975-11-05 1981-09-15 Extracorporeal Medical Specialties, Inc. Hollow fiber dialysis
US4304670A (en) * 1979-04-03 1981-12-08 Terumo Corporation Blood filter with air trap and distributing chamber
US4490254A (en) * 1980-02-25 1984-12-25 Bentley Laboratories, Inc. Blood filter
US4352692A (en) * 1981-03-16 1982-10-05 Ralston Purina Company Modified vegetable protein adhesive binder
DE4118625C1 (en) 1991-06-06 1992-10-15 Fresenius Ag, 6380 Bad Homburg, De Sterile blood purifier filter for dialysis etc. - includes blood and dialysate chambers sepd. by semipermeable member with fluid supply- and run=off lines and hollow fibre filters for pyrogen retention
US5290449A (en) * 1991-07-22 1994-03-01 Lydall, Inc. Blood filter material
US5252206A (en) * 1992-07-16 1993-10-12 Carlos Gonzalez Filtration cartridge
US5266215A (en) * 1993-04-27 1993-11-30 Rolf Engelhard Water purification unit
JP2961481B2 (en) 1993-08-30 1999-10-12 サイテック株式会社 Hemodialyzer and hemofilter
IT1274840B (en) 1994-07-18 1997-07-25 Bellco Spa EQUIPMENT FOR DIALYSIS TREATMENTS.
IT1274841B (en) 1994-07-18 1997-07-25 Bellco Spa PERFECTED TYPE EQUIPMENT FOR DIALYSIS TREATMENTS.
US5540848A (en) * 1994-12-13 1996-07-30 Vortex Corporation Filter retainer for water purification unit
JPH09196911A (en) * 1996-01-19 1997-07-31 Fuji Photo Film Co Ltd Blood filter unit
US20010016699A1 (en) * 1997-02-14 2001-08-23 Jeffrey H. Burbank Hemofiltration system
US6171640B1 (en) * 1997-04-04 2001-01-09 Monsanto Company High beta-conglycinin products and their use
JP3903098B2 (en) * 1997-07-18 2007-04-11 富士フイルム株式会社 Blood filtration method
EP1063289A1 (en) * 1998-03-03 2000-12-27 JMS Co., Ltd. Liver cell clones for artifical liver and extracorporeal liver assist device
US6582385B2 (en) * 1998-02-19 2003-06-24 Nstage Medical, Inc. Hemofiltration system including ultrafiltrate purification and re-infusion system
US6405875B1 (en) * 1998-12-18 2002-06-18 Corning Incorporated Water filtration device and method
JP3715123B2 (en) * 1998-12-28 2005-11-09 富士写真フイルム株式会社 Blood filtration unit
CA2375505A1 (en) * 1999-06-21 2000-12-28 The General Hospital Corporation Cell culture systems and methods for organ assist devices
US6176904B1 (en) * 1999-07-02 2001-01-23 Brij M. Gupta Blood filter
ITTO990148U1 (en) * 1999-07-30 2001-01-30 Hospal Dasco Spa FILTRATION UNIT FOR A DIALYSIS MACHINE.
US6451257B1 (en) * 1999-09-16 2002-09-17 Terumo Kabushiki Kaisha Arterial blood filter
US6635179B1 (en) * 1999-12-30 2003-10-21 Nephros, Inc. Sterile fluid filtration cartridge and method for using same
JP2001276816A (en) * 2000-03-30 2001-10-09 Mitsubishi Rayon Co Ltd Water purifier
US6610027B1 (en) * 2000-08-17 2003-08-26 Mohamed Kaled Mohamed El Hatu Hemodialysis
EP1322352A4 (en) * 2000-09-27 2010-06-16 Sorin Group Usa Inc Disposable cartridge for a blood perfusion system
US7214237B2 (en) * 2001-03-12 2007-05-08 Don Michael T Anthony Vascular filter with improved strength and flexibility
US6800200B2 (en) * 2002-04-18 2004-10-05 Cuno Incorporated Dual-flow filter cartridge
US7422726B2 (en) * 2002-10-23 2008-09-09 Blood Cell Storage, Inc. Integrated container for lyophilization, rehydration and processing of biological materials
US20040099593A1 (en) * 2002-11-25 2004-05-27 Potito De Paolis Concurrent dialysate purification cartridge

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2848342A (en) * 1958-08-19 Protein compositions
US4213859A (en) * 1977-04-12 1980-07-22 Akzo N.V. Dialysis with ion exchange extraction of phosphates
US4581141A (en) * 1978-02-27 1986-04-08 Purdue Research Foundation Dialysis material and method for removing uremic substances
US4650587A (en) * 1982-09-09 1987-03-17 Akzona Incorporated Ammonia scavenger
US4460555A (en) * 1983-08-25 1984-07-17 Organon Teknika Corporation Ammonia scavenger
US4661246A (en) * 1984-10-01 1987-04-28 Ash Medical Systems, Inc. Dialysis instrument with dialysate side pump for moving body fluids
US4950224A (en) * 1988-08-05 1990-08-21 Healthdyne, Inc. Apparatus and method for in vivo plasma separation
US7033498B2 (en) * 2000-11-28 2006-04-25 Renal Solutions, Inc. Cartridges useful in cleaning dialysis solutions
US6579460B1 (en) * 2001-03-13 2003-06-17 Uop Llc Process and composition for removing toxins from bodily fluids
US7241272B2 (en) * 2001-11-13 2007-07-10 Baxter International Inc. Method and composition for removing uremic toxins in dialysis processes
US6878283B2 (en) * 2001-11-28 2005-04-12 Renal Solutions, Inc. Filter cartridge assemblies and methods for filtering fluids

Also Published As

Publication number Publication date
US7128836B2 (en) 2006-10-31
US20050194304A1 (en) 2005-09-08

Similar Documents

Publication Publication Date Title
US20070062877A1 (en) Dialysis device
US4666425A (en) Device for perfusing an animal head
CN103038195A (en) Device and method for solubilizing, separating, removing and reacting carboxylic acids in oils, fats, aqueous or organic solutions by means of micro- or nanoemulsification
JPH09507414A (en) Hemofiltration and plasma filtration device and method
JPH07507558A (en) Device for producing activated platelet supernatant, method using the device, and supernatant obtained
CN102933595B (en) Atelocollagen separation method, method for preparing modified atelocollagen, and atelocollagen- and collagen-based matrix prepared by the methods
PL124730B1 (en) Method of obtaining a serum protein preparation for intravenous administration
JPS6145773A (en) Material and apparatus for purifying body fluids
JPH119688A (en) Apparatus for purifying solution containing protein, method for producing supporting material for the apparatus and method for using the apparatus
Leckie et al. Extracorporeal liver support
Hughes Review of methods to remove protein-bound substances in liver failure
JPH11137672A (en) Method for recovering and regenerating peritoneal dialyzane and apparatus therefor
EP3810771A1 (en) Urease purification and purified urease products thereof, and sorbent cartridges, systems, and methods using the same
JP2015515491A (en) Novel composition for in vitro reduction of β-amyloid and method for producing the same
Chang Artificial cell biotechnology for medical applications
Inoue et al. Continuous flow membrane plasmapheresis utilizing cellulose acetate hollow fiber in hepatic failure
JP2003250882A (en) Artificial organ system using new perfusion method
CN108578791A (en) A kind of hirudin is modified the preparation method of anticoagulant material
de Francisco et al. Hemodiafiltration with on-line endogenous reinfusion
JPH06510035A (en) Method of manufacturing biocompatible capsules containing cells
JPH1176400A (en) Artificial organ
CN102218080B (en) High-speed filtration preparation process of polypeptide donkey-skin gelatin plasma substitutes
JP4201313B2 (en) Toxic substance binding albumin removal system
US20050118274A1 (en) Method and device for feeding living cells into a biological body fluid
US4608253A (en) Process for removing immune complex in blood by use of the immobilized pepsin

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION