Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
  • B01D61/14—Ultrafiltration; Microfiltration
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
  • B01D61/24—Dialysis ; Membrane extraction
  • B01D61/243—Dialysis
  • B01D61/244—Dialysis comprising multiple dialysis steps
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
  • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
  • B01D69/08—Hollow fibre membranes
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
  • C12M29/16—Hollow fibers

Definitions

• This invention relates to fluid filtration devices, such as blood dialysis devices and bioreactors and membranes for such devices. More specifically, the invention relates to an improved dialysis device having rectifying filtration prop ⁇ erties, dual-skinned membranes for performance of such dialysis and other filtration procedures.
• This application is a continuation in part of our copending application Serial Number 07/818,851 filed January 10, 1992. Background of the Invention
• Dialysis membranes and. devices perform im- portant life sustaining functions when used in artificial kidneys and other types of filtration devices.
• a well recognized problem of high flux dialyzers is the back filtration from dialysate to the blood of undesirable molecules. Due to the high cost of using sterile, pyrogen-free dialysates, it would be highly desirable to have available a dialy ⁇ sis membrane which could remove relatively large solutes such as ⁇ -2 microglobulin while preventing passage of similarly sized molecules from dialysate to blood.
• Membranes, however, which offer a high rate of diffusion of solutes from the blood to dialysate also suffer from high rates of back diffusion of solutes from dialysate back to the blood.
• An important object of the invention is to provide new and improved membranes for filtration devices such as dialysis devices.
• a further aspect of the invention is to provide improved filtration devices containing membranes with rectifying proper ⁇ ties, i.e., have a greater sieving coefficient in one direction than the other, and improved filtration methods using such devices.
• a further important aspect of the present invention involves providing dual-skinned membranes such as hollow fibers in which the pore size and structure, and the resulting sieving coefficient, differs between the two opposed surfaces of the membrane.
• the mem- branes are in the shape of hollow fibers in which the sieving coefficient, or permeability to molecules of a particular size, of the inner wall or skin of the fiber is greater than that of the outer wall.
• Such fibers can be assembled into dialysis devices in accordance with known procedures to provide such dialysis devices in which large solutes can be removed from a fluid, such as blood, flowing within the interior of the fibers to a filtrate or dialysate liquid which surrounds the fibers. Since a tighter or less permeable skin is provided on the outside of the fibers, it has been found that back transport from the outside of the fibers to the inside is substantially reduced.
• Another important object of the invention is to provide dual-skinned membranes useful in dialysis as one way or rectifying membranes which reduce back filtration.
• the preferred membranes are dual-skinned polymeric materials preferably in the form of hollow fibers.
• the membranes have skins of polymer on their opposite sides with differing solute permeability or sieving coefficient characteristics.
• Such membranes can be formed by extruding a polymer dissolved in a solvent while contacting at least one surface with a non-solvent for the polymer that is miscible with the solvent.
• the other surface is also contacted with a non-sol ⁇ vent, but one which is either different from the first non-solvent or which contains a soluble ad ⁇ ditive that changes the pore size and structure of the skin formed on the dissolved extruded polymer.
• improved dialysis devices having rectifying properties are formed by using the membranes provided by the inven ⁇ tion.
• the preferred dialysis devices of the inven- tion are formed from hollow polymeric fiber mem ⁇ branes having a microporous structure within the walls thereof, with the microporous structure having a skin of polymer containing invisible pores formed integrally with the interior and exterior surfaces thereof.
• the exterior skin has a sieving coeffi- cient different from that of the internal skin.
• the rectifying dialysis devices of the invention provide a means for removing unwanted material from bodily fluids such as blood in which a high rate of filtration of solutes from blood to dialysate is offered, while a substantially lower rate of back filtration of undesired solutes from dialysate to blood is maintained.
• FIGURE 1 is a diagrammatic view illustrating the process for forming membranes of the invention in hollow fiber form
• FIGURE 2 is a cross-sectional view of an annular extrusion die used in the practice of the invention.
• FIGURE 3 is a side elevational view with portions in cross-section of a filtration device of the present invention.
• FIGURE 4 is a sketch in greatly enlarged scale illustrating, hypothetically, the mechanism of filtration that occurs in use of the filtration devices of the invention
• FIGURES 5 and 6 are cross-sectional views of a hollow fiber membrane of the invention of dif ⁇ ferent magnifications taken with an electron microscope; and, FIGURE 7 is a side elevational view of a bioreactor device in accordance with the invention.
• FIGURES 8-14 are graphical representations of the results obtained from testing of specific examples described herein. Detailed Description
• FIGURE 1 diagrammatically illustrates a hollow fiber spinning system 60.
• a solution 62 of a polymer in an organic solvent is contained in vessel 64 from where it is pumped to an annular extrusion die 68 by means of a metering pump 66.
• a coagulant solution 72 which is a non- solvent for the polymer is contained in a second vessel 70 and is transferred to die 68 by means of another pump 74.
• non-solvent 72 and the polymer solution 62 at the interface 63 formed as the solutions exit the die in contact with each other determined the ultimate structure and properties of the inner membrane.
• the formed extrudate then falls through an air gap 76 and enters a bath 78 containing a second non-solvent coagulant solution 80.
• the interaction of the extrudate with the second solution 80 determines the structure and properties of the outer membrane.
• the fiber is pulled through bath 78 by means of driver roller 82 and through one or more additional baths 84, as required, to completely extract the solvent from hollow fibers.
• the extracted fiber is finally taken up onto a multi- segment winder 86 and allowed to dry.
• Dried fibers 88 are cut to length and placed in a housing 90.
• the fibers 88 are sealed in the housing by means of a thermosetting resin 92.
• the assembly is fitted with end caps 94 and 96.
• An inlet 97 and outlet 98 for filtrate liquid are also provided on the housing.
• FIGURES 5 and 6 illustrate in magnified cross-section a typical fiber 88 of the invention showing internal microporous structure 83, an inner skin 85 and an outer skin 87 having different porosity than inner skin 85.
• Membranes of this invention preferably have an inner diameter of about 200 microns and generally range in inner diameter from about 100 to 1000 microns.
• the overall sieving coefficient is the fraction of the incoming solute that passes through the membrane along with the fluid that is being filtered. It is calculated by dividing the concentration of solute on the downstream side of the membrane by its concentration on the upstream side of the membrane.
• the overall sieving coefficient is equal to the sieving coeffi ⁇ cient of the skin, which is the fraction of solute that passes through that skin.
• the sieving coeffi ⁇ cient of the skin itself depends only on the relative sizes of the pore and the solute molecule. The tighter the skin (i.e. smaller the pores), the smaller the fraction of a given molecule which will pass through it.
• the concentration of solute which reaches the second skin depends on the characteristics of the first skin as well as the flow conditions, so the overall sieving coefficient is a property of both flow and membrane properties.
• the key to the rectifying membrane, in which the sieving coefficient in one direction is different from the sieving coefficient in the other direction, is that flow in one direction results in buildup of solute within the two skins of the membrane.
• FIGURE 4 is a schematic of a dual-skinned rectifying membrane 88 in which the outer skin 12 is tighter than the inside skin 14 and fluid is passing from the inside to the outside as a result of an im ⁇ posed pressure gradient.
• some of the molecules which enter the central area 16 of membrane 88 become trapped when they reach the tighter outer skin 12.
• the concentration inside the membrane goes up until it reaches a steady state value, and the resulting concentration in the fluid 20 outside the fiber goes up along with it.
• the concentration in the fiber lumen 18 has not changed, so the overall sieving coefficient increases with time until it reaches a steady-state value that is higher than would be obtained with the tight skin 12 alone.
• polymers can be employed in the process of the invention to form hollow fibers.
• the polymers must be soluble in at least one organic solvent and insoluble in another liquid that is miscible with the solvent.
• suitable polymers are polysulfone, polyetherimide, polyacrylonitrile, polyamide, polyvinylidene diflouride, polypropylene, and polyethersulfone.
• solvents for such polymers include N-methyl-2-pyrrolidone, N,N'- dimethylformamide, N,N'-dimethylacetamide and ⁇ butyrolactone.
• the preferred non-solvent which can be used as a coagulation or gelation agent for formation of the skins is water.
• suitable liquids include ethanol, ethanol-water mixtures such as 95 or 99.5 vol% ethanol in water, or isopropyl alcohol.
• Various materials can be added to the non-solvents to form skins of differing porosities. Examples include polyvinyl alcohol, Tetra-ethylene-glycol, poly-ethylene-glycol , perchlorate salts, and polyvinyl pyrrolidone.
• An important advantage of the present invention is the ability to provide fibers having different sieving coefficients depending on the direction of filtrate flow, for molecules to be filtered out of a liquid.
• a further advantage is the ability to provide fibers having different sieving coefficients for filtration out of a liquid of molecules having narrowly defined molecular weight ranges.
• fibers can be provided that have the ability to filter molecules in the range of 5000 to 10,000 differently from one side of the membrane than the other.
• the sieving coefficient differential can also be optimized for molecules having a molecular weight range of 10,000 to 100,000 or even 200,000. Optimization is achieved by adjusting the composition of the coagulant solution and the amount and type of dopants added, as well as by varying the spinning conditions such as flow rate, line speed and gap distance. Examples
• the lumen and filtrate compartments were primed with alcohol (isopropanol or ethanol) using a syringe.
• the test module was then rinsed with excess dialysate, pumping 250 ml through lumen with filtrate port closed and then 200 ml more with one filtrate port open.
• the dialysate ports were closed, the infusion pump was set to the desired speed (10.5 ml/min) , outflow was determined by timed collection.
• the test module was clamped in a vertical position, with fibers perpendicular to the table top. An infusion pump was connected to an inlet reservoir, and tubing from the infusion pump was connected to the bottom header. Tubing to waste was connected to the top header.
• the dialysate ports were closed, the pump was started, and the time at which the test solution reached the device was denoted as time zero. At time zero, the dialysate side was drained of priming solution by opening both dialysate stopcocks. The lower dialysate port was then closed, and the time zero filtrate sample was taken from the upper port as soon as the filtrate compartment was filled. At the same time, the outlet lumen sample was collected into another beaker. Inlet lumen samples were taken directly from the inlet reservoir. Subsequent filtrate samples were collected at 3 minute intervals, with no loss of filtrate between samples. All samples were measured for myoglobin content using a Gilford spectrophotometer. The sieving coefficient, S, was calculated using the following equation:
• the fibers were assembled into test modules and the sieving coefficients determined in accordance with the foregoing procedure.
• the sieving coefficients of the fibers of this example for myoglobin were found to be 0.35 when filtrate flow was directed radially outwardly and 0.80 when filtrate flow was inward. Table I
• FIGURES 5 and 6 are scanning electron micrographs of the resulting fiber in cross- section taken at 2000 times magnification and 400 times magnification, respectively, showing the finger-like structures extending from each boundary and meeting in the middle wall. Sieving coefficients for myoglobin were found to be 0.45 for outward filtrate and 0.90 for inward flow.
• Hollow fibers were prepared as in Example 1 except that the core fluid composition was 70% isopropyl alcohol and 30% water.
• the spinning solution concentration was 20 weight percent of polysulfone in N-methylpyrrolidone with 10% acetone.
• the precipitation bath was water.
• Sieving coefficients were determined for dextran using the following procedure:
• Dextran solution was perfused through the lumen, with filtrate collected from the shell side.
• Sieving coefficients for alcohol dehydrogenase (MW approximately 150,000) and ⁇ -amylase (MW approximately 200,000) were determined by the procedure outlined above, by with the samples analyzed by a commercially available assay kit (Sigma Chemical Co.).
• the sieving coefficients for 5 alcohol dehydrogenase were 0.05 for outward flow and 0.76 for inward flow.
• the sieving coefficients for ⁇ -amylase were 0.01 for outward flow and 0.17 for inward flow.
• Hollow fibers were prepared as in Example 1 except that the core fluid composition was 50% isopropyl alcohol and 50% water.
• the spinning solution contained 20% by weight of polysulfone and
• the spinning solution was
• N-methylpyrrolidone N-methylpyrrolidone.
• the core fluid composition was isopropyl alcohol and the precipitation bath was water.
• the sieving coefficient for dextran was
• Polysulfone hollow fiber membranes were 35 prepared with an outer skin having a 5,000 kilodalton (kD) nominal molecular weight (MW) cutoff and a skin with a larger, but unknown MW cutoff on the inner fiber surface.
• kD kilodalton
• MW molecular weight
• the sieving coefficients of dextrans of various molecular weight were found to be greater when filtrate flow was directed radially inward than when filtrate flow was directed outward.
• Polymer Polyetherimide Solvent: N-methylpyrrolidone
• Spinning solution concentration 20 wt %
• Core fluid composition Water Precipitation bath: Water The sieving coefficient data for dextran when tested as shown in FIGURE 12.
• Polymer Polyetherimide Solvent: N-methylpyrrolidone Spinning solution concentration: 25 wt % Core fluid composition: 50/50 Water/N-methylpyrrolidone
• solute internal concentration polarization of solute is responsible for the asymmetric sieving characteristics of the above examples.
• the accumulation of solute between the two skins of the membrane should require a finite amount of time to occur. Consequently, the sieving coefficient in one direction should increase with time until equilibrium is reached. For most common membranes, the sieving coefficient is generally greatest in early time measurements and may decrease with time as pores clog with retained solute.
• FIGURE 14 the sieving coefficient in the shell to lumen direction is shown as a function of time for the membrane of Example 3.
• filtrate was collected at one minute intervals for the first ten minutes of filtration.
• the sieving coefficient particularly in the 50,000 to 100,000 range, did increase significantly with time.
• a bioreactor is shown in FIGURE 7 and consists of a device somewhat similar to the dialysis device shown in FIGURE 3. In this case, however, the space 89 surrounding the fibers and en- closed by the interior of housing 90 and thermoset- ting resin 92 forms a reaction vessel for growth of living cells. Ports 97 and 98 are either omitted or can be closed by means of valves 99 and 100 as indicated. Depending on its size, the product may pass back through the membranes 88 and be purified from the waste stream or it may collect in the shell space which constitutes the reaction vessel from which it may be removed on either a semi-continuous or batch basis. Transport of nutrients, waste products and desired biological products across the membrane may be by diffusion and/or convection. The axial pressure drop which occurs within the hollow fibers leads to Starling's flow, with convection from the tube side to the shell side at the device inlet and convection from the shell side to the tube side at the device outlet.
• Some types of cells require expensive growth media which may contain 10% bovine fetal calf serum.
• Use of a rectifying membrane allows serum components to pass through the membranes to the cells and then be concentrated in the shell space, thereby reducing the volume of media required. This also reduces the cost of purifying products which pass through the membrane because the volume of the purification stream is smaller.
• Rectifying membranes can also be used to concentrate products directly. If the desired product is formed of molecules that are larger than the metabolic waste products as well as the nutrients, the rectifying membrane device can be used to concentrate the products in the shell space while allowing nutrients to reach the cells and waste products to be washed away by the fluid stream passing through the interiors of the hollow fiber membranes.
• Membranes in accordance with the present invention can thus be formed with the tighter skin either on the interior or exterior of a hollow membrane. In either event it is important that the skins on each side of the membrane contain pores that are invisible at 10,000 times magnification.

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• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
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• Health & Medical Sciences (AREA)
• Water Supply & Treatment (AREA)
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• General Engineering & Computer Science (AREA)
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• Genetics & Genomics (AREA)
• Biomedical Technology (AREA)
• Separation Using Semi-Permeable Membranes (AREA)
• External Artificial Organs (AREA)
• Apparatus Associated With Microorganisms And Enzymes (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Manufacture Of Porous Articles, And Recovery And Treatment Of Waste Products (AREA)

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Citations (6)

• 1994
  • 1994-02-28 CN CN94190114A patent/CN1056645C/zh not_active Expired - Fee Related
  • 1994-02-28 KR KR1019940703991A patent/KR100304224B1/ko not_active Expired - Fee Related
  • 1994-02-28 EP EP94910773A patent/EP0644928B1/en not_active Expired - Lifetime
  • 1994-02-28 WO PCT/US1994/002126 patent/WO1994020603A1/en not_active Ceased
  • 1994-02-28 ES ES94910773T patent/ES2135569T3/es not_active Expired - Lifetime
  • 1994-02-28 AT AT94910773T patent/ATE181357T1/de not_active IP Right Cessation
  • 1994-02-28 DE DE69419095T patent/DE69419095T2/de not_active Expired - Lifetime
  • 1994-02-28 CA CA002134327A patent/CA2134327C/en not_active Expired - Fee Related
  • 1994-02-28 JP JP52008094A patent/JP3396034B2/ja not_active Expired - Fee Related
  • 1994-03-16 TW TW083102262A patent/TW243417B/zh active

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