# US 10,500,328 B2 · Ceramic whole blood hollow fiber membrane filter medium and use thereof for separating blood plasma/serum from whole blood

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- Number: US 10,500,328 B2
- Document ID: US10500328B2
- Status: Granted
- Kind: B2
- Application number: 14/967,860
- Filed: 2015-12-14
- Published: 2016-04-07
- Granted: 2019-12-10
- Earliest claimed: 2013-06-27
- Assignees: Mann+Hummel GmbH
- Applicants: Mann+Hummel GMBH
- Inventors: Steffen Schuetz; Heike Rupp; Tobias Woerz; Dagmar Winkler; Kathrin Woerz; Frank Ehlen; Karlheinz Muenkel; Joachim Stinzendoerfer
- Web page: https://patentgrep.com/patent/US10500328B2

## CPC

- A61M 1/34: Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M 1/3403: {Regulation parameters}
- A61M 1/3496: {Plasmapheresis; Leucopheresis; Lymphopheresis (A61M1/3472 takes precedence)}
- B01D 67/00411: {by sintering}
- B01D 67/0088: {Physical treatment with compounds, e.g. swelling, coating or impregnation}
- B01D 69/02: characterised by their properties
- B01D 69/08: Hollow fibre membranes (manufacture of hollow fibres D01D5/24, D01F1/08)
- B01D 69/081: {characterised by the fibre diameter}
- B01D 69/087: {Details relating to the spinning process}
- B01D 71/025: {Aluminium oxide}
- B01D 71/027: {Silicium oxide}
- B01D 71/0271: {Perovskites}
- B01D 71/0281: {Zeolites}
- B01D 71/421: {Polyacrylonitrile}
- B01D 71/68: Polysulfones; Polyethersulfones
- B01D 71/70: Polymers having silicon in the main chain, with or without sulfur, nitrogen, oxygen or carbon only
- G01N 33/491: {by separating the blood components (G01N15/05 takes precedence)}
- A61M 2205/33: Controlling, regulating or measuring
- A61M 2205/3306: Optical measuring means
- B01D 2325/0283: Pore size
- B01D 2325/04: Characteristic thickness
- B01D 2325/14: Membrane materials having negatively charged functional groups
- B01D 2325/20: Specific permeability or cut-off range
- C08G 77/00: Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G 77/04: Polysiloxanes
- C08L 83/00: Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
- C08L 83/04: Polysiloxanes
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

A whole blood hollow fiber membrane filter medium is provided with a ceramic material having pores of a pore size that ensures permeability to blood plasma or serum and its molecular components while blood cells are retained. The whole blood hollow fiber membrane filter medium is used for separating blood plasma from whole blood, wherein the blood plasma preferably shows no hemolysis.

## Claims

### Claim 1

A whole blood hollow fiber membrane filter medium including
a ceramic material having pores of a pore size that ensures permeability to blood plasma or serum, but retains blood cells;
wherein hollow fibers of the whole blood hollow fiber membrane are tubular, having a radially inner surface in an interior of the hollow fiber, wherein the hollow fibers are ceramic hollow fibers
wherein the median pore diameter is in the range of from about 100 nm to about 1500 nm, or from about 150 nm to about 1300 nm, or from about 190 nm to about 1280 nm; and
wherein the whole blood hollow fiber membrane filter medium is coated on the radially inner surface of the surface of the hollow fiber membrane, the radially inner surface carrying at least one type of functional group from the carboxylate groups, and further carrying at least one type of functional groups selected from the group consisting of:
amino groups, silane groups, and any combinations thereof, and is coated with
a coating material further comprising bifunctional silanes with hydrolysable inorganic ethoxysilyl and fluoralkyl chains, or
fluoralkyl functional oligosiloxanes;
wherein the ceramic material comprises one or more ceramic materials selected from the group consisting of alumosilicate, magnesium silicate, and calcium titanate.

### Claim 2 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium consists of the ceramic material.

### Claim 3 (depends on 2)

The whole blood hollow fiber membrane filter medium according to claim 2, wherein
the pore size ensures permeability to blood plasma but retains blood cells.

### Claim 4 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the pore size ensures permeability to blood plasma but retains blood cells.

### Claim 5 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the pore size ensures permeability to electrolytes, lipid metabolism substances, markers, enzymes, substrates, proteins, pharmaceuticals, and vitamins.

### Claim 6 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium is a whole blood hollow fiber membrane cross-flow filter medium.

### Claim 7 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium is a whole blood hollow fiber membrane dead-end filter medium.

### Claim 8 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium has opposed ends and the opposed ends are open.

### Claim 9 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the pore size allows molecules of less than about 8,000 kDa to pass.

### Claim 10 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the median pore diameter is in a range of from about 190 nm to about 1,280 nm.

### Claim 11 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the pores have a D10 pore diameter that is in a range of from about 150 nm to about 5,000 nm, and
the pores have a D90 pore diameter that is in the range of from about 30 nm to about 1,000 nm.

### Claim 12 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the pores have an average pore diameter that is in a range of from about 100 nm to about 1,500 nm.

### Claim 13 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the pores have a median pore diameter that is in a range of from about 100 nm to about 1,500 nm, and
wherein the pores have an average pore diameter that is in the range of from about 100 nm to about 1500 nm.

### Claim 14 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the ceramic material comprises a silicon carbide.

### Claim 15 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the ceramic material further comprises a metal oxide selected from the group consisting of aluminum oxide, silicon oxide, titanium oxide, and any combination thereof.

### Claim 16 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the ceramic material further comprises at least one metal oxide selected from the group consisting of zirconium oxide and yttrium oxide.

### Claim 17 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the ceramic material further comprises a sintered alpha aluminum oxide.

### Claim 18 (depends on 17)

The whole blood hollow fiber membrane filter medium according to claim 17, wherein
the ceramic material further comprises titanium dioxide,
wherein the titanium dioxide is present in an amount of 0.1 wt.-% to 0.5 wt.-% based on the total weight of the ceramic material.

### Claim 19 (depends on 17)

The whole blood hollow fiber membrane filter medium according to claim 17, wherein
a volumetric medium particle size of the sintered alpha aluminum oxide is from about 0.1 μm to about 2.0 μm.

### Claim 20 (depends on 19)

The whole blood hollow fiber membrane filter medium according to claim 19, wherein
the whole blood hollow fiber membrane filter medium has an outer diameter Do of from about 0.4 mm to about 3.0 mm.

### Claim 21 (depends on 20)

The whole blood hollow fiber membrane filter medium according to claim 20, wherein
the whole blood hollow fiber membrane filter medium has an inner diameter Di of from about 0.2 mm to about 2.0 mm, provided that the inner diameter Di is smaller than the outer diameter Do.

### Claim 22 (depends on 21)

The whole blood hollow fiber membrane filter medium according to claim 21, wherein
a ratio D0/Di of the outer diameter Do to the inner diameter Di, is in a range of from about 1.3 to about 2.0.

### Claim 23 (depends on 21)

The whole blood hollow fiber membrane filter medium according to claim 21, wherein
the outer diameter Do is from about 0.5 mm to about 2.0 mm and the inner diameter Di is from about 0.3 mm to about 1.3 mm.

### Claim 24 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium has a wall thickness of about 0.1 mm to about 1.0 mm.

### Claim 25 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
a single hollow fiber membrane of the whole blood hollow fiber membrane filter medium comprises a length 0.5 cm to 8 cm length and a filtration area of from about 3 mm2 to about 500 mm2.

### Claim 26 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium comprises a porosity from about 30% to about 70%.

### Claim 27 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium is modified by coating or pre-wetting the whole blood hollow fiber membrane filter medium.

### Claim 28 (depends on 27)

The whole blood hollow fiber membrane filter medium according to claim 27, wherein
the whole blood hollow fiber membrane filter medium is pre-wetted with a salt solution, a solution of a blood stabilization agent, or a combination thereof.

### Claim 29 (depends on 28)

The whole blood hollow fiber membrane filter medium according to claim 28, wherein
the salt solution is a sodium chloride solution, and wherein the whole blood hollow fiber membrane is not dried after pre-wetting.

### Claim 30 (depends on 28)

The whole blood hollow fiber membrane filter medium according to claim 28, wherein
the blood stabilization agent is heparin.

### Claim 31 (depends on 27)

The whole blood hollow fiber membrane filter medium according claim 27, wherein
the whole blood hollow fiber membrane filter medium is pre-wetted with a citrate buffer solution.

### Claim 32 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium is modified so as to have a negative zeta potential.

### Claim 33 (depends on 1)

The whole blood hollow fiber membrane filter medium according to claim 1, wherein
the whole blood hollow fiber membrane filter medium is coated a coating material including bifunctional silanes with hydrolysable inorganic ethoxysilyl and fluoroalkyl chains.

### Claim 34 (depends on 1)

A method of separating blood plasma/serum from a whole blood sample, the method including the following steps:
providing a whole blood hollow fiber membrane filter medium according to claim 1;
providing a cylindrical filter housing having opposing ends and an opening for filtrate release in a cylindrical wall of the cylindrical filter housing, the opening arranged between the opposing ends of the housing;
embedding opposing ends of the whole blood hollow fiber membrane in a potting/sealing material, potting/sealing the whole blood hollow fiber membrane in an interior of the cylindrical filter housing;
pre-wetting the whole blood hollow fiber membrane filter medium with a citrate buffer solution or an EDTA (ethylenediaminetetraacetic acid) buffer solution;
filtering a whole blood sample with the pre-wet whole blood hollow fiber membrane filter medium so that blood plasma or serum passes through the whole blood hollow fiber membrane filter medium and blood cells are retained.

### Claim 35 (depends on 34)

The method according to claim 34, wherein
the blood plasma/serum shows no or substantially no hemolysis.

### Claim 36 (depends on 34)

The method according to claim 34, wherein
filtering is carried out by cross-flow filtration.

### Claim 37 (depends on 36)

The method according to claim 36, the cross-flow filtration including
passing the whole blood along a longitudinal extension of the whole blood hollow fiber membrane filter medium, optionally alternately in both directions of the longitudinal extension, by applying positive pressure or by applying negative pressure.

### Claim 38 (depends on 37)

The method according to claim 37, wherein
the positive pressure is in a range from about 0.5 bar to 1.5 bar and the negative pressure is in a range from about 0.5 bar to about 1.0 bar.

### Claim 39 (depends on 37)

The method according to claim 37, the cross-flow filtration being performed as in-out cross-flow filtration or out-in cross-flow filtration.

### Claim 40 (depends on 34)

The method according to claim 34, including
diluting the whole blood sample with isotonic sodium chloride solution in a ratio of from 0.5:1 to 1:5.

### Claim 41 (depends on 34)

The method according to claim 34, including
stabilizing the whole blood sample with an anti-coagulation agent selected from the group consisting of EDTA, citrate, heparin, and combinations thereof.

### Claim 42 (depends on 34)

The method according to claim 34, including
pre-treating the whole blood sample with lectin as a cell agglomeration agent.

### Claim 43

A method of manufacturing a whole blood hollow fiber filter, the method comprising the steps of:
forming a whole blood hollow fiber membrane filter medium by a phase inversion process from a spinning dope including at least one ceramic powder material, at least one polymer, and at least one solvent;
wherein the ceramic powder material comprises one or more ceramic materials selected from the group consisting of alumosilicate, magnesium silicate, and calcium titanate;
wherein the polymer is polyacrylonitrile or polyethersulfone;
wherein the solvent includes n-methyl-pyrrolidone;
conducting the spinning dope through the annulus cross-section of a nozzle to give a green hollow fiber;
sintering the green hollow fiber at a temperature from about 1,350° C. to about 1,700° C. for a time interval of at least 1 hour to form a ceramic hollow fiber having pores of a pore size that ensures permeability to blood plasma or serum, but retains blood cells, wherein a median pore diameter of the hollow fibers is in the range of from about 100 nm to about 1500 nm, or from about 150 nm to about 1300 nm, or from about 190 nm to about 1280 nm;
applying a coating onto a radially inner surface of the surface of the one or more ceramic hollow fibers, the coating having at least one type of functional group from the carboxylate groups, the coating further including at least one type of functional groups selected from the group consisting of: amino groups, silane groups, and any combinations thereof;
coating the radially inner surface of the surface of the ceramic hollow fibers with a coating material comprising bifunctional silanes with hydrolysable inorganic ethoxysilyl and fluoralkyl chains, or fluoralkyl functional oligosiloxanes;
forming a whole blood hollow fiber membrane from one or more coated ceramic hollow fibers;
providing a cylindrical filter housing having opposing ends and an opening for filtrate release in a cylindrical wall of the cylindrical filter housing, the opening arranged between the opposing ends of the housing;
embedding opposing ends of the whole blood hollow fiber membrane in a potting/sealing material, potting/sealing the whole blood hollow fiber membrane in an interior of the cylindrical filter housing.