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    • 专利摘要:
    The present invention relates to a hollow fiber module (hf) having fibers modified with a thin film composite (tfc) layer comprising aquaporin water channels .
    公开号:BR112015015985B1
    申请号:R112015015985-0
    申请日:2014-01-07
    公开日:2021-06-29
    发明作者:Jorg Vogel；Jesper S0Ndergaard Groth；Kent H0Ier Nielsen；Oliver Geschke
    申请人:Aquaporin A/S；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001] The present invention relates to a hollow fiber module (HF) provided with membranes of modified fibers of thin film composite (TFC), for example, provided with a TFC polyamide layer on the outside or inside of the fibers, or on both sides, comprising aquaporin water channels in said TFC layer. The present invention also relates to a hollow fiber membrane having a modified thin film composite (TFC) separating layer comprising aquaporin water channels, as having a TFC polyamide layer on the outside or inside of the fibers and a method of preparing said TFC modification directly on the fibers as mounted in the module and wherein said TFC layer comprises aquaporin water channels immobilized or incorporated in said layer. BACKGROUND OF THE INVENTION
    [002]Recently, it has been demonstrated how thin-film composite hollow fiber membranes can be prepared by advanced osmosis (Sukitpaneenit and Chung 2012) through interfacial polymerization creating a thin layer of polyamide on the inner surface of supporting membranes. hollow fiber PES, where a 2% by weight aqueous solution of meta-phenylene diamine (MPD) containing 0.5% by weight of triethylamine and 0.1% by weight of sodium dodecyl sulfate is introduced by pumping from a bottom inlet to a vertically positioned HF module followed by air drying and then introduction of 0.15% by weight trimesoyl chloride (TMC) in hexane solution to form the polyamide thin film and finally purging with air and cure at 65°C, wash with deionized water and store in deionized water. Furthermore, Peinemann et al. describes a method of preparing a similar TFC layer on the inner surface of a hollow fiber, cf. Published U.S. Patent Application No. 2007/0199892. In addition, Zhong et al. (2013) describe the development of hollow fiber membranes by TFC advanced osmosis using sulfonated polyphenylenesulfone directly as the membrane substrate. However, for a wide range of separation applications where hollow fiber modules are used, it is important to be able to separate or filter relatively low molecular weight organic solutes during the filtration process. For example, in hemodialysis where HF modules are widely used, a uremic toxin and organic degradation product such as indoxyl sulfate (indoxyl sulfate potassium salt, CAS No. 2642-37-7, molecular weight 251 .30) poses a particularly difficult problem. Indoxyl sulfate is accumulated in the serum of patients with chronic kidney disease. A portion of dietary protein-derived tryptophan is metabolized to indole by tryptophanase in intestinal bacteria. Indole is absorbed into the bloodstream from the intestine, and is metabolized to indoxyl sulfate in the liver. Indoxyl sulfate is normally excreted in the urine. In hemodialysis patients, however, an inadequate renal clearance of indoxyl sulphate leads to elevated serum levels, cf. Niwa T. (2010). Niwa et al. (1997) hypothesized that the accumulation of indoxyl sulfate accelerates glomerular sclerosis and the progression of kidney disease. Administration of an adsorbent orally reduces indoxyl sulfate levels in non-dialyzed uremic patients, cf Niwa et al. (1997). Current dialysis methods in place, ie hemodialysis and peritoneal dialysis, the latter being characterized by continuous ultrafiltration and solute removal, are not sufficient to remove some low molecular weight degradation products from the serum, such as indoxyl sulfate and p-cresol (4-methylphenol, CAS #106-44-5, molecular weight 108.13). Furthermore, small water-soluble molecules such as urea, uric acid and creatinine, and peptides/proteins such as β2-microglobulin should preferably be removed during dialysis. A direct association was found between p-cresol, which mainly reflects p-cresyl sulfate, and general mortality and cardiovascular disease in end-stage renal disease and chronic kidney disease. Likewise, direct associations between indoxyl sulfate and total mortality and cardiovascular disease have been reported. The loss by continuous hemofiltration therapy of vital physiological proteins should be minimized and the removal of uremic toxins and low and medium molecular weight peptides (<500 Da) (about 500 to about 40 kDa) should be optimized, cf. Wenhao Xie (2011).
    [003] Aoike (2011) mentions the most important characteristics or quality parameters for high performance membranes for use in hemopurification therapy therapies, that is, high water permeability, ability to remove a wide variety of uremic toxins and others characteristic features. However, Aoike also points out that the large pore size of existing high-performance membranes (HPM) will likely allow the blood to become contaminated by dialysis fluid, because HPMs, such as polyacrylonitrile (PAN) membranes, have a large size. The pores allow the rapid unfavorable diffusion of dialyzed endotoxin fragments back into the blood compartment.
    [004] Therefore, it remains a problem in the art to provide hollow fiber modules that are capable of separating low molecular weight compounds, allowing their removal from liquids in processes such as hemodialysis and in which the fiber module hollow combines high water permeability with smaller pore sizes. SUMMARY OF THE INVENTION
    [005] In general terms, the present invention provides a hollow fiber module that is capable of separating low molecular weight compounds, for example, allowing the HF module to concentrate organic compounds including urea, indoxyl sulfate, p-cresol and/or p-cresyl sulphate and preferably compounds having a molecular weight of less than about 500 Da and thus allow better removal of said compounds, for example, from a liquid. Alternatively or additionally, the present invention aims to provide a hollow fiber modulus having a high water permeability, but with smaller pore dimensions, such as with a smaller pore diameter of about 5 to 10 nm, cf. Clark & Gao (2002).
    [006] Therefore, in one aspect, the present invention provides a hollow fiber module (HF) having a TFC layer comprising aquaporin water channels formed in its fiber surfaces, such as the inner fiber surface (lumen).
    [007] In another aspect, the present invention provides a method of preparing a hollow fiber module comprising HF membranes modified with a thin film composite layer (TFC) comprising aquaporin water channels, said method comprising the steps of: a) obtaining a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes) endowed with about 25 to about 500 LPR/POPR of protein, b) preparation of an aqueous solution of a di- or triamine, c) dissolution of a di- or triacyl halide in a non-polar organic solvent, d) preparation of a mixture of amine and aquaporin vesicle by dissolving/mixing the vesicle preparation from step a) with the solution from step b), e) pumping the mixing from step d) through the lumen of the hollow fibers into a hollow fiber module using its end inlet, f) removing excess aqueous solution by a gas purge on the lumen side of the fibers using a module inlet, g ) inject the sun duction of acyl halide from step c) into the module through the lumen of the hollow fibers to allow an interfacial polymerization reaction to occur and, h) washing the module with an aqueous solvent, by injection through an inlet of the module.
    [008] In another aspect, the present invention provides a method of preparing a hollow fiber module comprising HF membranes modified with a thin film composite layer (TFC) comprising aquaporin water channels, said method comprising the steps of a ) obtaining a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes) having from about 25 to about 500 LPR/POPR of protein, b) preparation of an aqueous solution of 1,3-diaminobenzene of about 1% to about 5% (w/w) concentration, c) dissolution of benzene-1, 3,5-tricarbonyl chloride in an organic solvent selected from the group consisting of hexane, heptane, octane or a mixture of solvents to obtain a concentration of about 0.05% to about 1% (w/v), d) preparation of a 1,3-diaminobenzene/aquaporin vesicle mixture by dissolving/mixing the vesicle preparation from step a) with the solution from step b), e) pump the mixture from step d) through l hollow fiber humen in a hollow fiber module using its terminal inlet, f) remove excess aqueous solution by a gas purge on the lumen side of the fibers using a module inlet, g) inject the benzene chloride solution -1,3,5 tricarbonyl from step c) to the module through the hollow fiber lumen to allow an interfacial polymerization reaction to occur, and h) washing the module with an aqueous solvent, by injection through a module inlet.
    [009] In another aspect, the present invention provides a method of externally coating a hollow fiber membrane with a thin film composite layer (TFC) comprising aquaporin water channels, said method comprising the steps of: a) obtaining a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes), b) preparation of an aqueous solution of a di- or triamine, c) dissolution of a di- or triacyl halide in a nonpolar organic solvent, d) preparation of a mixture of amine and aquaporin vesicle by dissolving/mixing the vesicle preparation from step a) with the solution from step b), e) pass the hollow fiber membrane through the mixing solution from step d), f) remove the excess aqueous solution, g) pass the hollow fiber membrane through the acyl halide solution from step c) to allow an interfacial polymerization reaction to occur, h) washing the hollow fiber membrane with an aqueous solvent, for example, making passes r the hollow fiber through an aqueous bath.
    [010] Furthermore, the invention relates to a modified hollow fiber membrane with a thin film composite layer (TFC), which comprises aquaporin water channels.
    [011] In another aspect, the present invention provides the use of a module in hollow fiber (HF) as described herein for the extraction of pure water through advanced osmosis or for the new extraction of pure water from the loss of the plasma of a patient through hemodialysis.
    [012] In another aspect, the present invention provides a method of extracting water from an aqueous liquid comprising the following steps: a) placing a hollow fiber module (HF) of any one of claims 1 to 9, which is in controlled connection with a first aqueous liquid (aqueous feed solution) which has an osmotic pressure which is less than or equal to that of the liquid membrane matrix, and which is further in controlled connection with a second aqueous liquid (absorbent solution) which has an osmotic pressure that is higher than that of the matrix to create an osmotic pressure potential between said first and said second liquid, b) allowing the matrix to absorb pure water from said first liquid to mediate a flow of pure water into said second liquid, provided that an osmotic pressure gradient exists, c) optionally separating the extracted pure water from said second liquid.
    [013] Embodiments of the present invention will now be described by way of example and not limitation with reference to the attached figures. However, various other aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.
    [014]"and/or", where used herein, shall be taken as specific disclosure of each of the two specified elements or components, with or without the other. For example, "A and/or B" is to be regarded as specific disclosure of each of (i) A, (ii) B and (iii) A and B, as if each were set out individually herein.
    [015] Unless context indicates otherwise, the descriptions and definitions of the features set forth above are not limited to any particular aspect or embodiment of the invention and are equally applicable to all aspects and embodiments described. BRIEF DESCRIPTION OF THE DRAWINGS
    [016]a Fig. 1 A shows as a photograph and a drawing of an HF module with 9 hollow fibers, two extreme inputs/outputs (1, 2) and two side inputs/outputs (3, 4), as well as four covers ends (5) to seal said inlets/outlets. The total length of the module: 100 mm; fiber diameter: 10 mm; diameter to sealing: 130 mm.
    [017] Fig. 1B shows as a photograph and a drawing of an HF module with 984 fibers, having two end inputs/outputs (1, 2) and two side inputs/outputs (3, 4). Total length: 25 cm, fiber diameter: 700 μm.
    [018] Fig. 2 shows as a photograph and a cross-sectional drawing of part of a hollow fiber, UltraPES™, having a wall thickness of about 220 μm ± 15 μm, an inner diameter of about 760 μm ± 30 µm, a molecular weight range (MWCO, dextran, 90%, 0 bar) of 65 kDa ± 20 kDa, and a transmembrane water flux of > 0.65 mL/[min x cm2 > x bar] at 25°C. Figure obtained from Membrana GmbH.
    [019] Fig. 3 shows an outline of the principle of the microstructure of the thin film composite layer formed on a hollow fiber of the present invention, cf. Example 1 below.
    [020] Fig. 4 shows a principle sketch of a process for continuous automated outer coating of hollow fibers. DETAILED DESCRIPTION
    [021] More specifically, the present invention relates to an HF module having fibers of polyethersulfone (PES) or fibers of another suitable porous support material, such as polysulfone, polyphenylene sulfone, polyether imide, polyvinylpyrrolidone and polyacrylonitrile including their combinations and mixtures thereof, which have been modified by the formation of a thin-film composite layer, for example, by means of interfacial polymerization. In addition, various doping materials can be used when manufacturing hollow fiber support materials, cf. for example Qian Yang et al. (2009). These HF modules are commonly used in food and beverage applications such as beer and wine filtration, but also in some water and wastewater applications, including wastewater reuse and pool water recycling. For example, the German company Membrane supplies a hollow fiber module containing several thousand fibers with a total surface area of 75 square meters per module. Smaller modules, typically 1 to 2 square meters and around 8,000 to 20,000 fibers are commonly used in medical dialysis applications (Fresenius Medical Care, Gambro). In principle, all these commercial products can be coated by means of interfacial polymerization using the method of the invention, resulting in a thin-film composite layer, in which the aquaporin water channels are preferably incorporated during their formation, by for example, by adding a suitable protein suspension or solution, preferably in vesicle form, to the aqueous reactive amine solution, e.g., a meta-phenylene diamine solution, and injecting or pumping the combined solution through fibers of support, removing excess solution and subsequently pumping or injecting a reactive acyl chloride in organic solvent, eg trimesoyl chloride in hexane, and finally washing with deionized water eg MilliQ™ water . The packaging material of the HF modules of the invention can be any suitable material used for HF modules, such as polypropylene, polyethylene, PVDF and stainless steel. The fibers can be sealed within the HF module housing using commonly known epoxy adhesive materials and the like. Additional examples of HF modules that can be TFC modified according to the invention are found on membrane producer websites, such as:
    [022]http://www.membranafiltration.com/filtration-modules/documentation.cfm
    [023]http://www.kochmembrane.com/PDFs/KMS_Puron_Hollow_Fiber_PSH3 00_PSH600_PSH1800_Modul.aspx
    [024]http://www.kochmembrane.com/Membrane-Products/Hollow-Fiber/Ultrafiltration/PURON-Series.aspx
    [025]http://www.daicen.co.jp/english/membrane/kogata.html
    [026]http://www.spectrumlabs.com/filtration/hfmods.html
    [027]http://www.microdyn-nadir.com/en/Products/
    [028] In an embodiment of the present invention, the HF module is operated with a countercurrent flow of feed and absorption solutions. In another embodiment of the present invention, the HF module is operated with flow in accordance with the current of the absorption and feed solutions. In another embodiment of the invention, the HF module is operated with the absorption solution against the TFC layer. In yet another embodiment of the invention, the HF module is operated with the feed solution against the TFC layer. Furthermore, the modified hollow fibers of the invention can be assembled into a system or module for use as a membrane bioreactor (MBR), where the MBR module containing the hollow fibers is submerged in an aqueous liquid and where purified water is removed from the said liquid through the fibers by using an absorption solution or by applying moderate suction pressure.
    [029] Another aspect of the invention relates to a method of manufacturing a hollow fiber membrane modified with a thin film composite layer (TFC) comprising aquaporin water channels, where the TFC layer comprising aquaporin water channels is prepared directly on the surface of the membrane fibers assembled and sealed in an HF module, said method comprising the steps of: a) obtaining a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes) endowed with about 25 to about 500 LPR/POPR (ratio based on mole content) (preferably 100 LPR/POPR for lipid diblock copolymer, 50 POPR for triblock copolymer) of protein, b) preparation of an aqueous solution of a diamine, such as 1,3-diaminobenzene, to obtain a solution of about 1% to about 5%, such as about 2.5 to 4.2% (w/w) concentration, c) dissolution of an acyl chloride such as benzene-1,3,5-tricarbonyl chloride in a solvent of and hydrocarbon such as hexane, heptane, octane, nonane having a straight or branched hydrocarbon chain or mixtures thereof such as isoalkane hydrocarbon solvent to obtain a concentration of about 0.05% to about 1%, such as about 0.15% (w/v), d) preparation of a mixture of diamine/aquaporin vesicles, such as aquaporin/1,3-diaminobenzene vesicle mixture, by dissolving/mixing the vesicle preparation from step a) with the solution from step b), e) pump the mixture from step d) through the hollow fiber lumen of a hollow fiber module using its end inlet, f) remove excess diamine by a gas purge on the lumen side of the fibers using a module inlet, g) injecting the acyl chloride solution from step c) into the module through an inlet to allow an interfacial polymerization reaction to occur, and h) rinsing the module with an aqueous solvent, by injection through a module input.
    [030]Optionally, after filling with water, the module is sealed with watertight covers to prevent it from drying out.
    [031] Another aspect of the invention relates to a method of externally coating a hollow fiber membrane, with a thin film composite layer (TFC) comprising aquaporin water channels, said method comprising the steps of: a ) obtaining a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes), b) preparing an aqueous solution of a di- or triamine, c) dissolving a di- or triacyl halide in a nonpolar organic solvent, d) preparing a mixture of amine and aquaporin vesicle by dissolving/mixing the preparation of the vesicles from step a) with the solution from step b), e) pass the hollow fiber membrane through the mixture from step d), f) remove excess aqueous solution, g) passing the hollow fiber membrane through the acyl halide solution of step c) to allow an interfacial polymerization reaction to occur and h) washing the hollow fiber membrane with an aqueous solvent, for example, passing the hollow fiber through s from an aqueous bath.
    [032] In the above-described methods of coating the hollow fiber membrane and preparing the hollow fiber module, steps a) - c) can be performed in any convenient order. Furthermore, step c) can be carried out before or after step d).
    [033] In exemplary embodiments, said liposomes used in the preparation of the HF module of the invention are prepared from lipids, such as DPhPC, DOPC, mixed soy lipids, such as asolectin and soy lecithin, or mixed lipids of E. coli; and said polymersomes may comprise hydrophilic-hydrophobic-hydrophilic (A-B-A or A-B-C) type triblock copolymers or hydrophilic-hydrophobic (A-B) type diblock copolymers.
    [034] In another embodiment, said polymersomes may comprise a combination of hydrophilic-hydrophobic-hydrophilic type triblock copolymers and hydrophilic-hydrophobic type diblock copolymers. In the combinations the diblock copolymers can comprise from about 10 mol% to about 60 mol%, such as from about 25 mol% to about 50 mol%.
    [035] Said aquaporin water channels are preferably AqpZ channels, but in principle all water selective aquaporins, for example, such as Aquaporin Z (AqpZ), Aqp1, GlpF or SoPIP2; 1 are useful in the present invention.
    [036] Said TFC layer is preferably formed by interfacial polymerization of an aqueous solution of an amine with a solution of an acid chloride in an organic solvent, and wherein the aquaporin water channel vesicles are incorporated in the said aqueous solution. Said aquaporin water channels are preferably incorporated into vesicles prior to incorporation into the TFC layer of the hollow fiber membrane of the present invention, and said vesicles may be in the form of liposomes or polymersomes, wherein said liposomes are prepared from lipids, such as DPhPC, DOPC, mixed soy lipids, or mixed lipids from E. coli, and said polymersomes comprise triblock copolymers of the hydrophobic-hydrophilic hydrophilic type (ABA or ABC) or diblock copolymers of the hydrophilic-hydrophobic type (AB). In another embodiment, said polymersomes may comprise a combination of hydrophilic-hydrophobic-hydrophilic type triblock copolymers and hydrophilic-hydrophobic type diblock copolymers.
    [037] The HF membrane of the invention preferably has a TFC layer formed by interfacial polymerization of an aqueous solution of an amine with a solution of an acid chloride in an organic solvent, and in which the water channel vesicles aquaporin are incorporated in said aqueous solution.
    [038] In an embodiment of the method of preparing the HF module of the invention, the fibers are the purged gas to blow out excess water in step f) and the module is held upside down in step f).
    [039] In another aspect of the present invention, there is provided a hollow fiber module having a high water permeability and small pore sizes, such as with a pore diameter less than about 5 to 10 nm, such as equal to or less than about 1 nm. Formation of a separating layer in the form of a thin film layer as is known in the art on the surface of a supporting membrane fiber results in changes in the water transport mechanism. Instead of water transport taking place by normal diffusion through the pores of the supporting membrane, another type of water transport takes place, through the thin film layer as is known from this type of reverse osmosis membranes, in which membrane permeability is limited. The non-porous nature of the thin-film separating layer results in wastewater transport that requires "jump diffusion" as described in Kotelyanskii et al. 1998. Thus, thin-film modification of water membranes has found primary use in reverse osmosis, where a hydrostatic pressure is required to force water through the membrane, and the advantage gained lies in better separation of unwanted solutes in water to be filtered. These conventional reverse osmosis membranes are effectively 100 to 200 nm thick non-porous layers supported by a porous material. Water permeation in these membranes occurs as a process of diffusion through the non-porous layer established through the appearance and disappearance of interstitial spaces. The HF module of the present invention can be further improved over that of prior art reverse osmosis membranes by having the aquaporin water channels incorporated into the thin film layer making it a thin film composite (TFC) layer. The incorporation of aquaporins has the additional advantage of providing selective water transport through its pores, with a diameter of only 2.4 A at its narrowest passage (AqpZ pore, cf. Wang et al. 2005) where a transport Efficient water flow occurs. The HF module of the invention combines the advantages of having a thin film separating layer along with aquaporin water channels, thus improving separation as well as water flow through Angstrom sized pores making the HF module suitable , both for reverse osmosis, advanced osmosis, assisted advanced osmosis, nanofiltration etc. DEFINITIONS
    [040] The term "hollow fiber membrane" and "HF membrane" as used herein refers to any type of capillary membrane that can be used for liquid filtration purposes.
    [041] The term "polyethersulfone" as used herein refers to a membrane material used in the manufacture of hollow fiber modules. An example is the UltraPES™ membrane material marketed by Membrana GmbH. A microscopic cross-sectional photo of an UltraPes™ fiber is shown in Fig. 2, cf. Membrane GMBH.
    [042]"Aquaporin" as used herein refers to selective water channel proteins, including AqpZ and SoPIP2;1 prepared according to the methods described by Maria Karlsson et al. (FEBS Letters 537 (2003) 68-72) or as described in Jensen et al. US 2012/0080377 A1.
    [043]"Asolectin" as used herein refers to a fraction of soy lecithin [IV-S], which is a highly purified phospholipid product containing lecithin, cephalin, inositol phosphatides, and soybean oil (synonymous: azolectin) .
    [044] "Block copolymer" as used herein refers to membrane that forms or vesicle that forms di- and tri-block copolymers with both hydrophilic (A or C) and hydrophobic blocks; (B) the diblock copolymers being of the A-B or C-B type, which are capable of forming bilayers, and the triblock copolymers being of the A-B-A or A-B-C type, which form monolayers by self-assembly, where all membranes have the hydrophobic layer in the middle.
    [045]Examples of useful diblock copolymers and examples of useful triblock copolymers are as follows:
    where EO-block-DMS-block, like E025DMSg, represents poly(dimethylsiloxane-block-ethylene oxide-block),
    [046]EO-block-BO-block, as EO15B016, represents poly(butylene oxide-block-ethylene oxide-block), and MOXA-block-DMS-block-MOXA-block, as MOXA6DMS35MOXA6, represents poly(2 -methyloxazoline-block-dimethylsiloxane-block-2-methyloxazoline). Diblock and triblock copolymers can be used as individual components or as mixtures in creating biomimetic membranes, such as vesicles or planar membranes, for the incorporation of aquaporins having amphiphilic properties, due to their native transmembrane properties and functions.
    [047]"Liquid membrane" as used herein refers to membrane systems as described in WO2010/146365 (Aquaporin A/S) and WO 2012/080946 (Aquaporin A/S). Said liquid membrane is an integral component of the TFC HF membranes of the invention in which it is immobilized or encapsulated.
    [048] The term "advanced assisted osmosis" (or "pressure assisted advanced osmosis") as used herein refers to the concept of applying mechanical pressure to the feed side of the membrane to increase water flow through synergy of osmotic and hydraulic driving forces.
    [049]"Thin Film Composite" or (TFC) Hollow fiber membranes, as used herein, are prepared using an amine reagent, preferably an aromatic amine, such as a diamine or triamine, for example, 1,3- diaminobenzene (m-phenylenediamine >99%, e.g. as purchased from Sigma-Aldrich) in an aqueous solution, and an acyl halide reagent, such as a di- or triacid chloride, preferably an aromatic acyl halide, e.g. , benzene-1,3,5-tricarbonyl chloride (CAS No. 84270-84-8, trimesoyl chloride (TMC), 98%, eg as purchased from Sigma-Aldrich) dissolved in a organic solvent, where such reagents combine in an interfacial polymerization reaction, cf. U.S. 4,277,344, which describes in detail the formation of a composite membrane comprising a polyamide laminated to a porous membrane support, on the surface of the support membrane, for example, a polyethersulfone membrane. Benzene-1,3,5-tricarbonyl chloride is dissolved in a solvent such as a C6-C12 hydrocarbon group including hexane (>99.9%, Fisher Chemicals), heptane, octane, nonane, decane, etc. (straight or branched chain hydrocarbons) or other lower aromatic hydrocarbon solvent, eg Isopar™ G Fluid which is produced from petroleum based raw materials treated with hydrogen in the presence of a catalyst to produce a low odor fluid whose main components include isoalkanes. Isopar™ G Fluid: Chemical name: Hydrocarbons, C10-C12, isoalkanes, <2% aromatics; CAS: 64742-48-9, chemical name: naphtha (petroleum), hydrotreated heavy (from ExxonMobil Chemical). Alternatives to the 1,3-diaminobenzene reagent include diamines such as hexamethylenediamine etc., and alternatives to the 1,3,5-tricarbonyl benzene chloride reagent include a diacyl chloride, adipoyl chloride, etc., as known in the art .
    [050]"Gas" as used herein means any gaseous fluid, such as inert gases, di-nitrogen, atmospheric air, etc., which can be used to blow the solvent.
    [051]Proteoliposomes as used herein, typically have a lipid to protein ratio (LPR calculated on a molar basis) of between 25 to 500, such as about 100 to about 200.
    [052] Proteopolymersomes as used herein typically have a polymer to protein ratio (POPR calculated on a molar basis) of between 25 to 500, such as about 50 to about 100 when using a triblock copolymer and a ratio of polymer to protein from 25 to 500, such as about 100 to about 200 when using a diblock copolymer.
    [053] In a preferred embodiment of the invention, the hollow fiber bundles comprise a polyethersulfone (UltraPES™) support material in the form of a hydrophilic capillary membrane material, having the following characteristics (average values are given):
    [054]Physical characteristics: wall thickness 220 μm ± 15 μm; inner diameter 760μm ± 30μm; tensile strength > 410 cN; elongation at break > 40%; explosion pressure > 12 bar; implosion pressure > 7 bar; Minimum pore size of 6-7 nm.
    [055] Membrane performance characteristics: transmembrane flux (water, 25°C) > 0.65 mL/[min x cm2 x bar]; MWCO molecular weight range (dextran, 90%, 0 bar) 65 kDa ± 20 kDa.
    [056]The characteristics indicated are representative of a preferred Ultra-PES material supplied by Membrana GmbH, Oehder Strasse 28, D-42289 Wuppertal, Germany.
    [057] In another preferred embodiment of the invention, the hollow fiber bundles comprise polyethersulfone a MicroPES®, as the TF10 version also supplied by Membrana GmbH, support material, which differs from the UltraPES material by having a transmembrane flux (water, 25°C) > 35 mL/[min cm2 x bar]; wall thickness of 100 µm ± 25 µm; an internal diameter of 300μm ± 40μm; tensile strength > 50 cN; elongation at break > 30%; maximum pore size of 0.5μm ± 0.1μm. EXPERIMENTAL EXAMPLES
    [058] Preparation of 1 mg/ml proteoliposomes asolectin, and the lipid to protein ratio (LPR) 200 using AqpZ PM 27233 according to the following protocol: 1)Fill a 50 ml glass evaporation vial with 5 ml of a 2 mg/ml stock solution of asolectin (mw 786.11 g/mol, Sigma) in CHCl3. 2)Evaporate CHCl3 using a rotary evaporator for at least 2 h until complete drying. 3)Add 0.8 mL of buffer solution (1.3% octylglucoside (OG) in PBS pH 7.4) to rehydrate the film obtained in the evaporation flask in step 2. 4)Shake the flask at maximum rpm on a shaker of platform (Heidolph 2010 Unimax orbital platform shaker or equivalent) until the lipid is dissolved. 5) Add 1.73 mg of AqpZ in a protein buffer containing Tris pH8, glucose and OG, 10 mg/ml, and spin the flask for 15 minutes at 200 rpm, the AqpZ being prepared according to the present description. 6) Slowly add 9.03 ml PBS (pH 7.4 without OG), and shake the bottle for 15 minutes at 200 rpm. 7) Freeze/thaw the combined solution/suspension in a 40°C water bath/dry ice three times to eliminate possible multilamellar structures. 8)Add 250 mg of hydrated BIObeads (SM2 from BioRad) and rotate the bottle for 1 h at 200 rpm at 4°C to adsorb the detergent (OG). 9)Add another 250 mg of hydrated BIObeads and rotate the vial for 2 to 3 days at 200 rpm at 4°C. 10)BIObeads with adsorbed OG are then removed by pipetting from the suspension. 11) Extrude the obtained suspension about 11 times through a 200 nm polycarbonate filter using an extruder (such as an Emulsi-Flex-C5 from Avestin, Canada), at least once and up to about 22 times to obtain a uniform suspension of proteoliposome suspension (vesicles).
    [059] Protocol for 1 mg/mL proteopolymersomes, the protein to polymer ratio (POPR) 50
    [060] Triblock copolymers based on polyoxazoline, poly(2-methyl-oxazoline-b dimethyl siloxane-b-2-methyl oxazoline, Moxa 12: DMS 35, pm 3510) (P3691 purchased from Polymer Source™, Quebec, Canada ), AqpZ PM 27233 1)Fill a 50 ml glass evaporation vial with 5 ml of a 2 mg/ml stock solution of asolectin (MW 786.11 g/mol Sigma) in CHCl3. 2)Evaporate CHCl3 using a rotary evaporator for at least 2 h to complete drying. 3)Add 3.0 mL of buffer solution (1.3% OG; 200 mM sucrose; 10 mM Tris pH 8; 50 mM NaCl) to rehydrate the film obtained in the evaporation flask in step 2. 4)Shake the vial at 200 rpm on a platform shaker (Heidolph Unimax 2010 orbital platform shaker or equivalent) for 3 hours to achieve dissolution of the copolymer. 5)Add 1.55mg μL of AqpZ in a protein buffer containing Tris, glucose and OG, and spin the flask overnight at 200 rpm and 4°C. 6)Add 6.88ml of buffer (10 mM Tris, pH 8; 50 mM NaCl) slowly while mixing up and down with pipette. 7)Add 180 mg of hydrated Biobeads and rotate for 1h at 200 rpm. 8)Add 210 mg of hydrated Biobeads and rotate for 1h at 200 rpm. 9)Add 240 mg of hydrated Biobeads and rotate O.N. at 200 rpm. and 4°C 10) Add 240 mg of hydrated Biobeads and rotate O.N. at 200 rpm. and 4°C 11) Biobeads with adsorbed OG are then removed by pipetting out of the suspension. 12) extrude the suspension about 21 times through a 200 nm polycarbonate filter using an extruder, such as at least 1 time and up to about 22 times to obtain a uniform proteopolymersome suspension (vesicles).
    [061]Example 1 - Preparation of a hollow fiber module, in which the inner surface of the fibers was functionalized with immobilized AqpZ vesicles
    [062] Using a hollow fiber module having polyethersulfone membranes, as a custom-made module, such as nine fibers corresponding to about 10 cm2 of outer area and 5 cm2 of inner area, or as a membrane area of up to 0 .5m2 which can correspond to several hundred fibers depending on the length of the module (Membrana GmbH, Wuppertal, Germany), the module to be prepared essentially as described by Sukitpaneenit et al. 2011, a thin film composite layer is prepared on the surface of the inner fibers through interfacial polymerization which involves the following steps: 1) Obtaining 4 ml of AqpZ vesicles as prepared in the example above. 2) Dissolve 250 mg of 1,3-diaminobenzene in 6 ml of MilliQ water to obtain a 4.2% (w/w) concentration solution. 3) 75 mg of benzene-1,3,5-tricarbonyl chloride is dissolved in 50 ml of hexane to obtain a final concentration of 0.15% (w/v) 4) A 1,3-vesicle mixture diaminobenzene/AqpZ is prepared by dissolving/mixing 4 ml of the vesicle preparation from step 1 with 6 ml of the step 2 solution. 5) The mixture obtained in step 4 is constantly pumped through the module for 2 minutes using a end inlet (or inlet 2), cf. Fig. 1. 6)Excess of 1,3-diaminobenzene is removed by constant purging of air from the lumen side of the fibers for 2 minutes using, for example, inlet 1 cf. Fig. 1, preferably keeping the module upside down. 7) A steady stream of 1,3,5-tricarbonylbenzene chloride solution from step 3 is then injected into the module via inlet 1 for approximately 30 seconds using a syringe pump, eg TSE systems, cf. [Retrieved 11/09/2012 r from the Internet: (<URL: http://www.tse-systems.com/products/other-products/pumps-infusion/index.htm)] to allow the reaction to occur interfacial polymerization. 8) Finally, the module is preferably washed with MilliQ water, about 10 ml are used, by injection through the side inlet 3 and 4.
    [063]After filling with water, the module is sealed with the white sealing caps (5), cf. Fig. 1, to prevent them from drying out (the sealing caps are part of the module and are delivered with it).
    [064] Alternatively, steps 2 and 3 are described below, where all other steps are the same as indicated above: 2) Dissolve5 1,3-diaminobenzene in MilliQ water to obtain a 4.2% (w/w) solution ) of concentration. 3) Benzene-1,3,5-tricarbonyl chloride is dissolved in a solvent such as hexane or the isoalkane hydrocarbon solvent to obtain a final concentration of 0.15% (w/v).
    [065]Example 2. Preparation of a hollow fiber module, in which the inner surface of the fibers was functionalized with immobilized AqpZ vesicles
    [066] Using the same hollow fiber module as in Example 1, a thin film composite layer is prepared on the inner surface of the fibers through interfacial polymerization which involves the following steps: 1) Obtaining 4 mL of AqpZ vesicles as prepared in the example above. 2) Dissolve 250 mg of 1,3-diaminobenzene in 6 ml of MilliQ water to obtain a 4.2% (w/w) concentration solution. 3) 75 mg of benzene-1,3,5-tricarbonyl chloride is dissolved in 50 ml of hexane to obtain a final concentration of 0.15% (w/v) 4) An AqpZ/ 1.3 vesicle mixture -diaminobenzene is prepared by dissolving/mixing 4 ml of the vesicle preparation from step 1 with 6 ml of the solution from step 2. 5) The mixture obtained in step 4 is constantly pumped through the module for 2 minutes using an inlet end 1 (or inlet 2), cf. Fig. 1. 6)Excess 1,3-diaminobenzene is removed from the module by a steady stream of an organic fluid such as hexane for 1 min through inlet 1 using a syringe pump. 7) A constant flow of benzene-13,5-tricarbonyl chloride solution from step 3 is then injected into the module via inlet 1 for approximately 30 seconds, using a syringe pump, eg from TSE systems, cf . [retrieved on 11/09/2912 from the Internet: (<URL: http://www.tse-systems.com/products/other-products/pumps-infusion/index.htm)/ to allow the polymerization reaction to occur interfacial. 8) Finally, the module is preferably washed with MilliQ water, about 10 ml are used, by injection through the side inlet 1 and 3.
    [067]After filling with water the module is sealed with the white sealing caps (5), cf. Fig. 1, to prevent it from drying out (the sealing caps are part of the module and are delivered with it).
    [068] Alternatively, steps 2 and 3 are as described below, where all other steps are the same as indicated above: 2) Dissolve 1,3-diaminobenzene in MilliQ water to obtain a 4.2% solution ( w/w) of concentration. 3) benzene-1,3,5-tricarbonyl chloride is dissolved in a solvent, such as hexane or isoalkane hydrocarbon, to obtain a final concentration of 0.15% (w/v).
    [069]Example 3. - Preparation of a hollow fiber module, in which the inner surface of the fibers was functionalized with immobilized AqpZ vesicles
    [070] Using the same hollow fiber module as in Example 1, a thin-film composite layer is prepared on the surface of the inner fiber, through interfacial polymerization involving the following steps and using a syringe pump to push the solutions through the module: 1) Obtaining 4 ml of AqpZ vesicles as prepared in the example above. 2) Dissolve 250 mg of 1,3-diaminobenzene in 6 ml of MilliQ water to obtain a 4.2% (w/w) concentration solution. 3) 75 mg of benzene-1,3,5-tricarbonyl chloride is dissolved in 50 ml of hexane to obtain a final concentration of 0.15% (w/v). 4) An AqpZ/1,3-diaminobenzene vesicle mixture is prepared by dissolving/mixing 4 ml of the vesicle preparation from step 1 with 6 ml of the solution from step 2. 5) Adding the solution from step 2 through the interior of the fibers, keeping the module vertically with the inlet downwards making sure that the air is ventilated); the solution can preferably be pumped using a flow rate of about 5 ml/min and continue to pump the solution for 2 min, for example, such as starting timing immediately after the solution can be seen at the upper end. of the module. 6)Turn off the syringe pump module and rotate it to have excess solution flowing out of the collection glass. 7)Turn the module upside down to aerate and slowly start the air flow until 10 L/min is reached; let the air flow for 2 min. 8) Connect the module to a syringe with 1,3,5-tricarbonyl benzene chloride solution, hold the module in an upright position and start the flow of 1,3,5-tricarbonyl/hexane benzene chloride, for example, maintaining a flow rate of about 15 ml/min. 9)Turn off the hexane syringe module and turn it upside down to exhaust all the hexane; turn on the air purge at about 10 L/min for 5-10 sec. 10)Fill the module with MilliQ by sucking it from a glass container.
    [071] Alternatively, steps 2 and 3 are as described below, where all other steps are equally as indicated above: 2) Dissolve 1,3-diaminobenzene in MilliQ water to obtain a 4.2% solution (w/ p) of concentration. 3) benzene-1,3,5-tricarbonyl chloride is dissolved in a solvent such as hexane or isoalkane hydrocarbon solvent to obtain a final concentration of 0.15% (w/v).
    [072] Alternatively, in the pHF22 protocol we use a syringe pump to push the solutions through the module, such as a MicroPES-TF10 HF module, then after obtaining 4 mL of AqpZ vesicles prepared as in the example above, follow the steps below: 1) Dissolve MPD in MilliQ water and add the AqpZ vesicles to obtain a 2.5% concentration (w/w) of the MPD solution in water/vesicle. 2) Dissolve TMC in an organic solvent such as hexane or an isoalkane hydrocarbon solvent to a final concentration of 0.15% w/v 3) push the MPD solution through the interior of the fibers, keeping them vertical with the inlet upside down (when filling the module, shake it several times to remove air); flow rate :5 mL/min 4) continue to push the MPD solution for 1 min (time starts after the MPD solution can be seen at the top end of the module) and then soak with the MPD solution for 1 min 5) disconnect the syringe module and turn it over to drain excess MPD flow into the collection glass. 6) connect the module upside down (ie the end with the number on top) to atmosphere and slowly start the air flow; dry with controlled airflow for 1 to 2 min and turn the module between steps 7) connect the TMC solution, hold it vertically (end numbered at the bottom) and start the TMC solution flow (flow rate: 10 mL /min) 8) let the solution pass through the fibers for 45 s (after the module is filled, it can be tilted back to the horizontal position) 9) disconnect the module from the syringe and turn it upside down to empty the TMC solution; turn on to atmosphere and purge at 10 L/min for 5-10 sec.; 10) fill the module with MiliQ by sucking it from a beaker.
    [073]Following the various methods described above, a hollow fiber module modified with TFC-aquaporin is obtained, in which the inner surface of the fibers acquired a new microstructure as shown in Fig. 3, where (1) refers to the layer of TFC ~ 200 nm and (2) refers to the 220 µm supporting membrane, (1) and (2) together represent a hollow fiber wall cross section; (3) schematically represents the bilayer membrane in the case of lipids and diblock copolymers as amphiphilic membrane-forming materials with hydrophilic top groups and hydrophobic end groups. Feature (3) shows that a monolayer with a hydrophobic middle part and hydrophilic end parts, or would show a type of bilayer where the triblock copolymers assume a horseshoe shape or mixtures of both, when triblock copolymers are used for the amphiphilic membrane material. (4) Represents the aquaporin protein where its tetrameric form is shown. However, the protein can also be present as a monomer or as a dimer, both of which are also water channels. FILTRATION RESULTS USING ADVANCED OSMOSIS
    [074] Tables 1 and 2 below show the filtration results in the form of measured water flow, Jw, and measured inverse salt flow, Js, for HF modules prepared according to the invention, using a feed solution of 10 μM calcein (CAS No. 1461-15- 0, PM 622.55) and a 2 M NaCl extraction solution, both in deionized water (MiliQ water) and where the TFC-aquaporin layer is formed within the fibers hollow (lumen) and the extraction solution is applied to the outside or inside of the fibers. Countercurrent or cocurrent flow was used. With reference to Fig.1: Typically, the feed solution was pumped through the inlet (1) and out through the inlet (2), and the extraction solution was pumped through the inlet (3) and out through (4 ). In five experiments a countercurrent flow was used, cf. Tables 1 and 2 and the description below. The water channel AqpZ protein was used in all experiments, and both a lipid (asolectin) and various block copolymers (P3691, P8061) were the vesicle membrane materials.
    [075]Each experiment is characterized by water flow (Jw), reverse saline flow (Js) and calcein rejection. Water flux describes how much water is transported through a certain amount of membrane area at a given time (usually L/m2h) and is measured by monitoring the weight loss in the feed solution. Reverse saline flow characterizes the amount of extraction solute that diffuses back into the feed solution. It is an indicator of how salt-tight a membrane is. Js is determined by measuring changes in the conductivity of the feed solution. Calcein rejection is used to determine the advanced rejection properties of a membrane. Here, a fluorescent marker, which is easily detectable by a desktop fluorimeter (eg Qubit Fluorimeter, Invitrogen), is added to the feed solution. By measuring its concentration in the extraction we can determine how much of the marker is rejected.
    [076]The water flow is calculated as follows: Jw = Vt /(A*T); [L/m2h], where Vt is the transported volume, A is the area of the active membrane and t is the time in hours. To determine the reverse salt flow one has to measure the conductivity in the feed solution. With the help of a calibration curve it is then possible to relate the conductivity to a salt concentration and thus calculate the inverse salt flow as follows: Js= (cf,end*Vf,end-cf,start*Vf, start)/(A*t) ; [g/m2h], where Vf marks the initial and final volume and cf the initial and final concentration of salt in the feed.
    [077] Calcein rejection is approximated by: Rca=1-((Vd,end*cca,d,end-Vd,start*cca,d,start)/(Vt*cca,f,start))start) ) Where Vd is the beginning and end of the extraction volume and cca is the calcein reading in the extraction solution. The starting concentration of calcein in the feed (cca, f) is taken as a constant. This is an approximation because a membrane that rejects calcein will concentrate the concentration of calcein in the feed. However, this can be tolerated because leaving the starting concentration constant in the calculation underestimates the total rejection, which is acceptable.

    [078]Notes: a countercurrent flow; ab extraction inside & countercurrent flow; d, according to Ex. 1. HF module No. 12-0644 was modified with the thin film layer only that without vesicles and/or protein and thus represents the prior art as described by Chung Sukitpaneenit & 2012.
    [079] Table 1 clearly shows that, when using the HF module of the invention, it is possible to obtain a higher water flux, Jw, of up to 3 L/m2 h above the flux obtained by a HF module modified with the film thin with nine fibers and still maintain a good Js/Jw ratio as low as about 0.22. This will be an advantage for filtration purposes, where a high water flow is desirable while less salt retention can be tolerated, for example, in wastewater treatment. The results according to the invention shown in Table 1 are all obtained using countercurrent flow, which can prove to be an advantage for high water flow.

    [080]Notes: a = countercurrent flow; c = extraction from the inside; dd prepared according to Ex. 3. HF module No. 12-0644 was modified with thin film layer only without vesicles and/or protein and thus represents the prior art as described by Chung Sukitpaneenit & 2012 .
    [081] Table 2 clearly shows that, with the use of the HF module of the invention, it is possible to obtain an increase in inverse salt retention, Js, of about 0.5 g/m2/h corresponding to an increase of 25% compared to the reverse salt retention obtained for a thin film modified HF module having 9 fibers and still maintain a good water flow of about 8 to 9 L/m2 h. These results are obtained using the co-current flow with the extraction solution inside the HF module fibers. All calcein rejection values above are better than 99%, demonstrating that the HF modules used are extremely tight (no membrane leakage). The HF module of the invention can be used with either countercurrent flow or cocurrent flow, and as can be seen from the above results, it may be preferred to have countercurrent flow. In this case, the differences in osmotic pressure are more evenly distributed along the entire length of the fiber. When the feed and extraction solutions enter the same side (the co-current flow), then water is immediately pulled out of the feed stream into the extraction stream, and across the fiber the difference in osmotic pressure will rapidly decrease (a feed is concentrated and extraction is diluted). When the HF module is now operated with countercurrent flow, then we will have a cleaner feed encountering a dilute extraction at one end and a high osmotic extraction encountering a weakly osmotic (contaminated salt) feed at the other end. Thus, the osmotic pressure difference between both liquids is closer to being the same along the fiber length; and this can favor the countercurrent flow. However, what attests in favor of co-current flow is that the pressure that is generated by pumping inside the fiber meets an equal pressure that is generated by pumping from the outside of the fiber.


    [082] The inner lining of the 5 cm2 HF MicroPES TF10 active membrane area hollow fiber modules resulted in high reproducibility; All experiments in Tables 3 and 4 had comparable Js/Jw ratios with different Jw and Js, which may be due to differences/tolerances in experiments, differences in measurement accuracy, and possibly due to the fact that the coating was a handmade process. Thus, the two different experiments resulted in HF modules with comparable Js/Jw, but varying mean intervals of Jw and Js, cf. Table 3 shows the experimental results of moderate Jw and low Js, and Table 4 shows the experimental results of high Jw and moderate Js. Example 4. PREPARATION OF A HOLLOW FIBER MODULE, WHERE THE EXTERNAL SURFACE OF THE FIBERS WAS FUNCTIONALIZED WITH IMMOBILIZED AQPZ VESICLES
    [083] Using a hollow fiber module having polyethersulfone membranes, such as a custom-made module, with nine fibers corresponding to about 10 cm2, or having a membrane area of up to 0.5 m2, which can correspond to several hundreds of fibers, as a function of module length (Membrana GmbH, Wuppertal, Germany), a thin-film composite layer prepared on the outer surface of the fiber by means of interfacial polymerization involving the following steps of the PHF21 protocol: 1) obtain 4 ml of AqpZ vesicles as prepared in the example above. 2) Dissolve 1,3-diaminobenzene in MilliQ water to obtain a solution with a concentration of 4.2% (w/w). 3) benzene-1,3,5-tricarbonyl chloride is dissolved in an organic solvent such as hexane or an isoalkane hydrocarbon solvent to obtain a final concentration of 0.15% (w/v) 4) A vesicle mixture AqpZ/1,3-diaminobenzene is prepared by dissolving/mixing 4 mL of the vesicle preparation from step 1 with 6 mL of the solution from step 2. 5)Fill the solution from step 4. to the module on the outer side of the fibers (side inlets of the module); flow rate: 5 mL/min 6) Stop flow after 1 min and soak fibers for 1 min 7) Empty module and purge with air to let MPD solution out 8) Use air flow to remove the surface water of the fibers (25 L/min air flow rate) 9) pump the solution from step 3. into the module using a flow rate of 15 mL/min 10), after the module is filled continue to pump for 30 seconds 11) Disconnect the syringe module and turn it upside down to drain the last solution; air and purge at 10 L/min for 5-10 seconds 12) fill the module with MiliQ by sucking it from a beaker Table 5 shows the results of four runs using the method described above (PHF21)


    [084] The outer coating of the hollow fiber modules of the active membrane area of 5 cm2 resulted in high reproducibility: The experiments in Table 5 show sets of 2 (roughly 2 x 8 [L/m2 h] and 2 x 6 [L] /m2h]) which have comparable Jw and Js values. Example 5.
    [085]Internal coating for the creation of the TFC layer on the fibers in the HF MicroPES TF10 module
    [086] The HF24 protocol for the inner lining of 100 cm2 modules using a syringe pump to suck the solutions through the module:
    [087]Use a syringe pump to pump the solutions through the module 1) pre-soak the modules with MiliQ at least overnight 2) Obtain 16 mL of AqpZ vesicles as prepared in the example above. 3) Dissolve 1,3-diaminobenzene in MilliQ water to obtain a 4.2% (w/w) concentration solution. 4) 75 mg of benzene-1,3,5-tricarbonyl chloride is dissolved in 50 ml of hexane to obtain a final concentration of 0.15% (w/v) 5) An AqpZ/1.3 vesicle mixture -diaminobenzene is prepared by dissolving/mixing 16 mL of the vesicle preparation from step 1 with 24 mL of step 3 solution. 6) pumping the step 5 solution through the module for as long as necessary until no more bubbles appear (tap continuously to shake bubbles) at 10 mL/min; keep the module vertical. 7) Allow the solution to soak the fibers for 1 min 8) Disconnect the syringe module and let the excess solution flow into the collection beaker. 9) Connect the module upside down to atmosphere and start the air flow slowly until 20 L/min are reached 10) dry with controlled airflow for 3 to 5 minutes and turn the module from time to time 11) push the solution from step 4. through the fibers at a constant flow (flow rate: 15 mL/min) for 45sec. (starting when TMC enters the fibers) 12) empty the module by turning off the tube 13) blow air through the fibers for 5 to 10 sec. to eject the remaining solution 14) fill the fibers and module with MilliQ
    [088] Table 6 shows the results of 2 tests using the method described above (PHF24)


    [089] The inner lining of the hollow fiber modules of the 100 cm2 HF MicroPES TF10 active membrane area resulted in high reproducibility, cf. Tables 6 and 7 which show the experimental results with 2M NaCl as extraction solution and Table 6 which shows the experimental results with 1M NaCl extraction solution where a reduction in water flow is noticeable in contrast to a smaller reduction in inverse saline flow Example 6. - EXTERNAL CONTINUOUS COATING TESTS OF HOLLOW FIBERS
    [090]The aim of this experiment is to establish a method of continuous coating the outside of hollow fiber membranes through an automated production process. MATERIALS
    [091]The machine and fibers are supplied by Membrana and the coating chemicals and AqpZ vesicles are the same used in the previous examples. The different hollow fiber membranes tested are MicroPES® TF10 and DuraPES® 0.7 (Membrana GmbH, Wupperthal, Germany). Thus, the final coating contains an immobilized liquid membrane component containing aquaporin proteins. METHODS
    [092] Figure 4 illustrates, in the form of a sketch, the automated continuous outer coating of the hollow fibers (shown as a narrow line). In the figure: (1) is a coil of uncoated hollow fiber, preferably of a porous polyethersulfone (or polysulfone and the like) material. From here, they are transported to the liquid aquaporin/MPD membrane bath (2) where the aquaporin vesicles will absorb into the fiber and bond to its surface. Excess aquaporin/MPD solution is removed during a drying step (3), where an air knife can be used to improve removal of excess solution. From here, the fiber passes into the isoalkane/TMC hydrocarbon solvent bath in which the interfacial polymerization takes place (4). Thus, the aquaporin vesicles (liquid membrane proteopolymersomes) are encapsulated due to the TFC layer formed on the fiber. A drying step (5) ensures that all the organic solution is evaporated before soaking the fiber in a water bath to remove the remaining chemicals (6). Now the fiber is wound into a new bobbin. The coated hollow fibers are then cut to the proper length and constructed into suitable modules for the purposes of FO water extraction and separation. Example 7 - HOLLOW FIBER MODULE RETENTION AND TWO SMALL PEPTIDE SUPER CONCENTRATION TEST
    [093] In this example, HF modules with 5cm2 of active area were used, prepared according to Example 3 above.
    [094] Peptide A: GGG SGA GKT PM = 0.692 kDa
    [095]100 mL of peptide GGG SGA GKT PM = 0.692 kDa in TES buffer (feed solution) was filtered through an advanced osmosis HF module to the desired higher concentration (approximately 20x) using 1M NaCl as the extraction solution. The weight of the super-concentrated sample was measured to determine the volume reduction of the initial starting sample. 10 μl of the super-concentrated sample was mixed with 90 μl of 10x TES buffer to eliminate the buffer super-concentration factor when determining the final concentration of the super-concentrated peptide sample. The 100 μl total sample was then mixed with 100 μl of a LavaPep quantitation kit, and incubated for 1 h at room temperature, and then the fluorescence counts were read on a Qubit fluorimeter (Invitrogen). Fluorescence counts were then compared to a standard curve in which the actual concentration of the peptide sample was determined. From the same ultra-concentrated peptide sample, three samples (n = 3) were prepared and measured in Qubit and the mean number of fluorescence counts was used to determine the concentration of the standard curves. The sample volume was concentrated about 20 times, and the A-peptide was ultra concentrated up to about 18 to 19 times.
    [096] Peptide B: AGKT PM 0.375 kDa (experimental conditions closely corresponding to those described above for peptide A).
    [097]100 mL of AGKT peptide (0.375 kDa MW) in TES buffer was tested to the desired superconcentration (about 20x) with the hollow fiber module FO. The mass of the super-concentrated sample was measured to determine the volume reduction of the initial starting sample. The super-concentrated sample was then diluted four-fold with TES buffer to generate a 5-fold more concentrated peptide sample, prior to further processing of the sample. This is done to avoid quenching the fluorescence signal for the smaller peptide as this has been seen in previous assays. 10 μl of the most concentrated 5x sample was mixed with 90μl of 10x TES buffer to eliminate the buffer's superconcentration factor in determining the final concentration of the superconcentrated peptide sample. The 100 µl total sample was then mixed with 100 µl of LavaPep Quantitation Kit, incubated for 1 h at room temperature and then the fluorescence counts were read in a Qubit fluorimeter (Invitrogen). Fluorescence counts were then compared to a standard curve in which the actual concentration of the peptide sample was determined. From the same initial superconcentrated peptide sample, three samples (n = 3) were prepared and measured in Qubit and the mean number of fluorescence counts was used to determine the concentration of the standard curves. The sample volume was concentrated about 21 times, and the B-peptide was superconcentrated up to about 24 times.
    [098] In both cases the ultra-concentration factor of sample peptides A and B corresponds to the volume reduction factor, thus leading to the conclusion that hollow fiber modules with a TFC-active aquaporin layer inside them can be used to superconcentrate biomolecules, at least, up to sizes of 0.375 kDa. MATERIALS AND EQUIPMENT:
    [099]Peptides: GGG ASG GKT acquired from CASLO
    [0100]TES: N-(Tris(hydroxymethyl)methyl)-2-aminomethanesulfonic acid), Sigma Aldrich, Cas 7365-44-8
    [0101]LavaPep Peptide Quantitation Kit: purchased from www.lavapep.com
    [0102]Part A (LP-022010)
    [0103]Part B (LP-022010)
    [0104] Qubit Fluorimeter, Invitrogen
    [0105]Catalog number: Q32857
    [0106] Serial number: 45257-233
    [0107]Measurement definition: Quant-iT ssDNA
    [0108] TES buffer, 100mL
    [0109]m (TES) = 229.8 mg
    [0110]m (EDTA) = 37.2mg
    [0111]Adjust pH with 1M NaOH to 8 and fill with mQ water. Filter through a vacuum filter.
    [0112] For 10x TES buffer the amounts of TES and EDTA are multiplied by 10.
    [0113]LavaPep quantitation kit.
    [0114]Part A, Part B and mQ water are mixed together following the ratio (1:1:8).
    [0115]The Lavapep bench-top solution is mixed with the super-concentrated peptide sample following the ratio of (1:1). 8. CREATININE RETENTION OF THE HOLLOW FIBER MODULE
    [0116] In this example, the HF modules with 5 cm2 of active area prepared according to Example 3 above are used. The objective is to determine the retention rate of creatinine (MW 113.12 g mol-1), which occurs naturally in the blood and urine. If filtration in the kidney is deficient, blood creatinine levels will increase. The creatinine level in blood and urine is generally used to calculate creatinine clearance (CrCl), which correlates with glomerular filtration rate (GFR) which is clinically important as a measure of renal function. . CREATININE TEST
    [0117]Creatinine in a sample is detected with the abcam Creatinine Assay kit (ab65340). In the assay, creatinine is converted to creatine by creatinase, creatine is converted to sarcosine, which reacts with a sample to generate red color (lambda max = 570 nm) and fluorescence (Ex /Em = 538/587 nm).
    [0118]Kit instructions are followed without change. The creatininase, creatinase and creatine enzyme mixture is reconstituted with 220 μl of assay buffer each and aliquoted before use to avoid freeze-thaw cycles. The creatinine standard is reconstituted with 100 μl of deionized water to generate 100mM of standard creatinine. For the colorimetric assay the creatinine standard is diluted one hundred times in Assay Buffer to generate a stock stock solution of 1 nmol/μL. A series of dilutions is prepared in which 0, 2, 4, 6, 8 and 10 μl of working solution is mixed in assay buffer to a final volume of 50 μl.
    [0119]For each sample a reaction mixture is prepared with the following volumes.
    [0120] Assay Buffer: 42 µl
    [0121] Creatinase 2 μl
    [0122] Creatininase: 2 µl
    [0123] Enzyme mixture: 2 μl
    [0124]Probe: 2 μl
    [0125]The basic reaction mix contains the same reagents except for Creatininase. The amount of Assay Buffer is 44 µl this time. Standard samples (50 μl) are mixed with the reaction mix (50 μl), incubated at 37°C for one hour. O.D. is measured in microcuvettes at 570 nm and the excess is subtracted from all samples. O.D. it is then plotted against concentration to generate a standard curve.
    [0126] For creatinine samples in hollow fibers the same procedure will be done, where the super-concentrated sample will be diluted 100 times in Assay Buffer and 50 μl of the resulting sample will be mixed with 50 μl of the reaction mixture. The value of the O.D. measured and the sample concentration will be determined from the standard curves. REFERENCES
    [0127]All documents referred to in this descriptive report are hereby incorporated by reference in their entirety.
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    [0131]Wenhao Xie (2011) Alteration of Membrane Properties during Continuous Hemofiltration Therapy in vivo (dissertation,
    [0132]http://darwin.bth.rwth-aachen.de/opus3/volltexte/2011/3556/pdf/3556.pdf).
    [0133]Ikuo Aoike, Required Water Quality for the Use of High-Performance Membranes in Saito A, Kawanishi H, Yamashita AC, Mineshima M (eds): High-Performance Membrane Dialyzers. Contribution Nephrol. Basel, Karger, 2011, vol 173, pp 53-57.
    [0134]Clark & Gao, Properties of Membranes Used for Hemodialysis Therapy. Seminars in Dialysis, Vol 15, No. 1 (January - February) 2002, pp. 191-195.
    [0135]Qian Yang, Kai Yu Wang, Tai-Shung Chung. Dual-Layer Hollow Fibers with Enhanced Flux as Novel Forward Osmosis Membranes for Water Production. Environ. Sci. Technol. 2009, 43, 2800-2805.
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    [0139]Baihai Su, Shudong Sun and Changsheng Zhao (2011). Polyethersulfone Hollow Fiber Membranes for Hemodialysis, Progress in Hemodialysis - From Emergent Biotechnology to Clinical Practice, Prof. Angelo Carpi (Ed.), ISBN: 978953-307-377-4, InTech, Available from: Retrieved from the Internet: (<URL: http://www.intechopen.com/books/progress-in-hemodialysis-from -emergent- biotechnology-to-clinical-practice/polyethersulfone-hollow-fiber-membranes-for- hemodialysis >)
    [0140]“Polyethersulfone Hollow Fiber Membranes for Hemodialysis” Chapter 4, p. 65-88, in Progress in Hemodialysis - From Emergent Biotechnology to Clinical Practice, Edited by Angelo Carpi, Carlo Donadio and Gianfranco Tramonti, Published by InTech 2011, Janeza Trdine 9, 51000 Rijeka, Croatia. [retrieved on 2011-11-09].
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    [0146]Zhang, P., Fu, X., Chung, T.-S., Weber, M. and Maletzko, C.: Development of Thin-Film Composite forward Osmosis Hollow Fiber Membranes Using Direct Sulfonated Polyphenylenesulfone (sPPSU) as Membrane Substrates. Environ. Sci. Technol., 2013, 47 (13), pp 7430-7436
    权利要求:
    Claims (20)
    [0001]
    1. Hollow Fiber Module (HF), CHARACTERIZED by the fact that it has fibers modified with a thin film composite (TFC) layer comprising aquaporin water channels, wherein the TFC layer is a polyamide layer provided within the fibers.
    [0002]
    2. HF module according to claim 1, CHARACTERIZED by the fact that said aquaporin water channels are incorporated into vesicles before incorporation into the TFC layer.
    [0003]
    3. HF module, according to claim 1 or 2, CHARACTERIZED by the fact that said vesicles in which the aquaporin water channels are incorporated are liposomes or polymersomes.
    [0004]
    4. HF module, according to any one of claims 1 to 3, CHARACTERIZED by the fact that said liposomes are prepared from lipids such as DPhPC, DOPC, mixed soybean lipids, asolectin or mixed lipids from E. coli .
    [0005]
    5. HF module, according to any one of claims 1 to 3, CHARACTERIZED by the fact that said polymersomes comprise triblock copolymers of the hydrophilic-hydrophobic-hydrophilic type (ABA or ABC), diblock copolymers of the hydrophilic-hydrophobic type (AB), or a combination of these.
    [0006]
    6. HF module according to any one of claims 1 to 5, CHARACTERIZED by the fact that said aquaporin water channels are AqpZ channels or SoPIP2;1 water channels.
    [0007]
    7. HF module according to any one of claims 1 to 6, CHARACTERIZED by the fact that said TFC layer is formed through interfacial polymerization of an aqueous solution of a di- or triamine with a solution of di halide. - or triacyls in an organic solvent, and wherein the aquaporin water channel vesicles are incorporated in said aqueous solution.
    [0008]
    8. HF module, according to any one of claims 1 to 7, CHARACTERIZED by the fact that the hollow fiber support material is a polyethersulfone.
    [0009]
    9. HF module, according to any one of claims 1 to 8, CHARACTERIZED by the fact that the fiber area is from 0.1 cm2 to 0.5 m2.
    [0010]
    10. Hollow fiber membrane, CHARACTERIZED in that it is modified with a thin film composite (TFC) layer comprising aquaporin water channels, wherein the TFC layer is a polyamide layer provided within the fibers.
    [0011]
    11. Hollow fiber membrane according to claim 10, CHARACTERIZED by the fact that said aquaporin water channels are incorporated into vesicles before incorporation into the TFC layer.
    [0012]
    12. Hollow fiber membrane, according to claim 10 or 11, CHARACTERIZED by the fact that said vesicles in which the aquaporin water channels are incorporated are liposomes or polymersomes.
    [0013]
    13. Hollow fiber membrane, according to any one of claims 10 to 12, CHARACTERIZED by the fact that said liposomes are prepared from lipids such as DPhPC, DOPC, mixed soy lipids, asolectin or mixed lipids of E. coli.
    [0014]
    14. Hollow fiber membrane, according to any one of claims 10 to 12, CHARACTERIZED by the fact that said polymersomes comprise triblock copolymers of the hydrophilic-hydrophobic-hydrophilic type (ABA or ABC), diblock copolymers of the hydrophilic-type hydrophobic (AB) or a combination thereof.
    [0015]
    15. Hollow fiber membrane according to any one of claims 10 to 14, CHARACTERIZED by the fact that said aquaporin water channels are AqpZ channels or SoPIP2;1 water channels.
    [0016]
    16. Hollow fiber membrane according to any one of claims 10 to 15, CHARACTERIZED by the fact that said TFC layer is formed by the interfacial polymerization of an aqueous solution of a di- or triamine with a solution of a halide of di- or triacyl in an organic solvent, and wherein the aquaporin water channel vesicles are incorporated in said aqueous solution.
    [0017]
    17. Method of preparing a hollow fiber module comprising modified HF membranes within the fibers with a thin film composite (TFC) layer comprising aquaporin water channels, said method CHARACTERIZED by the fact that it comprises the steps of: a ) obtain a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes) having from 25 to 500 LPR/POPR of protein, b) prepare an aqueous solution of a di- or triamine, c) dissolve a di- or triacyl halide in an organic solvent apolar, d) prepare a mixture of amine and aquaporin vesicle by dissolving/mixing the vesicle preparation from step a) with the solution from step b), e) pumping the mixture from step d) through the lumen of the hollow fibers in a hollow fiber module using its end inlet, f) remove excess aqueous solution by a gas purge from the lumen side of the fibers using a module inlet, g) inject the acyl halide solution from step c ) inside modulus through the lumen of the hollow fibers to allow an interfacial polymerization reaction to occur, and h) washing the modulus with an aqueous solvent by injection through an inlet of the modulus.
    [0018]
    18. Method, according to claim 17, CHARACTERIZED by the fact that it comprises the steps of: a) obtaining a suspension of aquaporin vesicles (proteoliposomes or proteopolymersomes) having from 25 to 500 LPR/POPR of protein, b) preparing a solution aqueous 1,3-diaminobenzene of 1% to 5% concentration (w/w), c) dissolve benzene-1,3,5-tricarbonyl chloride in an organic solvent selected from the group consisting of hexane, heptane, octane or a mixture of solvents to obtain a concentration of 0.05% to 1% (w/v), d) prepare a mixture of 1,3-diaminobenzene/aquaporin vesicle by dissolving/mixing the vesicle preparation from step a) with the solution from step b), e) pump the mixture from step d) through the lumen of the hollow fibers into a hollow fiber module using its end inlet, f) remove excess aqueous solution by a purge of gas from the lumen side of the fibers using a module inlet, g) injecting the benzene chloride solution-1,3,5 - tricarbonyl from step c) into the module through the lumen of the hollow fibers to allow an interfacial polymerization reaction to occur, and h) washing the module with an aqueous solvent by injection through an inlet of the module.
    [0019]
    19. Method according to claim 17 or 18, CHARACTERIZED by the fact that said hollow fiber module comprises polyethersulfone fibers.
    [0020]
    20. Method according to claim 17 or 18, CHARACTERIZED by the fact that in step f) the fibers are purged with gas until dry and in which the module is kept upside down in step f).
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    同族专利:
    公开号 | 公开日
    EP2943270A1|2015-11-18|
    IL239703D0|2015-08-31|
    IL254270D0|2017-10-31|
    ES2678096T3|2018-08-08|
    DK201300650A|2014-07-12|
    AU2014206128C1|2016-04-28|
    WO2014108827A1|2014-07-17|
    AU2014206128B2|2016-01-28|
    JP2016221506A|2016-12-28|
    IL239703A|2017-11-30|
    SG10201604075SA|2016-07-28|
    JP2016505374A|2016-02-25|
    US10011692B2|2018-07-03|
    JP6141487B2|2017-06-07|
    DK2943270T3|2018-08-13|
    EP2943270B1|2018-05-16|
    GB201300465D0|2013-02-27|
    PL2943270T3|2018-11-30|
    CA2897354C|2019-03-26|
    DK177840B1|2014-09-08|
    TW201440881A|2014-11-01|
    JP5946591B2|2016-07-06|
    BR112015015985A2|2017-07-11|
    HK1217007A1|2016-12-16|
    SG11201504700RA|2015-07-30|
    TWI619542B|2018-04-01|
    US20150144553A1|2015-05-28|
    CA2897354A1|2014-07-17|
    AU2014206128A1|2015-07-09|
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    法律状态:
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-03-27| B25G| Requested change of headquarter approved|Owner name: AQUAPORIN A/S (DK) |
    2019-10-22| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-02-11| B06G| Technical and formal requirements: other requirements [chapter 6.7 patent gazette]|
    2021-06-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-29| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/01/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    GBGB1300465.0A|GB201300465D0|2013-01-11|2013-01-11|A hollow fiber module having tfc-aquaporin modified membranes|
    GB1300465.0|2013-01-11|
    PA201300650|2013-11-15|
    DKPA201300650A|DK177840B1|2013-01-11|2013-11-15|A hollow fiber module having tfc-aquaporin modified membranes|
    PCT/IB2014/058096|WO2014108827A1|2013-01-11|2014-01-07|A hollow fiber module having thin film composite- aquaporin modified membranes|
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