Small diameter hollow fiber membrane and method of making same

Abstract

The present invention relates to a porous hollow fiber membrane having a unique combination of physical parameters in terms of inner diameter of the lumen and wall thickness. More specifically, the inner diameter is small and the wall thickness is thin. The inner diameter can be from about 90 µm to about 160 µm, and the wall thickness can be from about 10 µm to about 30 µm. Methods of making the fiber and further parameters of the porous fiber membrane are further described.

Description

[0001] This application is entitled to the benefit of U.S. Provisional Patent Application No. 63 / 547,598, filed November 7, 2023, under 35 USC §119(e), which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to hollow fiber membranes and their manufacturing methods. Background Technology

[0003] Hollow fiber membranes are widely used for liquid filtration. In particular, they are used in medical applications to purify blood during dialysis treatment for kidney patients. Hollow fiber membranes are bundled within a filter module and used for extracorporeal blood therapy. This type of filter module, used for blood purification, is known as a hemodialysis machine and is mass-produced.

[0004] Conventional hollow fiber membranes used for blood purification typically have an inner diameter (ID) between 180 micrometers (i.e., micrometers or µm) and 250 micrometers, and a wall thickness between 30 micrometers and 50 micrometers, to maintain the structural integrity of the membrane and allow blood to pass through the lumen without causing unwanted shearing, contamination, and related blood compatibility issues.

[0005] WO2018 / 167280 describes a hollow fiber membrane dialyzer having wavy fibers with a wall thickness of 20 µm to 30 µm, an ID of 160 µm to 230 µm, and a fiber wavelength reduced to 1 mm to 4 mm to improve thermal stability during manufacturing.

[0006] WO2012 / 51595 describes a cell-adsorption filter cartridge incorporating hollow fiber membrane bundles for the therapeutic isolation of activated leukocytes from blood. The theoretical inner diameter (ID) of the fibers is 50 µm to 240 µm, and the wall thickness is approximately 40 µm. Blood is preferably passed at a low flow rate through the filter module on the outer side of the hollow fiber membrane to reduce shear stress and promote isolation on the membrane.

[0007] WO2008 / 046779 describes a hollow fiber membrane for hemodialysis with a theoretical inner diameter (ID) of 50 µm to 2000 µm and a wall thickness of 10 µm to 200 µm. The membrane has four to five independent layers, including a selective layer with minimal pore size on its outer surface, and a support layer in the middle of the membrane wall that is denser and has smaller pore size than the two adjacent layers.

[0008] Developing a hollow fiber membrane with thin walls and a small inner diameter (ID) would be beneficial, as it would maintain the structural integrity and performance of conventional membranes without increasing manufacturing complexity. The advantages of this design are further described in this paper. Summary of the Invention

[0009] One feature of the present invention is to provide a hollow fiber membrane with a narrow inner diameter (ID) for use in an inner cavity compartment.

[0010] A further feature of the present invention is to provide a hollow fiber membrane having a combination of a narrow inner diameter and a narrow wall thickness for use in the inner cavity compartment.

[0011] An additional feature of the invention is that it provides hollow fibers capable of removing at least partially larger uremic solutes from patient fluids (e.g., blood).

[0012] Another feature of the present invention is to provide a hollow fiber membrane having a high surface area relative to the weight of the fiber.

[0013] Additional features and advantages of the invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objects and other advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in the specification and the appended claims.

[0014] To achieve these and other advantages, and in accordance with the purposes of the invention, as embodied and summarized herein, the present invention relates to a porous hollow fiber membrane. The porous hollow fiber membrane includes an inner cavity, an inner surface adjacent to the inner cavity, and an outer surface. The porous hollow fiber membrane has a wall defined from the inner surface to the outer surface and has a wall thickness of about 10 µm to about 30 µm. The inner cavity has an inner diameter (ID) of about 90 µm to about 160 µm. An active or selective surface is further present at the inner surface of the porous hollow fiber membrane, and an inactive or supportive region is further present adjacent to the active surface. The membrane wall may have an overall asymmetric structure when the porous structure of the membrane wall is observed microscopically or its density is analyzed by other means. Optionally, the porous hollow fiber membrane has a porosity such that the porosity of the membrane generally increases from the active surface (inner surface) across the wall thickness to the outer surface.

[0015] The present invention also relates to porous hollow fiber membranes, wherein the porous hollow fiber membrane includes an inner cavity, an inner surface adjacent to the inner cavity, and an outer surface. The porous hollow fiber membrane has a wall defined from the inner surface to the outer surface and has a wall thickness of about 10 µm to about 30 µm. The inner cavity has an inner diameter (ID) of about 90 µm to about 160 µm. An active or selective surface is further present on the inner surface, or the outer surface, or both of the inner and outer surfaces of the porous hollow fiber membrane, and an inactive or supporting region adjacent to the active surface is further present. The porous hollow fiber membrane has a mass density over its entire wall thickness such that the mass density from the inner surface to the outer surface is an increasing or decreasing mass density gradient.

[0016] The present invention also relates to a porous hollow fiber membrane having an inner cavity compartment and prepared from a solution comprising at least one film-forming polymer and at least one solvent. The solution may comprise at least one hydrophobic polymer (e.g., polysulfone (PSF), polyethersulfone (PES), polyarylsulfone (PAS), and / or polyarylethersulfone (PAES)), at least one hydrophilic polymer, and at least one solvent. Alternatively, the solution may comprise one or more polymethyl methacrylate polymers (PMMA), cellulose triacetate (CTA), polyvinylidene fluoride (PVDF), and / or polyacrylonitrile (PAN) or any copolymer thereof, and at least one solvent, and may not include the hydrophilic polymer. The porous hollow fiber membrane has a wall thickness of about 10 µm to about 30 µm. The inner cavity compartment has an inner diameter (ID) of about 90 µm to about 160 µm. The porous hollow fiber membrane has a mass density over its entire wall thickness such that the mass density from the inner surface to the outer surface is an increasing or decreasing mass density gradient.

[0017] The present invention further relates to a porous hollow fiber membrane for extracorporeal blood therapy. The porous hollow fiber membrane includes an inner cavity, an inner surface adjacent to the inner cavity, and an outer surface. The porous hollow fiber membrane has a wall defined from the inner surface to the outer surface and has a wall thickness of about 20 µm to about 26 µm. The inner cavity has an inner diameter (ID) of about 110 µm to about 140 µm. An active surface is further present at the inner surface of the porous hollow fiber membrane, and an inactive or supporting region is further present adjacent to the active surface. Optionally, the porous hollow fiber membrane has a porosity such that the porosity of the membrane increases from the active surface across the wall thickness towards the outer surface.

[0018] The present invention also relates to a method for manufacturing the porous hollow fiber membrane described herein.

[0019] The present invention further relates to a porous hollow fiber membrane bundle and a dialyzer comprising such a fiber bundle, the dialyzer having an outer shell, an inner compartment defined by the inner wall of the shell for receiving the bundle, one or more blood ports for entering and exiting the shell, and one or more ports for dialysate entering and exiting the shell.

[0020] The present invention further relates to a method for dialysis, blood oxygenation, or blood separation, the method comprising contacting blood with a porous membrane of the present invention. For the purposes of this document, the term "dialysis" may refer to any primary and secondary type of dialysis, which may include, for example, hemodialysis, hemofiltration, and / or hemodiafiltration.

[0021] It should be understood that the above general description and the following detailed description are merely exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0022] The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate various features of the invention and, together with the description, serve to explain the principles of the invention. Attached Figure Description

[0023] Figure 1 This is a flowchart illustrating exemplary method steps that can be used to form the hollow fiber membrane of the present invention.

[0024] Figure 2 The following is a further flowchart illustrating other exemplary method steps that can be used to form the hollow fiber membrane of the present invention.

[0025] Figure 3 It is a graph that plots the relationship between the total sodium mass transfer coefficient and the water content of the pore fluid related to the hollow fiber membrane of this invention. Detailed Implementation

[0026] This invention relates to a novel porous hollow fiber membrane and a dialysis membrane. For the purposes of this invention, unless otherwise stated, the terms "membrane," "fiber membrane," "hollow fiber membrane," or "fiber" as used herein refer to the porous hollow fiber membrane of this invention.

[0027] The hollow fiber membrane has an inner cavity and an inner surface adjacent to the inner cavity. The hollow fiber membrane also has an outer surface.

[0028] The hollow fiber membrane has a unique combination of physical parameters in terms of the inner diameter and wall thickness of the lumen. More specifically, the inner diameter is small and the wall thickness is thin (therefore the overall diameter or outer diameter of the membrane is also narrow). For this reason, the hollow fiber membrane of the present invention may be referred to herein as a "narrow diameter fiber".

[0029] The hollow fiber membrane is essentially a hollow circular or cylindrical object. The inner diameter (ID), or internal diameter, of the hollow fiber membrane is a straight-line distance measured from a point on the inner wall of the object or membrane, passing through its center, to an opposite point on the inner wall of the membrane (perpendicular to the cylindrical axis of the inner cavity). Since the shape of the hollow fiber membrane defining the inner wall may not be a perfect circle, for the purposes of this invention, the inner diameter is the largest dimension or longest chord present in this measurement. The inner diameter can be an average inner diameter obtained by taking multiple measurements at multiple locations on the membrane. For example, the average inner diameter can be based on five inner diameters measured at five different locations along the axial length of the membrane.

[0030] Similarly, for the outer diameter (OD), or total diameter, or external diameter of a hollow fiber membrane, the outer diameter is a straight-line distance measured from a point on the outer wall of the object or membrane, through its center, to an opposite point on the outer wall of the membrane (perpendicular to the cylindrical axis of the inner cavity). Since the shape of the hollow fiber membrane defining the outer wall may not be a perfect circle, for the purposes of this invention, the outer diameter is the largest dimension or longest chord present in this measurement. The outer diameter can be an average outer diameter obtained by taking multiple measurements of the outer diameter at multiple locations on the membrane. For example, the average outer diameter can be based on five outer diameters measured at five different locations on the membrane.

[0031] Hollow fiber membranes have a wall thickness defined by the outer or external surface of the membrane and the inner or internal surface of the membrane. The wall thickness is the difference between the OD and ID. The wall thickness can be considered as an average wall thickness based on the average OD and average ID as defined above.

[0032] An inner lumen or inner lumen compartment refers to the interior of a membrane-bound cavity or tubular structure, and is a cavity or channel within a tube or tubular object or structure. The inner lumen is defined by the inner surface of the porous hollow fiber membrane and also by the inner diameter as described herein.

[0033] ID can range from approximately 90 µm to approximately 160 µm. ID can be 90 µm to 160 µm, or 100 µm to 140 µm, or 110 µm to 140 µm, or 95 µm to 160 µm, or 100 µm to 160 µm, or 105 µm to 160 µm, or 110 µm to 160 µm, or 115 µm to 160 µm, or 120 µm to 160 µm, or 125 µm to 160 µm, or 130 µm to 160 µm, or 135 µm to 160 µm, or 140 µm to 160 µm, or 90 µm to 155 µm, or 90 µm to 150 µm, or 90 µm to 145 µm, or 90 µm to 140 µm, or 90 µm to 135 µm, or 90 µm to 130 µm, or 90 µm to 130 µm, or 90 µm to 130 µm, or 90 µm to 140 µm, or 90 µm to 140 µm, or 90 µm to 135 µm, or 90 µm to 130 µm, or 90 µm to 14 ... µm to 125 µm, or 90 µm to 120 µm, or 90 µm to 115 µm, or 90 µm to 110 µm, or any range based on any two values ​​described herein.

[0034] The wall thickness of the hollow fiber membrane can be from about 10 µm to about 30 µm. The wall thickness can be 10 µm to 30 µm, or 10 µm to 25 µm, or 20 µm to 26 µm, or 10 µm to 20 µm, or 10 µm to 15 µm, or 15 µm to 30 µm, or 20 µm to 30 µm, or 25 µm to 30 µm, or any range based on any two values ​​described herein.

[0035] Previous efforts in manufacturing hollow fiber membranes have suggested lower limits for ID and / or wall thickness, partly due to concerns about fiber collapse and / or manufacturing challenges when handling fine fibers. However, using the methods disclosed herein, hollow fiber membranes with small dimensions (ID and wall thickness) are surprisingly easy to spin even at high speeds, partly because the fibers dry faster and are structurally more stable than, for example, hollow tubes with large ID / small wall thickness. Hollow fiber membranes manufactured using the disclosed methods can be produced with minimal or no fiber collapse or “flattening.” Not wishing to be bound by theory, a distinguishing feature of the membranes of this invention is the proportional reduction in their inner diameter / wall thickness, contrasting with previous attempts to achieve similar effects primarily by reducing the inner diameter, only the outer diameter, or only the wall thickness.

[0036] Alternatively, the porous hollow fiber membrane may be characterized by an inner diameter to wall thickness ratio (ID / wall thickness ratio). In some embodiments, the ID / wall thickness ratio may be 4.0 to 6.0, or 4.5 to 6.0, or 4.5 to 5.5, or 4.8 to 5.4, or 4.5 to 5.2, or 4.8 to 5.2, or any range based on any two values ​​described herein. Hollow fiber membranes with a diameter-to-wall thickness ratio between 4.5 and 5.5 have been found to offer excellent performance advantages, including superior small and medium molecule removal rates per square meter of membrane surface area and high hydraulic permeability, while maintaining structural integrity. However, other ID / wall thickness ratios may also achieve beneficial effects.

[0037] Furthermore, compared to conventional high-flux dialyzers, the hollow fiber membrane and dialyzer of the present invention have remarkably high urea and / or sodium mass transfer coefficients (KoA) per square meter of membrane surface area.

[0038] One advantage of the disclosed hollow fiber membrane is that the fiber weight required to achieve one square meter of membrane surface area in the fiber bundle is significantly lower than that required for conventionally sized hollow fiber membranes. Alternatively, the porous hollow fiber membrane may be characterized by its fiber weight. Conventional hollow fiber membranes used for applications such as hemodialysis may have a fiber weight of 16 grams or more per square meter of membrane surface area. The fiber weight per square meter of membrane area of ​​the membrane of the present invention may be less than 16 g, less than 15 g, less than 14 g, less than 13 g, less than 12 g, less than 11 g, less than 10 g, or 10 to 15.9 g, or 10 to 15.5 g, or 10 to 14.5 g, or 10 to 15 g, or 11 to 13 g per square meter of membrane.

[0039] The porous hollow fiber membrane can be characterized by an inactive region and one or more active surfaces. Alternatively, the inactive region of the membrane can be considered as a support layer or a support region. Alternatively, the active surface can be considered as a treated surface, a selective surface, or a selective layer. The active surface of the membrane can be located only on the inner surface of the membrane, only on the outer surface of the membrane, or simultaneously on both the inner and outer surfaces of the membrane.

[0040] In this document, "active surface," "selective surface," or "selective layer" generally refers to a surface that is in direct contact with the precipitation fluid during membrane fabrication steps. The active surface may include surface regions of the membrane. Inactive regions are defined as membrane regions that are not in direct contact with the precipitation fluid during membrane fabrication steps. However, it should be understood that at some stage of fabrication, when the composition of the precipitation fluid may change (e.g., a higher water content), the inactive regions may be exposed to the precipitation fluid. The inactive regions of the membrane may be the inactive surface of the membrane or the core (i.e., within the wall), or both. As used herein, the term "core" or "core region" may refer to the internal geometric center of the membrane body.

[0041] An active or selective surface can be characterized as a surface with a minimum pore size (e.g., minimum average pore size) and / or a surface capable of distinguishing between larger particles and proteins (e.g., molecules with a molecular weight of 60 kDa or higher, or 65 kDa or higher, or 66 kDa or higher, or 67 kDa or higher) that are preferably retained in the blood and smaller components, including water (e.g., molecules with a molecular weight of less than 60 kDa, or less than 65 kDa, or less than 66 kDa, or less than 67 kDa) that are preferably removed from the blood. For example, any substance smaller than albumin (about 66 kDa) can pass through an active or selective surface, but larger particles are largely or completely excluded. Therefore, an active or selective surface can be characterized as a surface directly exposed to blood.

[0042] Compared to inactive or support regions, active surfaces can have lower porosity or lower pore density. The porosity and / or pore density (e.g., number of pores per area) at active surfaces can be at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% lower than the highest porosity (e.g., average porosity) and / or pore density found elsewhere in the membrane (i.e., inactive regions).

[0043] One problem that thin-walled hollow fiber membranes can encounter is poor structural integrity, leading to fiber collapse, flattening, aggregation, or similar issues. However, using the disclosed method, the inventors have been able to overcome this limitation. An advantage of the disclosed hollow fiber membrane is that, despite the narrow inner diameter and thin wall thickness of the fibers, it may not be necessary to create significant dense regions in the membrane wall to provide structural integrity. The disclosed hollow fiber membrane can be manufactured using the disclosed method at a relatively low cost while retaining the benefits outlined herein.

[0044] Alternatively, the porosity (e.g., pore density) of the membrane can increase from the active or selective surface across the wall thickness to the opposite surface of the active surface (i.e., a) when the active surface is located on the inner surface of the membrane, the opposite surface is the outer surface; or b) when the active surface is located on the outer surface, the opposite surface of the active surface can be the inner surface). This increase in porosity can be an increasing porosity gradient (e.g., increasing pore density). This gradient can be linear or nonlinear (e.g., exponential and S-shaped). This characteristic of "increased porosity" as described herein and in a general sense can and preferably be demonstrated by using the procedure identified as Measurement Method 2 in the Examples section of this document.

[0045] If, as an option, an active surface is present on both the inner and outer surfaces, this increase in porosity excludes either the inner or outer surface and the region adjacent to that surface. For example, if an active surface is present on both surfaces, a porosity measurement starting from the inner surface and extending toward the outer surface can show an increasing porosity toward the outer surface until it reaches the region adjacent to the outer surface or the outer surface itself (i.e., ignoring the thin region of the film that constitutes the outer surface itself).

[0046] The active surface can be characterized by a higher mass density compared to the inactive or support regions. The mass density of the active surface can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more than 50% higher than the lowest mass density (e.g., average mass density) found elsewhere in the film (i.e., the inactive region).

[0047] Alternatively, the membrane's mass density can decrease from the active or selective surface, across the wall thickness, towards the surface opposite the active surface (i.e., a) when the active surface is located on the inner surface of the membrane, the opposite surface is the outer surface, or b) when the active surface is located on the outer surface, the surface opposite the active surface can be the inner surface. This decrease in mass density can be a decreasing mass density gradient. This gradient can be linear or nonlinear (e.g., exponential and S-shaped).

[0048] The porosity and / or mass density gradient described herein may be based on three measurements at three different locations along the same chord across the wall thickness (e.g., at the exposed active surface, at 1 / 3 of the wall thickness depth, and at 2 / 3 of the wall thickness depth measured at the self-exposed active surface). Alternatively, the gradient may be based on at least four measurements at four (or more) different locations along the same chord across the wall thickness (e.g., at the exposed active surface, at 1 / 4 of the wall thickness depth measured at the self-exposed active surface, at 1 / 2 of the wall thickness depth, and at 3 / 4 of the wall thickness depth).

[0049] Using the present invention, the porosity of the central wall region (i.e., the wall region located closest to the middle of the outer and inner surfaces, for example, the region from 1 / 3 to 2 / 3 depth from the inner or outer surface) is always higher than that of the exposed active surface and / or always higher than that of the region at 1 / 4 depth from the exposed active surface.

[0050] If, as an alternative, an active surface is present on both the inner and outer surfaces, this increase in porosity excludes either the inner or outer surface and the area typically adjacent to it. For example, if an active surface is present on both the inner and outer surfaces, the porosity at one-third of the depth from the inner surface and one-third of the depth from the outer surface is always higher than the porosity exactly at the inner and outer surfaces, and the porosity at two-thirds of the depth from the inner surface is approximately the same as the porosity at one-third of the depth from the inner surface. In this specific embodiment with two active surfaces, the porosity at one-half or approximately one-half of the depth will be the region with the highest porosity.

[0051] It should be understood that when a membrane has an active surface on one of its inner or outer surfaces (but not both), it can generally be described as structurally asymmetric in terms of porosity and / or mass density. However, when a membrane has active surfaces on both its inner and outer surfaces, it can generally be more structurally symmetrical. In this case, alternatively, the membrane porosity can be described as generally trending as follows: starting from the dense inner surface, porosity increases (mass density decreases) as it extends through the membrane wall toward the wall center, and then tends to become generally denser (porosity even lower) as it extends from the wall center toward the outer surface. As described herein, this structure is associated with significant precipitation occurring on both the inner and outer surfaces of the membrane.

[0052] Membrane structure can alternatively be characterized by the term dP / dW, where P is porosity and W is wall thickness. The term dP / dW describes the rate of change of porosity with respect to location. dP / dW can be calculated using the absolute value of dP / dW, and / or only for specific portions of the membrane wall (e.g., from one surface to the point closest to the midpoint of the membrane, or from one surface to a point one-third (or one-quarter) of the way towards the opposite surface), particularly when both the inner and outer surfaces are selective surfaces. In this case, dP / dW measured from the inner surface to a region approximately near the midpoint of the membrane wall (i.e., the region where porosity may begin to decrease again) is expected to have a positive rate of change / slope, while dP / dW measured from the region near the midpoint to the outer surface will have a negative rate of change / slope. Understandably, for such membranes, the inflection point or region where the porosity near the midpoint of the membrane wall transitions from a gradual increase to a gradual decrease can be located across the measurement midpoint of the membrane wall, or it can be slightly biased towards one surface or the other, depending on the precipitation conditions reflecting the specific environment experienced by each surface during membrane formation. When measured in this way, the disclosed thin-walled hollow fiber membranes, or portions reflecting approximately 1 / 4, 1 / 2, or 1 / 3 of the membrane wall width, exhibit significantly higher dP / dW ratios than conventional membranes, reflecting a membrane with a sharp or steep porosity gradient relative to its thickness. Alternatively, in cases where the membrane has an active surface only on one of its inner or outer surfaces (rather than both), it should be understood that the rate / slope of change of dP / dW from the active surface toward the other surface can be generally positive.

[0053] Membrane porosity can also be described as the pore volume ratio of the membrane material. For hollow fiber membranes, only the pore volume ratio on the membrane wall is considered here. The internal cavity of the hollow fiber membrane is not considered when calculating porosity. Porosity represents a measure of the permeability of a hollow fiber membrane to fluids, and therefore is also a measure of the membrane's ability to separate molecules of a specific size.

[0054] Using the present invention, as an alternative, the mass density of the central wall region (i.e., the wall region located between the outer and inner surfaces, for example, the region at a depth of 1 / 3 to 2 / 3 from the inner or outer surface) is always lower than that of the exposed active surface and / or always lower than that of the mass density at a depth of 1 / 4 from the exposed active surface.

[0055] If, as an option, an active surface exists on both the inner and outer surfaces, then this reduction in mass density excludes either the inner or outer surface, as well as the region typically adjacent to that surface.

[0056] One advantage or attractive feature of the present invention is that it avoids the formation of denser or less porosity regions in the central wall region (e.g., at the midpoint between the outer and inner surfaces and within approximately 10% or 20% of that midpoint), while achieving thin walls and a small inner diameter without membrane collapse or flattening. Therefore, this unique design of the present invention achieves physical or structural stability of the membrane.

[0057] It is further believed that by avoiding denser or less porous regions in the central wall area, improved sieving coefficients for one or more molecules can be achieved.

[0058] The active or selective surface may have a surface thickness (or depth of self-exposed surface) of about 2 µm or less, or about 1 µm or less, for example, 1 µm or less, or 0.9 µm or less, or 0.8 µm or less, or 0.7 µm or less, or 0.6 µm or less, or 0.5 µm or less, or 0.4 µm or less, or 0.3 µm or less, or 0.2 µm or less, or 0.1 µm or less, or 0.01 µm to 1 µm, or 0.05 µm to 1 µm, or 0.1 µm to 1 µm, or 0.15 µm to 1 µm, or 0.2 µm to 1 µm, or 0.25 µm to 1 µm, or 0.3 µm to 1 µm, or 0.35 µm to 1 µm, or 0.4 µm to 1 µm, or 0.45 µm to 1 µm, or 0.5 µm to 1 µm. µm, or 0.55 µm to 1 µm, or 0.6 µm to 1 µm, or 0.65 µm to 1 µm, or 0.7 µm to 1 µm, or 0.75 µm to 1 µm, or 0.01 µm to 0.9 µm, or 0.01 µm to 0.8 µm, or 0.01 µm to 0.7 µm, or 0.01 µm to 0.6 µm, or 0.01 µm to 0.5 µm, or 0.01 µm to 0.4 µm, or 0.01 µm to 0.3 µm, or 0.01 µm to 0.2 µm, or 0.01 µm to 0.1 µm, or any range based on any two values ​​described herein.

[0059] The walls of the membrane can be characterized as having an optional sponge-like morphology.

[0060] The walls of the membrane can be characterized as optionally having a macroporous morphology.

[0061] Optionally, the hollow fiber membrane may have no or substantially no macropores or dendrite cavities. A dendrite cavity is understood as a macropore with finger-like extensions. Macropores are described in the cited document (“Mulder”). Further examples of dendrite cavity formation can be found in WO2004 / 056460 A1. Figure 1 WO2013 / 034611 A1 Figure 1 , Figure 2 and Figure 3 Or find it in Figure 5 of WO2015 / 056460 A1. Films without dendrite cavities or macropores can exhibit higher mechanical stability.

[0062] As an alternative, the active surface of the membrane may have a composition containing an additive at a higher volume concentration in the spinning material or the pore fluid (precipitation fluid), or both, relative to the inactive or support regions. Alternatively, the active surface of the membrane may contain an additive at a concentration at least about 5 vol%, or at least about 10 vol%, or at least about 20 vol%, or at least about 30 vol%, or at least about 40 vol%, or at least about 50 vol%, or at least about 60 vol%, or at least about 70 vol%, or at least about 80 vol%, or at least about 90 vol%, or about 10 vol% higher to the total additive content, or 15 vol% higher to about 99 vol%, or about 20 vol% higher to about 80 vol%, or other higher concentrations, or any range based on any two values ​​described herein.

[0063] Alternatively, taking into account all additives in the membrane, at least about 10 wt.%, or at least about 20 wt%, or at least about 30 wt%, or at least about 40 wt%, or at least about 50 wt%, or at least about 60 wt%, or at least about 70 wt%, or at least about 80 wt%, or at least about 90 wt%, or about 10 wt% to about 99 wt%, or 15 wt% to about 90 wt%, or about 20 wt% to about 80 wt%, or about 30 wt% to about 70 wt%, or about 50 wt% to 99 wt%, or about 75 wt% to 99 wt%, or about 85 wt% to 99 wt%, or about 95 wt% to 99 wt% or other percentage amounts, or any range based on any two values ​​described herein, may be present in the active surface.

[0064] Alternatively, the additive or an additional additive may be or include a water-insoluble antioxidant, such as a fat-soluble vitamin (e.g., vitamin E). This type of additive may be present in the spinning material and / or the settling fluid (pore fluid). For example, its dosage may be at least about 0.001 wt% (e.g., from about 0.001 wt% to 0.05 wt%) based on the weight of the spinning material or the settling fluid.

[0065] Alternatively, the active surface may have a higher weight density than the inactive region or the inactive surface, or both, for example, at least about 5%, or at least about 10%, or at least about 20%, or at least about 25%, or 5% to 50%, or other values.

[0066] Regarding the additives mentioned above, an example of such additives is at least one hydrophilic polymer, such as polyvinylpyrrolidone (PVP). The PVP can be one type of PVP or more than one type of PVP, for example, two different types of PVP or three different types of PVP. The PVP can be a PVP having values ​​from K1 to K90. For example, the PVP can be K30, or it can be K90, or it can be K45-55, or any two or all three of these. K value is a term known in the art. The weight-average molecular weight of polyvinylpyrrolidone can be determined by the K value using the following equation, which is also graphically shown in Figure 15 of BASF's technical information document (titled "Kollidon: Polyvinylpyrrolidone for the Pharmaceutical Industry"), where MW is the weight-average molecular weight, K is the K value, and a is exp(1.055495): MW = a K2.97159.

[0067] Alternatively, taking into account all additives in the membrane, the amount of said additives in the membrane, based on the total weight of the membrane, may be at least about 0.1 wt.%, or at least about 0.25 wt%, or at least about 0.5 wt%, or at least about 0.75 wt%, or at least about 1 wt%, or at least about 1.25 wt%, or at least about 1.50 wt%, or at least about 2 wt%, or at least about 2.5 wt%, or at least about 3 wt%, or 4 wt%, or 5 wt%, or 6 wt%, or 7 wt%, or 8 wt%, or 9 wt%, or about 0.1 wt% to about 10 wt%, or 0.25 wt% to about 10 wt%, or about 0.5 wt% to about 8 wt%, or about 0.75 wt% to about 7 wt%, or about 1 wt% to about 6 wt%, or about 1.25 wt% to about 5 wt%, or any range or other percentage amount based on any two values ​​described herein.

[0068] As a preferred embodiment, the precipitation fluid itself is not formulated to form a self-supporting membrane structure, while the polymer spinning solution or spinning material is film-forming, i.e., the polymer spinning solution can form a polymer matrix that defines a self-supporting membrane structure.

[0069] The spinning material or polymer spinning solution may comprise a mixture of at least one polymer (e.g., at least one film-forming polymer) and at least one organic solvent capable of dissolving the polymer. Preferably, the mixture of the polymer and the organic solvent may be a homogeneous mixture.

[0070] In one embodiment, the film-forming polymer is a hydrophobic polymer. Alternatively, the film-forming polymer may be at least one of polysulfone (PSF), polyethersulfone (PES), polyarylsulfone (PAS), polyarylethersulfone (PAES), polyvinylidene fluoride (PVDF), polyacrylonitrile (PAN), or any copolymer thereof. The film-forming polymer (e.g., commercially available) may be premixed with small amounts of other co-additives, which are acceptable in the film compositions of the present invention. Alternatively, the film-forming polymer may be one or more polymethyl methacrylate (PMMA) polymers, cellulose triacetate, or polyacrylonitrile.

[0071] The organic solvent used to dissolve the film-forming polymer may, as an option, be at least one of dimethylacetamide (DMAC), dimethylformamide (DMF), tetrahydrofuran (THF), N-methylpyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), N-ethylpyrrolidone (NEP), N-octylpyrrolidone, dimethylformamide (DMF), or butyrolactone. Preferably, the organic solvent used to dissolve the film-forming polymer is a polar aprotic solvent. The organic solvent can dissolve the film-forming polymer, for example, through a wet phase inversion process.

[0072] The polymer spinning solution may, alternatively, further comprise at least one hydrophilic polymer, such as polyvinylpyrrolidone (PVP) (e.g., as described herein) or polyethylene glycol (PEG), or other hydrophilic polymers. If included, the amount of any hydrophilic polymer contained in the polymer spinning solution may be limited to an amount that will not cause leaching problems (e.g., less than 10 wt%, less than 5 wt%, or less than 1 wt% based on the total weight of the polymer spinning solution).

[0073] The polymer spinning solution may have a limited water content or be water-free. Premature solidification of the polymer spinning solution is undesirable, as it can interfere with the ability of the polymer spinning solution to be extruded, cast, or otherwise shaped into a desired film morphology for contact with the precipitating fluid, and / or its ability to interact with the precipitating fluid in a desired manner. Alternatively, the water content of the polymer spinning solution may be less than about 7 wt% water, for example, 0-6.9 wt% water, or 0-6 wt% water, or 0-5 wt% water, or 0-4 wt% water, or 0-3 wt% water, or 0-2 wt% water, or 0-1 wt% water, or other amounts based on the total weight of the polymer spinning solution.

[0074] Alternatively, the polymer spinning solution may have the following composition: about 12 wt% to about 30 wt% film-forming polymer, about 88 wt% to about 63 wt% organic solvent (e.g., a polar aprotic solvent), and less than or equal to about 7 wt% water, based on the total weight of the polymer spinning solution. In another alternative, the polymer spinning solution may have the following composition: about 13 wt% to about 19 wt% polymer, about 87 wt% to about 75 wt% polar aprotic solvent, and less than about 6 wt% water, based on the total weight of the polymer spinning solution. Other combinations of polymer spinning solutions containing these components may be used.

[0075] The combination of components obtained in the polymer spinning solution can be mixed, filtered, and spun into hollow fibers in contact with a precipitating fluid, and then further processed to form a porous hollow fiber membrane.

[0076] One or both surfaces of a hollow fiber membrane (i.e., the outer surface and / or the inner surface) can be characterized by surface roughness (e.g., measured by atomic force microscopy).

[0077] When one of the surfaces is an active surface and the other is an inactive surface, the surface roughness of the active surface can be lower than that of the other surface. For example, the surface roughness of the active surface can be 10 nm or less, such as 9 nm or less, or 7 nm or less, or 5 nm or less, or 1 nm to 10 nm, or 1 nm to 7 nm, or 1 nm to 5 nm, or 1 nm to 3 nm. Alternatively, the ratio between the surface roughness of the other surface (inactive surface) and the surface roughness of the active surface can be at least 20, such as 20 to 40, or 21 to 40, or 25 to 40, or 30 to 40. In these optional features, the active surface can be an inner surface, and the other surface can be an outer surface.

[0078] The surface roughness of the active surface of the fiber membrane can be measured using atomic force microscopy (AFM, Bruker Dimension Icon). In this procedure, if the inner surface is active, the fiber membrane is bonded to a glass substrate and cut axially using a razor blade. The membrane surface is imaged in tapping mode at a scan size of 1 μm x 1 μm, and the surface roughness parameters Ra and Rq are then calculated. Similarly, the surface roughness parameters of the inactive surface of the fiber membrane are evaluated using a profilometer (LEXT™ OLS5100 3D laser scanning microscope).

[0079] Optionally, when at least one surface of the hollow fiber membrane (e.g., the active surface or the inner surface) is wetted, the contact angle of the hollow fiber membrane can be characterized by using water. The contact angle of the active surface of the membrane can be less than 57°, particularly less than 55°, more particularly less than 47°, and the lower limit of the contact angle is generally less than 30°, preferably less than 25°, more preferably less than 20°. The contact angle is determined according to the method for "determining the contact angle θ" described in this application. A hydrophilic surface should be understood as a surface in the hollow fiber membrane that has high hydrophilicity, or a surface that forms a smaller contact angle with water relative to the other surface of the membrane. Preferably, the hydrophilic surface is formed in the inner cavity of the hollow fiber membrane.

[0080] Compared to commercially available membranes (such as, but not limited to, Optiflux 160 (Fresenius Medical Care, Waltham, MA), e.g., Optiflux 160NRe), the membranes of the present invention can reduce membrane resistance by at least 20%, at least 30%, at least 40%, or at least 50%. The hollow fiber membranes of the present invention can reduce membrane resistance by 50% or more and reduce total mass transfer resistance by up to 30%. Membrane resistance (membrane thickness) is based on or derived from the thickness of the membrane; therefore, reducing the wall thickness in the fibers, as in the present invention, will reduce resistance by the same percentage.

[0081] When the membrane of the present invention is running in a high-flux hemodialysis machine housing, measured at a blood flow rate of 300 ml / min, it may be associated with the pressure drop (ΔP) of the internal blood compartment filter, which is at least twice (e.g., at least three, four, or five times) that of a commercially available membrane (e.g., Optiflux 160). In some embodiments, at blood flow rates of 100 to 600 mL / min, the transmembrane pressure drop from one end of the dialyzer to the other is from about 50 mm Hg to about 1000 mm Hg.

[0082] Clotting, clogging, and contamination are common problems associated with hollow fiber membranes. Previous studies on small-diameter fibers used in hemodialysis therapy have shown a minimum threshold of inner diameter greater than 160 µm, below which the risk of coagulation, shearing, and related blood compatibility problems is too high. However, even when used in intraflow hemodialysis, high-flux hemodialysis, and related blood processing, the membrane of the present invention overcomes these limitations observed in the prior art at lower IDs (160 µm or lower, e.g., about 140 µm, 125 µm or lower).

[0083] The hollow fiber membrane of the present invention can optionally pass through its ultrafiltration coefficient (K). UF ) or hydraulic permeability (K per unit area) UF K is used to characterize it. UF Defined as the number of milliliters of fluid transferred across the membrane per hour under a transmembrane pressure gradient of one millimeter of mercury. Hollow fiber membranes manufactured according to the present invention may have, for example, at least 50 ml / hr·mm Hg·m. 2 Or higher hydraulic permeability, for example, about 50 to about 750 ml / hr·mm Hg·m 2 Approximately 75 to approximately 500 ml / hr·mm Hg·m 2 Approximately 100 to approximately 500 ml / hr·mm Hg·m 2 Approximately 100 to approximately 400 ml / hr·mm Hg·m 2 or approximately 150 to approximately 250 ml / hr·mm Hg·m2 Or other values. The hydraulic permeability can be at least 150 ml / hr·mm Hg·m 2 or at least 170 ml / hr·mmHg·m 2 or at least 200 ml / hr·mm Hg·m 2 For example, 150 ml / hr·mm Hg·m 2 Up to 300 ml / hr·mm Hg·m 2 .

[0084] Hollow fiber membranes with thin walls and small inner diameters have a high surface area relative to the amount of polymer used to form each fiber, which potentially reduces material requirements (e.g., spinning materials) and / or production costs, while achieving performance comparable to or superior to dialyzers containing conventional fibers.

[0085] Compared to commercially available membranes (e.g., but not limited to Optiflux F160NRe), the membranes of the present invention can reduce spinning material consumption by at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, or at least about 50 wt%. The savings in spinning material and / or the increase in efficiency can be calculated by generating one square meter of membrane surface area (in m²). 2 The weight (in grams) of the hollow fiber membrane bundles required is used to characterize the membrane. In this regard, a lower value is preferred. In some embodiments, the membrane of the present invention has a fiber weight of less than about 16 grams, less than about 15 grams, or less than about 14 grams, or less than about 13 grams, or less than about 12 grams, or less than about 11 grams, or less than about 10 grams per square meter of surface area.

[0086] Alternatively, the spinning material savings and / or efficiency improvements of the membranes of the present invention can be characterized by the weight (in grams) of hollow fiber membrane bundles required to achieve specific target performance indicators (e.g., removal of specific analytes from blood or ultrafiltration targets). For example, a sodium clearance target of 280 ml / min can be used as a reference point for conventional hemodialysis machines under conditions of a blood flow rate (Qb) of 300 ml / min and a dialysate flow rate (Qd) of 500 ml / min.

[0087] In some embodiments, the amount of fiber required to achieve a sodium removal target of 280 ml / min (Qb / Qd = 300 / 500 ml / min) using the hollow fiber membrane of the present invention is less than about 20 grams per dialyzer (or shell), or less than about 19 grams, or less than about 18 grams, or less than about 17 grams, or less than about 16 grams, or less than about 15 grams, or less than about 14 grams, or less than about 13 grams, or less than about 12 grams. It should be understood that the smaller amount of fiber required to achieve a given target threshold compared to conventional hollow fiber membranes and dialyzers reflects the improved performance advantages and cost savings.

[0088] refer to Figure 1 The method for forming a hollow fiber membrane according to an example of this application (indicated by identifier 100) includes steps 101A, 101B, 102, 103, and 104. In steps 101A and 101B, a polymer spinning solution and a precipitation fluid are provided for producing a porous hollow fiber membrane. After contacting the polymer spinning solution with the precipitation fluid in step 102, the membrane is rinsed in step 103, and the rinsed membrane is dried in step 104. Optionally, in step 101B, an additive may be included in the precipitation fluid. The additive may be hydrophilic, have low water solubility, and be soluble in a water-polar aprotic solvent mixture, as described herein. Alternatively, the precipitation fluid may exclude the additive.

[0089] After drying the rinsed membrane (e.g., as in step 104 above) and before use, the membrane can be pre-charged (e.g., in brine or other acceptable fluid) for a standard or extended period of time to rehydrate the membrane and any associated additives, for example, to achieve a predetermined moisture content, or for a predetermined period of time. For the purposes of this invention, a standard pre-charge with brine or other fluid typically lasts for 10 minutes or about 10 minutes. Furthermore, an extended pre-charge period with brine or other liquid can be 16 hours or about 16 hours. Other pre-charge times, longer or shorter than those mentioned herein, can also be used.

[0090] As an alternative, hollow fibers can be produced using the method of this invention, which includes: extruding or wet spinning a polymer spinning solution through an external annular channel of a spinneret, the spinneret comprising an external annular channel and an internal hollow core, while simultaneously allowing a precipitation fluid to pass through the internal hollow core, wherein the precipitation fluid acts directly on the polymer spinning solution after exiting the spinneret. The spun fibers can be cast into a water bath, with an air gap between the bottom of the spinneret and the water bath. Precipitation of the spinning solution can begin when the precipitation fluid comes into contact with the spinneret. The precipitation process can continue into the water bath. The precipitation process can typically be terminated before the hollow fibers reach the surface of the bath, where the bath also dissolves the organic liquid contained in the hollow fibers and ultimately fixes the fiber structure.

[0091] When precipitation occurs, the first step can be to solidify the inner surface of the fibrous structure, thereby forming a dense, selective layer that acts as a barrier against molecules larger than approximately 60,000 Daltons. That is, anything smaller than albumin can pass through. As the distance from this barrier increases (i.e., deeper into the fiber wall), the degree to which the precipitation solution is diluted by the solvent contained in the spinning composition increases. Alternatively, precipitation on the outer surface of the fibrous structure can be promoted by modifying the solvent mixture of the wash bath, adjusting the air gap height, modifying the solvent mixture for the precipitation / channel fluid, and / or using an improved spinneret with a third outermost ring for additional precipitation fluid. In this way, a dense, selective layer can be formed on the outer surface, the inner surface, or both surfaces.

[0092] The fibers can then be passed through a heat-drying zone. Optionally, the hollow fibers can be textured to improve their exchange properties. The fibers thus produced can then be processed in a conventional manner, for example, wound onto a spool, cut to the desired length, bundled, and / or used to manufacture a dialyzer.

[0093] refer to Figure 2 This illustration shows a method for producing hollow fiber membranes according to an example of this application, indicated by identifier 400, the method comprising steps 401, 402, and 403. As shown, in step 401, a polymer spinning solution is extruded through an annular channel outside the spinneret. In step 402, simultaneously with step 401, a precipitation fluid passes through the hollow core inside the spinneret. The precipitation fluid directly contacts the inner surface of the polymer spinning solution exiting from the spinneret. In step 403, the hollow fibers are rinsed and dried.

[0094] The spinning material of the present invention preferably contains a low water content. For example, the spinning material may contain 4 wt% or less water (based on the weight of the spinning material), such as 0.001 wt% to 4 wt%, 0.01 wt% to 4 wt%, 0.1 wt% to 4 wt%, 0.5 wt% to 3.5 wt%, 0.75 wt% to 3 wt%, 0.9 wt% to 1.7 wt%, etc.

[0095] Once formed, the spinning material solution is preferably clear rather than cloudy before use. In other words, the spinning material solution is transparent rather than opaque. The spinning material solution is preferably as clear as water (although the color is different from water).

[0096] The spinning material may have a viscosity of, for example, about 500 to 10,000 cps or higher, more specifically 1,000 to 2,500 cps (centipoise), at about 25°C (1 atmosphere) or about room temperature. These viscosity values ​​can be measured using a standard rotational viscometer (e.g., a Haake instrument). The casting solution may be filtered to remove any undissolved particles present before being supplied to the extrusion or wet spinning spinneret.

[0097] The wet spinning spinneret used to spin the hollow fibers of this invention can be, for example, a spinneret of the type shown in U.S. Patents 3,691,068, 4,906,375, and 4,051,300, the entire contents of which are incorporated herein by reference. For example, the spinneret or nozzle may have an annular channel with a diameter equal to or approximately equal to the desired outer diameter of the hollow fiber. For example, as wet spinning dimensions, the outer diameter orifice may optionally be from about 0.2 mm to about 0.5 mm, the inner diameter may optionally be from about 0.1 mm to about 0.4 mm, or other suitable dimensions. One advantage of the disclosed hollow fiber membrane is that the disclosed thin-walled, small-diameter fibers can be prepared using spinnerets commonly used for manufacturing conventional-sized hollow fiber membranes (e.g., spinnerets used for manufacturing Optiflux 160 (Fresenius Healthcare, Waltham, MA)). The hollow core of the spinneret typically coaxially extrudes the solution into and through a conduit, while a precipitation fluid and a polymer spinning solution are fed through the same conduit. The polymer spinning solution is fed between the outer surface of the hollow core and the inner hole of the annular conduit. The precipitation fluid can be pumped through the hollow core, causing the precipitation solution to flow out from the core tip and contact the hollow fiber structure formed by the extruded polymer spinning solution. As described above, after exiting the wet spinning spinneret, the precipitation fluid acts on the polymer solution in an outward direction, thereby forming hollow fibers or capillary membranes. This may result in the formation of a coarse-pore, sponge-like structure in the radially outward direction, which can serve as a support layer for the radially inward membrane.

[0098] The amount or ratio of the precipitation fluid supplied to the polymer spinning solution in the spinneret can depend, for example, on the size of the wet spinning spinneret, i.e., the size of the finished hollow fiber. In this regard, it is optionally desirable that the fiber size during precipitation does not change compared to the size of the hollow fiber structure after extrusion but before precipitation. Alternatively, the amount of the first composition of the active surface can be controlled by controlling the ratio of the precipitation fluid to the polymer spinning solution. The volume ratio of the precipitation fluid to the polymer spinning solution used can be within a range, optionally from about 1:0.5 to about 1:4, or other values, which, when the flow rates of the precipitation fluid and the polymer spinning solution are equal, is equal to the area ratio of the hollow fiber, i.e., the ratio of the annular area formed by the polymer material to the area of ​​the fiber lumen. The precipitation fluid can be supplied to the extrusion structure immediately upstream of the spinneret, such that the inner diameter or lumen diameter of the extruded but not yet precipitated structure generally corresponds to the size of the annular spinneret from which the material is extruded.

[0099] The amount or proportion of the precipitating solution supplied to the spinneret can depend, for example, on the size of the spinneret in wet spinning, and correspondingly on the size of the finished hollow fiber. During precipitation, optionally, the fiber size remains unchanged relative to the size of the hollow fiber structure before precipitation but after extrusion. For this purpose, the volume ratio of the precipitating solution to the polymer solution used can be within a range, for example, from about 1:0.5 to about 1:5. When the exit velocities of the precipitating solution and the casting solution are equal, such a volume ratio is equal to the area ratio of the hollow fiber, i.e., the ratio of the annular area formed by the polymer material to the area of ​​the fiber lumen. The precipitating solution can be supplied to the extrusion structure immediately upstream of the spinneret, such that the inner diameter or lumen diameter of the extruded but not yet precipitated structure generally corresponds to the size of the annular spinneret from which the material is extruded.

[0100] When precipitation occurs, a portion of the hydrophilic polymer used (e.g., PVP), in addition to the film-forming polymer, can dissolve or be washed out of the spinning composition during the rinsing step, while a portion can remain in the coagulated fiber. Approximately 5% to approximately 95% by weight of the second polymer (e.g., the hydrophilic polymer) can dissolve from the spinning composition, thus allowing approximately 95% (or more) to approximately 5% by weight of the hydrophilic polymer used to remain therein. As an example, most of the hydrophilic polymer, such as PVP, can remain in the fiber. For example, 50 wt% to 99 wt%, 51 wt% to 90 wt%, or 60 wt% to 80 wt% of the hydrophilic polymer can remain in the fiber. Pore formation can be caused by the movement of PVP toward the fiber lumen without necessarily being dissolved. By controlling the temperature of the annular spinneret, the spinning material and the coagulant within the filament are brought to the same or substantially the same temperature during transport. By adjusting the temperature of the extruded spinning material and the extruded coagulant, the coagulation process can be influenced as the filament passes through the precipitation gap. However, in particular, the temperature of the annular spinneret should be preset so that the hollow fiber membrane form also has the desired pore structure.

[0101] In one embodiment of the manufacturing method of the present invention, the temperature of the annular spinneret is controlled between 30°C and 85°C, for example, about 30°C to 45°C, or about 45°C to 65°C, or about 65°C to 85°C. In a preferred embodiment, the temperature of the annular spinneret is controlled between about 40°C and 45°C. In another embodiment of the present invention, the method of the present invention for manufacturing hollow fiber membrane bundles is characterized in that, during the spinning process, the temperature of the settling bath is controlled between 75°C and 85°C. This settling bath temperature helps to obtain high ultrafiltration coefficients and high sieving coefficients for high molecular weight molecules.

[0102] In addition to the above, other factors affecting fiber inner diameter, wall thickness, porosity, and separation performance include air gap height, spinning fluid velocity (Qd), pore fluid velocity (Qb), spinning solution velocity at the spinneret (Vd), pore fluid velocity at the spinneret (Vb), fiber take-up speed (Vt), and draw ratio DR (Vt / Vd). One or more of the following parameters can be used: A) Qd less than 15 mm 3 / s, for example, 8 to 14 mm 3 / s, or 9 to 14 mm 3 / s, or 10 to 14 mm 3 / s, or 8 to 12 mm 3 / s, or 8 to 10 mm 3 / s, or any range based on any two values ​​described herein; B) Qb is less than 9 mm 3 / s, for example, 2.5 to 8 mm 3 / s, or 2.5 to 7 mm 3 / s, or 2.5 to 6 mm 3 / s, or 2.5 to 5 mm 3 / s, or 3 to 8.5 mm 3 / s, or 4 to 8.5 mm 3 / s, or 5 to 8.5 mm 3 / s, or any range based on any two values ​​described herein; C) Vd less than 200 mm / s, or less than 175 mm / s, or less than 150 mm / s, for example, 90 to 150 mm / s, or 95 to 150 mm / s, or 100 to 150 mm / s, or 110 to 150 mm / s, or 120 to 150 mm / s, or 130 to 150 mm / s, or 90 to 145 mm / s, or 90 to 140 mm / s, or 90 to 135 mm / s, or 90 to 130 mm / s, or 90 to 120 mm / s, or any range based on any two values ​​described herein; D) Vb less than 250 mm / s, or less than 225 mm / s, or less than 200 mm / s, for example, 100 to 200 mm / s, or 100 to 190 mm / s, or 100 to 180 mm / s. mm / s, or 100 to 170 mm / s, or 100 to 160 mm / s, or 100 to 150 mm / s, or 100 to 150 mm / s, or 100 to 140 mm / s, or 100 to 130 mm / s, or 110 to 200 mm / s, or 120 to 200 mm / s, or 130 to 200 mm / s, or 140 to 200 mm / s, or 150 to 200 mm / s, or any range based on any two values ​​described herein; E) Vb / Vd ratio of about 1 to 1.7, or 1 to 1.6, or 1 to 1.5, or 1 to 1.4, or 1 to 1.3, or 1.1 to 1.7, or 1.2 to 1.7, or 1.3 to 1.7, or 1.4 to 1.7, or any range based on any two values ​​described herein. Unbound by theory, it is believed that reducing the spinning fluid velocity, the pore fluid velocity, and the air gap significantly contributes to the thin-walled, low-inner-diameter, and structurally robust hollow fiber membrane of the present invention.

[0103] The "air gap" or "sedimentation gap" height is the distance between the spinneret and the surface of the sedimentation bath. At a given downward velocity (i.e., a given extrusion rate), this gap controls the sedimentation time. This distance can depend on the solution viscosity, fiber weight, and sedimentation rate. The air gap can be set to, for example, a distance of 0.0 m to about 1.0 m. In some embodiments, the air gap can be expressed in millimeters, from about 10 mm to about 100 mm, or from about 15 mm to about 50 mm, or from about 20 mm to about 40 mm. The air gap can be from about 22 mm to about 29 mm. The term "processing time" refers to the length of time it takes for the spun material to travel from the spinneret through the air gap to the surface of the sedimentation bath. Processing time can be used to influence the external pore structure, but also the fiber diameter and wall thickness.

[0104] Optionally, the pumping rate Vd of the deposited fibers (i.e., the rate at which they are supplied to the spinneret) can be lower than the draw rate Vt from the spinneret, resulting in a "draw ratio" (DR) that also reduces the fiber diameter and may reduce the wall thickness. In some embodiments herein, the draw ratio is greater than 2.2, greater than about 2.5, or greater than about 2.8, or greater than about 3.0, or greater than about 3.3, or greater than about 3.5, or greater than about 4.0. DR can be 2.25 to 5, or 2.5 to 5, or 2.75 to 5, or 3 to 5, or 3.25 to 5, or 3.5 to 5, or 3.75 to 5, or 4 to 5, or 4.5 to 5, or 2.5 to 4.75, or 2.5 to 4.5, or any range based on any two values ​​described herein.

[0105] Unwilling to be bound by theory, the inventors have discovered that a draw ratio greater than 3.5 can provide a combination of thin-walled, small-diameter hollow fiber membranes with excellent water permeability, removal rate and / or related performance advantages, while still maintaining excellent structural integrity.

[0106] After precipitation, the coagulated fibers can be rinsed in a bath typically containing water, in which the hollow fibers are held, for example, about 3 to 10 minutes or longer, to wash away dissolved organic components and fix the microporous structure of the fibers. The fibers can then be passed through a heat-drying zone. The produced hollow fibers may have a thin radial inner barrier layer on their inner surface adjacent to the outer open-pore support region. For example, in the case where the hydrophilic polymer is contained in the spinning solution, the inner surface of the manufactured fibers may include a dense barrier layer having a pore size, for example, about 0.0005 µm to about 0.1 µm or other values. A foam-like support structure may be present adjacent to the outer surface of this inner barrier layer.

[0107] The hollow fiber dialyzer can also be sterilized using electron beam (e-beam) sterilization, gamma irradiation, steam sterilization (including online steam) or other methods known in the art.

[0108] The hollow fiber membrane of the present invention can optionally be used as a dialysis membrane, an ultrafiltration membrane, and a microfiltration membrane. The dialysis membrane can be, for example, a hemodialysis membrane or a blood filter. Semi-permeable membrane filtration is commonly used for protein purification, while microfiltration and ultrafiltration are the most frequently practiced techniques. Microfiltration can be defined as a low-pressure membrane filtration process that removes suspended solids and colloids, typically with a diameter greater than 0.1 µm. Such processes can be used to separate particles or microorganisms that can be observed under a microscope, such as cells, macrophages, and cell debris. Ultrafiltration membranes are characterized by their pore size, enabling them to retain macromolecules with a molecular weight range from about 500 Daltons to about 1,000,000 Daltons. Ultrafiltration is a low-pressure membrane filtration process that separates solutes in the range of about 0.01 µm to 0.1 µm. Ultrafiltration can be used to concentrate proteins and to remove bacteria and viruses from solutions. Ultrafiltration can also be used for purification processes, such as water purification. The dialysis membrane can be an ultrafiltration membrane comprising a biocompatible material, such as the hollow fiber membrane of the present invention.

[0109] The outer diameter of each hollow fiber can be, for example, from about 110 µm to about 220 µm or from about 100 µm to about 190 µm. The hollow fibers produced using this invention can at least partially approximate the function of a natural kidney in terms of separation performance (e.g., sieve coefficient).

[0110] The present invention also relates to a method for using the porous hollow fiber membrane for at least one of membrane filtration and / or solute and / or solvent exchange, the method comprising contacting an aqueous-based fluid with the porous hollow fiber membrane described herein, or contacting blood with the porous hollow fiber membrane described herein. The method of the present invention for dialysis, blood oxygenation, or blood separation filtration may include contacting blood with the porous hollow fiber membrane described herein.

[0111] The invention will be further illustrated by the following examples, which are intended to be illustrative only. Unless otherwise stated, all quantities, percentages, proportions, etc., used herein are by weight.

[0112] Example Measurement Method 1: Determine porosity (density-based method).

[0113] A bundle of hollow fiber membranes, dried in a drying cabinet at 105°C for 2 hours and composed of identical hollow fiber membranes, is weighed. The average length, average inner diameter, and average outer diameter of the fibers, as well as the number of fibers, are determined. The average size is determined for at least 10 different fibers of the hollow fiber membrane bundle. The size determination is performed at a constant temperature of 20°C. By assuming that the geometry of the hollow fiber membrane corresponds to a hollow cylinder, the volume of the membrane wall of the hollow fiber membrane permeating through the hollow fiber membrane bundle is calculated based on the size. Based on the determined volume and the measured weight, the average density of the inner membrane structure of the hollow fiber membrane can be calculated. The porosity, expressed as a percentage, is derived from the ratio between the measured density of the hollow fiber membrane and the theoretical density in the fully dense state of polysulfone material, determined according to the following formula: Porosity = (Measured fiber density / Dense polysulfone density) 100 Measurement Method 2: Determining Porosity (Image Analysis Method).

[0114] The porosity of the membrane can also be determined using image analysis of the hollow fiber membrane cross-section. The hollow fiber membrane is cut into segments along the axial direction. One of the following methods is used to measure the porosity.

[0115] The inner surface was observed using a scanning electron microscope (SEM) at an applied voltage of 15.0 kV and a magnification of 50,000x. All pores within an arbitrary 1 µm x 1 µm region were analyzed using image processing software (NIH's ImageJ). The SEM images were binarized using the automatic settings of ImageJ's "Image > Adjustments > Threshold" function to obtain images where hollow areas were black and structural areas were white. When it was impossible to clearly binarize hollow and structural areas due to insufficient contrast in the analyte image, the hollow areas were colored black before image processing, and the total pore (void) area was divided by the total field of view area to determine porosity.

[0116] The process was repeated three times for each sample, and the average porosity values ​​were taken. To determine the porosity at different regions of the membrane wall, the process was performed using randomly selected fields at the active surface, approximately 1 / 3 of the membrane wall from the active surface, and approximately 2 / 3 of the membrane wall from the active surface (repeated three times for each region). Alternatively, fields were selected at the active surface, approximately 1 / 4 of the membrane wall from the active surface, approximately 1 / 2 of the membrane wall from the active surface, and approximately 3 / 4 of the membrane wall from the active surface (repeated three times for each region). Similarly, regions representing only 1 / 4, 1 / 2, or 3 / 4 of the thickness could be selected to measure porosity, with the field selected only within the corresponding portion of the membrane wall. For example, the field could be selected only within the first 1 / 4 of the membrane thickness from the active surface to determine the porosity or porosity variation (dP / dW) only in the first region of the membrane wall closest to the active surface. Alternatively, the field can be selected only within a defined distance from the active surface, such as the first 2 µm, 3 µm, 4 µm, 5 µm, 6 µm, 7 µm, 8 µm, 9 µm, or 10 µm. The porosity in all such cases can be reported as a percentage (%) of porosity per unit length (µm).

[0117] Measurement method 3: Determine the contact angle θ.

[0118] The contact angle of a hollow fiber membrane was determined by capillary action, wherein the hollow fiber membrane served as the capillary. The hollow fiber membrane was fixed in a measuring holder. Deionized water, stained with 0.25 mg / ml methylene blue, was injected into a groove placed at the base of the measuring holder. The hollow fiber membrane, with a freshly cut edge previously made with a straight razor in a direction transverse to the longitudinal extension direction, was immersed in the solution. After waiting 20 minutes, the height (h) of the capillary above the test liquid surface in the groove was determined. A new hollow fiber membrane was used after each measurement. The internal radius r of each hollow fiber membrane was determined at the cut edge using an optical microscope.

[0119] The contact angle can be calculated using the Young-Laplace equation for capillary pressure: ρgh = (2γcosθ) / r (I) The equation for determining the contact angle based on a given inner radius, capillary height, and a known constant can be defined as follows: Arcos(ρghr / 2γ) = θ (II) in, The density of water at ρ = 25℃ is 0.997 kg / m³. 3 g = gravitational acceleration 9.8 m / s² 2 h = capillary height, m γ = the surface tension of water at room temperature, 0.0728 N / m r = capillary radius θ = the contact angle to be determined.

[0120] The contact angle is determined by the average of 12 measurements.

[0121] Measurement Method 4: Determination of polyvinylpyrrolidone and nitrogen in the near-surface layer (XPS).

[0122] The analysis of at least some of the properties mentioned herein can be performed using Raman spectroscopy, infrared spectroscopy, energy-dispersive X-ray spectroscopy (XPS or ESCA), energy-dispersive X-ray spectroscopy (EDS or EDX), or other analytical techniques suitable for this assessment. Generally, unless otherwise stated, all measurements are based on conditions of 25 degrees Celsius and 1 atmosphere. The polyvinylpyrrolidone (PVP) content in the near-surface layer can be determined, for example, using energy-dispersive X-ray spectroscopy (XPS or ESCA). This method can be used to determine the proportion of PPVP in a layer approximately 5–10 nm thick. This layer, sampled using the XPS method, is referred to below as the “near-surface layer” and is defined by the measurement conditions.

[0123] X-ray photoelectron spectroscopy (XPS, Kratos, Manchester, UK) can be used to quantify the elemental composition (particularly fluorine) in the top 10 nm of the inner cavity of the membranes of this invention and conventional Optiflux membranes. Under ultra-high vacuum, X-ray excitation of the material surface results in the emission of electrons with specific atomic characteristic binding energies. By measuring these characteristic energies, XPS analysis identifies the chemical elements present in the top 3–30 atomic layers (10–100 Å) of the sample.

[0124] The hollow fiber membrane is dissected using a scalpel or other sharp blade to expose its inner surface and, consequently, its selective layer. The sample is then fixed onto a sample plate and placed in the sample chamber. The measurement conditions are defined as follows: - Equipment: Thermo VG Scientific, K-Alpha model - Excitation radiation: Monochromatic X-rays, Al Kα, 75 W - Sample spot diameter: 200 µm - Through energy: 30 eV - Angle between source and analyzer: 54° - Spectral resolution of the Ag3d signal: 0.48 eV - Vacuum applied: 10 -8 mbar - Charge compensation is provided via a diffuser gun.

[0125] The PVP content in the near-surface layer was determined using values ​​measured for atomic percentage nitrogen (N) and sulfur (S) using the following equations: PVP content [mass%] = 100 (N) 111) / (N) 111 + S 442).

[0126] This equation applies to polysulfones based on bisphenol A; for polyethersulfones, the following equation should be used: PVP content [mass%] = 100 (N) 111) / (N) 111 + S 232).

[0127] For other polysulfones, the molecular weight of the monomer units attributable to sulfur needs to be determined; for copolymers, the proportion of sulfur-containing monomers in the copolymer needs to be considered. Each measurement was performed on three hollow fiber membranes, and the average of these measurements was calculated.

[0128] Example 1 – Comparison Conventional hollow fiber membranes (inner diameter ~185 µm, wall thickness ~35 µm) were prepared using a wet spinning annular spinneret with an outer diameter D1 of 0.4 mm and an inner diameter D2 of 0.2 mm. The spinning solution was prepared by dissolving 16 wt% polysulfone P3500 (PS, from Solvay) and 4 wt% polyvinylpyrrolidone K90 (PVP) in dimethylacetamide (DMAC) under stirring. The spinning solution was treated into a homogeneous mixture and, together with a centrally controlled precipitant (pore fluid) fed into the hollow filament, extruded through the outer ring of the spinneret. In this case, the pore fluid was a DMAC solution containing 45.5 wt% water. The annular gap width of the spinneret was 50 µm, and the inner diameter was 200 µm. The spinneret and precipitation bath temperatures, draw ratios, and other parameters are shown in Table 1. The extruded filament was guided through the precipitant chamber into a water precipitation bath heated to approximately 63°C, where it precipitated to form a hollow fiber membrane. The air gap is 30 mm. The hollow fiber membrane is then guided through a rinsing bath maintained at 75°C to 90°C. A fiber bundle consisting of 10,752 such fibers, each approximately 22.6 cm long, is collected and introduced into the housing of a hollow fiber membrane dialyzer with an inner diameter of 40.08 mm. The ends of the hollow fiber membrane are encapsulated within the housing of the hollow fiber membrane dialyzer in a manner generally known in the art, thereby forming a first chamber (blood side) within the collective lumen space of the hollow fibers and a second chamber (dialysate side) between the outer surface of the hollow fibers and the inner wall of the housing. The dialyzer is sterilized using electron beam (e-beam) radiation. With a fill factor (PF) of 44%, the total membrane area (A) of the hollow fiber bundle in the dialyzer housing is 1.4 m². 2 .

[0129] Example 2 – Example of the Invention The hollow fiber membrane was prepared according to Example 1, except that fibers with an inner diameter reduced to approximately 135 µm were prepared (Design 3). Spinning conditions and fiber properties are reported in Table 1. As shown in the figure, compared to Example 1, the spinning solution velocity (Qd), pore fluid velocity (Qb), spinning fluid velocity (Vd), and pore fluid velocity (Vb) at the spinneret were significantly reduced, while the draw ratio (DR) was significantly increased (over 65%). The inner diameter was 138.7 µm, the wall thickness was 25.9 µm, and the diameter-to-wall ratio (F-ID / FW) was 5.36.

[0130] Example 3 – Example of the Invention The hollow fiber membrane was prepared according to Example 2, except that a pore fluid of 43.3 wt% water was used to deposit the fibers, with other spinning parameters varying only slightly. The inner diameter was approximately 138 µm or 137.1 µm (Design 3), the wall thickness was 26.4 µm, and the diameter-to-wall ratio (F-ID / FW) was 5.19. Spinning conditions and dialyzer performance are reported in Table 1.

[0131] Example 4 – Example of the Invention Hollow fiber membranes with similar membrane areas were fabricated according to Example 1, but smaller fibers with an inner diameter of approximately 110 µm (Design 1) were obtained by altering the membrane permeability using different water concentrations in the pore fluid and further reducing the spinning fluid velocity (Qd) and pore fluid velocity (Qb). The results are shown in Table 1. The overall sodium mass transfer coefficient as a function of the percentage of water in the pore fluid (blood flow rate = 300 ml / min, dialysate flow rate = 500 ml / min) is plotted in Table 1. Figure 3 middle.

[0132] Example 5 – Example of the Invention Hollow fiber membranes were fabricated according to Example 1, except that the pore fluid composition was 44.2 wt% water, and different spinning fluid flow rates (Qd) and pore fluid flow rates (Qb) were used, resulting in smaller fibers with an ID of approximately 125 µm (Design 2). The results are shown in Table 1.

[0133] Example 6 – Example of the Invention A hollow fiber membrane was manufactured according to Example 1 with the following modifications: 1) the PVP content in the spinning solution was increased by 0.3 wt%; 2) 0.01 wt% vitamin E was added to the spinning solution; 3) a pore fluid containing 55 wt% water with 0.15% PVP was used to precipitate the fibers; and 4) a smaller shell with an effective length of 29 cm and an inner diameter of 25.8 mm was used to contain the fibers. The results and additional parameters are shown in Table 1.

[0134] For each of Examples 2 to 6 (examples of the present invention), the cross-section of the membrane (fiber) and the different layers within the membrane were imaged at 50,000x magnification, and these layers were analyzed using ImageJ analysis. For these membranes, the active surface is located at the inner surface of the porous hollow fiber membrane, and there are also inactive or support regions adjacent to the active surface. Based on ImageJ analysis, the membrane wall has a generally asymmetric structure, and the porous hollow fiber membrane has a porosity such that the membrane porosity increases from the active surface (inner surface) across the wall thickness to the outer surface. Furthermore, the porous hollow fiber membrane has a mass density across the entire wall thickness such that the mass density from the inner surface to the outer surface is a substantially decreasing mass density gradient.

[0135] For the films of Example 1 (4.5% / µm), Example 5 (8.1% / µm), and Example 6 (10.2% / µm), dP / dW was determined within the first quarter of the film thickness closest to the active surface.

[0136] 10,000 to 20,000 hollow fiber membranes prepared according to Examples 1-6 were bundled and assembled into a polycarbonate dialyzer housing, sealed, and sterilized by electron beam as described. The total membrane surface area (A) was 1.3 m². 2 and 1.6 m 2 Between. The shell volume is calculated as the total internal volume of the shell within the dialyzer compartment. The ratio of membrane surface area to shell volume is calculated, and the dialyzer of the present invention (Examples 2-6, 65-80 cm²) is determined. -1 It has significantly higher performance than the contrast dialyzer (Example 1, 50 cm). -1 The A / HV ratio.

[0137] Therefore, these examples demonstrate a range of conditions in hollow fiber membrane production that result in a range of inner diameter and wall thickness values.

[0138] While not wishing to be bound by theory, an F-ID / FW diameter-to-wall ratio between 4.5 and 5.5 can be associated with improved membrane structure stability and performance, especially when F-ID is already below 30 µm (i.e., thin-walled fibers).

[0139] This invention includes aspects / embodiments / features in any order and / or any combination of the following: This invention relates in part to a porous hollow fiber membrane, comprising: a. Internal compartment; b. The inner surface and outer surface adjacent to the said inner cavity compartment; c. A wall with a thickness of approximately 10 µm to approximately 30 µm; d. Inner diameter ID from approximately 90µm to approximately 160µm; e. A selective surface located at the inner surface; and f. The support region adjacent to the selective surface.

[0140] According to any of the foregoing or subsequent embodiments / features / aspects, the porous hollow fiber membrane wherein the ratio of the surface area of ​​the hollow fiber membrane to the capillary volume is between 250 and 450 cm². -1 or 275 to 450 cm -1 or 300 to 450 cm -1 or 325 to 450 cm -1or 350 to 450 cm -1 or 375 to 450 cm -1 Within the range.

[0141] According to any of the foregoing or subsequent embodiments / features / aspects of a porous hollow fiber membrane or method, wherein the porosity of the membrane increases from the selective surface across the wall thickness to the other side.

[0142] The present invention also relates to a porous hollow fiber membrane, comprising: a. Internal compartment; b. The inner surface and outer surface adjacent to the said inner cavity compartment; c. A wall with a thickness of approximately 10 µm to approximately 30 µm; d. Inner diameter ID from approximately 90µm to approximately 160µm; e. A selective surface located at the inner surface, the outer surface, or both; and f. The support region adjacent to the selective surface; The porous hollow fiber membrane has a mass density over its entire wall thickness, such that the mass density from the inner surface to the outer surface is an increasing or decreasing mass density gradient.

[0143] Porous hollow fiber membranes or methods according to any of the foregoing or subsequent embodiments / features / aspects, wherein the ID is about 100µm to about 140µm.

[0144] The porous hollow fiber membrane or method according to any of the foregoing or subsequent embodiments / features / aspects, wherein the wall thickness is about 20µm to about 26µm.

[0145] The porous hollow fiber membrane or method according to any of the foregoing or subsequent embodiments / features / aspects, wherein the outer diameter OD of the fiber membrane is from 100µm to 220µm.

[0146] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the weight of the fiber bundle per unit membrane area is less than 13 g.

[0147] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the selective surface has a thickness or depth of about 1 µm or less.

[0148] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the wall has a sponge-like or macroporous morphology.

[0149] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the water permeability is greater than 50 ml / h.mmHg.m2.

[0150] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, the contact angle at the inner surface is 40-90°.

[0151] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the PVP content at the inner surface, as determined by XPS, is greater than the PVP content at the outer surface or in the region between the inner and outer surfaces.

[0152] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane, wherein the surface roughness Ra of the inner surface is less than 10 nm.

[0153] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, the ratio between the surface roughness Ra of the non-selective surface and the selective surface is greater than 35.

[0154] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the water permeability is greater than about 150 ml / h.mmHg.m2.

[0155] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the hydraulic permeability is greater than about 170 ml / h.mmHg.m2.

[0156] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the water permeability is greater than about 200 ml / h.mmHg.m2.

[0157] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein, at a flow rate of Qb = 300, Qd = 500 and Qf = 0, the urea mass transfer coefficient Ko per unit fiber membrane area is in the range of 900-1400 mL / min.

[0158] According to the porous hollow fiber membrane or method described in any of the foregoing or subsequent embodiments / features / aspects, wherein, at flow rates of Qb = 300, Qd = 500 and Qf = 0, the urea mass transfer coefficient Ko is preferably higher than 1100 mL / min / m 2 .

[0159] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane, wherein, at a blood flow rate Qb = 300, a dialysate flow rate Qd = 500, and an ultrafiltration rate UFR = 0, the mass transfer coefficient Ko of β-2-microglobulin B2M is greater than 60 ± 15 mL / min / m 2 .

[0160] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein, at flow rates of Qb = 300, Qd = 500 and Qf = 0, the mass transfer coefficient Ko of β-2-microglobulin B2M is greater than 60 mL / min / m 2 .

[0161] According to any of the foregoing or subsequent embodiments / features / aspects, the porous hollow fiber membrane, wherein, under the conditions of Qb = 300 ml / min and UFR = 29 ml / min, the albumin sieving coefficient is less than 1%.

[0162] According to the porous hollow fiber membrane or method of any of the foregoing or subsequent embodiments / features / aspects, wherein, under the conditions of Qb = 300 ml / min and UFR = 29 ml / min, the albumin sieving coefficient is less than 0.01%.

[0163] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the ratio of the B2M mass transfer coefficient to the albumin sieving coefficient is in the range of 4500-750000 mL / min / m 2 Within the range.

[0164] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the selective surface exists at the inner surface and the outer surface.

[0165] According to any of the foregoing or subsequent embodiments / features / aspects, the porous hollow fiber membrane or method is characterized by a porosity change rate dP / dW, where P is the porosity (in percentage) and W is the wall thickness (in µm).

[0166] The present invention also relates to a porous hollow fiber membrane prepared by solution, said solution comprising: At least one polyarylether polymer, At least one hydrophilic polymer, and at least one solvent, Each of the hollow fibers has the following characteristics: An inner diameter of approximately 90 µm to approximately 160 µm, and Wall thickness of approximately 10 µm to approximately 30 µm; and The porous hollow fiber membrane has a mass density over its entire wall thickness, such that the mass density from the inner surface to the outer surface is an increasing or decreasing mass density gradient.

[0167] The present invention also relates to a porous hollow fiber membrane for extracorporeal blood therapy, the membrane comprising: a. Internal compartment; b. The outer surface and the inner surface adjacent to the inner cavity compartment; c. A wall with a thickness of approximately 20 µm to approximately 26 µm; d. Inner diameter ID of approximately 110-140µm; e. A selective surface located at the inner surface; and f. The support region adjacent to the selective surface; The porosity of the membrane increases from the selective surface across the wall thickness toward the outer surface.

[0168] The present invention also relates to a dialysis membrane prepared from a solution, said solution comprising: At least one polyarylether polymer, ranging from 10 to 30 wt.%. 1 to 10 wt.% of at least one hydrophilic polymer, And at least one solvent, wherein the dialysis membrane has: The molecular weight cutoff (MWRO) is 4.8 kDa to 5.2 kDa. And the molecular weight cutoff (MWCO) is 24.5 kDa to 28 kDa. It is determined by glucan sieving before blood comes into contact with the dialysis membrane.

[0169] In the method of the present invention, the polymer film formed by the method may have a molecular weight cutoff (MWCO) of about 24.5 kDa to about 28 kDa (e.g., about 25 kDa to about 27 kDa).

[0170] According to any of the foregoing or subsequent embodiments / features / aspects, the membrane or any method wherein, prior to contact of blood with the dialysis membrane, the molecular weight cutoff (MWCO) of the membrane, determined by dextran sieving, is between 24.5 kDa and 28 kDa, for example, between about 25 kDa and about 27 kDa. This MWCO can be a value used to describe the membrane's retention performance and refers to the molecular weight of the solute at which the membrane retains 90% of that solute (corresponding to a sieving coefficient of 0.1). MWCO can also be described as the molecular weight of a solute (e.g., dextran or protein) that the membrane allows 10% of these molecules to pass through. For the purposes of this invention, the MWCO can be determined based on or using a dextran solution in water, following DIN EN 1508637:2014.

[0171] The present invention also relates to a method for manufacturing a porous hollow fiber membrane according to any one of the preceding claims, the method comprising: a) A solution comprising at least one polyarylether polymer and at least one hydrophilic polymer, at least one polymer and at least one solvent; b) Forming the porous hollow fiber membrane by passing the solution through a spinneret; c) Pass the porous hollow fiber membrane from step (b) through at least one precipitation bath comprising an aqueous solution; d) Pass the porous hollow fiber membrane from step (c) through at least one washing bath; e) Passing the porous hollow fiber membrane from step (d) through at least one drying chamber; and f) Collect the porous hollow fiber membrane from step (e).

[0172] According to any of the foregoing or subsequent embodiments / features / aspects of the method or membrane, wherein the formation occurs in a spinneret, and the passage of the solution further includes passing a precipitating fluid through the spinneret to form the porous hollow fiber membrane.

[0173] According to any of the foregoing or subsequent embodiments / features / aspects of the method or membrane, wherein the at least one polymer comprises at least one hydrophobic polymer and at least one hydrophilic polymer in a solvent comprising at least one polar aprotic solvent.

[0174] According to any of the foregoing or subsequent embodiments / features / aspects of the method or membrane, wherein the at least one hydrophobic polymer is poly(aryl) ether sulfone (PAES), polysulfone (PSF) or polyether sulfone (PES), or any combination thereof.

[0175] According to any of the foregoing or subsequent embodiments / features / aspects of the method or membrane, wherein the at least one hydrophobic polymer is at least one of polysulfone (PSF), polyethersulfone (PES), polyarylsulfone (PAS), polyarylethersulfone (PAES), polyvinylidene fluoride (PVDF), polyacrylonitrile (PAN), cellulose triacetate (CT), or copolymers thereof.

[0176] According to any of the foregoing or subsequent embodiments / features / aspects of the method or membrane, wherein the at least one hydrophilic polymer is polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), a copolymer of polypropylene oxide and polyethylene oxide (PPO-PEO), or any combination thereof.

[0177] According to the methods or membranes of any of the foregoing or subsequent embodiments / features / aspects, wherein the at least one polar aprotic solvent is dimethylacetamide (DMAC), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), diphenyl sulfone (DFS), or any combination thereof.

[0178] According to the method or membrane of any of the foregoing or subsequent embodiments / features / aspects, wherein the solution comprises 10 wt% to about 30 wt% of the at least one hydrophobic polymer, about 2 wt% to about 30 wt% of the at least one hydrophilic polymer, and about 60 wt% to about 90 wt% of the at least one polar aprotic solvent.

[0179] According to the method of any of the foregoing or subsequent embodiments / features / aspects, wherein the spinning block includes at least one spinneret having an external annular channel for the solution (spinning material) and a hollow core, through which the precipitated solution is simultaneously fed.

[0180] The present invention also relates to a method for forming porous hollow fiber membrane polymer fibers according to any of the foregoing embodiments / features / aspects, the method comprising simultaneously supplying spinning material and channel fluid to a spinneret and casting polymer fibers, wherein the spinning material comprises at least one polymer and at least one organic solvent, and the channel fluid comprises at least one aqueous solvent and / or at least one organic solvent.

[0181] The present invention also relates to a method for manufacturing a hollow fiber membrane according to any of the foregoing or subsequent embodiments / features / aspects, the method comprising the following steps: - Prepare at least one spinning material, said spinning material comprising a hydrophobic polymer and a hydrophilic polymer, and at least one aprotic polar solvent. - Prepare at least one precipitating fluid or coagulant, said precipitating fluid or coagulant comprising at least one aprotic polar solvent and / or at least one non-solvent (e.g., water). - The spinning material is conveyed into hollow filaments through at least one annular gap in the spinneret. - The precipitated fluid is delivered into the inner cavity of the filament through the central channel of the spinneret. - The filaments are introduced into a precipitation bath to obtain the hollow fiber membrane.

[0182] The present invention also relates to a method for manufacturing a hollow fiber membrane according to any of the foregoing or subsequent embodiments / features / aspects, the method comprising: - Provide spinning materials or spinning solutions, said spinning materials or spinning solutions comprising polysulfone-based materials, particularly polysulfone; vinylpyrrolidone-based polymers, particularly polyvinylpyrrolidone; and aprotic solvents, particularly dimethylacetamide. - Provide a precipitation fluid or coagulant liquid, said precipitation fluid or coagulant liquid comprising water and aprotic solvents, particularly dimethylacetamide. - The spinning solution and the coagulant liquid are co-extruded into hollow filaments through a concentric annular spinneret, thereby filling the cavity of the filaments with the coagulant liquid. - Guide the filaments through the sedimentation gap. - The filaments are introduced into a sedimentation bath consisting primarily of water to obtain the porous hollow fiber membrane. - The hollow fiber membrane is guided through at least one rinsing bath and the resulting hollow fiber membrane is dried; and optionally... - Arrange the obtained hollow fiber membrane into a hollow fiber membrane bundle.

[0183] According to the method of any of the foregoing or subsequent embodiments / features / aspects, the stretch ratio is increased by at least 50% compared to conventional hollow fiber membranes.

[0184] According to the method of any of the foregoing or subsequent embodiments / features / aspects, the stretch ratio is increased by 60-110% compared to conventional hollow fiber membranes.

[0185] According to the method of any of the foregoing or subsequent embodiments / features / aspects, the draw ratio is greater than 2.2, and the velocity of the channel fluid / spinning solution leaving the spinneret is greater than 0.9.

[0186] According to the method of any of the foregoing or subsequent embodiments / features / aspects, wherein the membrane is configured to allow blood to pass through the interior of the hollow fibers.

[0187] According to any of the foregoing or subsequent embodiments / features / aspects of the membrane or method, the pore size across the wall thickness gradually increases from the selective surface through the support region toward the opposite surface.

[0188] According to any of the foregoing or subsequent embodiments / features / aspects of the membrane or method, wherein the membrane is prepared from a solution comprising: At least one polyarylether polymer, At least one hydrophilic polymer, At least one solvent, and Each of the hollow fibers has an inner diameter of about 90µm to about 140µm and a wall thickness of about 20µm to about 28µm.

[0189] According to any of the foregoing or subsequent embodiments / features / aspects, the porous hollow fiber membrane or method is characterized by a porosity change rate dP / dW, where P is the porosity (in percentage) and W is the wall thickness (in µm).

[0190] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the dP / dW measured in a region not less than 1 / 4 of the membrane wall thickness is at least 5.0 % / µm.

[0191] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the dP / dW measured in a region not less than 1 / 4 of the membrane wall thickness is at least 8.0% / µm.

[0192] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the dP / dW measured in a region not less than 1 / 4 of the membrane wall thickness is at least 10.0% / µm.

[0193] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the dP / dW measured in the first quarter of the membrane wall thickness closest to the active surface is at least 5.0 % / µm, or at least 8.0 % / µm, or at least 10.0 % / µm.

[0194] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, there exists a thickness region below the selective surface with a thickness of not less than 2 micrometers, in which the slope of the increase in porosity is at least 5.0 % / µm (or at least 8.0 % / µm, or at least 10.0 % / µm).

[0195] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the dP / dW measured in a region not less than 1 / 4 of the membrane wall thickness is 5.0% / µm to 20% / µm, or 8.0% / µm to 20% / µm, or 10% / µm to 20% / µm, or 5.0% / µm to 18% / µm, or 8.0% / µm to 18% / µm, or 10% / µm to 18% / µm.

[0196] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein the dP / dW measured in the first 1 / 4 of the membrane wall thickness closest to the active surface is 5.0% / µm to 20% / µm, or 8.0% / µm to 20% / µm, or 10% / µm to 20% / µm, or 5.0% / µm to 18% / µm, or 8.0% / µm to 18% / µm, or 10% / µm to 18% / µm.

[0197] According to any of the foregoing or subsequent embodiments / features / aspects of the porous hollow fiber membrane or method, wherein, below the selective surface, there exists a thickness region with a thickness of not less than 2 micrometers, in which the slope of the increase in porosity is 5.0% / µm to 20% / µm, or 8.0% / µm to 20% / µm, or 10% / µm to 20% / µm, or 5.0% / µm to 18% / µm, or 8.0% / µm to 18% / µm, or 10% / µm to 18% / µm.

[0198] This invention may include any combination of the various features or embodiments set forth above and / or below, as set forth in sentences and / or paragraphs. Any combination of the features disclosed herein is considered part of this invention, and no limitation is intended for the composable features.

[0199] The applicant hereby incorporates the entire contents of all references cited in this disclosure. Furthermore, when quantities, concentrations, or other numerical values ​​or parameters are given in the form of ranges, preferred ranges, or lists of preferred upper and lower limits, it should be understood that all ranges formed by any pair of upper or lower limits are specifically disclosed, whether or not these ranges are disclosed individually. When numerical ranges are listed herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range. In defining the scope, the scope of the invention is not intended to be limited to the specific numerical values ​​listed.

[0200] Other embodiments of the invention will be apparent to those skilled in the art upon consideration of this specification and the practice of the invention disclosed herein. This specification and examples are intended to be illustrative, and the true scope and spirit of the invention are indicated by the appended claims and their equivalents.

Claims

1. A porous hollow fiber membrane, comprising: a. Internal compartment; b. The inner surface and outer surface adjacent to the said inner cavity compartment; c. A wall with a thickness of approximately 10 µm to approximately 30 µm; d. Inner diameter ID from approximately 90µm to approximately 160µm; e. A selective surface located at the inner surface; and f. The support region adjacent to the selective surface.

2. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The ratio of the surface area to the capillary volume of the hollow fiber membrane is between 250 and 450 cm². -1 Within the range.

3. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The porosity of the membrane increases from the selective surface across the wall thickness to the other side.

4. A porous hollow fiber membrane, comprising: a. Internal compartment; b. The inner surface and outer surface adjacent to the said inner cavity compartment; c. A wall with a thickness of approximately 10 µm to approximately 30 µm; d. Inner diameter ID from approximately 90µm to approximately 160µm; e. A selective surface located at the inner surface, the outer surface, or both; and f. The support region adjacent to the selective surface; The porous hollow fiber membrane has a mass density over its entire wall thickness, such that the mass density from the inner surface to the outer surface is an increasing or decreasing mass density gradient.

5. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The ID is approximately 100µm to approximately 140µm.

6. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The wall thickness is approximately 20µm to approximately 26µm.

7. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The outer diameter (OD) of the fiber membrane is between 100µm and 220µm.

8. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The weight of the fiber bundle per unit membrane area is less than 13 g.

9. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The selective surface has a thickness of about 1 µm or less.

10. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The wall has a sponge-like or macroporous shape.

11. The porous hollow fiber membrane according to any one of the preceding claims, wherein, Hydraulic permeability greater than 50 ml / h.mmHg.m 2 .

12. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The contact angle at the inner surface is 40-90°.

13. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The PVP content at the inner surface, as measured by XPS, is greater than the PVP content at the outer surface or in the region between the inner and outer surfaces.

14. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The surface roughness of the inner surface is less than 10 nm.

15. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The ratio between the surface roughness of the non-selective surface and the surface roughness of the selective surface is greater than 35.

16. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The hydraulic permeability is greater than approximately 150 ml / h·mmHg·m 2 .

17. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The hydraulic permeability is greater than approximately 170 ml / h·mmHg·m 2 .

18. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The hydraulic permeability is greater than approximately 200 ml / h·mmHg·m 2 .

19. The porous hollow fiber membrane according to any one of the preceding claims, wherein, At flow rates of Qb = 300, Qd = 500, and Qf = 0, the urea mass transfer coefficient Ko per unit fiber membrane area is in the range of 900-1400 mL / min.

20. The porous hollow fiber membrane according to any one of the preceding claims, wherein, At flow rates of Qb = 300, Qd = 500, and Qf = 0, the urea mass transfer coefficient Ko is preferably higher than 1100 mL / min / m. 2 .

21. The porous hollow fiber membrane according to any one of the preceding claims, wherein, At a blood flow rate Qb = 300, a dialysate flow rate Qd = 500, and an ultrafiltration rate UFR = 0, the mass transfer coefficient Ko of β-2-microglobulin B2M was higher than 60 ± 15 mL / min / m. 2 .

22. The porous hollow fiber membrane according to any one of the preceding claims, wherein, At flow rates of Qb = 300, Qd = 500, and Qf = 0, the mass transfer coefficient Ko of β-2-microglobulin B2M is higher than 60 mL / min / m. 2 .

23. The porous hollow fiber membrane according to any one of the preceding claims, wherein, Under the conditions of Qb = 300 ml / min and UFR = 29 ml / min, the albumin screening coefficient is less than 1%.

24. The porous hollow fiber membrane according to any one of the preceding claims, wherein, Under the conditions of Qb = 300 ml / min and UFR = 29 ml / min, the albumin sieving coefficient is less than 0.01%.

25. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The ratio of the mass transfer coefficient of B2M to the albumin sieving coefficient is between 4500 and 750000 mL / min / m 2 Within the range.

26. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The selective surface is present on both the inner and outer surfaces.

27. A porous hollow fiber membrane prepared by solution, said solution comprising: At least one polyarylether polymer, At least one hydrophilic polymer, and at least one solvent, Each of the hollow fibers has the following characteristics: An inner diameter of approximately 90 µm to approximately 160 µm, and Wall thickness of approximately 10 µm to approximately 30 µm; and The porous hollow fiber membrane has a mass density over its entire wall thickness, such that the mass density from the inner surface to the outer surface is an increasing or decreasing mass density gradient.

28. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The membrane is characterized in that it has a porosity change rate dP / dW, where P is the porosity (in percentage) and W is the wall thickness (in µm).

29. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The dP / dW measured in an area not less than 1 / 4 of the membrane wall thickness is at least 5.0 % / µm.

30. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The dP / dW measured in an area not less than 1 / 4 of the membrane wall thickness is at least 8.0 % / µm.

31. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The dP / dW measured in an area not less than 1 / 4 of the membrane wall thickness is at least 10.0% / µm.

32. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The dP / dW measured within the first quarter of the film wall thickness closest to the active surface is at least 5.0 % / µm.

33. The porous hollow fiber membrane according to any one of the preceding claims, wherein, Below the selective surface, there exists a thickness region of not less than 2 micrometers, in which the slope of the increase in porosity is at least 5.0% / µm.

34. The porous hollow fiber membrane according to any one of the preceding claims, wherein, The membrane includes at least one additive, which includes at least one fat-soluble vitamin.

35. A porous hollow fiber membrane for extracorporeal blood therapy, the membrane comprising: a. Internal compartment; b. The outer surface and the inner surface adjacent to the inner cavity compartment; c. A wall with a thickness of approximately 20 µm to approximately 26 µm; d. Inner diameter ID of approximately 110-140µm; e. A selective surface located at the inner surface; and f. The support region adjacent to the selective surface; The porosity of the membrane increases from the selective surface across the wall thickness toward the outer surface.

36. A dialysis membrane prepared from a solution, said solution comprising: At least one polyarylether polymer, ranging from 10 to 30 wt.%. 1 to 10 wt.% of at least one hydrophilic polymer, And at least one solvent, wherein the dialysis membrane has: The molecular weight cutoff point (MWRO) is from 4.8 kDa to 5.2 kDa. And molecular weight cutoff values ​​(MWCO) from 24.5 kDa to 28 kDa, It is determined by glucan sieving before blood comes into contact with the dialysis membrane.

37. A method for manufacturing a porous hollow fiber membrane according to any one of the preceding claims, the method comprising: a) A solution comprising at least one polyarylether polymer and at least one hydrophilic polymer, at least one polymer and at least one solvent; b) Forming the porous hollow fiber membrane by passing the solution through a spinneret; c) Pass the porous hollow fiber membrane from step (b) through at least one precipitation bath comprising an aqueous solution; d) Pass the porous hollow fiber membrane from step (c) through at least one washing bath; e) Passing the porous hollow fiber membrane from step (d) through at least one drying chamber; and f) Collect the porous hollow fiber membrane from step (e).

38. The method according to claim 37, wherein, The formation occurs in the spinneret, and the passage of the solution further includes passing the precipitating fluid through the spinneret to form the porous hollow fiber membrane.

39. The method according to claim 37 or 38, wherein, The at least one polymer includes at least one hydrophobic polymer and at least one hydrophilic polymer in a solvent comprising at least one polar aprotic solvent.

40. The method according to any one of claims 37-39, wherein, The at least one hydrophobic polymer is poly(aryl) ether sulfone (PAES), polysulfone (PSF), or polyether sulfone (PES), or any combination thereof.

41. The method according to any one of claims 37-40, wherein, The at least one hydrophobic polymer is at least one of polysulfone (PSF), polyethersulfone (PES), polyarylsulfone (PAS), polyaryl ethersulfone (PAES), polyvinylidene fluoride (PVDF), polyacrylonitrile (PAN), cellulose triacetate (CT), or copolymers thereof.

42. The method according to any one of claims 37-41, wherein, The at least one hydrophilic polymer is polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), a copolymer of polypropylene oxide and polyethylene oxide (PPO-PEO), or any combination thereof.

43. The method according to any one of claims 37-42, wherein, The at least one polar aprotic solvent is dimethylacetamide (DMAC), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), diphenyl sulfone (DFS), or any combination thereof.

44. The method according to any one of claims 37-43, wherein, The solution comprises 10 wt% to about 30 wt% of the at least one hydrophobic polymer, about 2 wt% to about 30 wt% of the at least one hydrophilic polymer, and about 60 wt% to about 90 wt% of the at least one polar aprotic solvent.

45. The method according to claims 37-44, wherein, The spinning block includes at least one spinneret, which has an external annular channel for the solution (spinning material) and a hollow core, through which the precipitating solution is simultaneously fed.

46. ​​A method for forming porous hollow fiber membrane polymer fibers according to any one of the preceding claims, the method comprising simultaneously supplying spinning material and channel fluid to a spinneret and casting polymer fibers, wherein, The spinning material includes at least one polymer and at least one organic solvent, and the pore fluid includes at least one aqueous solvent and / or at least one organic solvent.

47. A method for manufacturing a hollow fiber membrane according to any one of the preceding claims, the method comprising the following steps: Prepare at least one spinning material, the spinning material comprising a hydrophobic polymer and a hydrophilic polymer, and at least one aprotic polar solvent; Prepare at least one precipitating fluid or coagulant, said precipitating fluid or coagulant comprising at least one aprotic polar solvent and / or at least one non-solvent (e.g., water). The spinning material is conveyed into hollow filaments through at least one annular gap in the spinneret; The precipitated fluid is transported through the central channel of the spinneret to the inner cavity of the filament; The filaments are introduced into a precipitation bath to obtain the hollow fiber membrane.

48. A method for manufacturing a hollow fiber membrane according to any one of the preceding claims, the method comprising: Provide spinning materials or spinning solutions, wherein the spinning materials or spinning solutions include polysulfone-based materials and aprotic solvents; Provide a precipitation fluid or coagulant liquid, said precipitation fluid or coagulant liquid comprising water and aprotic solvents; The spinning solution and the coagulant liquid are co-extruded into hollow filaments through a concentric annular spinneret, thereby filling the cavity of the filaments with the coagulant liquid; Guide the filaments through the sedimentation gap; The filaments are introduced into a sedimentation bath consisting primarily of water in order to obtain the porous hollow fiber membrane; The hollow fiber membrane is guided through at least one rinsing bath and dried to obtain the hollow fiber membrane; and optional The resulting hollow fiber membranes are arranged into hollow fiber membrane bundles.

49. The method according to any one of the preceding claims, wherein, Compared to conventional hollow fiber membranes, the stretch ratio is increased by at least 50%.

50. The method according to any one of the preceding claims, wherein, Compared with conventional hollow fiber membranes, the stretch ratio is increased by 60-110%.

51. The method according to any one of the preceding claims, wherein, The draw ratio is greater than 2.2, and the velocity of the pore fluid / spinning solution leaving the spinneret is greater than 0.

9.

52. The method according to any one of the preceding claims, wherein, The membrane is configured to allow blood to pass through the interior of the hollow fibers.

53. The method according to any one of the preceding claims, wherein, The aperture, spanning the wall thickness, gradually increases from the selective surface through the support region toward the opposite surface.

54. The method according to any one of the preceding claims, wherein, The membrane is prepared from a solution comprising: At least one polyarylether polymer, At least one hydrophilic polymer, At least one solvent, and Each of the hollow fibers has an inner diameter of approximately 90µm to approximately 140µm; And a wall thickness of approximately 20µm to approximately 28µm.

Images