Hollow fiber membrane and method for producing the same, membrane lung oxygenator

Abstract

The present application relates to hollow fiber membrane and its preparation method, membrane lung oxygenator, the membrane structure of hollow fiber membrane comprises from inside to outside: porous layer, dense layer and microstructure layer; the dense layer is arranged on the porous layer, the microstructure layer is arranged on the dense layer, the surface of the microstructure layer away from the dense layer is rough surface. The surface of the hollow fiber membrane has better anticoagulation effect, and it has longer antiplasma leakage time and better oxygenation efficiency.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to hollow fiber membranes and their preparation methods, and membrane oxygenators. Background Technology

[0002] In the field of medical devices, the anticoagulant function of product surfaces has always been a key research focus for various research institutions and companies. Devices with good anticoagulant properties can significantly reduce surgical risks. Membrane lung consumables are a crucial component of membrane oxygenators, playing a vital role as artificial lungs and facilitating the exchange of oxygen (O2) and carbon dioxide (CO2) in the blood. Membrane lung consumables are hollow fiber membranes made from polyolefin materials, commonly polypropylene and poly-4-methyl-1-pentene. The membrane walls of hollow fiber membranes have uniformly distributed micron- or nanometer-sized pores, which are closely related to the gas exchange rate. To ensure both a high gas exchange rate and long-term resistance to plasma leakage, hollow fiber membranes are typically designed with an asymmetric structure: the inner surface in contact with oxygen is designed as a porous layer (support layer) with high porosity, while the outer surface in contact with blood is designed as a dense layer with low porosity.

[0003] However, hollow fiber membranes with simple porous and dense layered structures exhibit poor anticoagulant properties, necessitating further surface anticoagulant treatment. Currently, the primary method for surface anticoagulant treatment is surface heparinization, one of the most commonly used methods in medical devices. However, this method is unsuitable for membrane lung consumables with microporous structures and high surface impermeability requirements, as heparinization can damage the surface structure, leading to decreased gas flux or weakened anti-plasma leakage performance. Some literature proposes incorporating anticoagulant macromolecules through co-extrusion to prepare anticoagulant hollow fiber membranes. However, the introduction of additional anticoagulant components directly affects the phase separation process between the polymer and the diluent (solvent), and it remains uncertain whether the anticoagulant components can effectively migrate to the outer surface of the hollow fiber membrane. This method carries inherent uncertainties, ultimately affecting the final oxygenation efficiency of the hollow fiber membrane. Summary of the Invention

[0004] Therefore, it is necessary to provide a hollow fiber membrane, its preparation method, and a membrane oxygenator. The surface of this hollow fiber membrane exhibits superior anticoagulant properties, and it also possesses a longer anti-plasma leakage time and superior oxygenation efficiency.

[0005] A hollow fiber membrane, wherein the membrane structure of the hollow fiber membrane comprises, from the inside to the outside:

[0006] Porous layer;

[0007] A dense layer is disposed on the porous layer; and

[0008] A microstructure layer is disposed on the dense layer, and the surface of the microstructure layer away from the dense layer is a rough surface.

[0009] In one embodiment, the microstructure layer includes a plurality of protrusions arranged along a first direction and a second direction, the first direction and the second direction intersecting, and the protrusions being columnar.

[0010] In one embodiment, the direction perpendicular to the plane formed by the first direction and the second direction is taken as the third direction; the dimension L1 of the protrusion in the first direction is 100-1000 nm, the dimension L2 in the second direction is 100-1000 nm, and the dimension L3 of the protrusion in the third direction is 100-4000 nm; in the first direction, the distance L4 between two adjacent protrusions is 100-1000 nm, and in the second direction, the distance L5 between two adjacent protrusions is 100-1000 nm.

[0011] In one embodiment, L1 is 400–850 nm, L2 is 400–850 nm, L3 is 1000–3500 nm, L4 is 400–850 nm, and L5 is 500–850 nm.

[0012] In one embodiment, the thickness of the porous layer is 70–90 μm, the thickness of the dense layer is 0.3–3 μm, and the thickness of the microstructure layer is 0.01–4 μm.

[0013] In one embodiment, both the porous layer and the dense layer are functional layers containing pores, wherein the average pore size of the porous layer is 50–2000 nm; the average pore size of the dense layer is 1–200 nm; the porosity of the porous layer is 45%–75%; and the porosity of the dense layer is 5%–35%.

[0014] In one embodiment, the water contact angle of the outer surface of the microstructure layer is greater than 155 degrees and the roll-off angle is less than 10 degrees.

[0015] The above-mentioned method for preparing hollow fiber membranes includes the following steps:

[0016] A hollow fiber membrane precursor is provided, the hollow fiber membrane precursor comprising the porous layer and the dense layer disposed on the porous layer;

[0017] The surface of the dense layer is etched to form a microstructure layer, thereby obtaining the hollow fiber membrane.

[0018] In one embodiment, the step of etching the surface of the dense layer is performed by plasma etching, with a processing power of 200-1200W and a processing time of 10-60s.

[0019] In one embodiment, the step of providing the hollow fiber membrane precursor includes the following steps:

[0020] The raw materials used to form the hollow fiber membrane are mixed and extruded to obtain the extrudate;

[0021] The extrudate is subjected to cooling phase separation and cooling solidification treatment to obtain a nascent hollow fiber membrane.

[0022] The nascent hollow fiber membrane is sequentially stretched, extracted with a diluent, and dried to obtain the initial hollow fiber membrane product.

[0023] In one embodiment, the raw materials used to form the hollow fiber membrane include a polyolefin and a diluent; wherein the polyolefin is selected from one or more of polyethylene, polypropylene, and poly-4-methyl-1-pentene; and the diluent is selected from one or more of dioctyl adipate, dioctyl phthalate, isopropyl myristate, dibenzyl ether, dioctyl sebacate, dibutyl phthalate, dibutyl adipate, paraffin oil, sesame oil, dibutyl sebacate, castor oil, triacetin, mineral oil, and soybean oil.

[0024] In one embodiment, the bath solution used in the cooling and solidification process is triacetin or water.

[0025] In one embodiment, during the stretching step, the stretching temperature is 30–60°C, and the stretching ratio is 1.2–1.8 times that of the nascent hollow fiber membrane.

[0026] In one embodiment, the extractant used in the diluent extraction step is selected from one or more of ethanol, isopropanol, acetone and methanol.

[0027] A membrane oxygenator comprising the aforementioned hollow fiber membrane.

[0028] The present invention has the following beneficial effects:

[0029] By incorporating a microstructure layer with rough surfaces on a dense layer, the lower interfacial free energy of the microstructure layer reduces its interaction with blood components, resulting in less adsorption of plasma proteins and less platelet adhesion. This blocks or reduces the chain reaction process of coagulation, thereby preventing thrombus formation, improving the blood compatibility of the hollow fiber membrane, and ultimately enhancing its surface anticoagulant properties. Furthermore, the superhydrophobic structure of the hollow fiber membrane provided by this invention not only effectively prevents coagulation problems but also maintains optimal oxygenation efficiency, reducing or even eliminating the risk of plasma leakage. This effectively avoids the surface structural damage to the hollow fiber membrane caused by surface heparinization treatment in existing technologies, thus achieving superior anticoagulant performance without sacrificing plasma permeability resistance. Attached Figure Description

[0030] Figure 1 This is a schematic diagram of a hollow fiber membrane according to an embodiment of the present invention;

[0031] Figure 2 This is a schematic diagram of the protrusion according to an embodiment of the present invention;

[0032] Figure 3 This is a schematic diagram showing some of the protrusions arranged along a first direction and a second direction according to an embodiment of the present invention. Detailed Implementation

[0033] To facilitate understanding of the present invention, a more comprehensive description is provided below, along with preferred embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0035] like Figure 1 As shown, one embodiment of the present invention provides a hollow fiber membrane 10, which has a hollow inner cavity. The membrane structure of the hollow fiber membrane 10 includes, from the inside to the outside, a porous layer 100, a dense layer 200, and a microstructure layer 300, wherein the dense layer 200 is disposed on the porous layer 100, the microstructure layer 300 is disposed on the dense layer 200, and the surface of the microstructure layer 300 away from the dense layer 200 is a rough surface.

[0036] By providing a microstructure layer 300 with a rough surface on the dense layer 200, the lower interfacial free energy of the microstructure layer 300 can effectively reduce the adsorption capacity of the hollow fiber membrane 10 for blood components, thereby preventing thrombus formation, improving the blood compatibility of the hollow fiber membrane 10, and achieving the goal of improving the surface anticoagulant properties of the hollow fiber membrane 10. Furthermore, the superhydrophobic structure of the surface of the hollow fiber membrane 10 provided by this invention can not only effectively prevent coagulation problems but also maintain optimal oxygenation efficiency, eliminating the risk of plasma leakage and effectively avoiding the surface structure damage of the hollow fiber membrane caused by surface heparinization treatment in existing technologies. Thus, it has superior anticoagulant performance without sacrificing anti-plasma permeation properties. In addition, the hollow fiber membrane 10 with this structure does not require the addition of other anticoagulant components during the raw material blending and extrusion process, thus avoiding the problem of low oxygenation efficiency caused by the introduction of anticoagulant components.

[0037] Understandably, the boundaries between functional layers of the present invention (such as between porous layer 100 and dense layer 200, and between dense layer 200 and microstructure layer 300) can be obvious or vague. That is, the part in contact between two adjacent functional layers can present a clear structure of two functional layers stacked, or there can be a gradually changing fusion region. Specifically, it can be determined according to the preparation method or according to conventional methods in the art. No particular limitation is made here, and it should be understood that all of them are within the protection scope of the present invention.

[0038] In some embodiments, the microstructure layer 300 includes a plurality of protrusions 310; further, the protrusions 310 are micro / nano protrusion structures; further, such as Figure 2 As shown, several protrusions 310 are arranged along a first direction X and a second direction Y, and the first direction X and the second direction Y intersect to obtain a better anticoagulant effect. In some embodiments, the first direction X and the second direction Y are perpendicular to each other.

[0039] Understandably, in this invention, "micro-nano protrusion structure" refers to a protrusion with a depth in the micrometer or nanometer range.

[0040] In some embodiments, the protrusion 310 is prepared by plasma etching. By controlling the conditions of plasma etching, the shape and size of the protrusion can be controlled, thereby controlling the surface properties of the hollow fiber membrane, which is convenient and quick.

[0041] Understandably, the shape of the protrusion 310 is not particularly limited and can be selected according to the specific manufacturing process. It can be cylindrical, including but not limited to cylindrical and elliptical cylindrical shapes. Understandably, the shape, size, and distance between the protrusions of the present invention can be the same or different, and can be adjusted according to the actual production process. Preferably, all relevant parameters are within the range defined by the present invention.

[0042] In some embodiments, such as Figure 2 As shown, the two directions in which the protrusions are arranged are the first direction X and the second direction Y, and the direction perpendicular to the plane formed by the first direction X and the second direction Y and away from the surface of the dense layer is the third direction Z; the size of the protrusion 310 in the first direction X is L1, the size in the second direction Y is L2, and the size in the third direction Z is L3, wherein L1 is 0.025L3 to 10L3, and L2 is 0.025L3 to 10L3; further, the size range of L3 is 100 to 4000 nm.

[0043] In some embodiments, such as Figure 3 As shown, in the first direction X, the minimum boundary distance L4 between two adjacent protrusions 310 is 0.025L3 to 10L3, and in the second direction Y, the minimum boundary distance L5 between two adjacent protrusions 310 is 0.025L3 to 10L3.

[0044] In some embodiments, the dimension L1 of the protrusion 310 in the first direction X is 100-1000 nm, and the dimension L2 in the second direction Y is 100-1000 nm; in some embodiments, the dimension L3 of the protrusion in the third direction Z is 100-4000 nm; in some embodiments, the distance L4 between two adjacent protrusions in the first direction X is 100-1000 nm, and the distance L5 between two adjacent protrusions in the second direction Y is 100-1000 nm.

[0045] In some embodiments, the dimension L1 of the protrusion 310 in the first direction X is 300–980 nm; further, L1 is 400–850 nm; further, L1 is 500–700 nm; further, L1 is 150 nm, 180 nm, 200 nm, 250 nm, 300 nm, 310 nm, 320 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 960 nm, 966 nm, or 980 nm.

[0046] In some embodiments, the dimension L2 of the protrusion 310 in the second direction Y is 190–980 nm; further, L2 is 400–850 nm; further, L2 is 500–700 nm; further, L2 is 150 nm, 180 nm, 195 nm, 200 nm, 250 nm, 300 nm, 310 nm, 320 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 960 nm, 970 nm, or 980 nm.

[0047] In some embodiments, the dimension L3 of the protrusion in the third direction Z is 500–4000 nm; further, L3 is 1000–3500 nm; further, L3 is 2000–3500 nm; further, L3 is 500 nm, 526 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1000 nm, 1100 nm, 1200 nm, 1300 nm, 1400 nm, 1500 nm, 1600 nm, 1700 nm, 1800 nm, 1900 nm, 2000 nm, 2100 nm, etc. nm、2200nm、2300nm、2350nm、2400nm、2450nm、2500nm、2550nm、2600nm、2650nm、2700nm、2750nm、2800nm、2850nm、2900n m, 2950nm, 3000nm, 3100nm, 3200nm, 3300nm, 3400nm, 3500nm, 3600nm, 3700nm, 3800nm, 3900nm, 3920nm, 3950nm or 4000nm.

[0048] In some embodiments, in the first direction X, the distance L4 between two adjacent protrusions is 100–980 nm; further, L4 is 400–850 nm; further, L4 is 500–800 nm; further, L4 is 150 nm, 180 nm, 200 nm, 250 nm, 300 nm, 310 nm, 320 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 960 nm, 966 nm, or 980 nm.

[0049] In some embodiments, in the second direction Y, the distance L5 between two adjacent protrusions is 100–960 nm; further, L5 is 500–850 nm; further, L5 is 500–800 nm; further, L5 is 150 nm, 180 nm, 200 nm, 250 nm, 300 nm, 310 nm, 320 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 960 nm, 966 nm, or 980 nm.

[0050] By setting protrusions of the aforementioned size and density, hollow fiber membranes can achieve excellent anticoagulant properties.

[0051] Understandably, the structures of the dense layer 200 and the porous layer 100 in this invention can be the same as those of conventional hollow fiber membranes in the art. The porous layer 100 has a high porosity to ensure the permeation rate of oxygen and carbon dioxide, while the dense layer 200 has a low porosity and fewer pores and smaller pore sizes on the surface near the microstructure layer to ensure that the hollow fiber membrane has a longer plasma permeation time and improves its service life.

[0052] In some embodiments, the porosity of the porous layer 100 is 45%–75%; in some embodiments, the porosity of the dense layer 200 is 5%–35%. In some embodiments, the average pore size of the pores in the porous layer 100 is 50–2000 nm. In some embodiments, the average pore size of the pores in the dense layer 200 is 1–200 nm. By controlling the average pore sizes of the porous layer 100 and the dense layer 200 within the above ranges, a better combined effect can be obtained after combining with the microstructure layer 300, so as to ensure the permeation rate of oxygen and carbon dioxide while improving the anti-plasma permeation time, resulting in better overall performance.

[0053] In some embodiments, the thickness of the hollow fiber membrane is D, the thickness of the porous layer D1 is 0.91–0.98D, the thickness of the dense layer D2 is 0.003–0.05D, and the thickness of the microstructure layer L3 is 0.0001–0.05D (the thickness of the microstructure layer is also the dimension L3 of the protrusion in the third direction). In some embodiments, the thickness D1 of the porous layer 100 is 70–90 μm; further, D1 is 82–90 μm; in some embodiments, the thickness D2 of the dense layer 200 is 0.3–4 μm; further, D2 is 0.3–3 μm.

[0054] One embodiment of the present invention provides a method for preparing the above-mentioned hollow fiber membrane, comprising the following steps:

[0055] S100: Provides hollow fiber membrane pre-processing, which includes a porous layer and a dense layer disposed on the porous layer.

[0056] Understandably, step S100 can be performed using conventional methods in the art to prepare a hollow fiber membrane precursor containing a porous layer and a dense layer. This is not particularly limited here, and should be understood as being within the protection scope of this invention.

[0057] In some embodiments, step S100 includes the following steps:

[0058] S101: Mix the raw materials used to form the hollow fiber membrane and extrude them to obtain the extrudate;

[0059] S102: The extrudate is subjected to cooling and phase separation and cooling and solidification treatment to obtain a nascent hollow fiber membrane;

[0060] S103: The nascent hollow fiber membrane is sequentially stretched, extracted with a diluent, and dried to obtain the initial hollow fiber membrane product.

[0061] In some embodiments, the raw materials used to form the hollow fiber membrane include polyolefins and diluents; further, the polyolefins are selected from one or more of polyethylene, polypropylene, and poly-4-methyl-1-pentene; the diluents are selected from one or more of dioctyl adipate, dioctyl phthalate, isopropyl myristate, dibenzyl ether, dioctyl sebacate, dibutyl phthalate, dibutyl adipate, paraffin oil, sesame oil, dibutyl sebacate, castor oil, triacetin, mineral oil, and soybean oil.

[0062] In some embodiments, in step S101, the raw materials are first mixed and kneaded under conditions higher than the melting point of the polymer to obtain a homogeneous solution. Then, the homogeneous solution is extruded through the die of an extruder at high temperature. During each extrusion process, a gas (e.g., nitrogen or other inert gas) or liquid is introduced into the middle of the die to form a core cavity to form a hollow fiber membrane.

[0063] In some embodiments, in step S101, the extrusion temperature is 0.9-1.2 times the melting point temperature of the polymer, and the mixture refers to the object formed after the homogeneous solution is solidified.

[0064] In some embodiments, during step S102, the melt extrusion process involves a residence time of 0.5-200 ms in a gas atmosphere, with the gas atmosphere temperature being 25-120°C. By controlling the residence time and temperature within the aforementioned ranges, dense and porous layers with superior microstructures can be obtained, along with layers of suitable thickness, thus facilitating the overall performance of the hollow fiber membrane. Those skilled in the art should understand that other gas atmosphere residence times and temperatures within the aforementioned ranges are also feasible.

[0065] In some embodiments, in step S103, after multiple studies and analyses, it was found that the glass transition temperature of poly-4-methyl-1-pentene is around 30°C. Therefore, the preferred stretching temperature should be 30°C-60°C, and the stretching ratio should be 1.2-1.8 times that of the nascent hollow fiber membrane. Analysis of multiple experimental results revealed that when poly-4-methyl-1-pentene is used as the polyolefin, if the stretching temperature of the polyolefin is below 30°C, the polyolefin cannot be transformed into a highly elastic polyolefin. If the stretching ratio of poly-4-methyl-1-pentene is below 1.2 times, although the etching effect is significant, the tensile strength is low, making it unsuitable for hollow fiber membranes made with poly-4-methyl-1-pentene. If the stretching temperature is above 60°C or the stretching ratio is above 1.8 times, creep is likely to occur, making it difficult to maintain stable deformation. This will alter the pore shape of the porous and dense layers, which is detrimental to the preparation of hollow fiber membranes with both anti-leakage and anticoagulant effects.

[0066] In some embodiments, in step S102, the coagulation bath used in the cooling and solidification process is one or more of water, diethyl phthalate, glyceryl triacetate, and diacetyl glycerol; in some embodiments, the bath is water. In some embodiments, the bath is glyceryl triacetate.

[0067] In some embodiments, in step S103, the extractant used is selected from one or more of ethanol, isopropanol, acetone, and methanol; further, the extractant is ethanol.

[0068] S200: The surface of the dense layer is etched to form a microstructure layer, thus producing a hollow fiber membrane.

[0069] This method allows for direct etching on the surface of the dense layer to form the desired microstructure layer. It is simple to operate and minimizes damage to the hollow fiber membrane surface. Compared to heparinization, it effectively avoids shortening the anti-plasma permeation time and reducing gas flux, and eliminates the need to introduce anticoagulant components into the homogeneous solution, thus avoiding the drawbacks of introducing additional components. Therefore, this method not only improves the anticoagulant effect of the hollow fiber membrane, prolongs the anti-plasma permeation time, and increases oxygenation efficiency, but also reduces the difficulty of preparation. Furthermore, the etching conditions can be controlled as needed, facilitating the adjustment of the surface properties of the hollow fiber membrane and offering greater ease of preparation, making it suitable for industrial production applications.

[0070] In addition, compared with the traditional method of using etching on pipes only as a means to increase the bonding strength between pipes and adhesives, the present invention obtains a hollow fiber membrane with a microstructure layer through etching, which can maintain the porosity and gas flux of the existing hollow fibers and improve the hydrophobicity of the hollow fiber membrane, thus achieving long-term anti-leakage and long-term anticoagulation effects.

[0071] In some embodiments, in step S200, plasma etching is used to perform etching to obtain a hollow fiber membrane with better anticoagulant properties, while facilitating the adjustment of the microstructure layer to match various needs in actual production applications. Specifically, the shape and density of the microstructure layer can be controlled by adjusting the bath liquid, stretching temperature, stretching ratio, processing power, processing time, etc., thereby enabling the regulation of the hollow fiber membrane's performance.

[0072] Achieving a certain stretch ratio for nascent hollow fiber membranes requires the use of stretching temperature. Therefore, those skilled in the art should understand that stretching temperature and stretch ratio are two related factors that jointly affect the performance of nascent hollow fiber membranes.

[0073] In some embodiments, the plasma etching process power is 200–1200W and the process time is 10–60s.

[0074] In some embodiments, the water contact angle of the hollow fiber membrane is greater than 155° (i.e., 155 degrees), and the roll-off angle is less than 10° (i.e., 10 degrees).

[0075] One embodiment of the present invention provides a membrane oxygenator, comprising the aforementioned hollow fiber membrane. This hollow fiber membrane has a superior anticoagulant surface and a long anti-plasma leakage time (the anti-plasma leakage time of hollow fiber membranes made of polypropylene is short, generally around 10 hours; while that made of poly-4-methyl-1-pentene has a long anti-plasma leakage time, reaching up to 160 hours), and high oxygenation efficiency, making it particularly suitable as a consumable material for membrane oxygenators.

[0076] The present invention is illustrated below with specific examples. It should be understood that the following examples are merely illustrations and should not be construed as limiting the present invention.

[0077] Example 1

[0078] The following preparation method was used:

[0079] (1) Poly-4-methyl-1-pentene, dioctyl adipate, and dioctyl phthalate used to form hollow fiber membranes are mixed and kneaded under conditions above the critical stratification temperature to obtain a homogeneous solution. The homogeneous solution is then extruded through the die of an extruder at a temperature of 240°C. Nitrogen gas is introduced into the middle of the die during each extrusion process to form a core cavity.

[0080] (2) The extrudate is subjected to cooling phase separation and cooling solidification treatment to obtain a nascent hollow fiber membrane. During the phase separation process, the membrane is held in a gas atmosphere for 100 ms at a temperature of 80°C. Triacetyl glycerol is used as the coagulation bath for cooling solidification treatment.

[0081] (3) The nascent hollow fiber membrane is sequentially stretched, extracted with a diluent, and dried to obtain the initial hollow fiber membrane product; wherein, the stretching temperature is 30℃, the stretching ratio is 1.2 times that of polyolefin, and the extractant for diluent extraction is ethanol;

[0082] (4) The surface of the dense layer is etched by plasma etching to form the microstructure layer mentioned above, and a hollow fiber membrane is obtained. The processing power is 800W and the processing time is 35s.

[0083] The hollow fiber membrane obtained by the above preparation method includes a porous layer, a dense layer, and a microstructure layer. The dense layer is disposed on the porous layer, and the microstructure layer is disposed on the dense layer. The thickness D1 of the porous layer is 84.52 μm, and the average pore size is 855 nm. The thickness D2 of the dense layer is 1.68 μm, and the average pore size is 46 nm. The microstructure layer includes several protrusions arranged along a first direction and a second direction. The protrusions are cylindrical. The dimensions L1 of the protrusions in the first direction are 561 nm, the dimensions L2 in the second direction are 553 nm, and the dimensions L3 in the third direction are 2841 nm (L3 is the thickness of the microstructure layer). The distance L4 between two adjacent protrusions in the first direction is 732 nm, and the distance L5 between two adjacent protrusions in the second direction is 747 nm.

[0084] Example 2

[0085] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0086] Example 3

[0087] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0088] Example 4

[0089] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 60℃, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0090] Example 5

[0091] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 60℃ and the stretching ratio is 1.5, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0092] Example 6

[0093] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 60℃ and the stretching ratio is 1.8, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0094] Example 7

[0095] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5; in step (4), the plasma etching power is 200W and the processing time is 10s, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0096] Example 8

[0097] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 200W and the processing time is 35s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0098] Example 9

[0099] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 200W and the processing time is 60s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0100] Example 10

[0101] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 800W and the processing time is 10s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0102] Example 11

[0103] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 800W and the processing time is 60s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0104] Example 12

[0105] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 1200W and the processing time is 10s, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0106] Example 13

[0107] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 1200W and the processing time is 35s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0108] Example 14

[0109] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 45℃ and the stretching ratio is 1.5. In step (4), the plasma etching power is 1200W and the processing time is 60s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0110] Example 15

[0111] Preparation method: The difference from Example 1 is that in step (3), the stretching temperature is 60℃ and the stretching ratio is 1.8. In step (4), the plasma etching power is 200W and the processing time is 10s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0112] Example 16

[0113] Preparation method: The difference from Example 1 is that in step (4), the plasma etching power is 1200W and the processing time is 60s, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0114] Example 17

[0115] Preparation method: The difference from Example 1 is that the coagulation bath in step (2) is water, the stretching temperature in step (3) is 45℃ and the stretching ratio is 1.5, and the plasma etching power in step (4) is 800W and the processing time is 30s. The specific details are shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0116] Comparative Example 1

[0117] The difference from Example 1 is that the step of preparing the microstructure layer is omitted. After the hollow fiber membrane is prepared, the hollow fiber membrane is immersed in heparin solution to carry out the grafting reaction to obtain the hollow fiber membrane of this comparative example. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0118] Comparative Example 2

[0119] The difference from Example 1 is that the step of preparing the microstructure layer is omitted, and the hollow fiber membrane obtained is used as the hollow fiber membrane of this comparative example. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0120] Comparative Example 3

[0121] Preparation method: The difference from Example 1 is that the stretching temperature is 45℃, the stretching ratio is 1.5, the plasma etching power is 170W, and the processing time is 5s, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0122] Comparative Example 4

[0123] Preparation method: The difference from Example 1 is that the stretching temperature is 45℃, the stretching ratio is 1.5, the plasma etching power is 1500W, and the processing time is 80s, as shown in Table 1. The relevant dimensional parameters of the hollow fiber membrane are shown in Table 2.

[0124] Table 1

[0125]

[0126]

[0127] Performance verification

[0128] The hollow fiber membranes of the above embodiments and comparative examples were subjected to performance tests, as detailed below:

[0129] Test method:

[0130] (1) Hydrophobicity test:

[0131] Referring to the methods in GB / T 24368-2009, HY / T 212-2016, and HY / T 266-2018, the hollow fiber membrane was rinsed three times alternately with anhydrous ethanol and test water to remove surface contaminants. After drying, it was placed in a desiccator for testing. The hollow fiber membrane was placed straight on the sample stage of the contact angle meter, and its position was adjusted so that it was directly below the needle of the test solution syringe. The single water droplet feed volume was 0.5 μL. The high-definition camera on the contact angle meter recorded an image of the hollow fiber membrane surface in contact with the water droplet for 2 seconds, which was transmitted to the calculation system to calculate the water contact angle. The hollow fiber membrane sample was tilted, and an image of the water droplet about to roll was recorded using the high-definition camera. The rolling angle was calculated, and the test results are shown in Table 3.

[0132] (2) Nitrogen flux test:

[0133] Nitrogen flux is used to characterize the gas flux performance of hollow fiber membranes, further indicating their oxygenation performance. A bundle of hollow fiber membranes is cast into a test module, with one end sealed and the other open. The open end of the hollow fiber membrane is connected to a pore size analyzer, set to nitrogen flux test mode, inputting the total outer surface area of ​​the hollow fiber membrane, setting the target pressure to 2 bar, obtaining a pressure-flow curve, importing the test area, and obtaining the nitrogen flow rate per unit area, unit pressure, and unit time, which is the nitrogen flux (ml / cm²). 2 (·min·bar). In Table 2 below, flux 1 is the nitrogen flux before the leakage resistance test, and flux 2 is the nitrogen flux after the leakage resistance test. The test results are shown in Table 3.

[0134] (3) Plasma leakage time test:

[0135] The method cited in patent CN1136035C specifically involves dissolving 1.5 g / L α-lecithin in 500 ml of physiological saline solution at 37°C at a rate of 61 / (min*m). 2 A pressure of 1.0 bar is applied to the outer surface of the membrane sample. Air is allowed to flow along the inner cavity of the hollow fiber membrane sample, and the air after flowing through the membrane sample passes through a cold trap. The weight of the liquid accumulated in the cold trap is measured as a function of time. The time when a significant increase in weight occurs, i.e., the first significant accumulation of liquid in the cold trap, is defined as the plasma leakage time. In this invention, the time when plasma leakage begins to occur is mainly collected during the test. If the time when plasma leakage begins to occur exceeds 180 hours, the test is terminated. The test results are shown in Table 3.

[0136] Table 2

[0137]

[0138]

[0139] Table 3

[0140]

[0141]

[0142] The criteria for evaluating the hydrophobicity and long-lasting anticoagulant effect of each embodiment are as follows: Hydrophobicity is assessed by the contact angle and roll-off angle. A larger contact angle and a smaller roll-off angle indicate better hydrophobicity. A smaller difference between the nitrogen flux before and after the anti-leakage test indicates less test solution adhering to the hollow fiber membrane, thus characterizing the hollow fiber membrane as having a long-lasting anticoagulant effect. Of course, the evaluation of these performance effects needs to be based on maintaining the hollow fiber membrane's optimal anti-plasma leakage time.

[0143] Comparative Examples and Comparative Examples 1-4: Comparative Example 1 is a conventionally heparinized hollow fiber membrane; Comparative Example 2 is a blank control, i.e., without a microstructure layer; Comparative Examples 3 and 4 are other embodiments whose processing power and processing time are not within the scope of protection of this invention.

[0144] As shown in Table 3, compared with Comparative Example 1, Examples 1-17 exhibit larger contact angles and smaller roll-off angles, indicating better hydrophobicity, while Comparative Example 1 demonstrates better hydrophilicity. This is because the test solution is rapidly absorbed by the hollow fiber membrane of Comparative Example 1, preventing the measurement of the test solution's roll-off angle. Furthermore, the heparin-treated hollow fiber membrane forms a denser tubular layer on its surface, affecting the initial gas flux. Due to the superior hydrophilicity of Comparative Example 1, plasma coagulation is more likely to occur on its surface, ultimately hindering long-term gas exchange within the hollow fiber membrane, resulting in lower oxygenation efficiency, poor long-term anticoagulation, and increased thrombus formation. Therefore, although the hollow fiber membrane of Comparative Example 1 exhibits longer anti-plasma leakage time, its long-term anticoagulation effect is poor.

[0145] As shown in Table 3, comparing Examples 1-17 with Comparative Example 2, Examples 1-17 exhibit larger contact angles and smaller roll-off angles, indicating better hydrophobicity, while Comparative Example 1 shows poor hydrophobicity. Therefore, since Comparative Example 2 does not contain a microstructure layer, its initial gas flux is lower, and due to its superior hydrophilicity, more plasma adheres to the surface during long-term use, resulting in even lower nitrogen flux after the anti-leakage test and a greater likelihood of thrombus formation. Thus, although the hollow fiber membrane of Comparative Example 2 exhibits longer anti-plasma leakage time, its long-term anticoagulant effect is poor.

[0146] As can be seen from Table 3, comparing Examples 1-17 with Comparative Examples 3 and 4, it can be found that when the processing power and processing time are limited outside the scope of protection of this invention, if the processing power is small, the initial gas flux also decreases significantly. At the same time, the hydrophobicity is poor, resulting in more plasma adhering to the surface during long-term use, and the long-term anticoagulation effect is poor. If the processing power is large, the surface of the hollow fiber membrane is rough, and the hydrophilicity is greatly increased, so the rolling angle of the test solution cannot be obtained. Therefore, in the examples of Comparative Example 4, even though the initial flux increases significantly, the anti-plasma leakage time decreases significantly. At the same time, due to the poor hydrophobicity, the long-term anticoagulation effect is poor, and it is impossible to take into account both the advantages of long anti-plasma leakage time and long-term anticoagulation.

[0147] The above comparison reveals the superiority of the present invention over comparative examples 1-4, as it combines the advantages of long-lasting anti-plasma leakage time and long-acting anticoagulation. Furthermore, the effects of different embodiments of the present invention vary, as detailed in the following comparison:

[0148] As can be seen from Table 3, the hollow fiber membranes of Examples 1-17 have larger contact angles and smaller roll-off angles. Among them, the roll-off angles of the hollow fiber membranes of Examples 1-6, Examples 9-13, and Examples 17 are less than 10 degrees and the contact angles are greater than 149 degrees. This indicates that the hollow fiber membrane of the present invention has a better hydrophobic surface, which can effectively improve the blood compatibility of the hollow fiber membrane and achieve the purpose of improving the surface anticoagulant properties of the hollow fiber membrane.

[0149] The hollow fiber membranes of Examples 1-17 exhibit a relatively long anti-plasma leakage time, especially Examples 1-15 and Example 17, which are all greater than 180 hours, indicating that the hollow fiber membrane of the present invention can effectively reduce or even eliminate the risk of plasma leakage. Furthermore, Examples 1-17 all have high nitrogen flux, and the difference between the nitrogen flux before and after the anti-leakage test is small, with the difference in Example 3 even reaching below 0.1, indicating that the hollow fiber membrane of the present invention has a long-lasting anticoagulant effect.

[0150] Comparing Example 3 and Example 17, the difference lies in the type of bath liquid. In Example 3, L1 is 628nm, L2 is 615nm, L3 is 2648nm, L4 is 648nm, and L5 is 665nm, while in Example 17, L1 is 616nm, L2 is 598nm, L3 is 2732nm, L4 is 658nm, and L5 is 675nm. In comparison, the contact angle of Example 3 is larger than that of Example 17, the roll-off angle is smaller than that of Example 17, the nitrogen flux before the anti-leakage test of Example 3 is larger than that of Example 17, and the difference between the nitrogen flux before and after the anti-leakage test of Example 3 is smaller than that of Example 17. It can be seen that under the same conditions, the size range of the protrusion obtained by Example 3 is more suitable, and the combined effects of long anti-plasma leakage time and long-term anticoagulation are more prominent.

[0151] Comparing Examples 1, 2, and 4, the difference lies in the stretching temperature. In Example 1, L1 is 561 nm, L2 is 553 nm, L3 is 2841 nm, L4 is 732 nm, and L5 is 747 nm; in Example 2, L1 is 581 nm, L2 is 574 nm, L3 is 2826 nm, L4 is 726 nm, and L5 is 735 nm; and in Example 4, L1 is 546 nm, L2 is 553 nm, L3 is 2814 nm, L4 is 746 nm, and L5 is 753 nm. As can be seen from Table 3, the contact angle, roll-off angle, and anti-plasma leakage time are not significantly different among the three examples, but there is a certain difference in the values. This indicates that when the stretching ratio is 1.2, the long-lasting anticoagulant effect is better when the stretching temperature is between 30℃ and 45℃. The aforementioned comparison focuses on the effects at lower draw ratios. As the draw ratio increases, achieving a higher draw ratio requires different draw temperatures; therefore, both factors need to be varied synergistically. For example, comparing Examples 1, 3, and 6, the difference lies in the draw temperature and draw ratio. In Example 1, L1 is 561 nm, L2 is 553 nm, L3 is 2841 nm, L4 is 732 nm, and L5 is 747 nm; in Example 3, L1 is 628 nm, L2 is 615 nm, and L5 is 615 nm.

[0152] The values ​​for L1, L2, L3, L4, and L5 are 2648 nm, 648 nm, and 665 nm, respectively. For Example 6, the values ​​for L1, L2, L3, L4, L5, and L5 are 719 nm, 727 nm, 2058 nm, 596 nm, and 607 nm, respectively. The contact angle, roll-off angle, and anti-plasma leakage time of the three examples are not significantly different. However, there are certain differences in the flux before and after the test, as well as the difference. It can be found that when other conditions are the same, Example 1 and Example 3 have a more prominent effect in balancing long anti-plasma leakage time and long-lasting anticoagulation.

[0153] Comparing Examples 13 and 14, the difference lies in the plasma etching time. In Example 13, L1 is 512 nm, L2 is 524 nm, L3 is 2869 nm, L4 is 722 nm, and L5 is 715 nm. In Example 14, L1 is 332 nm, L2 is 351 nm, L3 is 3365 nm, L4 is 873 nm, and L5 is 884 nm. Table 3 shows that Example 13 has a larger contact angle and a smaller roll-off angle than Example 14. The nitrogen flux in Example 13 is also greater than in Example 14, and the difference between the nitrogen flux before and after the anti-leakage test is smaller than that in Example 14. This indicates that the microstructure layer formed with a plasma etching time of 35 s has a more suitable size range for the protrusions, achieving a better balance between long-lasting anti-plasma leakage time and long-term anticoagulation effects.

[0154] Comparing Examples 6 and 15, the difference lies in the plasma etching power and time. In Example 6, L1 is 719 nm, L2 is 727 nm, L3 is 2058 nm, L4 is 596 nm, and L5 is 607 nm; in Example 15, L1 is 966 nm, L2 is 974 nm, L3 is 526 nm, L4 is 127 nm, and L5 is 132 nm. It can be seen that the contact angle of Example 6 is larger than that of Example 15, the roll-off angle is smaller, the nitrogen flux of Example 6 is greater than that of Example 15, and the difference between the nitrogen flux before and after the anti-leakage test is smaller than that of Example 15. This indicates that the size range of the protrusions obtained by plasma etching under the processing power and time of Example 6 is more suitable, achieving a more prominent balance between long-term anti-plasma leakage time and long-lasting anticoagulation effects.

[0155] Comparing Examples 1 and 16, the difference lies in the plasma etching power and time. In Example 1, L1 is 561 nm, L2 is 553 nm, L3 is 2841 nm, L4 is 732 nm, and L5 is 747 nm. In Example 16, L1 is 189 nm, L2 is 195 nm, L3 is 3921 nm, L4 is 974 nm, and L5 is 962 nm. It can be seen that the contact angle of Example 1 is larger than that of Example 16, the roll-off angle is smaller, the anti-plasma permeation time of Example 1 is longer than that of Example 16, the nitrogen flux is greater than that of Example 16, and the difference between the nitrogen flux before and after the anti-permeation test is smaller than that of Example 16. Therefore, the size range of the protrusions obtained by plasma etching under the processing power and time of Example 1 is more suitable, and it more effectively balances both the long-term anti-plasma permeation time and the long-lasting anticoagulant effect.

[0156] This demonstrates that by adjusting parameters such as bath type, drawing temperature, drawing ratio, processing power, and processing time, the microstructure layer can be adjusted to meet the needs of various products. The preferred drawing temperature is 30-60℃, the preferred drawing ratio is 1.2-1.8, the preferred bath is triacetin, the preferred plasma etching power is 200-1200W, and the preferred processing time is 10-60s. Furthermore, by controlling the dimensions of the protrusions within specific ranges, the long-term anticoagulant effect of the hollow fiber membrane can be effectively improved. The preferred dimensions are L1 400-850nm, L2 400-850nm, L3 1000-3500nm, L4 400-850nm, and L5 500-850nm.

[0157] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0158] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A hollow fiber membrane, characterized in that, The hollow fiber membrane structure, from the inside out, includes: Porous layer; A dense layer is disposed on the porous layer; and A microstructure layer is disposed on the dense layer, and the surface of the microstructure layer away from the dense layer is a rough surface. The microstructure layer includes several protrusions arranged along a first direction and a second direction, the first direction and the second direction intersecting each other, and the protrusions are columnar; the direction perpendicular to the plane formed by the first direction and the second direction is the third direction; the size L1 of the protrusion in the first direction is 100-1000 nm, the size L2 in the second direction is 100-1000 nm, and the size L3 in the third direction is 1800-3200 nm; the distance L4 between two adjacent protrusions in the first direction is 100-1000 nm, and the distance L5 between two adjacent protrusions in the second direction is 100-1000 nm.

2. The hollow fiber membrane according to claim 1, characterized in that, Both the porous layer and the dense layer are functional layers containing pores; L3 is 2200–2850 nm; The water contact angle of the outer surface of the microstructure layer is greater than 155 degrees, and the roll-off angle is less than 10 degrees. The thickness of the dense layer is 0.3–3 µm; The thickness of the porous layer is 82–90 µm; The average pore size of the dense layer is 1–200 nm, and the porosity of the dense layer is 5%–35%. The average pore size of the porous layer is 50–2000 nm; the porosity of the porous layer is 45%–75%.

3. The hollow fiber membrane according to claim 1, characterized in that, The thickness of the porous layer is 70–90 µm, the thickness of the dense layer is 0.3–3 µm, and L3 is 2300–2850 nm.

4. The hollow fiber membrane according to claim 1, characterized in that, Both the porous layer and the dense layer are functional layers containing pores. The average pore size of the porous layer is 50–2000 nm; the average pore size of the dense layer is 1–200 nm; the porosity of the porous layer is 45%–75%; and the porosity of the dense layer is 5%–35%.

5. A method for preparing a hollow fiber membrane, characterized in that, The preparation of the hollow fiber membrane according to any one of claims 1-4 comprises the following steps: A hollow fiber membrane precursor is provided, the hollow fiber membrane precursor comprising the porous layer and the dense layer disposed on the porous layer; The surface of the dense layer is etched to form the microstructure layer, thereby obtaining the hollow fiber membrane.

6. The preparation method according to claim 5, characterized in that, In the step of etching the surface of the dense layer, plasma etching is used for etching, with a processing power of 200-1200W and a processing time of 10-60s.

7. The preparation method according to claim 5, characterized in that, The steps for providing hollow fiber membrane pre-products include the following: The raw materials used to form the hollow fiber membrane are mixed and extruded to obtain the extrudate; The extrudate is subjected to cooling phase separation and cooling solidification treatment to obtain a nascent hollow fiber membrane. The nascent hollow fiber membrane is sequentially stretched, extracted with a diluent, and dried to obtain the initial hollow fiber membrane product.

8. The preparation method according to claim 7, characterized in that, The raw materials used to form hollow fiber membranes include polyolefins and diluents; The polyolefin is selected from one or more of polyethylene, polypropylene, and poly-4-methyl-1-pentene; the diluent is selected from one or more of dioctyl adipate, dioctyl phthalate, isopropyl myristate, dibenzyl ether, dioctyl sebacate, dibutyl phthalate, dibutyl adipate, paraffin oil, sesame oil, dibutyl sebacate, castor oil, triacetin, mineral oil, and soybean oil.

9. The preparation method according to claim 7, characterized in that, In the cooling and solidification step, the bath solution used is triacetin or water; and / or In the stretching step, the stretching temperature is 30–60°C, and the stretching ratio is 1.2–1.8 times that of the nascent hollow fiber membrane; and / or In the step of diluent extraction, the extractant used is selected from one or more of ethanol, isopropanol, acetone and methanol.

10. A membrane oxygenator, characterized in that, Includes the hollow fiber membrane according to any one of claims 1-4.

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