CN113069598A

CN113069598A - Anticoagulation modification method of hemodialyzer

Info

Publication number: CN113069598A
Application number: CN202010008583.8A
Authority: CN
Inventors: 韩秋; 刘富; 柳杨; 林海波
Original assignee: Ningbo Institute of Material Technology and Engineering of CAS
Current assignee: Ningbo Institute of Material Technology and Engineering of CAS
Priority date: 2020-01-06
Filing date: 2020-01-06
Publication date: 2021-07-06
Anticipated expiration: 2040-01-06
Also published as: CN113069598B

Abstract

The invention provides an anticoagulation modification method of a hemodialyzer, which comprises the following steps: (1) introducing the initiator 1 solution into a hemodialyzer at 30-80 ℃, staying for 2-10h, and drying to uniformly disperse the initiator 1 in the hemodialysis membrane; (2) in protective atmosphere, introducing the sodium alginate, the initiator 2 and the aqueous solution of the vinyl monomer into the hemodialyzer treated in the step (1) to react for 4-24h at 50-100 ℃; (3) and cleaning and drying after one-step polymerization reaction to obtain the modified hemodialyzer. According to the invention, through free radical polymerization reaction and by utilizing the bridging effect of vinyl monomers, sodium alginate and a hemodialysis membrane matrix form an interpenetrating network stable structure, and the sodium alginate is uniformly distributed on the surface and in the pores of the hemodialysis membrane, so that the reaction rate with calcium ions is greatly improved; sodium alginate and calcium ions in blood are utilized to form soluble chelate, so that the calcium ions lose the coagulation effect, and the anticoagulation performance of the hemodialysis membrane is effectively improved.

Description

Anticoagulation modification method of hemodialyzer

Technical Field

The invention relates to a modification method of a substance separation membrane in the biological field, in particular to a modification method for improving the anticoagulation performance of a hemodialyzer.

Background

The data show that the number of Chinese chronic kidney disease patients reaches 1.2 hundred million, and the number of the developed terminal kidney disease patients is 200 ten thousand; however, only 30 or more than ten thousand people receive dialysis treatment at present, and the treatment rate is only 15 percent and is far lower than 90 percent of that in European and American countries. The main modes of treating uremia currently include blood purification and kidney transplantation. Because the kidney source is in short supply, the kidney transplantation rate of Chinese uremia patients is less than 1 percent, and the problem of the kidney source is difficult to solve in a short time, the blood purification becomes a main means for treating the uremia.

Hemodialysis is the process of draining blood from the body to the outside, removing excess water and toxins from the blood through a dialyzer, and returning the purified blood. A key component of an artificial kidney (hemodialyzer) is the hemodialysis membrane. Hemodialysis membrane is a semi-permeable membrane. During hemodialysis, when dialysate and blood are introduced into two sides of a hemodialysis membrane in a dialyzer at the same time, osmotic gradient and water pressure gradient of solutes are generated on the two sides of the membrane, so that the aim of removing toxins and excessive moisture in the blood is fulfilled.

The polymer membrane becomes the mainstream of the dialysis membrane material due to the characteristics of large pore diameter and certain biocompatibility. The polymer dialysis membrane with wider clinical application comprises a polysulfone membrane PS, a polyether sulfone membrane PSF, polymethyl methacrylate PMMA, a polyamide membrane PA and ethylene vinyl alcohol copolymer EVAL. However, the surface of such polymer membrane is hydrophobic, and the membrane can adsorb proteins in blood during hemodialysis. At the same time, the adhesion and rupture of platelets can lead to severe coagulation reactions. Therefore, heparin is required to be introduced during hemodialysis to prevent coagulation reaction. However, long-term use of heparin is likely to cause bleeding, thrombocytopenia, heparin resistance, osteoporosis, and other conditions. Excessive heparin doses can also cause spontaneous bleeding. Therefore, the compatibility problem of the dialysis membrane with the human body in hemodialysis is a core problem of the dialysis membrane in practical application. The existing hemodialysis membrane is modified to have good anticoagulation performance, so that the use of heparin in dialysis is reduced or even avoided, some adverse reactions of hemodialysis are eliminated, and the reduction of patient pain is an important research direction for development of the hemodialysis membrane.

At present, many researches on modifying and improving the anticoagulation performance of a hemodialysis membrane are reported, and the prepared hydrophilic auto-anticoagulation functional polymer mainly comprises polyvinylpyrrolidone (PVP), zwitterionic compounds (such as MPC (poly-phospholipide) and sulfonated (also called heparinized) functional polymer. The hydrophilic macromolecular PVP is always easy to elute when being used, the preparation cost of zwitterionic compounds such as MPC is higher, and the improvement of the anticoagulation performance is limited. Due to the hydrophilicity and anticoagulation activity of the sulfonate group, the hydrophilic additive can be slowly separated out in the use process, so that the membrane prepared by the method has low structure and performance stability. CN108893873B discloses an anticoagulant fiber membrane modified by metal organic framework material, which has good anticoagulant stability, but the synthesis process of metal organic framework material is complex, the period is long (4.5-5.5 weeks), and the industrial production is not easy.

Disclosure of Invention

Aiming at the defects of the anticoagulation modified hemodialyzer in the prior art, the invention mainly aims to provide the anticoagulation modification method of the hemodialyzer, sodium alginate is adopted for modifying the hemodialyzer by utilizing free radical polymerization reaction, the modification process is simple and easy to operate, toxic solvents are not used, the pollution is small, no adverse effect is caused to the use of the subsequent hemodialyzer, and the obtained anticoagulation performance of the hemodialyzer is stable and excellent.

The technical scheme of the invention is to provide an anticoagulation modification method of a hemodialyzer, which comprises the following steps:

(1) introducing the initiator 1 solution into a hemodialyzer at 30-80 ℃, staying for 2-10h, and drying to uniformly disperse the initiator 1 in the hemodialysis membrane;

(2) in protective atmosphere, introducing the sodium alginate, the initiator 2 and the aqueous solution of the vinyl monomer into the hemodialyzer treated in the step (1) to react for 4-24h at 50-100 ℃;

(3) and cleaning and drying after one-step polymerization reaction to obtain the modified hemodialyzer.

Further, the initiator 1 includes any one or a combination of two or more of azobisisobutyronitrile, azobisisoheptonitrile, and dibenzoyl peroxide.

Further, the solvent of the initiator 1 solution is any one or a combination of two or more of methanol, ethanol, diethyl ether and ethyl acetate.

Further, the initiator 2 is a water-soluble initiator.

Preferably, the initiator 2 comprises any one or a combination of two or more of azobisisobutyramidine hydrochloride, azobisisobutyrimidazoline hydrochloride, azobiscyanovaleric acid, azobisisopropylimidazoline and potassium persulfate.

Further, the vinyl monomer is a water-soluble vinyl monomer.

Preferably, the vinyl monomer comprises any one or a combination of two or more of N-methylolacrylamide, N-hydroxyethyl acrylamide, acrylic acid, methacrylic acid, phenylacrylic acid and sorbic acid.

Further, the mass ratio of the initiator 1 in the step (1) to the combination of the vinyl monomer and the sodium alginate in the step (2) is 0.01-0.03: 1; in the step (2), the mass ratio of the initiator 2 to the combination of the vinyl monomer and the sodium alginate is 0.01-0.03: 1.

further, the mass ratio of the vinyl monomer to the sodium alginate in the step (2) is 0.2-1.5: 1, and the mass ratio of the water to the combination of the vinyl monomer and the sodium alginate in the aqueous solution is 100: 3 to 15. Water includes purified water, deionized water, and the like, preferably deionized water.

Further, the protective atmosphere includes a nitrogen atmosphere and/or an inert gas atmosphere.

Compared with the prior art, the invention has the beneficial effects that:

(1) the anticoagulation modification method of the hemodialyzer provided by the invention is characterized in that sodium alginate and a hemodialysis membrane matrix form an interpenetrating network stable structure by utilizing the bridging action of vinyl monomers through free radical polymerization reaction, and the sodium alginate is uniformly distributed on the surface and in the pores of the hemodialysis membrane, so that the reaction rate with calcium ions is greatly improved; sodium alginate and calcium ions in blood are utilized to form soluble chelate, so that the calcium ions lose the coagulation effect, and the anticoagulation performance of the hemodialysis membrane is effectively improved.

(2) According to the anticoagulant modified hemodialyzer provided by the invention, an interpenetrating network stable structure is formed by the sodium alginate and the hemodialysis membrane substrate, the sodium alginate is uniformly distributed on the surface and in the pores of the hemodialysis membrane, the hydrophilicity is greatly improved, and the adhesion of blood cells and blood platelets on the surface of the membrane is reduced, so that the occurrence of blood coagulation is greatly reduced.

(3) The modified anticoagulant hemodialyzer provided by the invention has the membrane structure basically unchanged after modification. Since the hydrophilicity is increased, the ultrafiltration coefficient of the membrane is increased, and thus the removal rate of harmful components in blood is increased.

(4) The anticoagulation modification method of the hemodialyzer provided by the invention does not use toxic solvents in the whole modification process, is green and pollution-free, and is particularly simple in subsequent cleaning, drying and post-treatment of the hemodialyzer.

(5) The anticoagulation modification method of the hemodialyzer can obtain a stable anticoagulation structure by one-step polymerization reaction, and has the advantages of simple process steps, easy operation and easy industrial production.

Drawings

Fig. 1 is SEM photographs of the inner surface (a) and the cross section (b) of the hemodialyzer membrane of comparative example 1.

FIG. 2 is SEM photographs of the inner surface (a) and cross section (b) of the membrane of the highly anticoagulated hemodialyzer prepared in example 1 of the present invention.

FIG. 3 is a graph comparing the highly anticoagulated hemodialyzer membrane prepared in example 1 of the present invention, the hemodialyzer membrane of comparative example 1, and Activated Partial Thromboplastin Time (APTT) of blood.

FIG. 4 is a graph comparing the Thrombin Time (TT) of the highly anticoagulated hemodialyzer membrane prepared in example 1 of the present invention with that of the hemodialyzer membrane of comparative example 1 and blood.

FIG. 5 is a graph comparing the platelet adhesion after hemodialysis of the highly anticoagulated hemodialyzer membrane prepared in example 1 of the present invention with that of the hemodialyzer membrane of comparative example 1.

FIG. 6 is a graph comparing the ultrafiltration coefficients of the highly anticoagulated hemodialyzer membrane prepared in example 1 of the present invention and the hemodialyzer membrane of comparative example 1.

FIG. 7 is a graph comparing the contact angles of the inner surface of the membrane of the highly anticoagulated hemodialyzer prepared in example 1 of the present invention and the inner surface of the membrane of the hemodialyzer of comparative example 1.

Detailed Description

The present invention will be further described with reference to the following embodiments.

At present, the demand for anticoagulation of hemodialyzers is urgent, various functional polymers are in great variety, but the obtained hemodialysis membranes are easy to elute, high in preparation cost, low in anticoagulation performance and unstable in performance. In view of the defects of the prior art, the inventor of the invention provides a technical scheme of the invention through long-term research and a large amount of practice, and provides a surface modification method for improving the hemocompatibility of a dialyzer so as to realize high anticoagulation characteristic of the hemodialyzer.

In order to better illustrate the anticoagulation modification method of the hemodialyzer and the high anticoagulation characteristic of the hemodialyzer prepared by modification, a commercially available hemodialyzer product (packaging polysulfone membrane) is selected as a comparative example 1, and the commercially available hemodialyzer with the same specification and the same model is modified by the method disclosed by the invention, which is shown in examples 1 to 5.

Example 1

Step (1): dissolving 0.2g of azobisisobutyronitrile in 200g of ethanol solution, introducing the solution into a commercially available hemodialyzer (encapsulating polysulfone membrane, i.e., the same product as in comparative example 1) at 50 ℃, standing for 2 hours, and drying to uniformly disperse azobisisobutyronitrile in the hemodialysis membrane;

step (2): in a protective atmosphere, 8g of sodium alginate, 0.2g of azodiisobutyramidine hydrochloride and 4g of aqueous solution of N-hydroxymethyl acrylamide (100g of deionized water is used as a solvent) are introduced into a hemodialyzer, the reaction is carried out for 10 hours at the temperature of 80 ℃, and the hemodialyzer with stable and excellent anticoagulation performance is obtained after one-step polymerization reaction, cleaning and drying.

The membrane filaments of the hemodialyzer in comparative example 1 and the highly anticoagulated hemodialyzer obtained in this example were taken out, respectively, and the microstructure of the inner surface of the membrane filaments was observed by a scanning electron microscope. As shown in fig. 1 and fig. 2, the inner surface micro-pore structure and distribution of the membrane filaments of the hemodialyzer with high anticoagulation degree obtained in this example are very similar to those of the membrane filaments of the hemodialyzer described in comparative example 1, which shows that the inner surface micro-structure of the membrane filaments encapsulated in the hemodialyzer is substantially maintained after the modification by the anticoagulation modification technique described in this invention.

The membrane filaments of the hemodialyzer of comparative example 1 and the highly anticoagulated hemodialyzer obtained in this example were taken out, respectively, to conduct the coagulation test. As shown in fig. 3, the Activated Partial Thromboplastin Time (APTT) of the highly anticoagulated hemodialyzer membrane filaments prepared in this example exceeded 360 seconds, whereas the APTT time of the hemodialyzer membrane filaments of comparative example 1 was only 50 seconds; as shown in FIG. 4, the Thrombin Time (TT) of the highly anticoagulated hemodialyzer membrane filaments prepared in this example was 27 seconds, whereas the TT time of the hemodialyzer membrane filaments of comparative example 1 was only 15 seconds. The method of the invention is proved that the anticoagulant performance of the hemodialyzer is obviously improved.

The membrane filaments of the hemodialyzer of comparative example 1 and the highly anticoagulated hemodialyzer obtained in this example were each taken out and subjected to a hemodialysis test, and the adhesion of cellular platelets to the inner surface of the membrane filaments was observed. As shown in fig. 5, the membrane filaments of the highly anticoagulated hemodialyzer obtained in the present example have very little adhesion of blood cells and platelets after the hemodialysis test (the color of the membrane filaments is shown in the figure); the hemodialyzer of comparative example 1 exhibited severe poor adhesion of blood cells and platelets (membrane filaments appear dark in color in the picture). This shows that the hemocompatibility of the hemodialyzer is significantly improved after modification by the anticoagulation modification technique of the present invention.

The membrane filaments of the hemodialyzer in comparative example 1 and the highly anticoagulated hemodialyzer obtained in this example were taken out, respectively, and subjected to ultrafiltration coefficient testing. As shown in fig. 6, the ultrafiltration coefficient of the membrane filaments of the high anticoagulation hemodialyzer obtained in the present example is higher than that of the hemodialyzer described in comparative example 1, which shows that after the anticoagulation modification technology is modified, the hydrophilicity of the membrane surface is improved (as shown in fig. 7), and the water flux of the membrane filaments packaged by the hemodialyzer is improved, so that the removal rate of harmful components in blood is increased, and the dialysis efficiency is improved.

The test methods can be referred to as YY 0053-2016 hemodialysis and related treatments hemodialyzer, hemodiafiltration filter, hemofilter, and hemoconcentrator.

Example 2

Step (1): dissolving 0.15g of azobisisoheptonitrile in 200g of ethanol solution, introducing the solution into a hemodialyzer (packaged polyether sulfone membrane) purchased in the market at 50 ℃, standing for 5 hours, and drying to uniformly disperse the azobisisoheptonitrile in the hemodialysis membrane;

step (2): introducing 6g of sodium alginate, 0.2g of azobisisobutyrimidazoline hydrochloride and 9g of aqueous solution of N-hydroxyethyl acrylamide (100g of deionized water is used as a solvent) into a hemodialyzer in a protective atmosphere, reacting for 12 hours at 70 ℃, and cleaning and drying after one-step polymerization to obtain the hemodialyzer with stable and excellent anticoagulation performance;

the Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane filaments with high anticoagulation performance prepared in the example is up to 325 seconds, and the Thrombin Time (TT) is 24 seconds as tested by a coagulation test.

Example 3

Step (1): dissolving 0.2g of dibenzoyl oxide in 200g of methanol solution, introducing the solution into a commercially available hemodialyzer (packaged polyamide membrane) at 40 ℃, standing for 6 hours, and drying to uniformly disperse the dibenzoyl oxide in the hemodialysis membrane;

step (2): in a protective atmosphere, introducing 8g of sodium alginate, 0.3g of azodicyano valeric acid and 9g of acrylic acid aqueous solution (150g of deionized water as a solvent) into a hemodialyzer, reacting for 15h at 70 ℃, and performing one-step polymerization reaction, cleaning and drying to obtain the hemodialyzer with stable and excellent anticoagulation performance;

the Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane filaments with high anticoagulation performance prepared in the example is up to 340 seconds and the Thrombin Time (TT) is 25 seconds as tested by a coagulation test.

Example 4

Step (1): dissolving 0.45g of azobisisobutyronitrile into 200g of ether solution, introducing the solution into a hemodialyzer (packaging polysulfone membrane) purchased in the market at 60 ℃, staying for 2 hours, and drying to uniformly disperse the azobisisobutyronitrile in the hemodialysis membrane;

step (2): in a protective atmosphere, introducing 8g of sodium alginate, 0.3g of azodiisopropyl imidazoline and 9g of an aqueous solution of acrylic acid (150g of deionized water is used as a solvent) into a hemodialyzer, reacting for 18h at 80 ℃, and performing one-step polymerization reaction, cleaning and drying to obtain the hemodialyzer with stable and excellent anticoagulation performance;

the Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane filaments with high anticoagulation performance prepared in the example is up to 350 seconds, and the Thrombin Time (TT) is 24 seconds as tested by a coagulation test.

Example 5

Step (1): dissolving 0.15g of azobisisoheptonitrile into 200g of ethyl acetate solution, introducing the solution into a hemodialyzer (packaged polyether sulfone membrane) purchased in the market at 50 ℃, standing for 5 hours, and drying to uniformly disperse the azobisisoheptonitrile in the hemodialysis membrane;

step (2): in a protective atmosphere, introducing 8g of sodium alginate, 0.15g of potassium persulfate and 6g N-hydroxyethyl acrylamide aqueous solution (200g of deionized water is used as a solvent) into a hemodialyzer, reacting for 12 hours at 70 ℃, and cleaning and drying after one-step polymerization to obtain the hemodialyzer with stable and excellent anticoagulation performance;

the Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane filaments with high anticoagulation performance prepared in the example is up to 342 seconds, and the Thrombin Time (TT) is 24 seconds as tested by a coagulation test.

In addition, the inventor also utilizes other raw materials listed above and other process conditions to replace various raw materials and corresponding process conditions in examples 1-5 to carry out corresponding experiments, and the obtained modified hemodialyzer has the anticoagulation performance and excellent hemocompatibility, and is basically similar to the products of examples 1-5.

Comparative example 2

step (2): introducing 6g of sodium alginate, 0.2g of azobisisobutyrimidazoline hydrochloride and 1g of N-hydroxyethyl acrylamide aqueous solution into a hemodialyzer in a protective atmosphere, reacting for 12 hours at 70 ℃, and cleaning and drying after one-step polymerization to obtain the hemodialyzer with stable and excellent anticoagulation performance;

the Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane filaments with high anticoagulation performance prepared in comparative example 2 was only 80 seconds and the Thrombin Time (TT) was 18 seconds, as tested by the coagulation test. The addition amount of the N-hydroxyethyl acrylamide is insufficient, and the sodium alginate and the matrix film do not form a stable network interpenetrating structure, so that the anticoagulation effect is poor.

The invention adopts a free radical polymerization method, sodium alginate and a hemodialysis membrane matrix form an interpenetrating network stable structure through the bridge action of vinyl monomers, the sodium alginate is uniformly distributed on the surface and in the pores of the hemodialysis membrane, the hydrophilicity is greatly improved, and the adhesion of blood cells and blood platelets on the surface of the membrane is reduced, so that the occurrence of blood coagulation is greatly reduced; in addition, because the diameter of the membrane wire of the dialyzer is usually only 1mm, the modification difficulty of the inside of the pores of the dialysis membrane is very high outside the hemodialyzer, substances such as an initiator 1, sodium alginate, an initiator 2, a vinyl monomer and the like are directly introduced into the hemodialyzer for modification, the modified substances can smoothly enter the hemodialysis membrane by utilizing the characteristics of the hemodialyzer, and the inner surface of the hemodialysis membrane is slightly swollen (slightly swollen means that a solution has a solvation effect on molecular chain segments or groups on the surface of the membrane, so that holes among the chain segments are enlarged and movement is easy to occur, and the chain segments move under the interaction of the solution and the membrane material, but are limited by the influences of factors such as the solution concentration, the solvent type, the temperature and the movement resistance of the chain segments on the surface of the membrane which are far smaller than the movement resistance of the chain segments inside the membrane, so that the swelling, facilitates modification of the membrane) and is uniformly distributed on the membrane surface (including the inner surfaces of pores), so that the modification operability is improved. As shown in figures 1 and 2, the modified membrane structure is basically unchanged, the original pore structures on the inner and outer surfaces of the membrane filaments are not affected, and the dialysis performance of the dialyzer is not reduced. Because of the increased hydrophilicity, the ultrafiltration coefficient of the membrane is increased, and thus the removal rate of harmful components in blood is increased; in addition, the anticoagulation modification method of the hemodialyzer provided by the invention does not use toxic solvents in the whole modification process, is green and pollution-free, and has simple subsequent cleaning, drying and post-treatment; the stable anti-coagulation structure can be obtained through one-step polymerization reaction, and the method has the advantages of simple process steps, easy operation and easy industrial production.

Materials, reagents and experimental equipment related to the embodiments of the present invention are commercially available products conforming to the field of separation membrane preparation unless otherwise specified.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, modifications and decorations can be made without departing from the core technology of the present invention, and these modifications and decorations shall also fall within the protection scope of the present invention. Any changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

1. the anticoagulation modification method of hemodialyzer, is characterized in that, step comprises:

(1) Pass the initiator 1 solution into the hemodialyzer at 30-80°C, stay for 2-10 hours, and then dry, so that the initiator 1 is evenly dispersed in the hemodialysis membrane;

(2) in a protective atmosphere, pass the aqueous solution of sodium alginate, initiator 2 and vinyl monomer into the hemodialyzer treated in step (1), and react at 50-100°C for 4-24h;

(3) The modified hemodialyzer is obtained by washing and drying after one-step polymerization.

2 . The anticoagulation modification method of hemodialyzer according to claim 1 , wherein the initiator 1 comprises azobisisobutyronitrile, azobisisoheptanenitrile, and dibenzoyl peroxide. 3 . any one or a combination of two or more.

3. the anticoagulation modification method of hemodialyzer as claimed in claim 1 is characterized in that, the solvent of described initiator 1 solution is any one or two or more in methanol, ethanol, ether, ethyl acetate The combination.

4. The anticoagulation modification method of a hemodialyzer according to claim 1, wherein the initiator 2 is a water-soluble initiator.

5. The anticoagulation modification method of hemodialyzer according to claim 1, wherein the initiator 2 comprises azobisisobutyramidine hydrochloride, azobisisobutylimidazoline hydrochloride, Any one or a combination of two or more of azodicyanovaleric acid, azodiisopropylimidazoline, and potassium persulfate.

6 . The anticoagulation modification method of a hemodialyzer according to claim 1 , wherein the vinyl monomer is a water-soluble vinyl monomer. 7 .

7. The anticoagulation modification method of hemodialyzer according to claim 1, wherein the vinyl monomer comprises N-methylol acrylamide, N-hydroxyethyl acrylamide, acrylic acid, methyl methacrylate Any one or a combination of two or more of acrylic acid, phenylacrylic acid and sorbic acid.

8. the anticoagulation modification method of hemodialyzer as claimed in claim 1 is characterized in that, the combination of initiator 1 of described step (1), vinyl monomer of step (2), sodium alginate The mass ratio is 0.01-0.03:1; in step (2), the mass ratio of the combination of initiator 2, vinyl monomer and sodium alginate is 0.01-0.03:1.

9 . The anticoagulation modification method of hemodialyzer according to claim 1 , wherein in the step (2), the mass ratio of vinyl monomer to sodium alginate is 0.2-1.5:1, and the aqueous solution The mass ratio of the combination of reclaimed water, vinyl monomer and sodium alginate is 100:3-15.

10. The anticoagulation modification method of a hemodialyzer according to claim 1, wherein the protective atmosphere comprises a nitrogen atmosphere and/or an inert gas atmosphere.