CN109675134B - Anticoagulation modification method of hemodialyzer and application thereof - Google Patents
Anticoagulation modification method of hemodialyzer and application thereof Download PDFInfo
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Abstract
The invention discloses an anticoagulation modification method of a hemodialyzer and application thereof. The anticoagulation modification method of the hemodialyzer comprises the following steps: in protective atmosphere, polymerizing and crosslinking a uniformly mixed reaction system containing an olefinic acid monomer, a sodium sulfonate monomer, a crosslinking agent monomer, an initiator and water to obtain an active heparinoid aqueous solution; contacting the inner surface of the membrane filaments of the hemodialyzer with the active heparan aqueous solution, followed by separation; and heating the hemodialyzer under an acidic condition, and obtaining the hemodialyzer with high anticoagulation performance through self-polymerization crosslinking. The hemodialyzer prepared by the invention has excellent blood compatibility and high anticoagulation performance, the anticoagulation modification technology is based on a water-based system in the whole process, only necessary heparinoid and water are introduced in the whole modification process, and the subsequent post-treatment such as cleaning of membrane wires is very simple; meanwhile, the method has simple process steps, is easy to operate and realize, and is easy for industrial production and popularization.
Description
Technical Field
The invention belongs to the field of blood purification, and particularly relates to an anticoagulation modification method of a hemodialyzer and application thereof in blood purification.
Background
Acute or chronic renal insufficiency develops to a severe stage, and a series of autotoxicosis symptoms of the body are called uremia due to endocrine dysfunction caused by metabolite accumulation and water, electrolyte and acid-base balance disorder. The nitrogen-containing metabolites and other toxic substances are not excreted and accumulated in the body of a patient due to uremia, resulting in pathological changes of various organs and systems. For patients with renal failure, kidney source is a difficult problem in kidney transplantation, and it takes a week to find a suitable kidney source. In this case, hemodialysis techniques are critical to the maintenance of the life of patients with renal disease. Hemodialysis, one of the renal replacement therapies for patients with renal failure, drains body blood to the outside of the body, removes excess water and toxins from the blood through a dialyzer, and returns 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 membranes which are widely used in clinical applications include polysulfone membrane PS (fersenus, beran, dongli, belck, weigao), polyethersulfone membrane PES (pely, nepalo, belck), polymethylmethacrylate PMMA (dongli), polyamide membrane PA (jinbao), ethylene vinyl alcohol copolymer EVAL (chu cheng, xu dynasty kf series). However, such polymer membranes tend to be hydrophobic, and the membranes adsorb proteins in the 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.
In recent years, with the intensive research on the anticoagulant mechanism of heparin, it is found that the anticoagulant function of heparin benefits from the existence of two functional groups, namely a carboxylic acid group and a sulfonic acid group. Studies have shown that macromolecules containing carboxylic or sulfonic acid groups have an anticoagulant function and that such macromolecules are called heparinoids. However, it has been reported how to achieve stable loading of heparinoids on the inner surface of hemodialysis membranes, especially for anticoagulation modification of packaged hemodialyzers. In addition, in other modification technology systems based on organic solvents, the organic solvents are very difficult to remove in the subsequent cleaning process, and the residue of the organic solvents has a great potential safety hazard to patients in the dialysis process.
Disclosure of Invention
The invention mainly aims to provide an anticoagulation modification method of a hemodialyzer, thereby overcoming the defects of the prior art.
Another object of the present invention is to provide the use of said method for the anticoagulation modification of a hemodialyzer in the field of blood purification.
In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:
the embodiment of the invention provides an anticoagulation modification method of a hemodialyzer, which comprises the following steps:
in a protective atmosphere, carrying out polymerization crosslinking reaction on a uniformly mixed reaction system containing an olefinic acid monomer, a sodium sulfonate monomer, a crosslinking agent monomer, an initiator and water at 50-100 ℃ for 4-24 h to obtain an active heparan aqueous solution;
contacting the inner surface of the membrane filaments of the hemodialyzer with the active heparan aqueous solution, followed by separation; and
and (3) placing the hemodialyzer in an acidic condition, heating for 6-24 hours at 45-80 ℃, and carrying out self-polymerization crosslinking to obtain the hemodialyzer with high anticoagulation performance.
In some embodiments, the anticoagulation modification method specifically comprises: adding an acrylic monomer, a sodium sulfonate monomer and a cross-linking agent monomer into deionized water, and stirring for more than 30min in a protective atmosphere;
and then adding an initiator, stirring while maintaining a protective atmosphere, and heating to 50-100 ℃ to react for 4-24 hours to obtain an active heparinoid aqueous solution.
In some embodiments, the membrane silk material of the hemodialyzer comprises any one or a combination of two or more of polysulfone membrane, polyethersulfone membrane, polymethyl methacrylate, polyamide membrane and vinyl alcohol copolymer membrane.
The embodiment of the invention also provides the application of the hemodialyzer with high anticoagulation performance obtained by the method in the field of blood purification.
Compared with the prior art, the invention has the beneficial effects that:
1) the anticoagulation modification method of the hemodialyzer provided by the invention realizes the stable immobilization of the active heparinoid polymer on the inner surface of the membrane wire of the hemodialyzer by synthesizing the active heparinoid polymer containing heparin functional groups (sulfonic groups and carboxyl groups), adsorbing the active heparinoid polymer on the inner surface of the membrane wire of the hemodialyzer and self-polymerization crosslinking under the acidic water condition, thereby endowing the hemodialyzer with extremely strong anticoagulation characteristics, and the prepared hemodialyzer has excellent blood compatibility and high anticoagulation performance;
2) the invention adopts a water-based system, and in the whole modification process, the poor swelling of the inner and outer surfaces of the membrane wire of the hemodialyzer can be avoided, the original gap structure of the inner and outer surfaces of the membrane wire can not be influenced, and the ultrafiltration coefficient and the dialysis performance of the membrane wire can not be influenced;
3) the whole process of the anticoagulation modification technology provided by the invention is based on a water-based system, only necessary heparinoid and water are introduced in the whole modification process, and the subsequent post-treatment such as cleaning of membrane wires is very simple;
4) the method for anticoagulation modification of the hemodialyzer has simple process steps, is easy to operate and implement, and is easy for industrial production and popularization.
Drawings
FIG. 1 is an SEM photograph of the inner surface of the membrane filaments of the hemodialyzer described in comparative example 1.
FIG. 2 is an SEM photograph of the inner surface of the membrane wire of the high anticoagulation hemodialyzer prepared in example 1 of the present invention.
FIG. 3 is an SEM photograph of the inner surface of the membrane filaments of the hemodialyzer after the platelet adhesion experiment as described in comparative example 1.
FIG. 4 is an SEM photograph of the inner surface of the membrane filaments of the highly anticoagulated hemodialyzer prepared in example 1 of the present invention after the platelet adhesion experiment.
FIG. 5 is a schematic comparison of the ultrafiltration coefficients of the highly anticoagulated hemodialyzer membrane filaments prepared in example 1 of the present invention and those of comparative example 1.
FIG. 6 is a schematic diagram comparing the Activated Partial Thromboplastin Time (APTT) of the highly anticoagulated hemodialyzer membrane filaments prepared in example 1 of the present invention and the hemodialyzer membrane filaments described in comparative example 1.
FIG. 7 is a schematic diagram showing the comparison of Thrombin Time (TT) between the highly anticoagulated hemodialyzer membrane filaments prepared in example 1 of the present invention and the hemodialyzer membrane filaments described in comparative example 1.
FIG. 8 is a schematic diagram comparing the Prothrombin Time (PT) of the highly anticoagulated hemodialyzer membrane filaments prepared in example 1 of the present invention and the hemodialyzer membrane filaments described in comparative example 1.
Fig. 9 is a schematic comparison of fibrinogen content (FIB) of the highly anticoagulated hemodialyzer membrane filaments prepared in example 1 of the present invention and the hemodialyzer membrane filaments described in comparative example 1.
Detailed Description
As described above, in view of the deficiencies of the prior art, the present inventors have conducted extensive studies and extensive practices, and as a result, the present invention provides a surface modification method for improving hemocompatibility of dialyzers to achieve high anticoagulation characteristics of hemodialyzers, which is mainly based on a water-based system, and provides excellent hemocompatibility to dialyzers by synthesizing an active heparinoid polymer containing heparin functional groups (sulfonic acid group and carboxyl group) and stably immobilizing the active heparinoid polymer on the inner surfaces of membrane filaments of dialyzers through self-polymerization crosslinking. The technical solution, its implementation and principles, etc. will be further explained as follows.
One aspect of the embodiments of the present invention provides a method for anticoagulation modification of a hemodialyzer, which comprises:
in a protective atmosphere, carrying out polymerization crosslinking reaction on a uniformly mixed reaction system containing an olefinic acid monomer, a sodium sulfonate monomer, a crosslinking agent monomer, an initiator and water at 50-100 ℃ for 4-24 h to obtain an active heparan aqueous solution;
contacting the inner surface of the membrane filaments of the hemodialyzer with the active heparan aqueous solution, followed by separation; and
and (3) placing the hemodialyzer in an acidic condition, heating for 6-24 hours at 45-80 ℃, and carrying out self-polymerization crosslinking to obtain the hemodialyzer with high anticoagulation performance.
In some embodiments, the anticoagulation modification method specifically comprises: adding an acrylic monomer, a sodium sulfonate monomer and a cross-linking agent monomer into deionized water, and stirring for more than 30min in a protective atmosphere;
and then adding an initiator, stirring while maintaining a protective atmosphere, and heating to 50-100 ℃ to react for 4-24 hours to obtain an active heparinoid aqueous solution.
As a more preferable embodiment of the invention, the method for synthesizing the active heparinoid aqueous solution comprises the following steps:
(1) adding quantitative olefine acid monomer, sodium sulfonate monomer and cross-linking agent monomer into 100 parts by mass of deionized water, and stirring for no less than 30min in nitrogen or argon atmosphere to remove oxygen in the reaction solution;
(2) adding a certain amount of initiator, keeping the nitrogen or argon atmosphere for stirring, heating to 50-100 ℃, and reacting for 4-24 hours to obtain the active heparinoid aqueous solution.
Further, in step (1), the olefinic monomer includes, but is not limited to, one or more of acrylic acid, methacrylic acid, phenylacrylic acid, sorbic acid, and the like.
Further, the sodium sulfonate monomer includes, but is not limited to, one or more of sodium p-styrene sulfonate, sodium propylene sulfonate, sodium vinyl sulfonate, and the like.
Further, the cross-linking agent monomer includes but is not limited to one or a mixture of two of N-methylol acrylamide, N-hydroxyethyl acrylamide and the like.
Further, the mass ratio of the olefinic acid monomer to the sodium sulfonate monomer is (0.3: 0.7) - (0.6: 0.4).
Further, the mass ratio of the cross-linking agent monomer to the combination of the olefine acid monomer and the sodium sulfonate monomer is 0.3-1.5: 1.
further, the mass ratio of the deionized water to the combination of the olefine acid monomer, the sodium sulfonate monomer and the cross-linking agent monomer is 100: 3-12, namely, the total amount of the acrylic acid monomer, the sodium sulfonate monomer and the cross-linking agent monomer added in every 100 parts by mass of the deionized water is 3-12 parts by mass.
Further, the protective atmosphere includes, but is not limited to, a nitrogen atmosphere, an inert gas atmosphere such as argon, and the like.
Further, the protective atmosphere is used for removing dissolved oxygen in the reaction system before the reaction is started, the preferred stirring time is 30 min-1 h, the stirring speed is 200-500 r/min, and longer stirring time and higher stirring speed are effective, but the production efficiency and energy consumption are not high.
Further, in step (2), the initiator is a water-soluble initiator including, but not limited to, one or more of azobisisobutyramidine hydrochloride, azobisisobutyrimidazoline hydrochloride, azobiscyanovaleric acid, azobisisopropylimidazoline, and the like.
Further, the mass ratio of the initiator to the combination of the olefine acid monomer, the sodium sulfonate monomer and the cross-linking agent monomer is 0.01-0.03: 1, namely, the mass usage amount of the initiator is 0.01-0.03 time of the total amount of the olefine acid monomer, the sodium sulfonate monomer and the cross-linking agent monomer.
As a more specific embodiment, the anticoagulation modification method of the hemodialyzer comprises the following steps:
s1: synthesizing an active heparinoid aqueous solution;
s2: injecting the synthesized active heparinoid water solution into a hemodialyzer to completely wet the inner surface of a membrane wire of the hemodialyzer for 0.5-4 h;
s3, discharging the active heparinoid aqueous solution out of the hemodialyzer, injecting acidic deionized water with the pH value of 0-4, heating at 45-80 ℃ for 6-24 h, discharging the acidic deionized water, injecting deionized water, cleaning, and performing vacuum drying to obtain the hemodialyzer with high anticoagulation performance.
In some embodiments, in step S2, in order to better complete the initial adsorption of the active heparinoid substance on the inner surface of the membrane wire of the hemodialyzer, the retention time of the active heparinoid aqueous solution after being injected into the hemodialyzer is preferably 0.8-2.8 h. Shorter or longer residence times are of course also possible. But the shorter retention time may cause that the adsorption amount of the inner surface of the hemodialyzer to the active heparinoid substance is less, and the anticoagulation effect of the hemodialyzer is discounted; the longer residence time can further improve the anticoagulation effect of the hemodialyzer, but the hemodialyzer is generally a disposable product for clinical application, and the anticoagulation effect of the hemodialyzer prepared by the preferred recommended residence time is sufficient, and the timeliness of the production process is also suitable.
In some embodiments, in step S3, in order to better achieve stable immobilization of the active heparinoid substance on the inner surface of the membrane wire of the hemodialyzer, the preferred pH value of the acidic deionized water is 0 to 3, the preferred temperature of the deionized water (i.e., the temperature of the water bath) is 50 to 70 ℃, and the preferred residence time of the deionized water (i.e., the time of the water bath reaction) is 10 to 18 hours. Of course, when selecting the acidic deionized water with higher pH value, the temperature of the high deionized water is increased and the retention time is prolonged, and the stable immobilization of the active heparinoid substance on the inner surface of the hemodialysis membrane can also be realized.
In some embodiments, the membrane silk material of the hemodialyzer includes, but is not limited to, any one or a combination of two or more of polysulfone membrane, polyethersulfone membrane, polymethylmethacrylate, polyamide membrane, vinyl alcohol copolymer membrane, and the like. The membrane filaments of the hemodialyzer are generally hollow fiber membranes with a gradient void structure, wherein the inner wall of the hollow fiber membranes presents smaller pore size distribution, and the outer wall of the hollow fiber membranes presents larger pore size distribution.
The anticoagulation modification method provided by the invention is mainly characterized in that the synthesized active heparinoid substance is fixed on the inner surface of a membrane wire of a hemodialyzer in a self-crosslinking mode. The technology does not basically affect the inner and outer membrane filaments of the dialyzer and the gradient gap structure. Therefore, the hemodialyzer has good applicability to various hemodialyzers commonly available in the market at present.
Another aspect of the embodiments of the present invention also provides a hemodialyzer having high anticoagulation property prepared by the foregoing method.
Another aspect of the embodiments of the present invention also provides the use of a hemodialyzer with high anticoagulation property obtained by the aforementioned method in the field of blood purification.
In conclusion, the invention refers to the mechanism of heparin anticoagulation, and realizes the stable immobilization of the active heparinoid polymer on the inner surface of the membrane wire of the hemodialyzer by synthesizing the active heparinoid polymer containing heparin functional groups (sulfonic groups and carboxyl groups), adsorbing the active heparinoid polymer on the inner surface of the membrane wire of the hemodialyzer and self-polymerization crosslinking under the acidic water condition, thereby endowing the hemodialyzer with extremely strong anticoagulation characteristic, and the prepared hemodialyzer has excellent hemocompatibility and high anticoagulation performance. Meanwhile, the invention adopts a water-based system, and can not cause poor swelling on the inner and outer surfaces of the membrane wire of the hemodialyzer, influence the original gap structure of the inner and outer surfaces of the membrane wire and influence the ultrafiltration coefficient and the dialysis performance of the membrane wire in the whole modification process. Furthermore, the invention adopts a water-based system, only necessary heparinoid and water are introduced in the whole modification process, and the subsequent post-treatment such as cleaning of the membrane silk is very simple. Moreover, the anticoagulation modification method of the hemodialyzer has simple process steps, is easy to operate and realize, and is easy for industrial production and popularization.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the embodiments of the present invention is provided in conjunction with the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention, and that experimental conditions and set parameters therein are not to be considered as limitations of the basic embodiments of the invention. And the scope of the present invention is not limited to the following examples. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
To better illustrate the anticoagulation modification method of hemodialyzer and the high anticoagulation property of hemodialyzer prepared by modification, a commercially available hemodialyzer product (encapsulating polysulfone membrane) was selected as comparative example 1.
Example 1
Adding 200g of deionized water into a three-neck flask, then adding 6g of acrylic acid, 8g of sodium p-styrene sulfonate and 10g of N-hydroxymethyl acrylamide, and stirring for 40min at 250 revolutions per minute under a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 0.4g of azodiisobutyl amidine hydrochloride into the mixture obtained in the step (2), keeping the nitrogen atmosphere for stirring, heating to 80 ℃, and reacting for 10 hours to obtain an active heparinoid aqueous solution;
step (3) injecting the commercially available hemodialyzer product (packaging polysulfone membrane, namely the product in the comparative example 1) into a deionization washing machine for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into the hemodialyzer, and staying for 1.5 hours to completely wet the inner surface of the membrane filaments of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of a hemodialyzer, then injecting acid deionized water with the pH value of 2 at 60 ℃, standing for 18 hours at constant temperature, then discharging the acid deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
And respectively taking out the membrane filaments of the hemodialyzer in the comparative example 1 and the highly anticoagulated hemodialyzer obtained in the embodiment, and observing the inner surface micro-topography structure of the membrane filaments by a scanning electron microscope. As can be seen from fig. 1 and fig. 2, the micro-void structure and distribution of the inner surface of the membrane filament of the hemodialyzer with high anticoagulation degree obtained in this example are very similar to those of the inner surface of the membrane filament of the hemodialyzer described in comparative example 1, which indicates that the micro-structure of the inner surface of the membrane filament encapsulated in the hemodialyzer is substantially maintained after modification by the anticoagulation modification technique described in this invention.
The membrane filaments of the hemodialyzer in comparative example 1 and the highly anticoagulated hemodialyzer obtained in this example were taken out, respectively, subjected to a platelet adhesion test, and the platelet adhesion on the inner surface of the membrane filaments was observed under a microscope. As can be seen from fig. 3 and fig. 4, the membrane filaments of the highly anticoagulated hemodialyzer obtained in the present example have very little platelet adhesion on the inner surface when observed under a microscopic electron microscope after being soaked in a platelet solution; the membrane filaments of the hemodialyzer of comparative example 1, on the other hand, were observed under a microscopic electron microscope, and had severe poor platelet adhesion on the inner surface. This shows that the hemocompatibility of the inner surface of the membrane filaments encapsulated by the hemodialyzer is significantly improved after the modification by the anticoagulation modification technology.
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 test and coagulation test. As can be seen from fig. 5, the ultrafiltration coefficient of the membrane filaments of the hemodialyzer with high anticoagulation property obtained in this example is very close to that of the membrane filaments of the hemodialyzer described in comparative example 1, which indicates that the water flux of the membrane filaments packaged in the hemodialyzer is substantially maintained after modification by the anticoagulation modification technique described in the present invention. As can be seen in fig. 6, the Activated Partial Thromboplastin Time (APTT) of the highly anticoagulated hemodialyzer membrane filaments prepared in this example was more than 600 seconds, whereas the APTT time of the hemodialyzer membrane filaments described in comparative example 1 was less than 50 seconds; as can be seen in fig. 7, 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 described in comparative example 1 was only 15 seconds; as can be seen in FIG. 8, the Prothrombin Time (PT) of the highly anticoagulated hemodialyzer membrane filaments prepared in this example was 33 seconds, whereas the PT time of the hemodialyzer membrane filaments described in comparative example 1 was only 14 seconds; as can be seen in FIG. 9, the fibrinogen content (FIB) of the high anticoagulation hemodialyzer membrane filaments prepared in this example was 139mg/dL, while the FIB content of the hemodialyzer membrane filaments described in comparative example 1 was 187 mg/dL.
Example 2
Adding 200g of deionized water into a three-neck flask, then adding 2g of methacrylic acid, 2g of sodium propylene sulfonate and 2g of N-hydroxyethyl acrylamide, and stirring for 30min at 200 revolutions per minute under an argon atmosphere to remove argon in a reaction solution;
adding 0.07g of azobisisobutyric imidazoline hydrochloride into the step (2), keeping argon atmosphere, stirring, heating to 100 ℃, and reacting for 4 hours to obtain an active heparinoid aqueous solution;
step (3) injecting a commercially purchased hemodialyzer product (packaging polyether sulfone membrane) into a deionized water tank for washing for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into a dialyzer, and staying for 0.5 hour to completely wet the inner surface of a membrane wire of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of a hemodialyzer, then injecting acid deionized water with the pH value of 0 at 45 ℃, standing for 6 hours at constant temperature, then discharging the acid deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
The Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane silk with high anticoagulation performance prepared in the embodiment is up to 230 seconds, the Thrombin Time (TT) is 21 seconds, the Prothrombin Time (PT) is 23 seconds, and the fibrinogen content (FIB) is 153mg/dL through a coagulation test.
Example 3
Adding 200g of deionized water into a three-neck flask, then adding 2g of phenylacrylic acid, 2g of sorbic acid, 6g of sodium vinyl sulfonate and 3g of N-hydroxymethyl acrylamide, and stirring for 35min at 300 revolutions per minute under a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 0.35g of azodiisopropyl imidazoline into the step (2), keeping nitrogen atmosphere and stirring, heating to 50 ℃, and reacting for 24 hours to obtain an active heparinoid aqueous solution;
step (3) injecting the commercially available hemodialyzer product (packaging polymethyl methacrylate membrane) into a deionized water for washing for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into the hemodialyzer, and staying for 4 hours to completely wet the inner surface of a membrane wire of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of a hemodialyzer, then injecting acid deionized water with the pH value of 1 at 70 ℃, standing for 24 hours at constant temperature, then discharging the acid deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
The Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane silk with high anticoagulation performance prepared in the embodiment is up to 490 seconds, the Thrombin Time (TT) is 25 seconds, the Prothrombin Time (PT) is 28 seconds, and the fibrinogen content (FIB) is 143mg/dL through a coagulation test.
Example 4
Adding 200g of deionized water into a three-neck flask, then adding 7g of acrylic acid, 2g of sodium vinyl sulfonate, 3g of sodium p-styrene sulfonate and 10g of N-hydroxymethyl acrylamide, and stirring for 45min at 350 r/min under an argon atmosphere to remove oxygen in a reaction solution;
adding 0.4g of azodiisobutyl amidine hydrochloride and 0.2g of azodicyano valeric acid into the step (2), keeping the argon atmosphere for stirring, heating to 75 ℃, and reacting for 16 hours to obtain an active heparinoid aqueous solution;
step (3) injecting a commercially available hemodialyzer product (packaging polyamide membrane) into a deionized water for washing for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into a dialyzer, and staying for 3 hours to completely wet the inner surface of a membrane wire of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of a hemodialyzer, then injecting acid deionized water with the pH value of 3 at 70 ℃, standing for 15 hours at constant temperature, then discharging the acid deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
The Activated Partial Thromboplastin Time (APTT) of the hemodialyzer membrane silk with high anticoagulation performance prepared in the embodiment is up to 430 seconds, the Thrombin Time (TT) is 24 seconds, the Prothrombin Time (PT) is 27 seconds, and the fibrinogen content (FIB) is 147mg/dL through a coagulation test.
Example 5
Adding 200g of deionized water into a three-neck flask, then adding 4g of acrylic acid, 6g of sodium p-styrene sulfonate, 4g of N-hydroxymethyl acrylamide and 4g of N-hydroxyethyl acrylamide, and stirring for 50min at 500 revolutions per minute under a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 0.35g of azodiisobutyl amidine hydrochloride into the mixture obtained in the step (2), keeping the nitrogen atmosphere for stirring, heating to 65 ℃, and reacting for 12 hours to obtain an active heparinoid aqueous solution;
step (3) injecting the commercially available hemodialyzer product (packaging polyvinyl alcohol copolymer membrane) into a deionization washing machine for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into a dialyzer, and staying for 1 hour to completely wet the inner surface of the membrane wire of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of the hemodialyzer, then injecting acidic deionized water with the pH value of 2.5 at 55 ℃, standing for 14 hours at constant temperature, then discharging the acidic deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
The Activated Partial Thromboplastin Time (APTT) of the high anticoagulation hemodialyzer membrane filament prepared in the example is as high as 465 seconds, the Thrombin Time (TT) is 25 seconds, the Prothrombin Time (PT) is 28 seconds, and the fibrinogen content (FIB) is 141mg/dL through a coagulation test.
Example 6
Adding 200g of deionized water into a three-neck flask, then adding 3g of sorbic acid, 7g of sodium vinyl sulfonate and 15g of N-hydroxymethyl acrylamide, and stirring for 60min at 200 revolutions per minute under a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 0.11g of azodiisobutyl amidine hydrochloride into the mixture obtained in the step (2), keeping the mixture in a nitrogen atmosphere, stirring, heating to 70 ℃, and reacting for 12 hours to obtain an active heparinoid aqueous solution;
step (3) injecting the commercially available hemodialyzer product (packaging polyvinyl alcohol copolymer membrane) into a deionization washing machine for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into a dialyzer, and staying for 0.8h to completely wet the inner surface of the membrane wire of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of a hemodialyzer, then injecting acidic deionized water with the pH value of 4 at 50 ℃, standing for 10 hours at constant temperature, then discharging the acidic deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
The Activated Partial Thromboplastin Time (APTT) of the high anticoagulation hemodialyzer membrane filament prepared in the example is up to 468 seconds, the Thrombin Time (TT) is 28 seconds, the Prothrombin Time (PT) is 29 seconds, and the fibrinogen content (FIB) is 145mg/dL as tested by a coagulation test.
Example 7
Adding 100g of deionized water into a three-neck flask, then adding 6g of phenylacrylic acid, 4g of sodium vinylsulfonate and 5g of N-hydroxyethyl acrylamide, and stirring for 45min at 400 r/min in a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 0.45g of azodiisopropyl imidazoline into the step (2), keeping nitrogen atmosphere and stirring, heating to 90 ℃, and reacting for 8 hours to obtain an active heparinoid aqueous solution;
step (3) injecting the commercially available hemodialyzer product (packaging polyamide membrane) into a deionization washing machine for 5 minutes, then injecting the active heparan aqueous solution synthesized in the step (2) into a dialyzer, and staying for 2.8 hours to completely wet the inner surface of a membrane wire of the hemodialyzer;
and (4) discharging the active heparinoid aqueous solution out of the hemodialyzer, then injecting acid deionized water with the pH value of 3.5 at the temperature of 80 ℃, standing for 6 hours at constant temperature, then discharging the acid deionized water, injecting deionized water, cleaning for 5 minutes, and then drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
The Activated Partial Thromboplastin Time (APTT) of the high anticoagulation hemodialyzer membrane silk prepared in the example is up to 492 seconds, the Thrombin Time (TT) is 27 seconds, the Prothrombin Time (PT) is 31 seconds, and the fibrinogen content (FIB) is 146mg/dL through a coagulation test.
In addition, the inventor also carries out corresponding experiments by using other raw materials listed above and other process conditions and the like to replace various raw materials and corresponding process conditions in the examples 1 to 7, and the obtained modified hemodialyzer has the anticoagulation performance and excellent hemocompatibility and is basically similar to the products of the examples 1 to 7.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (17)
1. A method for anticoagulation modification of a hemodialyzer is characterized by comprising:
in a protective atmosphere, carrying out polymerization crosslinking reaction on a uniformly mixed reaction system containing an olefinic acid monomer, a sodium sulfonate monomer, a crosslinking agent monomer, an initiator and water at 50-100 ℃ for 4-24 h to obtain an active heparan aqueous solution, wherein the crosslinking agent monomer is selected from N-hydroxymethyl acrylamide and/or N-hydroxyethyl acrylamide, the mass ratio of the olefinic acid monomer to the sodium sulfonate monomer is (0.3: 0.7) - (0.6: 0.4), and the mass ratio of the crosslinking agent monomer to a combination of the olefinic acid monomer and the sodium sulfonate monomer is 0.3-1.5: 1;
injecting the active heparinoid aqueous solution into a hemodialyzer, completely wetting the inner surface of the membrane wire of the hemodialyzer by the active heparinoid aqueous solution, keeping for 0.5-4 h, adsorbing the active heparinoid on the inner surface of the membrane wire of the hemodialyzer, and then separating; and
and (2) placing the hemodialyzer in an acidic condition with the pH value of 1-4, heating for 6-24 h at 45-80 ℃, and carrying out self-polymerization crosslinking to stably fix the active heparinoid polymer obtained by self-polymerization crosslinking on the inner surface of the membrane wire of the hemodialyzer so as to obtain the hemodialyzer with high anticoagulation performance.
2. The method of claim 1, wherein the method specifically comprises: adding an acrylic monomer, a sodium sulfonate monomer and a cross-linking agent monomer into deionized water, and stirring for more than 30min in a protective atmosphere;
and then adding an initiator, stirring while maintaining a protective atmosphere, and heating to 50-100 ℃ to react for 4-24 hours to obtain an active heparinoid aqueous solution.
3. The method of claim 1 or 2, wherein: the olefine acid monomer is selected from any one or combination of more than two of acrylic acid, methacrylic acid, phenylacrylic acid and sorbic acid.
4. The method of claim 1 or 2, wherein: the sodium sulfonate monomer is selected from one or the combination of more than two of sodium p-styrene sulfonate, sodium propylene sulfonate and sodium vinyl sulfonate.
5. The method of claim 1 or 2, wherein: the mass ratio of the initiator to the combination of the olefine acid monomer, the sodium sulfonate monomer and the cross-linking agent monomer is 0.01-0.03: 1.
6. the method of claim 1 or 2, wherein: the initiator is selected from water-soluble initiators.
7. The method of claim 6, wherein: the initiator is selected from any one or the combination of more than two of azodiisobutyl amidine hydrochloride, azodiisobutyl imidazoline hydrochloride, azodicyano valeric acid and azodiisopropyl imidazoline.
8. The method of claim 2, wherein: the mass ratio of the deionized water to the combination of the olefine acid monomer, the sodium sulfonate monomer and the cross-linking agent monomer is 100: 3 to 12.
9. The method of claim 1 or 2, wherein: the protective atmosphere is selected from inert gas atmospheres.
10. The method of claim 2, wherein: the stirring time is 30 min-1 h, and the stirring speed is 200-500 r/min.
11. The method of claim 1, wherein the method specifically comprises: and injecting the active heparinoid aqueous solution into a hemodialyzer, so that the active heparinoid aqueous solution completely wets the inner surface of the membrane wire of the hemodialyzer and keeps for 0.8-2.8 h, and the active heparinoid is adsorbed on the inner surface of the membrane wire of the hemodialyzer.
12. The method of claim 11, which comprises: discharging the active heparinoid aqueous solution out of the wetted hemodialyzer, injecting an acidic aqueous solution with the pH value of 1-4 into the hemodialyzer, heating to 45-80 ℃ to perform a water bath reaction for 6-24 hours, stably immobilizing the active heparinoid polymer obtained by self-polymerization on the inner surface of the membrane wire of the hemodialyzer, discharging the acidic aqueous solution, and finally cleaning and drying.
13. The method of claim 12, wherein: the temperature of the water bath reaction is 50-70 ℃.
14. The method of claim 12, wherein: the water bath reaction time is 10-18 h.
15. The method of claim 12, wherein: the pH value of the water bath reaction is 1-3.
16. The method of claim 1, wherein: the membrane silk material of the hemodialyzer is selected from one or the combination of more than two of polysulfone membrane, polyethersulfone membrane, polymethyl methacrylate, polyamide membrane and vinyl alcohol copolymer membrane.
17. Use of a hemodialyzer with high anticoagulation properties obtained by the process according to any one of claims 1 to 16 in the field of blood purification.
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