CN111330090B - Surface anticoagulation modification method of hemodialyzer and application thereof - Google Patents
Surface anticoagulation modification method of hemodialyzer and application thereof Download PDFInfo
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1621—Constructional aspects thereof
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- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/12—Esters of monohydric alcohols or phenols
- C08F220/16—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms
- C08F220/18—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms with acrylic or methacrylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0413—Blood
Abstract
The invention discloses a surface anticoagulation modification method of a hemodialyzer and application thereof. The surface anticoagulation modification method comprises the following steps: reacting a uniformly mixed reaction system containing a sodium sulfonate monomer containing unsaturated double bonds, an acrylic monomer, a long-carbon alkene ester monomer, an initiator and a first organic solvent at 50-100 ℃ for 8-24 hours in a protective atmosphere to obtain an amphiphilic anticoagulant copolymer; mixing the modified solution with a mixed solvent to form a modified solution, wherein the mixed solvent comprises a combination of a second organic solvent, water and an interface melting agent; and contacting the inner surface of the membrane wire of the hemodialyzer with the modified solution to obtain the hemodialyzer with high anticoagulation performance. The invention can realize the rapid adsorption of heparinoid anticoagulant molecules on the surface of the membrane wires of the dialyzer, provide enough adsorption acting force, ensure that the heparinoid molecules do not fall off in the dialysis process and have good anticoagulation effect; meanwhile, the process flow is simple, and the industrial production and popularization are easy.
Description
Technical Field
The invention belongs to the field of blood purification, and particularly relates to a surface anticoagulation modification method of a hemodialyzer and application thereof in blood purification.
Background
Uremia is a disease which causes a series of toxic symptoms due to endocrine dysfunction caused by renal insufficiency and metabolite accumulation of a patient. The nitrogenous metabolites and other toxic substances of the patient can not be normally discharged and accumulated in the body, so that the organs and systems of the body are affected, and series complications are caused to endanger life safety. Currently, hemodialysis has developed into a key to maintaining the life of renal patients relative to the difficulty of proper renal source in renal transplant surgery. The key component of hemodialysis is the hemodialysis membrane. At present, the mature hemodialysis membrane mostly adopts a high molecular base material. However, the polymer membrane is often hydrophobic, and the membrane adsorbs proteins in blood during hemodialysis. The plasma protein is adsorbed on the contacted biomaterial surface within a few seconds, and then the platelet and the coagulation factor on the protein adsorption layer are activated, so that the coagulation is caused to occur within 1-2 minutes. At present, the occurrence of coagulation reaction is avoided mainly by introducing heparin at the time of hemodialysis. However, chronic heparin use can cause bleeding, thrombocytopenia, heparin resistance, and osteoporosis in patients. Therefore, the excellent blood compatibility and good anticoagulation activity have important significance for reducing the dependence on heparin in the dialysis process.
The existing hemodialysis membrane is modified to have good anticoagulation performance, so that the use of heparin in dialysis is reduced or even avoided, and the reduction of patient pain is an important research direction for developing the hemodialysis membrane. In recent years, with the continuous and intensive research on the anticoagulant mechanism of heparin, researchers found that the core of the anticoagulant function of heparin is the presence of carboxylic acid groups and sulfonic acid groups in the molecule (mol. cell. biochem.48,1982, 161-182.). Researchers have also shown that other heparinoid molecules containing carboxylic or sulfonic acid groups also have anticoagulant function (Colloids surf., B10, 1998263-271). However, heparin or heparan molecules are often poor in compatibility with the surface of a high polymer material, and researchers generally fix the heparin or heparan molecules on the surface of a dialysis membrane material by means of modification such as grafting and crosslinking. The method is easy to lose the activity of heparin or heparinoid because the original molecular structure of the heparin or heparinoid needs to be destroyed, so that the anticoagulation performance of the modified material is weaker in improvement effect. Therefore, how to realize the stable loading of the heparinoid on the inner surface of the hemodialysis membrane and reduce the damage to the functional activity of the heparinoid at the same time has important research and application values particularly aiming at the anticoagulation modification of the packaged hemodialyzer.
The research and development team (with publication number of CN109675134A) of the inventor introduces hydroxymethyl acrylamide or hydroxyethyl acrylamide which can continue to react at the later stage in the process of artificially synthesizing heparinoid, and then initiates self-condensation of hydroxymethyl acrylamide or hydroxyethyl acrylamide through adsorption and subsequent hydrothermal treatment, thereby realizing cross-linking of artificial heparinoid on the surface of dialysis membrane and improving the anticoagulation property of dialysis membrane. The technical scheme is not the traditional blending modification, but an interfacial adsorption and interfacial crosslinking technology. Meanwhile, the technical scheme is a technical scheme which relates to a heparinoid functional group by simulating a natural substance-heparin anticoagulation mechanism. However, the inventor of the present invention has found that the artificial synthesis of heparinoids and the surface interface of the dialyzer does not require very strong cross-linking ability but requires to ensure that the heparinoids do not fall off during the one-time dialysis process, thereby causing hemolytic injury to the patient, in combination with the low operating pressure (13.3kPa) during the dialysis process and the disposable characteristics of the dialyzer. In CN109675134A, the inventor of the present invention adopts a process technology combining adsorption and hydrothermal crosslinking, and although the artificial heparan loading on the surface of the finally prepared modified dialyzer is very stable, the whole process flow needs to perform multiple process flows such as liquid filling, hydrothermal crosslinking, and flushing on the modified dialyzer, and especially the hydrothermal crosslinking process has high energy consumption and long time consumption.
Disclosure of Invention
The invention mainly aims to provide a surface 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 the surface anticoagulation modification method of 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 a surface anticoagulation modification method of a hemodialyzer, which comprises the following steps:
reacting a uniformly mixed reaction system containing a sodium sulfonate monomer containing unsaturated double bonds, an acrylic monomer, a long-carbon alkene ester monomer, an initiator and a first organic solvent at 50-100 ℃ for 8-24 hours in a protective atmosphere to obtain an amphiphilic anticoagulant copolymer;
mixing the amphiphilic anticoagulant copolymer with a mixed solvent to form a modified solution, wherein the mixed solvent comprises a combination of a second organic solvent, water and an interface melting agent;
and contacting the inner surface of the membrane wire of the hemodialyzer with the modified solution to obtain the hemodialyzer with high anticoagulation performance.
In some embodiments, the method for surface anticoagulation modification is characterized by specifically comprising: adding a sodium sulfonate monomer containing unsaturated double bonds, an acrylic monomer and a long-carbon olefin ester monomer into a first organic solvent, and stirring for more than 30min at a speed of 200-600 r/min in a protective atmosphere;
and then adding an initiator, keeping stirring in a protective atmosphere, heating to 50-100 ℃, and reacting for 8-24 hours to obtain the amphiphilic anticoagulant copolymer.
Further, the carbon chain contained in the long-carbon alkene ester monomer is an alkane chain, and the number of carbons in the alkane chain is more than 12.
The embodiment of the invention also provides a hemodialyzer with high anticoagulation performance obtained by the method.
The embodiment of the invention also provides the application of the hemodialyzer with high anticoagulation performance in the field of blood purification.
Compared with the prior art, the surface anticoagulation modification method of the hemodialyzer has the following advantages:
1) based on the mechanism of heparin anticoagulation, the invention synthesizes amphiphilic heparan anticoagulation polymer containing heparin anticoagulation functional groups (sulfonic group and carboxyl group), then realizes the good load of the amphiphilic heparan polymer on the inner surface of the membrane silk of the dialyzer through the similar compatibility between long carbon chain hydrophobic groups contained in the molecules of the amphiphilic heparan polymer and the polymer material of the membrane silk of the dialyzer and further through the permeation promotion and shallow cortex adsorption of a trace organic solvent/water system on the inner surface of the membrane silk of the dialyzer;
2) the invention can realize the rapid adsorption of heparinoid anticoagulant molecules on the surface of the membrane wires of the dialyzer, and provide adsorption acting force with enough degree, and under the adsorption acting force, the heparinoid molecules can be ensured not to fall off in the dialysis process;
3) the heparinoid synthesized by the invention does not damage the activity of heparinoid molecules and core functional groups in the process of modifying the dialyzer; meanwhile, based on the adsorption effect of a molecular interface, the anticoagulation modification of a packaged dialyzer can be quickly realized, and a good anticoagulation effect can be realized only by flowing the amphipathic heparinoid solution of the invention through the dialyzer once;
4) the dialyzer surface anticoagulation modification method provided by the invention has the advantages of simple overall process flow, easy operation and realization, and easy industrial production and popularization.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is an SEM photograph of the inner surface of the modified pre-dialyzer membrane filaments after the platelet adhesion experiment described in example 1 of the present invention.
FIG. 2 is an SEM photograph of the inner surface of the membrane filaments of the highly anticoagulated hemodialyzer obtained in example 1 of the present invention after the platelet adhesion test.
Detailed Description
As described above, in view of the deficiencies of the prior art, the inventors of the present invention have made extensive studies and practice, and as a result, the present invention provides a method for modifying the anticoagulation surface of a hemodialyzer, which can modify the anticoagulation surface of a packaged hemodialyzer.
In the process of research, the inventor finds that the long-carbon alkene ester has good adsorption stability with the surface interface of the polymer membrane, and even in the process of pressure more than 3 times of the normal operating pressure of a dialyzer, the long-carbon alkene ester is not obviously desorbed after being adsorbed to the surface of the polymer membrane. Based on this finding, the present inventors have conducted studies to introduce a long-carbon olefin ester into a synthetic heparinoid molecule and directly adsorb the synthetic heparinoid to the surface interface of a dialyzer by virtue of an excellent adsorption effect between the long-carbon olefin ester and the surface interface of a polymer membrane, thereby achieving an anticoagulation modification of the dialyzer. Through experimental verification, the inventor also finds that when the number of alkane chain carbon atoms of the long-carbon alkene ester exceeds 12, the long-carbon alkene ester is introduced into the artificial heparinoid molecule, so that the artificial heparinoid molecule can be ensured not to obviously fall off under the pressure process which exceeds the normal operation pressure of a dialyzer by more than 3 times (in the embodiment, detection of the heparinoid falling object is involved, and the national standard requirement is met). Therefore, based on the process technology, the inventor only needs to simply flow the artificial heparinoid solution through the inner surface of the dialyzer, so that the stable adsorption of the artificial heparinoid on the surface interface of the dialyzer can be realized, and the anticoagulation modification of the packaged dialyzer can be quickly realized.
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 performing anticoagulation modification on the surface of a hemodialyzer, which includes:
reacting a uniformly mixed reaction system containing a sodium sulfonate monomer containing unsaturated double bonds, an acrylic monomer, a long-carbon alkene ester monomer, an initiator and a first organic solvent at 50-100 ℃ for 8-24 hours in a protective atmosphere to obtain an amphiphilic anticoagulant copolymer;
mixing the amphiphilic anticoagulant copolymer with a mixed solvent to form a modified solution, wherein the mixed solvent comprises a combination of a second organic solvent, water and an interface melting agent;
and contacting the inner surface of the membrane wire of the hemodialyzer with the modified solution to obtain the hemodialyzer with high anticoagulation performance.
In some embodiments, the surface anticoagulation modification method specifically comprises: adding a sodium sulfonate monomer containing unsaturated double bonds, an acrylic monomer and a long-carbon olefin ester monomer into a first organic solvent, and stirring at the speed of 200-600 r/min for more than 30min, preferably 30-60 min, in a protective atmosphere; the purpose of this step is to discharge the dissolved oxygen in the reaction system by a shielding gas, and the rotation speed and time are mainly directed to the operability and the degree of discharge of the dissolved oxygen.
And then adding an initiator, keeping stirring in a protective atmosphere, heating to 50-100 ℃, and reacting for 8-24 hours to obtain the amphiphilic anticoagulant copolymer.
In some preferred embodiments, the unsaturated double bond-containing sulfonic acid sodium salt monomer includes any one or a combination of two or more of sodium p-styrene sulfonate, sodium methallyl sulfonate, sodium vinyl sulfonate, and the like, but is not limited thereto.
In some preferred embodiments, the acrylic monomer includes any one or a combination of two or more of acrylic acid, methacrylic acid, phenylacrylic acid, sorbic acid, and the like, but is not limited thereto.
In some preferred embodiments, the long-carbon alkene ester monomer contains a carbon chain that is an alkane chain, and the number of carbons in the alkane chain is greater than 12.
Further, the long carbon olefin ester monomer includes any one or a combination of two or more of tetradecyl acrylate, hexadecyl acrylate, octadecyl acrylate, tetradecyl methacrylate, hexadecyl methacrylate, and octadecyl methacrylate, etc., but is not limited thereto.
Further, the initiator includes any one or a combination of two or more of azobisisobutyronitrile, azobisisoheptonitrile, azobisdimethylformate, dibenzoyl peroxide, and the like, but is not limited thereto.
Further, the first organic solvent includes any one or a combination of two or more of ethanol, n-hexane, acetone, tetrahydrofuran, chloroform, and the like, but is not limited thereto.
In some preferred embodiments, the mass-to-volume ratio of the unsaturated double bond-containing sulfonic acid sodium salt monomer, the acrylic monomer, the long-carbon olefin ester monomer, the initiator and the first organic solvent is (5-10 g): (1-3 g): (6-12 g): (0.2-1 g): 100 mL.
Furthermore, the amount of the unsaturated double-bond sulfonic acid sodium salt monomer added is 5-10 g, the amount of the acrylic monomer added is 1-3 g, the amount of the long-carbon olefin ester monomer added is 6-12 g, and the amount of the initiator added is 0.2-1 g per 100ml of the first organic solvent.
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 surface anticoagulation modification method further comprises the following steps: and after the reaction is finished, transferring the reaction solution to an environment with the temperature of 20-50 ℃ to remove the first organic solvent, thereby obtaining the amphiphilic anticoagulant copolymer.
As a more preferred embodiment of the present invention, the method for synthesizing the amphiphilic anticoagulant copolymer comprises the following steps:
adding a certain amount of unsaturated double-bond sodium sulfonate monomer, acrylic acid monomer and long-carbon olefin ester monomer into 100ml of first organic solvent, and stirring for not less than 30min in a nitrogen or argon atmosphere to remove oxygen in a reaction liquid;
adding a certain amount of initiator, keeping the nitrogen or argon atmosphere for stirring, heating to 50-100 ℃, and reacting for 8-24 hours;
and (3) transferring the solution to an environment with the temperature of 20-50 ℃, and drying to remove the first organic solvent to obtain the amphiphilic anticoagulant copolymer.
In some preferred embodiments, the surface anticoagulation modification method specifically comprises: and dissolving the amphiphilic anticoagulant copolymer in a mixed solvent to form the modified solution.
In some preferred embodiments, the content of the second organic solvent in the mixed solvent is 5 to 15vol%, and the content of the interfacial melting agent in the mixed solvent is 0.1 to 1g/100ml, that is, the mixed solvent is a blend of the second organic solvent, water and the interfacial melting agent, the volume ratio of the second organic solvent to the mixed solvent is 5 to 15%, and the mass/volume ratio of the interfacial melting agent to the mixed solvent is 0.1 to 1g/100 ml.
Further, the second organic solvent includes any one or a combination of two or more of N, N-dimethylacetamide, triethyl phosphate, trimethyl phosphate, dimethylsulfoxide, N-methylpyrrolidone, and the like, but is not limited thereto.
The interface melting agent is added into the mixed solvent, and the function of the invention is to improve the dispersion uniformity of the anticoagulant copolymer in the mixed solvent; on the other hand, the adsorption of the anticoagulant copolymer to the surface of the membrane yarn can be promoted when the anticoagulant copolymer flows through the inner surface of the membrane yarn, the contact efficiency of the anticoagulant copolymer and the inner surface of the membrane yarn is improved, and the anticoagulant copolymer is more uniformly loaded on the surface of the membrane yarn.
Further, the interfacial melting agent includes any one or a combination of two or more of sodium dodecylbenzene sulfonate, sodium dodecyl sulfate, polyoxyethylene-polyoxypropylene copolymer, span 80, and the like, but is not limited thereto.
Further, the mass-volume ratio of the amphiphilic anticoagulant copolymer to the mixed solvent is (0.5-5 g): 100mL, that is, the adding dissolution amount of the amphiphilic anticoagulant copolymer in each 100mL of the mixed solvent is 0.5-5 g.
In some preferred embodiments, the surface anticoagulation modification method specifically comprises: and (3) inputting the modified solution into a hemodialyzer, and enabling the modified solution to flow through the inner surface of the membrane wire of the hemodialyzer, so that the amphiphilic anticoagulant copolymer is adsorbed on the inner surface of the membrane wire of the hemodialyzer.
Further, the speed of the modified solution flowing through the inner surface of the membrane wire of the hemodialyzer is 30-300 ml/dm.
Further, the contact time of the modified solution and the inner surface of the membrane wire of the hemodialyzer is 1-10 min.
Further, the surface anticoagulation modification method further comprises the following steps: and discharging the modified solution out of the hemodialyzer, cleaning, and carrying out vacuum drying at 40-80 ℃ for 12-48 h to obtain the hemodialyzer with high anticoagulation performance.
The material of the membrane filaments of the hemodialyzer may include one or a combination of two or more of hollow fiber membranes such as polysulfone, polyethersulfone, cellulose acetate, and polylactic acid, but is not limited thereto.
As a more specific embodiment, the method for surface anticoagulation modification of a hemodialyzer comprises the following steps:
synthesizing an amphiphilic anticoagulant copolymer;
dissolving the synthesized amphiphilic anticoagulant copolymer in a mixed solvent to obtain a modified solution;
at normal temperature, conveying the modified solution into a dialyzer at a constant speed, and enabling the modified solution to flow through the inner surface of a membrane wire of the dialyzer;
and (4) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and drying in vacuum to obtain the hemodialyzer with high anticoagulation performance.
Another aspect of an embodiment of the present invention also provides a hemodialyzer with high anticoagulation performance obtained by the aforementioned 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 summary, based on the mechanism of heparin anticoagulation, the invention synthesizes the amphipathic heparin-like anticoagulation polymer containing heparin anticoagulation functional groups (sulfonic groups and carboxyl groups), then realizes the good load of the amphipathic heparin-like anticoagulation polymer on the inner surface of the membrane filament of the dialyzer through the similar compatibility between the long carbon chain hydrophobic group contained in the molecule of the amphipathic heparin-like anticoagulation polymer and the polymer material of the membrane filament of the dialyzer and further through the permeation promotion and the shallow cortex adsorption of a trace amount of organic solvent/water body/interface melting agent system on the inner surface of the membrane filament of the dialyzer. The heparinoid synthesized by the invention does not damage the activity of heparinoid molecules and core functional groups in the process of modifying the dialyzer; meanwhile, based on the adsorption effect of a molecular interface, the anticoagulation modification of the packaged and molded dialyzer can be quickly realized, and the good anticoagulation effect can be realized only by flowing the amphipathic heparinoid solution of the invention through the dialyzer once.
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.
Example 1
6 g of sodium p-styrene sulfonate, 2g of acrylic acid and 8 g of tetradecyl methacrylate which are added into 100ml of ethanol are stirred for 30min at the speed of 600r/min in a nitrogen atmosphere to remove oxygen in a reaction liquid;
adding 0.3 g of dimethyl azodiisoformate into the mixture obtained in the step (2), keeping the nitrogen atmosphere, stirring, heating to 80 ℃, and reacting for 16 hours;
transferring the solution to an environment of 50 ℃, and drying to remove ethanol to obtain an amphiphilic anticoagulant copolymer;
preparing 100ml of N, N-dimethylacetamide aqueous solution with the volume ratio of 10%, adding 0.3 g of polyoxyethylene-polyoxypropylene copolymer, and adding 3g of synthesized amphiphilic anticoagulant copolymer to obtain modified solution.
Conveying the modified solution into a dialyzer at the normal temperature at the speed of 100 ml/dm-min, and enabling the modified solution to flow through the inner surface of a membrane wire of the dialyzer and contact the membrane wire for 5min, wherein the membrane wire of the dialyzer is a polysulfone hollow fiber membrane;
and (6) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and vacuum-drying at 40 ℃ for 48h to obtain the hemodialyzer with high anticoagulation performance.
And respectively taking out the membrane filaments of the dialyzers before and after modification to perform a platelet adhesion test, and observing the platelet adhesion condition of the inner surfaces of the membrane filaments under a microscope electron microscope. As can be seen from fig. 1 and fig. 2, the surfaces of the membrane filaments of the dialyzer modified by the present embodiment are not substantially adhered with platelets, while the surfaces of the membrane filaments of the dialyzer before modification are seriously adhered with platelets. The surface anticoagulation modification technology is used for modifying the surface anticoagulation modification technology, so that the inner surface of the membrane wire packaged by the hemodialyzer has more excellent anti-platelet adhesion performance.
The removed membrane filaments were subjected to coagulation test. The results show that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzer modified in this example are 550 seconds, 47 seconds and 33 seconds respectively, while the APTT, TT and PT times of the membrane filaments of the dialyzer before modification are 50 seconds, 18 seconds and 14 seconds respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzer modified by this example was 131mg/dL, while the FIB test content of the membrane filaments of the dialyzer before modification was 183 mg/dL. This shows that the inner surface of the membrane yarn encapsulated by the hemodialyzer has more excellent blood compatibility after the modification by the surface anticoagulation modification technology.
Further, the result of the UV detection (250-320nm) and the reductive oxide detection of the eluted material of the membrane filament of the dialyzer modified by the embodiment shows that the UV detection value of the eluted material is 0.01, and the titration difference of potassium permanganate (0.002mol/L) is 0.3ml, which are both significantly lower than the detection limit required by the national standard (YY 0053-2008), which indicates that the amphiphilic anticoagulant polymer modified on the surface of the membrane filament has excellent stable load characteristics after the modification of the process technology of the embodiment.
Example 2
Adding 5g of sodium methallyl sulfonate, 3g of methacrylic acid and 6 g of octadecyl methacrylate into 100ml of n-hexane, and stirring for 40min at the speed of 400r/min in an argon atmosphere to remove oxygen in a reaction liquid;
adding 0.2 g of azobisisobutyronitrile into the mixture obtained in the step (2), stirring the mixture in an argon atmosphere, heating the mixture to 50 ℃, and reacting the mixture for 24 hours;
transferring the solution to an environment of 20 ℃, and drying to remove n-hexane to obtain an amphiphilic anticoagulant copolymer;
and (4) preparing 100ml of triethyl phosphate aqueous solution with the volume ratio of 15%, adding 0.5 g of span 80, and adding 4 g of the synthesized amphiphilic anticoagulant copolymer to obtain a modified solution.
Conveying the modified solution into a dialyzer at normal temperature at the speed of 200 ml/dm-min, and allowing the modified solution to flow through the inner surface of a membrane wire of the dialyzer and contact the membrane wire for 8min, wherein the membrane wire of the dialyzer is a polylactic acid hollow fiber membrane;
and (6) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and vacuum-drying at 60 ℃ for 24 hours to obtain the hemodialyzer with high anticoagulation performance.
The removed membrane filaments were subjected to coagulation test. The results showed that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzer modified in this example were 350 seconds, 33 seconds and 23 seconds, respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzer modified by this example was 151 mg/dL. Further, the membrane filaments of the dialyzer modified by the embodiment were subjected to the eluate UV (250-320nm) detection and the reduced oxide detection, and the result shows that the UV detection value of the eluate is 0.012, and the titration difference of potassium permanganate (0.002mol/L) is 0.34 ml.
Example 3
Step (1), 10g of sodium vinyl sulfonate, 3g of phenylacrylic acid and 12g of tetradecyl methacrylate which are added into 100ml of acetone are stirred for 35min at the speed of 200r/min in a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 1g of dibenzoyl peroxide, stirring in a nitrogen atmosphere, heating to 100 ℃, and reacting for 8 hours;
transferring the solution to an environment of 30 ℃, and drying to remove acetone to obtain an amphiphilic anticoagulant copolymer;
and (4) preparing 100ml of trimethyl phosphate aqueous solution with the volume ratio of 5%, adding 0.1 g of sodium dodecyl benzene sulfonate, and adding 0.5 g of the synthesized amphiphilic anticoagulant copolymer to obtain a modified solution.
Conveying the modified solution into a dialyzer at the normal temperature at the speed of 30 ml/dm-min, and enabling the modified solution to flow through the inner surface of a membrane wire of the dialyzer and contact the membrane wire for 1min, wherein the membrane wire of the dialyzer is a polyether sulfone hollow fiber membrane;
and (6) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and vacuum-drying at 80 ℃ for 12h to obtain the hemodialyzer with high anticoagulation performance.
The removed membrane filaments were subjected to coagulation test. The results showed that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzer modified in this example were 410 seconds, 41 seconds and 30 seconds, respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzer modified by this example was 141 mg/dL. Further, the membrane filaments of the dialyzer modified by the embodiment were subjected to the eluate UV (250-320nm) detection and the reduced oxide detection, and the result shows that the UV detection value of the eluate is 0.009, and the titration difference of potassium permanganate (0.002mol/L) is 0.27 ml.
Example 4
Adding 3g of sodium p-styrene sulfonate, 4 g of sodium vinyl sulfonate, 1g of sorbic acid, 6 g of hexadecyl methacrylate and 4 g of hexadecyl acrylate into 100ml of tetrahydrofuran, and stirring for 45min at the speed of 300r/min under the argon atmosphere to remove oxygen in a reaction liquid;
adding 0.5 g of dimethyl azodiisoformate into the mixture obtained in the step (2), keeping the mixture in a nitrogen or argon atmosphere, stirring, heating to 60 ℃, and reacting for 18 hours;
transferring the solution to an environment of 40 ℃, and drying to remove tetrahydrofuran to obtain an amphiphilic anticoagulant copolymer;
and (4) preparing a dimethyl sulfoxide aqueous solution with the volume ratio of 8%, adding 0.4 g of sodium dodecyl benzene sulfonate and 0.6 g of sodium dodecyl sulfate, and adding 5g of the synthesized amphiphilic anticoagulant copolymer to obtain a modified solution.
Conveying the modified solution into a dialyzer at normal temperature at the speed of 300 ml/dm-min, and allowing the modified solution to flow through the inner surface of membrane filaments of the dialyzer and contact the membrane filaments for 10min, wherein the membrane filaments of the dialyzer are polysulfone hollow fiber membranes;
and (6) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and vacuum-drying at 50 ℃ for 30h to obtain the hemodialyzer with high anticoagulation performance.
The removed membrane filaments were subjected to coagulation test. The results showed that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzer modified in this example were 510 seconds, 42 seconds and 29 seconds, respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzer modified by this example was 143 mg/dL. Further, the membrane filaments of the dialyzer modified by the embodiment were subjected to the eluate UV (250-320nm) detection and the reduced oxide detection, and the result shows that the UV detection value of the eluate is 0.014, and the titration difference of potassium permanganate (0.002mol/L) is 0.39 ml.
Example 5
Adding 9 g of sodium p-styrene sulfonate, 2g of acrylic acid, 1g of sorbic acid and 12g of tetradecyl acrylate into 100ml of chloroform, and stirring for 60min at the speed of 250r/min in a nitrogen atmosphere to remove oxygen in a reaction solution;
adding 0.8 g of azodiisoheptanonitrile into the mixture obtained in the step (2), keeping the nitrogen atmosphere, stirring, heating to 70 ℃, and reacting for 12 hours;
transferring the solution to an environment at 25 ℃, and drying to remove chloroform to obtain an amphiphilic anticoagulant copolymer;
and (4) preparing an N-methyl pyrrolidone aqueous solution with the volume ratio of 12%, adding 0.7 g of sodium dodecyl sulfate, and adding 2g of the synthesized amphiphilic anticoagulant copolymer to obtain a modified solution.
Conveying the modified solution into a dialyzer at the normal temperature at the speed of 70 ml/dm-min, and enabling the modified solution to flow through the inner surface of a membrane wire of the dialyzer and contact the inner surface for 6min, wherein the membrane wire of the dialyzer is a cellulose acetate membrane;
and (6) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and vacuum-drying at 60 ℃ for 20 hours to obtain the hemodialyzer with high anticoagulation performance.
The removed membrane filaments were subjected to coagulation test. The results showed that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzer modified in this example were 460 seconds, 37 seconds and 26 seconds, respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzer modified by this example was 145 mg/dL. Further, the membrane filaments of the dialyzer modified by the embodiment were subjected to the eluate UV (250-320nm) detection and the reduced oxide detection, and the result shows that the UV detection value of the eluate is 0.014, and the titration difference of potassium permanganate (0.002mol/L) is 0.37 ml.
Example 6
Adding 8 g of sodium methallyl sulfonate, 2.5 g of acrylic acid and 9 g of hexadecyl acrylate into a mixed solvent of 50 ml of ethanol and 50 ml of acetone, and stirring for 30min at the speed of 300r/min under the argon atmosphere to remove oxygen in a reaction solution;
adding 0.2 g of dimethyl azodiisoformate and 0.4 g of azodiisobutyronitrile into the mixture obtained in the step (2), keeping the mixture in a nitrogen or argon atmosphere, stirring, heating to 90 ℃, and reacting for 15 hours;
transferring the solution to an environment of 35 ℃, and drying to remove ethanol and acetone to obtain an amphiphilic anticoagulant copolymer;
preparing a mixed aqueous solution of N, N-dimethylacetamide and 7% triethyl phosphate according to the volume ratio of 3%, adding 0.1 g of polyoxyethylene-polyoxypropylene copolymer and 0.1 g of span 80, and adding 1g of the synthesized amphiphilic anticoagulant copolymer to obtain a modified solution.
Conveying the modified solution into a dialyzer at the normal temperature at the speed of 170 ml/dm-min, and enabling the modified solution to flow through the inner surface of a membrane wire of the dialyzer and contact the membrane wire for 3min, wherein the membrane wire of the dialyzer is a polyether sulfone hollow fiber membrane;
and (6) discharging the modified solution out of the dialyzer, injecting deionized water, cleaning at normal temperature, and vacuum-drying at 70 ℃ for 18h to obtain the hemodialyzer with high anticoagulation performance.
The removed membrane filaments were subjected to coagulation test. The results showed that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzer modified in this example were 400 seconds, 36 seconds and 25 seconds, respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzer modified by this example was 149 mg/dL. Further, the membrane filaments of the dialyzer modified by the embodiment were subjected to the eluate UV (250-320nm) detection and the reduced oxide detection, and the result shows that the UV detection value of the eluate is 0.017, and the titration difference of potassium permanganate (0.002mol/L) is 0.38 ml.
Comparative example 1
The present comparative example is different from example 1 in that: and replacing tetradecyl methacrylate with n-octyl methacrylate, and keeping other conditions unchanged to obtain the modified hemodialyzer.
The removed membrane filaments were subjected to coagulation test. The results showed that the Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and Prothrombin Time (PT) of the membrane filaments of the dialyzers modified in the control examples were 210 seconds, 24 seconds and 19 seconds, respectively. The fibrinogen test content (FIB) of the membrane filaments of the dialyzers modified in this control example was 159 mg/dL. Further, the membrane filaments of the dialyzer modified by the control example are subjected to the UV (250-320nm) detection of the eluted substances and the detection of the reducing oxides, and the results show that the UV detection value of the eluted substances is 0.19, and the titration difference of potassium permanganate (0.002mol/L) is 2.7ml, which are both higher than the detection limit required by the national standard (YY 0053-2008), which indicates that when the length of the hydrophobic group carbon chain is insufficient, the adhesion stability of the synthesized heparinoid polymer on the surface of the membrane filaments is poor, poor shedding is easy to occur, the risk of entering the human body is generated in the dialysis process, and the clinical risk is relatively high.
The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.
The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.
Throughout this specification, where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition of the present teachings also consist essentially of, or consist of, the recited components, and the process of the present teachings also consist essentially of, or consist of, the recited process steps.
Unless specifically stated otherwise, use of the terms "comprising", "including", "having" or "having" is generally to be understood as open-ended and not limiting.
It should be understood that the order of steps or the order in which particular actions are performed is not critical, so long as the teachings of the invention remain operable. Further, two or more steps or actions may be performed simultaneously.
In addition, the inventors of the present invention have also made experiments with other materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.
While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.
Claims (14)
1. A surface anticoagulation modification method of a hemodialyzer is characterized by comprising the following steps:
adding an unsaturated double bond-containing sulfonic acid sodium salt monomer, an acrylic acid monomer and a long-carbon olefin ester monomer into a first organic solvent, and stirring at a speed of 200-600 r/min for more than 30min in a protective atmosphere, wherein a carbon chain of the long-carbon olefin ester monomer is an alkane chain, and the long-carbon olefin ester monomer is selected from one or a combination of more than two of tetradecyl acrylate, hexadecyl acrylate, octadecyl acrylate, tetradecyl methacrylate, hexadecyl methacrylate and octadecyl methacrylate;
and then adding an initiator, keeping stirring in a protective atmosphere, heating to 50-100 ℃, and reacting for 8-24 hours to obtain the amphiphilic anticoagulant copolymer, wherein the mass-to-volume ratio of the unsaturated double bond-containing sodium sulfonate salt monomer, the acrylic acid monomer, the long-carbon olefin ester monomer, the initiator and the first organic solvent is (5-10 g): (1-3 g): (6-12 g): (0.2-1 g): 100 mL;
mixing the amphiphilic anticoagulant copolymer with a mixed solvent to form a modified solution, wherein the mixed solvent comprises a combination of a second organic solvent, water and an interfacial melting agent, the interfacial melting agent is selected from any one or a combination of more than two of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate, a polyoxyethylene-polyoxypropylene copolymer and span 80, and the mass-volume ratio of the amphiphilic anticoagulant copolymer to the mixed solvent is (0.5-5 g): 100 mL;
inputting the modified solution into a hemodialyzer, and enabling the modified solution to flow through the inner surface of the membrane wire of the hemodialyzer, so that the amphiphilic anticoagulant copolymer is adsorbed on the inner surface of the membrane wire of the hemodialyzer; the speed of the modified solution flowing through the inner surface of the membrane wire of the hemodialyzer is 30-300 ml/dm; and the contact time of the modified solution and the inner surface of the membrane wire of the hemodialyzer is 1-10 min, so that the hemodialyzer with high anticoagulation performance is obtained.
2. The method for surface anticoagulant modification according to claim 1, which comprises: adding a sodium sulfonate monomer containing unsaturated double bonds, an acrylic monomer and a long-carbon olefin ester monomer into a first organic solvent, and stirring for 30-60 min at a speed of 200-600 r/min in a protective atmosphere.
3. A surface anticoagulation modification method according to claim 1 or 2, characterized in that: the sodium sulfonate monomer containing unsaturated double bonds is selected from any one or the combination of more than two of sodium p-styrene sulfonate, sodium methyl propylene sulfonate and sodium vinyl sulfonate; and/or the acrylic monomer is selected from any one or the combination of more than two of acrylic acid, methacrylic acid, phenylacrylic acid and sorbic acid.
4. A surface anticoagulation modification method according to claim 1 or 2, characterized in that: the initiator is selected from any one or the combination of more than two of azodiisobutyronitrile, azodiisoheptonitrile, azodiisoformic acid dimethyl ester and dibenzoyl peroxide; and/or the first organic solvent is selected from any one or the combination of more than two of ethanol, normal hexane, acetone, tetrahydrofuran and chloroform.
5. The method for surface anticoagulant modification according to claim 2, wherein: the protective atmosphere is selected from a nitrogen atmosphere and/or an inert gas atmosphere.
6. The method for surface anticoagulant modification according to claim 1, further comprising: and after the reaction is finished, transferring the reaction solution to an environment with the temperature of 20-50 ℃ to remove the first organic solvent, thereby obtaining the amphiphilic anticoagulant copolymer.
7. The method for surface anticoagulant modification according to claim 1, which comprises: and dissolving the amphiphilic anticoagulant copolymer in a mixed solvent to form the modified solution.
8. The method for surface anticoagulant modification according to claim 1, wherein: the content of the second organic solvent in the mixed solvent is 5-15 vol%.
9. The method for surface anticoagulant modification according to claim 8, wherein: the second organic solvent is any one or combination of more than two of N, N-dimethylacetamide, triethyl phosphate, trimethyl phosphate, dimethyl sulfoxide and N-methylpyrrolidone.
10. The method for surface anticoagulant modification according to claim 1, wherein: the content of the interfacial melting agent in the mixed solvent is 0.1-1 g: 100 ml.
11. The method for surface anticoagulant modification according to claim 1, further comprising: and discharging the modified solution out of the hemodialyzer, cleaning, and carrying out vacuum drying at 40-80 ℃ for 12-48 h to obtain the hemodialyzer with high anticoagulation performance.
12. The method for surface anticoagulant modification according to claim 1, wherein: the membrane silk material of the hemodialyzer is selected from one or the combination of more than two of polysulfone, polyethersulfone, cellulose acetate and polylactic acid.
13. A hemodialyzer having high anticoagulation properties obtained by the process of any one of claims 1 to 12.
14. A hemodialyzer with high anticoagulation property according to claim 13, characterized in that: the hemodialyzer with high anticoagulation performance is used for blood purification.
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