CN113797900A - Adsorbing material for blood purification, preparation method and application thereof, adsorption column and blood adsorbing device - Google Patents
Adsorbing material for blood purification, preparation method and application thereof, adsorption column and blood adsorbing device Download PDFInfo
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- CN113797900A CN113797900A CN202111149337.5A CN202111149337A CN113797900A CN 113797900 A CN113797900 A CN 113797900A CN 202111149337 A CN202111149337 A CN 202111149337A CN 113797900 A CN113797900 A CN 113797900A
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- hollow fiber
- blood
- blood purification
- adsorbing material
- adsorbing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J20/28023—Fibres or filaments
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- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
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- D06M13/244—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing sulfur or phosphorus
- D06M13/248—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing sulfur or phosphorus with compounds containing sulfur
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Abstract
The invention provides an adsorbing material for blood purification, which is formed by modifying EVOH hollow fiber matrix with organic sulfonyl chloride to form a graft chain with sulfonyl ester group, and then connecting the sulfonyl ester group and an amino compound ligand in a covalent bond manner; the preparation method of the adsorption material mainly comprises the steps of grafting and activating the surface of the EVOH hollow fiber and immobilizing an amino compound ligand. The adsorbing material for purifying blood is safe and efficient, can selectively adsorb various pathogenic factors, and has high clearance rate and simple preparation process.
Description
Technical Field
The invention relates to the field of biomedical materials, in particular to an adsorbing material for blood purification, a preparation method and application thereof, an adsorbing column and a blood adsorbing device.
Background
Bilirubin is a metabolite of heme in senescent red blood cells, and is normally further metabolized and excreted after the liver is combined with glucuronic acid. When liver function is abnormal, bilirubin metabolism is disturbed, and thus bilirubinemia (Hyperbilirubinemia) accumulates in the blood, and bilirubinemic encephalopathy jaundice or nuclear jaundice further occur, which may eventually lead to necrosis of tissue cells, absentmindedness, paralysis, or death. Blood perfusion (Hemoperfusion) is an effective method for treating hyperbilirubinemia, and various blood purification materials for removing bilirubin have been developed, but most of them are easy to remove free bilirubin in an alkaline solution, and the removal effect of albumin-bound bilirubin is not ideal. Particularly in the actual human plasma environment, due to the complexity of the plasma environment, many other substances including albumin can be adsorbed while bilirubin is adsorbed, which causes non-specific adsorption, and the adsorption capacity of the material for bilirubin is reduced.
Sepsis is a complex process of infection by a variety of microorganisms (bacteria, fungi, viruses and parasites, etc.) and systemic inflammatory responses. Infection at essentially any site can lead to sepsis, such as pneumonia, enteritis, peritonitis, cholangitis, urinary system infection, cellulitis, meningitis, and the like. Sepsis is a global medical problem, has the characteristics of high incidence of disease and high mortality, and is a leading cause of death in Intensive Care Units (ICU). The gram bacteria comprise gram-negative bacteria and gram-positive bacteria, most of the intestinal bacteria belong to the gram-negative bacteria, and the intestinal bacteria generate endotoxin which can induce sepsis; most pyogenes belong to gram-positive bacteria, which can produce exotoxin to cause diseases, and the common gram-positive bacteria include: staphylococci, streptococci, pneumococci, anthrax bacillus, diphtheria bacillus, tetanus bacillus, etc. Large-scale epidemiological data show that sepsis and septic shock caused by gram-positive bacteria are increased remarkably in recent years, and the incidence rate of the sepsis reaches over 50 percent at present. Common complications of sepsis include shock, acute lung injury, acute respiratory distress syndrome, deep vein thrombosis, stress ulcers, metabolic acidosis, Disseminated Intravascular Coagulation (DIC), and even multiple organ insufficiency.
Since many diseases occur and progress as a result of accumulation of pathogenic factors in the body, the specific and effective removal of these pathogenic factors from the body by blood purification without causing damage to the body has been a problem that clinical medicine has been exploring for decades. The traditional hemodialysis or hemodiafiltration can only remove medium and small molecules, cannot effectively remove macromolecular pathogenic substances, and needs to perform hemoperfusion. And the coupling reagents used in the traditional blood perfusion technical research are cyanogen bromide, trichlorotriazine, carbonyl diimidazole, sodium periodate, epichlorohydrin and the like generally, wherein the cyanogen bromide is a highly toxic substance, the synthetic process has great harm to human bodies and environment, and the cyanogen bromide method is used for coupling ligands which are easy to fall off and enter the human bodies, so that great side effects are generated on patients. In addition, epichlorohydrin and carbonyldiimidazole are used as coupling reagents to activate carriers to couple PMB in the traditional method, although the use of virulent cyanogen bromide is avoided, the reaction steps in the preparation process are more, the adsorption material can be synthesized only by five chemical reactions, and the method is complex, so that the obtained adsorption material product has large batch difference and unstable performance. The endotoxin adsorption material is prepared by a traditional method, is a polystyrene woven fiber with polymyxin B on the surface, is easy to cause the residue of a strong irritant chemical substance chloromethyl ether in a technical route, and has great potential safety hazard because the chloromethyl ether is a strong carcinogen.
Disclosure of Invention
Based on the adsorption material, the adsorption material for blood purification is safe and efficient, can selectively adsorb various pathogenic factors, and has high clearance rate and simple preparation process.
The invention is realized by the following technical scheme.
An adsorbing material for blood purification, which is formed by modifying organic sulfonyl chloride to form a graft chain with a sulfonyl ester group on an EVOH hollow fiber matrix and then covalently connecting the sulfonyl ester group with an amino compound ligand.
In one embodiment, the amino compound is selected from at least one of n-butylamine, polymyxin B sulfate, lysozyme and kukoamine B.
In one embodiment, the organic sulfonyl chloride is at least one selected from the group consisting of p-toluenesulfonyl chloride, 2, 2, 2-trifluoroethanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2, 4, 6-triisopropylbenzenesulfonyl chloride and chlorobenzene sulfonyl chloride.
In one embodiment, the EVOH hollow fiber matrix is a hollow fiber braided tube, a hollow fiber braided mesh, or a hollow fiber tubular nonwoven material; and/or
The inner diameter of the EVOH hollow fiber matrix is 200-300 mu m.
The invention also provides a preparation method of the adsorbing material, which comprises the following steps:
and mixing the EVOH hollow fiber substrate with the organic sulfonyl chloride for activation reaction, mixing with the amino compound, and performing covalent coupling reaction.
In one embodiment, the temperature of the activation reaction is 20-30 ℃, and the time of the activation reaction is 1-3 h; and/or
The solvent adopted by the activation reaction is an organic solvent; and/or
Mixing the EVOH hollow fiber substrate with the organic sulfonyl chloride, and then mixing with pyridine; the mass ratio of the EVOH hollow fiber matrix to the organic sulfonyl chloride to the pyridine is (15-30) to 1 (1-5); and/or
The amino compound is added in the form of a solution, and the concentration of the solution is 1 mg/mL-50 mg/mL.
In one embodiment, the conditions of the covalent coupling reaction are: the conditions of the covalent coupling reaction are: the temperature is 4-40 ℃, the time is 8-24 h, and the pH is 4.5-9.5; and/or
The covalent coupling reaction is followed by a capping step: and (3) soaking a substrate subjected to the covalent coupling ligand reaction and trihydroxymethyl aminomethane hydrochloride with the pH value of 7.5-9.5 at the temperature of 20-30 ℃ for reaction for 6-24 h, and sealing redundant active groups on the substrate.
The invention also provides the use of an adsorbent material for blood purification as described above for adsorption of biological components in blood for non-disease diagnostic and therapeutic purposes.
The invention also provides an adsorption column containing the adsorption material for blood purification.
The present invention also provides a blood adsorbing device comprising the adsorbing material for blood purification as described above or the adsorption column as described above.
Compared with the prior art, the adsorbing material for purifying blood has the following beneficial effects:
the research of the invention finds that after functional group sulfonyl ester groups are introduced on the surface of the EVOH hollow fiber through organic sulfonyl chloride activation, the EVOH hollow fiber can be coupled with various ligands containing amino groups, thereby having the function of selectively adsorbing various pathogenic factors and achieving higher pathogenic factor clearance rate; in addition, the adsorbing material for purifying blood also has good blood compatibility.
Furthermore, the adsorbing material for purifying blood is safe and nontoxic, has simple preparation process, does not need to use strong irritant chemical substances or highly toxic substances, and is suitable for industrialization.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the accompanying examples. The preferred embodiments of the present invention are given in the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
An adsorbing material for purifying blood is prepared through modifying EVOH to form graft chain with sulfonyl ester group on its hollow fibre matrix by organic sulfonyl chloride, and linking it with amino compound ligand by covalent bond.
It is understood that, in the present invention, EVOH is an ethylene-vinyl alcohol copolymer.
According to the invention, EVOH hollow fibers are screened out as a specific matrix, organic sulfonyl chloride is screened out to activate the EVOH hollow fibers, a specific sulfonyl ester group and an amino compound ligand are introduced for coupling, the matrix, the coupling group and the ligand are matched with each other to synergistically improve the adsorption effect, and the finally obtained adsorption material has a remarkably enhanced adsorption effect on pathogenic components compared with the traditional adsorption material.
In the present invention, the amino compound binds to at least one pathogenic component in blood or plasma. More specifically, the pathogenic component includes bilirubin, endotoxin, sepsis pathogen molecules (endotoxin, peptidoglycan, and DNA), or sepsis pathogenic bacteria (gram positive bacteria, gram negative bacteria, and fungi).
In a specific example, the amino compound is selected from at least one of n-butylamine, polymyxin B sulfate, lysozyme and kukoamine B.
In a specific example, the organic sulfonyl chloride is selected from at least one of p-toluenesulfonyl chloride, 2, 2, 2-trifluoroethanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2, 4, 6-triisopropylbenzenesulfonyl chloride and chlorobenzene sulfonyl chloride.
In one particular example, the EVOH hollow fiber matrix is a hollow fiber braided tube, a hollow fiber braided mesh, or a hollow fiber tubular nonwoven material.
The hollow fiber braided tube is a tubular material braided by hollow fibers, the hollow fiber braided net is a reticular material braided by the hollow fibers, the hollow fiber tubular non-woven material can be a short hollow fiber tubular non-woven material or a long hollow fiber tubular non-woven material, and the short hollow fiber tubular non-woven material is a tubular material which is cut by the long hollow fibers into the short hollow fibers and is not braided.
In a specific example, the EVOH hollow fiber matrix has an inner diameter of 200 to 300 μm. It is understood that, in the present invention, the inner diameter of the EVOH hollow fiber matrix includes, but is not limited to, 200 μm, 210 μm, 220 μm, 230 μm, 240 μm, 250 μm, 260 μm, 270 μm, 280 μm, 290 μm, 300 μm.
The invention also provides a preparation method of the adsorbing material for purifying blood, which comprises the following steps:
mixing EVOH hollow fiber matrix with organic sulfonyl chloride for activation reaction, mixing with amino compound for covalent coupling reaction.
In the invention, a functional group sulfonyl ester group is introduced on the surface of the EVOH hollow fiber substrate through organic sulfonyl chloride activation, and a nucleophilic group amino of an amino compound replaces a sulfonyl group during covalent coupling.
In one specific example, the temperature of the activation reaction is 20 ℃ to 30 ℃. It is understood that, in the present invention, the temperature of the activation reaction includes, but is not limited to, 20 deg.C, 21 deg.C, 22 deg.C, 23 deg.C, 24 deg.C, 25 deg.C, 26 deg.C, 27 deg.C, 28 deg.C, 29 deg.C, 30 deg.C.
In a specific example, the time of the activation reaction is 1 to 3 hours. It is understood that in the present invention, the time of the activation reaction includes, but is not limited to, 1h, 1.5h, 2h, 2.5h, 3 h.
In a specific example, the solvent used in the activation reaction is an organic solvent. More specifically, the solvent used in the activation reaction is an organic phase free of water and active hydrogen. Preferably, the solvent used in the activation reaction is acetone.
In one specific example, EVOH hollow fiber matrix is mixed with organic sulfonyl chloride and then mixed with pyridine; the mass ratio of the EVOH hollow fiber matrix to the organic sulfonyl chloride to the pyridine is (15-30) to (1-5).
It is understood that in the present invention, the mass ratio of EVOH hollow fiber matrix, organic sulfonyl chloride to pyridine includes, but is not limited to: 15:1:1, 20:1:1, 25:1:1, 30:1:1, 15:1:2, 20:1:2, 25:1:2, 30:1:2, 15:1:3, 20:1:3, 25:1:3, 30:1:3, 15:1:4, 20:1:4, 25:1:4, 30:1:4, 15:1:5, 20:1:5, 25:1:5, 30:1: 5.
In one particular example, the amino compound is added as a solution, and the concentration of the solution is 1mg/mL to 50 mg/mL. It is understood that, in the present invention, the concentration of the amino compound includes, but is not limited to, 1mg/mL, 5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50 mg/mL.
In one specific example, the temperature of the covalent coupling reaction is between 4 ℃ and 40 ℃. It is understood that, in the present invention, the temperature of the covalent coupling reaction includes, but is not limited to, 4 deg.C, 10 deg.C, 15 deg.C, 20 deg.C, 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C.
In a specific example, the time of the covalent coupling reaction is 8h to 24 h. It is understood that in the present invention, the time of the covalent coupling reaction includes, but is not limited to, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24 h.
In a specific example, the pH of the covalent coupling reaction is 4.5 to 9.5. It is understood that in the present invention, the pH of the covalent coupling reaction includes, but is not limited to, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5.
In a specific example, the covalent coupling reaction is followed by a capping step: and soaking the substrate subjected to covalent coupling reaction and trihydroxymethyl aminomethane hydrochloride for reaction, and sealing redundant active groups on the substrate.
In a specific example, tris hydrochloride has a pH of 7.5 to 9.5. It is understood that in the present invention, the pH of tris hydrochloride includes, but is not limited to, 7.5, 8, 8.5, 9, 9.5.
In one specific example, the temperature of the soaking reaction is 20 ℃ to 30 ℃. It is understood that, in the present invention, the temperature of the soaking reaction includes, but is not limited to, 20 deg.C, 21 deg.C, 22 deg.C, 23 deg.C, 24 deg.C, 25 deg.C, 26 deg.C, 27 deg.C, 28 deg.C, 29 deg.C, 30 deg.C.
In a specific example, the soaking reaction time is 6-24 h. It is understood that in the present invention, the soaking reaction time includes, but is not limited to, 6h, 8h, 10h, 12h, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 24 h.
In a more specific example, the preparation method of the adsorption material comprises the following steps:
mixing an EVOH hollow fiber matrix, organic sulfonyl chloride and pyridine according to a mass ratio of (15-30) to (1-5), and carrying out an activation reaction at a temperature of 20-30 ℃ for 1-3 h;
then adding the mixture into 1-50 mg/mL amino compound solution, adjusting the pH value to 4.5-9.5, and soaking the mixture at the temperature of 4-30 ℃ for covalent coupling reaction for 8-24 h;
and (3) soaking a product of the covalent coupling reaction in trihydroxymethyl aminomethane hydrochloride with the pH value of 7.5-9.5 at the temperature of 20-30 ℃ for reaction for 6-24 h, and sealing redundant active groups on the substrate.
The invention also provides the application of the adsorption material for purifying blood in adsorbing biological components in blood for non-disease diagnosis and treatment.
It is understood that biological components include, but are not limited to bilirubin, endotoxin, sepsis pathogen molecules (endotoxin, peptidoglycan and DNA) or sepsis pathogenic bacteria (gram positive bacteria, gram negative bacteria and fungi).
The invention also provides an adsorption column containing the adsorption material for purifying blood.
The invention also provides a blood adsorption device comprising the adsorption material for blood purification or the adsorption column.
The adsorbent for blood purification and the method for producing the same according to the present invention will be described in further detail with reference to specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a bilirubin adsorption material with n-butylamine as a ligand, which is specifically as follows:
100g of dry EVOH hollow fiber (tubular, 200 μm inner diameter), 5g of paratoluensulfonyl chloride (dissolved in 100mL of acetone) and 10g of pyridine were placed in a container, soaked and reacted at 25 ℃ for 1.5h, taken out, washed with 1L of acetone, and then mixed with water in a ratio of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, the substrate was washed 2 times each and finally with 1mmol/L hydrochloric acid to give a tosylated substrate, which was stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and labeled B0.
Placing 5g of B0 prepared above in a 0.15M boric acid buffer solution containing 15mg/mL of n-butylamine, carrying out soaking reaction at the pH of 8.2 for 24h at 25 ℃, washing with deionized water with the volume of 20 times, carrying out soaking reaction at the temperature of 25 ℃ with Tris-HCl of 0.0 and 0.1mol/L at the pH of 8.0 for 12h, sealing redundant active groups on the matrix, and finally fully washing the matrix with 1.0mol/L of NaCl and water to obtain the bilirubin adsorbing material, wherein the mark is B1.
Example 2
The present embodiment provides an endotoxin adsorbing material using polymyxin B sulfate as a ligand, which is specifically as follows:
100g of dry EVOH hollow fiber (tubular, 200 μm inner diameter), 5g of p-toluenesulfonyl chloride (dissolved in 100mL of acetone), and 10g of pyridine were placed in a vessel, soaked and reacted for 1.5h, taken out, washed with 1L of acetone, and then mixed with water in a ratio of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, the substrate was washed 2 times each and finally with 1mmol/L hydrochloric acid to give a tosylated substrate, which was stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and labeled B0.
5g of B0 prepared above was placed in a PMB solution (dissolved in PBS pH 7.4) containing 50mg/mL, and soaked at 25 ℃ for 24 hours, then washed with 20 times the volume of deionized water, soaked with 0.1mol/L of LTris-HCl at 25 ℃ for 12 hours at pH 8.0, and the excess active groups on the substrate were blocked, and finally the substrate was washed thoroughly with 1.0mol/L of NaCl and water to obtain an endotoxin-adsorbing material, labeled B2.
Example 3
The embodiment provides a sepsis pathogenic bacteria adsorbing material taking lysozyme as a ligand, which comprises the following specific steps:
100g of dry EVOH hollow fiber (tubular, 200 μm inner diameter), 5g of p-toluenesulfonyl chloride (dissolved in 100mL of acetone), and 10g of pyridine were placed in a vessel, soaked and reacted for 1.5h, taken out, washed with 1L of acetone, and then mixed with water in a ratio of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, the substrate was washed 2 times each and finally with 1mmol/L hydrochloric acid to give a tosylated substrate, which was stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and labeled B0.
Placing 5g of B0 prepared above in 0.2M phosphate buffer solution with pH7.4 containing 20mg/mL of lysozyme, soaking and reacting for 24h at 25 ℃, cleaning with 20 times volume of deionized water, soaking and reacting for 12h at 25 ℃ with Tris-HCl with pH 8.0 and 0.1mol/L, sealing redundant active groups on the substrate, and finally fully washing the substrate with 1.0mol/L of NaCl and water to obtain the sepsis pathogenic bacteria adsorbing material marked as B3.
Example 4
The embodiment provides a sepsis pathogen molecule adsorption material with kukoamine B as a ligand, which comprises the following specific steps:
100g of dry EVOH hollow fiber (tubular, 200 μm inner diameter), 5g of p-toluenesulfonyl chloride (dissolved in 100mL of acetone), and 10g of pyridine were placed in a vessel, soaked and reacted for 1.5h, taken out, washed with 1L of acetone, and then mixed with water in a ratio of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, the substrate was washed 2 times each and finally with 1mmol/L hydrochloric acid to give a tosylated substrate, which was stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and labeled B0.
Placing 5g of B0 prepared above in 0.2M phosphate buffer solution with pH7.4 containing kukoamine B of 5mg/mL, soaking at 25 deg.C for 24h, cleaning with 20 times volume of deionized water, soaking at 0.1mol/L Tris-HCl25 deg.C with pH 8.0 for 12h, blocking redundant active groups on the substrate, and washing the substrate with 1.0mol/L NaCl and water sufficiently to obtain sepsis pathogenic bacteria adsorbing material marked as B4.
Example 5
The present embodiment provides an endotoxin adsorbing material using polymyxin B sulfate as a ligand, which is specifically as follows:
100g of dry EVOH hollow fiber (tubular, 200 μm inner diameter), 5g of 2, 2, 2-trifluoroethanesulfonyl chloride (dissolved in 100mL of acetone), and 10g of pyridine were placed in a vessel, soaked and reacted for 1.5h, taken out, washed with 1L of acetone, and then mixed with a solvent in a ratio of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, each 2 times and finally with 1mmol/L hydrochloric acid, to give a 2, 2, 2-trifluoroethanesulfonylated substrate which is stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and is labeled B5.
5g of B0 prepared above was placed in a PMB solution (dissolved in PBS pH 7.4) containing 50mg/mL, and soaked at 4 ℃ for 24 hours, then washed with 20 times the volume of deionized water, soaked with 0.1mol/L of LTris-HCl at 25 ℃ for 12 hours at pH 7.0 to block excess active groups on the substrate, and finally the substrate was washed thoroughly with 1.0mol/L of NaCl and water to obtain an endotoxin-adsorbing material, labeled B5'.
Comparative example 1
The comparative example provides an endotoxin adsorption material with polymyxin B sulfate as a ligand, which comprises the following specific components:
100g of dried agarose gel, 5g of p-toluenesulfonyl chloride (dissolved in 100mL of acetone) and 10g of pyridine are placed in a container, soaked and reacted for 1.5h, taken out, washed by 1L of acetone, and then mixed with the agarose gel in a ratio of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, each 2 times and finally washed with 1mmol/L hydrochloric acid to give a tosylated matrix which is stored at 4 ℃ in 1mmol/LHCl for several weeks without loss of coupling efficiency and labelled C0.
5g of C0 prepared above was placed in a PMB solution (dissolved in PBS pH 7.4) containing 50mg/mL, and the mixture was soaked at 25 ℃ for 24 hours, washed with 20 times the volume of deionized water, soaked with 0.1mol/L of LTris-HCl at 25 ℃ for 12 hours at pH 8.0 to block excess reactive groups on the substrate, and finally the substrate was washed thoroughly with 1.0mol/L of NaCl and water to obtain an endotoxin-adsorbing material labeled C1.
Comparative example 2
The comparative example provides a bilirubin adsorbing material with n-butylamine as a ligand, which comprises the following specific components:
100g of dried PVA, 5g of p-toluenesulfonyl chloride (dissolved in 100mL of acetone) and 10g of pyridine are placed in a container, soaked and reacted for 1.5h, taken out, washed by 1L of acetone and then mixed with water according to the proportion of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, each 2 times and finally 1mmol/L hydrochloric acid, to give a tosylated substrate, which is stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and labeled D0.
5g of D0 prepared above was placed in a PMB solution (dissolved in PBS pH 7.4) containing 50mg/mL, and the mixture was soaked at 25 ℃ for 24 hours, washed with 20 times the volume of deionized water, soaked with 0.1mol/L of LTris-HCl at 25 ℃ for 12 hours at pH 8.0 to block excess active groups on the substrate, and finally the substrate was washed thoroughly with 1.0mol/L of NaCl and water to obtain an endotoxin-adsorbing material labeled D1.
Comparative example 3
The comparative example provides a bilirubin adsorbing material with n-butylamine as a ligand, which comprises the following specific components:
100g of dry EVOH hollow fiber (tubular, the inner diameter of which is 200 mu m), 6g of epichlorohydrin and 10g of pyridine are placed in a container, soaked and reacted for 1.5h, taken out, washed by 1L of acetone, and then mixed with water according to the proportion of 30: 70. 50: 50. 70: 30 of a 1mmol/L hydrochloric acid-acetone mixture, each 2 times and finally washed with 1mmol/L hydrochloric acid to give a modified substrate which is stored at 4 ℃ in 1mmol/L HCl for several weeks without loss of coupling efficiency and is labelled E0.
5g of E0 prepared above was placed in a PMB solution (dissolved in PBS pH 7.4) containing 50mg/mL, and soaked at 25 ℃ for 24 hours, then washed with 20 times the volume of deionized water, soaked with 0.1mol/L of LTris-HCl at 25 ℃ for 12 hours at pH 8.0, to block excess reactive groups on the substrate, and finally the substrate was washed thoroughly with 1.0mol/L of NaCl and water to obtain an endotoxin adsorbing material, labeled E1.
Effect verification test-adsorption Performance test
The adsorption performance test of the adsorption materials prepared in the above examples 1 to 5 and comparative examples 1 to 3 was carried out by the following specific operations:
adsorption of bilirubin experiment: washing the prepared bilirubin adsorption material with a large amount of water, draining to constant weight, weighing 3g, and packaging
And pre-charging the column with normal saline, adding 30mL of bovine plasma added with bilirubin, performing dynamic adsorption circulation for 2h, and testing the bilirubin content in the bovine plasma before and after adsorption.
Endotoxin adsorption experiment: washing the prepared endotoxin adsorbing material with a large amount of water, pumping to constant weight for later use,
soaking the column with 1M sodium hydroxide overnight, cleaning with pyrogen-free water, weighing 3g, placing into the column washed with the alkali bubble, pre-charging with normal saline, adding 30mL bovine plasma with endotoxin, performing dynamic adsorption circulation for 2h, and testing endotoxin content in the bovine plasma before and after adsorption.
Experiment for adsorbing sepsis pathogenic bacteria: washing the prepared endotoxin adsorbing material with a large amount of water, pumping to constant weight for later use,
soaking the column with 1M sodium hydroxide overnight, cleaning with pyrogen-free water, weighing 3g, placing into the column, pre-charging with normal saline, adding 30mL bovine plasma with addition of Escherichia coli (E.coli), Staphylococcus aureus (S.aureus) and Candida albicans (C.albicans), dynamic adsorption circulating for 2h, and testingAnd (4) adsorbing the sepsis pathogenic bacteria content in the bovine plasma before and after adsorption.
Molecular experiment for adsorbing sepsis pathogens: washing the prepared endotoxin adsorbing material with a large amount of water, pumping to constant weight for later use,
soaking the column with 1M sodium hydroxide overnight, cleaning with pyrogen-free water, weighing 3g, placing into the column washed with the alkali bubble, pre-charging with normal saline, adding 30mL bovine plasma added with endotoxin, peptidoglycan, DNA and IL-6, performing dynamic adsorption circulation for 2h, and testing the contents of endotoxin, peptidoglycan, DNA and IL-6 in the bovine plasma before and after adsorption.
The results of the adaptivity and the appreciable efficacy of the adsorbent materials prepared in examples 1-5 and comparative examples 1-3 for selective adsorption of various components from whole blood or plasma are shown in table 1.
TABLE 1
Note: the organic sulfonyl chloride method in B5' is 2, 2, 2-trifluoro ethanesulfonyl chloride, and the rest is p-toluenesulfonyl chloride
Effect test two blood compatibility test
The blood compatibility test was performed on the adsorbing materials prepared in examples 1 to 5 and comparative examples 1 to 3, and the following specific operations were performed:
hemolysis experiment: hemolysis experiments are carried out according to the experimental selection of interaction with blood in GB/T16886.4-2003 section 4 of medical device biology evaluation and the experimental method of GB/T16175-2008 of biological evaluation of medical organosilicon materials. 1g of the adsorbing material prepared in the embodiment 2-5 is added into each tube of the sample group, and then 10ml of sodium chloride injection is added; adding 10ml of sodium chloride injection into each tube of the negative control group; 10ml of distilled water was added to each tube of the positive control group. Each set operated 3 tubes in parallel. Placing all test tubes in constant temperature water bath (37 + -1) deg.C, keeping the temperature for 30min, adding 0.2ml diluted rabbit blood into each test tube, mixing, and placing in water bath (37 + -1) deg.C for keeping the temperature for 60 min. The liquid in the pouring tube was centrifuged at 800g for 5 min. The supernatant was pipetted into a cuvette and the absorbance was measured with a spectrophotometer at 545nm wavelength. The absorbance of the sample combination control group was averaged over 3 tubes. The absorbance of the negative control tube should not be greater than 0.03, the absorbance of the positive control tube should be 0.8 + -0.3, otherwise, the test should be repeated. Hemolysis rate ═ a-B)/(C-B) × 100%, where a is the absorbance of the sample group; b is the absorbance of the negative control group; and C is the absorbance of the positive control group.
Blood compatibility test: 1g of each of the adsorbing materials prepared in examples 1 to 5 and comparative examples 1 to 3 was soaked in physiological saline for 10 hours and then placed in a column, 10mL of rabbit whole blood anticoagulated with heparin sodium was injected by a syringe, and the rabbit whole blood was adsorbed at a flow rate of 20mL/min for 2 hours while a control experiment was carried out by applying a hollow column. The change of each component of the blood before and after adsorption is measured by a Beckman LH750 blood cell analyzer.
The results show that: (1) the hemolysis rates of the adsorbing materials prepared in the examples 1-5 and the comparative examples 1-3 are less than 2 percent and less than 5 percent which is lower than the national standard requirement. (2) The change of each main component in blood before and after adsorption of the adsorbing materials prepared in examples 1-5 and comparative examples 1-3 is not large, and the reduction percentage is within 5%. The results show that the adsorbing materials prepared by the invention all have good blood compatibility.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the patent of the invention is subject to the content of the appended claims, and the description can be used for explaining the content of the claims.
Claims (10)
1. An adsorbing material for blood purification, which is characterized in that the adsorbing material is formed by modifying EVOH hollow fiber matrix with organic sulfonyl chloride to form a graft chain with a sulfonyl ester group, and then the sulfonyl ester group is covalently linked with an amino compound ligand.
2. The adsorbent material for blood purification according to claim 1, wherein the amino compound is at least one selected from the group consisting of n-butylamine, polymyxin B sulfate, lysozyme and kukoamine B.
3. The adsorption material for blood purification according to claim 1, wherein the organic sulfonyl chloride is at least one selected from the group consisting of p-toluenesulfonyl chloride, 2, 2, 2-trifluoroethanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2, 4, 6-triisopropylbenzenesulfonyl chloride and chlorobenzene sulfonyl chloride.
4. The adsorbing material for blood purification according to claim 1, wherein the EVOH hollow fiber matrix is a hollow fiber woven tube, a hollow fiber woven mesh, or a hollow fiber tubular nonwoven material; and/or
The inner diameter of the EVOH hollow fiber matrix is 200-300 mu m.
5. A method for producing an adsorbing material for blood purification according to any one of claims 1 to 4, comprising the steps of:
and mixing the EVOH hollow fiber substrate with the organic sulfonyl chloride for activation reaction, mixing with the amino compound, and performing covalent coupling reaction.
6. The method for preparing an adsorbing material for blood purification according to claim 5, wherein the temperature of the activation reaction is 20 to 30 ℃, and the time of the activation reaction is 1 to 3 hours; and/or
The solvent adopted by the activation reaction is an organic solvent; and/or
Mixing the EVOH hollow fiber substrate with the organic sulfonyl chloride, and then mixing with pyridine; the mass ratio of the EVOH hollow fiber matrix to the organic sulfonyl chloride to the pyridine is (15-30) to 1 (1-5); and/or
The amino compound is added in the form of a solution, and the concentration of the solution is 1 mg/mL-50 mg/mL.
7. The method for preparing an adsorbing material for blood purification according to any one of claims 5 to 6, wherein the conditions of the covalent coupling reaction are as follows: the temperature is 4-40 ℃, the time is 8-24 h, and the pH is 4.5-9.5; and/or
The covalent coupling reaction is followed by a capping step: and (3) soaking a substrate subjected to the covalent coupling ligand reaction and trihydroxymethyl aminomethane hydrochloride with the pH value of 7.5-9.5 at the temperature of 20-30 ℃ for reaction for 6-24 h, and sealing redundant active groups on the substrate.
8. Use of the adsorbent material for blood purification according to any one of claims 1 to 4 for adsorption of biological components in blood for non-disease diagnosis and treatment purposes.
9. An adsorption column comprising the adsorbent for blood purification according to any one of claims 1 to 4.
10. A blood adsorbing device comprising the adsorbing material for blood purification of any one of claims 1 to 4 or the adsorption column of claim 9.
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