CN117696017A - Blood purification adsorption modified material and preparation method thereof - Google Patents

Blood purification adsorption modified material and preparation method thereof Download PDF

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CN117696017A
CN117696017A CN202410165242.XA CN202410165242A CN117696017A CN 117696017 A CN117696017 A CN 117696017A CN 202410165242 A CN202410165242 A CN 202410165242A CN 117696017 A CN117696017 A CN 117696017A
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CN117696017B (en
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付平
张凌
李林华
张翔
杨梅
梁婉荧
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West China Hospital of Sichuan University
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    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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Abstract

The invention belongs to the field of blood purification materials, and particularly relates to a blood purification adsorption modified material and a preparation method thereof. The preparation method comprises the following steps: soaking the blood purification and adsorption material in an oxidant acid solution, and performing reaction and cleaning to obtain a carboxylation purification and adsorption material; EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylation purification adsorption material for reaction, then amine-containing hydrophobic compound-ethanol/water solution is added for reaction, finally NO catalyst solution is added for reaction, and after completion, the blood purification adsorption modified material is obtained through cleaning and drying. According to the invention, the hydrophobic compound and the NO catalyst are modified on the surface of the blood purification adsorption material, so that the biocompatibility of the adsorption material can be effectively ensured, and the coagulation and inflammatory reaction can be reduced; also improves the removal of non-polar harmful substances, fat-soluble drugs, fat-soluble substances, non-polar bacterial endotoxins and harmful proteins which can coordinate with NO catalysts.

Description

Blood purification adsorption modified material and preparation method thereof
Technical Field
The invention belongs to the field of blood purification materials, and particularly relates to a blood purification adsorption modified material and a preparation method thereof.
Background
Blood purification therapy is an extracorporeal circulation type life support technology, and has been used clinically for treating various diseases such as poisoning (drugs, pesticides, heavy metals, biotoxins, drugs, etc.), uremia, liver diseases, hyperlipidemia, septicemia, autoimmune diseases, etc. Patients with these diseases accumulate large amounts of exogenous or endogenous toxins in the body either by ingestion of toxic substances or by dysfunction of their own detoxification, immune, metabolic systems. Under the condition that the function of the detoxification organs (kidneys and livers) of the patient is invalid, the blood purification therapy can lead the blood of the patient out of the body and pass through the purification device to purify and remove toxins in the blood, and the purified blood is returned to the body of the patient, so that the detoxification system of the patient is replaced to remove the toxins. The blood purification modes include: hemodialysis, hemofiltration and hemodiafiltration. The core purification material for blood perfusion is a blood perfusion adsorbent, and toxins in blood are removed through broad-spectrum adsorption and specific adsorption of the adsorbent based on an adsorption principle. The broad-spectrum adsorbent plays an important role in the process, and can simultaneously remove various harmful substances including but not limited to urinary toxins, creatinine, bilirubin, endotoxin, inflammatory factors, drug residues, toxins and the like, shorten the treatment time and times, and lighten the organ burden, thereby reducing the pain and the economic pressure of patients.
Although widely used in clinic, broad spectrum adsorption columns still face a number of difficulties and challenges during use. Comprising the following steps: 1) Equilibrium of selectivity and affinity: broad spectrum adsorbents require high adsorption capacity for a variety of substances, but at the same time do not wish to produce excessive adsorption of normal blood components (e.g., proteins, electrolytes, nutrients, etc.). Thus, it is a significant challenge to design and produce a broad-spectrum adsorbent having both high selectivity and high affinity. 2) Biocompatibility: the adsorbent needs to be in direct contact with blood and thus must have good biocompatibility to avoid adverse reactions such as thrombus, inflammation or immune response. Currently, many adsorbents have not achieved the desired biocompatibility. 3) Easy blockage: blood contains various solid components such as red blood cells, white blood cells, platelets, fibrin, etc., which may clog the pores of the adsorbent, thereby affecting its adsorption effect and perfusion efficiency. 4) Broad spectrum performance: the harmful substances in blood are various, including organic substances, inorganic substances, drugs, toxins, pathogens, cells, etc. It is a great challenge to develop an adsorbent that has efficient adsorption properties for these various substances. 5) Adsorption of proteins: blood contains a large amount of proteins, and some adsorbents may have nonspecific adsorption of proteins, thereby changing the composition and properties of blood.
In blood perfusion, the broad-spectrum adsorption of the adsorbent mainly comprises van der Waals force, hydrogen bonding force, electrostatic force, hydrophobic effect, coordination effect and the like. Therefore, the surface modification technology enables the broad-spectrum adsorbent to have various acting forces, and is an effective means for realizing efficient adsorption of various substances.
Therefore, the technical scheme of the invention is provided based on the above.
Disclosure of Invention
In order to solve the problems in the prior art, the scheme of the invention is to provide a preparation method of a blood purification adsorption modified material, which comprises the following steps:
(1) Soaking the blood purification and adsorption material in an oxidant acid solution, and performing reaction and cleaning to obtain a carboxylation purification and adsorption material;
(2) EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylation purification adsorption material for reaction, then amine-containing hydrophobic compound-ethanol/water solution is added for reaction, finally NO catalyst solution is added for reaction, and after completion, the blood purification adsorption modified material is obtained through cleaning and drying.
To facilitate understanding of the present invention, the reaction process of the present invention will be described:
firstly, generating carboxyl on the surface of a blood purification adsorption material by utilizing the oxidation action of an oxidant; and then under the action of carboxyl activator EDC/NHS, the hydrophobic compound is combined with carboxyl on the surface of the adsorption material and a catalyst capable of catalyzing NO donor to decompose and release NO respectively through amide reaction and chelation, and the hydrophobic compound and the catalyst capable of catalyzing NO donor to decompose and release NO are efficiently and firmly fixed on the surface of the adsorption column material through a chemical grafting mode. The hydrophobicity of the surface of the blood purification and adsorption modified material is increased, so that the adsorption capacity of the blood purification process to toxins and wastes is improved; the catalyst capable of catalyzing the decomposition of the NO donor to release NO can catalyze the endogenous NO donor in blood to continuously release NO, so that the biocompatibility of the blood purification and adsorption modified material is ensured. The catalysis synergistic effect of the hydrophobic compound and the catalyst for decomposing NO donor to release NO improves the adsorption performance of the blood purification adsorption modified material. The invention can be applied to the surface modification treatment of blood purification materials and instruments.
Wherein, CAS number of NHS is: 6066-82-6, the English name is: n-hydroxycicinimide, chinese name: n-hydroxysuccinimide.
The CAS number of EDC is: 25952-53-8, english name:
1- (3-Dimethylmineopyl) -3-ethylcarbodiimide hydrochloride, chinese name: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
The CAS number for MES is: 4432-31-9, chinese name: 2-morpholinoethanesulfonic acid.
Preferably, in the step (1), the blood purification adsorption material is one of activated carbon resin, cation exchange resin, anion exchange resin, polystyrene, polyoxymethylene, polypropylene, polysulfone, polyethersulfone, nano activated carbon, nano graphene, and agarose.
Preferably, in step (1), the oxidant acid solution is prepared by mixing an oxidant and an acidic aqueous solution;
and/or the oxidant is one or the combination of more than two of nitric acid, potassium permanganate and hydrogen peroxide; the concentration of the nitric acid and the hydrogen peroxide is 0.5-15%, and the concentration of the potassium permanganate is 0.5-5 mg/mL;
and/or the pH value of the acidic aqueous solution is 3-6.5.
Preferably, in the step (1), the reaction temperature is 10-40 ℃ and the reaction time is 1-48 h.
Preferably, in the step (2), the EDC/NHS-MES buffer is prepared by mixing EDC/NHS and MES buffer;
and/or the amino-containing hydrophobic compound-ethanol/water solution is prepared by mixing the amino-containing hydrophobic compound and the ethanol/water solution;
and/or the NO catalyst solution is prepared by mixing a catalyst for catalyzing the decomposition of a NO donor to release NO with water.
Preferably, the pH of the MES buffer solution is 3-6.5;
and/or EDC/NHS-MES buffer solution, wherein the concentration of EDC is 0.75-7.5 mmol/L, and the concentration of NHS is 0.5-5 mmol/L;
and/or the amino-containing hydrophobic compound is one or more than two of hexadecylamine, dodecylamine, N-palmitoylethanolamine, N-oleoylethanolamide, leucine, isoleucine, phenylalanine, polydimethylsiloxane amine, dodecyltrimethylamine, fluorododecylamine, fluorinated polyamine and poly-p-aminophenether;
and/or, in the amino-containing hydrophobic compound-ethanol/water solution, the concentration of the amino-containing hydrophobic compound is 0.1-10 mg/mL;
and/or the catalyst for catalyzing the decomposition of the NO donor to release NO is Cu 2+ 、Fe 2+ 、Fe 3+ 、Mn 2+ 、Co 2+ 、Ag + One or more than two of ascorbic acid, iron phthalocyanine, cobalt phthalocyanine, ebselen and selenocysteine;
and/or the concentration of the catalyst for catalyzing the decomposition of the NO donor to release NO in the NO catalyst solution is 0.1-10 mg/mL.
Preferably, in the step (2), the reaction temperature is 10-40 ℃ and the reaction time is 1-48 h.
Based on the same technical concept, a further aspect of the present invention is to provide a blood purification and adsorption modified material obtained by the above preparation method.
The beneficial effects of the invention are as follows:
1. according to the preparation method, carboxyl is generated on the surface of the hemoperfusion adsorbent in situ by utilizing the oxidization of the oxidant in an acidic aqueous solution, so that the inert surface is converted into an active surface. The carboxylation surface process has no material dependence, can fully oxidize the surface of the adsorbent and generate carboxyl, does not have adverse effect on the adsorbent material, and has wide applicability and safety.
2. The carboxylated adsorbent and the hydrophobic compound containing amino react in amide, and the hydrophobic compound molecules are fixed on the surface of the material in a chemical bonding mode, so that the hydrophobicity of the adsorbent material is obviously improved, and the pore size of an adsorption column is not influenced.
3. When the NO catalyst chemically immobilized on the surface of the adsorbent contacts with blood, NO donors in the blood are catalyzed to decompose and release NO, and the NO is taken as a vascular signal molecule, so that activation and aggregation of blood platelets can be effectively inhibited, thereby reducing the formation of thrombus on the surface of the adsorbent and improving the blood compatibility; meanwhile, NO can inhibit the adhesion and migration of white blood cells, inhibit the release of inflammatory cytokines (such as TNF-alpha, IL-1 and IL-6) and chemokines (such as MCP-1), and has excellent anti-inflammatory effect. The excellent blood compatibility and anti-inflammatory effect can further improve the biocompatibility of the adsorbent, reduce the blocking rate of the pores of the adsorbent, and improve the adsorption effect and the perfusion efficiency of the adsorbent.
4. The modified adsorbent and the adsorbate have various acting forces, including comprehensive performance of the adsorbent material, hydrophobic effect, coordination effect of the NO catalyst, van der Waals force, hydrogen bond and electrostatic acting force, and two or more of the various acting forces can cooperatively realize efficient adsorption of various harmful substances in blood.
5. The method has the advantages of simple operation, high efficiency in reaction, NO need of expensive equipment, broad-spectrum practicability, and capability of fixing different hydrophobic compounds and NO catalysts on the surface of the adsorbent to prepare the blood purification adsorption column with excellent adsorption performance.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph of water contact angle before/after modification of polystyrene as described in example 1.
FIG. 2 shows the creatinine (a) and urea nitrogen (b) contents of blood reacted with blood of an acute kidney injury rabbit before/after modification of the polyoxymethylene adsorption column material described in example 2.
FIG. 3 is an SEM topography (b) of the polyethersulfone hemoperfusion adsorption column and microspheres (a) described in example 3, the polyethersulfone microspheres before/after modification reacting with platelet rich plasma.
FIG. 4 shows XPS full spectrum (a) of the back surface of the modified polypropylene and high resolution spectrum (b) of Se element as described in example 4, and the rate (c) of NO release by the catalytic NO donor.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, based on the examples herein, which are within the scope of the invention as defined by the claims, will be within the scope of the invention as defined by the claims.
Example 1
The embodiment provides a preparation method of a blood purification adsorption modified material, which comprises the following steps:
(1) Mixing hydrogen peroxide with an acidic aqueous solution having a ph=6 to obtain an aqueous hydrogen peroxide solution having a concentration of 5%;
(2) Mixing EDC/NHS with MES buffer solution with pH=5 to obtain EDC/NHS-MES buffer solution; wherein, the concentration of EDC is 1mmol/L, and the concentration of NHS is 1.5mmol/L;
(3) Mixing dodecylamine with ethanol/water solution to obtain dodecylamine-ethanol/water solution with concentration of 2 mg/mL; wherein, in the ethanol/water solution, the volume ratio of ethanol to water is 4:1;
(4) Copper chloride is mixed with water to obtain a copper chloride solution with the concentration of 1 mg/mL;
(5) Fully soaking the polystyrene serving as a blood purification adsorption material in a 5% hydrogen peroxide aqueous solution, reacting for 2 hours at 20 ℃, and then cleaning to obtain a carboxylated polystyrene purification adsorption material;
(6) EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylated polystyrene purification adsorption material for reaction, dodecylamine-ethanol/water solution is then added for reaction, copper chloride solution is finally added for reaction, and after the reaction is completed, the purification adsorption modified material for blood is obtained by cleaning and drying; the reaction was carried out at 20℃for a total reaction time of 5h.
Example 2
The embodiment provides a preparation method of a blood purification adsorption modified material, which comprises the following steps:
(1) Mixing nitric acid with an acidic aqueous solution with ph=3 to obtain an aqueous nitric acid solution with a concentration of 1%;
(2) Mixing EDC/NHS with MES buffer solution with pH=3 to obtain EDC/NHS-MES buffer solution; wherein, the concentration of EDC is 0.75mmol/L, and the concentration of NHS is 0.5mmol/L;
(3) Mixing isoleucine with ethanol/water solution to obtain isoleucine-ethanol/water solution with concentration of 0.1 mg/mL; wherein, in the ethanol/water solution, the volume ratio of ethanol to water is 4:1;
(4) Mixing ascorbic acid with water to obtain ascorbic acid solution with concentration of 0.1 mg/mL;
(5) Fully soaking the blood purification adsorption material polyformaldehyde in 1% nitric acid aqueous solution, reacting for 12 hours at 10 ℃, and then cleaning to obtain carboxylated polyformaldehyde purification adsorption material;
(6) EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylated polyformaldehyde purification adsorption material for reaction, isoleucine-ethanol/water solution is then added for reaction, and finally ascorbic acid solution is added for reaction, and after completion, the blood purification adsorption modified material is obtained by washing and drying; the reaction was carried out at 10℃for a total reaction time of 12h.
Example 3
The embodiment provides a preparation method of a blood purification adsorption modified material, which comprises the following steps:
(1) Mixing potassium permanganate with an acidic aqueous solution with ph=6.5 to obtain a potassium permanganate aqueous solution with a concentration of 5mg/mL;
(2) Mixing EDC/NHS with MES buffer with pH=6.5 to obtain EDC/NHS-MES buffer; wherein, the concentration of EDC is 7.5mmol/L, and the concentration of NHS is 5mmol/L;
(3) Mixing dodecyl trimethylamine with ethanol/water solution to obtain dodecyl trimethylamine-ethanol/water solution with the concentration of 10 mg/mL; wherein, in the ethanol/water solution, the volume ratio of ethanol to water is 4:1;
(4) Mixing cobalt phthalocyanine with water to obtain a cobalt phthalocyanine solution with the concentration of 10 mg/mL;
(5) Fully soaking the blood purification adsorption material polyethersulfone in 5mg/mL potassium permanganate aqueous solution, reacting for 1h at 40 ℃, and then cleaning to obtain carboxylated polyethersulfone purification adsorption material;
(6) EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylated polyether sulfone purification and adsorption material for reaction, dodecyl trimethylamine-ethanol/water solution is then added for reaction, cobalt phthalocyanine solution is finally added for reaction, and after the reaction is completed, the material is washed and dried to obtain the blood purification and adsorption modified material; the reaction was carried out at 40℃for a total reaction time of 1h.
Example 4
The embodiment provides a preparation method of a blood purification adsorption modified material, which comprises the following steps:
(1) Mixing potassium permanganate with an acidic aqueous solution with ph=6.5 to obtain a potassium permanganate aqueous solution with a concentration of 2 mg/mL;
(2) Mixing EDC/NHS with MES buffer with pH=6.5 to obtain EDC/NHS-MES buffer; wherein, the concentration of EDC is 7.5mmol/L, and the concentration of NHS is 5mmol/L;
(3) Mixing the fluorinated polyamine with an ethanol/water solution to obtain a fluorinated polyamine-ethanol/water solution with a concentration of 10 mg/mL; wherein, in the ethanol/water solution, the volume ratio of ethanol to water is 4:1;
(4) Mixing ebselen with water to obtain ebselen solution with concentration of 5mg/mL;
(5) Fully soaking the blood purification adsorption material polypropylene in 1mg/mL potassium permanganate aqueous solution, reacting for 48 hours at 40 ℃, and then cleaning to obtain carboxylated polypropylene purification adsorption material;
(6) EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylated polypropylene purification adsorption material for reaction, then fluorinated polyamine-ethanol/water solution is added for reaction, and finally ebselen solution is added for reaction, and after completion, the material is washed and dried to obtain the blood purification adsorption modified material; the reaction was carried out at 40℃for a total reaction time of 48h.
Verification example
Fig. 1 is a graph of water contact angle before/after modification of polystyrene described in example 1, from which it can be seen that water contact on the surface of the adsorption column material is significantly improved after modification.
FIG. 2 shows the creatinine (a) and urea nitrogen (b) contents of blood reacted with blood of an acute kidney injury rabbit before/after modification of the polyoxymethylene adsorption column material described in example 2. The graph shows that the modified polyformaldehyde material can obviously reduce the contents of creatinine and urea nitrogen in blood, and the modified adsorption column has excellent adsorption performance on toxic substances in blood.
FIG. 3 is an SEM topography (b) of the polyethersulfone hemoperfusion adsorption column and microspheres (a) described in example 3, the polyethersulfone microspheres before/after modification reacting with platelet rich plasma. From the figure, it can be seen that the modified polyethersulfone still has excellent blood compatibility.
FIG. 4 shows XPS full spectrum (a) of the back surface of the modified polypropylene and high resolution spectrum (b) of Se element as described in example 4, and the rate (c) of NO release by the catalytic NO donor. From the figure, it can be found that ebselen which catalyzes the decomposition of the NO donor and releases NO is successfully modified to the surface of the material, and can catalyze the release of NO in the physiological concentration range.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (8)

1. A method for preparing a blood purification adsorption modified material, which is characterized by comprising the following steps:
(1) Soaking the blood purification and adsorption material in an oxidant acid solution, and performing reaction and cleaning to obtain a carboxylation purification and adsorption material;
(2) EDC/NHS-MES buffer solution is firstly added to the surface of the carboxylation purification adsorption material for reaction, then amine-containing hydrophobic compound-ethanol/water solution is added for reaction, finally NO catalyst solution is added for reaction, and after completion, the blood purification adsorption modified material is obtained through cleaning and drying.
2. The method for producing a modified blood purification and adsorption material according to claim 1, wherein in the step (1), the blood purification and adsorption material is one of activated carbon resin, cation exchange resin, anion exchange resin, polystyrene, polyoxymethylene, polypropylene, polysulfone, polyethersulfone, nano activated carbon, nano graphene, and agarose.
3. The method for producing a blood purification adsorption-modified material according to claim 1, wherein in the step (1), the oxidizing agent acidic solution is prepared by mixing an oxidizing agent and an acidic aqueous solution;
and/or the oxidant is one or the combination of more than two of nitric acid, potassium permanganate and hydrogen peroxide; the concentration of the nitric acid and the hydrogen peroxide is 0.5-15%, and the concentration of the potassium permanganate is 0.5-5 mg/mL;
and/or the pH value of the acidic aqueous solution is 3-6.5.
4. The method for producing a modified adsorbent for blood purification according to claim 1, wherein in the step (1), the reaction temperature is 10 to 40 ℃ and the reaction time is 1 to 48 hours.
5. The method for preparing a blood purification and adsorption modified material according to claim 1, wherein in the step (2), the EDC/NHS-MES buffer is prepared by mixing EDC/NHS and MES buffer;
and/or the amino-containing hydrophobic compound-ethanol/water solution is prepared by mixing the amino-containing hydrophobic compound and the ethanol/water solution;
and/or the NO catalyst solution is prepared by mixing a catalyst for catalyzing the decomposition of a NO donor to release NO with water.
6. The method for preparing a blood purification and adsorption modified material according to claim 5, wherein the MES buffer has a pH of 3 to 6.5;
and/or EDC/NHS-MES buffer solution, wherein the concentration of EDC is 0.75-7.5 mmol/L, and the concentration of NHS is 0.5-5 mmol/L;
and/or the amino-containing hydrophobic compound is one or more than two of hexadecylamine, dodecylamine, N-palmitoylethanolamine, N-oleoylethanolamide, leucine, isoleucine, phenylalanine, polydimethylsiloxane amine, dodecyltrimethylamine, fluorododecylamine, fluorinated polyamine and poly-p-aminophenether;
and/or, in the amino-containing hydrophobic compound-ethanol/water solution, the concentration of the amino-containing hydrophobic compound is 0.1-10 mg/mL;
and/or the catalyst for catalyzing the decomposition of the NO donor to release NO is Cu 2+ 、Fe 2+ 、Fe 3+ 、Mn 2+ 、Co 2+ 、Ag + One or more than two of ascorbic acid, iron phthalocyanine, cobalt phthalocyanine, ebselen and selenocysteine;
and/or the concentration of the catalyst for catalyzing the decomposition of the NO donor to release NO in the NO catalyst solution is 0.1-10 mg/mL.
7. The method for producing a modified adsorbent for blood purification according to claim 1, wherein in the step (2), the reaction temperature is 10 to 40 ℃ and the reaction time is 1 to 48 hours.
8. The modified blood purification and adsorption material obtained by the preparation method according to any one of claims 1 to 7.
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