CN115414539B - Preparation method of polyphenol-polymer coating and application of polyphenol-polymer coating in enhancing procoagulant property of material - Google Patents
Preparation method of polyphenol-polymer coating and application of polyphenol-polymer coating in enhancing procoagulant property of material Download PDFInfo
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- CN115414539B CN115414539B CN202211070011.8A CN202211070011A CN115414539B CN 115414539 B CN115414539 B CN 115414539B CN 202211070011 A CN202211070011 A CN 202211070011A CN 115414539 B CN115414539 B CN 115414539B
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- polyphenol
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- polymer coating
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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Classifications
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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
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- 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
- A61L31/08—Materials for coatings
-
- 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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- 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
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
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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
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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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
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/02—Methods for coating medical devices
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Abstract
The invention discloses a preparation method of a polyphenol-polymer coating and application thereof in enhancing procoagulant property of a material, wherein the preparation method comprises the following steps: soaking the substrate in the mixed solution of polyphenol hydroxyl substances and hydrophilic uncharged or hydrophilic negatively charged polymers at room temperature for 0.7-4 hours to obtain the material with polyphenol/polymer codeposition coagulation promoting and hemostasis coating; the mass ratio of the polyphenol hydroxyl substances to the hydrophilic uncharged or hydrophilic negatively charged polymers is 1:2-8. The coating converts key coagulation proteins into activated conformation through moderate plasma protein adhesion, and promotes adhesion of platelets, so that optimal procoagulant performance is achieved.
Description
Technical Field
The invention belongs to the field of medical hemostatic materials, and relates to a preparation method of a polyphenol-polymer coating and application of the polyphenol-polymer coating in enhancing procoagulant property of a material.
Background
Uncontrolled bleeding is a significant cause of injury and death in traffic accidents, surgical procedures, and natural disasters. The existing common hemostatic materials/medical instruments have the defect of insufficient performance, so that the development of efficient and safe novel hemostatic materials is very important. The novel procoagulant coating is constructed to carry out surface modification on the existing medical hemostatic material/instrument, so that the hemostatic performance of the hemostatic material/instrument can be improved on the basis of not changing the application scene of the existing hemostatic material/instrument, and the clinical requirements can be better met. In the current study of the anticoagulation of surface materials (Acta Biomaterialia,2017, 64:187-199), it has been found that when the adhesion capability of the surface of the material to proteins is too strong, a stronger interaction with proteins occurs, and during the contact of the surface with blood, the stronger adhesion is unfavorable for the conversion of fibrinogen into its effective conformation, thereby inhibiting the adhesion and activation of platelets, resulting in anticoagulation. Therefore, there is a need to develop procoagulant coatings with controlled/gentle protein adhesion capability that promote platelet adhesion and activation by promoting the conversion of key coagulation proteins into an effective conformation, ultimately promoting coagulation. The technology for preparing the composite hemostatic coating by codeposition of the polyphenol substance and the polyhydroxy polymer is not reported in China.
Disclosure of Invention
In view of this, the present invention provides a method for preparing a polyphenol-polymer coating and its application in enhancing procoagulant properties of materials. The invention specifically provides the following technical scheme:
a preparation method of a polyphenol-polymer coating and application thereof in enhancing procoagulant property of materials are provided, wherein the preparation method comprises the following steps: 1) Preparing a mixed solution of a polyphenol hydroxyl substance and a hydrophilic uncharged or hydrophilic negatively charged polymer, wherein the mass ratio of the polyphenol hydroxyl substance to the hydrophilic uncharged or hydrophilic negatively charged polymer is 1:2-8; 2) Soaking the base material in the mixed solution for 0.7-4 hours; 3) Washing and drying to obtain the material with polyphenol-polymer codeposition coagulation promoting and hemostasis coating.
Further, the mass ratio of the polyphenol hydroxyl substances in the step 1) to the hydrophilic uncharged or hydrophilic negatively charged polymers is 1:2-5, the concentration of the polyphenol hydroxyl substances in the mixed solution is 0.25-3 mg/mL, and the soaking time in the step 2) is 0.7-1.5 hours.
Further, the mixed solution in the step 1) is an alkaline aqueous solution, and the pH value is 8-9.
Further, the polyphenol hydroxyl substances in the step 1) are dopamine, tannic acid, gallic acid, catechin, epicatechin, epigallocatechin gallate, theaflavin-3-gallate, 5-hydroxydopamine hydrochloride or baicalein, the hydrophilic uncharged polymer in the step 1) is dextran, hydroxypropyl cellulose, hydroxyethyl starch, hydroxyethyl cellulose, pullulan, pramipernine or polyethylene glycol, and the hydrophilic negatively charged polymer in the step 1) is carboxymethyl cellulose or alginic acid, sodium alginate, hyaluronic acid, sodium hyaluronate or carboxymethyl starch.
Further, the concentration of the polyphenol hydroxyl substance in the step 1) in the mixed solution is 1-1.5 mg/mL, and the concentration of the hydrophilic uncharged or hydrophilic negative polymerization in the mixed solution is 3-5 mg/mL.
Further, the polyphenol hydroxyl substance in the step 1) is dopamine, tannic acid or gallic acid, the hydrophilic uncharged polymer in the step 1) is dextran, hydroxypropyl cellulose or polyethylene glycol, and the hydrophilic negatively charged polymer in the step 1) is carboxymethyl cellulose.
Further, the base material in the step 2) is a high molecular medical material, an inorganic medical material or a metal medical material; the high molecular medical material is gauze, polyvinyl alcohol sponge, polyvinyl alcohol micron-sized particles, polyvinyl alcohol microspheres, chitosan sponge, chitosan non-woven fabric, gelatin sponge micron-sized particles, alginic acid dressing, alginic acid microspheres, alginic acid non-woven fabric or collagen sponge; the inorganic medical material is bioglass and bioceramic; the metal medical material is nickel-titanium alloy instrument, titanium alloy medical instrument and shape memory metal microcoil.
Furthermore, when the substrate in the step 2) is a metal medical material, the substrate may be pretreated with a polyphenol hydroxyl substance before soaking the mixed solution, so as to form a polyphenol coating on the surface of the substrate.
Further, the pretreatment method comprises the following steps: soaking the base material in alkaline water solution with pH of 8-9 for 4-24 hr.
Further, the substrate in the step 2) is gauze, polyvinyl alcohol sponge, polyvinyl alcohol micron-sized particles, polyvinyl alcohol microspheres, gelatin sponge micron-sized particles, collagen sponge, bioglass or titanium alloy medical equipment.
The invention has the beneficial effects that: the present invention utilizes oxidative autopolyzation of polyphenol hydroxyl species in combination with hydrophilic uncharged or negatively charged polymers to form a coating on a substrate surface. The polyphenol hydroxyl substance has strong hydrogen bond interaction with protein, and provides acting force on blood coagulation key components such as plasma protein (fibrinogen and the like) in blood in the composite coating so as to cause the blood coagulation key components to adhere and aggregate; in the process of co-depositing the hydrophilic uncharged or negatively charged polymer with the anti-protein adhesion effect and the polyphenol hydroxyl substance, the effect between the phenolic hydroxyl and the protein is regulated, and the ' mild '/medium-strength ' protein adhesion is realized by weakening the acting force of the phenolic hydroxyl and the hydrogen bond of key blood coagulation proteins in blood plasma, so that the protein is converted into a conformation which is easy to adhere to blood platelets, the adhesion of the blood platelets is promoted, and the effect of promoting blood coagulation is further achieved.
The polyphenol/hydrophilic uncharged or negatively charged polymer forms a procoagulant coating, can be compounded with the existing hemostatic devices (such as gelatin sponge, gauze, embolic coil, and the like), and can enhance the procoagulant performance of the hemostatic devices without changing the original application scene. The ratio of polyphenol to polymer and the treatment time can be regulated to form coagulation promoting coating on different substrates, and the coating can convert key coagulation proteins into activated conformation through moderate plasma protein adhesion to promote the adhesion of platelets, so as to achieve optimal coagulation promoting performance.
The electropositivity of the electropositive polymer has a strong attraction to negatively charged blood cells in the blood, and if the electropositive polymer is used for co-deposition (whatever polyphenol/polymer ratio and treatment time), the resulting polyphenol/electropositive polymer coating does not significantly reduce or even potentially enhance the strong interaction of the protein compared to the strong force of the pure polyphenol coating on the protein. Therefore, in the presence of these two strong interactions, the plasma proteins are instead inhibited from transforming into an effective conformation to promote clotting, failing to adhere effectively to the platelets, and the surface losing the procoagulant effect. The present invention therefore can only employ hydrophilic uncharged or negatively charged polymer phases and cannot use positively charged polymers.
Detailed Description
Preferred embodiments of the present invention are described in detail below.
Example 1
Dopamine hydrochloride (50 mg) and glucan (250 mg) are dissolved in 50mL of Tris buffer solution (10 mM), the pH is adjusted to 8.5, a commercial gelatin sponge is soaked in the solution, the commercial gelatin sponge is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which are not formed into a coating are removed, and the GS1 is obtained through freeze drying.
In the embodiment, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1:5.
Example 2
50mg of dopamine hydrochloride and 250mg of glucan are dissolved in 50mL of Tris buffer solution (10 mM), the pH is adjusted to 8.5, the commercial gelatin sponge micron-sized particles are soaked in the solution, the solution is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which are not formed into a coating are removed, and GSP1 is obtained through freeze drying.
In the embodiment, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1:5.
Example 3
50mg of tannic acid and 150mg of polyethylene glycol were dissolved in 50mL of Tris buffer solution (10 mM), pH was adjusted to 8.5, a commercially available gelatin sponge was added to the solution, immersed at 25℃for 1 hour, washed three times with a large amount of deionized water, and the tannic acid and polyethylene glycol which did not form a coating were removed, and dried to obtain GS2.
In the embodiment, the polyphenol hydroxyl substance is tannic acid, the hydrophilic uncharged polymer is polyethylene glycol, and the mass ratio is 1:3.
Example 4
Gallic acid 75mg and hydroxypropyl cellulose 150mg were dissolved in 50mL Tris buffer solution (10 mM), pH was adjusted to 8.5, commercial gauze was soaked in the solution, soaked at 25 ℃ for 1h, taken out, washed three times with a large amount of deionized water, gallic acid and hydroxypropyl cellulose which did not form a coating were removed, and freeze-dried to obtain G1.
In the embodiment, the polyphenol hydroxyl substance is gallic acid, the hydrophilic uncharged polymer is hydroxypropyl cellulose, and the mass ratio is 1:2.
Example 5
Gallic acid 50mg and carboxymethyl cellulose 250mg are dissolved in 50mL Tris buffer solution (10 mM), pH is adjusted to 8.5, commercial gauze is soaked in the solution, the gauze is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, gallic acid and carboxymethyl cellulose which do not form a coating are removed, and G2 is obtained through freeze drying.
In the embodiment, the polyphenol hydroxyl substance is gallic acid, the hydrophilic electronegative polymer is carboxymethyl cellulose, and the mass ratio is 1:5.
Example 6
1) Preparing 1mg/mL dopamine hydrochloride solution by using Tris buffer solution (10 mM), regulating the pH value to 8.5, soaking a medical experimental titanium alloy wafer in the solution for 12 hours at 25 ℃, and washing the wafer with a large amount of deionized water for three times;
2) And 5mg of dopamine hydrochloride and 25mg of glucan are dissolved in 5mL of Tris buffer solution (10 mM), the titanium alloy wafer treated in the step 1) is soaked in the solution, the titanium alloy wafer is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which are not coated are removed, and the titanium alloy wafer is dried by nitrogen to obtain Ti1.
In the embodiment, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1:5.
Example 7
50mg of dopamine hydrochloride and 250mg of glucan are dissolved in 50mL of Tris buffer solution (10 mM), the pH value is adjusted to 8.5, a medical glass sheet is soaked in the solution, the medical glass sheet is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which are not formed into a coating are removed, and GL1 is obtained through nitrogen blow-drying.
In the embodiment, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, the mass ratio is 1:5, and the soaking time is 1h.
Example 8
5mg of dopamine hydrochloride and 25mg of glucan are dissolved in 5mL of Tris buffer solution (10 mM), a medical experimental titanium alloy wafer is soaked in the mixed solution, the medical experimental titanium alloy wafer is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which do not form a coating are removed, and nitrogen is blown dry to obtain Ti2.
In this comparative example, the surface of the titanium alloy wafer was prepared without polyphenol pretreatment (i.e., without using step 1) of example 6) directly using step 2)
Comparative example 1
Dopamine hydrochloride (50 mg) and dextran (500 mg) are dissolved in 50mL of Tris buffer solution (10 mM), the pH value is adjusted to 8.5, a commercial gelatin sponge is soaked in the solution, the commercial gelatin sponge is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the dextran which do not form a coating are removed, and GS3 is obtained through freeze drying.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1:10.
Comparative example 2
Dopamine hydrochloride 50mg and dextran 50mg are dissolved in 50mL Tris buffer solution (10 mM), the pH value is adjusted to 8.5, commercial gelatin sponge is soaked in the solution, the commercial gelatin sponge is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the dextran which do not form a coating are removed, and GS4 is obtained through freeze drying.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1:1.
Comparative example 3
Dopamine hydrochloride 50mg is dissolved in 50mL Tris buffer solution (10 mM), the pH is adjusted to 8.5, commercial gelatin sponge is soaked in the solution, the solution is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and glucan which do not form a coating are removed, and GS5 is obtained through freeze drying.
In this comparative example, the polyphenol hydroxy group is dopamine, and no polymer component is added.
Comparative example 4
Dopamine hydrochloride (50 mg) and glucan (250 mg) are dissolved in 50mL of Tris buffer solution (10 mM), the pH is adjusted to 8.5, a commercial gelatin sponge is soaked in the solution, the commercial gelatin sponge is taken out after being soaked for 5 hours at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which are not formed into a coating are removed, and GS6 is obtained through freeze drying.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, the mass ratio is 1:5, and the soaking time is 5 hours.
Comparative example 5
Dopamine hydrochloride (50 mg) and glucan (250 mg) are dissolved in 50mL of Tris buffer solution (10 mM), the pH is adjusted to 8.5, a commercial gelatin sponge is soaked in the solution, the commercial gelatin sponge is taken out after being soaked for 0.5h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the glucan which do not form a coating are removed, and GS7 is obtained through freeze drying.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, the mass ratio is 1:5, and the soaking time is 0.5h.
Comparative example 6
50mg of dopamine hydrochloride and 250mg of quaternized amylopectin are dissolved in 50mL of Tris buffer solution (10 mM), the pH is adjusted to 8.5, a commercial gelatin sponge is soaked in the solution, the commercial gelatin sponge is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, the dopamine and the quaternized amylopectin which do not form a coating are removed, and GS8 is obtained through freeze drying.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic electropositive polymer is quaternized amylopectin, and the mass ratio is 1:5.
The quaternized amylopectin in this example was prepared as follows: 1.8g of sodium hydroxide and 6g of 2, 3-epoxypropyl trimethyl ammonium chloride (GTA) were weighed and dissolved in 50mL of deionized water, 6g of pullulan was dispersed in 200mL of deionized water to form a dispersion, and then, the mixed solution of NaOH and GTA was slowly dropped into the starch dispersion, and stirred at 25℃for reaction for 24 hours. After the reaction is completed, pouring the reaction solution into a dialysis bag (MWCO, 1000 Da) and dialyzing with deionized water for 2 days, changing water for at least 8 times, and freeze-drying the solution in the dialysis bag after the completion of the dialysis to obtain the quaternized amylopectin.
Comparative example 7
Gallic acid 50mg and polylysine 250mg are dissolved in 50mL Tris buffer solution (10 mM), the pH is adjusted to 8.5, commercial gauze is soaked in the solution, the gauze is taken out after being soaked for 1h at 25 ℃, a large amount of deionized water is used for washing for three times, gallic acid and polylysine which do not form a coating are removed, and G3 is obtained through freeze drying.
In the comparative example, the polyphenol hydroxyl substance is gallic acid, the hydrophilic electropositive polymer is polylysine, and the mass ratio is 1:5.
Comparative example 8
Preparing 1mg/mL dopamine hydrochloride solution by using Tris buffer solution (10 mM), regulating the pH value to 8.5, soaking a medical experimental titanium alloy wafer in the solution for 12 hours at 25 ℃, washing for three times by using a large amount of deionized water, removing dopamine and glucan which do not form a coating, and drying by nitrogen to obtain Ti3.
In this comparative example, the surface of the titanium alloy wafer was pretreated with polyphenol only (step 1) of example 6 was performed), and the surface was not coated with the polyphenol/polymer hemostatic coagulation promoting coating (step 2) of example 6 was not performed).
Comparative example 9
Commercial gelatin sponge GS (without any modification).
Comparative example 10
Commercial gelatin sponge particle GSP (without any modification).
Comparative example 11
Commercial gauze G (without any modification).
Comparative example 12
Medical experimental titanium alloy wafer Ti (without any modification).
Comparative example 13
Medical glass sheet (without any modification).
Test example 1 in vitro coagulation Effect test
Detection conditions: the materials obtained in each experimental example and comparative example were subjected to a coagulation effect comparison experiment, and the blood for detection was fresh sodium citrate anticoagulated blood taken from rat hearts.
The testing method comprises the following steps: the gelatin sponge material is weighed 3mg, the gauze material is cut into four layers of 0.5 multiplied by 0.5cm, the gelatin sponge particle material is weighed 5mg, and the medical experimental titanium alloy wafer is taken into a piece with the diameter of 10 mm. 100. Mu.L of fresh anticoagulant and 10. Mu.L of 0.2M CaCl were taken 2 After the solution was thoroughly mixed, it was quickly added to the material and the tube was placed in a 37 ℃ thermostat water bath for 1 minute of incubation. Excess blood that did not form a blood clot was then thoroughly lysed with 10mL deionized water and incubated in a 37 ℃ thermostat water bath for 3 minutes. 1mL of the lysed liquid was pipetted and centrifuged (2500 rpm,3 min). 100. Mu.L of the centrifuged supernatant was added to a 96-well plate, and absorbance (Abs) at 545nm was measured with an ELISA. The blank group was prepared by adding 100. Mu.L of fresh anticoagulant to 10mL of deionized water, incubating in a constant temperature water bath at 37℃for 3 minutes, adding 100. Mu.L to a 96-well plate, and measuring absorbance Abs at 545 nm. Finally, the coagulation index (BCI) is calculated by the following formula.
Coagulation index% (BCI) = (Abs) Sample of /Abs Blank space ) X 100%...................% 1
Wherein: abs Sample of Absorbance at 545nm for examples and comparative examples; abs Blank space Is the absorbance of the blank at 545 nm.
TABLE 1 in vitro coagulation Effect test
BCI (Blood clotting index, coagulation index) can characterize the coagulation effect of a material, and generally the smaller the value of BCI, the better the coagulation effect of the material. As can be seen from Table 1, the materials coated with the polyphenol/polymer procoagulant coating obtained in examples 1 to 6 of the present invention have a BCI index of only 16.3% at a minimum and 44.8% at a maximum, indicating that the polyphenol/polymer procoagulant coating modified materials have more excellent procoagulant properties. Thus, by adopting the preparation method of the invention, the polyphenol/polymer coagulation promoting coating for promoting the coagulation promoting effect of the material can be obtained by adding the uncharged or electronegative polymer into polyphenol, and the coating can gently adhere to proteins and adjust the conformation of key plasma proteins by adding the uncharged or electronegative polymer to regulate the interaction of polyphenol groups and proteins, thereby promoting the adhesion of platelets to achieve the purpose of hemostasis. The reason why the comparative example is poor in hemostatic effect is as follows:
comparative example 1 was prepared by increasing the amount of glucan added in example 1 from 5mg/mL to 10mg/mL, the BCI in example 1 was 43.6%, and the BCI in comparative example 1 was 57.6%. The result shows that the polyphenol/polymer composite coating material obtained by increasing the addition amount of glucan has higher BCI and poor procoagulant effect. Because the improvement of the glucan content in the composite coating can enhance the shielding effect on the strong action force of the polyphenol group and the coagulation protein, the effective interaction between the surface and the protein is weaker, and the adhesion of platelets is difficult, so that the coagulation process is influenced.
Comparative example 2 was prepared by reducing the amount of glucan added in example 1 from 5mg/mL to 1mg/mL, the BCI of example 1 was 43.6%, and the BCI of comparative example 2 was 75.1%. The result shows that the polyphenol/polymer composite polymer material obtained by reducing the addition amount of glucan has higher BCI and poor procoagulant effect. Because the reduction of the content of glucan in the composite coating weakens the shielding effect on the strong force of polyphenol groups and the coagulation proteins, the proteins are not easy to activate, and the surface cannot effectively adhere to platelets, so that the coagulation is affected.
Comparative example 3 was prepared by removing the uncharged polymer from example 1 to directly form a polyphenol coating, the BCI of example 1 was 43.6% and the BCI of comparative example 3 was 77.1%. The results show that the coating is carried out by using polyphenol only, and the coating is not coated by uncharged polymer, so that the material BCI of the obtained coating is higher, and the procoagulant effect is poor. Because the interaction force of the phenolic hydroxyl groups and the coagulation proteins in the pure polyphenol coating is too strong, the activation of the pure polyphenol coating is inhibited, so that the pure polyphenol coating can not be converted into the conformation of the effectively adhered platelets, the adhesion of the platelets is inhibited, and the coagulation is further influenced.
Comparative example 4 was prepared by extending the coating time of example 1 from 1h to 5h, the BCI of example 1 was 43.6%, and the BCI of comparative example 4 was 57.7%. The result shows that the polyphenol/polymer composite coating material obtained by prolonging the coating time has higher BCI and poor procoagulant effect. Because the coating thickness is increased by prolonging the coating covering time, the polymer can be covered by thicker polydopamine, and the surface performance of the coating cannot be regulated through the protein adhesion resistance.
Comparative example 5 the coating time in example 1 was reduced from 1h to 0.5h, the BCI of example 1 was 43.6% and the BCI of comparative example 5 was 64.7%. The result shows that the polyphenol/polymer composite coating material obtained by reducing the coating time has higher BCI and poor procoagulant effect. Because reducing the time for coating application may result in the surface of the material not forming a uniform and complete coating, the procoagulant effect of the coating is limited.
Comparative example 6 is the replacement of uncharged polymer (dextran) in example 1 with positively charged polymer (quaternized amylopectin), the BCI of example 1 is 43.6% and the BCI of comparative example 6 is 59.3%. The results show that the material BCI obtained by coating with the electropositive polymer is higher and has poor procoagulant effect. Because the electropositive polymer has an attraction effect on negatively charged blood cells and blood platelets in blood, the strong force of polyphenol in the coating on protein can not be effectively shielded after the uncharged polymer component with protein adhesion resistance is replaced by the electropositive polymer, and the addition of a large amount of electropositive polymer can promote the direct strong interaction between the surface of the material and the blood component. In the presence of the two strong interactions, the conversion of plasma proteins into the effective conformation for promoting coagulation is inhibited, platelets cannot be effectively adhered, and the procoagulant effect of the surface is lost.
Comparative example 7 is the replacement of the electronegative polymer (carboxymethyl cellulose) in example 5 with an electropositive polymer (polylysine). The BCI of example 5 was 42.9% and that of comparative example 7 was 62.7%. The results show that the material BCI obtained by coating with the electropositive polymer is higher and has poor procoagulant effect. Because the electropositive polymer has a certain attraction effect on cells in blood, after the electronegative polymer with bioadhesion resistance is replaced by the electropositive polymer, the strong force of polyphenol in the coating on protein cannot be effectively shielded, so that the plasma protein can be inhibited from being transformed into an effective conformation for promoting blood coagulation, and the addition of a large amount of electropositive polymer can also promote the direct generation of strong interaction between the surface of the material and blood components, and the strong interaction can inhibit the blood coagulation process. In the presence of two strong interactions, the surface is not able to effectively adhere to platelets, thus losing procoagulant effects.
Comparative example 8 is a material corresponding to example 6 in which the metal surface was subjected to polyphenol pretreatment alone, and no covering of the polyphenol/polymer composite coating was performed. The BCI of example 6 was 44.8% and that of comparative example 8 was 61.0%. The BCI result shows that the BCI of the material subjected to the long-time polyphenol pretreatment is higher, and the interaction force of phenolic hydroxyl groups and thromboplastin in the pure polyphenol coating is too strong because the surface of the material subjected to the pretreatment is composed of polydopamine, so that the activation of the material is inhibited, the material cannot be converted into the conformation of effectively adhered platelets, the adhesion of the platelets is inhibited, and the coagulation is further influenced.
Comparative examples 9 to 13 the substrates of examples 1 to 7 were not modified at all, and the gelatin sponge had a BCI of 83.7% and a modified BCI of 43.6%; the BCI of the gelatin sponge particles is 41.9%, the BCI of the modified gelatin sponge particles is 16.6%, the BCI of the commercial gauze is 70.4%, the BCI of the modified gelatin sponge particles is 34.2%, the BCI of the medical experimental titanium alloy wafer is 57.3%, the BCI of the medical experimental titanium alloy wafer is 44.8%, the BCI of the medical glass sheet is 71.7%, and the BCI of the medical glass sheet is 37.5%. Thus, after the substrate is coated by the polyphenol/polymer coating, the BCI index is obviously reduced, and the procoagulant effect is obviously enhanced.
Test example 2 in vitro platelet adhesion Effect test
Detection conditions: the materials obtained in each experimental example and comparative example were subjected to an in vitro platelet adhesion effect test, and the test blood was fresh sodium citrate anticoagulated blood obtained from rat hearts, and a Lactate Dehydrogenase (LDH) kit was used for the test.
The testing method comprises the following steps: the gelatin sponge material was weighed 3mg and the gelatin sponge particle material was weighed 5mg and placed into 2mL plastic centrifuge tubes, respectively. Fresh sodium citrate anticoagulated blood from rat hearts was centrifuged at 150g for 10min, and the supernatant PRP was collected and diluted to the volume of original blood with PBS. To the material was added 100. Mu.L of diluted PRP and incubated in a thermostatic waterbath at 37℃for 5 minutes. After incubation was completed, the material was washed three times with 100 μl PBS each to remove surface non-adherent platelets. The washes were collected and diluted to 1mL with PBS, to which 1mL was added a 2% solution of Triton X-100 (used to lyse the platelets, releasing LDH) and incubated in a 37℃thermostat water bath for 60 minutes. The LDH content in the lysate was determined using a lactate dehydrogenase kit. The blank group was obtained by diluting 100. Mu.L of diluted PRP with PBS to 1mL, adding 2% Triton X-100 solution to 1mL of the diluted PRP to lyse all platelets, and measuring the LDH content in the lysate using a lactate dehydrogenase kit. Finally, the platelet adhesion rate was calculated by the following formula.
Platelet adhesion rate η% = (1-LDH content) Sample of LDH content Blank space ) X 100%.........% 2
Wherein: LDH content Sample of LDH content in lysates determined by LDH kit for examples and comparative examples; LDH content Blank space Is the LDH content in the lysates of the blank group determined by the LDH kit.
TABLE 2 in vitro platelet adhesion Effect test
The platelet adhesion test can characterize the adhesion effect of a material on platelets, and generally the higher the adhesion rate of the material on platelets, the better the procoagulant effect of the material.
As can be seen from table 2, the platelet adhesion rate of the materials coated with the polyphenol/polymer procoagulant coating obtained in examples 1 and 2 of the present invention is significantly higher than that of comparative examples 1 to 3, comparative examples 9 and comparative example 10, demonstrating that the polyphenol/polymer procoagulant coating modified materials have better platelet adhesion properties, and the procoagulant properties of the materials can be improved by the polyphenol/polymer procoagulant coating modification by increasing the platelet adhesion rate.
The concrete explanation is as follows:
comparative example 1 was conducted in such a manner that the amount of glucan added in example 1 was increased from 5mg/mL to 10mg/mL, the platelet adhesion rate in example 1 was 44.1%, and the platelet adhesion rate in comparative example 1 was 39.5%. The result shows that the material platelet adhesion rate of the polyphenol/polymer composite coating obtained by increasing the addition amount of glucan is lower, and the procoagulant effect is poor corresponding to higher BCI. Because the improvement of the content of glucan in the composite coating can enhance the shielding effect on the strong action force of polyphenol groups and the coagulin, the effective interaction between the surface and the protein is weaker, and the adhered platelets are fewer.
Comparative example 2 was conducted in such a manner that the amount of glucan added in example 1 was reduced from 5mg/mL to 1mg/mL, the platelet adhesion rate in example 1 was 44.1%, and the platelet adhesion rate in comparative example 2 was 33.9%. The result shows that the material platelet adhesion rate of the polyphenol/polymer composite coating obtained by reducing the addition amount of glucan is lower, and the procoagulant effect is poor corresponding to higher BCI. Because the reduction of the content of glucan in the composite coating weakens the shielding effect on the strong force of polyphenol groups and the coagulation proteins, the proteins are not easy to activate, and cannot form protein conformations which are favorable for platelet adhesion, so that the platelets are difficult to adhere.
Comparative example 3 was prepared by removing the uncharged polyhydroxypolymer (dextran) in example 1, and the platelet adhesion rate of example 1 was 44.1% and that of comparative example 3 was 24.3%. The results show that when only polyphenol is used for coating and uncharged polymer (glucan) is not added, the platelet adhesion rate of the material obtained by the coating is lower, and the procoagulant effect is poor because the BCI is higher. Because the polyphenol coating is directly formed, the interaction force of phenolic hydroxyl groups and the coagulation proteins in the pure polyphenol coating is too strong to inhibit activation of the phenolic hydroxyl groups and the coagulation proteins, and a protein conformation favorable for platelet adhesion cannot be formed.
Comparative example 9 and comparative example 10 correspond to the substrates of examples 1 and 2 without any modification, the platelet adhesion rate of the gelatin sponge was 23.1%, and the platelet adhesion rate after modification was 44.1%; the adhesion rate of the platelet of the gelatin sponge particles is 20.4%, and the adhesion rate of the platelet after modification is 37.1%. The results show that: the invention can increase the adhesion rate of platelets by coating the polyphenol/polymer coagulation promoting coating on the commercial hemostatic material, thereby improving the procoagulant property.
Test example 3 rat femoral artery hemostatic Effect test
For gelatin sponge-based materials: SD rats weighing 160-190g were selected for anesthesia by intraperitoneal injection of chloral hydrate (10% deionized water, 0.5mL/100g body weight). Left hind limb epithelial tissue was cut with surgical scissors to expose rat femoral artery and vein. The femoral artery (along with veins and peripheral nerves that are difficult to separate from the artery) is rapidly severed with a scalpel. The femoral artery was cut and allowed to bleed freely for 10 seconds while blood loss was collected 10s before using pre-weighed gauze (m 1) and weighed to give m1'. After 10 seconds of free bleeding, a pre-weighed material (m 2, gelatin sponge based material pre-cut to a size of 1.5x2 cm) was quickly covered over the bleeding site and immediately covered with a standard weight (100 g). In the hemostatic process, the overflowed blood is timely scraped by pre-weighed filter paper (m 3), hemostatic is carried out for 1.5 minutes, whether the bleeding occurs or not is observed, and if the bleeding still occurs, the bleeding is observed every 1 minute until the bleeding is stopped. Bleeding time was recorded, collected and weighed to give m2 'and m3'. Rat samples with pre-bleeding abnormalities (> 400mg or <200 mg) in the experiment were excluded from the final analysis of blood loss and hemostasis time to reduce the effects of individual differences and misoperation in rats.
The pre-blood loss and blood loss were calculated by the following formula:
front blood loss m1=m1' -m1................................................ Type 3
Blood loss m=m2 '-m2+m3' -M3............................................, 4
TABLE 3 blood loss and hemostatic time for rat femoral artery hemostasis
The rat femoral artery hemostasis test is to simulate and evaluate the hemostasis effect of a material in a real application scene by measuring the hemostasis time and the blood loss amount of the material when the material is used for treating a damage position in a rat femoral artery damage model, and generally, the better the coagulation promoting effect of the material is, the shorter the time required for hemostasis in the treatment process is, and the less the blood loss amount of the damage position is.
As can be seen from Table 3, the material coated with the polyphenol/polymer procoagulant coating obtained in example 1 of the present invention has lower blood loss and lower hemostatic time in rat femoral artery injury hemostasis than comparative examples 3 and 9, and shows that the polyphenol/polymer procoagulant coating modified material has better therapeutic effect in treatment of rat femoral artery injury model. The concrete explanation is as follows:
comparative example 3 was prepared by removing the hydrophilic uncharged polymer (dextran) in example 1 to directly form a polyphenol coating, and the bleeding amount (33.9 mg) of example 1 was smaller than that of comparative example 3 (146.2 mg), and the hemostatic time (2 min) of example 1 was shorter than that (13.3 min) of comparative example 3.
The results show that: when only the pure polyphenol coating is coated and no uncharged polymer component is added, the obtained sponge has larger blood loss in the hemostatic process and longer time for hemostasis, which indicates that the sponge cannot play a better hemostatic effect in injury.
Comparative example 10 corresponds to the substrate of example 1 without any modification, the blood loss of the commercial gelatin sponge (353.1 mg) was greater than that of example 1 (33.9 mg), and the hemostatic time of the commercial gelatin sponge (7.5 min) was longer than that of example 1 (2 min).
The results show that: after the medical base material is coated by the coating according to the invention, the coating has excellent sufficient coagulation promoting capability, small blood loss in a rat femoral artery injury model, short hemostasis time and good hemostasis effect in injury.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (8)
1. A method for preparing a polyphenol-polymer coating, which is characterized by comprising the following steps:
step 1) preparing a mixed solution of polyphenol hydroxyl substances and hydrophilic uncharged or hydrophilic negatively charged polymers;
step 2) soaking the base material in the mixed solution for 0.7-1.5 hours;
step 3) washing and drying to obtain the material with the polyphenol-polymer codeposition coagulation promoting and hemostasis coating;
the concentration of the polyphenol hydroxyl substances in the step 1) in the mixed solution is 0.25-3 mg/mL; the concentration of the hydrophilic uncharged or hydrophilic negatively charged polymer in the mixed solution is 2-9 mg/mL;
the polyphenol hydroxyl substances in the step 1) are dopamine, tannic acid or gallic acid, the hydrophilic uncharged polymer in the step 1) is glucan, hydroxypropyl cellulose or polyethylene glycol, and the hydrophilic negatively charged polymer in the step 1) is carboxymethyl cellulose;
the mass ratio of the polyphenol hydroxyl substances to the glucan is 1:5; the mass ratio of the polyphenol hydroxyl substances to the hydroxypropyl cellulose is 1:2; the mass ratio of the polyphenol hydroxyl substances to the polyethylene glycol is 1:3; the mass ratio of the polyphenol hydroxyl substances to the carboxymethyl cellulose is 1:5.
2. The method for preparing a polyphenol-polymer coating according to claim 1, wherein the mixed solution in step 1) is an alkaline aqueous solution with a pH of 8-9.
3. The method for preparing a polyphenol-polymer coating according to claim 1, wherein the substrate in step 2) is a polymer medical material, an inorganic medical material, or a metal medical material; the high molecular medical material is gauze, polyvinyl alcohol sponge, polyvinyl alcohol micron-sized particles, polyvinyl alcohol microspheres, chitosan sponge, chitosan non-woven fabric, gelatin sponge micron-sized particles, alginic acid microspheres, alginic acid non-woven fabric or collagen sponge; the inorganic medical material is biological ceramic; the metal medical material is a titanium alloy medical instrument and a shape memory metal microcoil.
4. The method for preparing a polyphenol-polymer coating according to claim 1, wherein the substrate in step 2) is gauze, polyvinyl alcohol sponge, polyvinyl alcohol micron-sized particles, polyvinyl alcohol microspheres, gelatin sponge micron-sized particles, collagen sponge, bioglass or titanium alloy medical device.
5. The method for preparing a polyphenol-polymer coating according to claim 1, wherein in the step 2), when the substrate is a metal medical material, the substrate is pretreated with a polyphenol hydroxyl substance before soaking the mixed solution, and a polyphenol coating is formed on the surface of the substrate.
6. The method for preparing a polyphenol-polymer coating according to claim 5, wherein the pretreatment method comprises: soaking the base material in alkaline water solution with pH of 8-9 for 4-24 hr.
7. A polyphenol-polymer coating prepared by the method of preparing a polyphenol-polymer coating according to any of claims 1-6.
8. Use of a polyphenol-polymer coating according to claim 7 in the preparation of a procoagulant property enhancing material.
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