CN115414539A - Preparation method of polyphenol-polymer coating and application of polyphenol-polymer coating in enhancing procoagulant performance of material - Google Patents
Preparation method of polyphenol-polymer coating and application of polyphenol-polymer coating in enhancing procoagulant performance of material Download PDFInfo
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- CN115414539A CN115414539A CN202211070011.8A CN202211070011A CN115414539A CN 115414539 A CN115414539 A CN 115414539A CN 202211070011 A CN202211070011 A CN 202211070011A CN 115414539 A CN115414539 A CN 115414539A
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- Prior art keywords
- polyphenol
- polymer
- coating
- hydrophilic
- procoagulant
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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
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a preparation method of a polyphenol-polymer coating and application thereof in enhancing procoagulant performance of a material, wherein the preparation steps are as follows: soaking the base material in the mixed solution of polyphenol hydroxyl substance and hydrophilic uncharged or hydrophilic negatively charged polymer at room temperature for 0.7-4 hr to obtain the polyphenol/polymer co-deposited coagulation promoting hemostatic coating material; the mass ratio of the polyphenol hydroxyl substance to the hydrophilic uncharged or hydrophilic negative-charged polymer is 1. The coating converts key blood coagulation protein into activated conformation through mild plasma protein adhesion, promotes the adhesion of blood platelets, and thus achieves the optimal procoagulant performance.
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 performance of materials.
Background
Uncontrolled bleeding is a significant cause of injury and death in traffic accidents, surgical procedures, and natural disasters. The existing commonly used hemostatic materials/medical devices have the defect of insufficient performance, so that the development of novel efficient and safe hemostatic materials is very important. The surface modification is carried out on the existing medical hemostatic material/apparatus by constructing the novel procoagulant coating, so that the hemostatic performance of the hemostatic material/apparatus can be improved on the basis of not changing the application scene of the existing hemostatic material/apparatus, and the clinical requirement can be better met. In the related research on the anticoagulant property of the current surface material (Acta biomaterials, 2017, 64. Therefore, there is a need to develop procoagulant coatings with controlled/mild protein adhesion capability to promote platelet adhesion and activation, and ultimately, clotting, by promoting the conversion of key clotting proteins to an active conformation. The polyphenol substances and the polyhydroxy polymers are co-deposited to prepare the composite hemostatic coating, and the technology is not reported at home.
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 polyphenol-polymer coating and application thereof in enhancing procoagulant performance of materials are disclosed, wherein the preparation method comprises the following steps: 1) Preparing a polyphenol hydroxyl substance and a hydrophilic uncharged or hydrophilic negatively-charged polymer into a mixed solution, wherein the mass ratio of the polyphenol hydroxyl substance to the hydrophilic uncharged or hydrophilic negatively-charged polymer is 1; 2) Soaking the base material in the mixed solution for 0.7-4 hours; 3) And washing and drying to obtain the material with the polyphenol-polymer codeposition coagulation promoting hemostasis coating.
Further, the mass ratio of the polyphenol hydroxyl substance in the step 1) to the hydrophilic uncharged or hydrophilic charged negative polymer is 1 to 2-5, the concentration of the polyphenol hydroxyl substance 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 substance in the step 1) is dopamine, tannic acid, gallic acid, catechin, epicatechin, epigallocatechin gallate, theaflavin-3-gallate, 5-hydroxydopamine hydrochloride or baicalein, the hydrophilic non-charged polymer in the step 1) is dextran, hydroxypropyl cellulose, hydroxyethyl starch, hydroxyethyl cellulose, pullulan, pluronic or polyethylene glycol, and the hydrophilic negative-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 substances in the mixed solution in the step 1) is 1-1.5 mg/mL, and the concentration of hydrophilic uncharged or hydrophilic negative electric 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 non-charged polymer in the step 1) is dextran, hydroxypropyl cellulose or polyethylene glycol, and the hydrophilic negative electrode polymer in the step 1) is carboxymethyl cellulose.
Further, the base material in the step 2) is a polymer medical material, an inorganic medical material or a metal medical material; the polymer 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 or bioceramic; the metal medical material is nickel-titanium alloy apparatus, titanium alloy medical apparatus, shape memory metal microcoil.
Further, when the base material in the step 2) is a metal medical material, the base material can be pretreated with polyphenol hydroxyl substances before being soaked in the mixed solution, so that a polyphenol coating is formed on the surface of the base material.
Further, the pretreatment method comprises the following steps: soaking the base material in alkaline water solution of polyphenol hydroxyl matter in pH 8-9 for 4-24 hr.
Further, the base material 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 instruments.
The invention has the beneficial effects that: the invention utilizes the combination of oxidative self-polymerization of polyphenol hydroxyl substances and hydrophilic uncharged or negative polymers to form a coating on the surface of a base material. The polyphenol hydroxyl substance has strong hydrogen bond interaction with protein, and provides acting force for blood coagulation key components such as plasma protein (fibrinogen and the like) in the blood in the composite coating to enable the blood coagulation key components to be adhered and aggregated; the hydrophilic uncharged or negative electric polymer with the function of resisting protein adhesion regulates and controls the action between phenolic hydroxyl and protein in the process of co-deposition with polyphenol hydroxyl substances, and realizes mild/medium-strength protein adhesion by weakening the acting forces of the phenolic hydroxyl, hydrogen bonds of key blood coagulation proteins in plasma and the like, so that the protein is converted into a conformation easy to adhere to platelets, the platelet adhesion is promoted, and the effect of promoting blood coagulation is further achieved.
The polyphenol/hydrophilic uncharged or negative charged polymer forms a procoagulant coating, can be compounded with the existing hemostatic instruments (such as gelatin sponge, gauze, embolic coil and the like), and enhances the procoagulant performance of the hemostatic instruments without changing the original application scene. The ratio of polyphenol to polymer and the treatment time can be adjusted to form procoagulant coatings on different substrates, and the coatings can convert key blood coagulation proteins into activated conformations through mild plasma protein adhesion and promote the adhesion of platelets, thereby achieving the optimal procoagulant performance.
The electropositivity of the electropositive polymer has a strong attraction to the negatively charged blood cells in the blood, and if the electropositive polymer is used for co-deposition (regardless of the polyphenol/polymer ratio and the treatment time), the formed polyphenol/electropositive polymer coating does not significantly reduce the strong interaction of the protein, or even possibly enhance the strong interaction of the protein, compared with the strong action of the pure polyphenol coating on the protein. Therefore, in the presence of these two strong interactions, the plasma proteins are inhibited from converting to the effective conformation promoting hemagglutination, and the platelets cannot be effectively adhered to the surface, so that the surface loses the effect of promoting hemagglutination. The present invention therefore can only use hydrophilic uncharged or negatively charged polymer phases, and cannot use positively charged polymers.
Detailed Description
The following describes in detail preferred embodiments of the present invention.
Example 1
50mg of dopamine hydrochloride and 250mg of dextran are dissolved in 50mL of Tris buffer solution (10 mM), the pH value is adjusted to 8.5, commercially available 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 three times to remove dopamine and dextran which are not formed into a coating, and the solution is frozen and dried to obtain GS1.
In the embodiment, the polyphenol hydroxyl substance is dopamine, the hydrophilic non-charged polymer is dextran, and the mass ratio is 1.
Example 2
Dissolving 50mg of dopamine hydrochloride and 250mg of dextran in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking the commercial gelatin sponge micron-sized particles in the solution for 1h at 25 ℃, taking out the gelatin sponge micron-sized particles, washing the gelatin sponge micron-sized particles with a large amount of deionized water for three times to remove dopamine and dextran which do not form a coating, and freeze-drying to obtain GSP1.
In this example, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1.
Example 3
Dissolving tannic acid 50mg and polyethylene glycol 150mg in 50mL Tris buffer solution (10 mM), adjusting pH to 8.5, adding commercially available gelatin sponge into the solution, soaking at 25 deg.C for 1h, washing with large amount of deionized water for three times, removing tannic acid and polyethylene glycol without forming coating, and drying to obtain GS2.
In this example, the polyphenol hydroxyl substance is tannic acid, the hydrophilic non-charged polymer is polyethylene glycol, and the mass ratio is 1.
Example 4
Dissolving gallic acid 75mg and hydroxypropyl cellulose 150mg in 50mL Tris buffer solution (10 mM), adjusting pH to 8.5, soaking commercial gauze in the solution, soaking at 25 deg.C for 1h, taking out, washing with large amount of deionized water for three times, removing gallic acid and hydroxypropyl cellulose without coating, and freeze drying 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.
Example 5
Dissolving 50mg of gallic acid and 250mg of carboxymethyl cellulose in 50mL of Tris buffer solution (10 mM), adjusting the pH to 8.5, soaking commercial gauze in the solution at 25 ℃ for 1h, taking out, washing with a large amount of deionized water for three times, removing gallic acid and carboxymethyl cellulose which do not form a coating, and freeze-drying to obtain G2.
In this example, the polyphenol hydroxyl substance is gallic acid, the hydrophilic electronegative polymer is carboxymethyl cellulose, and the mass ratio is 1.
Example 6
1) Preparing 1mg/mL dopamine hydrochloride solution by using Tris buffer solution (10 mM), adjusting the pH to 8.5, soaking a medical experimental titanium alloy wafer in the solution at 25 ℃ for 12 hours, and washing the wafer three times by using a large amount of deionized water;
2) Dissolving 5mg of dopamine hydrochloride and 25mg of glucan in 5mL of Tris buffer solution (10 mM), soaking the titanium alloy wafer treated in the step 1) in the solution at 25 ℃ for 1h, taking out the titanium alloy wafer, washing the titanium alloy wafer with a large amount of deionized water for three times to remove dopamine and glucan which do not form a coating, and drying the titanium alloy wafer with nitrogen to obtain Ti1.
In this example, the polyphenol hydroxyl substance is dopamine, the hydrophilic uncharged polymer is dextran, and the mass ratio is 1.
Example 7
Dissolving 50mg of dopamine hydrochloride and 250mg of glucan in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking a medical glass sheet in the solution for 1h at 25 ℃, taking out the medical glass sheet, washing the medical glass sheet for three times by using a large amount of deionized water, removing dopamine and glucan which do not form a coating, and drying the medical glass sheet by nitrogen to obtain GL1.
In the embodiment, the polyphenol hydroxyl substance is dopamine, the hydrophilic non-charged polymer is dextran, the mass ratio is 1.
Example 8
Dissolving 5mg of dopamine hydrochloride and 25mg of glucan in 5mL of Tris buffer solution (10 mM), soaking the medical experimental titanium alloy wafer in the mixed solution, soaking for 1h at 25 ℃, taking out, washing with a large amount of deionized water for three times, removing dopamine and glucan which do not form a coating, and drying with nitrogen to obtain Ti2.
In this comparative example, the surface of the titanium alloy wafer was prepared without the polyphenol pretreatment (i.e., without step 1 of example 6) and directly with step 2)
Comparative example 1
50mg of dopamine hydrochloride and 500mg of dextran are dissolved in 50mL of Tris buffer solution (10 mM), the pH value is adjusted to 8.5, commercially available 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 three times to remove dopamine and dextran which are not formed into a coating, and the solution is frozen and dried to obtain GS3.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic non-charged polymer is dextran, and the mass ratio is 1.
Comparative example 2
Dissolving 50mg of dopamine hydrochloride and 50mg of glucan in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking commercial gelatin sponge in the solution for 1h at 25 ℃, taking out, washing with a large amount of deionized water for three times, removing the dopamine and glucan which do not form a coating, and freeze-drying to obtain GS4.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic non-charged polymer is dextran, and the mass ratio is 1.
Comparative example 3
Dissolving 50mg of dopamine hydrochloride in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking a commercial gelatin sponge in the solution at 25 ℃ for 1h, taking out the solution, washing the solution with a large amount of deionized water for three times to remove dopamine and glucan which do not form a coating, and freeze-drying the solution to obtain GS5.
In this comparative example, the polyphenolic hydroxyl species was dopamine and no polymeric component was added.
Comparative example 4
Dissolving 50mg of dopamine hydrochloride and 250mg of glucan in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking commercial gelatin sponge in the solution for 5 hours at 25 ℃, taking out, washing with a large amount of deionized water for three times, removing the dopamine and glucan which do not form a coating, and freeze-drying to obtain GS6.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic non-charged polymer is glucan, the mass ratio is 1.
Comparative example 5
Dissolving 50mg of dopamine hydrochloride and 250mg of glucan in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking a commercially available gelatin sponge in the solution, taking out the solution after soaking for 0.5h at 25 ℃, washing the solution three times by using a large amount of deionized water to remove dopamine and glucan which do not form a coating, and freeze-drying the solution to obtain GS7.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic non-charged polymer is glucan, the mass ratio is 1.
Comparative example 6
Dissolving 50mg of dopamine hydrochloride and 250mg of quaternized amylopectin in 50mL of Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking commercially available gelatin sponge in the solution, taking out after soaking for 1h at 25 ℃, washing three times by using a large amount of deionized water, removing the dopamine and the quaternized amylopectin which do not form a coating, and freeze-drying to obtain GS8.
In the comparative example, the polyphenol hydroxyl substance is dopamine, the hydrophilic electropositive polymer is quaternized amylopectin, and the mass ratio is 1.
The quaternized amylopectin starch of this example was prepared as follows: 1.8g of sodium hydroxide and 6g of 2, 3-epoxypropyltrimethylammonium chloride (GTA) were weighed out and dissolved in 50mL of deionized water, 6g of pullulan was dispersed in 200 mL of deionized water to form a dispersion, and then a mixed solution of NaOH and GTA was slowly added dropwise to the starch dispersion and reacted with stirring at 25 ℃ for 24 hours. After the reaction is finished, pouring the reaction solution into a dialysis bag (MWCO, 1000 Da) for dialysis for 2 days by using deionized water, changing water for at least 8 times, and after the dialysis is finished, freeze-drying the solution in the dialysis bag to obtain the quaternized amylopectin.
Comparative example 7
Dissolving 50mg of gallic acid and 250mg of polylysine in 50mL of Tris buffer solution (10 mM), adjusting the pH to 8.5, soaking commercial gauze in the solution at 25 ℃ for 1h, taking out the gauze, washing the gauze with a large amount of deionized water for three times to remove gallic acid and polylysine without forming coatings, and freeze-drying to obtain G3.
In the comparative example, the polyphenol hydroxyl substance is gallic acid, the hydrophilic electropositive polymer is polylysine, and the mass ratio is 1.
Comparative example 8
Preparing a 1mg/mL dopamine hydrochloride solution by using a Tris buffer solution (10 mM), adjusting the pH value to 8.5, soaking a medical experimental titanium alloy wafer in the solution at 25 ℃ for 12 hours, washing the solution with a large amount of deionized water for three times, removing dopamine and glucan which do not form a coating, and drying the solution by using nitrogen to obtain Ti3.
In this comparative example, the titanium alloy wafer surface was pretreated with only polyphenol (step 1 of example 6), and was not coated with a polyphenol/polymer hemostatic coagulation promoting coating (step 2 of example 6)).
Comparative example 9
Commercial gelatin sponge GS (without any modification).
Comparative example 10
Commercial gelatin sponge particles GSP (without any modification).
Comparative example 11
Gauze G (without any modification) was commercially available.
Comparative example 12
Medical experimental titanium alloy disks Ti (without any modification).
Comparative example 13
Medical glass slides (without any modification).
Test example 1 in vitro blood coagulation Effect test
Detection conditions are as follows: the materials obtained in the experimental examples and the comparative examples are subjected to a blood coagulation effect comparison experiment, and the blood for detection is fresh sodium citrate anticoagulated blood taken from rat hearts.
The test method comprises the following steps: weighing 3mg of gelatin sponge material, cutting four layers of gauze material into 0.5 multiplied by 0.5cm, weighing 5mg of gelatin sponge particle material, and taking a piece of medical experimental titanium alloy round piece with the diameter of 10 mm. Mixing 100 μ L of fresh anticoagulated blood with 10 μ L of 0.2M CaCl 2 After the solution was mixed well, it was quickly added to the material, and the tube was incubated in a constant temperature water bath at 37 ℃ for 1 minute. The excess blood that did not form clots was then lysed well with 10mL of deionized water and incubated in a thermostatted water bath at 37 ℃ for 3 minutes. 1mL of the lysed liquid was aspirated and centrifuged (2500 rpm,3 minutes). 100 μ L of the centrifuged supernatant was added to a 96-well plate, and the absorbance (Abs) at 545nm was measured using an enzyme-linked immunosorbent assay. The blank group was prepared by adding 100. Mu.L of fresh anticoagulated blood to 10mL of deionized water, incubating in a 37 ℃ thermostat water bath for 3 minutes, adding 100. Mu.L of the incubated solution to a 96-well plate, and measuring absorbance Abs at 545 nm. Finally, the Blood Coagulation Index (BCI) was calculated by the following formula.
Blood coagulation index% (BCI) = (Abs) Sample (I) /Abs Blank space ) The
In the formula: abs Sample(s) Is the absorbance at 545nm for the 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) can characterize the Blood coagulation effect of the material, and generally, the smaller the value of BCI, the better the Blood coagulation effect of the material. As can be seen from Table 1, the lowest BCI index of the polyphenol/polymer procoagulant coating coated materials obtained in examples 1-6 of the invention is only 16.3%, and the highest BCI index is 44.8%, which indicates that the polyphenol/polymer procoagulant coating modified materials have more excellent procoagulant performance. Therefore, by adopting the preparation method, the uncharged or electronegative polymer is added into the polyphenol for codeposition, so that the polyphenol/polymer procoagulant coating for improving the procoagulant effect of the material can be obtained, the interaction between polyphenol groups and protein is regulated by adding the uncharged or electronegative polymer, the protein can be gently adhered, the conformation of key plasma protein is regulated, and the platelet adhesion is promoted so as to achieve the aim of stopping bleeding. The reason why the comparative example has poor hemostatic effect is as follows:
comparative example 1 is to increase the amount of dextran added in example 1 from 5mg/mL to 10mg/mL, the BCI of example 1 is 43.6%, and the BCI of comparative example 1 is 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. The shielding effect on the strong action force of polyphenol groups and blood coagulation protein can be enhanced by increasing the content of glucan in the composite coating, so that the effective interaction between the surface and the protein is weak, and blood platelets are difficult to adhere to the surface, thereby influencing the blood coagulation process.
Comparative example 2 was conducted to reduce the amount of dextran added in example 1 from 5mg/mL to 1mg/mL, with the BCI of example 1 being 43.6% and the BCI of comparative example 2 being 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 shielding effect on the strong acting force of polyphenol groups and blood coagulation proteins is weakened due to the reduction of the content of the glucan in the composite coating, the proteins are not easy to activate, so that blood platelets cannot be effectively adhered to the surface, and the blood coagulation is further influenced.
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 result shows that only polyphenol is used for coating, and no uncharged polymer is used for coating, so that the BCI of the obtained coating material is higher, and the procoagulant effect is poor. Because the interaction force between phenolic hydroxyl in the pure polyphenol coating and blood coagulation protein is too strong, the activation of the pure polyphenol coating is inhibited, the pure polyphenol coating cannot be converted to a conformation which can effectively adhere to blood platelets, the adhesion of the blood platelets is inhibited, and the blood coagulation is further influenced.
Comparative example 4 is to extend the coating application time from 1h to 5h in example 1, the BCI of example 1 is 43.6%, and the BCI of comparative example 4 is 57.7%. The result shows that the polyphenol/polymer composite coating obtained by prolonging the coating time has higher BCI (brain cell adhesion) and poor procoagulant effect. Because the coating thickness of the self-polymerized dopamine coating is increased due to the prolonged coating covering time, the polymer can be wrapped by the thicker polydopamine, and the surface performance of the coating cannot be regulated through the anti-protein adhesion effect.
Comparative example 5 is to reduce the coating time in example 1 from 1h to 0.5h, the BCI of example 1 is 43.6%, and the BCI of comparative example 5 is 64.7%. The result shows that the polyphenol/polymer composite coating obtained by reducing the coating time has higher BCI (bulk continuous interface) and poor procoagulant effect. Because the time for coating is reduced, the surface of the material cannot form a uniform and complete coating, and the coagulation promoting effect of the coating is limited.
Comparative example 6 was prepared by replacing the uncharged polymer (dextran) in example 1 with a positively charged polymer (quaternized pullulan), the BCI of example 1 was 43.6%, and the BCI of comparative example 6 was 59.3%. The result shows that the positive electric polymer is adopted for coating, the obtained material has high BCI and poor procoagulant effect. Because the electropositive polymer has attraction to blood cells and platelets with negative electricity in blood, after the electropositive polymer component with the anti-protein adhesion is replaced by the electropositive polymer, the strong action of polyphenol in the coating to protein cannot be effectively shielded, and the addition of a large amount of electropositive polymer can also promote the direct strong interaction between the surface of the material and the blood component. In the presence of the two strong interactions, the two strong interactions can inhibit the transformation of plasma proteins to effective conformations promoting blood coagulation, and the blood platelets cannot be effectively adhered to the surfaces of the blood platelets to lose the blood coagulation promoting effect.
Comparative example 7 is a case where the electronegative polymer (carboxymethyl cellulose) in example 5 was replaced with an electropositive polymer (polylysine). The BCI for example 5 was 42.9% and the BCI for comparative example 7 was 62.7%. The result shows that the positive electric polymer is adopted for coating, the obtained material has high BCI and poor procoagulant effect. Because the electropositive polymer has a certain attraction effect on cells in blood, after the electronegative polymer with the biological adhesion resistance is replaced by the electropositive polymer, the strong action of polyphenol in the coating on protein cannot be effectively shielded, the effective conformation transformation of plasma protein to the blood coagulation promotion can be inhibited, and the addition of a large amount of electropositive polymer can also promote the direct 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 unable to adhere platelets effectively, thereby losing procoagulant action.
Comparative example 8 is a material corresponding to example 6 in which only polyphenol pretreatment was performed on the metal surface without coating of the polyphenol/polymer composite coating. The BCI for example 6 was 44.8% and the BCI for comparative example 8 was 61.0%. The BCI result shows that the BCI of the material which is only subjected to long-time polyphenol pretreatment is high, and the pretreated surface consists of polydopamine, so that the interaction force between phenolic hydroxyl in the pure polyphenol coating and blood coagulation protein is too strong, the activation of the phenolic hydroxyl and the blood coagulation protein is inhibited, the phenolic hydroxyl and the blood coagulation protein cannot be converted to the conformation of effectively adhered blood platelets, the adhesion of the blood platelets is inhibited, and the blood coagulation is further influenced.
Comparative examples 9 to 13 correspond to the substrates of examples 1 to 7 without any modification, the BCI of the gelatin sponge being 83.7% and 43.6% after modification; the BCI of the gelatin sponge particles is 41.9 percent, the BCI after modification is 16.6 percent, the BCI of the commercial gauze is 70.4 percent, the BCI after modification is 34.2 percent, the BCI of the medical experimental titanium alloy wafer is 57.3 percent, the BCI after modification is 44.8 percent, the BCI of the medical glass sheet is 71.7 percent, and the BCI after modification is 37.5 percent. Therefore, after the base material 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 are as follows: the materials obtained in the experimental examples and the comparative examples were subjected to in vitro platelet adhesion test, and the blood used for detection was fresh sodium citrate anticoagulated blood obtained from rat heart, and Lactate Dehydrogenase (LDH) kit was used for detection.
The test method comprises the following steps: 3mg of gelatin sponge material and 5mg of gelatin sponge particle material are respectively put into a 2mL plastic centrifuge tube. 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 the original blood with PBS. To the material was added 100. Mu.L of diluted PRP and incubated for 5 minutes in a 37 ℃ thermostatted water bath. After the incubation was completed, the material was washed with PBS for three times, 100 μ L of PBS was used for each time, and the surface non-adhered platelets were removed. The wash was collected and diluted to 1mL with PBS, to which 1mL 2% Triton X-100 solution (used to lyse platelets and allow them to release LDH) was added and incubated in a constant temperature water bath at 37 ℃ for 60 minutes. The LDH content in the lysate was determined using a lactate dehydrogenase kit. The blank group was prepared by diluting 100. Mu.L of diluted PRP to 1mL with PBS, 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 lactate dehydrogenase kit. Finally, the platelet adhesion rate was calculated by the following formula.
Platelet adhesion rate eta% = (1-LDH content) Sample (I) LDH content Blank space ) X 100
In the formula: LDH content Sample (I) The LDH content in the lysate is determined by the LDH kit in the examples and the comparative examples; LDH content Blank space Is the LDH content in the lysate determined by the LDH kit for the blank group.
Table 2 in vitro platelet adhesion test
The platelet adhesion test can characterize the adhesion effect of the material on the platelets, and generally, the higher the adhesion rate of the material on the platelets, the better the procoagulant effect of the material.
As can be seen from Table 2, the platelet adhesion rate of the polyphenol/polymer procoagulant coating coated materials obtained in example 1 and example 2 of the invention is obviously higher than that of comparative examples 1-3, 9 and 10, which shows that the polyphenol/polymer procoagulant coating modified material has better platelet adhesion performance, and the polyphenol/polymer procoagulant coating modification can improve the procoagulant performance of the material by improving the platelet adhesion rate.
The concrete description is as follows:
in comparative example 1, the addition amount of dextran in example 1 was increased from 5mg/mL to 10mg/mL, the platelet adhesion rate of example 1 was 44.1%, and the platelet adhesion rate of comparative example 1 was 39.5%. The result shows that the material of the polyphenol/polymer composite coating obtained by increasing the addition amount of the glucan has low platelet adhesion rate, relatively high BCI and poor procoagulant effect. Because the shielding effect on the strong action force of polyphenol groups and blood coagulation proteins can be enhanced by increasing the content of glucan in the composite coating, the effective interaction between the surface and the proteins is weak, and the adhered platelets are few.
In comparative example 2, the amount of dextran added in example 1 was reduced from 5mg/mL to 1mg/mL, the platelet adhesion rate of example 1 was 44.1%, and the platelet adhesion rate of comparative example 2 was 33.9%. The result shows that the polyphenol/polymer composite coating obtained by reducing the addition amount of glucan has low platelet adhesion rate, relatively high BCI and poor procoagulant effect. Because the reduction of the content of the glucan in the composite coating weakens the shielding effect of strong action force on polyphenol groups and blood coagulation proteins, the proteins are not easy to activate, and protein conformation favorable for platelet adhesion cannot be formed, so that the platelets are difficult to adhere.
Comparative example 3 was prepared by removing the uncharged polyhydroxypolymer (dextran) from 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 no uncharged polymer (glucan) component is added, the platelet adhesion rate of the obtained coating material is low, and correspondingly, the BCI is high, and the procoagulant effect is poor. Because the polyphenol coating is directly formed, the interaction force between phenolic hydroxyl groups in the pure polyphenol coating and the blood coagulation protein is too strong, the activation of the phenolic hydroxyl groups is inhibited, and a protein conformation which is favorable for the adhesion of blood platelets cannot be formed.
Comparative examples 9 and 10 correspond to the base material in examples 1 and 2 without any modification, and the gelatin sponge has a platelet adhesion rate of 23.1% and a platelet adhesion rate of 44.1% after modification; the adhesion rate of the gelatin sponge particle platelet is 20.4%, and the adhesion rate of the modified platelet is 37.1%. The results show that: according to the invention, the adhesion rate of platelets can be increased by coating the polyphenol/polymer procoagulant coating on the commercially available hemostatic material, so that the procoagulant performance is improved.
Test example 3 rat femoral artery hemostatic effect test
For gelatin sponge-based materials: SD rats weighing 160-190g were anesthetized by intraperitoneal injection of chloral hydrate (10% deionized water, 0.5mL/100g body weight). The left hind limb epithelial tissue was cut with surgical scissors to expose the rat femoral arteriovenous. The femoral artery (along with veins and peripheral nerves that are difficult to separate from the artery) is cut off rapidly with a scalpel. The femoral artery was allowed to bleed freely for 10 seconds after cutting, while the first 10s of blood loss was collected using a 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 1.5 × 2 cm) was quickly covered on the bleeding site and immediately covered with a standard weight (100 g). In the hemostasis process, pre-weighed filter paper (m 3) is used for timely wiping off overflowed blood, hemostasis is carried out for 1.5 minutes, whether bleeding occurs or not is observed, and if bleeding still occurs, the bleeding is observed every 1 minute until the bleeding stops. Bleeding time was recorded, collected and weighed to give m2 'and m3'. Rat samples with pre-bleeding abnormalities (> 400mg or <200 mg) in the experiments were excluded from the final analysis of blood loss volume and hemostasis time to reduce the effects of individual rat differences and operator error.
The amount of pre-lost blood and the amount of lost blood were calculated by the following formula:
a blood loss from the anterior is M1= M1' -M1.
The blood loss M = M2'-M2+ M3' -M3
TABLE 3 blood loss and hemostasis time for femoral artery hemostasis in rats
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 of the material when the material treats an injury position in a rat femoral artery injury model, generally, the better the procoagulant effect of the material is, the shorter the time required for hemostasis in the treatment process is, and the less the blood loss of the injury position is.
As can be seen from Table 3, the polyphenol/polymer procoagulant coating coated material obtained in example 1 of the invention has lower blood loss and lower hemostasis time in wound hemostasis of femoral artery of rats than comparative example 3 and comparative example 9, which shows that the polyphenol/polymer procoagulant coating modified material has better treatment effect in the treatment of femoral artery injury model of rats. The concrete description is as follows:
comparative example 3 in which the hydrophilic non-charged polymer (dextran) in example 1 was removed to directly form a polyphenol coating, the blood loss of example 1 was (33.9 mg) less than that of comparative example 3 (146.2 mg), and the hemostasis time (2 min) of example 1 was shorter than that of comparative example 3 (13.3 min).
The results show that: only the pure polyphenol coating is coated, and when the uncharged polymer component is not added, the obtained sponge has larger blood loss in the hemostasis process, and the time required for hemostasis is longer, which indicates that the sponge cannot play a better hemostasis effect in injury.
Comparative example 10 corresponds to the substrate of example 1 without any modification, the blood loss of the commercially available gelatin sponge (353.1 mg) was larger than that of example 1 (33.9 mg), and the hemostatic time of the commercially available 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 with the coating according to the invention, the medical base material has excellent enough procoagulant capability, small blood loss in a rat femoral artery injury model, short hemostasis time and better hemostasis effect in injury.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (10)
1. A preparation method of a polyphenol-polymer coating and application thereof in enhancing procoagulant performance of materials are characterized in that the preparation method comprises the following steps:
1) Preparing a polyphenol hydroxyl substance and a hydrophilic uncharged or hydrophilic negatively-charged polymer into a mixed solution, wherein the mass ratio of the polyphenol hydroxyl substance to the hydrophilic uncharged or hydrophilic negatively-charged polymer is 1;
2) Soaking the base material in the mixed solution for 0.7-4 hours;
3) And washing and drying to obtain the material with the polyphenol-polymer codeposition coagulation promoting hemostasis coating.
2. The method for preparing a polyphenol-polymer coating according to claim 1 and its application in enhancing procoagulant property of materials, wherein the mass ratio of the polyphenol hydroxyl group substances and hydrophilic uncharged or hydrophilic negatively charged polymers in step 1) is 1.
3. The method of claim 1, wherein the polyphenol hydroxyl compound of step 1) is dopamine, tannic acid, gallic acid, catechin, epicatechin, epigallocatechin gallate, theaflavin-3-gallate, 5-hydroxydopamine hydrochloride or baicalein, the hydrophilic non-charged polymer of step 1) is dextran, hydroxypropyl cellulose, hydroxyethyl starch, hydroxyethyl cellulose, pullulan, pluronic or polyethylene glycol, and the hydrophilic negative-charged polymer of step 1) is carboxymethyl cellulose or alginic acid, sodium alginate, hyaluronic acid, sodium hyaluronate or carboxymethyl starch.
4. The method of claim 1, wherein the polyphenol hydroxyl group compound of step 1) is dopamine, tannic acid or gallic acid, the hydrophilic non-charged polymer of step 1) is dextran, hydroxypropyl cellulose or polyethylene glycol, and the hydrophilic negative-charged polymer of step 1) is carboxymethyl cellulose.
5. The method for preparing a polyphenol-polymer coating layer according to claim 1 and the application thereof in enhancing the procoagulant performance of materials, wherein the concentration of the polyphenol hydroxyl substances in the mixed solution in the step 1) is 1-1.5 mg/mL, and the concentration of the hydrophilic uncharged or hydrophilic negative electric polymerization in the mixed solution is 3-5 mg/mL.
6. The method for preparing a polyphenol-polymer coating and the application thereof in enhancing the procoagulant performance of materials according to claim 1, wherein the mixed solution in the step 1) is an alkaline aqueous solution, and the pH value is 8-9.
7. The method for preparing a polyphenol-polymer coating and the application thereof in enhancing the procoagulant performance of materials according to claim 1, wherein the base material in the step 2) is a polymer medical material, an inorganic medical material or a metal medical material; the polymer 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 or bioceramic; the metal medical material is a nickel-titanium alloy instrument, a titanium alloy medical instrument and a shape memory metal microcoil.
8. The method of claim 1, wherein the substrate in step 2) is gauze, polyvinyl alcohol sponge, polyvinyl alcohol microparticles, polyvinyl alcohol microspheres, gelatin sponge microparticles, collagen sponge, bioglass, or titanium alloy medical devices.
9. The method for preparing a polyphenol-polymer coating and the application thereof in enhancing the procoagulant property of materials according to claim 1, wherein, when the substrate in the step 2) is a metal medical material, the substrate can be pretreated with polyphenol hydroxyl substances before being soaked in the mixed solution, so that the polyphenol coating is formed on the surface of the substrate.
10. The method for preparing a polyphenol-polymer coating and the application thereof in enhancing procoagulant property of materials according to claim 8, wherein the pretreatment method comprises the following steps: soaking the base material in alkaline water solution of polyphenol hydroxyl matter in pH 8-9 for 4-24 hr.
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