CN119455062A - Hemostatic powder with rapid liquid absorption and antibacterial functions and preparation method thereof - Google Patents
Hemostatic powder with rapid liquid absorption and antibacterial functions and preparation method thereof Download PDFInfo
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- CN119455062A CN119455062A CN202411446143.5A CN202411446143A CN119455062A CN 119455062 A CN119455062 A CN 119455062A CN 202411446143 A CN202411446143 A CN 202411446143A CN 119455062 A CN119455062 A CN 119455062A
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Abstract
The invention discloses a hemostatic powder with rapid high-strength liquid absorption capacity and antibacterial function and a preparation method thereof, wherein chitosan derivative and deionized water are uniformly mixed to prepare chitosan derivative solution; and (3) uniformly mixing acrylic acid and methacryloyloxyethyl trimethyl ammonium chloride in the chitosan derivative solution, adding a cross-linking agent and a photoinitiator for polymerization reaction to obtain a cross-linked product, and performing freeze drying and grinding to obtain hemostatic powder with rapid imbibition and antibacterial functions. The hemostatic powder provided by the invention can be used for obtaining a material with good biocompatibility, strong antibacterial function, rapid imbibition and timely hemostasis by regulating and controlling the proportion of polycation and anion, and aims to solve the problems of poor biocompatibility, poor imbibition capability of the hemostatic powder and the like of the cationic material.
Description
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to hemostatic powder with rapid liquid absorption and antibacterial functions and a preparation method thereof.
Background
Wound bleeding control, particularly non-compressible wound bleeding, accounts for 30% to 40% of preventable deaths, and is top of the leadership, a great challenge for worldwide military injuries and accident wounds. There is an urgent need to develop strategies to control non-compressible bleeding.
For non-compressible bleeding, researchers have focused on developing more effective hemostatic materials, and have developed various forms of hemostatic materials such as hemostatic sponges, adhesives, powders, etc., wherein, for irregularly shaped wounds, the powder can be directly applied to the wound to fill the irregular shape and absorb the blood to concentrate the clotting factors for hemostatic purposes. However, most powders have insufficient liquid absorption capacity, which affects the hemostatic effect. Therefore, there is an urgent need to develop hemostatic powder having a highly efficient liquid absorbing ability.
Chitosan is a natural cationic polymer, has strong biocompatibility, biodegradability, antibacterial property and hemostatic property, and can promote the whole process of wound healing. However, most chitosan hemostatic powders have poor water solubility, poor tissue adhesion and mechanical properties, and difficult to form an effective physical seal. The chitosan (such as HTCC) modified by the quaternary ammonium salt has better water solubility, stronger antibacterial activity and can enhance hemostatic property, however, the cytotoxicity of HTCC limits the application of HTCC in biomedicine. The molecular chain of polyacrylic acid (PAA) contains a large number of carboxylic acid groups, has good hydrophilicity, and can form a network structure with positively charged polymers through electrostatic action and hydrogen bonds in solution. The cationic unit-N (CH 3)3) exists in the [2- (methacryloyloxy) ethyl ] trimethyl ammonium chloride (MTAC), electrostatic repulsion generated by ionic charges exists in a polymer network, and more moisture can be locked.
Therefore, there is a need in the art for a rapid hemostatic material that has good biosafety, strong liquid absorption capacity, certain tissue adhesion and antibacterial function.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the application and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description of the application and in the title of the application, which may not be used to limit the scope of the application.
The present invention has been made in view of the above and/or problems occurring in the prior art.
Therefore, the invention aims to overcome the defects in the prior art and provide a preparation method of hemostatic powder with rapid high-strength liquid absorbing capacity and antibacterial function.
In order to solve the technical problems, the invention provides a preparation method of hemostatic powder with rapid high-strength liquid absorption capacity and antibacterial function, which comprises the following steps of,
Uniformly mixing chitosan derivative with deionized water to prepare chitosan derivative solution;
And (3) uniformly mixing acrylic acid and methacryloyloxyethyl trimethyl ammonium chloride in the chitosan derivative solution, adding a cross-linking agent and a photoinitiator for polymerization reaction to obtain a cross-linked product, and performing freeze drying and grinding to obtain hemostatic powder with rapid imbibition and antibacterial functions.
As a preferable scheme of the preparation method, the chitosan derivative comprises one or more of chitosan quaternary ammonium salt and carboxymethyl chitosan.
As a preferable scheme of the preparation method, the mass concentration of the chitosan derivative solution is 5-10%.
As a preferable scheme of the preparation method, the molar ratio of the methacryloyloxyethyl trimethyl ammonium chloride to the acrylic acid is 0.01-3:0.01-3, and the preferable molar ratio of the methacryloyloxyethyl trimethyl ammonium chloride to the acrylic acid is 1:2.
As a preferred embodiment of the preparation method, the cross-linking agent comprises polyethylene glycol diacrylate, and the photoinitiator comprises 2-hydroxy-2-methyl-1-phenyl-1-acetone.
As a preferable scheme of the preparation method, the cross-linking agent accounts for 2% -4% of the sum of the molar masses of the methacryloyloxyethyl trimethyl ammonium chloride and the acrylic acid, and the photoinitiator accounts for 2% -4% of the sum of the molar masses of the methacryloyloxyethyl trimethyl ammonium chloride and the acrylic acid.
As a preferable scheme of the preparation method, the polymerization reaction comprises an illumination polymerization reaction under 365nm ultraviolet light, and the illumination polymerization reaction time is 50-70 min.
It is still another object of the present invention to overcome the deficiencies of the prior art and to provide a hemostatic powder having a rapid high-strength wicking ability and antimicrobial function.
The invention further aims to overcome the defects in the prior art and provide application of the hemostatic powder in preparing medical hemostatic materials.
The invention has the beneficial effects that:
(1) The invention provides a preparation method of hemostatic powder with rapid high-strength liquid absorption capacity and antibacterial function, which can obtain a material with good biocompatibility, stronger antibacterial function, rapid liquid absorption and timely hemostasis by regulating and controlling the proportion of polycation and anion, and solves the technical problems of poor biocompatibility of cationic materials, poor liquid absorption capacity of hemostatic powder and the like.
(2) The hemostatic powder can quickly absorb blood, adsorb and gather red blood cells and platelets through positive charges, and realize quick hemostasis, and compared with a commercial hemostatic material, the hemostatic powder has the advantages of less blood loss and shorter hemostatic time in a tail vein bleeding model and a femoral artery puncture bleeding model.
(3) The hemostatic powder disclosed by the invention is simple in preparation process, high in productivity and capable of being produced in a large scale.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a diagram showing the liquid absorption amount experiment of the hemostatic powder prepared by the present invention.
FIG. 2 is a diagram showing cytotoxicity test of the hemostatic powder prepared according to the present invention.
FIG. 3 is a diagram showing the antibacterial property test of the hemostatic powder prepared by the present invention.
FIG. 4 is a display of an in vitro coagulation test of the hemostatic powder prepared according to the present invention.
FIG. 5 is a display of an in vivo coagulation test of hemostatic powder made in accordance with the present invention.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
In the embodiment of the invention, chitosan quaternary ammonium salt (HTCC, substitution degree > 95%) is purchased from Shanghai of China in microphone);
acrylic acid (AA, weight percent in water > 99%) was purchased from aladine (Shanghai, china);
Methacryloxyethyl trimethyl ammonium chloride solution (MTAC, 75% by weight in water) was purchased from aladine (Shanghai, china);
Polyethylene glycol diacrylate (PEGDA, molecular weight 600, weight percent in water 98%) was purchased from aladine (shanghai, china);
2-hydroxy-2-methyl propanone (1173, 97% by weight in water) was purchased from aladine (Shanghai, china).
Other raw materials are purchased commercially and used directly without any special treatment.
Example 1
The embodiment provides a preparation method of hemostatic powder with rapid liquid absorption and antibacterial functions, which mainly comprises the following steps:
(1) Adding 0.2g of chitosan quaternary ammonium salt into 2mL of deionized water, and uniformly stirring to prepare a 10% chitosan quaternary ammonium salt solution;
(2) 2.77mL (1 mol) of a methacryloyloxyethyl trimethyl ammonium chloride solution and 1.44mL (2 mol) of an acrylic acid solution were added to the chitosan quaternary ammonium salt solution prepared in (1), and finally water was added to 10mL;
(3) Uniformly stirring the mixed solution in the step (2), adding 10.5mg of PEGDA and 10.5mg of photo-crosslinking agent 1173, uniformly stirring, injecting into a mold, and standing for polymerization under 365nm ultraviolet irradiation for 60min;
(4) After the reaction was completed, the hydrogel was taken out, and the prepared hydrogel was freeze-dried, ground into powder, and named HTCC-pM 1A2.
Example 2
The embodiment provides a preparation method of hemostatic powder with rapid liquid absorption and antibacterial functions, which mainly comprises the following steps:
(1) Adding 0.2g of chitosan quaternary ammonium salt into 2mL of deionized water, and uniformly stirring to prepare a 10% chitosan quaternary ammonium salt solution;
(2) To the chitosan quaternary ammonium salt solution prepared in (1), 4.155mL (1.5 mol) of a methacryloyloxyethyl trimethyl ammonium chloride solution and 1.08mL (1.5 mol) of an acrylic acid solution were added, and finally water was added to 10mL;
(3) Uniformly stirring the mixed solution in the step (2), adding 12.6mg of PEGDA and 12.6mg of photo-crosslinking agent 1173, uniformly stirring, injecting into a mold, and standing for polymerization under 365nm ultraviolet irradiation for 50min;
(4) After the reaction was completed, the hydrogel was taken out, and the prepared hydrogel was freeze-dried, ground into powder, and named HTCC-pM 1.5A1.5.
Example 3
The embodiment provides a preparation method of hemostatic powder with rapid liquid absorption and antibacterial functions, which mainly comprises the following steps:
(1) Adding 0.2g of chitosan quaternary ammonium salt into 2mL of deionized water, and uniformly stirring to prepare a 10% chitosan quaternary ammonium salt solution;
(2) 5.54mL (2 mol) of methacrylic oxyethyl trimethyl ammonium chloride solution and 0.72mL (1 mol) of acrylic acid solution are added to the chitosan quaternary ammonium salt solution prepared in the step (1), and finally water is added to 10mL;
(3) Uniformly stirring the mixed solution in the step (2), adding 14.6mg of PEGDA and 14.6mg of photo-crosslinking agent 1173, uniformly stirring, injecting into a mold, and standing for 365nm ultraviolet irradiation polymerization for 40min;
(4) After the reaction was completed, the hydrogel was taken out, and the prepared hydrogel was freeze-dried, ground into powder, and named HTCC-pM 2A1.
Comparative example 1
(1) Adding 0.2g of chitosan quaternary ammonium salt into 2mL of deionized water, and uniformly stirring to prepare a 10% chitosan quaternary ammonium salt solution;
(2) Adding 2.16mL (3 mol) of acrylic acid solution into the chitosan quaternary ammonium salt solution prepared in the step (1), and finally adding water to 10mL;
(3) Uniformly stirring the mixed solution in the step (2), adding 6.48mg of PEGDA and 6.48mg of photo-crosslinking agent 1173, uniformly stirring, injecting into a mold, and standing for 365nm ultraviolet irradiation polymerization for 90min;
(4) After the reaction is completed, the hydrogel is taken out, the prepared hydrogel is freeze-dried and ground into powder, and the powder is named HTCC-pA.
Comparative example 2
(1) Adding 0.2g of chitosan quaternary ammonium salt into 2mL of deionized water, and uniformly stirring to prepare a 10% chitosan quaternary ammonium salt solution;
(2) To the chitosan quaternary ammonium salt solution prepared in (1), 8.310mL (3 mol) of methacryloyloxyethyl trimethyl ammonium chloride solution was added;
(3) And (3) uniformly stirring the mixed solution in the step (2), adding 19mg of PEGDA and 19mg of photo-crosslinking agent 1173, uniformly stirring, injecting into a mold, and placing for polymerization under 365nm ultraviolet irradiation for 30min.
(4) After the reaction was completed, the hydrogel was taken out. The prepared hydrogel was freeze-dried and ground to a powder, designated pM.
FIG. 1 shows the liquid absorption experiments of examples 1 to 3 and comparative examples 1 to 2, and the blood absorption was measured as follows:
deionized water was added to 100mg of hemostatic powder until the hemostatic powder no longer absorbed liquid.
The commercial hemostatic powder Boyi (BYC) is used as a control, the mass of hemostatic powder is recorded as m milligrams, and the liquid absorption ratio is calculated;
liquid absorption ratio= (m-100)/100×100%;
The test was repeated 3 times and the average was taken.
As can be seen from FIG. 1, as the content ratio of Methacryloyloxyethyl Trimethyl Ammonium Chloride (MTAC) increases, the water absorption increases, and the result shows that HTCC-pMA has a strong liquid absorbing capacity.
FIG. 2 shows cytotoxicity tests of examples 1 to 5, which are carried out as follows:
Rat fibroblasts (RS 1) cells were seeded in 96-well plates containing 10% fetal bovine serum and 1% penicillin-streptomycin medium at a density of 10000 per well;
after 24h growth in humidified 5% co 2 incubator at 37 ℃, PBS extract (1:10) containing different hemostatic powders (commercial hemostatic powder BYC, pM, HTCC-pA and HTCC-pMA) was replaced with DMEM medium at a ratio of 1:9;
After incubating the cells for 24h, the viability of the cells was tested by using a cell proliferation-toxicity assay (CCK-8) and measured by an enzyme-labeled instrument at 450 nm;
Complete DMEM medium containing PBS and 10mg/mL zinc diethyldithiocarbamate medium were used as negative and positive controls.
As can be seen from FIG. 2, the commercial hemostatic powders BYC and HTCC-pA have a cell viability of more than 80%, whereas the HTCC-pMA has a cell viability related to the MTAC content, and the powder cell viability is more than 80% when the molar ratio of MTAC to AA is 1:2, whereas pM, HTCC-pM 1.5A1.5 and HTCC-pM 2A1 have a cell viability of less than 80% due to the high MTAC content, and have a high cytotoxicity, and by balancing, HTCC-pMA powders having an optimal ratio of 1:2 are selected.
The good antibacterial capability is also one aspect which should be considered when the hemostatic powder is applied to wound hemostasis, so that the antibacterial effect of the hemostatic powder on escherichia coli and staphylococcus aureus is explored, and the test method is as follows:
After co-culturing 10mg of different hemostatic powders (BYC, HTCC-pA and HTCC-pM 1A2) with 1mL of diluted E.coli suspension (10 5 CFU/mL) in a 37℃incubator for 4 hours, 100. Mu.L of the above suspension was spread on an agar plate with PBS as a blank, and incubated at 37℃for 12 hours;
The results are shown in figure 3, and the results show that the HTCC-pM 1A2 hemostatic powder can effectively inhibit the growth of escherichia coli and staphylococcus aureus, can provide a sterile environment for wound hemostasis and can reduce bacterial infection.
Fig. 4 is an in vitro hemostatic performance test, which is tested as follows:
100. Mu.L of 0.1mol/L calcium chloride aqueous solution was added to 900. Mu.L of citric acid blood and vortexed for 10s. 10mg of different hemostatic powders (BYC, HTCC-pA and HTCC-pM 1A2) were placed in successive wells on a 96-well plate and 100. Mu.L of recalcified blood was added dropwise to the different hemostatic powders;
Then, at a preset time point, removing the blood coagulation part by using PBS;
the time after washing to form a uniform and stable clot in the well is defined as the clotting time.
From FIG. 4, it can be seen that the clotting time of the HTCC-pM 1A2 powder is 30s, and the clotting time is shorter than that of other materials, and the result shows that the HTCC-pM 1A2 powder can achieve good hemostatic effect in vitro.
To demonstrate the hemostatic properties of the hemostatic powders obtained in this example in vivo, the hemostatic effect of the different powders (BYC, HTCC-pA and HTCC-pM 1A2) was evaluated by the rat tail-breaking bleeding model in this experiment:
Rats were randomly divided into 4 groups (n=3) and were anesthetized with 2% phenobarbital sodium prior to surgery;
placing pre-weighed filter paper on the tail of a rat, cutting off the tail at a position 8cm away from the tail root by using surgical scissors, and rapidly placing 100mg of powder on the tail of the rat;
Bleeding volume and bleeding time were recorded, and rats not subjected to hemostatic treatment were used as a control group.
The results are shown in fig. 5, and the results show that the HTCC-pM 1A2 powder has less blood loss compared with the blank group, BYC powder and HTCC-pA powder, and the results show that the HTCC-pM 1A2 powder can effectively realize in-vivo hemostasis and has greater potential value in clinical application.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, and it should be covered in the scope of the present invention.
Claims (9)
1. A preparation method of hemostatic powder with rapid high-strength liquid absorption capability, antibacterial function and good biocompatibility is characterized by comprising the steps of,
Uniformly mixing chitosan derivative with deionized water to prepare chitosan derivative solution;
Adding acrylic acid and methacryloxyethyl trimethyl ammonium chloride into chitosan derivative solution, mixing uniformly, adding cross-linking agent and photoinitiator for polymerization reaction to obtain cross-linked product, freeze drying and grinding to obtain biocompatible hemostatic powder with high-strength liquid absorbing capacity and antibacterial function.
2. The method of claim 1, wherein the chitosan derivative comprises one or more of chitosan quaternary ammonium salt and carboxymethyl chitosan.
3. The method of claim 1 or 2, wherein the mass concentration of the chitosan derivative solution is 5-10%.
4. The method of claim 1, wherein the molar ratio of the methacryloxyethyl trimethyl ammonium chloride to the acrylic acid is 0.01-3:0.01-3.
5. The method of claim 4, wherein the cross-linking agent comprises polyethylene glycol diacrylate and the photoinitiator comprises 2-hydroxy-2-methyl-1-phenyl-1-propanone.
6. The method according to claim 5, wherein the crosslinking agent is 2 to 4% of the sum of the molar masses of the methacryloxyethyl trimethyl ammonium chloride and the acrylic acid, and the photoinitiator is 2 to 4% of the sum of the molar masses of the methacryloxyethyl trimethyl ammonium chloride and the acrylic acid.
7. The method of claim 1 or 6, wherein the polymerization reaction comprises an ultraviolet 365nm light polymerization reaction for 50-70 min.
8. The hemostatic powder with rapid high-strength liquid absorbing capacity, antibacterial function and good biocompatibility prepared by the preparation method of any one of claims 1-7.
9. Use of a hemostatic powder according to claim 8 for the preparation of a hemostatic material for medical use.
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