CN114832148A - Hemostatic material with antibacterial and anti-inflammatory functions and preparation method and application thereof - Google Patents
Hemostatic material with antibacterial and anti-inflammatory functions and preparation method and application thereof Download PDFInfo
- Publication number
- CN114832148A CN114832148A CN202210420974.XA CN202210420974A CN114832148A CN 114832148 A CN114832148 A CN 114832148A CN 202210420974 A CN202210420974 A CN 202210420974A CN 114832148 A CN114832148 A CN 114832148A
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- CN
- China
- Prior art keywords
- chitosan
- antibacterial
- hyaluronic acid
- hemostatic material
- hemostatic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 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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Abstract
The invention provides a hemostatic material with antibacterial and anti-inflammatory functions, which comprises: hydrophobized chitosan and adenosine diphosphate modified hyaluronic acid, wherein the hydrophobized chitosan is crosslinked with the adenosine diphosphate modified hyaluronic acid; the invention also provides a preparation method of the hemostatic material with the antibacterial and anti-inflammatory functions, the hyaluronic acid can improve the activation of blood platelets in blood by ADP modification, the blood coagulation is accelerated, the hydrophobic chitosan material can promote the adsorption of blood cells and improve the antibacterial property of the material, the hemostatic material is obtained by crosslinking the hydrophobic chitosan material and the hydrophobic chitosan material under the electrostatic action, the preparation method is simple, the preparation period is short, and the usability is strong; the invention also provides the application of the hemostatic material with the antibacterial and anti-inflammatory functions, which is used for preparing anti-adhesion hemostatic dressings, hemostatic bandages, wound-protecting dressings, tissue injury repair films, drug sustained-release carriers, absorption and plugging materials of effusion or antibacterial agents.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a hemostatic material with antibacterial and anti-inflammatory functions, a preparation method and application thereof.
Background
Uncontrolled bleeding caused by medical, military conflicts, traffic accidents, etc. sometimes occurs and results in a great deal of casualties. When an accidental wound occurs, the structure of a blood vessel wall is damaged, axonal nerve reflex contraction occurs immediately to an organism, meanwhile, local blood viscosity at the damaged part is increased, blood platelets are easy to adhere and aggregate at a bleeding part, stability of subsequent thrombosis is facilitated, and hemostasis can be completed by virtue of contraction of the blood vessel wall for the wound of a small blood vessel; in the case of large vessel trauma, vasoconstriction can cause the fracture of the vessel to retract deep within the barrier, blocking blood flow. However, the hemostatic bag is low in rescue success rate for large wound surface injury or artery injury caused by accidents, high blood pressure, blood ejection, massive hemorrhage in a short time and the like, so that timely, effective and rapid hemostasis is vital to the success of saving the life of a patient, stabilizing the injury and clinical operation, and is an important rescue element. In addition, in subsequent wound healing, hemostatic dressings need to facilitate wound healing and reduce the potential risk of infection of the wound. Therefore, a good hemostatic dressing should accelerate wound closure and have a certain antibacterial ability while having efficient hemostasis.
The existing hemostatic materials mainly comprise a zeolite hemostatic, a gelatin sponge, an alginate dressing and the like, but have certain disadvantages. For example, zeolite hemostats are associated with strong heat release during use, which is likely to cause secondary tissue burns and cause inflammatory reactions. The gelatin sponge prepared by taking gelatin as a material has the advantages of in vivo absorption time of more than 8 weeks, poor adhesion with bleeding wound surfaces and easy shedding, and because of containing protein components, the probability of infection is increased, so the gelatin hemostatic has good hemostatic effect only by being matched with other hemostatic. The alginate dressing can absorb the exudate at the wound up to 30 times of the wound volume, the alginate at the wound interacts with the exudate, certain humidity is kept, the wound healing is facilitated, but the alginate material has peculiar smell, other dressings are required to be fixed during use, and the dressing cannot be covered and sealed on the infected wound. In addition, most of the hemostatic materials have no antibacterial and anti-inflammatory functions.
The chitosan is a deacetylated derivative of chitin, contains a large number of amino groups and hydroxyl groups on a molecular structure, and a large number of hydrogen bonds are accumulated in macromolecules, so that the formation of a crystalline state is facilitated, the molecular bonds are more regular, and the rigidity is higher, so that the chitosan is insoluble in water and alkaline solution. Chitosan has stable chemical properties, good biological functions and degradability such as hemostasis, bacteriostasis, healing promotion and the like, and is widely applied to the biological field, but the chitosan is insoluble in water, so that the application of the chitosan in multiple fields is limited. Therefore, chitosan needs to be modified to be applicable to hemostatic materials.
Disclosure of Invention
In view of the above disadvantages of the prior art, an object of the present invention is to provide a hemostatic material with antibacterial and anti-inflammatory functions, a preparation method and a use thereof, which are used to solve the problem that the hemostatic material in the prior art cannot simultaneously achieve antibacterial and anti-inflammatory functions while stopping bleeding.
To achieve the above and other related objects, a first aspect of the present invention provides a hemostatic material having antibacterial and anti-inflammatory functions, comprising: hydrophobized chitosan and Adenosine Diphosphate (ADP) modified hyaluronic acid, wherein the hydrophobized chitosan is crosslinked with the ADP modified hyaluronic acid.
Preferably, the mass ratio of the ADP modified hyaluronic acid to the hydrophobized chitosan is 1-10: 2 to 12.
Preferably, the mass ratio of hyaluronic acid to adenosine diphosphate in the adenosine diphosphate modified hyaluronic acid is 1: 0.3-0.5.
Preferably, the hydrophobized chitosan is chitosan obtained by modifying undecanal.
The second aspect of the invention provides a preparation method of a hemostatic material with antibacterial and anti-inflammatory functions, which at least comprises the following steps:
1) mixing the adenosine diphosphate modified hyaluronic acid solution with the hydrophobized chitosan solution, and reacting to obtain a cross-linked product;
2) purifying and removing the solvent from the cross-linked product prepared in the step 1) to obtain the adenosine diphosphate modified hyaluronic acid/hydrophobic chitosan (HA-ADP/UCS) material, namely the hemostatic material with the functions of antibiosis and antiphlogosis.
Preferably, the step 1) further comprises: step 1a), preparation of adenosine diphosphate modified hyaluronic acid: reacting hyaluronic acid with adenosine diphosphate under the action of a catalyst to obtain the adenosine diphosphate modified hyaluronic acid.
Preferably, the step 1) further comprises: step 1b), preparation of hydrophobized chitosan: the hydrophobic chitosan is prepared by the reaction of chitosan and undecanal.
Preferably, the concentration of the ADP modified hyaluronic acid solution in the step 1) is 1-3 wt%.
Preferably, the concentration of the hydrophobized chitosan solution in the step 1) is 1-3 wt%.
Preferably, the volume ratio of the adenosine diphosphate modified hyaluronic acid solution to the hydrophobized chitosan solution in the step 1) is 6-12: 4-12.
Preferably, the solvent of the adenosine diphosphate modified hyaluronic acid solution and the hydrophobized chitosan solution in step 1) is a polar solvent, preferably water.
The invention provides an application of the hemostatic material with the antibacterial and anti-inflammatory functions, which is used for preparing anti-adhesion hemostatic dressings, hemostatic bandages, wound-protecting dressings, tissue injury repair films, drug slow-release carriers, absorption and plugging materials of effusion or antibacterial agents.
As mentioned above, the hemostatic material with antibacterial and anti-inflammatory functions, the preparation method and the use of the hemostatic material have the following beneficial effects:
the hemostatic material with the antibacterial and anti-inflammatory functions is obtained by means of electrostatic crosslinking, and has the advantages of simple preparation method, no need of complicated crosslinking process, short preparation period and strong usability.
The hyaluronic acid and the chitosan in the hemostatic material with the antibacterial and anti-inflammatory functions have good biocompatibility and biodegradability, and can improve the activation of blood platelets in blood and accelerate blood coagulation by the modification of ADP, and the hydrophobic chitosan material can promote the adsorption of blood cells and improve the antibacterial property of the material.
The hemostatic material with the antibacterial and anti-inflammatory functions has small toxic and side effects, good water absorption performance, and can shorten the blood coagulation time through effective adsorption and promote wound healing.
Drawings
Fig. 1 shows fourier infrared spectra of ADP-modified hyaluronic acids with degrees of substitution of 10%, 30%, 50% according to the invention.
FIG. 2 shows a Fourier infrared spectrum of undecalaldehyde-modified chitosan of the present invention.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Please refer to 1-2. It should be noted that the drawings provided in the present embodiment are only for illustrating the basic idea of the present invention, and the components related to the present invention are only shown in the drawings rather than drawn according to the number, shape and size of the components in actual implementation, and the type, quantity and proportion of the components in actual implementation may be changed freely, and the layout of the components may be more complicated.
The invention provides a hemostatic material with antibacterial and anti-inflammatory functions, which comprises: hydrophobized chitosan and adenosine diphosphate modified hyaluronic acid, wherein the hydrophobized chitosan is crosslinked with the adenosine diphosphate modified hyaluronic acid.
Adenosine diphosphate is the most important substance inducing platelet aggregation in vivo, is present in high-density particles in platelet cells, is released when platelet aggregation reaction occurs, and further accelerates the aggregation process of platelets through the influence of ADP receptors on platelets on the shape and biological behavior of platelets.
The chitosan is prepared by extracting chitin as a raw material, and the high molecular weight chitosan is insoluble in water, soluble in dilute acid and absorbable by human bodies. The chemical structure of the polysaccharide is a high molecular basic polysaccharide polymer with cations, and the polysaccharide has unique physical and chemical properties and biological activation property. The chitosan has effects of promoting blood coagulation, can be used as wound filler, and has effects of sterilizing, promoting wound healing, absorbing wound exudate, and preventing syneresis. The chitosan and its derivatives have good antibacterial activity, and can inhibit growth and reproduction of fungi, bacteria and viruses.
Hyaluronic acid is an acidic mucopolysaccharide, can improve skin nutrition metabolism, make skin tender and smooth, remove wrinkles, increase elasticity, prevent aging, and is a good transdermal absorption enhancer while keeping moisture.
The hemostatic material has the functions of promoting coagulation and resisting bacteria, stops bleeding and can promote wound healing.
The hydrophobic chitosan and the hyaluronic acid modified by adenosine diphosphate are crosslinked, wherein the mass ratio of the hyaluronic acid modified by adenosine diphosphate to the hydrophobic chitosan is (1-10): 2 to 12, for example, 1 to 2:2 to 12, 2 to 4:2 to 12, 4 to 6:2 to 12, 6 to 8:2 to 12, 8 to 10:2 to 12, 1 to 10:2 to 4, 1 to 10:4 to 6, 1 to 10:6 to 8, 1 to 10:8 to 10, or 1 to 10:10 to 12. Preferably, the mass ratio of the adenosine diphosphate modified hyaluronic acid to the hydrophobized chitosan is 4-8: 6-8.
In the adenosine diphosphate modified hyaluronic acid, the mass ratio of hyaluronic acid to adenosine diphosphate is 1: 0.3-0.5, for example, 1: 0.3-0.4 or 1: 0.4-0.5. In a preferred embodiment of the invention, the mass ratio of hyaluronic acid to adenosine diphosphate is 1: 0.35.
The hydrophobic chitosan adopted by the invention is obtained by modifying chitosan through undecanal. By utilizing the hydrophobic characteristic of the undecanal, the modified chitosan has a hydrophobic effect, can promote adhesion of erythrocytes to promote blood coagulation, and can destroy cell membranes of bacteria to perform antibiosis. The mass ratio of the chitosan to the undecanal is 1: 0.016-0.083, such as 1: 0.016-0.020, 1: 0.020-0.030, 1: 0.030-0.040, 1: 0.040-0.050, 1: 0.050-0.060, 1: 0.060-0.070, 1: 0.070-0.080 or 1: 0.080-0.083.
The invention also provides a preparation method of the hemostatic material with antibacterial and anti-inflammatory functions, which at least comprises the following steps:
1) mixing ADP modified hyaluronic acid solution with hydrophobized chitosan solution, and reacting to obtain a cross-linked product;
2) purifying and removing the solvent from the cross-linked product prepared in the step 1) to obtain the ADP modified hyaluronic acid/hydrophobic chitosan material, namely the hemostatic material with the antibacterial and anti-inflammatory functions.
The invention provides a preparation method of a hemostatic material with antibacterial and anti-inflammatory functions, which comprises the following steps of 1):
step 1a) preparation of adenosine diphosphate modified hyaluronic acid: reacting hyaluronic acid with adenosine diphosphate under the action of a catalyst to obtain the adenosine diphosphate modified hyaluronic acid.
The molecular weight of hyaluronic acid is usually tens of thousands to millions, and it is generally considered that high molecular weight hyaluronic acid with molecular weight higher than 2000KDa can form a breathable film on the surface layer of skin, lock water on the surface of skin, and prevent water from evaporating, but the penetration is poor and cannot be absorbed by skin. The hyaluronic acid with medium molecular weight is 500-2000 KDa, and can form gas-permeable membrane on skin surface layer to lock water. The low molecular weight hyaluronic acid has a molecular weight of 10-500 KDa, can permeate into the dermis layer of skin, and has effects in the inner part of skin, but has relatively poor ability to prevent water evaporation. The molecular weight of the oligomeric hyaluronic acid is less than 10KDa, and the oligomeric hyaluronic acid can penetrate into the dermis layer to play a role. Considering that the product of the present invention is mainly used for hemostasis, not only has proper water absorption performance, but also needs to stay in the wound for a proper time to achieve the purpose of rapid hemostasis, the hyaluronic acid is preferably low molecular weight hyaluronic acid. In a preferred embodiment, the molecular weight of the hyaluronic acid is 30000Da to 100000 Da. In a preferred embodiment of the invention, the hyaluronic acid has a molecular weight of 30000 Da.
In the present invention, ADP is used to modify hyaluronic acid. ADP can induce platelet aggregation, hyaluronic acid has certain water absorption performance, and after ADP modifies hyaluronic acid, the ADP and hyaluronic acid cooperate to achieve the purpose of stopping bleeding more quickly. The mass ratio of the hyaluronic acid to the ADP is 1: 0.3-0.5, such as 1: 0.3-0.4 or 1: 0.4-0.5. In a preferred embodiment of the invention, the mass ratio of hyaluronic acid to ADP is 1: 0.35.
The catalyst used for ADP modification of hyaluronic acid can be 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide. In the present invention, the mass ratio of hyaluronic acid to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide is 1: 0.1-0.3: 0.1-0.2, for example, 1: 0.1-0.2, 1: 0.2-0.3: 0.1-0.2, preferably 1: 0.1-0.2: 0.1, 1: 0.1-0.2: 0.2, 1:0.1: 0.1-0.2, or 1:0.2: 0.1-0.2. In a preferred embodiment of the invention, the mass ratio of hyaluronic acid to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N-hydroxysuccinimide is 1:0.17: 0.10.
The pH value of the ADP modified hyaluronic acid reaction is generally controlled to be 5-6. In general, hyaluronic acid is dissolved in solvent water, the pH is adjusted to 5-6, catalyst EDC is added to obtain a mixed solution, ADP and NHS are weighed after stirring reaction and added into the mixed solution for continuous reaction, and after the reaction is finished, the reaction solution is dialyzed or settled to obtain a product.
The product can be directly applied to the subsequent reaction, and can also be dried and temporarily stored for later use. The product is dried by a freeze-drying method, for example, without limitation. The temperature of freeze drying can be-40 to-80 ℃. The freeze-drying may be carried out in a freeze dryer.
The invention provides a preparation method of a hemostatic material with antibacterial and anti-inflammatory functions, which comprises the following steps of 1):
step 1b), preparation of hydrophobized chitosan: the hydrophobic chitosan is prepared by the reaction of chitosan and undecanal.
Chitosan is a macromolecule, the source of which is chitin, and because the source and the preparation method of the chitin are different, the relative molecular weight of the chitosan is tens of thousands to millions. The molecular weight of the low molecular weight chitosan is generally considered to be 50KDa to 190 KDa. The low molecular weight chitosan can be dissolved in water, and has good water solubility, moisturizing and humidifying, and antibacterial effects. And the bacteriostatic action of the chitosan is gradually enhanced along with the reduction of the average molecular weight of the chitosan. Chitosan accelerates the formation of blood vessels by releasing chitosan oligomers to the wound site, allowing collagen fibrils to enter the cell matrix, and promoting wound healing. The chitosan is a hemostatic material for resisting bacteria and diminishing inflammation, so the chitosan with low molecular weight is selected. In a preferred embodiment of the invention, the chitosan has a molecular weight of 50000Da to 190000 Da.
According to the invention, the hydrophobic chitosan is prepared by modifying chitosan with undecanal, and the modified chitosan has hydrophobic effect by utilizing the hydrophobic characteristic of undecanal, so that the adhesion of erythrocytes can be promoted to promote blood coagulation, and meanwhile, the cell membrane of bacteria can be destroyed to perform antibiosis. The mass-to-volume ratio of chitosan to undecanal is 1g:0.02 to 0.1mL, for example, 1g:0.02 to 0.03mL, 1g:0.03 to 0.04mL, 1g:0.04 to 0.05mL, 1g:0.05 to 0.06mL, 1g:0.06 to 0.07mL, 1g:0.07 to 0.08mL, 1g:0.08 to 0.09mL, or 1g:0.09 to 0.1 mL. In a preferred embodiment of the invention, the undecanal is undecanal having a density of 0.825 g/mL. In a preferred embodiment of the invention, the mass to volume ratio of chitosan to undecanal is 1g:0.1 mL.
Reacting chitosan with ethanol solution of undecanal. The volume percentage concentration of the ethanol solution of the undecanal is 2.5-10%, for example, 2.5-3%, 3-4%, 4-5%, 5-6%, 6-7%, 7-8%, 8-9% or 9-10%. In a preferred embodiment of the invention, the ethanol solution of undecanal has a concentration of 10% by volume. Ethanol is used as a solvent, and the volatile property of the ethanol enables the ethanol to be easily removed in the subsequent preparation process.
In the reaction of modifying chitosan by undecanal, chitosan and undecanal react in the presence of sodium borohydride cyanide. The mass ratio of the chitosan to the sodium cyanoborohydride is 1: 0.02-0.1, such as 1: 0.02-0.03, 1: 0.03-0.04, 1: 0.04-0.05, 1: 0.05-0.06, 1: 0.06-0.07, 1: 0.07-0.08, 1: 0.08-0.09 or 1: 0.09-0.1. In a preferred embodiment of the invention, the mass ratio of chitosan to sodium cyanoborohydride is 1: 0.1.
The pH value of the reaction for modifying chitosan by undecanal is generally controlled to be 5-6. Usually, the chitosan is dissolved in solvent water, the pH value is adjusted to 5-6, then an ethanol solution of undecanal is added, stirring reaction is carried out, then sodium cyanoborohydride is added, stirring reaction is continued, and after the reaction is finished, the reaction solution is dialyzed or settled to obtain the hydrophobized chitosan product.
The hydrophobized chitosan product can be directly applied to subsequent reaction, and can also be dried and temporarily stored for later use. The product is dried by a freeze-drying method, for example, without limitation. The temperature of freeze drying can be-40 to-80 ℃. The freeze-drying may be carried out in a freeze dryer.
According to the preparation method of the hemostatic material with the antibacterial and anti-inflammatory functions, the concentration of the adenosine diphosphate modified hyaluronic acid solution in the step 1) is 1-3 wt%, for example, 1-2 wt% or 2-3 wt%. In a preferred embodiment of the present invention, the concentration of the adenosine diphosphate modified hyaluronic acid solution is 2 wt%.
The preparation method of the hemostatic material with antibacterial and anti-inflammatory functions provided by the invention comprises the step 1) of adding 1-3 wt% of the hydrophobized chitosan solution, for example, 1-2 wt% or 2-3 wt%. In a preferred embodiment of the present invention, the concentration of the hydrophobized chitosan solution is 2 wt%.
The preparation method of the hemostatic material with the antibacterial and anti-inflammatory functions, provided by the invention, in the step 1), the volume ratio of the adenosine diphosphate modified hyaluronic acid solution to the hydrophobized chitosan solution is 6-12: 4-12, such as 6-8: 4-6, 6-8: 6-8, 6-8: 8-10, 6-8: 10-12, 8-10: 4-6, 8-10: 6-8, 8-10: 8-10, 8-10: 10-12, 10-12: 4-6, 10-12: 6-8, 10-12: 8-10 or 10-12: 10-12. In a preferred embodiment of the present invention, the volume ratio of the adenosine diphosphate modified hyaluronic acid solution to the hydrophobized chitosan solution is 1: 1. In general, an adenosine diphosphate-modified hyaluronic acid solution and a hydrophobized chitosan solution are mixed in proportion, and stirred to cause a crosslinking reaction to occur, thereby obtaining a crosslinked product. ADP modified hyaluronic acid and hydrophobic chitosan are subjected to electrostatic crosslinking under a stirring state to generate a product.
The solvents of the adenosine diphosphate modified hyaluronic acid solution and the hydrophobized chitosan solution are both polar solvents. The polar solvent is preferably water. In a preferred embodiment of the present invention, the solvents of the adenosine diphosphate modified hyaluronic acid solution and the hydrophobized chitosan solution are both deionized water.
The preparation method of the hemostatic material with the antibacterial and anti-inflammatory functions provided by the invention has the advantage that the purification method of the cross-linked product in the step 2) is washing. The uncrosslinked molecules are removed by washing. In a preferred embodiment of the invention, the solvent used for washing is deionized water.
In the preparation method of the hemostatic material with antibacterial and anti-inflammatory functions, the method for removing the solvent from the cross-linked product in the step 2) is drying. In a preferred embodiment of the invention, the drying is freeze-drying at-40 to-80 ℃. The freeze-drying may be carried out in a freeze dryer.
The third aspect of the invention also provides an application of the hemostatic material with the antibacterial and anti-inflammatory functions, which is used for preparing an anti-adhesion hemostatic dressing, a hemostatic bandage, a wound dressing, a tissue injury repair film, a drug sustained-release carrier, an absorption and blocking material of effusion or an antibacterial agent. Anti-adhesion hemostatic dressings include, but are not limited to, hemostatic powders, hemostatic films, hemostatic sprays, hemostatic particles, hemostatic microspheres, hemostatic sponges, hemostatic foams, or hemostatic gels. The hemostatic material with the antibacterial and anti-inflammatory functions can also be used for preparing damage-prevention repair stents, vascular occlusion or embolization agents, other tissue engineering repair stents and the like.
The preparation method of the hemostatic material with the antibacterial and anti-inflammatory functions, provided by the invention, is obtained by effective electrostatic crosslinking between ADP modified hyaluronic acid and hydrophobic chitosan, has water absorption performance, and can shorten the blood coagulation time through effective adsorption. Meanwhile, the composition has good biocompatibility and antibacterial and anti-inflammatory properties, and can accelerate tissue healing.
Example 1
Preparation of ADP modified hyaluronic acid: dissolving 1.0g of hyaluronic acid with the molecular weight of 30000Da in deionized water, adjusting the pH value to 5.5, adding 0.17g of EDC, reacting for 1 hour to obtain a mixed solution, adding 0.10g of NHS and 0.35g of ADP into the mixed solution, continuing the reaction, dialyzing the reaction solution after the reaction is finished, washing a product, and freeze-drying at-40 to-80 ℃ to obtain ADP modified hyaluronic acid with the substitution degree of 30% (figure 1) for later use.
Preparation of hydrophobized chitosan: dissolving 1.0g of chitosan with the molecular weight of 50 KDa-190 Kda in deionized water, adjusting the pH value to 5.5, adding 1mL of 10% ethanol solution of undecanal (the density of the undecanal is 0.825g/mL), stirring for reacting for 1 hour, adding 0.1g of sodium cyanoborohydride, continuing stirring for reacting, dialyzing the reaction solution after the reaction is finished, washing the product, and freeze-drying at-40-80 ℃ to obtain the hydrophobic chitosan (figure 2) for later use.
The preparation of the hemostatic material with the antibacterial and anti-inflammatory functions comprises the following steps: respectively dissolving the prepared ADP modified hyaluronic acid and the prepared hydrophobic chitosan into deionized water to obtain an ADP modified hyaluronic acid solution with the uniform mass fraction of 2 wt% and a hydrophobic chitosan solution with the mass fraction of 2 wt%; mixing the two solutions according to the volume ratio of 1:1, intensively stirring, centrifugally collecting the obtained cross-linked product, re-dispersing the collected product in deionized water to wash off non-cross-linked molecules, and freeze-drying at-40 to-80 ℃ to obtain the spongy HA-ADP/UCS material, namely the hemostatic material with the antibacterial and anti-inflammatory functions.
Example 2
Efficacy experiments:
in vitro antibacterial test: the hemostatic material prepared in example 1 above was used in an antibacterial test for detecting staphylococcus aureus, escherichia coli, and methicillin-resistant staphylococcus. The antibacterial property was evaluated by co-culturing the hemostatic material having antibacterial and anti-inflammatory functions prepared in example 1 with a bacterial solution. The specific process is as follows:
(1) respectively weighing 10g of hemostatic material with antibacterial and anti-inflammatory effects in 2mL EP tube, weighing three groups as sample groups, each group comprises three parts, and a blank control group, and sterilizing by irradiating with ultraviolet rays for 30 min;
(2) adding 100 mu L of staphylococcus aureus, escherichia coli and methicillin-resistant staphylococcus into 5mL of sterile LB liquid culture medium, culturing for 6h at 37 ℃ by using a shaking table at 200rpm, and measuring an OD value at 625nm by using an enzyme-linked immunosorbent assay (ELISA) instrument to calculate the number of bacteria;
(3) diluting the bacterial liquid obtained in the step (2) with normal saline to obtain a final concentration of 10 8 CFU/mL; respectively dripping 10 mu L of diluted bacterial liquid on the surfaces of the corresponding sample group materials in the step (1), and directly dripping the blank control groupCulturing at the bottom of EP tube in 37 deg.C incubator for 2 h;
(4) after 990 mu L of physiological saline is added into each tube, the EP tube is placed in an ultrasonic cleaner to carry out ultrasonic treatment for 10min at the power of 300W so as to elute bacteria on the surface of the material;
(5) dripping 100 μ L of the eluate on the surface of agar plate, uniformly coating with triangular glass rod, and culturing in 37 deg.C incubator for 16-24 hr;
(6) and (3) photographing: observing colony density difference of qualitative experiment; the colony number of the LB agar plate is recorded in a quantitative experiment, and the antibacterial rate is calculated according to the following formula:
the antibacterial rate (%) -, of SP /C C *F*100%
Wherein, C SP And C C Respectively representing the colony numbers of the sample group and the control group; f is the dilution factor, and because the bacterial amount of the control group is large, the bacterial colony amount cannot be measured by directly coating the plate, so the plate is usually coated after dilution.
The results of the bacteriostatic test of the hemostatic material with antibacterial and anti-inflammatory functions on staphylococcus aureus, escherichia coli and methicillin-resistant staphylococcus are shown in table 1 in detail.
TABLE 1
Staphylococcus aureus | Escherichia coli | Methicillin-resistant staphylococci | |
Bacteriostatic ratio (%) | 99.55 | 99.97 | 100 |
As can be seen from the data in Table 1, the HA-ADP/UCS hemostatic material with antibacterial and anti-inflammatory functions prepared in example 1 HAs a concentration of 10 8 The concentration of the CFU/mL staphylococcus aureus and the concentration of the escherichia coli are respectively 99.55 percent and 99.97 percent, and the concentration is 10 8 The CFU/mL methicillin-resistant staphylococcus bacteriostatic rate reaches 100%. Fully shows that the HA-ADP/UCS hemostatic material with the antibacterial and anti-inflammatory functions HAs good antibacterial action.
Rat tail-broken hemostasis experiment: the hemostatic material prepared in example 1 was used for hemostasis of rat tail, and the hemostatic effect was evaluated by the hemostatic time and amount of bleeding of the rat. The specific process is as follows:
(1) 20 rats weighing 250-300 g are randomly divided into 4 groups, and each group comprises 5 rats, namely a blank group (using filter paper to stop bleeding), a gelatin sponge (Jiangxi Xiangen medical development science and technology Limited company), a CELOX chitosan hemostatic powder (Evarready First Aid) group and an HA-ADP/UCS group.
(2) After anesthetizing each group of rats, the tails of the rats were cut off at the midpoint of the length, hemostasis was performed with each group of materials after 20 seconds of free bleeding and the time was recorded, and after complete hemostasis, timing was stopped and the amount of blood was weighed (averaged) and shown in table 2.
TABLE 2
Blank group | Gelatin sponge | Chitosan styptic powder | HA-ADP/UCS | |
Hemostasis time/second | 230.2±22.6 | 160.0±42.0 | 117.0±11.7 | 46.6±3.8 |
Amount of bleeding/mg | 1116.7±86.4 | 143.8±62.1 | 69.8±10.9 | 35.5±4.9 |
As can be seen from the data in Table 2, the rats in the blank group, which were not treated after the tail breakage, exhibited a bleeding amount of 1116mg and a self-hemostasis time of 230 seconds. The gelatin sponge group rats treated with gelatin sponge (Jiangxi Xiangen medical development science and technology Limited) after 20 seconds of tail-breaking bleeding stop bleeding, the bleeding amount of the rats is reduced to 143mg, and the bleeding can be stopped in 160 seconds. The chitosan hemostatic powder group rats adopt CELOX chitosan hemostatic powder (Everready First Aid) to treat hemostasis after 20 seconds of tail-breaking bleeding, the bleeding amount of the rats is reduced to 69mg, and hemostasis can be achieved in 117 seconds.
Rats adopting the HA-ADP/UCS hemostatic material can stop bleeding after 20 seconds of broken tail bleeding and the bleeding amount is as low as 35mg after 46 seconds of treatment by the HA-ADP/UCS hemostatic material.
The data show that compared with gelatin sponge (Jiangxi Xiangen medical development science and technology Limited) and CELOX chitosan hemostatic powder (Evarready First Aid), the HA-ADP/UCS hemostatic material prepared by the invention HAs more effective hemostatic effect on broken tail rats, and the rats have less bleeding amount and high hemostatic speed.
In conclusion, the hemostatic material with the antibacterial and anti-inflammatory functions has good biocompatibility and high-efficiency antibacterial action, can accelerate wound healing, and has good application prospect, and the preparation method of the hemostatic material with the antibacterial and anti-inflammatory functions is simple, does not need a complicated cross-linking process, and has short preparation period; meanwhile, the hemostatic material with the antibacterial and anti-inflammatory functions can be used for preparing anti-adhesion hemostatic dressings, hemostatic bandages, wound protecting dressings, tissue injury repairing films, drug sustained-release carriers, absorption and plugging materials of effusion or antibacterial agents, and has wide market prospects. Therefore, the invention effectively overcomes various defects in the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (12)
1. A hemostatic material having antibacterial and anti-inflammatory functions, comprising: hydrophobized chitosan and adenosine diphosphate modified hyaluronic acid, wherein the hydrophobized chitosan is crosslinked with the adenosine diphosphate modified hyaluronic acid.
2. The hemostatic material with antibacterial and anti-inflammatory functions according to claim 1, wherein the mass ratio of the adenosine diphosphate modified hyaluronic acid to the hydrophobized chitosan is 1-10: 2 to 12.
3. The hemostatic material having an antibacterial and anti-inflammatory function according to any one of claims 1 to 2, wherein the mass ratio of hyaluronic acid to adenosine diphosphate in the adenosine diphosphate-modified hyaluronic acid is 1:0.3 to 0.5.
4. The hemostatic material with antibacterial and anti-inflammatory functions according to any one of claims 1 to 2, wherein the hydrophobic chitosan is chitosan obtained by modifying undecanal.
5. The hemostatic material with antibacterial and anti-inflammatory functions according to claim 4, wherein the mass ratio of chitosan to undecanal is 1: 0.016-0.083.
6. A method for preparing a hemostatic material with antibacterial and anti-inflammatory functions according to any one of claims 1 to 5, characterized by comprising at least the following steps:
1) mixing the adenosine diphosphate modified hyaluronic acid solution and the hydrophobized chitosan solution, and reacting to obtain a cross-linked product;
2) purifying and removing the solvent from the cross-linked product prepared in the step 1) to obtain the adenosine diphosphate modified hyaluronic acid/hydrophobic chitosan material, namely the hemostatic material with the antibacterial and anti-inflammatory functions.
7. The method for preparing hemostatic material with antibacterial and anti-inflammatory functions according to claim 6, wherein the step 1) further comprises:
step 1a), preparation of adenosine diphosphate modified hyaluronic acid: reacting hyaluronic acid with adenosine diphosphate under the action of a catalyst to obtain adenosine diphosphate modified hyaluronic acid;
and/or, step 1b), preparation of hydrophobized chitosan: the hydrophobic chitosan is prepared by the reaction of chitosan and undecanal.
8. The method for preparing a hemostatic material with antibacterial and anti-inflammatory functions according to claim 7, wherein in step 1a), the catalyst is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide.
9. The method for preparing a hemostatic material with antibacterial and anti-inflammatory functions according to claim 8, wherein the mass ratio of the hyaluronic acid to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and the N-hydroxysuccinimide is 1: 0.1-0.3: 0.1-0.2.
10. The method for preparing hemostatic material with antibacterial and anti-inflammatory functions according to claim 7, wherein in step 1b), chitosan is reacted with ethanol solution of undecanal;
and/or, in step 1b), reacting the chitosan with undecanal in the presence of sodium cyanoborohydride.
11. The method for preparing a hemostatic material with antibacterial and anti-inflammatory functions according to claim 6, wherein in the step 1), the concentration of the adenosine diphosphate modified hyaluronic acid solution is 1-3 wt%;
and/or in the step 1), the concentration of the hydrophobized chitosan solution is 1-3 wt%;
and/or in the step 1), the volume ratio of the adenosine diphosphate modified hyaluronic acid solution to the hydrophobized chitosan solution is 6-12: 4-12;
and/or, in the step 1), the solvents of the adenosine diphosphate modified hyaluronic acid solution and the hydrophobized chitosan solution are both polar solvents;
and/or, in the step 2), the crosslinked product purification method is washing;
and/or, in the step 2), the crosslinked product desolvation method is drying.
12. Use of the hemostatic material with antibacterial and anti-inflammatory functions of any one of claims 1 to 5, in the preparation of an anti-adhesion hemostatic dressing, a hemostatic bandage, a wound dressing, a tissue injury repair membrane, a drug sustained-release carrier, a hydrops absorption and blocking material or an antibacterial agent.
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