CN119455075A - Marine polymer polysaccharide hydrogel wound dressing and preparation method thereof and application in preparation of medical devices - Google Patents
Marine polymer polysaccharide hydrogel wound dressing and preparation method thereof and application in preparation of medical devices Download PDFInfo
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- CN119455075A CN119455075A CN202411618224.9A CN202411618224A CN119455075A CN 119455075 A CN119455075 A CN 119455075A CN 202411618224 A CN202411618224 A CN 202411618224A CN 119455075 A CN119455075 A CN 119455075A
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Abstract
The invention discloses a preparation method and application of a marine polymer polysaccharide hydrogel wound dressing. The hydrogel is formed by crosslinking a marine polysaccharide composition and a crosslinking agent, has short gelation time of about 15 seconds, uniform and moderate pores, self-healing property, adhesiveness, high swelling property, strong antibacterial effect, high inhibition rate to escherichia coli and staphylococcus aureus of more than 90%, no skin irritation and skin allergy, high biological safety, rapid hemostasis within 10 seconds, remarkably reduced bleeding amount, capability of enabling a wound surface to rapidly shrink and scab, and simultaneously has the effect of promoting wound healing, and the effect of stopping and promoting wound healing is remarkably superior to that of a commercially available hydrogel dressing (German Boehmann Hydrosorb Gel) (P < 0.05), and is a safe and effective high-performance wound dressing. In addition, the hydrogel has simple formula and high industrialization prospect, is hopeful to be developed into novel wound dressing and medical equipment, and breaks the dilemma that domestic hydrogel dressing depends on import.
Description
Technical Field
The invention belongs to the field of biomedical engineering polymer materials, and particularly relates to a marine polymer polysaccharide hydrogel wound dressing, and a preparation method and application thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
The skin is the most exposed and most fragile organ of human body, plays an important role in protecting internal tissues from the interference of external environment, maintaining stable internal environment and regulating body temperature. Once an injury occurs, it is often necessary to undergo a lengthy self-healing process and cause a complex series of health problems, including inflammation, secondary injury, bacterial infection, and the like. Accidents, war and surgery often cause severe skin wounds, especially full-thickness lesions, which, if left untreated, can form chronic wounds, which are difficult to heal, and uncontrolled bleeding from the wounds is a major cause of global death. The first hour after a wound is the life-to-death critical "golden one hour" in which rapid hemostasis of the wound of a wounded person is critical in rescuing the life of the wounded person. The rapid and effective hemostasis means can improve the survival rate and reduce complications of wounded persons. Skin damage, bleeding, bacterial infection are often accompanied, and therefore, development of bioactive dressings which can rapidly stop bleeding and have antibacterial and wound healing promoting effects has become a research hotspot in the medical field.
Aiming at wounds, the traditional bandage mainly uses cotton yarn as a base material, and has certain air permeability and wound surface protection capability, but the sore liquid absorption capability is insufficient, the packing compression effect is poor for severe bleeding, and the infection prevention and wound healing promotion capability is limited. Studies have shown that wounds heal faster in the moist state, and wet therapy has become a major theoretical basis for the design of new medical dressings. More and more researchers develop a series of moist wound dressings, such as hydrogel dressings, hydrocolloid dressings, etc., which are more suitable for the specific needs of the wound healing process, and which also shorten the wound healing time and improve the therapeutic effect. The ideal wound dressing should be capable of covering wounds rapidly and effectively, have excellent mechanical properties, good biosafety, antibacterial and bacteriostatic functions and hemostatic effects, thereby promoting wound healing. The existing researches, patents or products show that the wet dressing prepared by combining macromolecules with the functions of resisting bacteria, inhibiting bacteria, promoting wound healing and the like in various modes can well realize the treatment and nursing of wounds, and has great market prospect.
With the development of biotechnology, natural high molecular polysaccharide chitosan, alginate, fucoidan, hyaluronic acid and the like are gradually applied to research in the hemostatic field. They have good biocompatibility, hemostatic and wound healing promoting capabilities, and the formed dressing can be gradually peeled off from the healing site, and these characteristics greatly promote the progress of the corresponding dressing in the fields of hemostasis and wound healing. Chitosan is a natural high molecular polysaccharide derived from the ocean, has good biocompatibility, and is often used as a wound dressing in recent years. However, chitosan itself has limited hemostatic effect, is not ideal for the hemostatic effect of a wide range of bleeding wound surfaces, is often used in combination with other hemostatic materials in clinical application, and can also be subjected to chemical modification by utilizing the structural characteristics of the chitosan, for example, carboxymethyl chitosan has better antibacterial activity and hemostatic effect compared with chitosan, and chitosan quaternary ammonium salt not only inherits the characteristics of film forming property, antibacterial property, flocculation property, biodegradability and the like of chitosan, but also has better water solubility, stronger electropositivity and wider pH value application range. In addition to chitosan, other natural polymeric polysaccharides have been studied for promoting wound healing. Sodium alginate is a natural linear polysaccharide polymer and has high safety. Hyaluronic acid has moisturizing and wound healing promoting properties and is often used in the manufacture of dressings to accelerate wound healing and reduce scar formation. Fucoidan is a marine sulfated polysaccharide that, at low concentrations, accelerates blood clotting, exhibiting procoagulant activity. Related researches show that fucoidan with procoagulant function can be used for the development of Miao nationality compound for treating hemophilia and novel medical hemostatic material. The ocean-derived high molecular polysaccharide has good biocompatibility and biosafety.
The prior hydrogel has a plurality of related literature reports, but has certain defects of long gelation time, unequal (Wang H,Huang R,Bai L,et al.Extracellular Matrix-Mimetic Immunomodulatory Hydrogel for Accelerating Wound Healing.AdvHealthc Mater.2023,12(27),e2301264;Guo S,Ren Y,Chang R,et al.Injectable Self-Healing Adhesive Chitosan Hydrogel with Antioxidative,Antibacterial,and Hemostatic Activities for Rapid Hemostasis and Skin Wound Healing.ACS Appl Mater Interfaces.2022,14(30):34455-34469 minutes to tens of minutes and the like, certain limitations, weak mechanical properties and the like in a using method, such as non-conforming of dressing and wound, low adhesiveness, limited capability of absorbing sore liquid (Yang Yongyan. Preparation of multifunctional high-molecular hydrogel wound dressing [ D ] Jilin university, 2024.), complex formula, expensive price and strong toxicity of used reagents, low industrialization prospect, such as commonly used cross-linking agent, namely four-arm polyethylene glycol derivative (such as four-arm polyethylene glycol succinimidyl succinate and the like), high price, high toxicity of used matrix materials such as acrylic acid, acrylamide, cross-linking agent, methylene bisacrylamide and the like (a garcinia water-contacting adhesive hydrogel, a preparation method and application thereof, 202311079058.5), and high-quality products, especially domestic products, multi-needle bionic skin injury, and poor wound healing performance.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide the marine high-molecular polysaccharide hydrogel wound dressing which is formed by crosslinking a polysaccharide composition and a crosslinking agent, wherein the coagulation capability of the polysaccharide composition is superior to that of Yunnan white drug powder and commercial chitosan hemostatic powder, the gelation time of the hydrogel is short, the pores are uniform and moderate, the hydrogel dressing has self-healing property, is placed at normal temperature, can be recombined to form complete hydrogel under the condition of no external stimulus, is not separated under the action of external force, has adhesion, can be adhered to plastics, rubber, metal, glass and skin, paper, has a swelling property of about 2000 percent, has an inhibition effect on escherichia coli and staphylococcus aureus, has no skin irritation and skin allergy, has high biological safety, has a rapid hemostasis effect in 10 seconds, has a remarkably reduced bleeding amount, has an effect superior to that of commercial hydrogel dressing (Baohman Hydrosorb Gel) (P < 0.05), can effectively protect a wound surface from being polluted under the condition of no external stimulus, has a wound shrinkage effect, has a swelling rate of about 2000 percent after the swelling performance of 20min, has a swelling performance of about 90 percent, has a swelling performance of about 7 percent, has a wound healing performance of the commercial hydrogel (P <0.05 percent) after the commercial hydrogel group is remarkably healed after the wound is healed, and has a wound healing performance of the commercial hydrogel group is remarkably healed up to about 7 percent after the wound group is healed. Therefore, the hydrogel dressing has the advantages of short gelation time, high degree of fit with the wound, strong adhesiveness, high swelling property, infection prevention, rapid hemostasis and wound healing promotion, and is safe and effective.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
The invention also provides a marine high polymer polysaccharide hydrogel wound dressing, which consists of a polysaccharide composition and a cross-linking agent, wherein the mass ratio of the polysaccharide composition to the cross-linking agent is 1-3:1-2:
The polysaccharide composition is selected from at least three of modified carboxymethyl chitosan, sodium alginate, fucoidin, chitosan quaternary ammonium salt and hyaluronic acid.
Based on the problems of complex formula, insufficient performance, insufficient safety evaluation, low industrialization prospect and the like of the traditional hydrogel, the invention provides the marine polymer polysaccharide hydrogel with short gelation time, high fit with a wound, strong adhesiveness, high swelling property, infection prevention, rapid hemostasis and wound healing promotion, is safe and effective, has a simple formula and high industrialization prospect, and can be applied to the preparation of wound dressing and medical equipment.
The hydrogel dressing is formed by crosslinking a polysaccharide composition and a crosslinking agent, the coagulation capacity of the polysaccharide composition is superior to that of Yunnan white drug powder and commercially available chitosan hemostatic powder, the gelation time of the hydrogel is short, the pore distribution is uniform, the size is moderate, the hydrogel dressing is self-healing, the hydrogel dressing is placed at normal temperature, the hydrogel dressing can be combined again to form complete hydrogel under the condition of no external stimulus, the hydrogel dressing is not separated under the action of external force, the hydrogel dressing has adhesion, can be adhered to plastics, rubber, metal, glass, skin and paper, the swelling capacity is high, the swelling rate can reach about 2000% after 20min, the hydrogel dressing has inhibition effect on escherichia coli and staphylococcus aureus, the inhibition rate is higher than 90%, the skin irritation and skin allergy are avoided, the hydrogel dressing can be used for rapidly stopping bleeding within 10s, the bleeding amount is remarkably reduced, the effect is superior to that of commercially available hydrogel dressing (Boehmann Hydrosorb Gel) (P < 0.05), the wound surface can be rapidly contracted into scab, the wound surface can be rapidly combined to form complete hydrogel under the condition of no external stimulus, the wound healing effect is not separated under the action of external force, the wound surface can reach 68% after the wound surface is far from the influence, the hydrogel dressing is adhered to the commercial hydrogel set, the swelling rate is higher than 29% after 7 days, the wound is far, the wound has the effect is high, the wound healing effect is superior to the commercial hydrogel dressing is superior to the wound healing effect to the wound has the effect and has high-healing effect and has high effect and high-sealing effect and is superior to the effects to rapidly-sealing performance and has high-sealing effect and has high effects.
In some embodiments, the modified carboxymethyl chitosan is used in an amount of 100 to 400 parts;
In some embodiments, the carboxymethyl chitosan is used in an amount of 1000 to 3000 parts;
in some embodiments, the sodium alginate is used in an amount of 200-1000 parts
In some embodiments, fucoidan is used in an amount of 1-5 parts;
In some embodiments, the chitosan quaternary ammonium salt is used in an amount of 500 to 2000 parts;
in some embodiments, the hyaluronic acid is 500-2000 parts.
Preferably, the polysaccharide composition comprises, by weight, 1000-3000 parts of carboxymethyl chitosan, 200-1000 parts of sodium alginate and 1-5 parts of fucoidin.
More preferably, the polysaccharide composition comprises the following raw materials, by weight, 2000 parts of carboxymethyl chitosan, 1000 parts of sodium alginate and 1 part of fucoidin.
In some embodiments, the modified carboxymethyl chitosan is a catechol group modified carboxymethyl chitosan.
In some embodiments, the preparation method of the catechol group modified carboxymethyl chitosan comprises the steps of fully dissolving carboxymethyl chitosan, adding N, N-dimethylformamide solution of 3, 4-dihydroxybenzaldehyde under the protection of inert atmosphere, carrying out reaction, adding NaBH 3 CN solution after the reaction is finished, continuing the reaction, adding ethanol solution into the reaction solution after the reaction is finished, obtaining flocculent precipitate, dissolving the precipitate again by water after centrifugation, dialyzing, and freeze-drying to obtain the catechol group modified carboxymethyl chitosan.
In some embodiments, the molecular weight of both sodium alginate and fucoidan is 20kDa to 300kDa.
In some embodiments, the cross-linking agent consists of oxidized starch and tannic acid, and the mass ratio of the oxidized starch to the tannic acid is 1-2:2-4.
In some embodiments, the aldehyde content of the oxidized starch is not less than 60%.
In a second aspect of the present invention, there is also provided a method for preparing a marine polymeric polysaccharide hydrogel wound dressing, comprising:
uniformly mixing at least three of modified carboxymethyl chitosan, sodium alginate, fucoidin, chitosan quaternary ammonium salt and hyaluronic acid to obtain a polysaccharide composition;
uniformly mixing oxidized starch and tannic acid to obtain a cross-linking agent;
And (3) reacting the polysaccharide composition with a cross-linking agent to obtain the marine polymer polysaccharide hydrogel wound dressing.
In some embodiments, the gel time is 10-20s, or 15s.
More specifically, it comprises:
S1, extracting algal polysaccharides from brown algae, including sodium alginate, fucoidin and the like;
s2, preparing catechol group modified carboxymethyl chitosan by taking carboxymethyl chitosan as a raw material;
s3, mixing three or more of modified carboxymethyl chitosan, chitosan quaternary ammonium salt, sodium alginate, hyaluronic acid and fucoidin according to a certain proportion to obtain a polysaccharide hemostatic composition, preferably a polysaccharide composition with good coagulation activity;
S4, weighing oxidized starch and tannic acid according to the mass ratio of 1:2, and fully mixing to prepare the cross-linking agent, wherein the aldehyde group content of the oxidized starch is not less than 60%.
S5, based on the polysaccharide composition, adding a cross-linking agent, wherein the mass percentage of the cross-linking agent and the polysaccharide composition is 1-3:1-2, and preparing hydrogel wound dressing;
The hydrogel dressing prepared by the method has short gelation time of about 15s, uniform and moderate pore distribution, self-healing property, normal temperature placement, capability of being recombined to form complete hydrogel without external stimulus, no separation under the action of external force, adhesiveness to plastics, rubber, metal, glass, skin and paper, high swelling property, swelling rate of about 2000 percent in 20 minutes, inhibition effect on escherichia coli and staphylococcus aureus, high inhibition rate of over 90 percent, no skin irritation and skin allergy, high biological safety, rapid hemostasis within 10 seconds, remarkably reduced bleeding amount, remarkable effect superior to that of commercial hydrogel dressing (German Boehmann Hydrosorb Gel), and remarkable wound contraction, scabbing and wound healing promoting effects superior to those of commercial hydrogel dressing.
The invention also provides an application of the marine high polymer polysaccharide hydrogel wound dressing in preparing a medical material for stopping bleeding or promoting wound healing.
The invention also provides an application of the marine high polymer polysaccharide hydrogel wound dressing in preparing medical equipment.
The beneficial effects of the invention are as follows:
the hydrogel dressing is prepared by the method:
(1) Forming hydrogel after rapid gel formation for about 15 s;
(2) The self-healing property is strong, the wound with irregular shape can be filled, and the fit degree with the wound is high;
(3) The adhesive is high, and can be adhered to plastics, rubber, metal, glass, skin and paper;
(4) The swelling property is high, the sore liquid absorbing capacity is high, and the moist environment of the wound part is maintained;
(5) The antibacterial performance is strong, and the inhibition rate to escherichia coli and staphylococcus aureus reaches more than 90%;
(6) The skin irritation and skin allergy are avoided, and the biological safety is high;
(7) Rapid hemostasis within 10s, significantly reduced bleeding volume, significantly better effect than commercial hydrogel dressing (boehmann Hydrosorb Gel, germany) (P < 0.05);
(8) The wound surface can be quickly contracted and crusted, the wound can be effectively protected, the infection risk is reduced, the commercial hydrogel dressing has no effect, and the wound healing promoting effect is obviously better than that of the commercial hydrogel dressing (P < 0.05).
(9) Compared with the hydrogel wound dressing in the current literature and patent, the hydrogel disclosed by the application has the advantages of simple formula, no toxic or harmful reagent, no skin irritation or allergy, high biological safety, capability of rapidly stopping bleeding and promoting wound healing, better effect than that of the commercially available hydrogel dressing (German Boehmann Hydrosorb Gel) (P < 0.05), extremely high industrialization prospect, and the possibility of developing novel wound dressing and medical instrument, and breaks the dilemma that the domestic hydrogel dressing depends on import.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a graph showing the clotting time test of the polysaccharide composition of example 1 of the present invention;
FIG. 2 is a graph showing the comparison of the coagulation effect of the polysaccharide composition of example 1 of the present invention;
FIG. 3 is a schematic diagram showing the preparation of hydrogel and the planning of the product according to example 1 of the present invention;
FIG. 4 is a scanning electron microscope image of the microstructure of the hydrogel of example 1 of the present invention;
FIG. 5 is a graph showing the self-healing property of the hydrogel according to example 1 of the present invention;
FIG. 6 is a graph showing the adhesion test of the hydrogel according to example 1 of the present invention;
FIG. 7 is a graph showing the swelling property test of the hydrogel according to example 1 of the present invention;
FIG. 8 is a graph showing the antibacterial property of the hydrogel according to example 1 of the present invention;
FIG. 9 is a chart of the skin irritation test and HE staining of the hydrogel of example 1 of the present invention;
FIG. 10 is a chart showing the skin allergy test of hydrogel of example 1 of the present invention;
FIG. 11 is a drawing showing the hemostatic performance test chart of the hydrogel according to example 1 of the present invention, wherein a is a hemostatic performance test chart, and b is a partial enlarged view after the hydrogel is applied;
FIG. 12 is a chart showing the bleeding performance of hydrogel hemostatic test according to example 1 of the present invention;
FIG. 13 is a graph showing the healing promoting performance of the hydrogel according to example 1 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In view of the problems of complex formula, insufficient performance, insufficient and poor safety evaluation, low industrialization prospect and the like of the traditional hydrogel, the invention provides the safe and effective hydrogel wound dressing based on the marine high-molecular polysaccharide, which has the advantages of simple formula, high performance and strong industrialization prospect.
According to a typical implementation mode of the invention, the marine high polymer polysaccharide hydrogel wound dressing is formed by crosslinking a polysaccharide composition and a crosslinking agent, the coagulation capacity of the polysaccharide composition is better than that of Yunnan white drug powder and commercially available chitosan hemostatic powder, the gelation time is short and is about 15s, the pore distribution is uniform and moderate, the hydrogel dressing has self-healing property, can be placed at normal temperature, can be recombined to form complete hydrogel without being stimulated by the outside, is not separated under the action of the outside, has adhesion, can be adhered to plastics, rubber, metal, glass, skin and paper, has high swelling property, has a swelling rate of about 2000 percent after 20 minutes, has inhibition effect on escherichia coli and staphylococcus aureus, has inhibition rate of over 90 percent, has no skin irritation and skin allergy, has high biosafety, can quickly stop bleeding within 10s, can quickly shrink a wound surface to form scab, has a wound healing promoting effect, has the wound healing effect remarkably better than that of a commercially available hydrogel dressing (German (Heman Hydrosorb Gel) (P < 0.05), has the characteristics of strong time, short time, high biological adhesion, high biological safety, and high wound healing performance, and high wound healing promoting performance.
On the other hand, according to the preparation method of the hydrogel wound dressing, the hydrogel comprises a polysaccharide composition and a cross-linking agent, and the mass percentage of the polysaccharide composition and the cross-linking agent is 1-3:1-2.
S1, the polysaccharide composition is prepared by mixing three or more of modified carboxymethyl chitosan, chitosan quaternary ammonium salt, sodium alginate, hyaluronic acid and fucoidin according to a certain proportion, and the polysaccharide composition with good coagulation activity is optimized;
In some embodiments, the components of the polysaccharide hemostatic composition are mixed in proportion and stirred for 1-2 hours to achieve sufficient mixing between the components of the polysaccharide composition, and the polysaccharide composition is obtained after freeze drying, and has better clotting activity than the commercially available chitosan hemostatic powder and Yunnan white drug powder.
S2, the preparation method of the modified carboxymethyl chitosan comprises the steps of fully dissolving carboxymethyl chitosan, slowly dropwise adding an N, N-dimethylformamide solution of 3, 4-dihydroxybenzaldehyde under the protection of nitrogen, stirring at room temperature for 7 hours, adding a NaBH 3 CN solution, and continuing to react for 7 hours. After the reaction is finished, adding 4 times of ethanol solution into the reaction solution to obtain a large amount of flocculent precipitate, centrifuging, redissolving the precipitate by using deionized water, dialyzing for 3d at room temperature, and freeze-drying to obtain the modified carboxymethyl chitosan modified by catechol groups.
S3, extracting the sodium alginate and the fucoidin from brown algae, wherein the molecular weight of the sodium alginate and the fucoidin is 20kDa-300kDa.
S4, the brown algae comprise kelp, phyllophyllum nodosum, undaria pinnatifida and the like.
S5, the sodium alginate is extracted by placing the brown algae powder in water and heating. In one or more embodiments, the heating temperature is 60-70 ℃, the extraction time is 2-3 hours, the steps are repeated for at least 2 times, and the supernatant is collected and subjected to acid precipitation and alkali dissolution.
In some examples of this embodiment, the acid precipitation and dissolution process is to add acid to the material solution to adjust the pH to be acidic, produce a precipitate, and collect the precipitate and dissolve the precipitate with an alkali solution.
In some embodiments, the pH is adjusted to 0.8-1.2. Under the condition, the algin can be better extracted. The alkali solution is sodium carbonate solution, and the sodium carbonate solution has weak alkalinity, so that the structure of sodium alginate can be prevented from being damaged.
S6, the fucoidin is extracted by placing brown algae powder into CaCl 2 solution, heating and extracting, in one or more embodiments, heating at 70-80 ℃ for 2-4 h, repeating for at least 2 times, and collecting supernatant;
In some embodiments, the mass percent of CaCl 2 solution is 1.5% -2%.
In some embodiments, after the supernatant is filtered, the liquid volume is concentrated to 1/10 to 1/6 of the original volume, and then alcohol precipitation is performed.
Further, the solution for the alcohol precipitation was 95% ethanol.
S7, weighing oxidized starch and tannic acid according to the mass ratio of 1:2, and fully mixing to obtain the cross-linking agent, wherein the aldehyde group content of the oxidized starch is not less than 60%.
S8, adding a cross-linking agent based on the polysaccharide composition, and mixing to form the hydrogel dressing, wherein the mass percentage of the cross-linking agent to the hydrogel dressing is 1-3:1-2.
In some embodiments, the polysaccharide composition is weighed in mass percent and then fully dissolved in water.
In some embodiments, the cross-linking agent is weighed in mass percent and then fully dissolved in water.
In some embodiments, the polysaccharide composition and the crosslinker solution are placed separately and mixed prior to use to form the hydrogel dressing.
The invention also provides application of the hydrogel in bacteriostasis, rapid hemostasis, wound dressing promoting wound healing and medical equipment.
Example 1
A marine polymeric polysaccharide hydrogel wound dressing comprising the steps of:
S1, preparation of polysaccharide composition
The preparation of the modified carboxymethyl chitosan is that mussels still maintain strong adhesion capability in a complex and moist marine environment, which is mainly attributed to the abundant catechol groups in mussel foot-filament proteins, which are considered as the main reasons for the adhesion function of the mussel foot-filament proteins. At present, many topic groups at home and abroad perform bionic research on mussel mucin, and natural polysaccharide such as chitosan and the like is modified to increase the adhesiveness of the mussel mucin.
Carboxymethyl chitosan is fully dissolved, placed in a round bottom flask, and under the protection of nitrogen, 60mg/mL of N, N-dimethylformamide solution of 3, 4-dihydroxybenzaldehyde is slowly added dropwise, stirred for 7 hours at room temperature, 300mg/mL of NaBH 3 CN solution is added, and the reaction is continued for 7 hours. After the reaction is finished, adding 4 times of ethanol solution into the reaction solution to obtain a large amount of flocculent precipitate, centrifuging, redissolving the precipitate by using deionized water, dialyzing for 3d at room temperature, and freeze-drying to obtain modified carboxymethyl chitosan modified by catechol groups, and storing at-20 ℃.
The preparation method of sodium alginate comprises air drying brown algae, and pulverizing to obtain brown algae powder. Adding the mixture into water according to the ratio of the feed liquid to the water of 1:20, stirring and extracting for 3 hours at the temperature of 60-70 ℃, repeating for 2 times, and collecting supernatant.
The pH of the supernatant was adjusted to 1.0, allowed to stand overnight, centrifuged, and the precipitate was collected.
Re-dissolving the precipitate with 2% sodium carbonate solution, regulating pH to 1.0 again, standing, centrifuging, washing the precipitate with distilled water for several times, dehydrating with absolute ethyl alcohol, and oven drying.
Re-dissolving and precipitating with 2% sodium carbonate solution, dialyzing (with molecular weight cut-off of 3.5 kDa), concentrating the rest, and lyophilizing to obtain sodium alginate crude product.
Dissolving the sodium alginate crude product in water, regulating pH to neutrality, ultrafiltering (with molecular weight cut-off of 10 kDa), collecting cut-off part, concentrating, and lyophilizing to obtain sodium alginate.
The fucoidin is prepared by air drying brown algae, pulverizing to obtain brown algae powder, adding into 1.56% CaCl 2 solution at a ratio of 1:30, extracting at 80deg.C for 2 hr, repeating for 2 times, centrifuging, and collecting supernatant;
concentrating the volume of the supernatant to 1/6-1/10 of the original volume, adding 4 times of 95% ethanol, precipitating with ethanol, standing at 4 ℃ overnight, centrifuging, collecting the precipitate, and drying at 40 ℃. Re-dissolving the sample, ultrafiltering (with molecular weight cut-off of 30000 kDa), concentrating, and spray drying to obtain fucoidin.
The preparation of the polysaccharide composition comprises the steps of selecting modified carboxymethyl chitosan (modified carboxymethyl chitosan modified by catechol groups), carboxymethyl chitosan, sodium alginate, fucoidan, chitosan quaternary ammonium salt and hyaluronic acid as influencing factors, determining the dosage level, determining the proportion of each influencing factor of the polysaccharide composition by means of orthogonal experiments, and designing six-factor four-level experiments by using an orthogonal experimental design table L 32(49).
TABLE 1 factors and dosage ranges
According to the requirements of Table 2, six polysaccharide solutions were mixed and stirred thoroughly, and then freeze-dried to obtain polysaccharide compositions, a total of 32.
TABLE 2 orthogonal experimental design
Coagulation time measurement, namely taking 100 mu L of anticoagulated rabbit blood, adding 100 mu L (20 mg/mL) of polysaccharide composition solution and 100 mu L of calcium chloride solution (preheated at 37 ℃), starting coagulation and starting timing, taking out the centrifuge tube from the water bath kettle every 10s, continuously tilting the centrifuge tube in a bright environment, and observing the flowing state of blood. Once blood clotting was observed, the table was stopped immediately, the time was recorded, and each group was repeated 3 times. 100. Mu.L of anticoagulated rabbit blood was additionally taken, 100. Mu.L of water and 100. Mu.L of calcium chloride solution (preheated at 37 ℃) were added, and the clotting time was recorded as a blank. After a clotting time of more than 600s, no further recordings were made, in 600 s. Polysaccharide compositions with short clotting times are preferred, in contrast to Yunnan white drug powder, commercially available chitosan hemostatic powder.
S2, preparing a cross-linking agent:
Weighing a certain amount of oxidized starch and tannic acid, wherein the mass percentage of the oxidized starch and the tannic acid is 1:2, and the aldehyde group content of the oxidized starch is not less than 60%.
S3, preparation of a hydrogel dressing:
and adding the prepared cross-linking agent solution into the polysaccharide composition solution, wherein the mass percentage of the cross-linking agent solution and the polysaccharide composition solution is 1-3:1-2, fully mixing to form the hydrogel dressing, and recording the gelation time, preferably hydrogel with optimal gelation state and short gelation time.
The results of physical and chemical properties, biological safety and biological activity tests on the hydrogel wound dressing are shown below, wherein the physical and chemical properties comprise gelation time, internal morphology, self-healing property, adhesion property and swelling property of the hydrogel, the biological safety comprises skin irritation and skin allergy tests, and the biological activity tests comprise antibacterial, hemostatic and wound healing promoting activity tests.
The coagulation time of the 32 polysaccharide compositions is shown in FIG. 1, and the coagulation time of the polysaccharide composition 10 and the polysaccharide composition 14 is the shortest, so that the two are preferably combined for the subsequent experiments.
As shown in figure 2, after the coagulation effect of the polysaccharide composition is uniformly mixed with blood, the blood of the two polysaccharide composition groups can be coagulated and not flow in a short time, and the blood of the Yunnan white drug and the commercially available chitosan hemostatic powder group can not be coagulated in the same time, so that the coagulation activity of the polysaccharide composition is superior to that of the Yunnan white drug and the commercially available chitosan hemostatic powder.
Hydrogels based on polysaccharide composition 10 and polysaccharide composition 14 were designated H1 and H2, respectively. As shown in Table 3, the gelation time is generally longer or the gelation time of H1 is not longer, the gelation time of H2 is shorter, and preferably, H2-2 having a shorter gelation time and a better gelation state is used for the subsequent experiments.
The preparation schematic diagram of the hydrogel is shown in fig. 3, and after the polysaccharide composition and the crosslinking agent are fully mixed, the gel can be quickly formed. The hydrogel product of the application can be designed into a double-tube form, and the polysaccharide composition and the cross-linking agent in the tube are fully mixed through the transfer port and then are smeared on wounds.
TABLE 3 gelation time statistics of hydrogels
The internal morphology of the hydrogel is shown in fig. 4, and the hydrogel generally has certain pores, so that for biomedical materials for wound healing, the larger pores can ensure sufficient oxygen to enter, which is beneficial to wound healing, but the pores with too large pore diameters often lead to loose hydrogel structure. The hydrogel dressing obtained by the application has uniform pore distribution and moderate size, can ensure sufficient oxygen to enter, is beneficial to wound healing and can not cause the hydrogel structure to be loose.
The self-healing performance of the hydrogel is shown in fig. 5, the heart-shaped hydrogels with different colors are spliced together and placed for 1h at normal temperature, the two hydrogels can be combined again to form complete hydrogel under the condition of no external stimulus, the gel interface is observed, the hydrogel is visible to be crosslinked into a whole again, and separation does not occur under the action of external force, so that the self-healing performance of the hydrogel is good, and the hydrogel can be effectively filled in wounds with irregular shapes due to the self-healing performance.
The adhesiveness is one of important indexes of hydrogel wound dressings, and the hydrogel obtained by the method can be adhered to plastics, rubber, metal, glass, skin and paper, and has good adhesiveness (figure 6).
Soaking hydrogels in solution will continue to swell over time until the swelling is balanced, an important feature of the gel. The hydrogel dressing obtained by the application has good water absorption capacity, the swelling rate can reach about 2000% after 20min, and the swelling balance can be reached about 1 h. The swelling properties reflect the water content and water retention capacity of the hydrogel, and hydrogels with high swelling capacity can absorb sore fluid while also helping to maintain a moist environment at the wound site and promote wound healing (fig. 7).
Infection is a common complication in war wounds and can cause morbidity and mortality in a large number of wounded persons. The escherichia coli and the staphylococcus aureus are two common pathogenic bacteria which can cause wound infection clinically, and the hydrogel dressing obtained by the application has inhibition effects on the escherichia coli (1X 10 6 CFU/mL) and the staphylococcus aureus (1X 10 6 CFU/mL), the inhibition rates are 92.37 percent and 95.01 percent respectively, and the inhibition effect is strong (figure 8).
The biological safety is an important index for evaluating the hydrogel dressing, and is also a basic index for future industrialization of the hydrogel dressing. At present, related patents and documents of hydrogels have many reports, but some of the problems of high toxicity and insufficient safety evaluation of the reagents used. The application tests skin irritation and skin allergy, and evaluates the biosafety of the hydrogel.
Skin irritation evaluation:
male Kunming (KM) mice, 4-5 weeks old, were acclimatized for 7d, randomly divided into 2 groups of hydrogels and commercial hydrogels (Buch-Highn Hydrosorb Gel, germany), 10 each. The back and spine of the mice were shaved 24h before the experiment, and 6% sodium sulfide was dehaired, 3x 3cm each. The integrity of the pelt skin was checked prior to administration and the wounded had not been included.
And (3) drug administration, namely, anesthesia is carried out before drug administration, a self-comparison method of the left side and the right side of the homozygote is adopted, hydrogel is directly smeared on the dehaired skin on the left side, and warm water is smeared on the right side to serve as a blank control. After 6 hours of application, the test substance was removed, and the administration site was cleaned with warm water 1 time/d for 14 days.
The skin irritation evaluation was performed according to the skin irritation response scoring criteria in the guidelines for drug irritation, allergy and hemolysis study (tables 4 to 5). 1h after each drug removal, 1, 24, 48 and 72h after the last drug removal, visually observing whether the application part has erythema and edema, whether the application part has pigmentation, bleeding spots, rough skin or thin skin, and occurrence time and fading time of the pigmentation, bleeding spots, rough skin or thin skin, and scoring the erythema and the edema. Based on the scoring results, the mean of the stimulation scores per mouse per day over the observation period was calculated.
Skin irritation response and irritation intensity were scored as indicated, with skin irritation response mean = (total erythema + total edema)/total animal number.
After 72 hours of observation of the reaction condition, the mice are sacrificed, skin and subcutaneous tissues at the administration part are cut off, fixation, dehydration, transparency and wax dipping are carried out, the conventional paraffin embedded slice is cut, and the histopathological changes are observed after HE staining.
TABLE 4 skin irritation response scoring criteria
TABLE 5 skin irritation intensity evaluation criteria
The results showed that KM mice did not show irritation symptoms such as erythema, edema, etc. on both the administration side and control side of the hydrogel group during the administration and recovery observation period, the skin irritation score was 0, the skin irritation intensity was non-irritating, and there was no pathological changes such as necrosis of epidermis and inflammatory infiltrate (fig. 9), whereas the commercial hydrogel group showed slight irritation at the early stage of administration (tables 6 to 7).
TABLE 6 skin irritation score for mice after dosingn=10)
TABLE 7 skin irritation intensity in mice after multiple administrations
Skin allergy evaluation:
Male Kunming (KM) mice, 4-5 weeks old, were randomized into 4 groups after 7d of adaptive feeding, blank (warm water), positive (2-4 dinitrochlorobenzene, sensitized 1.0%0.2 ml/l, challenged 0.1%0.2 ml/l), commercial hydrogel groups (Boehmann Hydrosorb Gel, germany) and hydrogel groups, 10 each. The two sides of the back of the mice are dehaired 24 hours before sensitization, 6% sodium sulfide is dehaired, and the area is about 3cm multiplied by 3cm. The hydrogel, commercial hydrogel, warm water and 1.0%2-4 dinitrochlorobenzene are smeared on the left dehaired skin, and after 6 hours, the left dehaired skin is washed by warm water, and the right dehaired skin is carried out 24 hours before excitation.
Sensitization administration, namely, corresponding medicines are respectively smeared on the left shaving area of the mice at the 0 th, the 7 th and the 14d, and after 6 hours of administration, the administration part is cleaned by warm water after the test object is removed.
And (3) carrying out excitation administration, namely, on the 14 th day after the end of the last sensitization, taking the corresponding medicine to be smeared on a right shaving area, carrying out excitation contact, washing with warm water after maintaining for 6 hours, and observing other allergic reaction conditions such as skin erythema, edema and the like of the mice in the 1 st, 24 th, 48 th and 72 th hours. Skin allergy was evaluated according to the skin allergy scoring criteria and evaluation criteria in the guidelines for drug irritation, allergy and hemolysis study techniques (Table 8).
The average value of skin allergic reaction and sensitization rate were calculated. Average value of skin allergy = (total erythema formation fraction + total edema formation fraction)/total animal number, sensitization rate = (number of skin allergy positive (whether degree light or heavy) animals/total number of tested animals: sensitization rate 0-10%, no sensitization, 11-30%, mild sensitization, 31-60%, moderate sensitization, 61-80%, high sensitization, 81-100%, extreme sensitization.
TABLE 8 skin allergy scoring criteria
The skin allergy results 1, 24, 48, 72h after challenge are shown in table 9. The skin of the mice in both the control group and the administration group (hydrogel group and commercial hydrogel group) showed no formation of erythema and edema (fig. 9), the score was 0, and no systemic allergic reaction such as asthma and unstable standing was observed, the sensitization rate was 0, and the sensitization rate of the positive control group was 100%.
Table 9 mouse skin allergy score (n=10)
In the skin irritation test, the average value of the skin irritation reaction at the administration side of the hydrogel group is 0, the skin at the administration side does not have abnormal manifestations such as erythema, edema and the like, and also has no pathological changes such as epidermis necrosis, inflammatory infiltration and the like, and the commercial hydrogel group shows slight skin irritation at the early stage of administration, so the hydrogel is considered to have no irritation reaction to the skin of mice, which is superior to the commercial hydrogel group.
In the skin allergy test, after 3 times of sensitization, the hydrogel group, the commercial hydrogel group administration group and the control group have no abnormal manifestations such as erythema, edema and the like. In the excitation stage, the animal administration positions of the hydrogel group, the commercial hydrogel group administration group and the control group do not have abnormal manifestations such as erythema, edema and the like, and serious systemic allergic reactions such as asthma, standing instability, shock and the like, the sensitization rate is 0, and the average value of skin allergic reactions is 0. It is therefore believed that hydrogel dressings and commercially available hydrogel dressings are not allergic to mouse skin.
In summary, the hydrogel obtained by the application has no skin irritation and no sensitization, and the commercial hydrogel has slight skin irritation and no sensitization in early stage of administration, so the hydrogel obtained by the application has higher safety than the commercial hydrogel.
The first hour after a wound is the life-to-death critical "golden one hour" in which rapid hemostasis of the wound of a wounded person is critical in rescuing the life of the wounded person. The rapid and effective hemostasis means can improve the survival rate and reduce complications of wounded persons. The hemostatic performance of the hydrogel dressing is evaluated by using a mouse liver puncture model. The results showed that hydrogel wound dressing can rapidly stop bleeding within 10 seconds, the amount of bleeding was significantly reduced, and the effect was superior to that of commercially available hydrogel dressing (fig. 11-12). The rapid hemostatic properties of hydrogels are not only beneficial for the good clotting ability of the polysaccharide composition, but also related to its excellent adhesion, as can be seen visually from fig. 11 b, after application of the hydrogel, it can adhere to the mouse liver, whereas commercially available hydrogels can slip off the liver surface, resulting in a reduced hemostatic effect.
Skin is the largest, most exposed and fragile organ of the human body and, once damaged, often needs to undergo a lengthy self-healing process. Severe skin wounds, especially full-thickness lesions, can form chronic wounds that are difficult to heal if left untreated. The application adopts a full-layer skin defect model to evaluate the promotion effect of series of hydrogels on wound healing. Wound repair and healing generally requires two main processes, rapid clotting and crusting to seal the wound, followed by tissue regeneration to heal the wound. The hydrogel obtained by the application can enable the wound surface to shrink and scab rapidly (the scab shell is hard and has no fluctuation), the wound can be protected rapidly and effectively, the infection risk is reduced (figure 13), the commercial hydrogel group has no effect, the hydrogel has excellent effect of promoting wound healing, the wound healing rate at the initial stage of the wound (1 day) is 68 percent, which is far higher than 29 percent of the commercial hydrogel group, the wound healing rate after 7 days can reach 98 percent, which is far higher than 76 percent of the commercial hydrogel group, and the effect of promoting wound healing is obviously better than that of the commercial hydrogel group (P < 0.05) (figure 13).
Example 2
The difference from example 1 is that the polysaccharide composition is composed of 1000 parts by weight of carboxymethyl chitosan, 200 parts by weight of sodium alginate and 1 part by weight of fucoidin.
Example 3
The difference with the embodiment 1 is that the polysaccharide composition consists of 3000 parts of carboxymethyl chitosan, 1000 parts of sodium alginate and 5 parts of fucoidin by weight.
The performance of the medical dressings prepared in the examples 2 and 3 is tested by adopting the same method as in the example 1, and the results show that the medical dressings prepared in the examples 2 and 3 also have the advantages of strong self-healing property, high adhesiveness, high swelling property, strong antibacterial property, no skin irritation and allergy, high biological safety, rapid hemostasis, rapid wound contraction and crusting, wound healing promotion and the like.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
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