CN114957714A - Curcumin-containing hydrogel material capable of promoting wound healing and preparation method thereof - Google Patents
Curcumin-containing hydrogel material capable of promoting wound healing and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a curcumin-containing hydrogel capable of promoting wound healing and a preparation method thereof. The curcumin-containing hydrogel material is prepared by the method comprising the following steps: 1) dissolving a water-soluble polymer containing phenylboronic acid groups in an aqueous phase solution, adding curcumin, and then fully mixing to ensure that the curcumin reacts with the water-soluble polymer to be combined and dissolved to obtain a mixed solution A; 2) dissolving polyvinyl alcohol in the aqueous phase solution to obtain a solution B; 3) and (3) taking a proper amount of the mixed solution A and the solution B to carry out full mixing reaction, and forming the curcumin-containing hydrogel material in a short time. The hydrogel has good self-healing property and fluidity, can entrap curcumin and realize a slow release effect. Cell experiments show that the self-healing hydrogel containing curcumin has the potential of promoting wound healing; animal experiments show that the hydrogel-curcumin composite material has good biological safety. The hydrogel is expected to be applied to various medical applications such as drug carriers, dressings and the like.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a curcumin-containing hydrogel material capable of promoting wound healing and a preparation method thereof.
Background
Curcumin is a natural molecule extracted from plants, has anti-inflammatory and antioxidant effects, but is not easily utilized due to problems such as poor water solubility. As an aggregated material with solid and liquid properties, the hydrogel has natural advantages in the application field of wound dressings, but the traditional hydrogel has poor fitting property with wounds and is not beneficial to the effect of the contained drugs.
Therefore, if the function of curcumin and the advantage of hydrogel as a dressing can be combined, a brand-new functional hydrogel preparation is developed, and the hydrogel preparation has important application value.
Disclosure of Invention
The invention aims to provide a curcumin-containing hydrogel material capable of promoting wound healing. The hydrogel has good self-healing property and fluidity, can entrap curcumin and realize a slow release effect. Cell experiments show that the self-healing hydrogel containing curcumin has the potential of promoting wound healing; animal experiments show that the hydrogel-curcumin composite material has good biological safety.
The curcumin-containing hydrogel material provided by the invention is prepared by the following steps:
1) dissolving a water-soluble polymer containing a dihydropyridine ring and a phenylboronic acid group in a proper amount of aqueous solution, adding a proper amount of curcumin, and then fully mixing to ensure that the curcumin reacts with the water-soluble polymer, combines and dissolves to obtain a mixed solution A;
2) dissolving a proper amount of polyvinyl alcohol in the aqueous phase solution to obtain a solution B;
3) and (3) taking a proper amount of the mixed solution A and the solution B to carry out full mixing reaction, and forming the curcumin-containing hydrogel material in a short time.
The hydrogel prepared by the invention can stably entrap curcumin therein and realize slow release. The gel has good self-healing property, fluidity and biocompatibility, and the strength of the gel can be changed by changing the proportioning relation of A/B.
The invention utilizes the interaction of borate and curcumin in the synthesized water-soluble polymer to promote the turmeric to be dissolved in a water phase system, and then polyvinyl alcohol solution is added into the system to react to form the hydrogel material. The obtained hydrogel has fluidity, self-healing property and biocompatibility, and has the function of obviously promoting wound healing at a cell level.
The water-soluble polymer containing the dihydropyridine ring and the phenylboronic acid group can be specifically a polymer P1, the structural formula of which is shown as follows,
wherein x/y is 1/1-5, preferably 1/1; n is 18, 19 or 20.
The polymer P1 can be prepared as follows:
a) preparing a polymerizable small molecular monomer M1 containing dihydropyridine and phenylboronic acid groups;
b) polymer P1 was prepared by free-radical polymerization using the above monomers.
The preparation method of the monomer M1 comprises the following steps: in the presence of a catalyst glycine, acetoacetoxy ethyl methacrylate, dimedone, ammonium acetate and p-aldehyde phenylboronic acid are subjected to Hantzsch synthesis reaction to obtain the compound.
A process for preparing a water-soluble polymer having the formula M1 as a monomer, comprising the steps of: and (2) carrying out free radical polymerization reaction on the monomer M1 in the absence of oxygen and in the presence of a free radical initiator to obtain the monomer M1.
Specifically, the number average molecular weight of the polymer P1 (polymer a) may be 156000(GPC measurement).
The polymer synthesized by the method has good water solubility, and the phenylboronic acid group can respectively react with curcumin and polyvinyl alcohol to realize the effects of solubilization, crosslinking and the like.
Further, the method for preparing the curcumin-containing hydrogel material by using the polymer P1 as a raw material comprises the following steps:
A) dissolving the polymer A in a phosphate buffer salt solution containing ethanol, adding curcumin, and performing ultrasonic mixing to obtain a mixed solution 1; in the mixed solution 1, the mass fraction of the polymer A is 8-12%, preferably 12%; the mass concentration of the curcumin is 0.5-2 mg/mL, preferably 1 mg/mL;
B) adding polyvinyl alcohol (PVA) into phosphate buffer salt solution, and fully dissolving the PVA to obtain solution 2; the mass fraction of the polyvinyl alcohol in the solution 2 is 4-6%, preferably 6%;
C) respectively sucking a certain volume of the mixed solution 1 and 2 (generally 1:1), fully mixing, and standing for 10-60 seconds to obtain the product; the volume ratio of the mixed solution 1 to the solution 2 is (0.8-1.2): 1, preferably 1: 1.
In the step A), the volume fraction of ethanol in the ethanol-containing phosphate buffer salt solution is 3-5%; the concentration of the phosphate buffer solution in the phosphate buffer salt solution containing ethanol is 0.1M, and the pH value is 7.4.
In step B), the polyvinyl alcohol may be PVA 1788; the concentration of the phosphate buffer solution is 0.1M, and the pH value is 7.4.
In step C) of the above process, the temperature of the standing is room temperature (e.g., 15 to 25 ℃).
The invention also provides a method for controlling the strength of the hydrogel, namely the hydrogel strength is regulated and controlled by changing the amount of the added polymer in the preparation process.
The invention provides a thought for the slow release of curcumin, namely the curcumin is encapsulated in hydrogel to realize the long-time slow release effect of the curcumin.
The invention also protects the application of the hydrogel material containing curcumin.
The application of the curcumin-containing hydrogel material provided by the invention comprises at least one aspect of the following steps:
1) the application in preparing products for promoting wound healing;
2) the application in the preparation of drug carriers;
3) the application in preparing dressing.
The invention also protects a product for promoting wound healing.
The active ingredient of the product for promoting wound healing provided by the invention is the curcumin-containing hydrogel material provided by the invention.
The hydrogel prepared by the invention combines curcumin by utilizing dynamic covalent action, so that the curcumin stably exists in a gel system mainly containing water and is gradually released slowly, and the effects of resisting inflammation, resisting oxidation and the like are exerted. The hydrogel has the characteristics of strong fluidity and good self-healing property, and can be self-adaptively attached to wounds. In combination with the above advantages, the hydrogel material of the present invention can be applied to the fields of promoting wound healing, etc.
The objects of some of the inventions outlined above are not intended to represent an exhaustive set of all of the objects of the invention. Other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings, examples and examples, and certain specific embodiments of this invention. These matters form part of the description and include exemplary embodiments of the invention, illustrating various objects and features of the invention.
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The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the claims at the conclusion of the specification. The foregoing and other objects, features, and advantages of the invention, as embodied in the following detailed description of preferred embodiments, are apparent from the accompanying drawings and description. The embodiments (steps) illustrated in the drawings are intended to illustrate the present invention only and should not be construed as limiting the illustrated embodiments (steps) of the present invention.
Fig. 1 is a flow chart of hydrogel preparation for encapsulating curcumin in example 1.
FIG. 2 shows a hydrogel material prepared in example 1.
FIG. 3 is the results of rheological measurements of hydrogels (yes/no curcumin) of different polymer contents in example 2; gel8 represents the polymer content of 8%, Gel8-Cur represents the curcumin-containing hydrogel and the polymer content of 8%, and so on.
FIG. 4 shows the results of rheological measurements on a 12% polymer hydrogel of example 2; the test conditions were 120 seconds of 1% strain alternating with 60 seconds of 400% strain, with the frequency fixed at 1 Hz.
Fig. 5 is a release profile of curcumin in example 3; gel-cur is hydrogel containing curcumin, P1-cur is polymer a solution combined with curcumin.
FIG. 6 is a confocal micrograph of FDA-PI stained cells of example 4 cultured in curcumin-containing hydrogel for a period of time.
FIG. 7 is a photomicrograph of wound healing at the cell level under different dressings in example 5; wherein a, b and c are initial cell wound pictures, and culture medium, curcumin-free hydrogel and curcumin-containing hydrogel are respectively added on the surfaces of the initial cell wound pictures; a ', b' and c 'are photographs of a, b and c, respectively, after 24 hours of cultivation, and a' and the like are photographs of a, b and c, respectively, after 48 hours of cultivation.
FIG. 8 is a photograph of mice in example 6 injected with hydrogel for a certain period of time.
FIG. 9 is a photograph of a tissue section of the mouse 72 hours after the mouse in example 6 was injected with the hydrogel.
Detailed Description
The method of the present invention is illustrated by the following specific examples, but the present invention is not limited thereto, and any modifications, equivalents and improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The present invention relates to a method for preparing a hydrogel containing curcumin. The hydrogel prepared by the invention mainly comprises four components, namely polymer A containing borate, curcumin, polyvinyl alcohol and water. Wherein polymer a is prepared by reaction.
Mouse fibroblasts L929 used in the following examples were purchased from American Type Culture Collection (ATCC).
Example 1 preparation of curcumin-containing hydrogel
1) According to the preparation route of FIG. 1, polymer A (P1) was first synthesized.
First, ethyl 2- (acetoacetoxy) methacrylate (AEMA,8.58g, 40mmol), dimethyl ketone (5.60g, 40mmol), 4-formylphenylboronic acid (6.00g, 40mmol), ammonium acetate (4.64g, 60mmol), glycine (0.30g, 4mmol) were dissolved in 20mL of acetonitrile. The mixture was kept in an oil bath at 70 ℃ for 4 hours. Precipitation twice in ether and deionized water gave monomer M1(20.0 g). Then, M1(1.84g, 4mmol), polyethylene glycol dimethacrylate (PEGMA, 7.60g, 8mmol), azobisisoheptonitrile (ABVN, 0.06g, 0.24mmol) were dissolved in 10mL of N, N-Dimethylformamide (DMF). The mixture was purged with a stream of nitrogen to remove oxygen and then held in an oil bath at 70 ℃ for 8 hours. The polymerization was quenched in an ice-water bath. Precipitation in diethyl ether three times gives polymer A, which can have a number average molecular weight of 156000(GPC measurements).
2) Dissolving the polymer A obtained in the step 1) in phosphate buffered saline (PBS,0.1M) with the ethanol content (volume fraction) of 5%, adding curcumin (1mg/mL), and performing ultrasonic mixing to obtain a mixed solution 1; wherein the concentration (mass fraction) of the polymer A is 8-12%, and the mass concentration of the curcumin is 1 mg/mL;
3) polyvinyl alcohol (PVA1788, molecular weight-85000) was added to a PBS solution (0.1M) at a concentration (mass fraction) of 6%, and shaken at 80 ℃ for 7 hours to dissolve it sufficiently to obtain solution 2.
4) Respectively sucking a certain volume of the mixed solution 1 and the solution 2 (generally 1:1, v/v), fully mixing, and standing for about 10-60 seconds to obtain the hydrogel material, as shown in figure 2.
Example 2 hydrogel rheology testing
1) The polymer content of example 1 was adjusted to obtain a series of hydrogels (e.g., the concentration (mass fraction) of polymer a in step 2) of example 1 was set to 8%, 10%, 12%, respectively). Hydrogels of different solids content (about 0.6mL, about 2.0cm in diameter) were placed on the measurement plates of the rheometer, respectively. The storage modulus (G') and loss modulus (G ") of the hydrogel were recorded under frequency sweep (strain ═ 1%), to determine the strength of the hydrogel as shown in fig. 3. The strength of the hydrogel gel gradually decreases (from 130Pa to about 50 Pa) along with the gradual decrease of the polymer content (from 12% to 8%).
2) The modulus (frequency 1Hz) of the hydrogel (polymer content 12%) in step 1) at different strains was tested. Then, different strains (1%, 400%) were applied to the hydrogel using a rheometer at a fixed frequency (1.0 Hz). Record G' and G ". The self-healing properties of the hydrogels were investigated by comparing the change in modulus of the hydrogels under different strains, and the results are shown in fig. 4. At 1% strain, G' is greater than G ", showing significant solid properties; at 400% strain, G' is less than G ", exhibiting fluid properties, which are characteristic of shear-thinning. When the strain is changed from 400% to 1%, the hydrogel is mainly converted from the fluid characteristic to the solid characteristic, and good self-healing is shown.
Example 3 curcumin sustained release effect test in hydrogel
1) Firstly, polymer a (P1) was dissolved in a phosphate buffer/ethanol mixture (mass fraction of polymer a: 12%, ethanol: and (3) adding 5/95 (volume ratio) buffer solution, pH 7.4 and 0.10M, adding curcumin powder to form a P1-curcumin (P1-Cur.) suspension (the curcumin concentration is 1mg/mL), and performing ultrasonic dispersion on the suspension for 30 minutes to completely combine the polymer and the small molecules to obtain the P1-Cur. P1-Cur (40mL) was sealed in a dialysis bag (MWCO:. about.3.5K). The bag was placed in a beaker containing 5% (volume fraction) ethanol in PBS (360mL, pH 7.4, 0.1M) and set aside on a shaker (90 rpm).
2) The hydrogel prepared in example 1 (40mL, polymer a content: 12%) were sealed in a dialysis bag (MWCO:. about.3.5K). The bag was placed in a beaker containing 5% (volume fraction) ethanol in PBS solution (360mL, pH 7.4, 0.1M) and set aside on a shaker (90 rpm).
3) Samples (2mL) were taken from the external solution in steps 1) and 2) at different time points, and the released curcumin (UV: 359nm), and then replaced for continued dialysis. The resulting release profile is shown in figure 5. In the release time of 36 hours, the curcumin loaded in the hydrogel is only released by about 10 percent, and is obviously superior to the release effect of only combining the curcumin with the polymer (the release is about 30 percent).
Example 4 hydrogel biosafety testing
1) Normal cells (e.g., mouse fibroblast L929) were cultured in the mixed solution 1 in example 1 (polymer a content: 12%). Then, the mixed solution 2 was added to the same petri dish in a volume ratio of 1: 1. The dish was gently shaken to form a hydrogel uniformly.
2) Subjecting the gel obtained in step 1) to 5% CO at 37 deg.C 2 And (4) performing lower incubation and imaging. To observe the survival of the inner cells, after 24 hours or 48 hours, they were stained with FDA-PI (FDA: 5. mu.g/mL; PI: 5. mu.g/mL, 1 mL). After storage in the dark for 10 minutes, the cells were observed with a confocal microscope, as shown in FIG. 6. Cell viability was characterized by the percentage of FDA stained cells (green in the figure) to total cells. After 48 hours of culture, the survival rate of the cells is still over 90 percent, which proves that the biological safety of the cells is good.
Example 5 hydrogel wound healing promoting Performance test
1) Culturing L929 cells in a culture dish (diameter 3.5 mm); then, an artificial wound was created by scraping the bottom with a 200 μ L pipette tip, and the cells were washed with PBS.
2) 1mL of the hydrogel (with/without curcumin) prepared in example 1 and 1mL of a medium (RPMI1640 medium, 1% of a diabody (penicillin streptomycin), 10% of Fetal Bovine Serum (FBS) were added to the artificial wound created in step 1) respectively and observed for 48 hours. Optical images were taken at different time points as shown in fig. 7, and the healing process was observed. Comparison shows that the experimental group taking the hydrogel containing curcumin as the dressing can obviously promote the cells to proliferate faster at the scarred part and promote wound healing.
Example 6 animal experiments with hydrogels
1) Balb/c type mice (6-8 week old females, 18-21g) were selected and the hair on the lumbar region of the mice was removed with depilatory cream. The curcumin-containing hydrogel prepared in example 1 (400 μ L, 12% by mass of polymer a, i.e., Gel12-Cur.) was injected subcutaneously into Balb/c mice.
2) After 72h, the skin was observed for inflammation and edema and recorded by photography, as shown in fig. 8. The mice were then euthanized by carbon dioxide asphyxiation, respectively. These mice were dissected and the area near the injection area was histologically sectioned, as shown in FIG. 9. As can be seen, the tissue surrounding the Gel12-cur Gel injection was almost identical to normal tissue (Control), indicating that neither hydrogel nor curcumin caused allergic reactions in mice.
Claims (10)
1. A preparation method of a curcumin-containing hydrogel material comprises the following steps:
1) dissolving a water-soluble polymer containing a dihydropyridine ring and a phenylboronic acid group in an aqueous solution, adding curcumin, and then fully mixing to ensure that the curcumin reacts with the water-soluble polymer, combines and dissolves the curcumin and the water-soluble polymer to obtain a mixed solution A;
2) dissolving polyvinyl alcohol in the aqueous phase solution to obtain a solution B;
3) and (3) fully mixing the mixed solution A and the solution B for reaction to form the curcumin-containing hydrogel material in a short time.
3. The method of claim 2, wherein: the water-soluble polymer containing the dihydropyridine ring and the phenylboronic acid group is a polymer P1, and the preparation method of the curcumin-containing hydrogel material comprises the following steps:
A) dissolving the polymer P1 in a phosphate buffer salt solution containing ethanol, adding curcumin, and performing ultrasonic mixing to obtain a mixed solution 1;
B) adding polyvinyl alcohol into phosphate buffer solution, and fully dissolving the polyvinyl alcohol to obtain solution 2;
C) respectively sucking a certain volume of the mixed solution 1 and the solution 2, fully mixing, and standing for 10-60 seconds to obtain the product.
4. The production method according to claim 3, characterized in that:
in the step A), in the mixed solution 1, the mass fraction of the polymer A is 8-12%; the mass concentration of the curcumin is 0.5-2 mg/mL;
the volume fraction of ethanol in the phosphate buffer solution containing ethanol is 3-5%;
the concentration of phosphate buffer in the phosphate buffered saline solution containing ethanol was 0.1M.
5. The production method according to claim 3, characterized in that:
in the step B), the mass fraction of the polyvinyl alcohol in the solution 2 is 4-6%;
the polyvinyl alcohol is PVA 1788; the concentration of the phosphate buffer was 0.1M.
6. The production method according to claim 3, characterized in that:
in the step C), the volume ratio of the mixed solution 1 to the solution 2 is (0.8-1.2): 1;
the standing time is 10-60 seconds, and the standing temperature is room temperature.
7. A curcumin-containing hydrogel material produced by the method of any one of claims 1 to 6.
8. Use of a curcumin-containing hydrogel material as claimed in claim 7 in at least one of the following aspects:
1) the application in preparing products for promoting wound healing;
2) the application in the preparation of drug carriers;
3) the application in preparing dressing.
9. A product comprising a curcumin-containing hydrogel material of claim 7.
10. The product of claim 9, wherein: the product is at least one of the following:
1) products for promoting wound healing;
2) a drug carrier;
3) a dressing is provided.
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Cited By (2)
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CN115737838A (en) * | 2022-11-11 | 2023-03-07 | 上海交通大学医学院附属第九人民医院 | Curcumin-containing polymer and application thereof in promoting healing of burn |
CN115998943A (en) * | 2022-12-20 | 2023-04-25 | 北京中医药大学 | Hydrogel for promoting skin wound healing and application thereof |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115737838A (en) * | 2022-11-11 | 2023-03-07 | 上海交通大学医学院附属第九人民医院 | Curcumin-containing polymer and application thereof in promoting healing of burn |
CN115998943A (en) * | 2022-12-20 | 2023-04-25 | 北京中医药大学 | Hydrogel for promoting skin wound healing and application thereof |
CN115998943B (en) * | 2022-12-20 | 2024-05-24 | 北京中医药大学 | Hydrogel for promoting skin wound healing and application thereof |
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