CN115337446A - Preparation method of bio-based adhesive hydrogel patch for promoting wound healing, product and application thereof - Google Patents
Preparation method of bio-based adhesive hydrogel patch for promoting wound healing, product and application thereof Download PDFInfo
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- CN115337446A CN115337446A CN202210804537.8A CN202210804537A CN115337446A CN 115337446 A CN115337446 A CN 115337446A CN 202210804537 A CN202210804537 A CN 202210804537A CN 115337446 A CN115337446 A CN 115337446A
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- based adhesive
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0038—Gelatin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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- A61L26/0061—Use of materials characterised by their function or physical properties
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0066—Medicaments; Biocides
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention discloses a preparation method of a bio-based adhesive hydrogel patch for promoting wound healing, which comprises the following steps: (1) Lipoic acid and cytosine nucleoside are mixed and then react to obtain lipoic acid cytosine; (2) Mixing gelatin and methacrylic anhydride, and reacting to obtain methacrylated gelatin GelMA; (3) And blending lipoic acid cytosine and GelMA, heating and polymerizing to obtain the bio-based adhesive hydrogel patch. The invention also discloses the bio-based adhesive hydrogel patch prepared by the preparation method and application of the bio-based adhesive hydrogel patch in preparation of skin wound repair products. The preparation method provided by the invention is simple and environment-friendly, and the prepared hydrogel patch combines natural molecules of lipoic acid, cytidine and gelatin, and can be effectively used for promoting wound healing.
Description
Technical Field
The invention relates to the field of hydrogel materials prepared by chemical synthesis, in particular to a preparation method of a bio-based adhesive hydrogel patch for promoting wound healing, a product and application thereof.
Background
The skin is covered on the surface of human body, and has the functions of protecting, excreting, regulating body temperature, and sensing external stimulation. As the first major organ of the human body, the skin occupies about 16% of the body weight, and the skin area of an adult is about 1.2 to 2.0 square meters. Skin is the tissue that comes into direct contact with the external environment and is a natural barrier protecting the body against external infections and damage.
However, the skin is damaged by infection of external pathogenic microorganisms or internal pathological changes, resulting in the formation of wounds. Wounds can be classified as acute wounds and chronic wounds according to the time for the wound to return to a normal state. Acute wounds refer to wounds caused by external stimuli such as sharp instruments, and generally heal within several months according to the depth of the wounds and the size of the wound surface. Chronic wounds heal longer and the healing process is slow or even difficult.
Traditional wound dressings are passive, mainly gauze and bandages, and are suitable for drying and cleaning well wounds. Gauze is primarily made of woven or non-woven cotton fibers, viscose and polyester, the fibrous structure being capable of absorbing exudates and liquids from open wounds. Such dressings are useful for the treatment of lower limb ulcers, burns and pressure sore wounds, but they require frequent replacement and are not suitable for use with dry wounds and dry scars.
Hydrogel is a three-dimensional network polymer capable of being enriched with a large amount of water or biological fluid, has an ultra-high water absorption capacity because it has a cross-linked structure, swells without dissolving in a liquid environment, and has a structure similar to that of a relevant tissue of a human body, and is widely used for various biomaterials. Hydrogels not only provide a suitable microenvironment, but also act as a physical barrier to bacteria and prevent wound infection, providing an advantage for wound repair. For example, chinese patent No. CN113999426a discloses a method for preparing a porous structure double-layer gelatin hydrogel driver, which specifically includes the following steps: (1) preparation of gelatin solution: adding water into gelatin in proportion, and magnetically stirring in water bath to obtain gelatin solution; (2) preparation of solid gelatin: injecting the gelatin solution into a mold, and refrigerating to obtain the dust-free paper-solid gelatin; (3) Constructing a porous structure, namely putting the preformed solid gelatin into a refrigerator to be frozen to construct the porous structure; (4) And (4) crosslinking, namely soaking the gelatin hydrogel with the porous structure obtained in the step (3) in a crosslinking agent to obtain the gelatin hydrogel with the disordered porous structure. For example, chinese patent publication No. CN109749098a discloses a physical/chemical double-crosslinked network high-strength gelatin hydrogel and a preparation method thereof, comprising: modifying gelatin and chitosan by using a Traut's reagent and a methacrylic anhydride reagent respectively; preparing a hydrogel; physical and chemical crosslinking is introduced by using an alkaline sulfate solution soaking method to prepare the double-crosslinking-network high-strength gelatin-chitosan hydrogel.
However, the hydrogel material has poor adhesion performance, difficult shape control, poor strength and other factors, which restrict the wide application of the hydrogel in the skin wound repair. The existing solution is to mix natural high molecular material with synthetic hydrophilic high molecular polymer, but the formed hydrogel has insufficient adhesiveness, and the hydrogel is easy to swell in water environment, the generated stress is easy to separate the material from the substrate, the weak adhesion of the hydrogel in water is reduced, and the patch is easy to fall off.
Disclosure of Invention
The invention aims to provide a preparation method of a bio-based adhesive hydrogel patch for promoting wound healing, a product and an application thereof.
The invention provides the following technical scheme:
a method of making a bio-based adhesive hydrogel patch for promoting wound healing, the method of making comprising:
(1) Lipoic acid and cytosine nucleoside are mixed and then react to obtain lipoic acid cytosine;
(2) Mixing gelatin and methacrylic anhydride, and reacting to obtain methacrylated gelatin GelMA;
(3) And blending lipoic acid cytosine and GelMA, heating and polymerizing to obtain the bio-based adhesive hydrogel patch.
According to the invention, two kinds of green natural molecular gelatin and lipoic acid are respectively modified to prepare an intermediate GelMA containing a polymerization double bond and lipoic acid cytosine containing a disulfide bond, and then the disulfide bond of the lipoic acid and the double bond of the methacrylated gelatin can be subjected to polymerization reaction under a certain condition by means of blending and heating, so that the bio-based adhesive hydrogel which is strong in adhesion, adjustable in shape and high in strength and can promote wound healing is prepared.
In the step (1), the feed ratio of the lipoic acid to the cytosine nucleoside is 0.1-0.5 mol:0.12 to 0.6mol.
In the step (1), the reaction conditions are as follows: reacting for 12-48 h at 0-50 ℃. The disulfide bond that exerts the adhesive effect is derived from lipoic acid and its derivatives. The disulfide bond is easily polymerized at 0-50 ℃, so that the temperature control in the reaction process is very important.
In the step (1), after the reaction is finished, the required product is obtained by TLC and column chromatography separation, and the product is subjected to nuclear magnetic characterization. Infrared comparison of the starting materials and the final product of the reaction was used to determine the change in the functional groups during the reaction.
In the step (2), the feeding ratio of the gelatin to the methacrylic anhydride is 0.1-0.5 mol:0.5 to 5mol. When the grafting efficiency is reduced, most of the product is unreacted amino groups. Only when the amount of methacrylic anhydride charged is increased and the reaction time is prolonged, the grafting efficiency is more than 70%, which is a high grafting ratio.
In step (2), the reaction conditions are: reacting for 4-48 h at 0-100 ℃.
In step (2), after the reaction is finished, the required product is separated by a dialysis method, and the product is frozen and dried. Comparing the initial raw materials and the final product of the reaction by nuclear magnetism, and determining the change of the functional group in the reaction process.
In the step (3), the feed ratio of the lipoic acid cytosine to the GelMA is as follows: 1: 2-2: 1; the temperature is increased to 90 to 110 ℃. By controlling the polymerization ratio and reaction temperature of the two, a series of hydrogel patches with different viscosities can be obtained.
Preferably, the lipoic acid cytosine and the GelMA are mixed according to a feeding ratio of 1:1, and heating to 100 ℃ to solidify to obtain the bio-based adhesive hydrogel patch for promoting wound healing. The bio-based adhesive hydrogel patch prepared by the method is moderate in hardness and strong in adhesion.
The invention also provides the bio-based adhesive hydrogel patch prepared by the preparation method.
The invention also provides application of the bio-based adhesive hydrogel patch in preparation of a product for repairing a skin wound.
Lipoic acid and cytosine nucleoside are indispensable small molecules of human body, have certain promotion effect on the processes of wound repair, angiogenesis, cell proliferation and the like of injured skin, and can accelerate the process of skin wound repair. Methacrylated gelatin (GelMA) is a crosslinked hydrogel prepared by introducing methacryloyl groups into gelatin, and has the advantages of injectability, rapid gelling, good mechanical properties, good biocompatibility, suitability for customized biological printing, easy combination with various cell types, and the like. The advantages of the two points are combined to prepare the novel injectable adhesive hydrogel patch, so that the wound healing of a patient can be accelerated, and the pain of the patient can be reduced.
Compared with the prior art, the invention has the following advantages: the problem that the wound of a patient is difficult to heal is a difficult problem to be solved clinically. On the basis of referring to the traditional external application material, the invention modifies two bio-friendly materials, and the two bio-friendly materials are subjected to thermosetting polymerization to obtain the injectable adhesive hydrogel patch which has the functions of resisting inflammation and promoting repair, can be adhered to the surface of a wound, promotes the rapid healing of the wound and reduces the pain of patients. The preparation method of the hydrogel patch based on the modification of the green natural molecules is simple and environment-friendly, and has the advantages of wide raw material source, convenient use and little environmental pollution.
Drawings
FIG. 1 is a schematic diagram of a synthetic application process of a hydrogel patch according to the present invention;
FIG. 2 is a comparison of the nuclear magnetic content of GelMA material prepared in example 1.
Fig. 3 is a nuclear magnetic analysis diagram of lipoic acid cytosine material prepared in example 1.
Fig. 4 is a comparison graph of thioctic acid cytosine material prepared in example 1 before and after infrared reaction.
Fig. 5 is a sample view of a wound-healing promoting bio-based adhesive hydrogel prepared in example 1.
Detailed Description
In order to make the purpose and technical solution of the present invention more apparent, the present invention is further described in detail below with reference to the accompanying drawings. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Those skilled in the art will recognize that the specific techniques or conditions, not specified in the examples, are according to the techniques or conditions described in the literature of the art or according to the product specification.
As shown in figure 1, gelatin and lipoic acid are respectively modified to obtain intermediate GelMA and lipoic acid cytosine, and then the hydrogel patch is obtained through blending, heating and polymerization. The hydrogel patch prepared can be used for wound infected mice.
Example 1
Lipoic acid and cytidine are mixed according to a proper feeding ratio: the molar weight of the cytosine nucleoside is 0.12mol, the molar weight of the lipoic acid is 0.1mol, the mixture is put into a three-neck flask and reacts at 50 ℃ for 24 hours under the protection of nitrogen, after the reaction is finished, the required product is obtained by separation and chromatography through a column, and the chemical structure of the product is characterized, and the detailed results are shown in fig. 3 and fig. 4, and can be seen from fig. 3 and fig. 4: the characterization of the product accords with the structural formula of the lipoic acid cytosine, and the target product is successfully synthesized.
Gelatin and methacrylic anhydride are put into a three-neck flask according to a proper feeding ratio, the molar weight of the gelatin is 0.1mol, the molar weight of the methacrylic anhydride is 1mol, the mixture is reacted for 48 hours at 60 ℃ under the protection of nitrogen, after the reaction is finished, a required product is obtained by separation and chromatography through a column, and the chemical structure of the product is characterized, and the result is shown in figure 2 in detail, and can be seen in figure 2: before and after grafting, a characteristic peak of a carbon-carbon double bond newly appears between 5.0ppm and 6.0ppm, which indicates that the methacrylic group is successfully introduced.
Intermediate GelMA and lipoic acid cytosine were mixed according to 1:1, dissolving by blending and heating to 100 ℃, reacting for 3 hours, introducing into a polytetrafluoroethylene mold, standing and cooling to obtain the hydrogel patch which is adhered when meeting water, wherein the hydrogel patch has moderate hardness and adhesiveness, and the result is shown in figure 5.
Example 2
GelMA and lipoic acid cytosine as per 2:1, dissolving by blending and heating to 100 ℃, reacting for 3 hours, introducing into a polytetrafluoroethylene mold, standing and cooling to obtain the hydrogel patch which can be adhered when meeting water, wherein the hydrogel patch is hard and has poor adhesion.
Example 3
GelMA and lipoic acid cytosine as per 1:2, dissolving by blending and heating to 100 ℃, reacting for 3 hours, introducing into a polytetrafluoroethylene mold, standing and cooling to obtain the hydrogel patch adhered to the polytetrafluoroethylene in water, wherein the hydrogel patch is softer and has poorer molding.
Application example
6 male Sprague-Dawley (SD) rats (250. + -.20 g) were selected for the experiment. All rats were randomized into 2 groups and anesthetized with isoflurane. The back of each rat was shaved and two symmetrical incisions were cut and the following steps were performed on the wounds: (1) natural healing without treatment (2) the prepared lipoic acid cytosine patch (example 1) was applied to the wound and slightly compressed.
All rats were observed for wound recovery. The wound recovery of rats using the hydrogel patch prepared in example 1 was good.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Changes, modifications, additions and substitutions within the spirit and scope of the invention are intended to be covered by the following claims.
Claims (8)
1. A method of making a bio-based adhesive hydrogel patch for promoting wound healing, said method comprising:
(1) Lipoic acid and cytosine nucleoside are mixed and then react to obtain lipoic acid cytosine;
(2) Mixing gelatin and methacrylic anhydride, and reacting to obtain methacrylated gelatin GelMA;
(3) And blending lipoic acid cytosine and GelMA, heating and polymerizing to obtain the bio-based adhesive hydrogel patch.
2. The method for preparing a bio-based adhesive hydrogel patch for promoting wound healing according to claim 1, wherein the lipoic acid and cytosine nucleoside are fed in a ratio of 0.1-0.5 mol:0.12 to 0.6mol.
3. The method for preparing a bio-based adhesive hydrogel patch for promoting wound healing according to claim 1, wherein in the step (1), the reaction conditions are: reacting for 12-48 h at 0-50 ℃.
4. The method for preparing a bio-based adhesive hydrogel patch for promoting wound healing according to claim 1, wherein in the step (2), the gelatin and methacrylic anhydride are fed in a ratio of 0.1 to 0.5mol:0.5 to 5mol.
5. The method for preparing a bio-based adhesive hydrogel patch for promoting wound healing according to claim 1, wherein in the step (2), the reaction conditions are: reacting for 4-48 h at 0-100 ℃.
6. The method for preparing a bio-based adhesive hydrogel patch for promoting wound healing according to claim 1, wherein the lipoic acid cytosine and GelMA are dosed at a ratio of: 1: 2-2: 1, heating to 90-110 ℃.
7. A biobased adhesive hydrogel patch obtained by the production method according to any one of claims 1 to 6.
8. Use of the biobased adhesive hydrogel patch according to claim 7 for the preparation of a product for skin wound repair.
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