CN116212103A - Chitosan gel dressing for promoting healing as well as preparation method and application thereof - Google Patents
Chitosan gel dressing for promoting healing as well as preparation method and application thereof Download PDFInfo
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- CN116212103A CN116212103A CN202310524672.1A CN202310524672A CN116212103A CN 116212103 A CN116212103 A CN 116212103A CN 202310524672 A CN202310524672 A CN 202310524672A CN 116212103 A CN116212103 A CN 116212103A
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- chitosan
- tannic acid
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Abstract
The invention provides a chitosan gel dressing for promoting healing, a preparation method and application thereof. The provided chitosan gel dressing comprises the following components in parts by weight: 5 parts by weight of tannic acid; 10-15 parts by weight of chitosan or a derivative thereof; and Ca 2+ Ions, the tannic acid and the Ca 2+ The mass ratio of the ions is 1: (1-3); the tannic acid is crosslinked with the chitosan or its derivative and with the Ca 2+ Ion chelation forms the chitosan healing promoting gel dressing. The provided chitosan gel dressing for promoting healing has obvious promoting effect on wound healing.
Description
Technical Field
The invention relates to the field of medical materials, in particular to a chitosan gel dressing for promoting healing, a preparation method and application thereof.
Background
The skin, which is the first major organ of the human body in direct contact with the external environment, protects the human body from a number of different diseases and harmful substances, and plays an important role in maintaining the homeostasis of the body. Therefore, once our skin is damaged, the rate of wound healing should be focused after achieving the goal of rapid hemostasis. There are many objective factors that affect wound healing, such as the age of the patient, the physical health, the administration of chronic medications, and the change in microenvironment at the wound.
In recent years, the therapeutic impedance of wounds has become a major challenge in clinic and has placed a great economic burden on the patient's home. Due to the complexity of wound repair itself, in the case of severe wounds, an ideal multi-dimensional healing strategy is required to affect all four phases of the wound healing process, including hemostasis, inflammation, proliferation and remodeling. Although various biomaterial-based products have been developed to promote wound healing, the low-cost healing-promoting and anti-bleeding hydrogels are mediated in the four stages of recovery, reducing the economic burden on the patient's home, remains an unrealized goal. For example, a multifunctional, pro-healing hydrogel can perform a great function in all four stages of wound healing, and the preferred multifunctional formulation for wound healing can inhibit the overproduction of free radicals and the long-term secretion of pro-inflammatory cytokines in wound tissue in addition to anti-bleeding and antibacterial effects.
What kind of healing promoting hydrogel can achieve the purpose is also in need of improvement.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. The invention aims at the expansion utilization of natural products chitosan and tannic acid, and provides a method for crosslinking the tannic acid with chitosan and metal Ca 2+ Ion chelation to form the composite gel dressing. The gel dressing provided can be externally applied, can be quickly formed into a film when being applied to a wound, protects the wound and has the function of promoting wound healing.
Specifically, the invention provides the following technical scheme:
the first aspect of the invention provides a chitosan healing promoting gel dressing, which comprises the following components in parts by weight:
tannic acid, wherein the tannic acid is 5 parts by weight;
10-15 parts by weight of chitosan or a derivative thereof;
Ca 2+ ions, the tannic acid and the Ca 2+ The mass ratio of the ions is 1: (1~3）；
The tannic acid is crosslinked with the chitosan or its derivative and with the Ca 2+ Ion chelation forms the chitosan healing promoting gel dressing.
According to the embodiment of the invention, the provided chitosan healing-promoting gel dressing can further comprise the following technical characteristics:
according to an embodiment of the present invention, the tannic acid and the Ca 2+ The mass ratio of the ions is 1: 1. 1:2 or 1:3. said tannic acid and said Ca 2+ The ion mass ratio is preferably 1:3. at this ratio, the resulting gel dressing has an optimal bactericidal effect and healing effect on wounds.
According to an embodiment of the present invention, the chitosan or the derivative thereof is selected from at least one of chitosan, quaternary ammonium salt chitosan or carboxymethyl chitosan.
According to an embodiment of the invention, the Ca 2+ The ions are calcium chloride solution.
The second aspect of the invention provides a preparation method of the chitosan healing-promoting gel dressing, wherein the chitosan healing-promoting gel dressing is the chitosan healing-promoting gel dressing of the first aspect, and the preparation method comprises the following steps:
(1) Providing an acid solution of chitosan or a derivative thereof, wherein the acid solution of chitosan or a derivative thereof is obtained by dissolving the chitosan or a derivative thereof in the acid solution, the mass concentration of the chitosan or a derivative thereof in the acid solution of chitosan or a derivative thereof is 1-5%, and the pH value of the acid solution of chitosan or a derivative thereof is 5.0-6.0;
(2) Providing a tannic acid aqueous solution, wherein the tannic acid aqueous solution is obtained by dispersing tannic acid in deionized water, the mass concentration of tannic acid in the tannic acid aqueous solution is 1-5%, and the pH value of the tannic acid aqueous solution is 5.0-6.0; according to a specific embodiment, the tannic acid can be dispersed in the deionized water by means of shaking or ultrasound;
(3) Dropwise adding the tannic acid aqueous solution into the acid solution of the chitosan or the derivative thereof, and stirring to perform a crosslinking reaction to obtain a crosslinking solution;
(4) Ca is added with 2+ Adding ions dropwise into the crosslinking solution to obtain a gel-like substance, centrifuging to remove supernatant, and dialyzing to remove the Ca 2+ Ions so as to obtain the chitosan healing promoting gel dressing.
According to an embodiment of the present invention, the preparation method described above may further include the following technical features:
according to the embodiment of the invention, the acid solution in the step (1) is an acetic acid solution, and the mass concentration of the acetic acid solution is 1-2%. The chitosan or the derivative thereof is dissolved by the acetic acid solution with the concentration, so that the chitosan or the derivative thereof can be dissolved, and the irritation to the skin wound surface can be reduced.
According to an embodiment of the present invention, the time of the crosslinking reaction in the step (3) is 30 to 60 minutes. Whereby a product of crosslinked tannic acid and chitosan or a derivative thereof can be obtained.
According to an embodiment of the present invention, the Ca in step (4) 2+ The ions are calcium chloride aqueous solution, and the mass concentration of the calcium chloride aqueous solution is 1-5%.
According to an embodiment of the present invention, the Ca is slowly added in step (4) 2+ Ions, the Ca 2+ The rate of addition of the ions was 0.5mL/min, which resulted in a change in the color of the reaction solution from light brown to dark blue. Ca (Ca) 2+ The adding speed of ions is not easy to be too high, and the chelating effect can be influenced, so that the sterilizing effect of the prepared chitosan gel dressing is poor. Ca (Ca) 2+ The introduction of ions enhances the adhesion of chitosan or derivatives thereof to the wound site and also promotes wound healing.
In a third aspect, the invention provides an application of the chitosan gel dressing for promoting healing in the preparation of antibacterial or antioxidant or wound healing medicines.
The invention has the following effective effects:
the chitosan gel dressing for promoting healing provided by the invention is prepared from natural singleThe Ning acid is crosslinked with chitosan or derivatives thereof to prepare a precursor for gel formation; the modification of the tannic acid on the chitosan or the derivative thereof is utilized to enhance the bacteriostasis of the chitosan or the derivative thereof on various microorganisms such as escherichia coli and staphylococcus aureus; simultaneously utilizes the unique physicochemical property of tannic acid and metal Ca 2+ While enhancing the adhesion of chitosan at the wound site, ca 2+ The introduction itself also promotes wound healing. The provided gel dressing for promoting healing has obvious promoting effect on wound healing.
Drawings
Fig. 1 is a schematic diagram of the synthesis of a chitosan healing promoting gel dressing provided according to an embodiment of the present invention.
Fig. 2 is a graph showing the wound area change results of the chitosan healing-promoting gel dressing provided in example 1 according to the present invention.
Fig. 3 is a graph showing comparison of oxidation resistance of the chitosan healing promoting gel dressing according to example 1 of the present invention.
Fig. 4 is a graph showing the comparison of the antibacterial properties of the chitosan healing promoting gel dressing provided in example 1 according to the present invention.
Fig. 5 is a graph showing the wound area change results of the carboxymethyl chitosan healing-promoting gel dressing provided in example 2 according to the present invention.
Fig. 6 is a graph showing comparison of oxidation resistance of carboxymethyl chitosan healing promoting gel dressing according to example 2 of the present invention.
Fig. 7 is a graph showing comparison of antibacterial properties of carboxymethyl chitosan healing-promoting gel dressing provided in example 2 according to the present invention.
Fig. 8 is a graph showing the wound area change results of the quaternary ammonium salt chitosan healing-promoting gel dressing according to example 3 of the present invention.
Fig. 9 is a graph showing comparison of oxidation resistance of a quaternary ammonium salt chitosan healing promoting gel dressing according to example 3 of the present invention.
Fig. 10 is a graph showing the comparison of antibacterial properties of quaternary ammonium salt chitosan healing-promoting gel dressing according to example 3 of the present invention.
FIG. 11 is provided in accordance with embodiment 4 of the present inventionDifferent tannic acid/Ca 2+ And (5) a graph of the effect of the proportion on wound healing.
FIG. 12 is a different tannic acid/Ca according to example 4 of the present invention 2+ And a result diagram of the influence of the proportion on the antibacterial effect.
Detailed Description
The following detailed description of embodiments of the invention, examples of which are illustrated in the accompanying drawings and, by way of example, are intended to be illustrative, and not to be construed as limiting, of the invention.
The invention aims to provide a chitosan healing-promoting gel dressing capable of promoting the healing of skin wound surfaces. According to the specific embodiment, the provided chitosan healing-promoting gel dressing is used as an external skin wound dressing, and can effectively promote the healing of wounds. The gel dressing provided is first crosslinked by adding a certain amount of tannic acid to an acidic solution of chitosan. After forming a network structure by utilizing the crosslinking effect of tannic acid and chitosan, a certain amount of calcium chloride aqueous solution is added into the system in the stirring process. Catechol or triphenol structure on tannic acid can be combined with Ca 2+ The ion is chelated, so that the adhesiveness of the gel on the skin is enhanced. And the skin wound surface is protected by chelation, so that the healing of the wound is promoted. The provided gel dressing can be particularly used for repairing skin wound surfaces of special groups. For example, the gel dressing provided by the invention can be used for effectively improving the repair force of skin wound surfaces of the aged by reducing the self-recovery and healing capacity of the aged caused by using medicines or diseases.
Referring to fig. 1, the present invention provides a chitosan healing promoting gel dressing, comprising, in 100 parts by weight: tannic acid, wherein the tannic acid is 5 parts by weight; 10-15 parts by weight of chitosan or a derivative thereof; ca (Ca) 2+ Ions, the tannic acid and the Ca 2+ The mass ratio of the ions is 1: (1-3); the tannic acid is crosslinked with the chitosan or its derivative and with the Ca 2+ Ion(s)Chelating to form the chitosan healing promoting gel dressing. Tannic acid, chitosan or derivatives thereof show a certain wound healing and antibacterial effect by crosslinking with Ca 2+ The ion can obtain ideal chitosan gel dressing for promoting healing, and the antibacterial effect and the wound healing effect of the chitosan gel dressing are superior to those of tannic acid or chitosan or derivatives thereof, or the crosslinked product of the tannic acid or chitosan or derivatives thereof. Under the content ratio, the obtained chitosan gel dressing for promoting healing of wounds shows more excellent effects of promoting healing of wounds, inhibiting bacteria and resisting oxidation.
Chitosan, the only natural alkaline polysaccharide in nature, has a wide source. Shrimp, crab, fungus and insect can be used as raw materials for extracting chitosan. Called as basic polysaccharide, the chitin is deacetylated and NH in its molecular structure 3 The radical is released. The chitosan has excellent biocompatibility, shows low toxicity to human body, and has wide application prospect in the fields of medicine, agriculture, instruments, food and cosmetics. However, the extremely low solubility of chitosan in water limits the medical use of chitosan in the above-mentioned fields. Chitosan is commonly used in the field of medical devices for wound hemostasis, wound sterilization and wound healing promotion. When chitosan is soluble in acetic acid, NH of chitosan 3 The radicals being protonated to form NH 4 + . The chitosan can rapidly gather red blood cells at the wound through electrostatic adsorption at the wound to form a protective film.
Tannic acid, also known as tannic acid, is a natural product which is widely distributed in the leaves, seeds, roots and other organs of plants, and endows the plant with a plurality of functions in a plurality of fields due to the polyhydroxy of the molecular structure, and the functional groups of catechol and pyrogallol. Tannic acid, for example, is a natural antioxidant, and is used in the cosmetic field; secondly, the molecular structure of tannic acid is similar to that of dopamine, and the tannic acid can stably adhere to the surface of a complex object, and is widely used for surface modification of pesticide particles so as to enhance the adhesion on the leaf surfaces of crops; tannic acid can react with various metal ions (Ag + 、Zn + 、Fe 3+ 、Ca 2 + Etc.) chelate or link with high molecular material polyvinylpyrrolidone (PVP) through hydrogen bond to form microcapsule structure, which is mostly used as nano delivery drug system; tannic acid can be combined with cell walls and components of cell membranes of bacteria through hydrogen bonds, so that the integrity of the cell membranes of the bacteria is destroyed.
The use of tannic acid in advanced multifunctional wound dressings can be considered a non-antibiotic treatment method during the healing process of wounds, because the long-term use of antibiotics in chronic skin ulcers is limited by serious cytotoxicity and adverse consequences of drug resistance. The introduction of tannic acid can not only make hydrogel possess inherent anti-inflammatory, antioxidant and antibacterial properties, but also improve the healing promoting effect of hydrogel through interaction with blood proteins.
According to a specific embodiment, the tannic acid and the Ca 2+ The mass ratio of the ions is 1: 1. 1:2 or 1:3. during the research, it is found that the chelation of tannic acid and metal calcium ions has a certain concentration relation, and the concentration of the metal calcium ions is not too high, so that precipitation occurs. When tannic acid/Ca 2+ The proportion of the mixture ratio is 1: 1. 1:2 or 1:3, gel can be formed. When tannic acid/Ca 2+ The ratio is 1:4, and a precipitate is formed. Especially when tannic acid/Ca 2+ When the ratio is 1:3, the sterilization effect and wound healing effect of the formed gel are optimal.
According to a specific embodiment, the chitosan or the derivative thereof is selected from at least one of chitosan, chitosan quaternary ammonium salt chitosan and carboxymethyl chitosan.
According to a specific embodiment, the Ca 2+ The ions are calcium chloride solution. The calcium chloride can carry out chelation reaction with tannic acid, and calcium ions can be slowly released, so that the calcium chloride can promote healing and play a role in promoting bacteriostasis.
The invention also provides a preparation method of the chitosan healing-promoting gel dressing, wherein the chitosan healing-promoting gel dressing is the chitosan healing-promoting gel dressing according to the first aspect, and the preparation method comprises the following steps:
(1) Providing an acid solution of chitosan or a derivative thereof, wherein the acid solution of chitosan or the derivative thereof is obtained by dissolving the chitosan or the derivative thereof in the acid solution, the mass concentration of the chitosan or the derivative thereof in the acid solution of the chitosan or the derivative thereof is 1-5%, and the pH value of the acid solution of the chitosan or the derivative thereof is 5.0-6.0 (for example, can be 5.0-5.5, and the proper pH value can ensure the dissolution and can also reduce the stimulation to skin wound surfaces);
(2) Providing a tannic acid aqueous solution, wherein the tannic acid aqueous solution is obtained by dispersing tannic acid in deionized water, the mass concentration of tannic acid in the tannic acid aqueous solution is 1-5%, the pH value of the tannic acid aqueous solution is 5.0-6.0 (for example, the tannic acid aqueous solution can be 5.0-5.5, and the proper pH value can ensure dissolution and can also reduce the irritation to skin wound surfaces);
(3) Dropwise adding the tannic acid aqueous solution into the acid solution of the chitosan, and stirring to perform a crosslinking reaction to obtain a crosslinking solution;
(4) Ca is added with 2+ Adding ions dropwise into the crosslinking solution to obtain gel-like substance, centrifuging to remove supernatant, and dialyzing to remove Ca 2+ Ions so as to obtain the chitosan healing promoting gel dressing.
The preparation method provided by the invention has simple preparation process, and all reactions are carried out at room temperature except for heat generated in the process of preparing the calcium chloride solution. The synthesis process does not need any freezing treatment, and can be realized only through a simple dialysis process. Thus, the gel dressing can be obtained and used for wound healing of skin.
According to a specific embodiment, the acid solution in the step (1) is an acetic acid solution, and the mass concentration of the acetic acid solution is 1-2%.
According to a specific embodiment, the Ca described in step (4) 2+ The ions are calcium chloride aqueous solution, and the mass concentration of the calcium chloride aqueous solution is 1-5%.
According to a specific embodiment, the Ca is slowly added in step (4) 2+ Ions, the Ca 2+ The ion adding speed is 0.5mL/min,so that the color of the reaction solution changed from light brown to dark blue.
According to a specific embodiment, the provided preparation method of the gel dressing for promoting healing comprises the following steps:
(1) Preparation of primary liquid of chitosan or its derivative
First, an acetic acid solution of 1-2% concentration, referred to as solution A, was prepared. Weighing a certain amount of chitosan or a derivative thereof, gradually dispersing the chitosan or the derivative thereof into the solution A under the condition of stirring at 800-1000 rpm, preparing an acid solution of the chitosan or the derivative thereof with the mass concentration of 1-5%, adjusting the pH value to be between 5.0 and 6.0, and continuously stirring the solution which is called as the solution B.
(2) Preparation of crosslinking liquid
And (3) weighing a certain amount of tannic acid, dissolving the tannic acid into deionized water under the condition of magnetic stirring at a rotating speed of 500-1000 rpm, and preparing a tannic acid solution with a mass concentration of 1-5%, wherein the solution is called solution C.
(3) Preparation of metal chelators
And weighing a certain amount of anhydrous calcium chloride, and preparing an aqueous solution with the mass concentration of 1-5%, wherein the process of dissolving the anhydrous calcium chloride in water is an exothermic process, and the aqueous solution is called solution E after being cooled to room temperature.
(4) Preparation of gel dressing for promoting healing
Gradually dropwise adding a solution C with the mass 1-3 times of that of chitosan or a derivative thereof into the solution B by using a dropper, continuously stirring at the stirring speed of 500-800 rpm for more than 30 min, wherein the formed system is a solution D, and the color in the beaker is light brown; and (3) sucking 0.5-1 times of the solution E by using a pipetting gun, slowly adding the solution E into the solution D, changing the color of the system from light brown to dark blue at the moment, subpackaging the gel into a centrifuge tube, centrifuging for 10 minutes under the condition of the rotating speed of 5000-8000 rpm, removing the supernatant, transferring the supernatant into a dialysis bag, dialyzing, and changing deionized water once a day until no precipitation occurs after carbonic acid is dripped into the dialyzate.
The principles and features of the present invention are described in connection with the following examples, which are intended to be illustrative of the invention and are not intended to limit the scope of the invention.
The chitosan used was purchased from Shandong Fengtai biotechnology Co., ltd;
carboxymethyl chitosan was purchased from Shandong Fengtai biotechnology Co., ltd;
the quaternary ammonium salt chitosan is purchased from Shandong Fengtai biotechnology Co., ltd;
tannic acid was purchased from the scientific company of belvedere.
Example 1
Example 1 a chitosan healing promoting gel dressing was prepared by the following method, comprising:
(1) 1g of chitosan is weighed and dissolved in acetic acid with the mass fraction of 1% (1 mL of acetic acid+99 mL of deionized water), and the pH value is regulated to be between 5.0 and 5.5, so as to obtain chitosan acetic acid solution;
(2) Weighing 0.3g of tannic acid to be dispersed in 30mL of deionized water, and adjusting the pH value to be 5.0-5.5 after shaking and ultrasonic assistance dissolution are needed in the dispersing process to obtain a tannic acid solution;
(3) Absorbing a certain amount of chitosan acetic acid solution, converting the chitosan acetic acid solution into mass according to volume, placing the mass on a magnetic stirrer, and continuously stirring at a rotating speed of 800-1000 rpm;
(4) Absorbing tannic acid solution 3 times of the chitosan, dropwise adding the tannic acid solution into the chitosan acetic acid solution, continuously stirring at 500-800 rpm in the process, and continuously stirring the reaction system for 30-60 min after the dropwise adding is finished;
(5) Absorbing a certain amount of calcium chloride aqueous solution with the mass fraction of 1-5%, slowly dripping the calcium chloride aqueous solution into the system, and noticing the change of the color of the system in the dripping process to obtain a gelatinous product;
(6) Subpackaging the gelatinous product obtained in the step (5) into a centrifuge tube, centrifuging for 10 minutes under the condition that the rotating speed is 5000-8000 rpm, and removing the supernatant;
(7) Transferring the product obtained in the step (6) into a dialysis bag, dialyzing the redundant chelating agent by deionized water, and dripping carbonic acid into the dialyzate for verification until no precipitate exists, so as to obtain the chitosan gel-promoting dressing.
The prepared chitosan gel dressing is characterized by the following methods:
1. 15 SD rats (200 g) were divided into 5 groups of 3. All procedures were performed under sterile conditions. During standard anesthesia, rats were induced to anesthetize by inhalation of sevoflurane and were intraperitoneally injected with 1ml of 5% chloral hydrate solution (350 mg/kg). The rats were fixed on the operating table on their backs and the back was fully exposed for depilation. A full-thickness defect of 1. 1cm a, one anterior and posterior, was created using a reamer. Each set of gel sponge dressings was cut to a diameter of 1cm and directly covered over the wound. And (3) suturing double-layer sterile gauze around the treated wound surface to prevent the rat from biting the wound surface and dressing, and putting the wound surface back into a squirrel cage for single-cage feeding. The dressing was changed every 3 days. Wound status was observed and recorded at days 0, 3, 6, 9, 12, respectively, and wound area of unhealed sites was measured and counted using Image J software (NIH).
The results are shown in FIG. 2. Wherein the control was wound done alone without any product applied. The simple tannic acid or chitosan treatment showed a certain wound healing effect, but the effect was inferior to tannic acid-chitosan (meaning that tannic acid and chitosan only cross-linked, not with Ca 2+ Chelation, i.e. the product obtained in step (4) above), is less than tannic acid/Ca 2 + Chitosan (i.e. the chitosan healing promoting gel dressing mentioned in example 1 above). The chitosan gel dressing has more remarkable healing effect on wounds.
2. A certain amount of DPPH (commercially available from shanghai source leaf biotechnology limited) was weighed into absolute ethanol to prepare a DPPH standard solution having a mass concentration of 0.05 mg/mL. A certain amount of ascorbic acid and a comparison product are respectively weighed, dissolved by absolute ethyl alcohol or DMSO, and prepared into sample solutions with mass concentration gradients of 0.5, 1, 2, 2.5, 5, 10, 12.5 and 15mg/mL, wherein the ascorbic acid is used as a positive control. Accurately transferring 3.90 mL of DPPH use solution, respectively adding 100 μL of each sample solution with each concentration, developing for 30 min, taking absolute ethanol as blank control, and measuring absorbance A of each sample solution at 517nm wavelength 1 . Meanwhile, the same amount of absolute ethyl alcohol is used for replacing a sample to be measured under the same condition, and the absorbance is recorded as A 0 3 times of parallel measurement, drawing a clearance curve, and calculating a radical half-inhibition rate IC according to the formula (1) 50 Values.
The results are shown in FIG. 3. The provided chitosan gel dressing has better antioxidation effect than pure chitosan or tannic acid.
3. To test the antimicrobial activity of the dressing, a typical bacteria that is prone to cause wound infection was used: staphylococcus aureus was used as an experimental species. Each set of gel sponge dressings was cut into 1cm diameter round samples using a disc diffusion method and placed in a Petri dish of Staphylococcus aureus. The dishes of each group were placed in a bacteria incubator at 37℃and after 24 hours of incubation, the diameter of the zone of inhibition was analyzed. Bacteria in the bacteria inhibition zone are prepared into bacterial suspension, and the concentration of the bacteria is quantitatively analyzed by a turbidimetry method. The optical density at 600 nm was measured with an ultraviolet-visible spectrophotometer and the concentration of the bacterial suspension was inversely proportional to the transmittance and directly proportional to the optical density over a range. Therefore, the optical density (OD value) can be used to represent the concentration of the sample bacterial liquid, and the higher the OD value, the higher the concentration of the bacteria. OD values after 1, 2, 3, 4, 5 days of bacterial culture were measured to obtain bacterial growth curves for each sample.
The results are shown in FIG. 4. The antibacterial effect of the provided chitosan gel dressing for promoting healing is superior to that of pure chitosan, pure tannic acid or tannic acid-chitosan.
Example 2
Example 2 a carboxymethyl chitosan healing promoting gel dressing was prepared by the following method, comprising the steps of:
(1) 1g of carboxymethyl chitosan is weighed and dissolved in acetic acid with the mass fraction of 1 percent (1 mL of acetic acid+99 mL of deionized water), and the pH value is regulated to be between 5.0 and 5.5, so as to obtain chitosan acetic acid solution;
(2) Weighing 0.3g of tannic acid, dispersing in 30mL of deionized water, and adjusting the pH value to 5.0-5.5 after shaking and ultrasonic assisted dissolution are needed in the dispersing process to obtain a tannic acid solution;
(3) Absorbing a certain amount of carboxymethyl chitosan acetic acid solution, converting the solution into mass according to volume, placing the solution on a magnetic stirrer, and continuously stirring at a rotating speed of 800-1000 rpm;
(4) Absorbing tannic acid solution 3 times of the carboxymethyl chitosan, dropwise adding the tannic acid solution into the chitosan solution, continuously stirring at 500-800 rpm in the process again, and continuously stirring the reaction system for 30-60 min after the dropwise adding is finished;
(5) Absorbing a certain amount of calcium chloride aqueous solution with the mass fraction of 1-5%, slowly dripping the calcium chloride aqueous solution into the system, and noticing the change of the color of the system in the dripping process to obtain a gelatinous product;
(6) Subpackaging the gelatinous product obtained in the step (5) into a centrifuge tube, centrifuging for 10 minutes under the condition that the rotating speed is 5000-8000 rpm, and removing the supernatant;
(7) Transferring the product obtained in the step (6) into a dialysis bag, dialyzing the redundant chelating agent by deionized water, and dripping carbonic acid into the dialyzate for verification until no precipitate exists, so as to obtain the carboxymethyl chitosan gel dressing for promoting healing.
The prepared carboxymethyl chitosan healing-promoting gel dressing is characterized by the following methods:
1. 15 SD rats (200 g) were divided into 5 groups of 3. All procedures were performed under sterile conditions. During standard anesthesia, rats were induced to anesthetize by inhalation of sevoflurane and were intraperitoneally injected with 1ml of 5% chloral hydrate solution (350 mg/kg). The rats were fixed on the operating table on their backs and the back was fully exposed for depilation. A full-thickness defect of 1. 1cm a, one anterior and posterior, was created using a reamer. Each set of gel sponge dressings was cut to 1cm diameter and directly covered over the wound. And (3) suturing double-layer sterile gauze around the treated wound surface to prevent the rat from biting the wound surface and dressing, and putting the wound surface back into a squirrel cage for single-cage feeding. The dressing was changed every 3 days. Wound status was observed and recorded at days 0, 3, 6, 9, 12, respectively, and wound area of unhealed sites was measured and counted using Image J software (NIH).
The results are shown in FIG. 5. Wherein the control was wound done alone without any product applied. Simple tannic acid or carboxymethylThe treatment with chitosan, although showing a certain wound healing effect, was less effective than tannic acid-carboxymethyl chitosan (meaning that tannic acid and carboxymethyl chitosan only crosslink, not with Ca 2+ Chelation, i.e. the product obtained in step (4) above), is less than tannic acid/Ca 2+ Carboxymethyl chitosan (i.e. the chitosan healing promoting gel dressing mentioned in example 1 above). The chitosan gel dressing has more remarkable healing effect on wounds.
2. A certain amount of DPPH is weighed and dissolved in absolute ethyl alcohol to prepare the DPPH standard solution with the mass concentration of 0.05 mg/mL. A certain amount of ascorbic acid and a comparison product are respectively weighed, dissolved by absolute ethyl alcohol or DMSO, and prepared into sample solutions with mass concentration gradients of 0.5, 1, 2, 2.5, 5, 10, 12.5 and 15mg/mL, wherein the ascorbic acid is used as a positive control. Accurately transferring 3.90 mL of DPPH use solution, respectively adding 100 mu L of each sample solution with each concentration, developing for 30 min, taking absolute ethyl alcohol as a blank control, and measuring the absorbance A1 of each sample solution at 517 and nm wavelength. Meanwhile, the same amount of absolute ethyl alcohol is used for replacing a sample to be measured under the same condition, the absorbance is recorded as A0, the measurement is performed in parallel for 3 times, a clearance curve is drawn, and the radical half inhibition rate IC50 value is calculated according to the formula (1).
The results are shown in FIG. 6. The provided chitosan gel dressing has better antioxidation effect than pure carboxymethyl chitosan or tannic acid. In fig. 6, CM chitosan is carboxymethyl chitosan.
3. To test the antimicrobial activity of the dressing, a typical bacteria that is prone to cause wound infection was used: staphylococcus aureus was used as an experimental species. Each set of gel sponge dressings was cut into round samples of diameter 1cm using a disc diffusion method and placed in a Petri dish of Staphylococcus aureus. Each group of dishes was placed in a bacteria incubator at 37 ℃ and after 24-h incubation, the diameter of the zone of inhibition was analyzed. Bacteria in the bacteria inhibition zone are prepared into bacterial suspension, and the concentration of the bacteria is quantitatively analyzed by a turbidimetry method. The optical density at 600 nm was measured with an ultraviolet-visible spectrophotometer and the concentration of the bacterial suspension was inversely proportional to the transmittance and directly proportional to the optical density over a range. Therefore, the optical density (OD value) can be used to represent the concentration of the sample bacterial liquid, and the higher the OD value, the higher the concentration of the bacteria. OD values after 1, 2, 3, 4, 5 days of bacterial culture were measured to obtain bacterial growth curves for each sample.
The results are shown in FIG. 7. The antibacterial effect of the provided chitosan gel dressing for promoting healing is superior to that of pure carboxymethyl chitosan, pure tannic acid or tannic acid-carboxymethyl chitosan.
Example 3
Example 3 provides a quaternary ammonium salt chitosan healing promoting gel dressing, comprising the following steps:
(1) 1g of carboxymethyl chitosan is weighed and dissolved in acetic acid with the mass fraction of 1 percent (1 mL of acetic acid+99 mL of deionized water), and the pH value is regulated to be between 5.0 and 5.5, so as to obtain chitosan acetic acid solution;
(2) Weighing 0.3g of tannic acid, dispersing in 30mL of deionized water, and adjusting the pH value to 5.0-5.5 after shaking and ultrasonic assisted dissolution are needed in the dispersing process to obtain a tannic acid solution;
(3) Absorbing a certain amount of carboxymethyl chitosan acetic acid solution, converting the solution into mass according to volume, placing the solution on a magnetic stirrer, and continuously stirring at a rotating speed of 800-1000 rpm;
(4) Absorbing tannic acid solution 3 times of the carboxymethyl chitosan, dropwise adding the tannic acid solution into the chitosan solution, continuously stirring at 500-800 rpm in the process again, and continuously stirring the reaction system for 30-60 min after the dropwise adding is finished;
(5) Absorbing a certain amount of calcium chloride aqueous solution with the mass fraction of 1-5%, slowly dripping the calcium chloride aqueous solution into the system, and noticing the change of the color of the system in the dripping process to obtain a gelatinous product;
(6) Subpackaging the gelatinous product obtained in the step (5) into a centrifuge tube, centrifuging for 10 minutes under the condition that the rotating speed is 5000-8000 rpm, and removing the supernatant;
(7) Transferring the product obtained in the step (6) into a dialysis bag, dialyzing the redundant chelating agent by deionized water, and dripping carbonic acid into the dialyzate for verification until no precipitate exists, so as to obtain the quaternary ammonium salt chitosan gel dressing for promoting healing.
The prepared chitosan gel dressing is characterized by the following methods:
1. 15 SD rats (200 g) were divided into 5 groups of 3. All procedures were performed under sterile conditions. During standard anesthesia, rats were induced to anesthetize by inhalation of sevoflurane and were intraperitoneally injected with 1ml of 5% chloral hydrate solution (350 mg/kg). The rats were fixed on the operating table on their backs and the back was fully exposed for depilation. A full-thickness defect of 1. 1cm a, one anterior and posterior, was created using a reamer. Each set of gel sponge dressings was cut to a diameter of 1cm and directly covered over the wound. And (3) suturing double-layer sterile gauze around the treated wound surface to prevent the rat from biting the wound surface and dressing, and putting the wound surface back into a squirrel cage for single-cage feeding. The dressing was changed every 3 days. Wound status was observed and recorded at days 0, 3, 6, 9, 12, respectively, and wound area of unhealed sites was measured and counted using Image J software (NIH).
The results are shown in FIG. 8. Wherein the control was wound done alone without any product applied. The simple tannic acid or quaternary ammonium salt chitosan treatment showed a certain wound healing effect, but the effect was inferior to that of tannic acid-quaternary ammonium salt chitosan (meaning that tannic acid and quaternary ammonium salt chitosan only crosslink, and do not bind with Ca 2+ Chelation, i.e. the product obtained in step (4) above), is less than tannic acid/Ca 2+ Quaternary ammonium salt chitosan (i.e. the chitosan healing promoting gel dressing mentioned in example 3 above). The chitosan gel dressing has more remarkable healing effect on wounds.
2. A certain amount of DPPH is weighed and dissolved in absolute ethyl alcohol to prepare the DPPH standard solution with the mass concentration of 0.05 mg/mL. A certain amount of ascorbic acid and a comparison product are respectively weighed, dissolved by absolute ethyl alcohol or DMSO, and prepared into sample solutions with mass concentration gradients of 0.5, 1, 2, 2.5, 5, 10, 12.5 and 15mg/mL, wherein the ascorbic acid is used as a positive control. Accurately transferring 3.90 mL of DPPH use solution, respectively adding 100 μL of each sample solution with each concentration, developing for 30 min, taking absolute ethanol as blank control, and measuring absorbance A of each sample solution at 517nm wavelength 1 . At the same time, the same amount of absolute ethyl alcohol is used to replace the sample under the same conditionThe absorbance was recorded as A by measurement 0 3 times of parallel measurement, drawing a clearance curve, and calculating a radical half-inhibition rate IC according to the formula (1) 50 Values.
The results are shown in FIG. 9. The provided chitosan gel dressing has better antioxidation effect than pure quaternary ammonium salt chitosan or tannic acid. In fig. 9 TGA chitosan represents quaternary ammonium chitosan.
2. To test the antimicrobial activity of the dressing, a typical bacteria that is prone to cause wound infection was used: staphylococcus aureus was used as an experimental species. Each set of gel sponge dressings was cut into 1cm diameter round samples using a disc diffusion method and placed in a Petri dish of Staphylococcus aureus. The dishes of each group were placed in a bacteria incubator at 37℃and after 24 hours of incubation, the diameter of the zone of inhibition was analyzed. Bacteria in the bacteria inhibition zone are prepared into bacterial suspension, and the concentration of the bacteria is quantitatively analyzed by a turbidimetry method. The optical density at 600 nm was measured with an ultraviolet-visible spectrophotometer and the concentration of the bacterial suspension was inversely proportional to the transmittance and directly proportional to the optical density over a range. Therefore, the optical density (OD value) can be used to represent the concentration of the sample bacterial liquid, and the higher the OD value, the higher the concentration of the bacteria. OD values after 1, 2, 3, 4, 5 days of bacterial culture were measured to obtain bacterial growth curves for each sample.
The results are shown in FIG. 10. The antibacterial effect of the provided chitosan gel dressing for promoting healing is superior to that of pure quaternary ammonium salt chitosan, pure tannic acid or tannic acid-quaternary ammonium salt chitosan.
Example 4
Example 4 comparison of different tannins/Ca 2+ The ratio has influence on wound healing and antibacterial effect. Reference example 1 produced different tannins/Ca 2+ The effect of the ratio (1:1, 1:2, 1:3) on the wound area and the bacteriostatic effect. For evaluation of wound area and bacteriostatic effect, reference was made to example 1 above.
The results are shown in fig. 11 and 12, respectively. FIG. 11 shows different tannic acid/Ca 2+ The effect of the formulation on wound healing is shown in figure 11, where the control is to make the wound alone without applying any product. Drawing of the figure12 is different tannic acid/Ca 2+ And a result diagram of the influence of the proportion on the antibacterial effect. From this, it can be seen that different ratios of tannic acid/ca2+ show a remarkable effect on wound area healing and bacteriostatic rate, especially tannic acid/ca2+ ratio is 1:3, the antibacterial rate can reach about 90%, and the wound healing effect is more obvious.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. A chitosan healing promoting gel dressing, which is characterized by comprising the following components in parts by weight (100):
tannic acid, wherein the tannic acid is 5 parts by weight;
10-15 parts by weight of chitosan or a derivative thereof;
Ca 2+ ions, the tannic acid and the Ca 2+ The mass ratio of the ions is 1: (1-3);
the tannic acid is crosslinked with the chitosan or its derivative and with the Ca 2+ Ion chelationThe chitosan gel dressing for promoting healing is formed.
2. The chitosan healing-promoting gel dressing according to claim 1, wherein the tannic acid and the Ca 2+ The mass ratio of the ions is 1: 1. 1:2 or 1:3.
3. the chitosan healing promoting gel dressing according to claim 1, wherein the chitosan or the derivative thereof is selected from at least one of chitosan, quaternary ammonium salt chitosan or carboxymethyl chitosan.
4. The chitosan healing-promoting gel dressing according to claim 1, wherein the Ca 2+ The ions are calcium chloride solution.
5. The method for preparing the chitosan healing-promoting gel dressing according to any one of claims 1 to 4, which is characterized by comprising the following steps:
(1) Providing an acid solution of chitosan or a derivative thereof, wherein the acid solution of chitosan or a derivative thereof is obtained by dissolving the chitosan or a derivative thereof in the acid solution, the mass concentration of the chitosan or a derivative thereof in the acid solution of chitosan or a derivative thereof is 1-5%, and the pH value of the acid solution of chitosan or a derivative thereof is 5.0-6.0;
(2) Providing a tannic acid aqueous solution, wherein the tannic acid aqueous solution is obtained by dispersing tannic acid in deionized water, the mass concentration of tannic acid in the tannic acid aqueous solution is 1-5%, and the pH value of the tannic acid aqueous solution is 5.0-6.0;
(3) Dropwise adding the tannic acid aqueous solution into the acid solution of the chitosan or the derivative thereof, and stirring to perform a crosslinking reaction to obtain a crosslinking solution;
(4) Ca is added with 2+ Adding ions dropwise into the crosslinking solution to obtain a gel-like substance, centrifuging to remove supernatant, and dialyzing to remove the Ca 2+ Ions so as to obtain the chitosan healing promoting gel dressing.
6. The preparation method of claim 5, wherein the acid solution in the step (1) is an acetic acid solution, and the mass concentration of the acetic acid solution is 1-2%.
7. The method according to claim 5, wherein the time for the crosslinking reaction in the step (3) is 30 to 60 minutes.
8. The process according to claim 5, wherein the Ca in the step (4) 2+ The ions are calcium chloride aqueous solution, and the mass concentration of the calcium chloride aqueous solution is 1-5%.
9. The method according to claim 5, wherein the Ca is slowly added in the step (4) 2+ Ions, the Ca 2+ The rate of addition of the ions was 0.5mL/min, which resulted in a change in the color of the reaction solution from light brown to dark blue.
10. The use of the chitosan healing-promoting gel dressing according to any one of claims 1 to 4 in the preparation of antibacterial and antioxidant drugs for wound healing.
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