CN115970040B - Hydrogel application capable of bonding wet surface and facilitating replacement and repair and preparation method thereof - Google Patents

Abstract

The present invention belongs to the field of wound dressing, and specifically relates to a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, and a preparation method thereof. The method provided by the present invention is to prepare an adhesive hydrogel by a rapid reaction of a polymer containing an amino group, phenylboronic acid containing an aldehyde group, and a compound containing multiple phthalic dihydroxy structures through a Schiff base and a phenylboronic acid bond. The hydrogel can effectively adhere to the wound without a large area of bandage; and the boric acid bond in the hydrogel can react quickly with glucose, so that the hydrogel can be quickly debonded, reducing the time for changing the dressing, and achieving painless replacement, thereby reducing medical expenses.

Description

Hydrogel patch capable of adhering to wet surface and being easily replaced to promote repair and preparation method thereof

Technical Field

The invention belongs to the field of burn wound dressings, and in particular relates to a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, and a preparation method thereof.

Background technique

According to statistics from the World Health Organization (WHO), millions of people are affected by burns every year, and about 200,000 people die from burns. Burns have become an important public health issue worldwide due to their high morbidity and mortality. Burns are injuries to the skin or other organ tissues caused mainly by heat, radiation, radioactivity, electricity, friction or contact with chemicals. Thermal (high temperature) burns occur when some or all cells of the skin or other tissues are damaged by the following: hot liquid burns, hot solid burns and flame burns. However, burn wounds are difficult to heal. In terms of treating burns, depending on the size and degree of the burn, its healing usually takes a long time, ranging from a few days to several months, so frequent dressing changes are required. Commonly used dressings are easy to adhere to wound tissues, and when replaced, they will tear the wound and cause secondary damage, causing pain to the patient, and causing re-destruction of part of the wound, which is not conducive to the recovery of the wound. At the same time, replacing a dressing that is firmly bonded to the wound requires professional skills and experience. Medical staff, it takes a lot of time.

There are also many burn dressings on the market, but these dressings usually adopt dry wound treatment methods, using fiber dressings to cover the wound surface. This is a semi-closed dressing that requires additional adhesive tape, requires a large area of bandage, is not easy to replace, and has poor usability for specific parts such as the groin and face, and is not suitable for wounds with large areas of bandage. For dry wound treatment methods, their barrier effect on microorganisms in the external environment is relatively poor, and the wound infection rate in clinical applications is relatively high, exceeding 10%. In addition, dry wound treatment methods have a weak effect on promoting wound healing, limited exudate management capabilities, and excessive evaporation of wound exudate can easily cause dry scabs. Therefore, when changing wound dressings, secondary mechanical damage will occur, which is not conducive to wound healing.

The water content of hydrogel can be as high as 90%, which is a biological material that is perfectly similar to the skin. And hydrogel has a wide range of applications in the field of dressings due to its inherent transparency, flexibility and biocompatibility. Hydrogel has the inherent characteristics of closed dressings, and has a barrier effect on microorganisms in the external environment, which can greatly reduce the infection rate of wounds. Hydrogel can not only provide protection for wounds and avoid external damage, but also hydrogel is rich in water and can absorb tissue fluid to provide a moist environment for dry wounds, which is conducive to cell proliferation, differentiation and migration, and accelerates wound healing.

Commercial hydrogel dressings in the prior art, such as 3M hydrogel dressings, are soft, transparent, have good elasticity, toughness, closure, high skin adhesion and rarely cause allergies. Hydrogel dressings are usually composed of natural polymer absorbent components (such as carboxymethyl cellulose, chitosan, pectin, gelatin and alginate). Although most existing dressings can effectively cover the wound surface, they usually do not contain surface strong adhesive groups, so the adhesion to the wet surface is poor, and they are not suitable for single use. They still need additional adhesive tape to fix the dressing to make the dressing fit tightly to the wound surface, reduce the risk of infection, and ensure that the dressing does not fall off. Moreover, when the dressing is replaced, it is still difficult to fall off, the replacement time is long, and secondary damage to the wound is caused. Most of the existing dressings do not have sufficient wet adhesion. Therefore, it is of great significance to develop a hydrogel dressing that can adhere to the wet wound surface and is easy to replace. Designing a dressing that can reduce adhesion to the wound when external stimulation is applied so as to reduce secondary damage to the wound when replaced is a way to solve this demand.

Summary of the invention

In view of the above technical problems, the present invention provides a hydrogel dressing that can adhere to wet surfaces and is easy to replace and promote repair, and a preparation method thereof. The adhesive hydrogel is prepared by rapid reaction of a polymer containing an amino group, phenylboronic acid containing an aldehyde group, and a compound containing multiple phthalic dihydroxy structures through Schiff base and phenylboronic acid bonds. The hydrogel can effectively adhere to the wound without large-area bandaging; and the boric acid bonds in the hydrogel can react quickly with glucose, so that the hydrogel can be quickly debonded, reducing the time for changing the dressing, achieving painless replacement, and reducing medical expenses.

The present invention is achieved through the following technical solutions:

A method for preparing a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, comprising the following steps:

(1) reacting a polymer containing an amino group with phenylboronic acid containing an aldehyde group via a Schiff base to obtain a polymer containing a boronic acid group;

(2) dissolving the polymer containing boronic acid groups prepared in step (1) in water at a certain temperature to prepare a polymer solution;

(3) adding a compound containing a phthalic acid dihydroxy structural group to the solution obtained in step (2), and rapidly stirring and mixing the mixture to obtain a uniform mixture; wherein the compound containing a phthalic acid dihydroxy structural group comprises n phthalic acid dihydroxy structural groups, and n≥2;

(4) using a coating machine, uniformly coating the solution obtained in step (3) onto the base film, and lowering the temperature to room temperature; reacting the polymer containing the boronic acid group with m phthalic acid dihydroxy groups in the compound containing n phthalic acid dihydroxy groups, m < n, for a certain reaction time to obtain a hydrogel containing both borate ester bonds and free unreacted phthalic acid dihydroxy groups;

(5) The surface of the hydrogel obtained in step (4) is covered with a protective layer and cut into pieces according to required sizes to obtain an easily replaceable and repair-promoting hydrogel patch with adhesive properties.

Furthermore, in step (1), the polymer containing amino groups includes one or more of polyacrylamide, chitosan, polyasparagine, polyacetimide, and polylysine;

The aldehyde-containing phenylboronic acid is one or more of 3-fluoro-4-aldehyde phenylboronic acid, 4-fluoro-3-aldehyde phenylboronic acid and 4-aldehyde phenylboronic acid.

Furthermore, in step (1), the molar ratio of the amino-containing polymer to the aldehyde-containing phenylboronic acid is (5-10):1; the reaction temperature of the Schiff base reaction is 40-60°C, and the reaction time is 3-6h.

Furthermore, step (2) further comprises adding a wound healing promoting drug component to the polymer solution and mixing and dispersing the mixture uniformly;

The mass percentage of the wound healing promoting drug added to the polymer solution is 0.5%-1%;

Calculated by mass ratio, the added wound healing promoting drug ingredients include: 15-30 parts of rhizoma yunnanensis, 12-25 parts of safflower, 5-15 parts of phellodendron amurense, 6-18 parts of gardenia jasminoides and 3-25 parts of borneol.

Furthermore, in step (3), the molar ratio of the compound containing phthalic acid structural groups to the boric acid group in the polymer containing boronic acid groups is (2-4):1; the excess phthalic acid-containing compound is added to ensure that there are surplus unreacted phthalic acid units.

The temperature conditions in step (2) and step (3) are 50-60 degrees;

The compound containing the o-phthalic acid dihydroxy structural group is one or more of caffeic acid dopamine, 1,2,3,4,6-O-pentagalloyl glucose, ellagic acid, 3,3′-digallate theaflavins, and proanthocyanidin B2-3,3′-di-O-gallate.

Furthermore, the reaction time in step (4) is 1-5h.

Furthermore, when the hydrogel patch is replaced, a glucose solution of a certain concentration is applied to the hydrogel patch, and the borate bonds in the hydrogel patch react rapidly with the glucose to destroy the borate bonds, causing the compound containing the o-phthalic dihydroxy structural group with adhesion to detach from the hydrogel, thereby causing the hydrogel patch to fall off.

Furthermore, the concentration of the glucose solution is 15mmol/L-50mmol/L; when the hydrogel patch is replaced, the reaction time between the hydrogel and the glucose solution is 2-10min. The normal blood glucose concentration is 6-8mmol/L, which is not enough to destroy the boric acid bond and cause the patch to fall off. However, the concentration of the glucose solution is higher than 50mmol/L, which will affect the repair of the wound. Therefore, the concentration of the glucose solution selected is 15mmol/L-50mmol/L.

A hydrogel patch that can adhere to a wet surface and is easy to replace to promote repair, the hydrogel patch being prepared by the method, the hydrogel patch containing both borate bonds and free unreacted phthalic acid dihydroxy structural groups;

The unreacted phthalic acid dihydroxy structural groups in the hydrogel dressing make the hydrogel have strong adhesion under wet conditions, so that the hydrogel dressing can effectively fit the wet wound;

The borate bonds in the hydrogel dressing can react with glucose, causing the hydrogel dressing to fall off the wound.

Furthermore, the hydrogel dressing is used for difficult-to-heal wounds that are not suitable for large-area bandaging and require frequent dressing changes, including bandaging wounds in the groin and face.

Beneficial technical effects of the present invention:

1) The unreacted phthalic dihydroxy structural groups in the hydrogel dressing provided by the present invention make the hydrogel have strong adhesion under wet conditions, which enhances the adhesion of the hydrogel to the wet wound, so that the hydrogel dressing can effectively fit the wet wound and can be effectively adhered to the wound surface without the need to use additional auxiliary materials such as tape for fixing and bandaging. In addition, the tightly fitting hydrogel dressing can greatly reduce the chance of wound infection.

2) The hydrogel dressing provided by the present invention not only has enhanced wet wound adhesion, but the borate bonds in the hydrogel dressing can react with glucose, so that the hydrogel can be quickly detached from the wound. When changing the dressing, the patient's pain can be relieved, secondary damage to the wound can be avoided, the time for changing the dressing can be shortened, and the replacement can be achieved painlessly, thereby reducing medical expenses.

3) The hydrogel dressing prepared by the method of the present invention has a three-dimensional network structure, stable performance, similar to skin, contains a large amount of water, can provide a moist environment for dry burns, achieve a moist therapy effect, and is loaded with wound healing drugs, thereby promoting the rapid and effective healing of the wound surface.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a reaction mechanism of a rapid de-adhesion hydrogel dressing according to an embodiment of the present invention;

Figures 2a-d are actual pictures of the hydrogel patch of the present invention adhered to pig skin;

3a-c are the viscosity test and mechanical property changes of the rapid de-adhesion hydrogel dressing of the present invention.

Detailed ways

In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the specific implementation mode, structure, characteristics and effects of the present invention are described in detail below in combination with the accompanying drawings and preferred embodiments.

Example 1

This embodiment provides a method for preparing a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, comprising the following steps:

(1) Polyacrylamide containing amino groups is dissolved in water, and then 3-fluoro-4-formylphenylboronic acid is added, the molar ratio of polyacrylamide to 3-fluoro-4-formylphenylboronic acid is 10:1, the mixture is fully stirred, and the mixture is reacted at 40° C. for 5 hours, thereby obtaining a polymer containing boric acid.

(2) dissolving the prepared polymer containing boronic acid groups in water at a certain temperature to prepare a polymer solution; adding a wound healing drug to the polymer solution, wherein the mass percentage of the wound healing drug in the polymer solution is 0.4%; the components of the added wound healing drug include, by mass ratio, 15 parts of Rhizoma Cibotii, 12 parts of Carthamus tinctorius, 5 parts of Phellodendron amurense, 18 parts of Gardenia jasminoides and 3-25 parts of Borneol.

(3) adding caffeic acid dopamine to the solution obtained in step (2), wherein the molar ratio of the added caffeic acid dopamine to the boric acid group in the boric acid group-containing polymer is 2:1; stirring thoroughly;

(4) Using a coating machine, evenly coat the solution obtained in step (3) onto the base film, and lower the temperature to room temperature; react for 1-5 hours to obtain a hydrogel patch containing both borate ester bonds and free unreacted phthalic acid dihydroxy structural groups.

The hydrogel patch was applied on pig skin, and then a glucose solution with a concentration of 15 mmol/L was added to the surface of the patch and reacted for 10 minutes. The adhered hydrogel and pig skin were easily separated.

Example 2

This embodiment provides a method for preparing a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, comprising the following steps:

(1) Chitosan containing amino groups is dissolved in water, and then 4-formylphenylboronic acid is added, the molar ratio of chitosan to 4-formylphenylboronic acid is 5:1, the mixture is fully stirred, and the mixture is reacted at 40° C. for 5 h, thereby obtaining a polymer containing boric acid.

(2) dissolving the prepared polymer containing boronic acid groups in water at a certain temperature to prepare a polymer solution; adding a wound healing drug to the polymer solution, wherein the mass percentage of the wound healing drug in the polymer solution is 0.4%; in terms of mass ratio, the added wound healing drug comprises: 5 parts of Rhizoma Cibotii, 25 parts of Carthamus tinctorius, 7 parts of Phellodendron amurense, 12 parts of Gardenia jasminoides and 7 parts of Borneol.

(3) adding ellagic acid to the solution obtained in step (2), wherein the molar ratio of the added ellagic acid to the boric acid group in the polymer containing the boric acid group is 3:1; stirring thoroughly;

(4) Using a coating machine, evenly coat the solution obtained in step (3) onto the base film, and lower the temperature to room temperature; react for 1-5 hours to obtain a hydrogel patch containing both borate ester bonds and free unreacted phthalic acid dihydroxy structural groups.

The hydrogel patch was applied on pig skin, and then a glucose solution with a concentration of 15 mmol/L was added to the surface of the patch and reacted for 40 minutes. The adhered hydrogel and pig skin were easily separated.

Example 3

This embodiment provides a method for preparing a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, comprising the following steps:

(1) Polyacrylamide containing amino groups is dissolved in water, and then 3-fluoro-4-formylphenylboronic acid is added, the molar ratio of polyacrylamide to 3-fluoro-4-formylphenylboronic acid is 10:1, the mixture is fully stirred, and the mixture is reacted at 40° C. for 5 hours, thereby obtaining a polymer containing boric acid.

(2) dissolving the prepared polymer containing boronic acid groups in water at a certain temperature to prepare a polymer solution; adding a wound healing drug to the polymer solution, wherein the mass percentage of the wound healing drug in the polymer solution is 1%; and the components of the wound healing drug added include, by mass ratio, 15 parts of Rhizoma Cibotii, 12 parts of Carthamus tinctorius, 10 parts of Phellodendron amurense, 6 parts of Gardenia jasminoides and 3 parts of Borneol.

(3) adding 3,3′-digallate theaflavins to the solution obtained in step (2), wherein the molar ratio of the added 3,3′-digallate theaflavins to the boric acid group in the boric acid group-containing polymer is 4:1; stirring thoroughly;

(4) Using a coating machine, evenly coat the solution obtained in step (3) onto the base film, and lower the temperature to room temperature; react for 1-5 hours to obtain a hydrogel patch containing both borate ester bonds and free unreacted phthalic acid dihydroxy structural groups.

The hydrogel was applied to pig skin, and then a glucose solution with a concentration of 50 mmol/L was added to the surface and reacted for 2 minutes. The adhered hydrogel was easily separated from the pig skin.

Example 4

This embodiment provides a method for preparing a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, comprising the following steps:

(1) Polyasparagine containing amino groups is dissolved in water, and then 4-formylphenylboric acid is added, the molar ratio of polyasparagine to 4-formylphenylboric acid is 8:1, the mixture is fully stirred, and the mixture is reacted at 50° C. for 6 hours to obtain a polymer containing boric acid.

(2) dissolving the prepared polymer containing boronic acid groups in water at a certain temperature to prepare a polymer solution; adding a wound healing drug to the polymer solution, wherein the mass percentage of the wound healing drug in the polymer solution is 1%; and the components of the added wound healing drug include, by mass ratio, 20 parts of Rhizoma Cibotii, 18 parts of Carthamus tinctorius, 8 parts of Phellodendron amurense, 14 parts of Gardenia jasminoides, and 20 parts of Borneol.

(3) adding proanthocyanidin B2-3,3′-di-O-gallate to the solution obtained in step (2), wherein the molar ratio of the proanthocyanidin B2-3,3′-di-O-gallate to the boric acid group in the boric acid group-containing polymer is 3:1; stirring thoroughly;

(4) Using a coating machine, evenly coat the solution obtained in step (3) onto the base film, and lower the temperature to room temperature; react for 1-5 hours to obtain a hydrogel patch containing both borate ester bonds and free unreacted phthalic acid dihydroxy structural groups.

The hydrogel was applied to pig skin, and then a glucose solution with a concentration of 30 mmol/L was added to the surface and reacted for 10 minutes. The adhered hydrogel was easily separated from the pig skin.

As shown in FIG1 , the reaction mechanism of the fast de-adhesive hydrogel in an embodiment of the present invention is as follows: an amino-containing polymer, an aldehyde-containing phenylboronic acid, and a compound containing multiple phthalic acid dihydroxy structures are rapidly reacted through a Schiff base and a phenylboronic acid ester bond to prepare an adhesive hydrogel. The phthalic acid dihydroxy structure groups in the hydrogel dressing give the hydrogel a strong adhesion under wet conditions, so that the hydrogel dressing can effectively fit a wet wound.

The borate bonds in the hydrogel can react quickly with glucose, causing the hydrogel to debond quickly, reducing the time for changing the dressing, achieving painless replacement, and reducing medical costs.

Figures 2a-d are actual pictures of the hydrogel of the present invention adhered to pig skin. It can be seen that the hydrogel patch can effectively adhere to the pig skin and does not fall off when changing different angles (Figures 2a-c), and it is not easy to fall off when adhered to the wound of the mouse (Figure 2d).

Figures 3a-c show the viscosity test and mechanical property changes of the fast de-adhesive hydrogel of the present invention. The hydrogel adheres to pig skin and undergoes a peeling test (Figure 3a); during peeling, the hydrogel easily falls off the pig skin after adding 15mmol/L glucose solution (Figure 3b); Figure 3c shows the change in adhesion before and after adding glucose solution.

The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims (6)

1. A method for preparing a hydrogel dressing that can adhere to a wet surface and is easy to replace and promotes repair, characterized in that it comprises the following steps: (1) reacting a polymer containing an amino group with phenylboronic acid containing an aldehyde group via a Schiff base to obtain a polymer containing a boronic acid group; (2) dissolving the polymer containing boronic acid groups prepared in step (1) in water at a certain temperature to prepare a polymer solution; (3) adding a compound containing a phthalic acid dihydroxy structural group to the solution obtained in step (2), and rapidly stirring and mixing the mixture to obtain a uniform mixture; wherein the compound containing a phthalic acid dihydroxy structural group comprises n phthalic acid dihydroxy structural groups, and n≥2; (4) using a coating machine, uniformly coating the solution obtained in step (3) onto the base film, and lowering the temperature to room temperature; reacting the polymer containing the boronic acid group with m phthalic acid dihydroxy groups in the compound containing n phthalic acid dihydroxy groups, m < n, for a certain reaction time to obtain a hydrogel containing both borate ester bonds and free unreacted phthalic acid dihydroxy groups; (5) Covering the surface of the hydrogel obtained in step (4) with a protective layer, and cutting it into pieces according to the required size to obtain an easily replaceable and repair-promoting hydrogel patch with adhesive properties; In step (1), the polymer containing amino group includes one or more of polyacrylamide, chitosan, polyasparagine, polyacetimide, and polylysine; the phenylboronic acid containing aldehyde group includes one or more of 3-fluoro-4-aldehyde phenylboronic acid, 4-fluoro-3-aldehyde phenylboronic acid, and 4-aldehyde phenylboronic acid; In step (1), the molar ratio of the polymer containing amino group to the phenylboronic acid containing aldehyde group is (5-10):1; the reaction temperature of the Schiff base reaction is 40-60°C, and the reaction time is 3-6h; In step (3), the molar ratio of the compound containing the o-phthalic acid dihydroxy structural group to the boric acid group in the polymer containing the boric acid group is (2-4):1; The temperature conditions in step (2) and step (3) are 50-60 degrees; The compound containing the o-phthalic acid dihydroxy structural group is one or more of caffeic acid dopamine, 1,2,3,4,6-O-pentagalloyl glucose, ellagic acid, 3,3′-digallate theaflavins, and proanthocyanidin B2-3,3′-di-O-gallate; When the hydrogel patch is replaced, a glucose solution of a certain concentration is applied to the hydrogel patch, and the borate bonds in the hydrogel patch react rapidly with the glucose to destroy the borate bonds, causing the compounds containing phthalic acid dihydroxy structural groups with adhesion to detach from the hydrogel, thereby causing the hydrogel patch to fall off, wherein the concentration of the glucose solution is 15 mmol/L. 2. The method for preparing the hydrogel patch that can adhere to wet surfaces and is easy to replace and promotes repair according to claim 1, characterized in that step (2) also includes adding a wound healing promoting drug component to the polymer solution and mixing and dispersing the mixture evenly; The mass percentage of the wound healing promoting drug added to the polymer solution is 0.5%-1%; Calculated by mass ratio, the added wound healing promoting drug ingredients include: 15-30 parts of rhizoma yunnanensis, 12-25 parts of safflower, 5-15 parts of phellodendron amurense, 6-18 parts of gardenia jasminoides and 3-25 parts of borneol. 3. A method for preparing a hydrogel dressing that can adhere to wet surfaces and is easy to replace and promotes repair according to claim 1, characterized in that the reaction time in step (4) is 1-5 hours. 4. A method for preparing a hydrogel patch that can adhere to a wet surface and is easy to replace and promotes repair according to claim 1, characterized in that when replacing the hydrogel patch, the reaction time between the hydrogel and the glucose solution is 2-10 minutes. 5. A hydrogel patch that can adhere to wet surfaces and is easy to replace to promote repair, characterized in that the hydrogel patch is prepared by the method according to any one of claims 1 to 4, characterized in that the hydrogel patch contains both borate ester bonds and free unreacted phthalic dihydroxy structural groups; The unreacted phthalic acid dihydroxy structural groups in the hydrogel dressing make the hydrogel have strong adhesion under wet conditions, so that the hydrogel dressing can effectively fit the wet wound; The borate bonds in the hydrogel dressing can react with glucose, causing the hydrogel dressing to fall off the wound. 6. According to claim 5, a hydrogel dressing that can adhere to wet surfaces and is easy to replace to promote repair is characterized in that the hydrogel dressing is used for difficult-to-heal wounds that are not suitable for large-area bandaging and require frequent dressing changes, including bandaging wounds in the groin and face.