Degradable, asymmetric-adhesion and non-swelling Janus hydrogel adhesive as well as preparation method and application thereof

Abstract

The invention discloses a degradable, asymmetric-adhesion and non-swelling Janus hydrogel adhesive as well as a preparation method and application thereof, and belongs to the technical field of functional composite materials and preparation thereof. The problems that an existing Janus hydrogel cannot be degraded, is weak in adhesive force, adheres and is high in swelling are solved. Polyethylene glycol with double bonds, sodium alginate and chitosan are used for physical and covalent cross-linking, a degradable hydrogel substrate is constructed and then soaked in a phosphate buffer solution for swelling equilibrium, then a solution containing chitosan is used for preparing an adhesion coating, and the degradable and asymmetrically-adhered non-swelling Janus hydrogel adhesive is obtained. The adhesive can be applied to the biomedical fields of wound healing anti-adhesion, in-vivo degradability, intestinal repair and the like, and can also be used for adhesion of bioelectronics, epidermal physiological signal monitoring sensors, epidermal muscle fatigue monitoring sensors, rat subcutaneous muscle physiological signal monitoring sensors and muscle fatigue monitoring sensors.

Description

TECHNICAL FIELD

[0001] The present application relates to a degradable, asymmetric adhesion and non-swelling Janus hydrogel adhesive and its preparation method and application, and belongs to the field of functional composite materials and its preparation technology. BACKGROUND

[0002] The existing surgical suture promotes wound healing method has the problems of long suture consumption, easy to cause secondary bleeding and scar, secondary damage to the tissue, and postoperative adhesion. Therefore, various types of commercial tissue adhesives have been developed, such as cyanoacrylate and fibrin, but these adhesives generally have weak adhesion strength, poor adhesion fatigue stability, postoperative adhesion, and cannot be degraded, resulting in the need for secondary creation to remove them.

[0003] In recent years, people have explored the use of hydrogel adhesives for suturing wounds and hemostasis. Compared with skin wound healing, it is more challenging to develop hydrogel adhesives for repairing internal soft tissue defects due to the extremely complex in vivo environment. For example, the instability and poor adhesion fatigue resistance of hydrogels to tissues make it difficult to close wounds. In addition, the swelling of hydrogels weakens the adhesion stability. Moreover, the adhesion of hydrogels on both sides will cause adhesion of other tissues and organs to the wound, further weakening the adhesion stability and biocompatibility of hydrogels.

[0004] Asymmetric adhesion Janus hydrogel adhesives can prevent postoperative adhesion problems, but their high swelling ratio still weakens the adhesion stability, and cannot ensure that the hydrogel is firmly adhered to the wet dynamic tissue surface. In addition, Janus hydrogel adhesives only form physical or covalent cross-linking with the tissue surface, so that when the tissue deforms, stress is concentrated at the adhesion interface, leading to interface fracture and adhesion failure, further weakening the adhesion stability. At the same time, the non-degradability of Janus hydrogels makes it necessary to remove the hydrogel through secondary creation after wound healing, greatly increasing the risk of surgery. Therefore, it is necessary to provide a hydrogel adhesive with degradability, anti-fatigue adhesion, asymmetric adhesion, and non-swelling properties. SUMMARY

[0005] The present application provides a degradable, asymmetric adhesion and non-swelling Janus hydrogel adhesive to solve the problems of non-degradability, weak adhesion, adhesion and high swelling of existing Janus hydrogels.

[0006] The technical solution of the present application is as follows: One of the purposes of the present application is to provide a preparation method of a Janus hydrogel adhesive, which comprises the following steps: (1) dissolving polyethylene glycol containing double bond, sodium alginate, chitosan, alpha-ketoglutaric acid, polyethylene glycol diacrylate and calcium sulfate solution in 2-morpholinoethanesulfonic acid solution to obtain a mixed solution, treating the mixed solution by ultraviolet irradiation, then immersing the mixed solution in a phosphate buffer solution until swelling equilibrium is reached to obtain a hydrogel; (2) coating a 2-morpholinoethanesulfonic acid solution containing chitosan on the surface of the hydrogel to obtain a Janus hydrogel adhesive.

[0007] Further limitation, the content of polyethylene glycol containing double bond in the mixed solution of (1) is 0.2~1 wt. %, the content of sodium alginate is 1~2 wt. %, the content of chitosan is 0.2~1 wt. %, the content of alpha-ketoglutaric acid is 0.2~1 wt. %, the content of calcium sulfate solution is 0.1~1 mL / g, and the content of 2-morpholinoethanesulfonic acid solution is 95~98.4 wt. %.

[0008] Further limitation, the concentration of calcium sulfate solution in (1) is 8~10 wt. %, and the solvent is deionized water.

[0009] Further limitation, the pH of 2-morpholinoethanesulfonic acid solution in (1) is 5~6.

[0010] Further limitation, the wavelength of ultraviolet irradiation treatment in (1) is 365 nm, the power is 40~2000 W, and the time is 5~60 min.

[0011] Further limitation, the pH of the phosphate buffer solution in (1) is 6.8, and the swelling time is 2~4 d.

[0012] Further limitation, the preparation method of polyethylene glycol containing double bond in (1) is as follows: dry polyethylene glycol is placed in dichloromethane, stirred until the solution is clear, then triethylamine is added and stirred uniformly, acryloyl chloride is added, stirred at room temperature for 12 h, potassium carbonate is added and stirred for 2 h, filtered and dried, then precipitated with diethyl ether and freeze-dried to obtain polyethylene glycol containing double bond.

[0013] Further limitation, the amount ratio of polyethylene glycol, dichloromethane, triethylamine, acryloyl chloride, potassium carbonate and diethyl ether is 5~10 g:40~50 mL:0.1~1 mL:0.1~1 mL:1~4 g:50~100 mL. The molecular weight of polyethylene glycol is 10000~20000.

[0014] Further limitation, the coating amount of 2-morpholinoethanesulfonic acid solution containing chitosan on the surface of the hydrogel in (2) is 2~4 mL / 2~4 cm 2; Further limit, the concentration of chitosan in the 2-morpholinoethanesulfonic acid solution containing chitosan in (2) is 10-50 wt.

[0015] Further limit, the pH of the 2-morpholinoethanesulfonic acid solution in (2) is 5-6.

[0016] The second object of the present application is to provide a Janus hydrogel adhesive prepared by the above method, which has degradable, asymmetric adhesion and non-swelling properties.

[0017] The third object of the present application is to provide an application of the above Janus hydrogel adhesive, specifically for preparing wound healing anti-adhesion dressing and adhesive for intestinal wound repair.

[0018] Further limit, the above Janus hydrogel adhesive can also be used for the adhesion of bioelectronic, epidermal physiological signal monitoring sensors, epidermal muscle fatigue monitoring sensors, rat subcutaneous muscle physiological signal monitoring sensors, and muscle fatigue monitoring sensors.

[0019] Advantages: The present application utilizes polyethylene glycol with double bonds, sodium alginate and chitosan for physical and covalent crosslinking to construct a degradable hydrogel base, then swells and balances in a phosphate buffer solution, and then uses a 2-morpholinoethanesulfonic acid solution containing chitosan to prepare an adhesion coating to obtain a degradable, asymmetric adhesion, non-swelling Janus hydrogel adhesive. The adhesive uses degradable hydrogel as the base and chitosan solution as the adhesion layer to construct a bidirectional topological adhesion interface on the Janus hydrogel adhesive and the tissue side to achieve a tough and fatigue-resistant adhesion strength. At the same time, the side without the adhesion layer has no adhesion to the tissue, showing significant asymmetric adhesion properties. In addition, after the hydrogel is pre-swelled and balanced in vitro, it shows non-swelling properties in vivo. These excellent properties are expected to repair the wound tissue while avoiding postoperative adhesion, and do not need to be removed by secondary creation, and can be degraded in vivo. It can be applied to the fields of wound healing anti-adhesion, in vivo degradable and intestinal repair, and can also be used for the adhesion of bioelectronic, epidermal physiological signal monitoring sensors, epidermal muscle fatigue monitoring sensors, rat subcutaneous muscle physiological signal monitoring sensors, and muscle fatigue monitoring sensors. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The degradation test results of the Janus hydrogel adhesive prepared in Example 1 in vivo are shown in the figure; Figure 2 The adhesion strength comparison chart of the adhesives prepared in Example 1 and Comparative Examples 1-2 is shown in the figure; Figure 3 ​A comparison chart of the friction coefficient of the non-adhesion interface of the adhesive prepared for Example 1 and Comparative Examples 1-2 is shown in the following table: Figure 4 A comparison chart of the mechanical properties of the adhesive prepared for Example 1 and Comparative Example 3 is shown in the following table: Figure 5 A comparison chart of the swelling ratio of the hydrogel prepared for Example 1 and Comparative Example 3 in vivo is shown in the following table. DETAILED DESCRIPTION

[0021] In order to make the above objectives, features and advantages of the present application more apparent, the specific embodiments of the present application will be described in detail below with reference to the description and examples.

[0022] In the following description, a large number of specific details are set forth in order to facilitate a thorough understanding of the present application, but the present application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the spirit of the present application, therefore the present application is not limited to the specific examples disclosed below.

[0023] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0024] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained by commercial channels by those skilled in the art.

[0025] The average particle size of the hydrogenated dehydrogenated titanium powder, pre-alloyed powder, TiB2 powder, target Ti3Al, target TiAl and TiB2 powder used in the following examples and comparative examples is 2.5 μm Example 1 The method for preparing the degradable, asymmetric adhesive and non-swelling Janus hydrogel adhesive of the present embodiment comprises the following steps: Step one, preparation of double bond-containing polyethylene glycol: 5 g of polyethylene glycol (molecular weight 20,000) was dried in a vacuum oven at 100°C for 7 h. Then, it was taken out and cooled to room temperature, and 50 mL of dichloromethane was added to dissolve it into a clear solution. Then, 0.75 mL of triethylamine was added dropwise, followed by the dropwise addition of 0.66 mL of acryloyl chloride. The reaction was carried out in the dark for 12 h. After the reaction was completed, 2 g of potassium carbonate was added, and the mixture was stirred for 2 h. Then, the precipitate was filtered, and the precipitate was dried in an oven at 40°C. After complete drying, it was precipitated in ether, and then it was freeze-dried in a freeze dryer until the solvent was completely removed. Thus, a double-bond-containing polyethylene glycol was obtained.

[0026] Step 2. Preparation of a degradable hydrogel 0.2 g of the double-bond-containing polyethylene glycol prepared in Step 1, 0.4 g of sodium alginate, 0.2 g of chitosan, 0.2 g of α-ketoglutaric acid, 0.2 g of polyethylene glycol diacrylate (molecular weight 400-600), and 360 μL of a calcium sulfate solution (concentration 10 wt. % ) were dissolved in 35 g of a 2-morpholinoethanesulfonic acid solution (pH = 6) to obtain a clear solution. Then, the solution was cured under UV light (wavelength 365 nm, power 40 W) for 60 min to obtain a degradable hydrogel.

[0027] Step 3. Preparation of a non-swellable hydrogel The hydrogel obtained above was immersed in a phosphate buffer solution (pH 6.8) for 3 days until it reached a swelling equilibrium.

[0028] Step 4. Preparation of a chitosan solution as an adhesive layer 0.2 g of chitosan was dissolved in 4.8 g of a 2-morpholinoethanesulfonic acid solution (pH = 6) to obtain a chitosan-containing 2-morpholinoethanesulfonic acid solution.

[0029] Step 5. Preparation of a degradable, asymmetrically adhesive, and non-swellable Janus hydrogel adhesive 4 mL of the chitosan-containing 2-morpholinoethanesulfonic acid solution was uniformly coated on the surface of the hydrogel having an area of 4 cm 2 to obtain a degradable, asymmetrically adhesive, and non-swellable Janus hydrogel adhesive.

[0030] Comparative Example 1 This comparative example is a commercially available in vivo wound repair anti-adhesion patch of a polylactic acid type.

[0031] Comparative Example 2 This comparative example is a commercially available in vivo wound repair anti-adhesion patch of a polylactic acid type.

[0032] Comparative Example 3 This comparative example differs from Example 1 in that Step 3 was not performed, and the remaining process steps and parameters were the same as in Example 1.

[0033] Effect example: (1) The Janus hydrogel adhesive prepared in Example 1 with an initial mass of m0 was transplanted into the subcutaneous muscle of an adult male rat, and the mass m after 14 days of implantation was measured, and the degradation ratio of the Janus hydrogel adhesive in vivo was represented by m / m0. The test results are shown in Figure 1 , and it can be seen from the figure that the mass ratio decreases to 0.38 after 14 days of implantation in vivo, indicating that the Janus hydrogel adhesive has good degradability in vivo.

[0034] (2) The adhesion strength of the adhesive prepared in Example 1 and the adhesives provided in Comparative Examples 1-2 was characterized. The specific characterization method was: the adhesion strength was measured by lap shear test on an electronic universal testing machine. The sample size was 2 cm (width) and 4 cm (length). The lap area was 2 cm -2 . The adhesion strength was measured 1 h after lapping. The adhesion strength was calculated by dividing the force by the peel area. At least 4 samples were tested under each condition. The test results are shown in Figure 2 , and it can be seen from the figure that the adhesion strength of the Janus hydrogel adhesive prepared in Example 1 is much better than that of the adhesives provided in Comparative Examples 1 and 2. Specifically, the adhesion strength of Comparative Example 1 is 10 kPa, the adhesion strength of Comparative Example 2 is 5 kPa, and the adhesion strength of Example 1 is 105 kPa. This indicates that the hydrogel of Example 1 has a tough and stable adhesion strength.

[0035] (3) The friction coefficient of the adhesive prepared in Example 1 and the adhesives provided in Comparative Examples 1-2 was characterized. The friction force between the hydrogel and the tissue was determined by a friction coefficient tester. The test results are shown in Figure 3 , and it can be seen from the figure that the friction coefficient of the hydrogel of Example 1 is lower than that of the adhesives provided in Comparative Examples 1 and 2. Specifically, the friction coefficient of Comparative Example 1 is 0.15, the friction coefficient of Comparative Example 2 is 0.27, and the friction coefficient of Example 1 is 0.13. This indicates that the hydrogel adhesive can effectively prevent adhesion between wounds and other tissues.

[0036] (4) The mechanical properties of the adhesive prepared in Example 1 and the adhesives provided in Comparative Examples 1-2 were measured on an electronic universal testing machine. As shown in Figure 4 , the mechanical properties of Example 1 are much better than those of Comparative Examples 1 and 2, and the breaking strain of Example 1 is much higher than that of the two comparative examples (more than 15 times), indicating good flexibility. This indicates that the adhesive prepared in Example 1 can seal the damaged wound.

[0037] (5) The swelling rate of the hydrogels obtained in Example 1 and Comparative Example 3 was characterized by implanting a hydrogel with a length of 1 cm, a width of 1 cm, and a thickness of 1 mm into the subcutaneous muscle of a rat, collecting the size after immersion for different times, calculating the volume as V, the initial volume as V0, and the swelling rate as V / V0. The results are shown in Table 1. Figure 5 As can be seen from Table 1, Figure 5 the hydrogel obtained in Example 1 hardly swells in vivo and can be ignored, and the swelling rate of Comparative Example 3 reaches 7, indicating that the hydrogel obtained in Example 1 exhibits a non-swelling property.

[0038] The above merely describes preferred embodiments of the present application, and the above-mentioned embodiments can be appropriately changed and modified by those skilled in the art to which the present application belongs. Therefore, the present application is not limited to the above-mentioned specific embodiments, and some modifications and changes of the present application should fall within the protection scope of the claims of the present application.

Claims

1. A method for preparing a Janus hydrogel adhesive, characterized in that, include: (1) Dissolve polyethylene glycol containing double bonds, sodium alginate, chitosan, α-ketoglutarate, polyethylene glycol diacrylate and calcium sulfate solution in 2-morpholine ethanesulfonic acid solution to obtain a mixture. Treat the mixture with ultraviolet irradiation and then soak it in phosphate buffer solution until swelling equilibrium is reached to obtain hydrogel. (2) A 2-morpholinoethanesulfonic acid solution containing chitosan was coated on the surface of the hydrogel to obtain Janus hydrogel adhesive.

2. The preparation method according to claim 1, characterized in that, (1) The content of polyethylene glycol containing double bonds in the mixture is 0.2~1 wt. The content of sodium alginate is 1~2%. wt. The chitosan content is 0.2-1%. wt. The content of α-ketoglutaric acid is 0.2-1%. wt. The content of calcium sulfate solution is 0.1~1 mL / g, and the content of 2-morpholine ethanesulfonic acid solution is 95~98.4%. wt. %.

3. The preparation method according to claim 1, characterized in that, (1) The concentration of the calcium sulfate solution is 8~10. wt. The solvent is deionized water; the pH of the 2-morpholine ethanesulfonic acid solution is 5-6; the molecular weight of polyethylene glycol diacrylate is 400-600.

4. The preparation method according to claim 1, characterized in that, (1) The wavelength of the ultraviolet irradiation treatment is 365nm, the power is 40~2000W, and the time is 5~60min.

5. The preparation method according to claim 1, characterized in that, (1) The pH of the phosphate buffer solution is 6.8 and the swelling time is 2~4 days.

6. The preparation method according to claim 1, characterized in that, (1) The preparation method of polyethylene glycol containing double bonds is as follows: dry polyethylene glycol is placed in dichloromethane and stirred until the solution is clear. Then triethylamine is added and stirred evenly. Acryloyl chloride is added and stirred at room temperature for 12 hours. Potassium carbonate is added and stirred for 2 hours. After filtration and drying, diethyl ether is added to precipitate and freeze-dry. Then polyethylene glycol containing double bonds is obtained.

7. The preparation method according to claim 6, characterized in that, The ratio of polyethylene glycol, dichloromethane, triethylamine, acryloyl chloride, potassium carbonate, and diethyl ether is 5~10g: 40~50mL: 0.1~1mL: 0.1~1mL: 1~4g: 50~100mL; The molecular weight of polyethylene glycol is 10,000 to 20,000.

8. The preparation method according to claim 1, characterized in that, (2) The coating amount of the 2-morpholinoethanesulfonic acid solution containing chitosan on the hydrogel surface is 2~4 mL / 2~4 cm. 2 ; The chitosan concentration in the 2-morpholinoethanesulfonic acid solution containing chitosan is 10~50%. wt. %; the pH of 2-morpholine ethanesulfonic acid solution is 5~6.

9. A Janus hydrogel adhesive prepared by the method according to any one of claims 1 to 8, characterized in that, It is biodegradable, asymmetrically adhesive, and non-swellable.

10. An application of the Janus hydrogel adhesive according to claim 9, characterized in that, Adhesives for preparing wound healing anti-adhesion dressings and intestinal trauma repair, as well as adhesives for physiological signal monitoring sensors.

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