Preparation method of degradable wet tissue antibacterial biological adhesive

Abstract

The invention belongs to the field of biological medicine tissue engineering, and provides a preparation method of a degradable wet tissue antibacterial biological adhesive. The antibacterial biological adhesive capable of degrading the wet tissues is prepared by taking citric acid, 1, 8-octylene glycol and epsilon-caprolactone as main raw materials through one-pot melt polycondensation and refining; the prepared product has the characteristics of strong wet tissue adhesion, biodegradability and antibacterial property. The raw materials required by the preparation method are easy to obtain, the preparation method is simple and easy to operate, and the reaction conditions are mild; no organic solvent is used in the preparation process, so that no pollution is caused; and the method has wide application potential.

Description

Technical Field

[0001] The invention belongs to the field of biomedical tissue engineering, and in particular relates to a method for preparing a degradable wet tissue antibacterial biological adhesive. Background Art

[0002] Bioadhesives are biomedical materials used to prevent tissue adhesion, stop bleeding, and prevent air and body fluid leakage during surgery. By reducing the use of auxiliary materials such as sutures and medical gauze, they have advanced surgical effects in facilitating surgical operations, improving patient compliance, and reducing medical costs.

[0003] Medical polymer hydrogel adhesives are soft and wet materials similar to soft tissues formed by physical or chemical crosslinking of hydrophilic molecules. They have great potential in soft tissue repair and replacement, but they have the problems of weak tissue adhesion and complex functional regulation. In addition, existing surgical adhesives are not suitable for wet tissue adhesion required for many surgeries (such as visceral organ surgery). Developing surgical adhesives with strong wet tissue adhesion, controllable degradability, antibacterial properties, mechanical properties, and excellent biocompatibility has always been a major challenge. Summary of the invention

[0004] In order to solve the problems of weak tissue adhesion, lack of wet tissue adhesion, non-biodegradability, and susceptibility to infection existing in the above-mentioned biological tissue adhesive, the present invention provides a method for preparing a degradable wet tissue antibacterial biological adhesive.

[0005] The method for preparing the degradable wet tissue antibacterial bioadhesive provided by the present invention comprises the following steps:

[0006] Step 1) melt-polycondensing citric acid, 1,8-octanediol, ε-caprolactone, a ring-opening catalyst, stannous octoate, and an initiator until a molten transparent mixture is formed;

[0007] Step 2) cooling the transparent mixture formed in step 1) and continuing the reaction until it becomes gel-like, thereby obtaining a crude adhesive product;

[0008] Step 3) dissolving the crude product obtained in step 2) with ultrapure water, precipitating, discarding the supernatant, repeating the operation for more than 3 times, and freeze-drying to a constant weight to obtain a degradable wet tissue antibacterial bioadhesive;

[0009] The ε-caprolactone initiator is 1,4-butanediol or n-butanol;

[0010] The molar ratio of the ε-caprolactone to citric acid is 1:1-2; the molar ratio of the citric acid to 1,8-octanediol is 1:1; the molar ratio of the ε-caprolactone to stannous octoate is 15000:1, and the molar ratio to the initiator is 20:1.

[0011] Preferably, in step 1) of the above preparation method, the melt polycondensation process is to first heat the reactants to 160° C., maintain the reaction temperature unchanged and stir until the reactants reach a molten transparent state.

[0012] Preferably, in step 2) of the above preparation method, the process of cooling and continuing the reaction is to first cool to 140° C. and then continue the reaction for 7 to 10 hours.

[0013] The invention uses citric acid, 1,8-octanediol and ε-caprolactone as main raw materials, adds stannous octoate as an ε-caprolactone ring-opening catalyst and 1,4-butanediol or n-butanol as an initiator, performs one-pot melt polycondensation, obtains a crude product by regulating reaction temperature, reaction time and stirring operation, repeatedly dissolves and precipitates the obtained crude product with ultrapure water, and then dries to constant weight to obtain a degradable wet tissue antibacterial bioadhesive.

[0014] The degradable wet tissue antibacterial biological adhesive of the present invention is an adhesive system composed of a polyester matrix composed of hydrophilic citric acid and 1,8-octanediol and hydrophobic ε-caprolactone, wherein the hydrophobic block can enhance the adhesion to the contact surface through its hydrophobic effect, which is beneficial to the cohesion between adhesive proteins; the introduction of the hydrophilic segment into the hydrophobic segment can give the adhesive good wettability, help the diffusion of the adhesive, and promote more uniform cross-linking; optionally, the monomer molar ratio of citric acid, 1,8-octanediol and ε-caprolactone is appropriately changed to obtain an adhesive with the required cross-linking degree, mechanical strength and degradation rate.

[0015] The preparation method provided in the present invention has the following advantages:

[0016] The raw materials required for the preparation of the degradable wet tissue antibacterial bioadhesive are all inexpensive, non-toxic, and easy to obtain; the preparation operation steps are simple and easy, and the reaction conditions are mild; the product refining process does not use any organic solvents and is pollution-free. Since citric acid with inherent antibacterial properties is used as the synthetic raw material, the final synthesized wet tissue bioadhesive has good biocompatibility, controllable degradability, and antibacterial properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 A real digital photo of the degradable wet tissue antibacterial bioadhesive prepared in Example 1 of the present invention is shown;

[0018] Figure 2 The nuclear magnetic resonance hydrogen spectrum of the degradable wet tissue antibacterial bioadhesive prepared in Example 1 of the present invention is shown;

[0019] Figure 3 The Fourier transform infrared spectrum of the degradable wet tissue antibacterial bioadhesive prepared in Example 1 of the present invention is shown;

[0020] Figure 4 The DSC curve of the degradable wet tissue antibacterial bioadhesive prepared in Example 1 of the present invention is shown;

[0021] Figure 5 The rheology of the degradable wet tissue antibacterial bioadhesive prepared in Example 1 of the present invention is shown. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0023] Example 1

[0024] In a glove box, citric acid, 1,8-octanediol and ε-caprolactone in a molar ratio of 1:1:1, and stannous octoate and 1,4-butanediol in molar ratios of 15000:1 and 1:20 to ε-caprolactone, respectively, were added to a clean and dried three-necked round-bottom flask, nitrogen was introduced for protection, the temperature was raised to 160°C, and the mixture was stirred until a molten transparent mixture was formed. The temperature was lowered to 140°C, and the reaction was continued for 7 hours to obtain a crude adhesive product; the crude product was dissolved in ultrapure water, precipitated, and the supernatant was discarded, and the operation was repeated for more than 3 times; and the finished degradable wet tissue antibacterial bioadhesive was obtained after freeze-drying to constant weight.

[0025] Example 2

[0026] In this example, the initiator 1,4-butanediol in Example 1 was replaced by n-butanol, and other conditions remained unchanged.

[0027] Other embodiments can be obtained by adjusting the reaction time of step 2) in claim 1; the preparation process is consistent with that of embodiment 1, and the properties of the obtained final product are similar to those of embodiment 1, which will not be repeated here.

[0028] Experimental example

[0029] This experimental example is used to verify whether the properties of the finished degradable wet tissue antibacterial bioadhesive prepared in Example 1 achieve the expected effects.

[0030] 1) Nuclear magnetic resonance hydrogen spectrum analysis

[0031] Take an appropriate amount of the finished adhesive prepared in Example 1 to the bottom of the nuclear magnetic resonance tube, pour deuterated chloroform (CDCl3) into it to dissolve it, and it can be used to obtain the nuclear magnetic resonance hydrogen spectrum of the degradable wet tissue biological antibacterial adhesive to analyze the hydrogen peak area of ​​each chemical position in the product; its nuclear magnetic resonance hydrogen spectrum is as follows Figure 2 As shown, the successful preparation of degradable wet tissue antibacterial bioadhesive was demonstrated.

[0032] 2) Infrared spectroscopy analysis

[0033] The degradable wet tissue antibacterial bioadhesive product prepared in Example 1 was flatly coated on a potassium bromide tablet and subjected to Fourier transform infrared spectroscopy testing at a wavelength range of 4000 to 400 cm -1 Its infrared spectrum is as follows Figure 3 As shown, the adhesive has ~1750, ~2960, ~2850 and ~3660 cm -1 The characteristic peaks at are assigned to carbonyl (C=C), methylene (CH2-C), (CH2-O) and hydroxyl (-OH) groups, respectively.

[0034] 3) Thermal performance analysis

[0035] The thermal properties of the adhesive product prepared in Example 1 were tested using a DSC tester at a temperature range of -30 to 200°C, a nitrogen atmosphere, and a heating rate of 10°C / min. The test results are as follows: Figure 4 As shown, the glass transition temperature of the degradable wet tissue antibacterial bioadhesive is 37.1°C, which is close to the human body temperature.

[0036] 4) Rheological properties test

[0037] The dynamic rheological properties of the adhesives were studied using a rotational rheometer, including complex viscosity η*, storage modulus G', loss modulus G", etc. Figure 5 The graphs showing the variation of G', G" and η* of the prepared adhesive with frequency show that the storage modulus G' and loss modulus G" of the adhesive are comparable, proving that the adhesive is in a semi-solid state, i.e., a gel state.

[0038] The degradable wet tissue antibacterial biological adhesive of the present invention is an adhesive system composed of a polyester matrix composed of hydrophilic citric acid and 1,8-octanediol and hydrophobic ε-caprolactone, wherein the hydrophobic block can enhance the adhesion to the contact surface through its hydrophobic effect, which is beneficial to the cohesion between adhesive proteins; the introduction of the hydrophilic segment into the hydrophobic segment can give the adhesive good wettability, help the diffusion of the adhesive, and promote more uniform cross-linking. Therefore, the monomer molar ratio of citric acid, 1,8-octanediol and caprolactone can be appropriately changed to obtain an adhesive with the required cross-linking degree, mechanical strength and degradation rate.

[0039] The specific implementation methods described above provide a detailed description of the present invention. However, these implementation method descriptions should not be understood as limitations of the present invention. Any modifications, replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a degradable wet tissue antibacterial bioadhesive, characterized in that: The preparation method comprises the following steps: Step 1) melt-polycondensing citric acid, 1,8-octanediol, ε-caprolactone, a ring-opening catalyst, stannous octoate, and an initiator until a molten transparent mixture is formed; Step 2) cooling the transparent mixture formed in step 1) and continuing the reaction until it becomes gel-like, thereby obtaining a crude adhesive product; Step 3) dissolving the crude product obtained in step 2) with ultrapure water, precipitating, discarding the supernatant, repeating the operation for more than 3 times, and freeze-drying to a constant weight to obtain a degradable wet tissue antibacterial bioadhesive; The ε-caprolactone initiator is 1,4-butanediol or n-butanol; The molar ratio of the ε-caprolactone to citric acid is 1:1-2; the molar ratio of the citric acid to 1,8-octanediol is 1:1; the molar ratio of the ε-caprolactone to stannous octoate is 15000:1, and the molar ratio to the initiator is 20:

1.

2. The method for preparing the degradable wet tissue antibacterial bioadhesive according to claim 1, characterized in that: In step 1), the melt polycondensation process is to first heat the reactants to 160° C., maintain the reaction temperature unchanged and stir until the reactants reach a molten transparent state.

3. The method for preparing the degradable wet tissue antibacterial bioadhesive according to claim 1, characterized in that: In step 2), the process of cooling and continuing the reaction is to first cool to 140° C. and then continue the reaction for 7 to 10 hours.

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