Chitosan / polyurethane biological tissue adhesive and preparation method thereof

Abstract

The invention discloses a chitosan / polyurethane biological tissue adhesive and a preparation method thereof. The tissue adhesive provided by the invention mainly comprises two main components, namely catechol grafted chitosan and light-cured waterborne polyurethane. The preparation method comprises the following steps: firstly, grafting a catechol group to chitosan by utilizing Schiff base reaction to prepare modified chitosan, and then preparing double-bond-terminated photocurable waterborne polyurethane from polyol, isocyanate, a small molecular chain extender and an end-capping reagent. And then blending the modified chitosan with light-cured waterborne polyurethane to prepare the chitosan / polyurethane biological tissue adhesive. The prepared biological tissue adhesive has the advantages of favorable underwater adhesion, excellent biocompatibility and degradability, and higher photocuring rate. The adhesive provided by the invention has a wide application prospect in the biomedical field.

Description

Technical Field

[0001] The invention relates to the field of wound suture materials, in particular to a method for preparing a chitosan / polyurethane biological tissue adhesive. Background Art

[0002] Every year, millions of people around the world need treatment for trauma or surgical injuries, mainly in the skin, muscles, and internal organs. Suturing is the most common treatment method, but its disadvantages are that the process is cumbersome, stress concentration is easily formed at the suture site, granulomas are formed when the body remains for too long, thrombosis is formed, and suture failure occurs, scars are easily left, and the removal of sutures will cause secondary pain. Therefore, in recent decades, domestic and foreign researchers have been continuously committed to the development of various types of bioadhesives to replace suture technology. However, the existing medical bioadhesives have low viscosity, insufficient biosafety, high infection risk, and toxic degradation products such as formaldehyde that are harmful to the human body during use. Therefore, people began to turn their attention to the adhesion behavior of organisms, hoping to find and develop a new type of bioadhesive through biomimetic methods.

[0003] As a natural biomacromolecule material, chitosan has excellent antibacterial properties, is non-toxic, has good biocompatibility and biodegradability, and has unique biological activity and physical and chemical properties. It has broad application prospects in the fields of textiles, printing and dyeing, papermaking, chemical industry, and medicine, and has attracted widespread attention.

[0004] Polyurethane is a polymer material with excellent mechanical properties. Due to its wide range of synthetic raw materials and diverse product forms, polyurethane has been widely used in many fields such as construction, textiles, packaging, furniture, etc. In the biomedical field, polyurethane with good biocompatibility is also used in various forms such as elastomers, foams, adhesives, hydrogels, etc., and is an excellent medical wound suture material.

[0005] Currently, there are relatively few studies on chitosan in the field of polyurethane material modification. Therefore, the applicant has developed a method for preparing chitosan / polyurethane biological tissue adhesive, which is intended to be used in the field of wound suture. Summary of the invention

[0006] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a chitosan / polyurethane biological tissue adhesive and a preparation method thereof. The biological adhesive provided by the present invention has good underwater adhesion, mechanical properties, biocompatibility and antibacterial properties, and has application potential as a wound suture.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] A chitosan / polyurethane biological tissue adhesive comprising

[0009] (a) Catechol grafted chitosan;

[0010] (b) Photocurable waterborne polyurethane;

[0011] (c) a photoinitiator;

[0012] The mass ratio of the (a) component, the (b) component and the (c) component is 50-67:200:1.

[0013] Preferably, the catechol-grafted chitosan comprises chitosan and 3,4-dihydroxybenzaldehyde, and the molar ratio of the chitosan to 3,4-dihydroxybenzaldehyde is 1:2.

[0014] Preferably, the catechol-grafted chitosan has the following structural formula:

[0015]

[0016] Preferably, the photocurable waterborne polyurethane comprises:

[0017] Polyol 67~71%

[0018] Diisocyanate 18~20%

[0019] Catalyst 0.1~0.2%

[0020] Small molecule chain extender 2.6~2.9%

[0021] Capping agent 7%~11%.

[0022] Preferably, the polyol is polyethylene glycol with a molecular weight range of 1500 to 2000; the diisocyanate is isophorone diisocyanate; the catalyst is bismuth neodecanoate; the small molecule chain extender is isosorbide; and the end-capping agent is hydroxyethyl acrylate.

[0023] Preferably, the photoinitiator is (±)-camphorquinone.

[0024] The present invention also provides a method for preparing a chitosan / polyurethane biological tissue adhesive, comprising the following steps:

[0025] S1. Synthesis of catechol grafted chitosan: chitosan and 3,4-dihydroxybenzaldehyde were used as main raw materials, and catechol grafted chitosan was prepared by Schiff base reaction;

[0026] S2. Synthesis of light-curable waterborne polyurethane: using polyol, diisocyanate, catalyst, small molecule chain extender and end-capping agent as main raw materials to prepare light-curable waterborne polyurethane end-capped with carbon-carbon double bonds;

[0027] S3, mixing the catechol-grafted chitosan prepared in S1, the photocurable waterborne polyurethane prepared in S2 and a photoinitiator, stirring evenly and standing to defoam, to prepare a photocurable chitosan / polyurethane biological tissue adhesive.

[0028] Preferably, in step S1, the preparation method of catechol-grafted chitosan comprises the following steps: dissolving chitosan in an acetic acid solution, adding 3,4-dihydroxybenzaldehyde dissolved in a mixed solution of distilled water and methanol, and then adding glacial acetic acid, and heating the reaction solution at a constant temperature and magnetically stirring for 4 hours under heating in an oil bath at 60°C.

[0029] Preferably, the viscosity of the chitosan is 100-200 mPa.s, and the deacetylation degree of the chitosan is above 95%.

[0030] Preferably, in step S2, the preparation method of the photocurable waterborne polyurethane comprises the following steps: reacting in a reaction container, setting the oil bath temperature to 70°C and the rotation speed to 400-450 r / min, adding the polyol, diisocyanate and catalyst after vacuum dehydration in sequence according to the ratio to react for 1-2 hours; keeping the temperature and stirring conditions unchanged, adding a small molecule chain extender dissolved in acetone to react for 2-3 hours; keeping the temperature and stirring conditions unchanged, adding a capping agent to react for 2-3 hours to obtain a polyurethane prepolymer; cooling the polyurethane prepolymer to room temperature, adding an appropriate amount of ultrapure water to disperse by high-speed stirring, and then removing the residual acetone in the system by reduced pressure distillation to obtain a photocurable waterborne polyurethane.

[0031] Preferably, after the adhesive is cured into a film, its color is yellow, the water absorption rate is 746% to 822.1%, the tensile strength is 0.49 to 0.60 MPa, the elongation at break is 60.38 to 423.93%, the bonding strength to pig skin is 5.04 to 8.70 kPa, and the antibacterial rate to Staphylococcus aureus is 100%.

[0032] The chitosan / polyurethane biological tissue adhesive of the present invention adopts a simple and mild technical route with simple reaction conditions to graft catechol on chitosan, and the raw materials for synthesizing the photocurable waterborne polyurethane are simple in type, the reaction conditions are mild, and the operation is easy.

[0033] The water absorption rate of the catechol-grafted photosensitive chitosan oligosaccharide modified polyurethane film prepared by the invention is 746%-822.1%, which ensures the absorption capacity of wound exudate; the tensile strength is 0.49-0.60MPa, and the elongation at break is 60.38-423.93%, which ensures that it is not easy to break during use; the bonding strength to pig skin close to human skin is 5.04-8.7kPa, which ensures sufficient adhesion to the skin; the antibacterial rate to Staphylococcus aureus is 100%, which ensures that a certain antibacterial capacity is provided to the wound. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 .Scanning electron microscope image of the cross section of catechol-grafted chitosan-modified polyurethane biological tissue adhesive. DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0036] Example 1

[0037] This embodiment provides a chitosan / polyurethane biological tissue adhesive, which is prepared according to the following method:

[0038] (1) Weigh 3.929 g of chitosan and dissolve it in 150 ml of 1% acetic acid solution (pH about 5.0). Weigh 0.898 g of 3,4-dihydroxybenzaldehyde and dissolve it in a mixed solution of distilled water and methanol (volume ratio 2:1, 30 ml). Quickly add the mixture to the chitosan solution. Add 1 ml of glacial acetic acid to the mixed solution and react in an oil bath at 60°C for 4 hours.

[0039] (2) Weigh 50.2 g of polyethylene glycol (PEG2000) in a four-necked flask and remove water under vacuum at 80°C for 8 h. After the polyol is dehydrated, add 12.9 g of isophorone diisocyanate and a few drops of bismuth neodecanoate catalyst, and react in an oil bath at 70°C for 1 h. Then weigh 2 g of vacuum-dried isosorbide, dissolve it in acetone, and add it to the reaction system, and continue to react for 2 h. Then weigh 5.06 g of hydroxyethyl acrylate and add it dropwise to the reaction system, and react for 3 h to obtain a polyurethane prepolymer.

[0040] An equal amount of ultrapure water was added to the polyurethane prepolymer, and the mixture was stirred at high speed for 10 minutes. The residual acetone in the system was then removed by reduced pressure distillation to obtain a light-curable waterborne polyurethane.

[0041] (3) 0.1 g of the photoinitiator camphorquinone was dissolved in anhydrous ethanol and added to 20 g of the photocurable waterborne polyurethane. 6.7 g of catechol-grafted chitosan was added to the photocurable waterborne polyurethane doped with the photoinitiator. The two were mixed evenly and poured into a polytetrafluoroethylene mold. The mold was cured under 460 nm wavelength light for 3 min to obtain an adhesive film.

[0042] Example 2

[0043] This embodiment provides a chitosan / polyurethane biological tissue adhesive, which is prepared according to the following method:

[0044] (1) Weigh 3.929 g of chitosan and dissolve it in 150 ml of 1% acetic acid solution (pH about 5.0). Weigh 0.898 g of 3,4-dihydroxybenzaldehyde and dissolve it in a mixed solution of distilled water and methanol (volume ratio 2:1, 30 ml). Quickly add the mixture to the chitosan solution. Add 1 ml of glacial acetic acid to the mixture and react in an oil bath at 60°C for 4 hours.

[0045] (2) Weigh 50.2 g of polyethylene glycol (PEG2000) in a four-necked flask and remove water under vacuum at 80°C for 8 h. After the polyol is dehydrated, add 12.9 g of isophorone diisocyanate and a few drops of bismuth neodecanoate catalyst, and react in an oil bath at 70°C for 1 h. Then weigh 2 g of vacuum-dried isosorbide, dissolve it in acetone, and add it to the reaction system, and continue to react for 2 h. Then weigh 5.06 g of hydroxyethyl acrylate and add it dropwise to the reaction system, and react for 3 h to obtain a polyurethane prepolymer.

[0046] (3) adding an equal amount of ultrapure water to the polyurethane prepolymer, stirring at high speed for 10 minutes, and then removing the residual acetone in the system by vacuum distillation to obtain a light-curable waterborne polyurethane.

[0047] 0.1 g of photoinitiator camphorquinone was dissolved in anhydrous ethanol and added to 20 g of photocurable waterborne polyurethane. 5 g of catechol-grafted chitosan was added to the photocurable waterborne polyurethane doped with the photoinitiator. The two were mixed evenly and poured into a polytetrafluoroethylene mold. The mixture was cured under light of 460 nm wavelength for 3 min to obtain an adhesive film.

[0048] The films prepared in Examples 1 and 2 were subjected to the following tests:

[0049] 1. Fourier transform infrared spectroscopy test: FTIR is used to verify whether CCS and PU are successfully synthesized, and ATR-FTIR is used to confirm the successful curing of PU and PU-CCS. The infrared spectrophotometer (Shimadzu, IRprestige-21, Japan) was used with a resolution of 4 cm -1 , and record 400cm -1 Up to 4000cm -1 Observe the difference between the spectral peaks of the raw material and the product to verify whether the product is consistent with the expected result.

[0050] 2. Water absorption test: Cut the film that has been dried to constant weight into 1cm×1cm size and weigh the initial mass. Soak it in ultrapure water at room temperature, take it out after a certain period of time, absorb the excess water on the surface of the film with filter paper and weigh it, and continue to soak until the film absorbs water to constant weight. Calculate the percentage of the mass after absorbing water to constant weight relative to the initial mass and calculate the water absorption rate.

[0051] 3. Mechanical properties test: The film was made into dumbbell-shaped specimens and its mechanical properties were tested using a universal tensile testing machine. The tensile speed was set to 50 mm / min, and its tensile strength and elongation at break were calculated.

[0052] 4. Bonding strength test: Cut the pigskin into 1.5cm×6cm size, clean the surface grease with ethanol, then wash with water, and dry it in a blast drying oven at 30℃ for 10min. After taking it out, use a 1.5cm×1.5cm film to bond two pigskins, and press with a 200g weight for 5min to fully bond. After bonding, use a universal tensile testing machine to measure the shear strength, and set the tensile speed to 20mm / min.

[0053] 5. Antibacterial test: Take Staphylococcus aureus grown to the logarithmic phase, adjust the OD value to 1.0 with PBS buffer, and dilute it to 1×10 5 CFU / mL. Take 1mL of bacterial solution into a culture tube and add the UV-sterilized film to be tested. Add only an equal amount of bacterial solution to the blank control. Incubate at 37°C for 24 hours after adding the sample. After the incubation, use sterile PBS buffer to perform a 10-fold gradient dilution, with a total of 4 gradients. Take 100μL of the dilution and evenly spread it on LB solid culture medium, culture it at 37°C overnight, and take pictures and count the plates.

[0054] like Figure 1 As shown in the figure, the microscopic morphology of the sample was observed by scanning electron microscopy. The cross section of the film showed a scaly structure with microphase separation of soft segments and hard segments, in which the brighter area was formed by the hard segment and the darker area was formed by the continuous phase formed by the soft segment. The microphase separation structure gave the film good mechanical properties.

[0055] Table 1 Performance test results of adhesive after curing film

[0056]

[0057] As can be seen from Table 1 above, the catechol grafted chitosan modified polyurethane biological tissue adhesive obtained by the present invention has good performance after curing into a film. The water absorption rate is 746% to 822.1%, which ensures the absorption capacity of wound exudate; the tensile strength is 0.49 to 0.60 MPa, and the elongation at break is 60 to 423.93%, which ensures that it is not easy to break during use; the bonding strength to pig skin close to human skin is 5.04 to 8.70 kPa, which ensures sufficient adhesion to the skin; the antibacterial rate to Staphylococcus aureus is 100%, which ensures that a certain antibacterial capacity is provided to the wound. Therefore, the present invention is expected to be applied in the field of biomedicine.

[0058] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A chitosan / polyurethane biological tissue adhesive, characterized in that: include: (a) Catechol grafted chitosan; (b) Photocurable waterborne polyurethane; (c) a photoinitiator; The mass ratio of the component (a), the component (b) and the component (c) is 50-67:200:1 。 2. The chitosan / polyurethane biological tissue adhesive according to claim 1, characterized in that: The catechol-grafted chitosan comprises chitosan and 3,4-dihydroxybenzaldehyde, and the molar ratio of the chitosan to the 3,4-dihydroxybenzaldehyde is 1:

2.

3. The chitosan / polyurethane biological tissue adhesive according to claim 1, characterized in that: The catechol grafted chitosan has the following structural formula:

4. The chitosan / polyurethane biological tissue adhesive according to claim 1, characterized in that: The photocurable waterborne polyurethane comprises: Polyol 67~71% Diisocyanate 18~20% Catalyst 0.1~0.2% Small molecule chain extender 2.6~2.9% Capping agent 7%~11%.

5. The chitosan / polyurethane biological tissue adhesive according to claim 4, characterized in that: The polyol is polyethylene glycol with a molecular weight range of 1500 to 2000; the diisocyanate is isophorone diisocyanate; the catalyst is bismuth neodecanoate; the small molecule chain extender is isosorbide; and the end-capping agent is hydroxyethyl acrylate.

6. The chitosan / polyurethane biological tissue adhesive according to claim 1, characterized in that: The photoinitiator is (±)-camphorquinone.

7. A method for preparing a chitosan / polyurethane biological tissue adhesive according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1. Synthesis of catechol grafted chitosan: chitosan and 3,4-dihydroxybenzaldehyde were used as main raw materials, and catechol grafted chitosan was prepared by Schiff base reaction; S2. Synthesis of light-curable waterborne polyurethane: using polyol, diisocyanate, catalyst, small molecule chain extender and end-capping agent as main raw materials to prepare light-curable waterborne polyurethane end-capped with carbon-carbon double bonds; S3, mixing the catechol-grafted chitosan prepared in S1, the photocurable waterborne polyurethane prepared in S2 and a photoinitiator, stirring evenly and standing to defoam, to prepare a photocurable chitosan / polyurethane biological tissue adhesive.

8. The method for preparing the chitosan / polyurethane biological tissue adhesive according to claim 7, characterized in that: In step S1, the preparation method of catechol-grafted chitosan includes the following steps: dissolving chitosan in acetic acid solution, adding 3,4-dihydroxybenzaldehyde dissolved in a mixed solution of distilled water and methanol, and then adding glacial acetic acid, and heating the reaction solution in an oil bath at 60°C and stirring the reaction solution under constant temperature for 4 hours, wherein the viscosity of the chitosan is 100-200 mPa.s, and the deacetylation degree of the chitosan is above 95%.

9. The method for preparing the chitosan / polyurethane biological tissue adhesive according to claim 7, characterized in that: In the step S2, the preparation method of the photocurable waterborne polyurethane comprises the following steps: reacting in a reaction container, setting the oil bath temperature to 70°C and the rotation speed to 400-450 r / min, adding the polyol, diisocyanate and catalyst after vacuum dehydration in sequence according to the ratio to react for 1-2 hours; keeping the temperature and stirring conditions unchanged, adding a small molecule chain extender dissolved in acetone to react for 2-3 hours; keeping the temperature and stirring conditions unchanged, adding a capping agent to react for 2-3 hours to obtain a polyurethane prepolymer; cooling the polyurethane prepolymer to room temperature, adding an appropriate amount of ultrapure water to disperse by high-speed stirring, and then removing the residual acetone in the system by reduced pressure distillation to obtain a photocurable waterborne polyurethane.

10. The method for preparing the chitosan / polyurethane biological tissue adhesive according to claim 7, characterized in that: After the adhesive is cured into a film, its color is yellow, its water absorption rate is 746% to 822.1%, its tensile strength is 0.49 to 0.60 MPa, its elongation at break is 60.38 to 423.93%, its bonding strength to pig skin is 5.04 to 8.70 kPa, and its antibacterial rate to Staphylococcus aureus is 100%.

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