Degradable soft tissue adhesives and methods of making and using the same

Abstract

The application belongs to the technical field of medical soft tissue adhesive, and discloses a degradable soft tissue adhesive and a preparation and use method thereof. A photoinitiator is dissolved in a crosslinking agent monomer to obtain a mixed solution; polypropylene fumarate is mixed into the mixed solution, and then bubbles are removed to obtain a mixed system A; polyethylene glycol is mixed into the mixed system A to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution; and the polypropylene fumarate-based organic gel prepolymer precursor solution is subjected to ultrasonic treatment in the dark to disentangle long-chain structures; wherein the addition amount of the photoinitiator is 1% of the total mass of polypropylene fumarate and the crosslinking agent monomer, the mass ratio of polypropylene fumarate to the crosslinking agent monomer is 1: (1-2), and the volume of polyethylene glycol is 20%-50% of the volume of the mixed system A. The application significantly improves the mechanical properties and bonding strength of the adhesive by modifying polypropylene fumarate.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical soft tissue adhesive, and particularly relates to a degradable soft tissue adhesive and a preparation and use method thereof. BACKGROUND

[0002] In recent years, with the rapid development of medical technology, the repair and regeneration of soft tissue has become an important issue in clinical treatment. As an effective medical device, soft tissue adhesive is widely used in surgical operation, wound treatment, plastic and cosmetic surgery, and organ transplantation. Compared with traditional suture and stapling technology, soft tissue adhesive has the advantages of simple operation, small trauma, fast recovery, and gradually becomes an important tool in surgical operation. However, the soft tissue adhesives on the current market still face some obvious challenges in practical application, such as weak degradability, insufficient adhesion strength, poor biocompatibility, lack of modulus adjustment, and low interfacial toughness, which to some extent limit their wide application and effectiveness in clinical treatment. Therefore, further research and improvement for these problems are the key to future development.

[0003] Polypropylene fumarate is a polymer with excellent biocompatibility and degradability, which has been widely studied and applied in the field of biomedical materials in recent years. The main advantage of this material is that its degradation products are non-toxic and can be absorbed by the human body, and it also has good mechanical properties. By adjusting its molecular structure and crosslinking density, the mechanical properties of the material can be effectively controlled. However, polypropylene fumarate has poor hydrophilicity, high viscosity, high hardness, and insufficient toughness, which leads to a mismatch between its modulus and that of soft tissue, which may cause damage to the tissue during use, limiting its application in soft tissue adhesive. SUMMARY

[0004] To solve the problems existing in the prior art, the purpose of the present application is to provide a degradable soft tissue adhesive and a preparation and use method thereof. By modifying polypropylene fumarate, adding a new crosslinking agent, and introducing polyethylene glycol with different molecular weights as a solvent phase, the mechanical properties and adhesion strength of the adhesive can be significantly improved, the curing time can be shortened, and the clinical application requirements can be met.

[0005] To achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0006] A preparation method of a degradable soft tissue adhesive, comprising the following processes:

[0007] Dissolve the photoinitiator in the crosslinking agent monomer to obtain a mixed solution;

[0008] Mix the polypropylene fumarate into the mixed solution, and then remove the bubbles to obtain a mixed system A;

[0009] The polypropylene glycol is mixed into the mixed system A to prepare a polypropylene glycol fumarate-based organic gel prepolymer precursor solution;

[0010] The polypropylene glycol fumarate-based organic gel prepolymer precursor solution is ultrasonically treated in the dark to disentangle long-chain structures to obtain the degradable soft tissue adhesive.

[0011] The amount of the photoinitiator is 1% of the total mass of the polypropylene glycol fumarate and the crosslinker monomer, the mass ratio of the polypropylene glycol fumarate to the crosslinker monomer is 1: (1-2), and the volume of the polyethylene glycol is 20%-50% of the volume of the mixed system A.

[0012] Preferably, the photoinitiator is 2-hydroxy-4'- (2-hydroxyethoxy) -2-methylpropiophenone.

[0013] Preferably, the crosslinker monomer is hydroxyethyl methacrylate, acrylic acid or N-hydroxyethyl acrylamide.

[0014] Preferably, after the polypropylene glycol fumarate is added into the mixed solution, the mixed solution is stirred uniformly, and then bubbles are removed by centrifugation to obtain the mixed system A.

[0015] Preferably, the molecular weight of the polyethylene glycol is 200-1500.

[0016] Preferably, when the molecular weight of the polyethylene glycol is greater than 600, the polyethylene glycol is melted and then mixed into the mixed system A.

[0017] Preferably, when the polypropylene glycol fumarate-based organic gel prepolymer precursor solution is ultrasonically treated in the dark, the ultrasonic power is 145-155 W, and the ultrasonic time is 9-11 min.

[0018] The application further provides a degradable soft tissue adhesive prepared by the preparation method.

[0019] The application further provides a use method of the degradable soft tissue adhesive, which comprises the following process: the degradable soft tissue adhesive is applied to a part to be connected, and then the part to be connected is connected by curing under ultraviolet light.

[0020] Preferably, the wavelength of the ultraviolet light is 320-380 nm, the curing distance is 5-10 cm, the irradiation time is 120-180 s, and the light source output power is 155 mW-310 mW.

[0021] The application has the following beneficial effects:

[0022] The preparation method of the degradable soft tissue adhesive of the present application is based on a polypropylene fumarate / hydroxyethyl methacrylate or acrylic acid or N-hydroxyethyl acrylamide / polyethylene glycol system, and is particularly used for the preparation of medical light-cured hard tissue adhesive. The method first selects polypropylene fumarate (PPF) as a base material, and the PPF is an injectable, in-situ crosslinking and degradable absorbable biomedical material. Due to the existence of unsaturated C=C double bond structure in the PPF molecule, the crosslinking reaction with the monomer can be carried out, and the cured body with a certain strength is formed. By increasing the content of the crosslinking agent monomer (such as hydroxyethyl methacrylate HEMA), not only the crosslinking structure is formed, but also the chain entanglement is promoted by increasing the polymer chain, so that the mechanical properties of the material are improved. At the same time, the degree of chain entanglement that is too high will reduce the flexibility and ductility, and the chain entanglement of the long chain structure can be disentangled through the polyethylene glycol solvent and the ultrasonic process, so that the flexibility can be adjusted within a certain range; in addition, the polyethylene glycol solvent helps to reduce the friction between the chains through the interaction with the polymer chain, and improves the flexibility and adjustability of the hydrogel. The low molecular weight polyethylene glycol contains ether chain structure, which can form hydrogen bonds with the hydroxyl or carboxyl in the polymer skeleton. These hydrogen bonds are broken as “reversible sacrificial bonds” under external force, releasing energy, thereby effectively improving the toughness of the hydrogel, so that it can dissipate energy during the external force stretching process, and enhance the mechanical properties of the soft tissue adhesive. The mechanism makes the degradable soft tissue adhesive of the present application have excellent toughness and biocompatibility, and is suitable for the repair and bonding of biological soft tissues. By adjusting the proportion of polyethylene glycol in the polypropylene glycol fumarate prepolymer precursor solution and its own molecular weight (length), the system realizes a large mechanical property adjustment window. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The PPF nuclear magnetic resonance spectrum prepared by ring-opening polymerization in the embodiments of the present application.

[0024] Figure 2 The tensile shear strength stress-strain curve diagram of Example 2 and the control group.

[0025] Figure 3 The glass transition temperature diagram of the degradable soft tissue adhesive prepared in Example 1-Example 6.

[0026] Figure 4 The wound closure strength test result diagram of the degradable soft tissue adhesive prepared in Example 1-Example 6.

[0027] Figure 5 The wound closure strength test result diagram of the tissue adhesive prepared in Example 7-Example 11. DETAILED DESCRIPTION

[0028] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application.

[0029] The degradable soft tissue adhesive of the present application is a photocured soft tissue adhesive, which takes polypropylene fumarate as a basic network of adhesive, uses a photocured monomer (such as hydroxyethyl methacrylate (HEMA), acrylic acid (AA) or N-hydroxyethyl acrylamide (HEAA)) as a crosslinking agent, and takes polyethylene glycol (PEG) as a solvent phase of an organic gel. Through this design, the flexibility, hydrophilicity and biocompatibility of the polypropylene fumarate-based organic gel are significantly improved.

[0030] Specifically, the preparation method of the degradable soft tissue adhesive of the present application comprises the following processes:

[0031] First, the photoinitiator is dissolved in the crosslinking agent precursor (such as hydroxyethyl methacrylate), and then the polypropylene fumarate is mixed into the crosslinking agent / photoinitiator mixed solution. The final solution is poured into a brown glass vial, and then the vial is centrifuged to remove bubbles, to obtain a mixed system A;

[0032] Then, a certain amount of polyethylene glycol is added to the mixed system A to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution. Then, ultrasonic treatment is carried out in the dark to disentangle the long-chain structure, to obtain the final degradable soft tissue adhesive of the present application.

[0033] In the above scheme of the present application, the photoinitiator is 2-hydroxy-4'- (2-hydroxyethoxy)-2-methylpropiophenone. The crosslinking agent monomer is hydroxyethyl methacrylate, acrylic acid or N-hydroxyethyl acrylamide. The molecular weight of the polyethylene glycol is 200-1500. When the molecular weight of the polyethylene glycol is greater than 600, it is a white waxy solid at room temperature and should be placed in a constant temperature oven at 60°C in advance to melt, and then taken out before use. Then, the melted polyethylene glycol is mixed into the mixed system A. When the polypropylene fumarate-based organic gel prepolymer precursor solution is ultrasonically treated in the dark, the ultrasonic power is 150±5W, and the ultrasonic time is 9-11min. Among them, 150W is the power setting value of the laboratory ultrasonic equipment, and the deviation ±5W is the power fluctuation range of the laboratory ultrasonic equipment. In the above scheme, the addition amount of the photoinitiator is 1% of the total mass of the polypropylene fumarate and the crosslinking agent monomer, the mass ratio of the polypropylene fumarate to the crosslinking agent monomer is 1: (1-2), and the volume of the polyethylene glycol is 20%-50% of the volume of the mixed system A.

[0034] In the above scheme of the present application, the preparation process of the polypropylene fumarate comprises:

[0035] Maleic anhydride is dissolved in three times the mass of anhydrous toluene, and an equal molar amount of propylene oxide is added. The system is then purged of air using argon, and stirring is continued to ensure uniform mixing. Then, 1 / 200th of an equivalent amount of magnesium ethoxide is added, and the system is again purged of air using argon and sealed. The system is then repeatedly frozen and thawed to remove residual oxygen from the system and solvent, and the system is maintained in an anhydrous and oxygen-free environment. The temperature is raised to 80°C using a gas ballast, and the reaction is allowed to proceed for 40 hours. After the reaction is complete, the crude product of polypropylene fumarate is obtained. The product is purified through acid washing, deionized water washing, saturated brine washing, and phase separation, and the final product is obtained as a yellow viscous substance. The isomerization of the product is carried out by dissolving the product in chloroform, purging the system of air using argon, adding 0.15 equivalents of diethylamine, and refluxing the system at 55°C for 24 hours. After the reaction is complete, the product is washed and precipitated repeatedly, and the isomerized product is obtained. The final product is stored at 0-4°C.

[0036] The nuclear magnetic resonance spectrum of the polypropylene fumarate (PPF) prepared according to the present application is shown in Figure 1. Figure 1 As can be seen from Figure 1, the polypropylene fumarate (PPF) is successfully prepared according to the present application.

[0037] Polypropylene fumarate is a linear unsaturated polyester, and the double bonds can form a crosslinking network alone or with other unsaturated agents, such as vinyl pyrrolidone (NVP), methyl methacrylate (MMA), diethyl fumarate (DEF), or polypropylene fumarate-diacrylate (PPF-DA) macromonomer, to provide a wide range of mechanical properties. The present application takes into account the particularity of soft tissue crosslinking, and selects a monomer with good hydrophilicity and low viscosity to improve the performance of polypropylene fumarate, which can be used as a reactive diluent and a crosslinking agent at the same time, such as hydroxyethyl methacrylate (HEMA), acrylic acid (AA), and N-hydroxyethyl acrylamide (HEAA). Polyethylene glycol (PEG) is a water-soluble polymer material with extremely low interfacial free energy, and the molecular chain has good flexibility and high activity, which makes it exhibit excellent biocompatibility in the body. When PEG is introduced into the polypropylene fumarate (PPF) gel system as a solvent phase, liquid oligomers or polymers act as solvents for the gel system, which can effectively introduce multivalent interactions between the main polymer networks and other solvent molecules. This interaction significantly affects the mechanical properties and stability of the polymer gel. At the same time, by adjusting the molecular chain length of the oligomeric solvent molecules, the physical properties of the hydrogel can be further enhanced and fine-tuned, thereby optimizing the performance of the gel.

[0038] The method for using the degradable soft tissue adhesive according to the present application includes the following steps:

[0039] The to-be-spliced part is fixed on the glass bottom plate, the light-cured soft tissue adhesive is applied to the to-be-connected part, and then the to-be-connected part is connected by ultraviolet light curing. The wavelength of the ultraviolet light is 320-380 nm, the curing distance is 5-10 cm, the irradiation time is 120-180 s, and the light source output power is 155 mW-310 mW.

[0040] Example 1

[0041] The preparation and use method of the degradable soft tissue adhesive of the present example are as follows:

[0042] 0.1 g of a photoinitiator BAPO is dissolved in 5 g of hydroxyethyl methacrylate, centrifuged to remove bubbles, and the initiator is uniformly dispersed in the system to obtain a crosslinking agent / photoinitiator mixed solution. Then 5 g of polypropylene fumarate is dissolved in the crosslinking agent / photoinitiator mixed solution, and the final solution is poured into a brown glass vial. Then the vial is centrifuged to remove bubbles to obtain a mixed system A. Then polyethylene glycol 200 is added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of polyethylene glycol 200 is 50% of the volume of the mixed system A. The polypropylene fumarate-based organic gel prepolymer precursor solution is then treated with ultrasonic waves in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power is set to 150 W. When using the degradable soft tissue adhesive of the present example, an ultraviolet lamp curing device is used for curing, wherein the ultraviolet wavelength is 365 nm, the curing distance is 10 cm, and the irradiation time is 180 s.

[0043] Example 2

[0044] The preparation and use method of the degradable soft tissue adhesive of the present example are as follows:

[0045] 0.1 g of a photoinitiator BAPO is dissolved in 5 g of hydroxyethyl methacrylate, centrifuged to remove bubbles, and the initiator is uniformly dispersed in the system to obtain a crosslinking agent / photoinitiator mixed solution. Then 5 g of polypropylene fumarate is dissolved in the crosslinking agent / photoinitiator mixed solution, and the final solution is poured into a brown glass vial. Then the vial is centrifuged to remove bubbles to obtain a mixed system A. Then polyethylene glycol 200 is added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of polyethylene glycol 200 is 50% of the volume of the mixed system A. The polypropylene fumarate-based organic gel prepolymer precursor solution is then treated with ultrasonic waves in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power is set to 150 W. When using the degradable soft tissue adhesive of the present example, an ultraviolet lamp curing device is used for curing, wherein the ultraviolet wavelength is 365 nm, the curing distance is 10 cm, and the irradiation time is 180 s.

[0046] Example 3

[0047] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0048] 0.1 g of photoinitiator BAPO was dissolved in 5 g of hydroxyethyl methacrylate, and the bubbles were removed by centrifugation to uniformly disperse the initiator in the system, to obtain a crosslinking agent / photoinitiator mixed solution, and then 5 g of polypropylene glycol fumarate was dissolved in the crosslinking agent / photoinitiator mixed solution, and the final solution was poured into a brown glass vial, and then the vial was centrifuged to remove the bubbles, to obtain a mixed system A; then polyethylene glycol 600 was added to prepare a polypropylene glycol fumarate-based organic gel prepolymer precursor solution, wherein the volume of polyethylene glycol 600 is 50% of the volume of mixed system A. The polypropylene glycol fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 9 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. When using the degradable soft tissue adhesive of the present example, an ultraviolet lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0049] Example 4

[0050] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0051] 0.1 g of photoinitiator BAPO was dissolved in 5 g of hydroxyethyl methacrylate, and the bubbles were removed by centrifugation to uniformly disperse the initiator in the system, to obtain a crosslinking agent / photoinitiator mixed solution, and then 5 g of polypropylene glycol fumarate was dissolved in the crosslinking agent / photoinitiator mixed solution, and the final solution was poured into a brown glass vial, and then the vial was centrifuged to remove the bubbles, to obtain a mixed system A; then polyethylene glycol 600 was added to prepare a polypropylene glycol fumarate-based organic gel prepolymer precursor solution, wherein the volume of polyethylene glycol 600 is 50% of the volume of mixed system A. The polypropylene glycol fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 9 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. When using the degradable soft tissue adhesive of the present example, an ultraviolet lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0052] Example 5

[0053] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0054] A mixture system A was prepared by dissolving 0.1 g of photoinitiator BAPO in 5 g of hydroxyethyl methacrylate, centrifuging to remove bubbles, and uniformly dispersing the initiator in the system, and then dissolving 5 g of polypropylene fumarate in the mixed solution of the crosslinking agent / photoinitiator, pouring the final solution into a brown glass vial, and then centrifuging the vial to remove bubbles. Then, polyethylene glycol 1000 (previously melted to a liquid state in a 60° oven, and mixed quickly after being taken out) was added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of the polyethylene glycol 1000 was 50% of the volume of the mixture system A. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 11 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the present example, an ultraviolet lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0055] Example 6

[0056] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0057] A mixture system A was prepared by dissolving 0.1 g of photoinitiator BAPO in 5 g of hydroxyethyl methacrylate, centrifuging to remove bubbles, and uniformly dispersing the initiator in the system, and then dissolving 5 g of polypropylene fumarate in the mixed solution of the crosslinking agent / photoinitiator, pouring the final solution into a brown glass vial, and then centrifuging the vial to remove bubbles. Then, polyethylene glycol 1000 (previously melted to a liquid state in a 60° oven, and mixed quickly after being taken out) was added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of the polyethylene glycol 1000 was 50% of the volume of the mixture system A. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 11 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the present example, an ultraviolet lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0058] Example 7

[0059] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0060] A mixture system A was prepared by dissolving 0.1 g of photoinitiator BAPO in 5 g of hydroxyethyl methacrylate, centrifuging to remove bubbles, and uniformly dispersing the initiator in the system, and then dissolving 5 g of polypropylene fumarate in the mixed solution of the crosslinking agent / photoinitiator, pouring the final solution into a brown glass vial, and then centrifuging the vial to remove bubbles. Then, 20% of the volume of the mixture system A was polyethylene glycol 400 to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the example, an ultraviolet lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0061] Example 8

[0062] The preparation and use method of the degradable soft tissue adhesive of the example were as follows:

[0063] A mixture system A was prepared by dissolving 0.1 g of photoinitiator BAPO in 5 g of hydroxyethyl methacrylate, centrifuging to remove bubbles, and uniformly dispersing the initiator in the system, and then dissolving 5 g of polypropylene fumarate in the mixed solution of the crosslinking agent / photoinitiator, pouring the final solution into a brown glass vial, and then centrifuging the vial to remove bubbles. Then, 20% of the volume of the mixture system A was polyethylene glycol 400 to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the example, an ultraviolet lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0064] Example 9

[0065] The preparation and use method of the degradable soft tissue adhesive of the example were as follows:

[0066] A mixture system A was prepared by dissolving 0.1 g of photoinitiator BAPO in 5 g of N-hydroxyethyl acrylamide, centrifuging to remove bubbles, and uniformly dispersing the initiator in the system, and then dissolving 5 g of polypropylene fumarate in the mixed solution of the crosslinking agent / photoinitiator, pouring the final solution into a brown glass vial, and then centrifuging the vial to remove bubbles. Then, polyethylene glycol 400 was added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of the polyethylene glycol 400 was 50% of the volume of the mixture system A. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the present example, a UV lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0067] Example 10

[0068] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0069] A mixture system A was prepared by dissolving 0.1 g of photoinitiator BAPO in 5 g of N-hydroxyethyl acrylamide, centrifuging to remove bubbles, and uniformly dispersing the initiator in the system, and then dissolving 5 g of polypropylene fumarate in the mixed solution of the crosslinking agent / photoinitiator, pouring the final solution into a brown glass vial, and then centrifuging the vial to remove bubbles. Then, polyethylene glycol 400 was added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of the polyethylene glycol 400 was 50% of the volume of the mixture system A. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasound in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the present example, a UV lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0070] Example 11

[0071] The preparation and use method of the degradable soft tissue adhesive of the present example is as follows:

[0072] 0.075 g of photoinitiator BAPO was dissolved in 5 g of hydroxyethyl methacrylate, centrifuged to remove bubbles, and the initiator was uniformly dispersed in the system to obtain a crosslinking agent / photoinitiator mixed solution, and then 2.5 g of polypropylene fumarate was dissolved in the crosslinking agent / photoinitiator mixed solution, and the final solution was poured into a brown glass vial, and then the vial was centrifuged to remove bubbles to obtain a mixed system A; then polyethylene glycol 400 was added to prepare a polypropylene fumarate-based organic gel prepolymer precursor solution, wherein the volume of polyethylene glycol 400 is 50% of the volume of mixed system A. The polypropylene fumarate-based organic gel prepolymer precursor solution was then treated with ultrasonic waves in the dark for 10 minutes to obtain the final degradable soft tissue adhesive of the present example, wherein the ultrasonic power was set to 150 W. In the use of the degradable soft tissue adhesive of the present example, a UV lamp curing device was used for curing, wherein the ultraviolet wavelength was 365 nm, the curing distance was 10 cm, and the light exposure time was 180 s.

[0073] Figure 2 The tensile shear strength stress-strain curves of Example 2 of the present application and the control group without the addition of polyethylene glycol are shown. The experimental mold design is based on the standard GB7124-86, the mold size is 100 mm × 25 mm × 2 mm, the lap area is 12.5 mm × 25 mm, and the material is selected as transparent acrylic plate. The adhesive was uniformly coated on the lap area of the acrylic mold, and after curing under ultraviolet light, it was fixed on the biomechanical testing machine, and the test rate was set to 1 mm / min. The results are shown in the figure. Compared with the control group, the sample with the addition of polyethylene glycol showed a longer strain plateau on the stress-strain curve, and then the bonding strength gradually decreased. It can be seen that the adhesive prepared by the present application has excellent flexibility and adhesion performance, and is suitable for soft, dynamic or larger deformation of soft tissue adhesion scenarios.

[0074] Figure 3The glass transition temperature of the degradable soft tissue adhesive prepared in Examples 1-6 of the present application is shown. To further confirm the relationship between the mechanical properties of PPF organic hydrogel and the chain flexibility, the present application determines the glass transition temperature (Tg) thereof by differential scanning calorimeter (DSC). When the molecular weight of polyethylene glycol is 200, the glass transition temperature is the lowest, showing a viscoelastic state at room temperature, better flexibility, and adaptability to various solid surfaces. It is shown that low molecular weight PEG helps to regulate the flexibility of the chain. The gel network formed by low molecular weight PEG (such as PEG200, PEG400, PEG600) is relatively dense, and the interaction between its molecular chains is weak, so the glass transition occurs at a lower temperature. While high molecular weight PEG (such as PEG800, 1000 and PEG1500) can form more entanglements and crosslinking points in the gel network due to its longer molecular chain, thereby improving the overall stability of the system, and increasing the glass transition temperature.

[0075] Figure 4 The wound closure strength test results of the degradable soft tissue adhesive prepared in Examples 1 to 6 of the present application are shown. The test method refers to ASTM F2458-2024 Standard Test Method for Wound Closure Strength of Tissue Adhesives and Sealants. In the experiment, pigskin is cut into a long strip of 40 mm × 10 mm × 2 mm, the adhesive is uniformly coated between the two pieces of pigskin in a 10 mm × 2 mm contact area, the thickness is controlled to be 2 mm, and the adhesion is ensured by curing under ultraviolet light. Subsequently, the sample is fixed on a biomechanical testing machine, and the test tensile rate is set to 5 mm / min. The experimental results show that the average bonding strength of Examples 1 to 6 is 0.35 MPa, 0.53 MPa, 0.46 MPa, 0.27 MPa, 0.22 MPa and 0.16 MPa, respectively. When the ratio of polypropylene fumarate and crosslinking agent is fixed, the adhesion strength increases first and then decreases with the increase of the molecular weight of polyethylene glycol. This is because the interaction between polymers is enhanced at the initial stage of the increase of the molecular weight of polyethylene glycol, thereby effectively improving the bonding strength. However, when the molecular weight is further increased, the flexibility of polyethylene glycol decreases, resulting in a decrease in adhesion performance. At the same time, the flowability of high molecular weight polyethylene glycol is poor, which weakens the intermolecular force during the adhesion process, and finally leads to a decrease in the adhesion strength. This shows that by optimizing the molecular weight of polyethylene glycol, the adhesion performance and mechanical properties of the adhesive can be effectively regulated to meet different application requirements.

[0076] Figure 5The results of the wound closure strength test of the degradable soft tissue adhesive in Example 7 to Example 11 of the present application are shown. The average adhesive strength of the resulting Example 7 to Example 11 is 0.45 MPa, 0.61 MPa, 0.38 MPa, 0.20 MPa, 0.59 MPa, respectively. When the mass ratio of polymer to crosslinking agent is 1:1, and the crosslinking agent is hydroxyethyl methacrylate, the adhesive strength performs best. With the increase of the content of hydroxyethyl methacrylate monomer, the adhesive performance is significantly improved. This phenomenon can be attributed to the hydroxyl structure at the molecular end, which can interact with the solid interface by forming hydrogen bonds, thereby effectively enhancing the adhesive performance.

[0077] Obviously, the described embodiments are only part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor should belong to the scope of protection of the present application.

[0078] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, not to limit it. Although the present application has been described in detail with reference to the above examples, those of ordinary skill in the art should understand that the specific embodiments of the present application can be modified or replaced by the equivalent, without departing from the spirit and scope of the present application. Any modification or equivalent replacement without departing from the spirit and scope of the present application should be covered within the protection scope of the claims of the present application.

Claims

1. A method of making a degradable soft tissue adhesive, characterized by, The method comprises the following steps: dissolving a photo initiator in a crosslinking agent monomer to obtain a mixed solution; mixing polypropylene fumarate into the mixed solution, and removing air bubbles to obtain a mixed system A; mixing polyethylene glycol into the mixed system A to obtain a polypropylene fumarate-based organic gel prepolymer precursor solution; ultrasonically treating the polypropylene fumarate-based organic gel prepolymer precursor solution in the dark to disentangle long-chain structures, and obtaining the degradable soft tissue adhesive; wherein the amount of the photo initiator is 1% of the total mass of the polypropylene fumarate and the crosslinking agent monomer, the mass ratio of the polypropylene fumarate to the crosslinking agent monomer is 1: (1-2), and the volume of the polyethylene glycol is 20%-50% of the volume of the mixed system A; the crosslinking agent monomer is hydroxyethyl methacrylate, acrylic acid or N-hydroxyethyl acrylamide; the molecular weight of the polyethylene glycol is 200-1500.

2. The method of claim 1, wherein the degradable soft tissue adhesive is prepared by the steps of: the photo initiator is 2-hydroxy-4'- (2-hydroxyethoxy) -2-methyl propiophenone.

3. The method of claim 1, wherein the degradable soft tissue adhesive is prepared by the steps of: After the polypropylene fumarate is added into the mixed solution, the solution is stirred uniformly, and then air bubbles are removed by centrifugation to obtain the mixed system A.

4. The method of claim 1, wherein the degradable soft tissue adhesive is prepared by the steps of: When the molecular weight of the polyethylene glycol is greater than 600, the polyethylene glycol is melted and mixed into the mixed system A.

5. The method of claim 1, wherein the degradable soft tissue adhesive is prepared by the steps of: When the polypropylene fumarate-based organic gel prepolymer precursor solution is ultrasonically treated in the dark, the ultrasonic power is 145-155 W, and the ultrasonic time is 9-11 min.

6. A degradable soft tissue adhesive, characterized in that, The degradable soft tissue adhesive is prepared by the method of any one of claims 1-5.

7. The method of using the degradable soft tissue adhesive of claim 6, wherein, The method comprises the following steps: coating the degradable soft tissue adhesive on a part to be connected, and then curing the adhesive by ultraviolet light to connect the part to be connected.

8. The method of using the degradable soft tissue adhesive of claim 7, wherein, The wavelength of the ultraviolet light is 320-380 nm, the curing distance is 5-10 cm, the irradiation time is 120-180 s, and the light source output power is 155 mW-310 mW.

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