Two-component injectable polyurethane biological adhesive as well as preparation method and application thereof

Abstract

The invention provides a two-component injectable polyurethane biological adhesive as well as a preparation method and application thereof, and belongs to the technical field of medical adhesives. The adhesive provided by the invention is prepared from a polyurethane prepolymer and a curing agent composition as raw materials, the polyurethane prepolymer is obtained by reacting aliphatic isocyanate and polyhydric alcohol; the curing agent composition is composed of a compound containing a catechol group, a compound containing a cationic group and an amino group, and a solvent. The two components in the polyurethane biological adhesive can be mixed through injection and can be rapidly cured after being mixed, and the adhesive can be degraded in vivo and is good in biocompatibility. And the adhesive has good wet adhesion and can meet various clinical requirements. After a developing agent is compounded in the adhesive, the adhesive has good developing property and can be used for radiotherapy positioning. Therefore, the polyurethane biological adhesive disclosed by the invention has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical adhesives, and particularly relates to a two-component injectable polyurethane bioadhesive, its preparation method and application. Background Art

[0002] As a substitute for traditional surgical sutures, medical tissue adhesives have attracted more and more extensive attention and research because they have characteristics such as real-time hemostasis, effective sealing, non-invasive adhesion, and simple operation, which can improve the surgical effect and success rate. Bioactive tissue adhesives have adjustable biomechanical and biochemical properties, can establish a firm bonding interface with tissues, and achieve the purposes of assisting surgical suturing, hemostasis, and preventing leakage, which is attractive for soft tissue wound management and wound healing.

[0003] Current medical adhesives mainly include fibrin-based, cyanoacrylate-based, polyethylene glycol-based, and polyurethane-based. Among them, polyurethane adhesives have advantages such as good biocompatibility, high bonding strength, low swelling rate, and good stability, and have great potential in the field of medical adhesives. In the Chinese patent application with the publication number CN116899007A, the use of secondary amine compounds as curing agents is proposed to solve the problem of slow curing process of polyurethane adhesives, but there is heat release during the curing process, and the synthesis of the curing agent requires processes such as column chromatography or extraction for purification, and the synthesis process is complex. In the Chinese patent application with the publication number CN116023623A, a degradable polyurethane adhesive is prepared by introducing an ester bond into the molecular structure of the polyurethane adhesive, but the preparation process is complex, and the use of the catalyst is prone to potential toxicity risks. In the Chinese patent application with the publication number CN116712595A, the curing time of the adhesive is adjusted by selectively adding tertiary amine compounds in the prepolymer, but small molecule polyhydroxy compounds are used as chain extenders, and the degradation rate of the prepared adhesive is relatively fast.

[0004] In addition, during actual clinical use, in the face of moist environments such as easy tissue fluid exudation and blood exudation, it is often difficult for adhesives to achieve firm adhesion to wet soft tissues. The Chinese patent application with the publication number CN118079061A provides a two-component polyurethane-based bioadhesive for soft tissues, which can be quickly cured, degradable, and has good hydrophilicity, excellent bonding performance and plugging effect. It is applicable to various tissue environments and can meet various actual clinical needs. However, the shear lap strength of this adhesive still needs to be improved. Summary of the Invention

[0005] In order to solve the problems existing in the prior art, the purpose of the present invention is to provide a two-component injectable polyurethane bioadhesive, its preparation method and application.

[0006] The present invention provides a two-component injectable polyurethane bioadhesive, which is prepared from a polyurethane prepolymer and a curing agent composition as raw materials; the polyurethane prepolymer is obtained by reacting an aliphatic isocyanate and a polyol; the curing agent composition consists of a compound containing a catechol group, a compound containing both a cationic group and an amino group, and a solvent.

[0007] Furthermore, the volume ratio of the polyurethane prepolymer to the curing agent composition is 1:(0.5 - 1);

[0008] And / or, in the polyurethane prepolymer, the molar ratio of the isocyanate group in the aliphatic isocyanate to the hydroxyl group in the polyol is (1.5 - 2):1;

[0009] And / or, in the curing agent composition, the mass ratio of the compound containing a catechol group to the compound containing both a cationic group and an amino group is 1:(0.25 - 4); the concentration of the compound containing both a cationic group and an amino group is 5 - 10 wt%.

[0010] Preferably,

[0011] the volume ratio of the polyurethane prepolymer to the curing agent composition is 1:(0.75 - 1);

[0012] And / or, in the curing agent composition, the mass ratio of the compound containing a catechol group to the compound containing both a cationic group and an amino group is 1:(0.25 - 0.5).

[0013] More preferably,

[0014] in the curing agent composition, the mass ratio of the compound containing a catechol group to the compound containing both a cationic group and an amino group is 1:0.25.

[0015] Furthermore, the preparation method of the polyurethane prepolymer includes the following steps: adding an aliphatic isocyanate and a catalyst to a polyol, and obtaining the product after reaction;

[0016] Preferably,

[0017] in the preparation method of the polyurethane prepolymer, the mass of the catalyst is 0.02 - 0.8% of the total mass of the polyol and the aliphatic isocyanate;

[0018] And / or, in the preparation method of the polyurethane prepolymer, the moisture in the raw materials is removed before the reaction, and the reaction is carried out in a vacuum environment;

[0019] And / or, in the preparation method of the polyurethane prepolymer, the reaction temperature is 60 - 80°C, and the reaction time is 2 - 7 h; the reaction end point is that the actual NCO value reaches the theoretical NCO value.

[0020] More preferably,

[0021] the catalyst is an organic bismuth catalyst, and the organic bismuth catalyst is bismuth neodecanoate.

[0022] Furthermore,

[0023] the polyol is selected from one or more of polyethylene glycol, castor oil, polycaprolactone diol, and polycaprolactone triol;

[0024] and / or, the aliphatic isocyanate is an aliphatic diisocyanate;

[0025] and / or, the compound containing a catechol group is selected from one or more of catechol, caffeic acid and its derivatives, gallic acid, lignin, tannic acid, dopamine, epicatechin, and catechol-functionalized polymers;

[0026] and / or, the compound containing both a cationic group and an amino group is selected from one or more of polylysine and its derivatives, chitosan and its quaternized derivatives, protamine, histone, gelatin-quaternary ammonium salt derivatives, cationized hyaluronic acid, and polyasparagine-lysine copolymers;

[0027] and / or, the solvent is water, an aqueous biocompatible medium, or an aqueous solution containing a developer;

[0028] Preferably,

[0029] the number average molecular weight of the polyol is 200 - 1000;

[0030] and / or, the aliphatic diisocyanate is selected from one or more of isophorone diisocyanate, hexamethylene diisocyanate, and lysine diisocyanate.

[0031] Furthermore,

[0032] the polyol is polyethylene glycol; preferably, the number average molecular weight is 200, 400, or 600;

[0033] and / or, the aliphatic diisocyanate is L-lysine diisocyanate;

[0034] and / or, the compound containing a catechol group is tannic acid;

[0035] and / or, the compound containing both a cationic group and an amino group is selected from polylysine.

[0036] The present invention also provides a method for preparing the aforementioned two-component injectable polyurethane bioadhesive, which comprises the following steps:

[0037] (1) Dissolve and mix the curing agent composition uniformly;

[0038] (2) Mix the polyurethane prepolymer with the curing agent composition that is uniformly mixed in step (1) to obtain the product.

[0039] The present invention also provides a two-component injectable polyurethane bioadhesive product box, which is composed of component A and component B stored separately. Component A is the polyurethane prepolymer described above, and component B is the curing agent composition described above.

[0040] The present invention also provides the use of the aforementioned two-component injectable polyurethane bioadhesive or the aforementioned two-component injectable polyurethane bioadhesive product box in the preparation of an adhesive for tissue site bonding and sealing.

[0041] The present invention also provides the use of the aforementioned two-component injectable polyurethane bioadhesive or the aforementioned two-component injectable polyurethane bioadhesive product box in the preparation of a biomaterial for wound hemostasis and / or closure.

[0042] The present invention also provides the use of the aforementioned two-component injectable polyurethane bioadhesive or the aforementioned two-component injectable polyurethane bioadhesive product box in the preparation of a CT contrast agent; a CT-developable component is added to the two-component injectable polyurethane bioadhesive.

[0043] When the present invention is used, a two-component syringe can be used to fully mix the polyurethane prepolymer and the curing agent composition according to a specific volume ratio and then apply it to the tissue site.

[0044] When measuring the shear lap strength of the present invention, it is measured under a wet environment, which can illustrate that the bioadhesive of the present invention is suitable for a wet tissue environment.

[0045] The present invention significantly improves the wet adhesion of the adhesive through the synergistic effect of cation-catechol. At the same time, the inventors studied the effects of different compounds containing catechol groups and compounds containing both cation groups and amino groups in the preparation of bioadhesives, and found that the combination of tannic acid and polylysine has the best effect.

[0046] The application scenarios of the two-component injectable polyurethane bioadhesive of the present invention are as follows:

[0047] (1) This adhesive can be used for wound hemostasis and closure; it can also be used as a surgical adhesive for patch fixation, soft tissue repair and reconstruction, etc.

[0048] (2) A CT-developable component is introduced into this adhesive for the precise positioning of tumors, enabling the adhesive to be clearly visualized under CT scanning, facilitating doctors to accurately delineate the tumor target area and achieving the precise positioning of tumors.

[0049] The present invention provides a two-component injectable polyurethane bioadhesive, which is composed of component A polyurethane prepolymer and component B curing agent composition. When in use, component A and component B are fully mixed according to a specific volume ratio. The two components in the polyurethane bioadhesive of the present invention can be mixed by injection, and can be quickly cured after mixing. This adhesive can be degraded in vivo and has good biocompatibility. Moreover, this adhesive has good wet adhesiveness and can meet various clinical needs. After a developer is compounded in this adhesive, it has good developability and can be used for radiotherapy positioning. Therefore, the polyurethane bioadhesive of the present invention has good application prospects.

[0050] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0051] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Brief Description of the Drawings

[0052] Figure 1 It is the image of the adhesive in Example 9 under CT.

[0053] Figure 2 It is the time-dependent result graph of the storage modulus G' and loss modulus G'' of the polyurethane bioadhesive prepared in Example 8 of the present invention.

[0054] Figure 3 It is the biocompatibility test result of the polyurethane bioadhesive prepared in Example 8 of the present invention: A is the live / dead determination result of L929 cells by the extraction solution of adhesives (BPU) with different concentrations; B is the cytotoxicity determination result of L929 by the extraction solution of adhesives with different concentrations within 72 hours. Detailed Description of the Invention

[0055] The raw materials and equipment used in the present invention are all known products, obtained by purchasing commercially available products.

[0056] Example 1. Preparation of the two-component injectable polyurethane bioadhesive of the present invention

[0057] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 200), L-lysine diisocyanate, tannic acid, polylysine.

[0058] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0059] (1) Preparation of Component A (Polyurethane Prepolymer): 5.00 g of PEG200 dried by molecular sieve was added to a single-necked flask and placed in an oil bath. Under the condition of vacuum pumping (-0.1 MPa) at 110 °C, it was stirred to remove water for 3 h until the water content was less than 200 ppm, and then cooled to 50 °C. 9.61 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to the ratio of R = 1.7 (R = NCO / OH, molar ratio). In polyurethane synthesis, the addition amount of organic bismuth is generally 0.02 - 0.8% of the total mass of polyethylene glycol and L-lysine diisocyanate. After adding it to the reaction flask, it was stirred, vacuum pumped and purged with nitrogen 3 times to evacuate the air, and then heated to 75 °C and reacted for about 4 h to obtain a prepolymer (the end point of this prepolymer reaction is that the actual NCO value reaches the theoretical NCO value).

[0060] (2) Preparation of Component B (Curing Agent Composition): 4 g of tannic acid and 1 g of polylysine were dissolved in 20 mL of water according to the mass ratio of 4:1 and mixed evenly, and then ultrasonicated to obtain an aqueous solution of the mixed curing agent.

[0061] (3) In-situ Curing: The prepolymer prepared in step (1) and the aqueous solution of the curing agent prepared in step (2) were mixed according to a volume ratio of 4:3 and could be used as an adhesive. Applying it to the tissue site could achieve in-situ curing.

[0062] According to the ASTM F2255-05 standard, the lap shear force of the adhesive of the present invention for wet pig skin was measured, and the force and displacement data during stretching were recorded until the bonded specimen was damaged. The ex vivo skin of the pig was cut into regular shapes and soaked in PBS buffer to keep it in a wet state before being bonded with the adhesive. During the test, two pieces of wet pig skin were bonded with the adhesive, the bonding area was 10×10 mm, and the stretching rate during the test was 50 mm / min.

[0063] The adhesive prepared in this example could complete curing within 5 min, its maximum load for fresh pig skin was 10.78 N, and the shear lap strength was 107.78 kPa.

[0064] Example 2. Preparation of the Two-component Injectable Polyurethane Bioadhesive of the Present Invention

[0065] The raw materials for preparing the polyurethane bioadhesive in this example were: polyethylene glycol (Mn = 200), L-lysine diisocyanate, tannic acid, polylysine.

[0066] The process for preparing the polyurethane bioadhesive in this example was as follows:

[0067] (1) Preparation of Component A (Polyurethane Prepolymer): Add 5.00 g of PEG200 dried by molecular sieve into a single-neck flask and place it in an oil bath. Stir to remove water under vacuum (-0.1 MPa) at 110 °C for 3 h until the water content is less than 200 ppm, and then cool down to 50 °C. Add 11.31 g of L-lysine diisocyanate and 0.02 g of organic bismuth catalyst (bismuth neodecanoate) according to the ratio of R = 2 (R = NCO / OH, molar ratio). After adding them into the reaction flask, stir, evacuate the air by vacuum and replace it with nitrogen three times, and then heat to 75 °C and react for about 4 h to obtain the prepolymer (the reaction end point of this prepolymer is that the actual NCO value reaches the theoretical NCO value).

[0068] (2) Preparation of Component B (Curing Agent Composition): Dissolve 4 g of tannic acid and 1 g of polylysine in 20 mL of water according to the mass ratio of 4:1 and mix them evenly, and obtain the mixed curing agent aqueous solution by ultrasonic treatment.

[0069] (3) In-situ Curing: Mix the prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) according to the volume ratio of 1:1, which can be used as an adhesive. Applying it to the tissue site can achieve in-situ curing.

[0070] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0071] The adhesive prepared in this example can complete curing within 5 min. Its maximum load on fresh pigskin is 9.31 N, and the shear lap strength is 93.13 kPa.

[0072] Example 3. Preparation of the Two-component Injectable Polyurethane Bioadhesive of the Present Invention

[0073] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 400), L-lysine diisocyanate, tannic acid, polylysine.

[0074] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0075] (1) Preparation of Component A (Polyurethane Prepolymer): Add 5.00 g of PEG400 dried by molecular sieve into a single-neck flask and place it in an oil bath. Stir to remove water under vacuum (-0.1 MPa) at 110 °C for 3 h until the water content is less than 200 ppm, and then cool down to 50 °C. Add 4.24 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) according to the ratio of R = 1.5 (R = NCO / OH, molar ratio). After adding them into the reaction flask, stir, evacuate the air by vacuum and replace it with nitrogen three times, and then heat to 75 °C and react for about 4 h to obtain the prepolymer (the reaction end point of this prepolymer is that the actual NCO value reaches the theoretical NCO value).

[0076] (2) Preparation of Component B (Curing Agent Composition): Dissolve 4 g of tannic acid and 1 g of polylysine in 20 mL of water in a mass ratio of 4:1 and mix evenly, and obtain a mixed curing agent aqueous solution by ultrasonic treatment.

[0077] (3) In-situ curing: Mix the prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) in a volume ratio of 4:3, which can be used as an adhesive. Applying it to the tissue site can achieve in-situ curing.

[0078] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0079] The adhesive prepared in this example can complete curing within 5 min. Its maximum load on fresh pigskin is 15.01 N, and the shear lap strength is 150.1 kPa.

[0080] Example 4. Preparation of the Two-component Injectable Polyurethane Bioadhesive of the Present Invention

[0081] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 400), L-lysine diisocyanate, tannic acid, polylysine.

[0082] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0083] (1) Preparation of Component A (Polyurethane Prepolymer): Add 5 g of PEG400 dried by molecular sieve to a single-neck flask and place it in an oil bath. Stir and remove water under vacuum (-0.1 MPa) at 110 °C for 3 h until the water content is less than 200 ppm, and then cool to 50 °C. Add 5.66 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) according to the ratio of R = 2 (R = NCO / OH, molar ratio). After adding them to the reaction flask, stir, evacuate the air by vacuum and replace it with nitrogen 3 times, and heat to 75 °C and react for about 4 h to obtain a prepolymer (the end point of this prepolymer reaction is that the actual NCO value reaches the theoretical NCO value).

[0084] (2) Preparation of Component B (Curing Agent Composition): Dissolve 2 g of tannic acid and 1 g of polylysine in 20 mL of water in a mass ratio of 2:1 and mix evenly, and obtain a mixed curing agent aqueous solution by ultrasonic treatment.

[0085] (3) In-situ curing: Mix the prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) in a volume ratio of 1:1, which can be used as an adhesive. Applying it to the tissue site can achieve in-situ curing.

[0086] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0087] The adhesive prepared in this example can be cured within 5 minutes. Its maximum load on fresh pigskin is 4.72 N, and the shear lap strength is 47.23 kPa.

[0088] Example 5. Preparation of the two-component injectable polyurethane bioadhesive of the present invention

[0089] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 600), L-lysine diisocyanate, tannic acid, and polylysine.

[0090] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0091] (1) Preparation of Component A (polyurethane prepolymer): Add 5 g of PEG600 dried by molecular sieve to a single-neck flask and place it in an oil bath. Stir to remove water under vacuum (-0.1 MPa) at 110 °C for 3 h until the water content is less than 200 ppm, and then cool to 50 °C. Add 2.83 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) according to the ratio of R = 1.5 (R = NCO / OH, molar ratio). After adding to the reaction flask, stir, evacuate the air by vacuum and replace it with nitrogen 3 times, and heat to 75 °C and react for about 4 h to obtain a prepolymer (the end point of this prepolymer reaction is that the actual NCO value reaches the theoretical NCO value).

[0092] (2) Preparation of Component B (curing agent composition): Dissolve 4 g of tannic acid and 1 g of polylysine in 20 mL of water according to a mass ratio of 4:1 and mix evenly, and obtain a mixed curing agent aqueous solution by ultrasonic treatment.

[0093] (3) In-situ curing: Mix the prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) according to a volume ratio of 1:1 to obtain an adhesive, and apply it to the tissue site to achieve in-situ curing.

[0094] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0095] The adhesive prepared in this example can be cured within 5 minutes. Its maximum load on fresh pigskin is 11.50 N, and the shear lap strength is 115.04 kPa.

[0096] Example 6. Preparation of the two-component injectable polyurethane bioadhesive of the present invention

[0097] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 600), L-lysine diisocyanate, tannic acid, and polylysine.

[0098] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0099] (1) Preparation of Component A (Polyurethane Prepolymer): Add 5 g of PEG600 dried by molecular sieve into a single-necked flask and place it in an oil bath. Stir to remove water under vacuum (-0.1 MPa) at 110 °C for 3 h until the water content is less than 200 ppm, and then cool down to 50 °C. Add 3.21 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) according to the ratio of R = 1.7 (R = NCO / OH, molar ratio). After adding them into the reaction flask, stir, evacuate the air by vacuum and replace it with nitrogen three times, and then heat to 75 °C and react for about 4 h to obtain a prepolymer (the end point of this prepolymer reaction is that the actual NCO value reaches the theoretical NCO value).

[0100] (2) Preparation of Component B (Curing Agent Composition): Dissolve 4 g of tannic acid and 1 g of polylysine in 20 mL of water according to the mass ratio of 4:1 and mix them evenly, and then obtain a mixed curing agent aqueous solution by ultrasonic treatment.

[0101] (3) In-situ Curing: Mix the prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) according to the volume ratio of 1:1, which can be used as an adhesive. Applying it to the tissue site can achieve in-situ curing.

[0102] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0103] The adhesive prepared in this example can complete curing within 5 min. Its maximum load on fresh pigskin is 6.30 N, and the shear lap strength is 62.95 kPa.

[0104] Example 7. Preparation of a Two-component Injectable Polyurethane Bioadhesive of the Present Invention

[0105] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 600), polycaprolactone triol, castor oil, hexamethylene diisocyanate, tannic acid, polylysine.

[0106] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0107] (1) Preparation of Component A (Polyurethane Prepolymer): 15.00 g of PEG 600 dried by molecular sieve, 4.57 g of polycaprolactone triol, and 7.78 g of castor oil were added to a single-neck flask and placed in an oil bath. Under the condition of vacuum pumping (-0.1 MPa) at 110 °C, stirring was carried out for 3 h to remove water until the water content was less than 200 ppm, and then the temperature was lowered to 50 °C. 16.82 g of hexamethylene diisocyanate and 0.04 g of organic bismuth catalyst (bismuth neodecanoate) were added according to the ratio of R = 2 (R = NCO / OH, molar ratio). After adding to the reaction flask, stirring, vacuum pumping, and nitrogen replacement were carried out 3 times to evacuate air, and the reaction was carried out at 75 °C for 4 h to obtain a prepolymer (the end point of this prepolymer reaction is that the actual NCO value reaches the theoretical NCO value).

[0108] (2) Preparation of Component B (Curing Agent Composition): 4 g of tannic acid and 1 g of polylysine were dissolved in 20 mL of water according to the mass ratio of 4:1 and mixed evenly, and then ultrasonic treatment was carried out to obtain an aqueous solution of the mixed curing agent.

[0109] (3) In-situ Curing: The prepolymer prepared in step (1) and the aqueous solution of the curing agent prepared in step (2) were mixed according to a volume ratio of 1:1 to be used as an adhesive. Applying it to the tissue site can achieve in-situ curing.

[0110] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0111] The adhesive prepared in this example can complete curing within 5 min. Its maximum load on fresh pigskin is 1.81 N, and the shear lap strength is 18.16 kPa.

[0112] Example 8. Preparation of a Two-component Injectable Polyurethane Bioadhesive of the Present Invention

[0113] The raw materials for preparing the polyurethane bioadhesive in this example are: polyethylene glycol (Mn = 400), L-lysine diisocyanate, tannic acid, and polylysine.

[0114] The process for preparing the polyurethane bioadhesive in this example is as follows:

[0115] (1) Preparation of Component A (Polyurethane Prepolymer): 5 g of PEG400 dried by molecular sieve was added to a single-neck flask and placed in an oil bath. Under the condition of vacuum pumping (-0.1 MPa) at 110 °C, stirring was carried out for 3 h to remove water until the water content was less than 200 ppm, and then the temperature was lowered to 50 °C. 4.8 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to the ratio of R = 1.7 (R = NCO / OH, molar ratio). After adding to the reaction flask, stirring, vacuum pumping, and nitrogen replacement were carried out 3 times to evacuate air, and then heated to 75 °C and reacted for about 4 h to obtain a prepolymer (the end point of this prepolymer reaction is that the actual NCO value reaches the theoretical NCO value).

[0116] (2) Preparation of Component B (Curing Agent Composition): Dissolve 4 g of tannic acid and 1 g of polylysine in 20 mL of water in a mass ratio of 4:1 and mix evenly, and obtain a mixed curing agent aqueous solution by ultrasonic treatment.

[0117] (3) In-situ curing: The prepolymer prepared in step (1) and the aqueous solution of the curing agent prepared in step (2) are mixed in a volume ratio of 1:1 and can be used as an adhesive. Applying it to the woven part can achieve in-situ curing.

[0118] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0119] The adhesive prepared in this example can complete curing within 5 minutes. Its maximum load on fresh pigskin is 12.33 N, and the shear lap strength is 123.30 kPa.

[0120] Example 9. Imaging Performance of the Two-Component Injectable Polyurethane Bioadhesive of the Present Invention

[0121] This example provides a polyurethane bioadhesive with imaging performance. The difference between this example and Example 8 is that the curing agent is dissolved in an iodixanol aqueous solution (i.e., the medical iodixanol injection) instead of water, and the remaining steps are the same. The concentration of iodixanol in the iodixanol aqueous solution is 300 - 370 mgI / mL.

[0122] The shear lap strength of the bioadhesive obtained after adding iodixanol decreases, but still meets the use requirements, and the imaging function is increased. The adhesive of the present invention has good imaging performance under CT and no artifacts. Figure 1 as shown.

[0123] Comparative Example 1. Preparation of Other Polyurethane Bioadhesives

[0124] This comparative example provides a polyurethane bioadhesive. The difference between this comparative example and Example 6 is that polylysine is not added to the curing agent, and the remaining steps are the same.

[0125] Measure the maximum load and shear lap strength according to the method described in Example 1.

[0126] The curing time of the adhesive prepared in this comparative example is greater than 5 minutes. Its maximum load on fresh pigskin is 4.71 N, and the shear lap strength is 47.11 kPa.

[0127] Comparative Example 2. Preparation of Other Polyurethane Bioadhesives

[0128] This comparative example provides a polyurethane bioadhesive. The difference between this comparative example and Example 6 is that the curing agent is F220 polyaspartate resin, and the remaining steps are the same.

[0129] The maximum load and shear lap strength were measured according to the method described in Example 1.

[0130] The curing time of the adhesive prepared in this comparative example was about 10 min. Its maximum load on fresh pigskin was 2.47 N, and the shear lap strength was 24.70 kPa.

[0131] The beneficial effects of the present invention are demonstrated by the following specific test examples.

[0132] Test Example 1. Rheological properties and biological safety test of the polyurethane bio - adhesive of the present invention

[0133] The polyurethane bio - adhesive prepared in Example 8 was subjected to rheological property and biological safety tests as follows:

[0134] (1) Rheological test: The gelation process of the adhesive was detected by a modular intelligent rheometer (MCR302). The prepolymer and the aqueous curing agent solution were mixed in the rheometer at 37 °C. The time - sweep analysis of the mixture was carried out at a strain of 1% and a frequency of 1 Hz. Figure 2 For the test results of rheological properties. From Figure 2 it can be seen that at the beginning, the storage modulus (G′) was lower than the loss modulus (G"). As time went on, the storage modulus and the loss modulus gradually increased. At about 160 s (2.8 min), the storage modulus was higher than the loss modulus, indicating that the adhesive formed a cross - linked network. As time was further extended, G′ and G" continued to increase, indicating that the cross - linked network was gradually improving with the extension of time and the interaction force was stronger.

[0135] (2) Biological safety test: According to the ISO10993 - 12 standard, the sample cured in Example 8 was immersed in the culture medium for 24 h to prepare an extract of 1 mg / mL, and was diluted 10 times and 100 times respectively, filtered through a 220 nm membrane, and the toxicity of the extract to L929 cells was determined by the CCK - 8 method and the live - dead staining method. The results showed that ( Figure 3 ) the viability of L929 cells remained above 80% after 24 h, 48 h and 72 h, and the fluorescence results showed that there were more live cells, indicating that the adhesive of the present invention had good biological safety.

[0136] In summary, the present invention provides a two-component injectable polyurethane bioadhesive, which is composed of component A polyurethane prepolymer and component B curing agent composition. When in use, component A and component B are fully mixed according to a specific volume ratio. The two components in the polyurethane bioadhesive of the present invention can be mixed by injection, and can be quickly cured after mixing. This adhesive can be degraded in vivo and has good biocompatibility. Moreover, this adhesive has good wet adhesion and can meet various clinical needs. After a developer is compounded in this adhesive, it has good developability and can be used for radiotherapy positioning. Therefore, the polyurethane bioadhesive of the present invention has good application prospects.

Claims

1. A two-component injectable polyurethane bioadhesive, characterized in that: It is prepared from polyurethane prepolymer and curing agent composition as raw materials; the polyurethane prepolymer is obtained by the reaction of aliphatic isocyanate and polyol; the curing agent composition is composed of a compound containing catechol group, a compound containing cationic group and amino group at the same time, and a solvent.

2. The two-component injectable polyurethane bioadhesive according to claim 1, characterized in that: The volume ratio of the polyurethane prepolymer to the curing agent composition is 1:(0.5-1); and / or, in the polyurethane prepolymer, the molar ratio of isocyanate in the aliphatic isocyanate to hydroxyl in the polyol is (1.5-2):1; And / or, in the curing agent composition, the mass ratio of the compound containing catechol group to the compound containing both cationic group and amino group is 1:(0.25-4); the concentration of the compound containing both cationic group and amino group is 5-10wt%.

3. The two-component injectable polyurethane bioadhesive according to claim 2, characterized in that: The preparation method of the polyurethane prepolymer comprises the following steps: adding aliphatic isocyanate and a catalyst into polyol to obtain the prepolymer after reaction; Preferably, In the preparation method of the polyurethane prepolymer, the mass of the catalyst is 0.02-0.8% of the total mass of the polyol and the aliphatic isocyanate; And / or, in the method for preparing the polyurethane prepolymer, water content of the raw materials is removed before the reaction, and the reaction is carried out under a vacuum environment; And / or, in the method for preparing the polyurethane prepolymer, the reaction temperature is 60-80° C. and the reaction time is 2-7 hours; More preferably, The catalyst is an organic bismuth catalyst.

4. The two-component injectable polyurethane bioadhesive according to any one of claims 1 to 3, characterized in that: The polyol is selected from one or more of polyethylene glycol, castor oil, polycaprolactone diol, and polycaprolactone triol; and / or, the aliphatic isocyanate is an aliphatic diisocyanate; And / or, the compound containing catechol group is selected from one or more of catechol, caffeic acid and its derivatives, gallic acid, lignin, tannic acid, dopamine, epicatechin, catechol functionalized polymer; And / or, the compound containing both a cationic group and an amino group is selected from one or more of polylysine and its derivatives, chitosan and its quaternary ammonium derivatives, protamine, histone, gelatin-quaternary ammonium salt derivatives, cationic hyaluronic acid, and polyasparagine-lysine copolymer; and / or, the solvent is water, a biocompatible medium containing water, or an aqueous solution containing a developer; Preferably, The number average molecular weight of the polyol is 200-1000; And / or, the aliphatic diisocyanate is one or more selected from isophorone diisocyanate, hexamethylene diisocyanate, and lysine diisocyanate.

5. The two-component injectable polyurethane bioadhesive according to claim 4, characterized in that: The polyol is polyethylene glycol; and / or, the aliphatic diisocyanate is L-lysine diisocyanate; and / or, the compound containing a catechol group is tannic acid; And / or, the compound containing both a cationic group and an amino group is selected from polylysine.

6. The method for preparing the two-component injectable polyurethane bioadhesive according to any one of claims 1 to 5, characterized in that: It includes the following steps: (1) dissolving the curing agent composition and mixing it uniformly; (2) Mixing the polyurethane prepolymer with the curing agent composition mixed evenly in step (1) to obtain.

7. A two-component injectable polyurethane bioadhesive product box, characterized in that: It consists of component A and component B which are stored separately. Component A is the polyurethane prepolymer described in any one of claims 1 to 5, and component B is the curing agent composition described in any one of claims 1 to 5.

8. Use of the two-component injectable polyurethane bioadhesive according to any one of claims 1 to 5 or the two-component injectable polyurethane bioadhesive product box according to claim 7 in the preparation of an adhesive for bonding and sealing tissue sites.

9. Use of the two-component injectable polyurethane bioadhesive according to any one of claims 1 to 5 or the two-component injectable polyurethane bioadhesive product kit according to claim 7 in the preparation of biomaterials for wound hemostasis and / or closure.

10. Use of the two-component injectable polyurethane bioadhesive according to any one of claims 1 to 5 or the two-component injectable polyurethane bioadhesive product box according to claim 7 in the preparation of CT developer; a CT developable component is added to the two-component injectable polyurethane bioadhesive.

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