Two-component injectable polyurethane bioadhesive, process for its preparation and use

Abstract

The application 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 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; and the curing agent composition is composed of a compound containing a catechol group, a compound containing a cationic group and an amino group at the same time, and a solvent.The two components in the polyurethane biological adhesive can be mixed by injection, and the adhesive can be quickly cured after mixing; the adhesive is degradable in vivo, has good biocompatibility, has good wet adhesion, and can meet various clinical requirements; and 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 has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of medical adhesive technology, specifically relating to a two-component injectable polyurethane bioadhesive, its preparation method, and its application. Background Technology

[0002] As an alternative to traditional surgical sutures, medical tissue adhesives have attracted increasing attention and research due to their advantages such as real-time hemostasis, effective sealing, non-invasive adhesion, and ease of use, which can improve surgical outcomes and success rates. Bioactive tissue adhesives possess tunable biomechanical and biochemical properties, enabling them to establish a strong adhesive interface with tissues, thus aiding in surgical suturing, hemostasis, and leakage prevention, making them attractive for soft tissue wound management and healing.

[0003] Currently, medical adhesives mainly include fibrous adhesives, cyanoacrylate adhesives, polyethylene glycol adhesives, and polyurethane adhesives. 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. Chinese patent application CN116899007A proposes using secondary amine compounds as curing agents to solve the problem of slow curing of polyurethane adhesives. However, its curing process is exothermic, and the synthesis of the curing agent requires purification processes such as column chromatography or extraction, making the synthesis process complex. Chinese patent application CN116023623A proposes preparing a biodegradable polyurethane adhesive by introducing ester bonds into the molecular structure of the polyurethane adhesive. However, the preparation process is complex, and the use of catalysts may pose potential toxicity risks. Chinese patent application CN116712595A proposes adjusting the curing time of the adhesive by selectively adding tertiary amine compounds to the prepolymer. However, it uses small molecule polyhydroxy compounds as chain extenders, resulting in a relatively fast degradation rate of the prepared adhesive.

[0004] Furthermore, in actual clinical use, adhesives often struggle to achieve strong adhesion to moist soft tissues, particularly in environments prone to tissue fluid or blood exudation. Chinese patent application CN118079061A discloses a two-component polyurethane-based bioadhesive for soft tissues. This adhesive is rapidly curing, biodegradable, and possesses good hydrophilicity, excellent adhesion, and sealing effects, making it suitable for various tissue environments and meeting diverse clinical needs. However, the shear overlap strength of this adhesive still needs improvement. Summary of the Invention

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

[0006] This 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 catechol groups, a compound containing both cationic groups and amino groups, and a solvent.

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

[0008] 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;

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

[0010] Preferably,

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

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

[0013] More preferably,

[0014] In the curing agent composition, the mass ratio of the compound containing catechol groups to the compound containing both cationic groups and amino groups 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 prepolymer after reaction;

[0016] Preferably,

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

[0018] And / or, in the method for preparing 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 method for preparing the polyurethane prepolymer, the reaction temperature is 60-80℃, the reaction time is 2-7h, and the reaction endpoint is when the actual NCO value reaches the theoretical NCO value.

[0020] More preferably,

[0021] The catalyst is an organobismuth catalyst. The organobismuth 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 the 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 cationic groups and amino groups is selected from one or more of polylysine and its derivatives, chitosan and its quaternized derivatives, protamine, histone, gelatin-quaternary ammonium salt derivatives, cationic 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 the catechol group is tannic acid;

[0035] And / or, the compound containing both cationic groups and amino groups is selected from polylysine.

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

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

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

[0039] The present invention also provides a two-component injectable polyurethane bioadhesive product box, which consists of separately stored component A and component B, wherein 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 adhesives 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 biomaterials 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 cartridge in the preparation of CT contrast agents; wherein a CT-contrast component is added to the two-component injectable polyurethane bioadhesive.

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

[0044] The shear overlap strength of this invention was measured in a wet environment, which indicates that the bio-adhesive of this invention is suitable for moist tissue environments.

[0045] This invention significantly enhances the wet adhesion of adhesives through the synergistic effect of cationic-catechol. The inventors also investigated the effects of different compounds containing cationic groups and compounds containing both cationic and amino groups in the preparation of bio-adhesives, finding that the combination of tannic acid and polylysine yielded the best results.

[0046] The application scenarios of the two-component injectable polyurethane bio-adhesive of this invention are as follows:

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

[0048] (2) The adhesive incorporates CT-detectable components for precise tumor localization, enabling the adhesive to be clearly visualized under CT scans, facilitating precise delineation of the tumor target area by doctors and achieving precise tumor localization.

[0049] This invention provides a two-component injectable polyurethane bioadhesive, which consists of a polyurethane prepolymer (component A) and a curing agent (component B). Components A and B are thoroughly mixed at a specific volume ratio before use. The two components of this polyurethane bioadhesive can be mixed via injection, and the mixture cures rapidly. The adhesive is biodegradable in vivo and exhibits good biocompatibility. Furthermore, the adhesive demonstrates excellent wet adhesion, meeting various clinical needs. When combined with a contrast agent, the adhesive exhibits excellent radioactivity and can be used for radiotherapy localization. Therefore, this polyurethane bioadhesive has promising application prospects.

[0050] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0051] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0052] Figure 1 The image shows the adhesive of Example 9 under CT scan.

[0053] Figure 2 The graph shows the time dependence of the storage modulus G' and loss modulus G” of the polyurethane bio-adhesive prepared in Example 8 of this invention.

[0054] Figure 3 The biocompatibility test results of the polyurethane bioadhesive prepared in Example 8 of the present invention are as follows: A is the result of the live / dead assay of L929 cells by different concentrations of adhesive (BPU) extract; B is the result of the cytotoxicity assay of L929 cells by different concentrations of adhesive extract within 72 h. Detailed Implementation

[0055] The raw materials and equipment used in this 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 embodiment are: polyethylene glycol (Mn=200), L-lysine diisocyanate, tannic acid, and polylysine.

[0058] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0059] (1) Preparation of component A (polyurethane prepolymer): 5.00 g of PEG200 dried through molecular sieves was added to a single-necked flask placed in an oil bath. The mixture was stirred and dried under vacuum (-0.1 MPa) at 110°C for 3 hours until the water content was less than 200 ppm. The temperature was then lowered to 50°C. 9.61 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 1.7 (R = NCO / OH, molar ratio). In polyurethane synthesis, the amount of organic bismuth added is generally 0.02-0.8% of the total mass of polyethylene glycol and L-lysine diisocyanate. After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0060] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

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

[0062] The lap shear force of the adhesive of this invention on moist pig skin was determined according to ASTM F2255-05 standard. Force and displacement data during tensile testing were recorded until the bonded specimen was destroyed. Ex vivo pig skin was cut into regular shapes and kept moist by soaking in PBS buffer before bonding with the adhesive. During testing, two pieces of moist pig skin were bonded together with the adhesive, with a bonding area of ​​10 × 10 mm, and the tensile rate was 50 mm / min.

[0063] The adhesive prepared in this embodiment can be cured within 5 minutes, and its maximum load on fresh pigskin is 10.78 N, and its shear overlap strength is 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 embodiment are: polyethylene glycol (Mn=200), L-lysine diisocyanate, tannic acid, and polylysine.

[0066] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0067] (1) Preparation of component A (polyurethane prepolymer): 5.00 g of PEG200 dried by molecular sieve was added to a single-necked flask placed in an oil bath. The mixture was stirred and dried under vacuum (-0.1 MPa) at 110°C for 3 hours until the water content was less than 200 ppm. The temperature was then lowered to 50°C. 11.31 g of L-lysine diisocyanate and 0.02 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 2 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was then heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0068] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

[0069] (3) In-situ curing: The prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) are mixed at a volume ratio of 1:1 and can be used as an adhesive. Applying it to the tissue can achieve in-situ curing.

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

[0071] The adhesive prepared in this embodiment can be cured within 5 minutes, and its maximum load on fresh pigskin is 9.31 N, and its shear overlap 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 embodiment are: polyethylene glycol (Mn=400), L-lysine diisocyanate, tannic acid, and polylysine.

[0074] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0075] (1) Preparation of component A (polyurethane prepolymer): 5.00 g of PEG400 dried by molecular sieve was added to a single-necked flask placed in an oil bath. The mixture was stirred at 110°C under vacuum (-0.1 MPa) for 3 hours to remove water until the water content was less than 200 ppm. The temperature was then lowered to 50°C. 4.24 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 1.5 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was then heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0076] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

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

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

[0079] The adhesive prepared in this embodiment can be cured within 5 minutes, and its maximum load on fresh pigskin is 15.01 N, and its shear overlap 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 embodiment are: polyethylene glycol (Mn=400), L-lysine diisocyanate, tannic acid, and polylysine.

[0082] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0083] (1) Preparation of component A (polyurethane prepolymer): 5 g of PEG4005 dried through molecular sieve was added to a single-necked flask placed in an oil bath. The mixture was stirred and dried under vacuum (-0.1 MPa) at 110°C for 3 hours until the water content was less than 200 ppm. The temperature was then lowered to 50°C. 5.66 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 2 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was then heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0084] (2) Preparation of component B (curing agent composition): Dissolve 2g of tannic acid and 1g of polylysine in 20mL of water at a mass ratio of 2:1 and mix evenly. Then, sonicate to obtain a mixed curing agent aqueous solution.

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

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

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

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

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

[0090] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0091] (1) Preparation of component A (polyurethane prepolymer): 5 g of PEG6005 dried through molecular sieve was added to a single-necked flask placed in an oil bath. The mixture was stirred and dried under vacuum (-0.1 MPa) at 110°C for 3 hours until the water content was less than 200 ppm. The temperature was then lowered to 50°C. 2.83 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 1.5 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was then heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0092] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

[0093] (3) In-situ curing: The prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) are mixed at a volume ratio of 1:1 and can be used as an adhesive. Applying it to the tissue can achieve in-situ curing.

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

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

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

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

[0098] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0099] (1) Preparation of component A (polyurethane prepolymer): 5 g of PEG6005 dried through molecular sieve was added to a single-necked flask placed in an oil bath. The mixture was stirred and dried under vacuum (-0.1 MPa) at 110°C for 3 hours until the water content was less than 200 ppm. The temperature was then lowered to 50°C. 3.21 g of L-lysine diisocyanate and 0.01 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 1.7 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was then heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0100] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

[0101] (3) In-situ curing: The prepolymer prepared in step (1) and the curing agent aqueous solution prepared in step (2) are mixed at a volume ratio of 1:1 and can be used as an adhesive. Applying it to the tissue can achieve in-situ curing.

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

[0103] The adhesive prepared in this embodiment can be cured within 5 minutes, and its maximum load on fresh pigskin is 6.30 N, and its shear overlap strength is 62.95 kPa.

[0104] Example 7: Preparation of the two-component injectable polyurethane bioadhesive of the present invention

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

[0106] The process for preparing the polyurethane bio-adhesive in this embodiment 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-necked flask placed in an oil bath. The mixture was stirred and dried under vacuum (-0.1 MPa) at 110 °C for 3 h until the water content was less than 200 ppm. The temperature was then lowered to 50 °C. 16.82 g of hexamethylene diisocyanate and 0.04 g of organic bismuth catalyst (bismuth neodecanoate) were added according to a ratio of R = 2 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The reaction was carried out at 75 °C for 4 h to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0108] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

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

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

[0111] The adhesive prepared in this embodiment can be cured within 5 minutes, and its maximum load on fresh pigskin is 1.81 N, and its shear overlap strength is 18.16 kPa.

[0112] Example 8: Preparation of the two-component injectable polyurethane bioadhesive of the present invention

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

[0114] The process for preparing the polyurethane bio-adhesive in this embodiment is as follows:

[0115] (1) Preparation of component A (polyurethane prepolymer): PEG4005 g dried by molecular sieve was added to a single-necked flask placed in an oil bath. The mixture was stirred at 110°C under vacuum (-0.1 MPa) for 3 hours to remove water until the water content was less than 200 ppm. The temperature was then 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 a ratio of R = 1.7 (R = NCO / OH, molar ratio). After being added to the reaction flask, the mixture was stirred, evacuated, and purged with nitrogen three times to remove air. The mixture was heated to 75°C and reacted for approximately 4 hours to obtain the prepolymer (the reaction endpoint of this prepolymer was when the actual NCO value reached the theoretical NCO value).

[0116] (2) Preparation of component B (curing agent composition): Dissolve 4g tannic acid and 1g polylysine in 20mL water at a mass ratio of 4:1 and mix evenly. The mixture is then sonicated to obtain a mixed curing agent aqueous solution.

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

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

[0119] The adhesive prepared in this embodiment can be cured within 5 minutes, and its maximum load on fresh pigskin is 12.33 N, and its shear overlap strength is 123.30 kPa.

[0120] Example 9: Development performance of the two-component injectable polyurethane bioadhesive of the present invention

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

[0122] The shear overlap strength of the bio-adhesive obtained after adding iodofol decreased slightly, but it still met the usage requirements, and the imaging performance was improved. The adhesive of this invention exhibits good imaging performance under CT scans, with no artifacts. Figure 1 As shown.

[0123] Comparative Example 1: Preparation of other polyurethane bio-adhesives

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

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

[0126] The adhesive prepared in this comparative example has a curing time of more than 5 minutes, a maximum load of 4.71 N on fresh pigskin, and a shear overlap strength of 47.11 kPa.

[0127] Comparative Example 2: Preparation of other polyurethane bio-adhesives

[0128] This comparative example provides a polyurethane bio-adhesive. The difference between this comparative example and Example 6 is that the curing agent is F220 polyaspartic acid ester resin, while the other steps are the same.

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

[0130] The adhesive prepared in this comparative example has a curing time of about 10 minutes, a maximum load of 2.47 N on fresh pigskin, and a shear overlap strength of 24.70 kPa.

[0131] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0132] Test Example 1: Rheological properties and biosafety testing of the polyurethane bio-adhesive of the present invention.

[0133] The rheological properties and biosafety of the polyurethane bio-adhesive prepared in Example 8 were tested, as follows:

[0134] (1) Rheological testing: The gelation process of the adhesive was detected by a modular intelligent rheometer (MCR302). The prepolymer and curing agent aqueous solution were mixed in the rheometer at 37°C. The time scan analysis of the mixture was performed at 1% strain and 1 Hz frequency. Figure 2 These are the results of rheological performance tests. (From...) Figure 2 It can be seen that initially the storage modulus (G′) was lower than the loss modulus (G”). As time progressed, both the storage modulus and the loss modulus gradually increased. Around 160 s (2.8 min), the storage modulus exceeded the loss modulus, indicating that the adhesive had formed a cross-linked network. With further extension of time, G′ and G” continued to increase, indicating that the cross-linked network was gradually improving and the interaction forces were becoming stronger.

[0135] (2) Biosafety test: Following ISO 10993-12 standard, the solidified sample from Example 8 was immersed in culture medium for 24 hours to prepare a 1 mg / mL extract. This extract was then diluted 10-fold and 100-fold, filtered through a 220 nm membrane, and the toxicity of the extract to L929 cells was determined using the CCK-8 assay and live-dead staining method. The results showed that ( Figure 3 The viability of L929 cells remained above 80% after 24h, 48h and 72h, and the fluorescence results showed that there were a large number of live cells, indicating that the adhesive of the present invention has good biosafety.

[0136] In summary, this invention provides a two-component injectable polyurethane bioadhesive, which consists of component A (polyurethane prepolymer) and component B (curing agent). Components A and B are thoroughly mixed at a specific volume ratio before use. The two components of this polyurethane bioadhesive can be mixed via injection, and the mixture cures rapidly. The adhesive is biodegradable in vivo and exhibits good biocompatibility. Furthermore, the adhesive demonstrates excellent wet adhesion, meeting various clinical needs. When combined with a contrast agent, the adhesive exhibits excellent radioactivity and can be used for radiotherapy localization. Therefore, this polyurethane bioadhesive has promising application prospects.

Claims

1. A two-component injectable polyurethane bioadhesive, characterized in that: It 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 catechol groups, a compound containing both cationic groups and amino groups, and a solvent; The polyol is polyethylene glycol; The aliphatic isocyanate is L-lysine diisocyanate; The compound containing the catechol group is tannic acid; The compound containing both cationic groups and amino groups is selected from polylysine.

2. The two-component injectable polyurethane bioadhesive according to claim 1, characterized in that: The volume ratio of the polyurethane prepolymer and 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 groups to the compound containing both cationic and amino groups is 1:(0.25-4); the concentration of the compound containing both cationic and amino groups is 5-10 wt%.

3. The two-component injectable polyurethane bioadhesive according to claim 2, characterized in that: The preparation method of the polyurethane prepolymer includes the following steps: adding aliphatic isocyanate and catalyst to polyol, and then reacting to obtain the prepolymer.

4. The two-component injectable polyurethane bioadhesive according to claim 3, characterized in that: In the method for preparing the polyurethane prepolymer, the mass of the catalyst is 0.02-0.8% of the total mass of the polyol and aliphatic isocyanate; And / or, in the method for preparing the polyurethane prepolymer, the moisture in the raw materials is removed before the reaction, and the reaction is carried out in a vacuum environment; And / or, in the method for preparing the polyurethane prepolymer, the reaction temperature is 60-80℃ and the reaction time is 2-7 h.

5. The two-component injectable polyurethane bioadhesive according to claim 4, characterized in that: The catalyst is an organic bismuth catalyst.

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) Dissolve the curing agent composition and mix it evenly; (2) Mix the polyurethane prepolymer with the curing agent composition that was mixed evenly in step (1) to obtain the product.

7. A two-component injectable polyurethane bioadhesive product box, characterized in that: It consists of separately stored component A and component B, wherein component A is the polyurethane prepolymer as described in any one of claims 1 to 5, and component B is the curing agent composition as 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 adhesives for tissue site bonding and sealing.

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 box according to claim 7 in the preparation of biomaterials for wound hemostasis and / or closure.

10. The 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 cartridge according to claim 7 in the preparation of CT contrast agents, characterized in that: A CT-detectable component is added to the two-component injectable polyurethane bioadhesive.

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