High-performance degradable biomedical tissue adhesive and preparation method and application thereof

Abstract

The application discloses a kind of high-performance degradable biomedical tissue adhesive and its preparation method and application, belong to medical tissue adhesive technical field, comprising: polyester polymer, high molecular with flexible segment and functional small molecule with reactive group are mixed to obtain mixture, chain extender is added, and high-performance degradable biomedical tissue adhesive is obtained.The biomedical tissue adhesive of the application is based on polyester-flexible segment-functional small molecule adhesive.The polyester is connected with flexible segment by chain extension reaction, and reactive group is introduced in side chain, and covalent bond is formed with tissue surface group, so as to realize firm adhesion.High molecular with flexible segment makes biomedical tissue adhesive have higher chain movement ability at physiological temperature, and good flexibility is given to adhesive, so that the elastic modulus matched with tissue is obtained.Polyester provides effective cohesive strength through its crystallization behavior.

Description

Technical Field

[0001] This invention belongs to the field of medical tissue adhesive technology. More specifically, this invention relates to a high-performance biodegradable biomedical tissue adhesive, its preparation method, and its application. Background Technology

[0002] Ideal medical tissue adhesives need to achieve strong and stable adhesion to moist biological tissue surfaces, while possessing excellent biocompatibility and a degradation cycle that matches the tissue healing process. However, several commonly used clinical adhesives fail to fully meet this comprehensive requirement due to their inherent limitations. For example, although cyanoacrylate adhesives have high adhesive strength, their degradation products often trigger severe inflammatory reactions and even toxicity, limiting their widespread use in vivo. In contrast, fibrin glue has good biocompatibility, but its significantly insufficient adhesive properties lead to easy failure at moist interfaces, typically limiting its use to suture aids. Similarly, polyethylene glycol (PEG)-based hydrogels not only suffer from poor adhesion but are also prone to swelling, compressing wound tissue and hindering healing.

[0003] To fundamentally address the issues of biocompatibility and degradation safety, poly(p-dioxanone) (PPDO), a high-performance biomaterial, has come into the research spotlight. The ester bonds in the PPDO backbone can be broken through a safe hydrolysis process under physiological conditions, ultimately metabolizing into non-toxic small molecules and excreting them from the body, thus effectively avoiding the risk of degradation toxicity. Furthermore, its molecular chain possesses both flexibility and moderate crystallinity, endowing the material with excellent cohesive strength, providing a foundation for withstanding tissue tension.

[0004] However, the excellent cohesive properties of PPDO alone are insufficient to achieve strong adhesion to tissues. Research and practice have shown that chemical covalent bonding (e.g., utilizing active functional groups such as N-hydroxysuccinimide ester and catechol) is an effective strategy for constructing high-strength, high-stability interfacial adhesions. Therefore, combining the superior matrix properties of PPDO with efficient covalent adhesion chemistry presents a promising yet challenging development path.

[0005] In summary, there is an urgent need in this field for an innovative technical solution that can organically integrate the intrinsic advantages of PPDO with the high-strength adhesion mechanism of covalent cross-linking, thereby creating a new generation of tissue adhesive that combines strong adhesion, controllable degradation, excellent biocompatibility, and sufficient mechanical strength. Summary of the Invention

[0006] One object of the present invention is to solve the above-mentioned problems and / or defects, and to provide advantages that will be described later.

[0007] This invention provides a high-performance, biodegradable poly(p-dioxanone)-based tissue adhesive, its preparation method, and its applications. This adhesive is based on PPDO (polydioxanone) – flexible segment – ​​functional small molecule. PPDO is linked to a biocompatible hydrophilic polymer (such as PEG or PTMEG) with high chain mobility under physiological conditions via a chain extension reaction. Succinimidyl ester groups are introduced onto the side chains, forming covalent bonds with tissue surface groups to achieve strong adhesion. The low melting point of PEG or PTMEG gives them high chain mobility at physiological temperatures, endowing the adhesive with good flexibility and thus achieving an elastic modulus matching the tissue. PPDO provides effective cohesive strength through its crystallization behavior.

[0008] A high-performance biodegradable biomedical tissue adhesive comprises: a polyester polymer, a polymer with flexible segments, a functional small molecule with reactive groups, and a chain extender; wherein the polyester polymer includes one of polydioxanone, polylactic acid, and polycaprolactone; the polymer with flexible segments includes one of polyethylene glycol, polytetrahydrofuran, and polytrimethylene carbonate; and the functional small molecule with reactive groups is the functional small molecule NHBP.

[0009] Preferably, the polyester polymer accounts for 10% to 90% of the total mass, the polymer with flexible segments accounts for 10% to 90% of the total mass, the functional small molecules with reactive groups account for 10% to 90% of the total mass, and the amount of chain extender added satisfies an R value of 0.1 to 2.

[0010] Preferably, the poly(p-dioxanone) has hydroxyl groups at both ends, and the molecular weight of the poly(p-dioxanone) is 2 × 10⁻⁶. 2 Da~1×10 5 Da.

[0011] Preferably, the polymer with flexible segments has hydroxyl groups at both ends, and the molecular weight of the polymer with flexible segments is 1×10⁻⁶. 2 Da~1×10 5 Da.

[0012] Preferably, the chain extender is 1,6-hexamethylene diisocyanate.

[0013] Preferably, the reactive groups in the functional small molecule having reactive groups include N-hydroxysuccinimide ester groups and hydroxyl groups.

[0014] Preferably, the structural formula of the functional small molecule NHBP is: .

[0015] The preparation methods of functional small molecule NHBP include: Step 1: Dissolve 2,2-bis(hydroxymethyl)propionic acid and 2,2-dimethoxypropane in acetone, then add p-toluenesulfonic acid and react at room temperature for 3-8 hours. Then add sodium bicarbonate to neutralize, stir for 15-45 minutes, filter to obtain a clear liquid, and rotary evaporate to obtain a white solid. Dissolve the white solid in dichloromethane, wash several times with deionized water, dry the organic phase with anhydrous magnesium sulfate, filter, and rotary evaporate to obtain a white solid product S1. The ratio of 2,2-bis(hydroxymethyl)propionic acid, 2,2-dimethoxypropane, acetone, p-toluenesulfonic acid, sodium bicarbonate, and dichloromethane is 15-25 mmol: 20-30 mmol: 50-100 mL: 0.5-1 g: 5-6 g: 50-100 mL. Step 2: Dissolve the white solid product S1 from Step 1 and N-hydroxysuccinimide in dichloromethane, then add 1-ethyl-3-(3-dimethylaminopropyl)diimide hydrochloride. React in an ice-water bath under a nitrogen atmosphere for 1-4 hours, then raise the temperature to room temperature and continue the reaction for 12-36 hours. After the reaction is complete, wash the system several times with deionized water, separate the liquid and liquid phases, dry the organic phase with anhydrous magnesium sulfate, filter, and rotary evaporate to obtain the white solid product S2. The ratio of white solid product S1, N-hydroxysuccinimide, dichloromethane, and 1-ethyl-3-(3-dimethylaminopropyl)diimide hydrochloride is 3 mmol-6 mmol: 5 mmol-8 mmol: 15 mL-30 mL: 10 mmol-15 mmol. Step 3: Bubbling methanol under nitrogen gas in a reaction vessel for 15-45 minutes, adding the white solid product S2 from Step 2 and trifluoroacetic acid, reacting at room temperature under nitrogen atmosphere for 6-12 hours, then adding molecular sieves for drying, filtering, rotary evaporation, and drying to obtain the functional small molecule NHBP; wherein, the ratio of methanol, white solid product S2 and trifluoroacetic acid is 50-100 mL: 5 mmol-15 mmol: 1-2 g.

[0016] A method for preparing a high-performance biodegradable biomedical tissue adhesive includes the following steps: mixing a polyester polymer, a polymer with flexible segments, and a functional small molecule with reactive groups to obtain a mixture; heating the mixture and adding a chain extender to carry out a chain extension reaction to obtain a high-performance biodegradable biomedical tissue adhesive; the heating reaction temperature of the mixture is 25℃~200℃, and the reaction time is 10min~360min.

[0017] A method for preparing a high-performance biodegradable biomedical tissue adhesive includes the following steps: First, a polymer with flexible chain segments and a functional small molecule with reactive groups are mixed to obtain a mixture. The mixture is then heated, and a chain extender is added to carry out a chain extension reaction to obtain a prepolymer. The heating reaction temperature of the mixture is 25℃~200℃, and the reaction time is 10~360min. The prepolymer and polyester polymer are mixed to obtain a mixture. The mixture is heated and a chain extender is added to carry out a chain extension reaction to obtain a high-performance biodegradable biomedical tissue adhesive. The heating reaction temperature of the mixture is 25℃~200℃ and the reaction time is 10min~360min.

[0018] Application of a high-performance biodegradable biomedical tissue adhesive, wherein the high-performance biodegradable biomedical tissue adhesive is used as a medical tissue adhesive.

[0019] The present invention has at least the following beneficial effects: (1) High adhesion strength and stable bonding: Through molecular design, succinimide ester active groups are introduced into the side chain. These groups can undergo efficient covalent cross-linking with amino groups on the tissue surface, thereby achieving strong and durable chemical adhesion to the tissue interface, which is far superior to existing products that rely on physical adsorption.

[0020] (2) Matching mechanical properties and good adhesion: By introducing polyethylene glycol (PEG) segments through chain extension reaction, and utilizing its high chain segment mobility at physiological temperature, the adhesive body is effectively endowed with excellent flexibility and extensibility, so that its elastic modulus matches that of human soft tissue, reducing the stress pressure on tissue caused by mechanical mismatch.

[0021] (3) Excellent cohesive strength and reliable use: The polydioxanone (PPDO) segments provide strong cohesive strength to the entire adhesive system through their regular molecular structure and controllable crystallization behavior. This ensures that the material will not undergo cohesive failure under stress, thereby guaranteeing the long-term stability of the adhesive interface. (4) Controllable degradation cycle to meet clinical needs: By precisely controlling the polymerization process, the molecular weight of the product is maintained within a specific range. This strategy directly endows the material with the characteristic of rapid degradation in vivo, and its degradation cycle can be adjusted according to the molecular weight, thereby actively adapting to the healing time window of different tissues and avoiding the associated risks of long-term retention.

[0022] This invention, through ingenious molecular structure design, successfully integrates three major functional elements into a single molecular structure: the crystallinity of PPDO (imparting cohesive strength to the material), the chain flexibility of PEG (imparting flexibility to the patch and ensuring that NHBP can move moderately within the patch for more effective contact with tissue amino groups), and the covalent cross-linking activity of N-hydroxysuccinimide (NHS) (providing strong covalent adhesion). This results in a novel polyester adhesive structure. Furthermore, this invention employs a one-pot synthesis method, simplifying the synthesis process and reducing its difficulty. By studying the formulation, a perfect balance between strength, flexibility, and degradation performance can be achieved.

[0023] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0024] Figure 1 The FT-IR infrared spectra of the biomedical tissue adhesive, PEG, and PPDO in Example 1 of this invention are shown below. Figure 2 The shear overlap strength diagrams are shown for the biomedical tissue adhesives in Examples 1-6 of this invention. Figure 3 This is a graph showing the in vitro adhesion performance verification results of the biomedical tissue adhesive prepared in Example 4 of the present invention; Figure 4 This is a schematic diagram of the comprehensive test of the biomedical tissue adhesive prepared in Example 4 on a pigskin model with wounds. Figure 5 The images show control images of hemostasis tests performed on mouse tails using the biomedical tissue adhesive prepared in Example 4 and Histoacryl@tissue adhesive, respectively. Figure 6 A comparison chart showing the amount of bleeding from a mouse's tail; Figure 7 A control figure showing hemostasis tests performed on mouse livers using the biomedical tissue adhesive prepared in Example 4 and Histoacry@tissue adhesive, respectively. Figure 8 A comparison chart showing the amount of liver bleeding in mice; Figure 9 The above are in vitro simulated degradation curves of the PDGN tissue adhesive in Examples 3 and 4 of this invention. Detailed Implementation

[0025] The present invention will now be described in further detail with reference to the accompanying drawings, so that those skilled in the art can implement it based on the description.

[0026] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof. This invention provides a method for preparing a high-performance biodegradable poly(p-dioxanone) tissue adhesive, comprising the following steps: weighing poly(p-dioxanone) (PPDO), polyethylene glycol (PEG) and functional small molecules, adding the three to a three-necked flask and mixing them evenly, heating, and adding a chain extender to carry out a chain extension reaction after the mixture is completely melted, the reaction is carried out under nitrogen protection to obtain a biomedical tissue adhesive.

[0027] The functional small molecule used in each embodiment is NHBP, and its preparation method includes: Step 1: Weigh 26.8 g (200 mmol) of 2,2-bis(hydroxymethyl)propionic acid and 27 g (260 mmol) of 2,2-dimethoxypropane into a 250 mL round-bottom flask and dissolve in 150 mL of acetone. Add 1.6 g of p-toluenesulfonic acid and react at room temperature for 6 h. Then add 10.5 g of sodium bicarbonate to neutralize, stir for 30 min, filter to obtain a clear liquid, and rotary evaporate to obtain a white solid. Dissolve the white solid in 150 mL of dichloromethane, wash three times with deionized water, dry the organic phase with anhydrous magnesium sulfate, filter, and rotary evaporate to obtain a white solid product S1.

[0028] Step 2: Weigh 8.7 g (50 mmol) of the white solid product S1 from Step 1 and 6.85 g (60 mmol) of N-hydroxysuccinimide into a 500 mL three-necked round-bottom flask. Add 200 mL of dichloromethane and stir to dissolve. Then add 23 g (120 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)diimide hydrochloride. React under a nitrogen atmosphere in an ice-water bath for 2 h, then raise the temperature to room temperature and continue the reaction for 24 h. After the reaction is complete, wash the system three times with deionized water, separate the liquid and liquid phases, dry the organic phase with anhydrous magnesium sulfate, filter, and rotary evaporate to obtain the white solid product S2.

[0029] Step 3: Measure 150 mL of methanol into a 250 mL three-necked round-bottom flask, bubble under nitrogen for 30 min, add 6.18 g (20 mmol) of the product S2 from Step 2 and 2.3 g of trifluoroacetic acid, react at room temperature under nitrogen atmosphere for 12 h, then add molecular sieves for drying, filter, rotary evaporate, and dry to obtain 5.01 g of a colorless viscous liquid, which is the functional small molecule NHBP, with a yield of 93.1%. The structural formula of the functional small molecule NHBP is: .

[0030] Example 1 Weigh 1g of poly(p-dioxanone) (PPDO, average molecular weight 4×10⁻⁶). 3Da), 8g of PEG (average molecular weight 1×10⁻⁸) 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PDGN-1.

[0031] Example 2 Weigh out 2g of PPDO (average molecular weight 4×10). 3 Da), 7g of PEG (average molecular weight 1×10⁻⁶) 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PDGN-2.

[0032] Example 3 Weigh out 3g of PPDO (average molecular weight 4×10). 3 Da), 6g of PEG (average molecular weight 1×10⁻⁶) 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PDGN-3.

[0033] Example 4 Weigh out 4g of PPDO (average molecular weight 4×10). 3 Da), 5g of PEG (average molecular weight 1×10⁻⁵) 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PDGN-4.

[0034] Example 5 Weigh out 5g of PPDO (average molecular weight 4×10). 3 Da), 4g of PEG (average molecular weight 1×10⁻⁴) 3Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PDGN-5.

[0035] Example 6 Weigh out 6g of PPDO (average molecular weight 4×10). 3 Da), 3g of PEG (average molecular weight 1×10⁻⁶) 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PDGN-6.

[0036] Example 7 Weigh out 4g of polylactic acid (PLA, average molecular weight 4×10³Da) and 5g of PEG (average molecular weight 1×10³Da). 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PLGN-4.

[0037] Example 8 Weigh out 4g of polylactic acid (PLA, average molecular weight 4×10³Da) and 5g of polytetrahydrofuran (PTMEG, average molecular weight 2×10³Da). 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PLTN-4.

[0038] Example 9 Weigh out 4g of polycaprolactone (PCL, average molecular weight 4×10³Da) and 5g of polytrimethylene carbonate (PTMC, average molecular weight 2×10³Da). 3 Da) and 1g of functional small molecule NHBP were added to a three-necked flask and mixed evenly. The mixture was heated to 120°C and allowed to melt completely. Then, 1,6-hexamethylene diisocyanate (HDI) was added to carry out a chain extension reaction (R=1). The reaction was carried out under nitrogen protection for 1.5h to obtain a biomedical tissue adhesive, denoted as PCMN-4.

[0039] Poly(p-dioxanone) (PPDO) is a semi-crystalline polymer with a glass transition temperature (T0). g The temperature is approximately -10℃, and the melting point (T) is approximately -10℃. m The temperature is approximately 105℃. This means that at the physiological temperature of the human body (37℃), PPDO is in the temperature range above its glass transition temperature and below its melting point. The movement of molecular chain segments is still limited to the crystalline region, and the material mainly exhibits rigid solid characteristics, lacking flow or viscoelasticity. Therefore, pure PPDO is rigid and lacks adhesion, making it unable to form an effective bond with soft, moist tissue surfaces, and thus cannot be directly used as a tissue adhesive.

[0040] Compared to pure PPDO, the introduction of PEG segments significantly improves the material's flexibility and reduces its elastic modulus, thus making it a better match for soft tissues. However, since this system does not introduce any active adhesive groups (such as NHS), its adhesion mainly relies on limited non-covalent interactions such as hydrogen bonds and van der Waals forces. The limited number of hydrogen bond sites provided by PPDO and PEG molecular chains results in inherent deficiencies in its interfacial affinity and binding strength. More importantly, this material completely lacks the ability to form specific covalent crosslinks with tissue proteins, making it impossible to construct strong and durable interfacial chemical bonds. Therefore, although its shear adhesion strength is improved compared to pure PPDO, it still falls far short of the level of the product of this invention, making it difficult to meet the requirements for high-strength, long-lasting adhesion in practical applications.

[0041] While NHS active groups are introduced into PPDO, the inherent rigidity of the pure PPDO matrix results in insufficient material flexibility and limited chain segment mobility. This hinders the full contact and efficient reaction between the NHS groups and tissue proteins. More importantly, there is a significant mechanical mismatch between rigid adhesives and soft tissues. When the tissue deforms under stress, stress concentrates at the adhesion interface, easily leading to interfacial delamination or cohesive failure, causing the adhesion to fail easily in practical applications.

[0042] In summary, the superior performance of this invention stems from the ingenious and indispensable synergistic combination of the three active groups: PPDO, PEG, and NHS. Without the flexibility provided by PEG and the strong interfacial bonding imparted by NHS, the material will completely fail due to excessive rigidity and lack of adhesion.

[0043] If only flexibility is improved without the covalent cross-linking ability of NHS, the interfacial bonding strength of the material will be limited to weak physical action, and high-strength adhesion cannot be achieved.

[0044] If only active groups are introduced without the flexibility and mechanical buffer provided by PEG segments, the modulus mismatch between the rigid matrix and the soft tissue will lead to stress concentration, causing the strong interfacial bonds to fail prematurely in the dynamic environment.

[0045] The comparison of the above effects fully demonstrates that PPDO, PEG, and NHS active groups form an "iron triangle" in this invention, and none of the three can be missing: the absence of any one link will result in fundamental defects in the material's adhesion strength, mechanical compatibility, or reliability. Only by integrating the strength of PPDO, the flexibility of PEG, and the strong adhesive chemistry of NHS as shown in this invention can a novel tissue adhesive with significantly improved performance be synergistically created.

[0046] Figure 1 The FT-IR images of the biomedical tissue adhesive, PEG, and PPDO in Example 1 of this invention are shown at 2250 cm⁻¹. -1 ~2270cm -1 The absence of characteristic peaks for -NCO functional groups at wavenumber indicates that all isocyanates in the added HDI participated in the reaction that led to the formation of carbamate bonds after chain extension.

[0047] Figure 2 The shear overlap strength diagrams of the poly(p-dioxanone) tissue adhesives (PDGN-1~PDGN-6) prepared in Examples 1-6 of this invention show that the shear strength first increases and then decreases with increasing PPDO content, reaching a peak (2.59 ± 0.13 MPa) at a PPDO content of 40%. This indicates that appropriate crystallinity is beneficial to enhancing the cohesive strength of the material, thereby improving macroscopic shear performance. However, excessive crystallinity leads to decreased material flexibility and limited chain segment movement, thus weakening its adhesion to the tissue surface. Tests showed that the biomedical tissue adhesives prepared in Examples 7-9 also achieved shear strengths of 1.5 MPa~2.1 MPa, exhibiting similarly excellent adhesion properties.

[0048] Figure 3 The results of the in vitro adhesion performance verification of the biomedical tissue adhesive prepared in Example 4 show that the biomedical tissue adhesive can form a strong interfacial bond with various isolated biological tissues (including but not limited to lung, kidney, liver, heart, and small intestine). This result fully demonstrates that the biomedical tissue adhesive of the present invention has universal and strong adhesion ability to different tissue types. Figure 4 As shown, a comprehensive test was conducted on a pigskin model with wounds. After being subjected to mechanical stresses such as stretching, bending, and twisting, as well as continuous water rinsing, the bonded interface of the wound remained intact, without detachment or leakage.

[0049] from Figure 5 , Figure 6 , Figure 7 , Figure 8 The image shows an in vivo hemostasis model of the biomedical tissue adhesive prepared in Example 4 (hemostasis tests on the mouse tail and liver, respectively). Compared with the control group, both model groups treated with PDGN patches showed the least amount of bleeding, with significant differences. This result fully demonstrates that the product of the present invention can quickly form a physical barrier on the wound surface, achieving rapid and effective hemostasis through efficient wound sealing. Figure 5 , Figure 6 , Figure 7 The control group was a blank control group that did not use tissue adhesive, while the Histoacryl@ group used commercially available Histoacryl@ tissue adhesive.

[0050] Figure 9 The in vitro simulated degradation curves of the biomedical tissue adhesives in Examples 3 and 4 of this invention show that the biomedical tissue adhesives exhibit a rapid decline in quality within 8 weeks, with a degradation rate of approximately 54%, significantly faster than most common aliphatic polyester materials. The degradation behavior of polymers is mainly regulated by their chemical structure and molecular weight. This invention achieves rapid degradation by precisely controlling the degree of polymerization of the biomedical tissue adhesive, maintaining its molecular weight within a relatively low specific range. This controllable rapid degradation characteristic directly translates into significant clinical advantages: it ensures that the material rapidly decomposes after fulfilling its mission of wound closure and support, significantly shortening its retention time in the body, thereby effectively reducing chronic inflammatory responses caused by long-term foreign body retention.

[0051] In summary, this invention provides a high-performance, biodegradable poly(p-dioxanone)-based tissue adhesive and its preparation method. The adhesive cleverly integrates multiple advantages, including covalent adhesion, mechanical compatibility, and rapid degradation, by extending the chain of PPDO and PEG and introducing succinimide ester active groups. Experimental data fully demonstrate that the product of this invention not only possesses universal and robust wet adhesion to various biological tissues but also maintains interfacial stability under external forces and fluid erosion. Simultaneously, its rapid degradation characteristics are achieved through molecular weight regulation, effectively shortening its retention time in vivo and significantly reducing the risk of inflammation caused by long-term retention. This invention thus provides a novel tissue bonding solution that combines high-strength adhesion, good biocompatibility, and rapid degradation capabilities.

[0052] The number of devices and processing scale described herein are for the purpose of simplifying the description of the invention. Applications, modifications, and variations of the invention will be readily apparent to those skilled in the art.

[0053] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and illustrations shown and described herein.

Claims

1. A high-performance biodegradable biomedical tissue adhesive, characterized in that, The raw materials of the high-performance biodegradable biomedical tissue adhesive include polyester polymers, polymers with flexible segments, functional small molecules with reactive groups, and chain extenders; wherein, the polyester polymer includes poly(p-dioxanone), the polymer with flexible segments includes polyethylene glycol, and the functional small molecule with reactive groups is the functional small molecule NHBP. The structural formula of the functional small molecule NHBP is: 。 2. The high-performance biodegradable biomedical tissue adhesive according to claim 1, characterized in that, The polyester polymer accounts for 10% to 90% of the total mass, the polymer with flexible segments accounts for 10% to 90% of the total mass, the functional small molecules with reactive groups account for 10% to 90% of the total mass, and the amount of chain extender added satisfies an R value of 0.1 to 2.

3. The high-performance biodegradable biomedical tissue adhesive according to claim 1, characterized in that, The poly(p-dioxanone) has hydroxyl groups at both ends, and its average molecular weight is 2 × 10⁻⁶. 2 Da~1×10 5 Da.

4. The high-performance biodegradable biomedical tissue adhesive according to claim 1, characterized in that, The polymer with flexible segments has hydroxyl groups at both ends, and the average molecular weight of the polymer with flexible segments is 1×10⁻⁶. 2 Da~1×10 5 Da.

5. The high-performance biodegradable biomedical tissue adhesive according to claim 1, characterized in that, The chain extender is 1,6-hexamethylene diisocyanate.

6. A method for preparing a high-performance biodegradable biomedical tissue adhesive according to any one of claims 1-5, characterized in that, The process includes the following steps: mixing a polyester polymer, a polymer with flexible segments, and a functional small molecule with reactive groups to obtain a mixture; heating the mixture and adding a chain extender to carry out a chain extension reaction to obtain a high-performance biodegradable biomedical tissue adhesive; the reaction temperature of the mixture is 120°C and the reaction time is 10 min to 360 min.

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