Degradable self-expanding bioactive bone cement and its use

Abstract

The application provides a degradable self-expanding bioactive bone adhesive and application thereof, and the degradable self-expanding bone adhesive comprises a bioactive reactive polyurethane and a foaming control agent; the bioactive reactive polyurethane contains a plurality of isocyanate groups at the terminal thereof, and the preparation raw material of the bioactive reactive polyurethane comprises a bioactive polyester polyol; the preparation raw material of the bioactive polyester polyol comprises a bioactive polybasic acid, a hydrophobic polyol A and an environmentally responsive degradable acid / alcohol / amine, and the environmentally responsive degradable acid / alcohol / amine contains one or both of a sulfide group and a disulfide bond; and the foaming control agent is a substance capable of reacting with carbon dioxide or adsorbing carbon dioxide. The bone adhesive provided by the application is degradable and self-expanding, can fix the tendon in the bone tunnel through faciality and uniformity extrusion of the tendon, avoids tendon rupture caused by stress concentration and uneven extrusion of the tendon, and can avoid tendon transverse swing and longitudinal stretching.

Description

Technical Field

[0001] This application relates to the field of medical materials technology, and in particular to a biodegradable, self-expanding, bioactive bone adhesive and its application. Background Technology

[0002] Anterior cruciate ligament (ACL) injury is one of the most common sports injuries, often leading to joint instability and dysfunction, cartilage and meniscus damage, osteoarthritis, and in severe cases, even total knee replacement. ACL reconstruction can quickly restore most of the function of the affected limb and has been considered the standard ACL injury repair surgery for over 30 years (Sanders TL, et.al.Am. J. Sports Med. 2016, 44(6), 1502-1507.). Clinically, autologous, allogeneic, or artificial tendons used as ACL grafts are inserted into bone tunnels formed in the tibia and femur, and then fixed to complete ACL reconstruction. However, the prognosis of ACL reconstruction is not optimistic, with a failure rate of approximately 11.2% (Rezansoff A, Arthroscopy 2023, doi:10.1016 / j.arthro.2023.05.019.); after surgery, especially after resuming sports activities, knee laxity often occurs, leading to secondary meniscus tears, cartilage damage, and even traumatic arthritis. Effective tendon-bone fixation and healing are crucial for ACL reconstruction.

[0003] Currently, tendon fixation in bone tunnels primarily relies on interfacial / compression bone screws made of metal and polymer materials. Titanium, magnesium, and zinc alloy bone screws are the main types of metal bone screws, with titanium screws being the most commonly used due to their high initial fixation strength, corrosion resistance, and low cost. However, the mismatch in elastic modulus between the metal and bone tissue often causes a stress shielding effect, leading to local bone demineralization or hindering callus formation (Zhang M, et al. J. Orthop. Res. 2020, 38(7), 1566-1574.). Polymer bone screws, including non-degradable bone screws such as polyetheretherketone (PEEK) bone screws and absorbable / degradable bone screws such as polylactic acid (PLLA)-based bone screws, generally have good biocompatibility and an elastic modulus similar to that of bone, and have become widely accepted alternatives to metal screws in recent years.

[0004] However, regardless of whether it is a metal or polymer bone screw, the fixation method of tendon grafts in the bone tunnel is a point fixation, which can easily compress the tendon, causing stress concentration or even tendon rupture. Moreover, because there is a large gap between the tendon and the bone tunnel in traditional fixation methods, it is easy to cause the "windshield wiper effect" (lateral swinging of the tendon) and the "bungee jumping effect" (longitudinal stretching of the tendon). Summary of the Invention

[0005] Based on this, this application provides a biodegradable, self-expanding, bioactive bone adhesive and its application to reduce or even avoid stress concentration and uneven compression of tendons, while reducing or even avoiding lateral swinging and longitudinal stretching of tendons.

[0006] The first aspect of this application provides a biodegradable, self-expanding bone adhesive comprising a bioactive reactive polyurethane and a foam control agent;

[0007] The bioactive reactive polyurethane has multiple isocyanate groups at its ends. The raw materials for preparing the bioactive reactive polyurethane include bioactive polyester polyols. The raw materials for preparing the bioactive polyester polyols include bioactive polyacids, hydrophobic polyol A, and environmentally responsive degradable acids / alcohols / amines. The environmentally responsive degradable acids / alcohols / amines contain one or both of thioether groups and disulfide bonds.

[0008] The foaming control agent is a substance that can react with or adsorb carbon dioxide.

[0009] In some embodiments, the environmentally responsive degrading acid / alcohol / amine includes one or more of the following: monobasic acid / alcohol / amine containing a thioether group, dibasic acid / alcohol / amine containing a disulfide bond, and dibasic acid / alcohol / amine containing a thioether group.

[0010] Optionally, the monocarboxylic acid / alcohol / amine containing a thioether group includes one or more of 2-(methylthio)acetic acid, 3-(methylthio)propionic acid, 2-(methylthio)ethanol, 3-methylthiopropanol, 4-(methylthio)butanol, 2-ethylthioethanol, and 3-(ethylthio)propanol.

[0011] Optionally, the thioether-containing dicarboxylic acid / alcohol / amine includes one or more of 2,2'-thiodiacetic acid and 3,6-dithia-1,8-octanediol;

[0012] Optionally, the dicarboxylic acid / alcohol / amine containing a disulfide bond includes one or more of L-cysteine ​​dimethyl ester and bis(2-hydroxyethyl) disulfide.

[0013] In some embodiments, the ratio of the total molar number of carboxyl groups to the total molar number of hydroxyl groups in the bioactive polyacid, the hydrophobic polyol A, and the environmentally responsive degrading acid / alcohol / amine is 1:(0.5-3); and / or

[0014] The acid value of the bioactive polyester polyol is 3 mg KOH / g - 500 mg KOH / g; and / or

[0015] The bioactive polyacids include one or more of citric acid, malic acid, succinic acid, and α-ketoglutarate; and / or

[0016] The hydrophobic polyol A includes hydrophobic polyols with 3-22 carbon atoms;

[0017] Optionally, the hydrophobic polyol A includes one or more of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and 1,12-dodecanediol.

[0018] In some embodiments, the foaming control agent includes one or more of sodium hydroxide, ammonia, N,N-dimethylethanolamine, triethylamine, morpholine, choline, magnesium oxide, calcium oxide, activated carbon, silica, and zeolite.

[0019] In some embodiments, the raw materials for preparing the bioactive reactive polyurethane further include hydrophobic polyol B, polyol containing tertiary amines, aliphatic chain polyisocyanate, and catalyst.

[0020] Optionally, the ratio of the total molar number of isocyanate groups to the total molar number of hydroxyl groups in the bioactive polyester polyol, the hydrophobic polyol B, the polyol containing tertiary amine, and the aliphatic chain polyisocyanate is 1.5-2.5, and optionally 1.8-2.2.

[0021] Optionally, the hydrophobic polyol B includes at least one of castor oil, polyglycerol, poly(ε-caprolactone) polyol, polylactic acid polyol, and polyglycolic acid polyol;

[0022] Optionally, the polyol containing tertiary amines includes one or more of triethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-n-propyldiethanolamine, tert-butyldiethanolamine, and N,N'-bis(2-hydroxyethyl)piperazine;

[0023] Optionally, the aliphatic chain polyisocyanate includes one or more of L-lysine ethyl diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, and dicyclohexylmethane diisocyanate;

[0024] Optionally, the catalyst includes one or more of organotin catalysts, organobismuth catalysts, and amine catalysts;

[0025] Optionally, by weight, the reaction raw materials of the bioactive reactive polyurethane include: 5-30 parts of the bioactive polyester polyol, 10-40 parts of the hydrophobic polyol B, 1-10 parts of the polyol containing a tertiary amine, 30-60 parts of the aliphatic chain polyisocyanate, and 0.01-5 parts of the catalyst.

[0026] In some embodiments, the method for preparing the bioactive reactive polyurethane includes:

[0027] The mixture containing the bioactive polyester polyol and the hydrophobic polyol B is vacuum dehydrated at 90℃-120℃ for 1h-5h to prepare dehydrated material.

[0028] The dehydrated material, the aliphatic chain polyisocyanate, and the catalyst are mixed and reacted at 40℃-90℃ for 1h-24h in a protective atmosphere to prepare an intermediate.

[0029] The intermediate is mixed with the polyol containing a tertiary amine and reacted at 40°C-90°C for 1-3 hours in a protective atmosphere to prepare the bioactive reactive polyurethane.

[0030] In some embodiments, inorganic fillers are also included;

[0031] Optionally, the inorganic filler includes one or more of modified and unmodified hydroxyapatite, calcium phosphate, calcium carbonate, zinc oxide, and magnesium oxide;

[0032] Alternatively, the modification method includes surface deposition of polyphenols, dopa, or dopamine on the material to be modified under alkaline or oxygen-containing conditions.

[0033] In some embodiments, the bone adhesive comprises, by weight, 60-90 parts of the bioactive reactive polyurethane, 0.1-40 parts of the inorganic filler, and 0.1-5 parts of the foaming control agent.

[0034] In some embodiments, an aqueous porogen is also included;

[0035] Optionally, the aqueous pore-forming agent includes one or more of polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol diethyl ester, polyvinylpyrrolidone, sodium chloride, and magnesium sulfate;

[0036] Optionally, the molecular weight of the aqueous pore-forming agent is 1000 Da-20000 Da;

[0037] Optionally, the bone adhesive contains 1 to 20 parts by weight of the aqueous pore-forming agent;

[0038] Optionally, the amount of the aqueous pore-forming agent contained in the bone adhesive is 1 to 10 parts by weight.

[0039] The second aspect of this application provides the use of the biodegradable, self-expanding bone adhesive of the first aspect of this application in the preparation of materials for tendon-bone healing, materials for bone defect repair, and / or porous biodegradable scaffolds.

[0040] The aforementioned biodegradable, self-expanding bone adhesive possesses a certain degree of fluidity, is injectable, self-foams and expands during humidification, and degrades to release active ingredients that promote bone regeneration. It has at least the following beneficial effects:

[0041] (1) Compared with the interface / compression bone screw, which fixes the tendon in the bone tunnel by point fixation and non-uniform compression, the bone adhesive provided in this application can simulate a tug-of-war competition and fix the tendon in the bone tunnel by surface and uniform compression, avoiding stress concentration and tendon rupture caused by uneven compression of the tendon. It can also avoid the "windshield wiper effect" (lateral swing of the tendon) and the "bungee jumping effect" (longitudinal stretching of the tendon) by fully filling the gap between the tendon and the bone tunnel.

[0042] (2) The bone adhesive provided in this application expands within the confined space between the tendon and the bone tunnel, enabling it to...

[0043] The tendon is fully and evenly compressed within the bone tunnel to achieve tendon-bone fixation; the bone adhesive can also be embedded in the gaps of the bone tunnel, improving tendon-bone bonding through mechanical locking and chemical bonding of residual NCO groups with active groups such as amino and thiol groups on the bone surface.

[0044] (3) The bone adhesive provided in this application has a porous structure obtained by foaming and expansion, which is conducive to bone ingrowth. The porous structure can buffer stress. When used for the repair of compression fractures caused by osteoporosis (as a substitute for bone cement in vertebroplasty), it can avoid the compression of adjacent vertebrae by conventional bone cement (polymethyl methacrylate) due to its high modulus, which can cause adjacent vertebral fractures.

[0045] (4) Because the bone adhesive provided in this application contains environmentally responsive groups, it can accelerate the degradation of the bone adhesive. At the same time, because the bone adhesive contains foam control agents, it is beneficial to control foaming, thereby controlling the formation of pores and the size of porosity, avoiding excessive expansion that could compress surrounding tissues and reduce material strength, and also helping to control the degradation time of the bone adhesive. In addition, because the bone adhesive can degrade to obtain bioactive components, as the bone adhesive degrades, the bioactive components are continuously released, which can promote bone regeneration, promote the narrowing of bone tunnels, and thus further increase tendon-bone bonding strength.

[0046] (5) The bone adhesive provided in this application cures rapidly during the self-foaming expansion process because the outer material preferentially contacts the water vapor, while the inner material cures relatively slowly. Therefore, it can form a biphase structure with a dense outer layer and a high porosity inner layer, which can simulate the biphase structure of natural bone composed of cortical bone and cancellous bone. Attached Figure Description

[0047] To more clearly illustrate the technical solutions in the embodiments of this application and to more completely understand this application and its beneficial effects, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0048] Figure 1 A schematic diagram illustrating the expansion of a bone adhesive within a confined space according to one embodiment;

[0049] Figure 2 A schematic diagram illustrating the synthesis of a bioactive polyester polyol according to one embodiment;

[0050] Figure 3 A schematic diagram illustrating the synthesis of a bioactive reactive polyurethane according to one embodiment;

[0051] Figure 4 The specific synthesis process of the citric acid-based bioactive polyester polyol and the citric acid-based bioactive reactive polyurethane (CPU-NCO) in Example 1 is as follows:

[0052] Figure 5 The infrared spectra of the citric acid-based bioactive reactive polyurethane (CPU-NCO) prepared in Example 1 before and after crosslinking (A), and the porosity of the crosslinked products obtained with different contents of the aqueous porogen PEG-DM under the same water dosage (B).

[0053] Figure 6 The expansion rate test results are for the CPU (containing sulfide) prepared in Example 1 compared with the CPU′ (not containing sulfide) prepared in Comparative Example 1.

[0054] Figure 7 The hardness test results are for the CPU (containing sulfide) prepared in Example 1 compared with those for the CPU′ (not containing sulfide) prepared in Comparative Example 1.

[0055] Figure 8 The degradation results of CPU (containing sulfide) prepared in Example 1 compared with those of CPU′ (not containing sulfide) prepared in Comparative Example 1 in PBS and PBS+H2O2 are shown.

[0056] Figure 9 The pull-out strength of the CPU obtained in Example 1 after 24 hours of external fixation of the artificial tendon was compared with that of a commercially available titanium screw (Ф8mm).

[0057] Figure 10 For Example 1, micro-CT images of CPU used for anterior cruciate ligament reconstruction in New Zealand rabbits were obtained at 4 and 14 weeks post-surgery, with commercially available titanium screws (Ф3mm) used as a reference.

[0058] Figure 11 Van Gieson (VG) staining images of hard tissue sections obtained 14 weeks after anterior cruciate ligament reconstruction surgery in New Zealand rabbits using CPU, as well as biomechanical strength (pulling strength of autologous tendon from the bone marrow tract) 14 weeks after repair and its comparison with commercial titanium screws (Ф3mm). Detailed Implementation

[0059] To facilitate understanding of the present invention, a more complete description of this application will be provided below with reference to relevant embodiments. Preferred embodiments of the present application are given below. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the disclosure of this application will be achieved.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0061] As used herein, the terms "and / or," "or / and," and "and / or" encompass any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR."

[0062] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0063] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0064] This document only specifically discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, just as any upper limit can be combined with any other upper limit to form an unspecified range. Furthermore, each individually disclosed point or single value can itself serve as a lower or upper limit and be combined with any other point or single value or with other lower or upper limits to form an unspecified range.

[0065] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows temperature fluctuations within the precision range controlled by the instrument, such as ±5°C, ±4°C, ±3°C, ±2°C, or ±1°C.

[0066] In this application, unless otherwise specified, the terms "size," "particle size," and "diameter" generally refer to average values. In this application, "particle size" and "particle diameter" have the same definition, both representing the average particle size of spheres or spheroids.

[0067] In this document, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0068] In this application, terms such as "further," "even more," and "particularly" are used for descriptive purposes and to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0069] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0070] In the description of the application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0071] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions. Unless otherwise specified, all technical features and optional technical features of this application can be combined to form new technical solutions.

[0072] Unless otherwise specified, all steps of this application may be performed sequentially or randomly, but sequentially is preferred.

[0073] Anterior cruciate ligament (ACL) injury is one of the most common sports injuries, and effective tendon-bone fixation and healing are crucial for ACL reconstruction. Currently, tendon fixation in bone tunnels primarily relies on interfacial / compression bone screws made of metal and polymer materials. However, regardless of whether metal or polymer bone screws are used, the fixation of tendon grafts in bone tunnels is a point fixation method, which can easily compress the tendon, causing stress concentration and even tendon rupture. Furthermore, due to the large gap between the tendon and the bone tunnel in traditional fixation methods, it is easy to cause the "wiper effect" (lateral tendon swing) and the "bungee jumping effect" (longitudinal tendon stretching).

[0074] To address the aforementioned issues, this application first prepares a bioactive polyester polyol through condensation polymerization of a bioactive polyacid, a hydrophobic polyol A, and an environmentally responsive degradable acid / alcohol / amine. Then, a bioactive reactive polyurethane is prepared based on the raw materials including the bioactive polyester polyol. Finally, a biodegradable, self-expanding bone adhesive comprising the bioactive reactive polyurethane and a foaming control agent is obtained. This bone adhesive exhibits a certain degree of fluidity, is injectable, self-foams and expands during wet curing, and is degradable, releasing active ingredients that promote bone regeneration.

[0075] The first aspect of this application provides a biodegradable, self-expanding bone adhesive, comprising a bioactive reactive polyurethane and a foam control agent; the bioactive reactive polyurethane has multiple isocyanate groups at its ends, and the raw materials for preparing the bioactive reactive polyurethane include a bioactive polyester polyol, the raw materials for preparing the bioactive polyester polyol include a bioactive polyacid, a hydrophobic polyol A, and an environmentally responsive degradable acid / alcohol / amine, the environmentally responsive degradable acid / alcohol / amine containing one or two of thioether groups and disulfide bonds; the foam control agent is a substance capable of reacting with or adsorbing carbon dioxide.

[0076] Bioactive reactive polyurethane refers to polyurethane that can self-foam, expand, and degrade, and whose degradation products contain specific bioactive components.

[0077] When an acid / alcohol / amine in response to environmental degradation contains one or both of thioether groups and disulfide bonds, changes in hydrophilicity or breakage of chemical bonds can occur in the microenvironment of high oxidative stress (i.e., high concentration of reactive oxygen species (ROS)) caused by inflammatory stimulation, thereby promoting the degradation of the material. Specifically, hydrophobic thioether groups (-S-) are oxidized to hydrophilic sulfone (-(O=S=O)-) or sulfoxide (-(S=O)-) groups in a high ROS microenvironment, increasing the hydrophilicity of the material and thus accelerating its degradation; while disulfide bonds can break in a high ROS microenvironment, thereby promoting the degradation of the material.

[0078] Understandably, compared to interface / compression bone screws which fix tendons in bone tunnels through point fixation and non-uniform compression, the bone adhesive provided in this application is degradable and self-expanding. It can simulate a tug-of-war competition and fix the tendon in the bone tunnel through planar and uniform compression, avoiding stress concentration and tendon rupture caused by uneven compression. Furthermore, it can avoid the "windshield wiper effect" (lateral tendon swing) and the "bungee jump effect" (longitudinal tendon stretch) by fully filling the tendon-bone tunnel gap.

[0079] Bone adhesive expands within the confined space between the tendon and the bone tunnel (see reference). Figure 1 The adhesive can fully and evenly compress the tendon in the bone tunnel to achieve tendon-bone fixation; the bone adhesive can also be embedded in the gaps of the bone tunnel, and improve tendon-bone bonding through mechanical locking and chemical bonding of residual NCO groups with active groups such as amino and thiol groups on the bone surface.

[0080] Because bone adhesives contain environmentally responsive groups, their degradation can be accelerated. Simultaneously, the presence of foam control agents facilitates foam control, thereby controlling pore formation and porosity, preventing excessive expansion that could compress surrounding tissues and reduce material strength. This also helps control the degradation time of the bone adhesive. Furthermore, since bone adhesives can degrade to release bioactive components, these components are continuously released during degradation, promoting bone regeneration and narrowing of bone tunnels, thus further increasing tendon-bone bonding.

[0081] Bone adhesives achieve a porous structure through foaming and expansion, which facilitates bone ingrowth. The porous structure can also buffer stress. When used to repair compression fractures caused by osteoporosis (as a substitute for bone cement in vertebroplasty), it can avoid the compression of adjacent vertebrae caused by the high modulus of conventional bone cement (polymethyl methacrylate), thus preventing adjacent vertebral fractures.

[0082] The bone adhesive of this application cures rapidly during the self-foaming expansion process because the outer material preferentially contacts water vapor, while the inner material cures relatively slowly. Therefore, it can form a biphase structure with a dense outer layer and a high porosity inner layer, which can simulate the biphase structure of natural bone composed of cortical bone and cancellous bone.

[0083] The bone adhesive of this application can expand in both free and confined spaces to produce a dense structure with low outer porosity and small pore size, and a loose porous structure with high inner porosity and large pore size. The degree of spatial confinement affects the porosity and strength of the molding material. The greater the degree of confinement, the smaller the average porosity of the molding material.

[0084] In some embodiments, the environmentally responsive degrading acid / alcohol / amine includes one or more of the following: monobasic acid / alcohol / amine containing a thioether group, dibasic acid / alcohol / amine containing a disulfide bond, and dibasic acid / alcohol / amine containing a thioether group.

[0085] As one possible implementation, the monocarboxylic acid / alcohol / amine containing a thioether group includes one or more of 2-(methylthio)acetic acid, 3-(methylthio)propionic acid, 2-(methylthio)ethanol, 3-methylthiopropanol, 4-(methylthio)butanol, 2-ethylthioethanol, and 3-(ethylthio)propanol.

[0086] In some alternative embodiments, the thioether-containing dicarboxylic acid / alcohol / amine includes one or more of 2,2'-thiodiacetic acid and 3,6-dithia-1,8-octanediol.

[0087] In some exemplary embodiments, the dicarboxylic acid / alcohol / amine containing a disulfide bond includes one or more of L-cysteine ​​dimethyl ester and bis(2-hydroxyethyl) disulfide.

[0088] It should be noted that the "acid / alcohol / amine" mentioned above refers to acids and / or alcohols and / or amines.

[0089] In some embodiments, the ratio of the total molar number of carboxyl groups to the total molar number of hydroxyl groups in the bioactive polyacid, hydrophobic polyol A, and environmentally responsive degradable acid / alcohol / amine is 1:(0.5-3); for example, it can be, but is not limited to, 1:0.5, 1:0.8, 1:1, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.3, 1:2.5, 1:2.8, 1:3, or any range between the above two ratios. Optionally, the ratio of the total molar number of carboxyl groups to the total molar number of hydroxyl groups is 1:(1.3-1.8). More preferably, the ratio of the total molar number of carboxyl groups to the total molar number of hydroxyl groups is 1:1.3, 1:1.5, or 1:1.8. Thus, when the ratio of the total molar number of carboxyl groups to the total molar number of hydroxyl groups is 1:(0.5-3), the resulting polyester can be controlled to have a certain degree of polymerization and contain multiple hydroxyl terminals to facilitate further reaction with polyisocyanates.

[0090] As one possible implementation, the acid value of the bioactive polyester polyol is 3 mg KOH / g - 500 mg KOH / g; for example, it can be, but is not limited to, 3 mg KOH / g, 50 mg KOH / g, 100 mg KOH / g, 150 mg KOH / g, 200 mg KOH / g, 250 mg KOH / g, 300 mg KOH / g, 350 mg KOH / g, 400 mg KOH / g, 450 mg KOH / g, 500 mg KOH / g, or any range between two of the above acid values. When the acid value of the bioactive polyester polyol is within the above-mentioned range, the carboxyl content of the resulting bioactive polyester polyol is controlled within a low range. Since the reactivity of carboxyl groups with isocyanates is much lower than that of hydroxyl groups with isocyanates, and the reaction between carboxyl groups and isocyanates removes carbon dioxide, the material cannot recover its original active polyacid structure after degradation, thus affecting the material's bioactivity. Therefore, controlling the carboxyl content of the resulting bioactive polyester polyol within a low range helps to reduce the impact on the material's bioactivity. Optionally, the acid value of the bioactive polyester polyol is 50 mg KOH / g - 250 mg KOH / g. More preferably, the acid value range of the bioactive polyester polyol is 50 mg KOH / g, 100 mg KOH / g, 150 mg KOH / g, 200 mg KOH / g, or 250 mg KOH / g.

[0091] In some embodiments, the bioactive polyacids include one or more of citric acid, malic acid, succinic acid, and α-ketoglutarate.

[0092] In some embodiments, hydrophobic polyol A comprises hydrophobic polyols having 3-22 carbon atoms.

[0093] In some alternative embodiments, the hydrophobic polyol A includes one or more of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and 1,12-dodecanediol.

[0094] As an example, refer to Figure 2 Bioactive polyester polyols are obtained by condensation polymerization of bioactive polyacids, hydrophobic polyol A, and environmentally responsive degradable acids / alcohols / amines.

[0095] In some embodiments, the foaming control agent includes one or more of sodium hydroxide, ammonia, N,N-dimethylethanolamine, triethylamine, morpholine, choline, magnesium oxide, calcium oxide, activated carbon, silica, and zeolite.

[0096] In some embodiments, the raw materials for preparing bioactive reactive polyurethane also include hydrophobic polyol B, polyols containing tertiary amines, aliphatic chain polyisocyanates, and catalysts.

[0097] As one possible implementation, the ratio of the total molar number of isocyanate groups to the total molar number of hydroxyl groups in the bioactive polyester polyol, hydrophobic polyol B, tertiary amine-containing polyol, and aliphatic chain polyisocyanate is 1.5-2.5; for example, it can be, but is not limited to, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, or any range between any two of the above values. This allows the resulting reactive polyurethane to have sufficient degree of polymerization and retain a large number of reactive isocyanate groups for moisture-curing crosslinking reactions. Optionally, the ratio of the total molar number of isocyanate groups to the total molar number of hydroxyl groups in the bioactive polyester polyol, hydrophobic polyol B, tertiary amine-containing polyol, and aliphatic chain polyisocyanate is 1.8-2.3. Alternatively, the ratio of the total number of moles of isocyanate groups to the total number of moles of hydroxyl groups in bioactive polyester polyols, hydrophobic polyols B, polyols containing tertiary amines, and aliphatic chain polyisocyanates is 1.8, 1.9, 2, 2.1, 2.2, or 2.3.

[0098] In some alternative embodiments, the ratio of the total number of moles of isocyanate groups to the total number of moles of hydroxyl groups in bioactive polyester polyols, hydrophobic polyols B, polyols containing tertiary amines, and aliphatic chain polyisocyanates is 1.8-2.2.

[0099] In some embodiments, hydrophobic polyol B includes one or more of castor oil, polyglycerol, poly(ε-caprolactone) polyol, polylactic acid polyol, and polyglycolic acid polyol.

[0100] It should be noted that poly(ε-caprolactone) polyol refers to poly(ε-caprolactone) containing at least 2 hydroxyl groups, polylactic acid polyol refers to polylactic acid containing at least 2 hydroxyl groups, and poly(glycolic acid) lactide polyol refers to polyglycolic acid containing at least 2 hydroxyl groups.

[0101] In some embodiments, the polyol containing a tertiary amine includes one or more of triethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-n-propyldiethanolamine, tert-butyldiethanolamine, and N,N'-bis(2-hydroxyethyl)piperazine.

[0102] In some exemplary embodiments, the aliphatic chain polyisocyanate includes one or more of L-lysine ethyl diisocyanate (LDI), isophorone diisocyanate (IPDI), hexamethylene diisocyanate (HDI), and dicyclohexylmethane diisocyanate (HMDI).

[0103] In some alternative embodiments, the catalyst includes one or more of organotin catalysts, organobismuth catalysts, and amine catalysts.

[0104] As one possible implementation, the reaction raw materials of the bioactive reactive polyurethane, by weight, include: 5-30 parts of bioactive polyester polyol, 10-40 parts of hydrophobic polyol B, 1-10 parts of polyol containing tertiary amine, 30-60 parts of aliphatic chain polyisocyanate and 0.01-5 parts of catalyst.

[0105] As an example, in the reaction raw materials of bioactive reactive polyurethane, the weight parts of bioactive polyester polyol can be, but are not limited to, 5 parts, 7 parts, 10 parts, 13 parts, 15 parts, 18 parts, 20 parts, 23 parts, 25 parts, 28 parts, 30 parts, or any range between any two of the above weight parts.

[0106] As an example, in the reaction raw materials of bioactive reactive polyurethane, the weight parts of hydrophobic polyol B can be, but are not limited to, 10 parts, 13 parts, 15 parts, 18 parts, 20 parts, 23 parts, 25 parts, 28 parts, 30 parts, 33 parts, 35 parts, 38 parts, 40 parts, or any range between any two of the above weight parts.

[0107] As an example, in the reaction raw materials of bioactive reactive polyurethane, the weight parts of the polyol containing tertiary amine can be, but are not limited to, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, or any range between any two of the above weight parts.

[0108] As an example, in the reaction raw materials of bioactive reactive polyurethane, the weight parts of aliphatic chain polyisocyanate can be, but are not limited to, 30 parts, 33 parts, 35 parts, 38 parts, 40 parts, 43 parts, 45 parts, 48 ​​parts, 50 parts, 53 parts, 55 parts, 58 parts, 60 parts, or any range between any two of the above weight parts.

[0109] As an example, in the reaction raw materials of bioactive reactive polyurethane, the weight parts of the catalyst can be, but are not limited to, 0.01 parts, 0.1 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, or any range between any two of the above weight parts.

[0110] In some embodiments, the preparation method of bioactive reactive polyurethane includes:

[0111] A mixture containing bioactive polyester polyol and hydrophobic polyol B is vacuum dehydrated at 90℃-120℃ for 1h-5h to prepare a dehydrated material; the dehydrated material, aliphatic chain polyisocyanate and catalyst are mixed and reacted at 40℃-90℃ for 1h-24h in a protective atmosphere to prepare an intermediate; the intermediate is mixed with a polyol containing tertiary amine and reacted at 40℃-90℃ for 1h-3h in a protective atmosphere to prepare a bioactive reactive polyurethane.

[0112] As an example, the temperature for vacuum dehydration of a mixture containing bioactive polyester polyol and hydrophobic polyol B can be, but is not limited to, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, or any two of the above temperatures. A vacuum dehydration temperature within the above range is beneficial for thorough water removal without causing the removal of volatile reactants, thus affecting the actual ratio of the total moles of isocyanate groups to the total moles of hydroxyl groups.

[0113] The vacuum dehydration time can be, but is not limited to, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or any two of the above times. Vacuum dehydration within these ranges ensures thorough water removal without excessively long total reaction time.

[0114] The reaction temperature for preparing the intermediate from the dehydrated material, aliphatic chain polyisocyanate, and catalyst can be, but is not limited to, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, or any range between two of the above temperatures. The reaction time for preparing the intermediate can be, but is not limited to, 1h, 3h, 5h, 8h, 10h, 13h, 15h, 18h, 20h, 22h, 24h, or any range between two of the above times.

[0115] The reaction temperature for preparing bioactive reactive polyurethane from an intermediate and a polyol containing a tertiary amine can be, but is not limited to, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, or any range between two of the above temperatures. The reaction time can be, but is not limited to, 1h, 1.5h, 2h, 2.5h, 3h, or any range between two of the above times.

[0116] In some implementations, the protective atmosphere includes nitrogen.

[0117] In some embodiments, refer to Figure 3In the preparation of bioactive reactive polyurethane, dehydrated bioactive polyester polyol and hydrophobic polyol B are mixed with aliphatic chain polyisocyanate and catalyst and reacted; then a polyol containing tertiary amine is added to continue the reaction to prepare bioactive reactive polyurethane.

[0118] In some embodiments, the bone adhesive further includes inorganic fillers. Increasing the inorganic fillers improves the strength and bioactivity of the bone adhesive and better mimics the chemical composition of natural bone. Natural bone consists of 65 wt% inorganic components (primarily hydroxyapatite) embedded within 35 wt% organic components (primarily collagen).

[0119] In some alternative embodiments, the inorganic filler includes one or more of modified and unmodified hydroxyapatite, calcium phosphate, calcium carbonate, zinc oxide, and magnesium oxide.

[0120] As one possible implementation method, the modification involves surface deposition of polyphenols, dopa, or dopamine onto the material to be modified under alkaline or oxygen-containing conditions. This yields phenol-modified inorganic components. The polyphenols deposited on the surface of the inorganic components can enhance their bioactivity by providing properties such as antioxidant and anti-inflammatory effects. Furthermore, the reaction of the phenolic hydroxyl groups with isocyanate groups results in easily broken phenol-carbamate bonds (which can be broken or repaired under heating conditions, representing dynamically reversible bonds), further accelerating the degradation rate of the resulting material.

[0121] In some embodiments, the bone adhesive comprises, by weight, 60-90 parts of bioactive reactive polyurethane, 0.1-40 parts of inorganic filler, and 0.1-5 parts of foam control agent.

[0122] The amount of bioactive reactive polyurethane contained in the bone adhesive, by weight, can be, but is not limited to, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, or any range between any two of the above weight parts.

[0123] The inorganic filler contained in the bone adhesive, by weight, can be, but is not limited to, 0.1 parts, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, or any range between any two of the above weight parts.

[0124] The number of parts by weight of foam control agent contained in bone adhesive can be, but is not limited to, 0.1 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, or any range between any two of the above parts by weight.

[0125] In some embodiments, the bone adhesive also includes an aqueous pore-forming agent; by adding the aqueous pore-forming agent, the porosity of the bone adhesive after foaming and expansion can be further improved, which is beneficial to bone ingrowth.

[0126] In some alternative embodiments, the aqueous pore-forming agent includes one or more of polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol diethyl ester, polyvinylpyrrolidone, sodium chloride, and magnesium sulfate.

[0127] In some alternative embodiments, the molecular weight of the aqueous porogen is 1000 Da to 20000 Da; for example, it can be, but is not limited to, 1000 Da, 3000 Da, 5000 Da, 8000 Da, 10000 Da, 13000 Da, 15000 Da, 18000 Da, 20000 Da, or any range between two of the above molecular weights.

[0128] In some embodiments, the amount of aqueous pore-forming agent contained in the bone adhesive is 1 to 20 parts by weight; for example, it can be, but is not limited to, 1 part, 3 parts, 5 parts, 8 parts, 10 parts, 13 parts, 15 parts, 18 parts, 20 parts, or any range between two of the above-mentioned amounts by weight.

[0129] In some exemplary embodiments, the bone adhesive contains 1 to 10 parts by weight of an aqueous pore-forming agent.

[0130] In some embodiments, the bone adhesive also includes water. Optionally, the bone adhesive includes 10 to 25 parts by weight of water.

[0131] It should be noted that the water and bioactive reactive polyurethane should only be mixed just before use. When not in use, the water and bioactive reactive polyurethane should be stored separately.

[0132] The bone adhesive provided in this application, when used, can expand and set within 5-200 minutes after mixing the components, and continue to harden until it reaches its final strength after 8-24 hours.

[0133] The second aspect of this application provides the use of the bone adhesive of the first aspect of this application in the preparation of materials for tendon-bone healing, materials for bone defect repair, and / or porous biodegradable scaffolds.

[0134] It should be noted that bone adhesives can be used as raw materials for preparing materials for tendon-bone healing and / or for bone defect repair, or they can be used directly as materials for tendon-bone healing and / or for bone defect repair. When used as a material for tendon-bone healing, it is fixed to the tendon within a bone tunnel; when used as a material for bone defect repair, it can replace bone cement in the repair of large-segment bone defects and vertebroplasty.

[0135] The technical solution of the present invention will be described in detail below with reference to specific embodiments. It should be understood that these embodiments are only for illustrating the present invention and are not intended to limit the scope of the present invention. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this invention, or follow experimental manuals or conventional conditions in the art, or follow the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0136] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0137] Example 1

[0138] Step S1. Take 23.05 g of citric acid (0.12 mol, as a bioactive polyacid), 14.62 g of 1,8-octanediol (0.10 mol, as hydrophobic polyol A), and 2.76 g of 2-(methylthio)ethanol (0.03 mol, as an environmentally responsive degradable alcohol) and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a homogeneous and transparent solution. Then, cool the mixture to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point where the stir bar is difficult to rotate at 60 rpm and the acid value is stable. Stop heating to obtain citric acid-based bioactive polyester polyol.

[0139] Step S2. 2.50 g of citric acid-based bioactive polyester, 11.25 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B), and 1.25 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. The mixture was then vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 19.0 g of isophorone diisocyanate (IPDI, 0.085 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the reaction was continued at 60°C under N2 protection for 1 hour to obtain citric acid-based bioactive reactive polyurethane (CPU-NCO).

[0140] Step S3. 0.5 g CPU-NCO, 0.1 g hydroxyapatite (HA, as an inorganic filler), 200 μL water (containing 0.05 g polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous phase porogen)), and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled CPU). CPU expanded and set within 105 minutes and continued to harden, reaching its final strength after 18 hours.

[0141] The specific synthesis process of the citric acid-based bioactive polyester polyol and the citric acid-based bioactive reactive polyurethane (CPU-NCO) in Example 1 is as follows: Figure 4 As shown.

[0142] Example 2

[0143] The difference between Example 2 and Example 1 is that the water in step S3 contains 0.1g of polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da). Step S3 is as follows:

[0144] Step S3. 0.5 g CPU-NCO, 0.1 g hydroxyapatite (HA, as an inorganic filler), 200 μL water (containing 0.1 g polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous porogen)) and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive. This citric acid-based biodegradable self-expanding bone adhesive expanded and set within 45 minutes and continued to harden, reaching its final strength after 18 hours.

[0145] Example 3

[0146] The difference between Example 3 and Example 1 is that the water in step S3 does not contain polyethylene glycol dimethyl ether. Step S3 is as follows:

[0147] Step S3. 0.5 g CPU-NCO, 0.1 g hydroxyapatite (HA, as an inorganic filler), 200 μL water, and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive. This citric acid-based biodegradable self-expanding bone adhesive expanded and set within 58 minutes and continued to harden, reaching its final strength after 19 hours.

[0148] The infrared spectrum of the CPU-NCO prepared in Example 1 is as follows: Figure 4 As shown in A, by Figure 4 As can be seen from A, the infrared spectrum contains a characteristic peak of isocyanate (NCO) (2260 cm⁻¹). -1The presence of the characteristic peaks of NCO after wet curing and crosslinking indicates that the NCO groups have chemically bonded with the active groups such as amino and thiol groups on the bone surface.

[0149] The porosity of the crosslinked products in Examples 1-3 is as follows: Figure 5 As shown in B, by Figure 5 As can be seen from B, different amounts of water used for cross-linking of bone adhesives will result in different expansion rates and porosities. Furthermore, with the same amount of water, different contents of the aqueous phase porogen will also result in different porosities.

[0150] Example 4

[0151] The difference between Example 4 and Example 1 is that magnesium oxide is used instead of hydroxyapatite in step S3; the details are as follows:

[0152] Step S3. 0.5 g CPU-NCO, 0.1 g magnesium oxide (as an inorganic filler and foaming control agent), and 200 μL water (containing 0.05 g polyvinylpyrrolidone (PVP, molecular weight 3000 Da, as an aqueous phase pore-forming agent)) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled CPU-MgO). CPU expanded and set within 85 minutes and continued to harden, reaching its final strength after 20 hours.

[0153] It should be noted that because magnesium oxide absorbs the generated carbon dioxide, its porosity decreases, resulting in a stronger material that is suitable for repairing large segmental bone defects.

[0154] A large-segment bone defect model was constructed using rabbits, and CPU-MgO was injected into the defect sites to solidify and cross-link, thus providing both filling and support. Samples were taken at 1, 3, and 6 months post-surgery for micro-CT scans, tissue section staining, and immunohistochemical staining to systematically investigate the role of CPU-MgO in the repair of large-segment bone defects.

[0155] Example 5

[0156] Step S1. Take 9.61 g of citric acid (0.05 mol, as a bioactive polyacid), 7.51 g of 2,2'-thiodiacetic acid (0.05 mol, as an environmentally responsive degradation acid), and 21.94 g of 1,8-octanediol (0.15 mol, as hydrophobic polyol B), and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a uniform and transparent solution. Then, cool the mixture to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point where the stir bar is difficult to rotate at 60 rpm and the acid value is stable. Stop heating to obtain citric acid-based bioactive polyester polyol.

[0157] Step S2. 2.20 g of citric acid-based bioactive polyester, 11.25 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B) and 1.25 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. The mixture was then vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 19.0 g of isophorone diisocyanate (IPDI, 0.085 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the reaction was continued at 60°C under N2 protection for 1 hour to obtain citric acid-based bioactive reactive polyurethane (CPU1-NCO).

[0158] Step S3. 0.5 g CPU1-NCO, 0.1 g zinc oxide (ZnO, as an inorganic filler), 200 μL water (containing 0.05 g sodium chloride (NaCl, as an aqueous phase pore-forming agent)), and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled CPU1-ZnO). CPU1-ZnO expanded and set within 115 minutes and continued to harden, reaching its final strength after 16 hours.

[0159] A large segmental bone defect model (approximately 6 mm in diameter, 2 cm long) was constructed using rabbits. First, CPU1-ZnO was injected into a cylindrical model with an inner diameter of 6 mm and a height of 2 cm, allowing it to self-expand, solidify, and cross-link, resulting in a biphasic structure with a dense outer layer and a loose, porous inner layer. Then, the solidified, cross-linked biphasic scaffold was implanted into the bone defect, serving both filling and support functions. At 1, 3, and 6 months post-surgery, samples were taken for micro-CT scans, tissue section staining, and immunohistochemical staining to systematically investigate the effect of CPU1-ZnO on the repair of large segmental bone defects.

[0160] Example 6

[0161] Step S1. Take 13.41 g L-malic acid (0.10 mol, as a bioactive polyacid), 7.71 g bis(2-hydroxyethyl) disulfide (0.05 mol, as an environmentally responsive degradable alcohol), and 7.31 g 1,8-octanediol (0.05 mol, as hydrophobic polyol A) and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a uniform and transparent solution. Then cool to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point that the stir bar is difficult to rotate at 60 rpm and its acid value is stable. Stop heating to obtain malic acid-based bioactive polyester polyol.

[0162] Step S2. 3.70 g of malic acid-based bioactive polyester, 8.45 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B) and 1.65 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. Then, the mixture was vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 21.0 g of isophorone diisocyanate (IPDI, 0.094 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the mixture was reacted again at 60°C under N2 protection for 1 hour to obtain malic acid-based bioactive reactive polyurethane (MPU-NCO).

[0163] Step S3. First, hydroxyapatite was surface-modified with proanthocyanidins (PC, a representative polyphenol) under weakly alkaline conditions (Tri-HCl, pH 8.5) to obtain PC-HA. Then, 0.5 g MPU-NCO, 0.1 g PC-HA (as an inorganic filler), 200 μL of water (containing 0.05 g polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous phase porogen)) and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled MPU-PC-HA). MPU-PC-HA expanded and set within 95 minutes and continued to harden, reaching its final strength after 14 hours.

[0164] A large segmental bone defect model (approximately 6 mm in diameter, 2 cm long) was constructed using rabbits. MPU-PC-HA was first injected into a cylindrical model with an inner diameter of 6 mm and a height of 2 cm, allowing it to self-expand, solidify, and cross-link, resulting in a biphasic structure with a dense outer layer and a loose, porous inner layer. This solidified, cross-linked biphasic scaffold was then implanted into the bone defect, serving both filling and support functions. Samples were taken at 1, 3, and 6 months post-surgery for micro-CT scans, tissue section staining, and immunohistochemical staining to systematically investigate the role of MPU-PC-HA in repairing large segmental bone defects.

[0165] Example 7

[0166] Step S1. Take 13.41 g L-malic acid (0.10 mol, as a bioactive polyacid), 17.06 g L-cysteine ​​dimethyl ester hydrochloride (0.05 mol, as an environmentally responsive degradable amine), and 7.31 g 1,8-octanediol (0.05 mol, as hydrophobic polyol A) and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a uniform and transparent solution. Then cool to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point that the stir bar is difficult to rotate at 60 rpm and its acid value is stable. Stop heating to obtain malic acid-based bioactive polyester polyol.

[0167] Step S2. 3.70 g of malic acid-based bioactive polyester, 8.45 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B) and 1.65 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. Then, the mixture was vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 21.0 g of isophorone diisocyanate (IPDI, 0.094 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the mixture was reacted again at 60°C under N2 protection for 1 hour to obtain malic acid-based bioactive reactive polyurethane (MPU-NCO').

[0168] Step S3. 0.5 g MPU-NCO', 0.1 g calcium carbonate (CaC, as an inorganic filler), 200 μL water (containing 0.05 g magnesium sulfate (MgSO4, as an aqueous phase pore-forming agent), and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled MPU-CaC). MPU-CaC expanded and set within 124 minutes and continued to harden, reaching its final strength after 18 hours.

[0169] A femoral condyle defect model was established using rats. MPU-CaC was injected into the bone defect and allowed to self-expand, solidify, and cross-link, serving as a filler and support. Samples were taken at 4, 8, and 14 weeks post-surgery for micro-CT, tissue section staining, and immunohistochemical staining to systematically investigate the role of MPU-CaC in femoral condyle defect repair.

[0170] Example 8

[0171] Step S1. Take 11.81 g of succinic acid (0.10 mol, as a bioactive polyacid), 7.71 g of bis(2-hydroxyethyl) disulfide (0.05 mol, as an environmentally responsive degradable alcohol), and 7.31 g of 1,8-octanediol (0.05 mol, as hydrophobic polyol A) and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a uniform and transparent solution. Then cool to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point that the stir bar is difficult to rotate at 60 rpm and its acid value is stable. Stop heating to obtain succinic acid-based bioactive polyester polyol.

[0172] Step S2. 5.50 g of succinic acid-based bioactive polyester, 9.42 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B) and 1.05 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. Then, the mixture was vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 19.0 g of isophorone diisocyanate (IPDI, 0.085 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.05 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the mixture was reacted again at 60°C under N2 protection for 1 hour to obtain succinic acid-based bioactive reactive polyurethane (SPU-NCO).

[0173] Step S3. 0.5 g SPU-NCO, 0.1 g calcium phosphate (CaP, as an inorganic filler), 200 μL water (containing 0.05 g polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous phase porogen)), and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled SPU-CaP). SPU-CaP expanded and set within 135 minutes and continued to harden, reaching its final strength after 20 hours.

[0174] A femoral condyle defect model was established in rats. SPU-CaP was injected into the bone defect and allowed to self-expand, solidify, and cross-link, serving as a filler and support. Samples were taken at 4, 8, and 14 weeks post-surgery for micro-CT, tissue section staining, and immunohistochemical staining to systematically investigate the effect of SPU-CaP on femoral condyle defect repair.

[0175] Example 9

[0176] Step S1. Take 14.61 g of α-ketoglutaric acid (0.10 mol, as a bioactive polyacid), 7.71 g of bis(2-hydroxyethyl) disulfide (0.05 mol, as an environmentally responsive degradable alcohol), and 7.31 g of 1,8-octanediol (0.05 mol, as hydrophobic polyol A) and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a homogeneous and transparent solution. Then, cool the mixture to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point where the stir bar is difficult to rotate at 60 rpm and the acid value is stable. Stop heating to obtain α-ketoglutaric acid-based bioactive polyester polyol.

[0177] Step S2. 4.90 g of α-ketoglutaric acid-based bioactive polyester, 9.42 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B) and 0.95 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. Then, the mixture was vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 19.0 g of isophorone diisocyanate (IPDI, 0.085 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the mixture was reacted again at 60°C under N2 protection for 1 hour to obtain α-ketoglutaric acid-based bioactive reactive polyurethane (KPU-NCO).

[0178] Step S3. 0.5 g KPU-NCO, 0.1 g magnesium oxide (MgO, as an inorganic filler), 200 μL water (containing 0.05 g polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous phase porogen)) and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled KPU-MgO). KPU-MgO expanded and set in 123 minutes and continued to harden, reaching its final strength after 17 hours.

[0179] A large segmental bone defect model (approximately 6 mm in diameter, 2 cm long) was constructed using rabbits. KPU-MgO was first injected into a cylindrical model with an inner diameter of 6 mm and a height of 2 cm, allowing it to self-expand, solidify, and cross-link, resulting in a biphasic structure with a dense outer layer and a loose, porous inner layer. This solidified, cross-linked biphasic scaffold was then implanted into the bone defect, serving both filling and support functions. Samples were taken at 1, 3, and 6 months post-surgery for micro-CT scans, tissue section staining, and immunohistochemical staining to systematically investigate the effect of KPU-MgO on the repair of large segmental bone defects.

[0180] Comparative Example 1

[0181] In Comparative Example 1, no environmentally responsive degrading acids / alcohols / amines were added during step S1 of the preparation of the bioactive polyester polyol, as detailed below:

[0182] Step S1. Take 23.05 g of citric acid (0.12 mol, as a bioactive polyacid) and 14.62 g of 1,8-octanediol (0.10 mol, as hydrophobic polyol A) and place them in a single-necked round-bottom glass flask equipped with a magnetic stir bar. Melt the mixture in an oil bath at 160°C to obtain a uniform and transparent solution. Then cool the mixture to 140°C and continuously stir the reaction mixture under vacuum (600 rpm). During the polymerization process, gradually reduce the stirring speed according to the polymer viscosity until the viscosity of the reaction system increases to the point that the stir bar is difficult to rotate at 60 rpm and its acid value is stable. Stop heating to obtain a sulfide-free citric acid-based bioactive polyester polyol.

[0183] Step S2. 2.15 g of sulfide-free citric acid-based bioactive polyester polyol, 11.25 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as hydrophobic polyol B), and 1.25 g of PCL triol (Mn = 370 Da, as hydrophobic polyol B) were mixed and heated to 100°C to melt them. The mixture was then vacuum-sealed at 100°C for 3 hours to remove moisture. The mixture was then cooled to 60°C, and 20 μg of stannous octoate (as a catalyst) and 19.0 g of isophorone diisocyanate (IPDI, 0.085 mol, as an aliphatic chain polyisocyanate) were added. The mixture was reacted under N2 protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a polyol containing a tertiary amine) was added, and the reaction was continued at 60°C under N2 protection for 1 hour to obtain citric acid-based bioactive reactive polyurethane (CPU-NCO′).

[0184] Step S3. 0.5 g CPU-NCO, 0.1 g hydroxyapatite (HA, as an inorganic filler), 200 μL water (containing 0.05 g polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous phase porogen)), and 0.05 mL triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled CPU′). CPU′ expanded and set within 150 minutes and continued to harden, reaching its final strength after 24 hours.

[0185] Test case

[0186] 1. Expansion Rate Test: To facilitate quantitative measurement of the volume of the crosslinked polymer containing sulfide (CPU prepared in Example 1) and the polymer without sulfide (CPU′ prepared in Comparative Example 1) before and after expansion, a 5 mL syringe and small NaCl salt particles filtered through a 120-mesh sieve (<125 μm) were used for the test. Specifically, all components of the adhesive were uniformly mixed in a 5 mL syringe, compacted through the syringe to remove air, and the volume scale (V) was recorded. mix After 24 hours, remove the cross-linked polymer solid from the syringe and place it in a new syringe. Fill the area around the solid with salt granules until the scale reads 5 mL. Then collect the salt granules in another new syringe and record the volume of salt (V). salt The inflation rate was calculated using the following equation. For each sample, at least 5 samples were tested, and the results were averaged. Inflation rate (%) = (5 - V) / (5 - V) salt ) / V mix × 100.

[0187] Test results are as follows Figure 6 As shown. By Figure 6It can be seen that the expansion rates of the CPU (containing sulfide) prepared in Example 1 and the CPU′ (not containing sulfide) prepared in Comparative Example 1 are both greater than 400%, around 500%.

[0188] 2. Hardness Testing: For hardness testing, the cross-linked bone adhesives from Example 1 and Comparative Example 1 were cut into cubes (5mm × 5mm × 5mm) and their hardness was measured using a Shore hardness tester (LX-A, Wenzhou, China). When the result was greater than 90HA, the hardness was measured using an LX-D Shore hardness tester. At least 5 samples were tested for each sample, and the average value of the results was taken.

[0189] Test results are as follows Figure 7 As shown. By Figure 7 It can be seen that the hardness of the CPU (containing sulfide) prepared in Example 1 and the CPU′ (not containing sulfide) prepared in Comparative Example 1 are both less than 90HA and are around 87HA.

[0190] 3. Degradation Assay: In vitro degradation experiments were conducted in phosphate-buffered saline (PBS, pH 7.4) at 37°C. Specifically, the cross-linked bone adhesives from Example 1 and Comparative Example 1 were cut into circular samples (diameter = 9 mm, ~0.01 g), accurately weighed (W0), immersed in capped tubes containing 10 mL of PBS, and incubated in a 37°C constant temperature shaking incubator. At predetermined time points, the samples were removed, washed at least three times with pure water, freeze-dried, and weighed (W0). t The mass loss rate was calculated according to the following equation. To simulate high concentrations of reactive oxygen species (ROS) in vivo, especially in inflammatory microenvironments such as osteoporosis, the material was also placed in PBS (pH 7.4) + H2O2 (0.1M) for degradation testing.

[0191] Quality loss rate (%) = (W0 / W t ) / W0×100%

[0192] Test results are as follows Figure 8 As shown. By Figure 8 It can be seen that in PBS, the CPU prepared in Example 1 (containing thioether) degrades slightly faster than the CPU′ prepared in Comparative Example 1 (without thioether); however, in PBS + 0.1M H2O2, the degradation rate of CPU is significantly higher than that of CPU′, indicating that the introduction of thioether can significantly accelerate the degradation of polyurethane. Even in PBS + 0.1M H2O2, the degradation rate of the CPU′ (without thioether) prepared in Comparative Example 1 is not significantly different from that in PBS.

[0193] 4. In vitro biomechanical testing: To simulate the effect of bone adhesive in tendon fixation during anterior cruciate ligament (ACL) reconstruction, braided nylon rope was used as a tendon substitute. A uniformly applied citrate-based biodegradable self-expanding bone adhesive (CPU) was implanted into an 8mm bone tunnel formed at the femoral end of the pig knee joint. After the adhesive had completely cured and hardened, a pull-out strength test was performed 24 hours later. The control group was fixed with commercially available clinical-grade 8mm diameter titanium screws. The pull-out strength of the tendon substitute from the bone tunnel was measured using an Instron 34TM-10 universal tensile tester equipped with a 10kN sensor at a displacement rate of 5mm / min. At least 10 samples were tested in each group, and the results were averaged.

[0194] Test results are as follows Figure 9 As shown. By Figure 9 It can be seen that the ultimate load (until failure) of the CPU group is 237.6±24.94 N, which is significantly lower than, but somewhat comparable to, the ultimate load of the titanium screw group (332.4±35.79 N). It is worth mentioning that the failure of the titanium screw group was almost entirely caused by the fracture of the tendon substitute at the outer edge of the bone tunnel fixed by the titanium screw, while the failure of the CPU group was caused by the tendon substitute being pulled out of the bone tunnel.

[0195] The above results not only demonstrate that titanium screws, as a traditional metal interference screw, can provide strong fixation in the early stages of ACL reconstruction, but also reflect the tendency of traditional interface screws to cause stress concentration and tendon rupture. Self-expanding bone adhesive, on the other hand, offers a game-changing solution that fundamentally addresses the stress concentration problem.

[0196] 5. In vivo experiment: Rabbits were anesthetized by intravenous injection of sodium pentobarbital (30 mg / kg). After shaving and disinfecting the left leg, the rabbit was placed supine on the operating table. The left leg was disinfected again and covered with surgical drape. An incision was made along the medial side of the patella, allowing it to be turned laterally, exposing and removing the anterior cruciate ligament (ACL). The semitendinosus muscle was then dissected and harvested as a tendon substitute (autologous tendon) for subsequent ACL reconstruction. The rabbit's knee joint was fixed in 45° flexion, and a 3 mm diameter drill was used to drill a hole posterolaterally from the ACL femoral appendage, forming a bone tunnel that sloped from the medial cortical bone of the tibial articular surface towards the joint. The bone tunnel was flushed with sterile saline. The tendon substitute was then pulled into the femoral tunnel at a 30° angle with the knee joint flexed. Self-expanding bone adhesive was injected and evenly applied into the gap between the tendon and the bone tunnel. To prevent pull-out of the tendon substitute before the self-expanding bone adhesive has fully cured, the end of the tendon substitute was secured to the tissue near the openings of the tibial and femoral tunnels by a knot. The tissue was then rinsed, sutured layer by layer, and disinfected with iodine. All rabbits regained free movement 2 hours post-surgery. Control samples were secured to the tendon within the bone tunnel using commercially available 3mm diameter titanium screws. Rabbits were euthanized at 4 and 14 weeks after ACL reconstruction, and tissue samples were harvested for micro-CT and stained hard tissue sections (VG staining). At week 14, a subset of samples (3 per group) were used for biomechanical testing to assess the pull-out strength of the tendon from the bone tunnel after ACL reconstruction and tissue regeneration.

[0197] Test results are as follows Figure 10 and Figure 11 As shown. From the micro-CT 3D reconstruction results ( Figure 10 As can be seen, compared to bone screws, self-expanding bone adhesive provides more even compression to the tendon, which is also evident in... Figure 11 As seen in Figure A, the number of newly formed bone (the colored portion in micro-CT) was greater in the self-expanding bone adhesive group, indicating that the self-expanding bone adhesive developed in Example 1 can promote osteogenesis to a certain extent.

[0198] from Figure 11 As can be seen from Figure A, self-expanding bone adhesives can fully fill the gap between the tendon and the bone tunnel and penetrate into the gaps within the bone tunnel, which is beneficial for improving tendon-bone bonding strength through mechanical locking. Because self-expanding bone adhesives can fully and uniformly fill the gap between the tendon and the bone tunnel and penetrate into the gaps within the bone tunnel, through mechanical locking and the possible chemical bonding between the -NCO groups and the surface-active groups (-NH2, -SH) of bone tissue, self-expanding bone adhesives can provide a certain degree of tendon-bone bonding strength, but their initial strength is lower than that of bone screws (see Figure A). Figure 9(In vitro biomechanical data); however, over time, self-expanding bone adhesives promote bone regeneration by releasing active ingredients through degradation, and the space created by degradation also promotes bone ingrowth. After 14 weeks of ACL reconstruction, the pull-out strength of the tendon from the bone tunnel exceeded that of the bone screw (e.g., Figure 11 (As described in section B). This fully demonstrates that biodegradable self-expanding bone adhesives can provide good initial tendon-bone bonding strength and promote subsequent bone regeneration, thereby promoting tendon-bone healing.

[0199] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0200] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A degradable self-expanding bone cement, characterized by, The bioactive reactive polyurethane and the foaming control agent; The bioactive reactive polyurethane has a plurality of isocyanate groups at the terminal thereof, and the raw material for preparing the bioactive reactive polyurethane includes a bioactive polyester polyol, the raw material for preparing the bioactive polyester polyol includes a bioactive polyacid, a hydrophobic polyol A, and an environmentally responsive degradable acid / alcohol / amine, the environmentally responsive degradable acid / alcohol / amine contains one or both of a thioether group and a disulfide bond; The foaming control agent is a substance capable of reacting with or adsorbing carbon dioxide.

2. The degradable self-setting bone glue of claim 1, wherein, The environmentally responsive degradable acid / alcohol / amine includes one or more of a monobasic acid / alcohol / amine containing a thioether group, a dibasic acid / alcohol / amine containing a disulfide bond, and a dibasic acid / alcohol / amine containing a thioether group.

3. The degradable self-setting bone glue of claim 2, wherein, The monobasic acid / alcohol / amine containing a thioether group includes one or more of 2-(methylthio)acetic acid, 3-(methylthio)propanoic acid, 2-(methylthio)ethanol, 3-methylthiopropanol, 4-(methylthio)butanol, 2-ethylthioethanol, and 3-(ethylthio)propanol.

4. The degradable self-setting bone glue of claim 2, wherein, The dibasic acid / alcohol / amine containing a thioether group includes one or more of 2,2'-thiodiacetic acid and 3,6-dithia-1,8-octanediol.

5. The degradable self-setting bone glue of claim 2, wherein, The dibasic acid / alcohol / amine containing a disulfide bond includes one or more of L-cystine dimethyl ester and bis(2-hydroxyethyl) disulfide.

6. The degradable self-setting bone glue of claim 1, wherein, The ratio of the total molar number of carboxyl groups to the total molar number of hydroxyl groups contained in the bioactive polyacid, the hydrophobic polyol A, and the environmentally responsive degradable acid / alcohol / amine is 1:(0.5-3); and / or The acid value of the bioactive polyester polyol is 3 mg KOH / g-500 mg KOH / g; and / or The bioactive polyacid includes one or more of citric acid, malic acid, succinic acid, and alpha-ketoglutaric acid; and / or The hydrophobic polyol A includes a hydrophobic polyol having a carbon atom number of 3-22.

7. The degradable self-setting bone glue of claim 6, wherein, The hydrophobic polyol A includes one or more of 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and 1,12-dodecanediol.

8. The degradable self-setting bone glue of claim 1, wherein, The foaming control agent includes one or more of sodium hydroxide, aqueous ammonia, N,N-dimethylethanolamine, triethylamine, morpholine, choline, magnesium oxide, calcium oxide, activated carbon, white carbon black, and zeolite.

9. The degradable self-setting bone glue of claim 1, wherein, The raw material for preparing the bioactive reactive polyurethane further includes a hydrophobic polyol B, a polyol containing a tertiary amine, a fatty chain polyisocyanate, and a catalyst.

10. The degradable self-setting bone glue of claim 9, wherein, The ratio of the total molar number of isocyanate groups to the total molar number of hydroxyl groups contained in the bioactive polyester polyol, the hydrophobic polyol B, the polyol containing a tertiary amine, and the fatty chain polyisocyanate is 1.5-2.

5.

11. The degradable self-setting bone glue of claim 10, wherein, The ratio of the total molar number of isocyanate groups to the total molar number of hydroxyl groups contained in the bioactive polyester polyol, the hydrophobic polyol B, the polyol containing a tertiary amine, and the fatty chain polyisocyanate is 1.8-2.

2.

12. The degradable self-setting bone glue of claim 9, wherein, The hydrophobic polyol B includes at least one of castor oil, polyglycerol, poly(ε-caprolactone) polyol, polylactic acid polyol, and polyglycolide polyol.

13. The degradable self-setting bone glue of claim 9, wherein, The tertiary amine-containing polyol includes one or more of triethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-n-propyldiethanolamine, t-butyldiethanolamine, and N,N'-bis(2-hydroxyethyl)piperazine.

14. The degradable self-setting bone glue of claim 9, wherein, The fatty chain polyisocyanate includes one or more of L-lysine ethyl diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, and dicyclohexylmethane diisocyanate.

15. The degradable self-setting bone glue of claim 9, wherein the degradable self- setting bone glue is characterized by, The catalyst includes one or more of organotin-based catalysts, organobismuth-based catalysts, and amine-based catalysts.

16. The degradable self-setting bone glue of claim 9, wherein, The reaction raw materials of the bioactive reactive polyurethane include, in parts by weight, 5-30 parts of the bioactive polyester polyol, 10-40 parts of the hydrophobic polyol B, 1-10 parts of the tertiary amine-containing polyol, 30-60 parts of the fatty chain polyisocyanate, and 0.01-5 parts of the catalyst.

17. The degradable self-setting bone glue of claim 9, wherein, The preparation method of the bioactive reactive polyurethane includes: vacuum dehydration of a mixture containing the bioactive polyester polyol and the hydrophobic polyol B at 90-120°C for 1-5h to prepare a dehydrated material; mixing the dehydrated material, the fatty chain polyisocyanate, and the catalyst, and reacting at 40-90°C in a protective atmosphere for 1-24h to prepare an intermediate; mixing the intermediate and the tertiary amine-containing polyol, and reacting at 40-90°C in a protective atmosphere for 1-3h to prepare the bioactive reactive polyurethane.

18. The degradable self-setting bone glue of any one of claims 1 to 17, wherein, The inorganic filler also includes modified and unmodified hydroxyapatite, calcium phosphate, calcium carbonate, zinc oxide, and magnesium oxide.

19. The degradable self-setting bone glue of claim 18, wherein, The modification method includes surface deposition of the material to be modified with polyphenol, dopamine, or dopamine in the presence of a base or oxygen.

20. The degradable self-setting bone glue of claim 19, wherein, The bone adhesive includes, in parts by weight, 60-90 parts of the bioactive reactive polyurethane, 0.1-40 parts of the inorganic filler, and 0.1-5 parts of the foaming control agent.

21. The degradable self-setting bone glue of claim 18, wherein, The aqueous phase porogen also includes polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol diethyl ester, polyvinylpyrrolidone, sodium chloride, and magnesium sulfate.

22. The degradable self-setting bone cement according to any one of claims 1 to 17, wherein The aqueous phase porogen has a molecular weight of 1000-20000 Da.

23. The degradable self-setting bone glue of claim 22, wherein, The bone adhesive contains the aqueous phase porogen in an amount of 1-20 parts by weight.

24. The degradable self-setting bone glue of claim 22, wherein, The bone adhesive contains the aqueous phase porogen in an amount of 1-10 parts by weight.

25. The degradable self-setting bone glue of claim 22, wherein, 27. Use of the degradable self-expanding bone adhesive according to any one of claims 1-26 in the preparation of a material for tendon-bone healing, a material for bone defect repair, and / or a porous degradable scaffold.

26. The degradable self-stiffening bone cement of claim 22, wherein, ​ ​

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