Degradable self-expanding bioactive bone adhesive and use thereof

Abstract

The present application provides a degradable self-expanding bioactive bone adhesive and a use thereof. The degradable self-expanding bone adhesive comprises bioactive reactive polyurethane and a foaming control agent; the bioactive reactive polyurethane contains multiple isocyanate groups at terminals thereof, the preparation raw material of the bioactive reactive polyurethane comprises a bioactive polyester polyol, the preparation raw materials of the bioactive polyester polyol comprise a bioactive polybasic acid, a hydrophobic polyol A and an environmentally responsive degradable acid / alcohol / amine, and the environmentally responsive degradable acid / alcohol / amine comprises one or both of a thioether group and a disulfide bond; and the foaming control agent is a substance capable of reacting with or adsorbing carbon dioxide. The bone adhesive provided by the present application is degradable and self-expanding, and fixes tendons within a bone tunnel by applying planar and uniform compression to the tendons, thereby avoiding stress concentration and uneven compression of the tendons that may lead to tendon rupture, and preventing lateral displacement and longitudinal stretching of the tendons.

Description

Degradable self-expanding bioactive bone adhesive and its application Technical Field

[0001] The present application relates to the technical field of medical materials, and in particular to a degradable self-expanding bioactive bone adhesive and its application. Background Art

[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 even requiring total knee replacement in severe cases. ACL reconstruction can quickly restore most of the function of the affected limb and has been considered the standard ACL injury repair surgery for more than 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, 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 mainly relies on interface / extrusion bone screws made of metal and polymer materials. Titanium, magnesium and zinc alloy bone screws are the main types of metal bone screws, among which titanium screws are the most commonly used due to their high initial fixation strength, corrosion resistance and low cost. However, the mismatch in elastic modulus between metal and bone tissue usually 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 include non-degradable bone screws such as polyetheretherketone (PEEK) bone screws and absorbable / degradable bone screws such as polylactic acid (PLLA)-based bone screws. They generally have good biocompatibility and an elastic modulus similar to that of bone, and have become a widely accepted alternative to metal screws in recent years.

[0004] However, whether using metal or polymer bone screws, tendon grafts are typically fixed in a point-like manner within the bone tunnel, which can easily compress the tendon, causing stress concentration and even tendon rupture. Furthermore, because traditional fixation methods leave a large gap between the tendon and the bone tunnel, they can easily cause a "wiper effect" (lateral swinging of the tendon) and a "bungee effect" (longitudinal stretching of the tendon).

[0005] Summary of the Invention

[0006] Based on this, the present application provides a degradable self-expanding bioactive bone adhesive and its application to reduce or even avoid stress concentration and uneven squeezing of tendons, while reducing or even avoiding lateral swing and longitudinal stretching of tendons.

[0007] A first aspect of the present application provides a degradable self-expanding bone adhesive comprising a bioactive reactive polyurethane and a foaming control agent;

[0008] The bioactive reactive polyurethane contains a plurality of isocyanate groups at its end, and the raw materials for preparing the bioactive reactive polyurethane include bioactive polyester polyols, and the raw materials for preparing the bioactive polyester polyols include bioactive polyacids, hydrophobic polyol A, and environmentally responsive degradable acids / alcohols / amines, wherein the environmentally responsive degradable acids / alcohols / amines contain one or both of thioether groups and disulfide bonds;

[0009] The foaming control agent is a substance that can react with carbon dioxide or absorb carbon dioxide.

[0010] In some embodiments, the environmentally responsive degradation acid / alcohol / amine comprises one or more of a monoacid / alcohol / amine containing a thioether group, a diacid / alcohol / amine containing a disulfide bond, and a diacid / alcohol / amine containing a thioether group;

[0011] Optionally, the monoacid / 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;

[0012] Optionally, 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;

[0013] Optionally, the disulfide bond-containing dibasic acid / alcohol / amine includes one or more of L-cystine dimethyl ester and bis(2-hydroxyethyl) disulfide.

[0014] In some embodiments, the ratio of the total number of moles of carboxyl groups to the total number of moles of hydroxyl groups contained in the bioactive polyacid, the hydrophobic polyol A, and the environmentally responsive degradation acid / alcohol / amine is 1:(0.5-3); and / or

[0015] The bioactive polyester polyol has an acid value of 3 mg KOH / g to 500 mg KOH / g; and / or

[0016] The bioactive polyacid comprises one or more of citric acid, malic acid, succinic acid and α-ketoglutaric acid; and / or

[0017] The hydrophobic polyol A comprises a hydrophobic polyol having 3 to 22 carbon atoms;

[0018] 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.

[0019] In some embodiments, the foam control agent includes one or more of sodium hydroxide, ammonia water, N,N-dimethylethanolamine, triethylamine, morpholine, choline, magnesium oxide, calcium oxide, activated carbon, white carbon black, and zeolite.

[0020] In some embodiments, the raw materials for preparing the bioactive reactive polyurethane further include a hydrophobic polyol B, a polyol containing a tertiary amine, a fatty chain polyisocyanate, and a catalyst;

[0021] Optionally, the ratio of the total number of moles of isocyanate groups to the total number of moles of hydroxyl groups contained in the bioactive polyester polyol, the hydrophobic polyol B, the tertiary amine-containing polyol and the fatty chain polyisocyanate is 1.5-2.5, optionally 1.8-2.2;

[0022] Optionally, the hydrophobic polyol B includes at least one of castor oil, polyglycerol, poly(ε-caprolactone) polyol, polylactic acid polyol and poly(lactide-glycolide) polyol;

[0023] Optionally, the tertiary amine-containing polyol includes one or more of triethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-n-propyldiethanolamine, tert-butyldiethanolamine and N,N'-bis(2-hydroxyethyl)piperazine;

[0024] Optionally, the fatty chain polyisocyanate includes one or more of L-lysine ethyl diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate and dicyclohexylmethane diisocyanate;

[0025] Optionally, the catalyst includes one or more of an organotin catalyst, an organobismuth catalyst and an amine catalyst;

[0026] Optionally, 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.

[0027] In some embodiments, the method for preparing the bioactive reactive polyurethane comprises:

[0028] Dehydrating a mixture comprising the bioactive polyester polyol and the hydrophobic polyol B under vacuum at 90° C. to 120° C. for 1 h to 5 h to prepare a dehydrated material;

[0029] The dehydrated material, the fatty chain polyisocyanate and the catalyst are mixed and reacted at 40° C. to 90° C. in a protective atmosphere for 1 hour to 24 hours to prepare an intermediate;

[0030] The intermediate is mixed with the polyol containing tertiary amine, and reacted at 40° C.-90° C. in a protective atmosphere for 1 h-3 h to prepare the bioactive reactive polyurethane.

[0031] In some embodiments, an inorganic filler is also included;

[0032] Optionally, the inorganic filler includes one or more of modified and unmodified hydroxyapatite, calcium phosphate, calcium carbonate, zinc oxide, and magnesium oxide;

[0033] Optionally, the modification method includes depositing polyphenol, dopa or dopamine on the surface of the material to be modified under alkaline or oxygen conditions.

[0034] 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.

[0035] In some embodiments, an aqueous porogen is also included;

[0036] Optionally, the aqueous phase porogen includes one or more of polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol diethyl ester, polyvinyl pyrrolidone, sodium chloride and magnesium sulfate;

[0037] Optionally, the molecular weight of the aqueous porogen is 1000Da-20000Da;

[0038] Optionally, the bone adhesive contains the aqueous porogen in an amount of 1 to 20 parts by weight;

[0039] Optionally, the bone adhesive contains the aqueous porogen in an amount of 1 to 10 parts by weight.

[0040] The second aspect of the present application provides a use of the degradable self-expanding bone adhesive of the first aspect of the present application in preparing a material for tendon-bone healing, a material for bone defect repair, and / or a porous degradable scaffold.

[0041] The above-mentioned degradable and self-expanding bone adhesive has a certain degree of fluidity, is injectable, can self-foam and expand during wetting, and can degrade and release active ingredients that promote bone regeneration. It has at least the following beneficial effects:

[0042] (1) Compared with the interface / extrusion bone screw that fixes the tendon in the bone tunnel through point fixation and non-uniform extrusion, the bone adhesive provided by the present application can simulate a tug-of-war game and fix the tendon in the bone tunnel by surface and uniform extrusion of the tendon, thereby avoiding stress concentration and tendon rupture caused by uneven extrusion of the tendon. It can also avoid the "wiper effect" (lateral swing of the tendon) and the "bungee effect" (longitudinal stretching of the tendon) by fully filling the tendon-bone tunnel gap.

[0043] (2) The bone adhesive provided in the present application expands in the confined space between the tendon and the bone tunnel, and can fully and evenly squeeze the tendon in the bone tunnel to achieve tendon-bone fixation. The bone adhesive can also be embedded in the gap of the bone tunnel, and improve the tendon-bone bonding force through mechanical locking and chemical bonding of residual NCO groups with active groups such as amino groups and thiol groups on the bone surface.

[0044] (3) The bone adhesive provided in this application obtains a porous structure through foaming and expansion, which is conducive to bone ingrowth. The porous structure can buffer stress and, when used to repair compression fractures caused by osteoporosis (replacing bone cement in vertebroplasty), can avoid conventional bone cement (polymethyl methacrylate) from compressing adjacent cones due to its high modulus, thereby causing adjacent vertebral fractures.

[0045] (4) Due to the presence of environmentally responsive groups in the bone adhesive provided herein, the degradation of the bone adhesive can be accelerated. Furthermore, the presence of a foaming control agent in the bone adhesive facilitates the control of foaming, thereby controlling the formation of pores and the size of the porosity, thereby avoiding excessive expansion that compresses surrounding tissues and reduces material strength, and also facilitates the control of the degradation time of the bone adhesive. Furthermore, since the bone adhesive can be degraded to produce bioactive components, the bioactive components are continuously released as the bone adhesive degrades, promoting bone regeneration and narrowing of the bone tunnel, thereby further increasing tendon-bone adhesion.

[0046] (5) The bone adhesive provided in the present application solidifies rapidly during the self-foaming expansion process because the outer material is preferentially exposed to water vapor, while the inner material solidifies relatively slowly. Therefore, a dual-phase structure with a dense and less porous outer layer and a high porosity inner layer can be formed, which can simulate the dual-phase structure of natural bone consisting of cortical bone and cancellous bone. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more fully understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present application. Those skilled in the art can also derive other drawings based on these drawings without inventive effort.

[0048] FIG1 is a schematic diagram of the expansion of a bone adhesive in a confined space provided by one embodiment;

[0049] FIG2 is a schematic diagram of the synthesis of a bioactive polyester polyol provided in one embodiment;

[0050] FIG3 is a schematic diagram of the synthesis of a bioactive reactive polyurethane provided in one embodiment;

[0051] FIG4 is a specific synthesis process of citric acid-based bioactive polyester polyol and citric acid-based bioactive reactive polyurethane (CPU-NCO) in Example 1;

[0052] FIG5 shows infrared spectra of the citric acid-based bioactive reactive polyurethane (CPU-NCO) prepared in Example 1 before and after cross-linking (A), and the porosity of the cross-linked products obtained when the bone adhesive formulation has the same water dosage but different contents of the aqueous porogen PEG-DM (B);

[0053] FIG6 shows the expansion rate test results of the CPU (containing sulfide) prepared in Example 1 and the CPU′ (not containing sulfide) prepared in Comparative Example 1;

[0054] FIG7 shows the hardness test results of the CPU (containing sulfide) prepared in Example 1 and the CPU′ (not containing sulfide) prepared in Comparative Example 1;

[0055] FIG8 shows the degradation experimental results of CPU (containing thioether) prepared in Example 1 and CPU′ (not containing thioether) prepared in Comparative Example 1 in PBS and PBS+H2O2;

[0056] FIG9 shows the pull-out strength of the CPU prepared in Example 1 after fixation of an artificial tendon in vitro for 24 hours, and its comparison with that of a commercial titanium screw (Ø8 mm);

[0057] FIG10 is a micro-CT image of the CPU prepared in Example 1 after 4 and 14 weeks of anterior cruciate ligament reconstruction surgery in New Zealand rabbits, using commercial titanium screws (Ø3 mm) as a reference;

[0058] Figure 11 is a Van Gieson (VG) staining of hard tissue sections of the CPU prepared in Example 1 used for anterior cruciate ligament reconstruction surgery in New Zealand rabbits 14 weeks after surgery, as well as the biomechanical strength (pull-out strength of the autologous tendon from the bone marrow tract) after 14 weeks of repair and its comparison with commercial titanium screws (Ф3mm). DETAILED DESCRIPTION

[0059] To facilitate understanding of the present invention, the present application will be described more fully below with reference to the relevant embodiments. The following provides preferred embodiments of the present application. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application.

[0061] The terms "and / or", "or / and", and "and / or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the any and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by 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 technical solutions connected by "logical AND" and technical solutions connected by "logical OR".

[0062] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0063] In this application, when referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0064] Only certain numerical ranges are specifically disclosed herein. However, any lower limit may be combined with any upper limit to form an unspecified range; and any lower limit may be combined with other lower limits to form an unspecified range, and similarly, any upper limit may be combined with any other upper limit to form an unspecified range. In addition, each individually disclosed point or single value may itself serve as a lower limit or upper limit and be combined with any other point or single value, or with other lower limits or upper limits, to form an unspecified range.

[0065] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are permitted.

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

[0067] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc. shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

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

[0069] In this application, the terms "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If a technical solution contains multiple "optional" clauses, each "optional" clause is independent unless otherwise specified and there are no contradictions or constraints.

[0070] In the description of the application, "multiple" means at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0071] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution. Unless otherwise specified, all technical features and optional technical features of the present application can be combined with each other to form a new technical solution.

[0072] Unless otherwise specified, all steps of the present application can be performed sequentially or randomly, preferably sequentially.

[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 mainly relies on interface / extrusion bone screws made of metal and polymer materials. However, whether it is metal or polymer bone screws, the fixation method of tendon grafts in bone tunnels is point fixation, which can easily squeeze the tendon, causing stress concentration and even tendon rupture. In addition, due to the large gap between the tendon and the bone tunnel in traditional fixation methods, it is easy to cause a "wiper effect" (lateral swing of the tendon) and a "bungee effect" (longitudinal stretching of the tendon).

[0074] To address these issues, the present invention 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. A bioactive reactive polyurethane is then prepared based on the bioactive polyester polyol. Finally, a degradable, self-expanding bone adhesive comprising the bioactive reactive polyurethane and a foaming control agent is prepared. The bone adhesive exhibits a certain degree of fluidity and is injectable. It self-foams and expands during moisture curing, degrading and releasing active ingredients that promote bone regeneration.

[0075] The first aspect of the present application provides a degradable self-expanding bone adhesive, comprising a bioactive reactive polyurethane and a foaming control agent; the end of the bioactive reactive polyurethane contains multiple isocyanate groups, 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 polyols A and environmentally responsive degradable acids / alcohols / amines, and the environmentally responsive degradable acids / alcohols / amines contain one or both of thioether groups and disulfide bonds; the foaming control agent is a substance that can react with carbon dioxide or adsorb carbon dioxide.

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

[0077] When environmentally responsive degradation acids / alcohols / amines contain one or both of thioether groups and disulfide bonds, they can undergo changes in hydrophilicity and hydrophobicity or chemical bond cleavage in the microenvironment of high oxidative stress (i.e., high reactive oxygen species (ROS) concentrations) in vivo due to inflammatory stimulation, thereby promoting material degradation. Specifically, the hydrophobic thioether group (-S-) is oxidized to a hydrophilic sulfone (-(O=S=O)-) or sulfoxide (-(S=O)-) group in a high ROS microenvironment, increasing the material's hydrophilicity and accelerating its degradation. Meanwhile, disulfide bonds can break in a high ROS microenvironment, thereby promoting material degradation.

[0078] Understandably, compared to interface / compression bone screws that fix the tendon in the bone tunnel through point fixation and non-uniform compression, the bone adhesive provided in the present application is degradable and self-expanding, and can simulate a tug-of-war game, and fix the tendon in the bone tunnel through surface and uniform compression of the tendon, thereby avoiding stress concentration and tendon rupture caused by uneven compression of the tendon, and can avoid the "wiper effect" (lateral swing of the tendon) and "bungee effect" (longitudinal stretching of the tendon) by fully filling the tendon-bone tunnel gap.

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

[0080] The presence of environmentally responsive groups in bone adhesive accelerates its degradation. Furthermore, the inclusion of a foaming control agent helps control foaming, thereby controlling pore formation and porosity, preventing excessive expansion that compresses surrounding tissue and reduces material strength. This also helps control the degradation time of the bone adhesive. Furthermore, since bone adhesive degrades to produce bioactive components, their continuous release as the adhesive degrades promotes bone regeneration and bone tunnel narrowing, further enhancing tendon-bone adhesion.

[0081] Bone adhesives obtain a porous structure through foaming and expansion, which is conducive to bone ingrowth. The porous structure can also buffer stress. When used to repair compression fractures caused by osteoporosis (replacing bone cement in vertebroplasty), it can prevent conventional bone cement (polymethyl methacrylate) from compressing adjacent cones due to its high modulus, causing adjacent vertebral fractures.

[0082] During the self-foaming expansion process, the bone adhesive of the present application solidifies rapidly because the outer material is exposed to water vapor first, while the inner material solidifies relatively slowly. Therefore, a dual-phase structure with a dense and less porous outer layer and a high porosity inner layer can be formed, which can simulate the dual-phase structure of natural bone composed of cortical bone and cancellous bone.

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

[0084] In some embodiments, the environmentally responsive degradation acid / alcohol / amine comprises one or more of a monoacid / alcohol / amine containing a thioether group, a diacid / alcohol / amine containing a disulfide bond, and a diacid / alcohol / amine containing a thioether group.

[0085] As a possible embodiment, the monoacid / 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 optional embodiments, 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.

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

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

[0089] In some embodiments, the ratio of the total number of carboxyl moles to the total number of hydroxyl moles contained 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 a range between any two of the above ratios. Alternatively, the ratio of the total number of carboxyl moles to the total number of hydroxyl moles is 1:(1.3-1.8). More preferably, the ratio of the total number of carboxyl moles to the total number of hydroxyl moles is 1:1.3, 1:1.5, or 1:1.8. Thus, when the ratio of the total number of carboxyl moles to the total number of hydroxyl moles is 1:(0.5-3), the resulting polyester can be controlled to have a certain degree of polymerization and contain multiple hydroxyl termini to facilitate further reaction with polyisocyanates.

[0090] As a possible embodiment, 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 a range between any two of the above acid values. When the acid value of the bioactive polyester polyol is within the above range, the carboxyl content of the resulting bioactive polyester polyol is controlled within a relatively low range. Since the reactivity of carboxyl groups with isocyanates is much lower than that of hydroxyl groups with isocyanates, and the reaction of carboxyl groups with isocyanates removes carbon dioxide, the material cannot be restored to its original active polyacid structure after degradation, thereby affecting the material's bioactivity. Therefore, when the carboxyl content of the resulting bioactive polyester polyol is controlled within a relatively low range, it is beneficial to reduce the impact on the material's bioactivity. Optionally, the acid value of the bioactive polyester polyol is 50 mg KOH / g to 250 mg KOH / g. Further optionally, the acid value of the bioactive polyester polyol ranges from 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 polyacid comprises one or more of citric acid, malic acid, succinic acid, and alpha-ketoglutaric acid.

[0092] In some embodiments, the hydrophobic polyol A comprises a hydrophobic polyol having 3 to 22 carbon atoms.

[0093] In some optional 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, referring to FIG2 , a bioactive polyester polyol is obtained by condensation polymerization of a bioactive polyacid, a hydrophobic polyol A, and an environmentally responsive degradation acid / alcohol / amine.

[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, white carbon black, and zeolite.

[0096] In some embodiments, the raw materials for preparing the bioactive reactive polyurethane further include a hydrophobic polyol B, a polyol containing a tertiary amine, a fatty chain polyisocyanate, and a catalyst.

[0097] As one possible embodiment, the ratio of the total number of moles of isocyanate groups to the total number of moles of hydroxyl groups in the bioactive polyester polyol, hydrophobic polyol B, tertiary amine-containing polyol, and fatty 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 a range between any two of the foregoing values. This facilitates the resulting reactive polyurethane to have a sufficient degree of polymerization and retain a large number of reactive isocyanate groups for moisture-curing crosslinking reactions. Alternatively, the ratio of the total number of moles of isocyanate groups to the total number of moles of hydroxyl groups in the bioactive polyester polyol, hydrophobic polyol B, tertiary amine-containing polyol, and fatty chain polyisocyanate is 1.8-2.3. More 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 tertiary amine-containing polyol and the fatty chain polyisocyanate is 1.8, 1.9, 2, 2.1, 2.2 or 2.3.

[0098] In some optional embodiments, 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 tertiary amine-containing polyol and the fatty chain polyisocyanate is 1.8-2.2.

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

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

[0101] In some embodiments, the tertiary amine-containing polyol 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 optional embodiments, the catalyst includes one or more of an organotin catalyst, an organobismuth catalyst, and an amine catalyst.

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

[0105] As an example, in the reaction raw materials of the bioactive reactive polyurethane, the weight proportion of the bioactive polyester polyol can be, but is 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 a range between any two of the above weight proportions.

[0106] As an example, in the reaction raw materials of the bioactive reactive polyurethane, the weight proportion of the hydrophobic polyol B can be, but is 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 a range between any two of the above weight proportions.

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

[0108] As an example, in the reaction raw materials of the bioactive reactive polyurethane, the weight proportion of the fatty chain polyisocyanate can be, but is 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 a range between any two of the above weight proportions.

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

[0110] In some embodiments, the method for preparing the bioactive reactive polyurethane comprises:

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

[0112] For example, the temperature for vacuum dehydration of the mixture comprising the bioactive polyester polyol and the hydrophobic polyol B may be, but is not limited to, 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., 120° C., or a range between any two of the foregoing temperatures. The vacuum dehydration temperature within the foregoing range facilitates sufficient water removal while preventing the removal of volatile reactants, which would affect the actual ratio of the total moles of isocyanate groups to the total moles of hydroxyl groups.

[0113] The time for vacuum dehydration can be, but is not limited to, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or a range before any two of the above times. When the time for vacuum dehydration is within the above range, it is beneficial to fully remove water without making the total reaction time too long.

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

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

[0116] In some embodiments, the protective atmosphere comprises nitrogen.

[0117] In some embodiments, referring to FIG3 , when preparing a bioactive reactive polyurethane, a dehydrated bioactive polyester polyol and a hydrophobic polyol B are mixed with a fatty chain polyisocyanate and a catalyst and reacted; then a polyol containing a tertiary amine is added to continue the reaction to prepare a bioactive reactive polyurethane.

[0118] In some embodiments, the bone adhesive further comprises an inorganic filler. The addition of the inorganic filler enhances the strength and bioactivity of the bone adhesive and better simulates the chemical composition of natural bone. Natural bone is composed of 65 wt% inorganic components (primarily hydroxyapatite) embedded in 35 wt% organic components (primarily collagen).

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

[0120] As a possible embodiment, the modification method includes depositing polyphenols, dopa, or dopamine on the surface of the material to be modified under alkaline or oxygen conditions. This produces a phenolic surface-modified inorganic component. The polyphenols deposited on the surface of the inorganic component can enhance the biological activity of the inorganic component by imparting antioxidant and anti-inflammatory properties. Furthermore, the phenolic hydroxyl groups of the phenols react with isocyanate groups to form easily breakable phenol-carbamate bonds (which can be broken or repaired under heating and are 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 foaming control agent.

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

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

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

[0125] In some embodiments, the bone adhesive further comprises an aqueous porogen; by adding the aqueous porogen, the porosity of the bone adhesive after foaming and expansion can be further increased, which is beneficial for bone ingrowth.

[0126] In some optional embodiments, the aqueous porogen includes one or more of polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol diethyl ester, polyvinyl pyrrolidone, sodium chloride and magnesium sulfate.

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

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

[0129] In some exemplary embodiments, the bone adhesive contains the aqueous porogen in an amount of 1 to 10 parts by weight.

[0130] In some embodiments, the bone adhesive further comprises water. Optionally, the bone adhesive comprises 10-25 parts of water by weight.

[0131] It should be noted that water and bioactive reactive polyurethane are mixed before use. When not in use, water and bioactive reactive polyurethane are placed independently of each other.

[0132] The bone adhesive provided in the present application can expand and set to its original shape within 5-200 minutes after mixing the various components during use, and can continue to harden to reach its final strength after 8-24 hours.

[0133] The second aspect of the present application provides a use of the bone adhesive of the first aspect of the present application in preparing a material for tendon-bone healing, a material for bone defect repair and / or a porous degradable scaffold.

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

[0135] The technical solutions of the present invention are described in detail below with reference to specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. For experimental methods in the following examples where specific conditions are not specified, reference should be made to the instructions provided in the present invention, or to experimental manuals or conventional conditions in the art, or to conditions recommended by the manufacturer, or to experimental methods known in the art.

[0136] In the following specific examples, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument testing accuracy or operational accuracy are allowed.

[0137] Example 1

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

[0139] Step S2: 2.50 g of a citric acid-based bioactive polyester, 11.25 g of poly(ε-caprolactone) (PCL) diol (Mn = 530 Da, as the hydrophobic polyol B), and 1.25 g of PCL triol (Mn = 370 Da, as the hydrophobic polyol B) were mixed and heated to 100°C to melt. The mixture was then vacuumed 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 the aliphatic polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Subsequently, 1.01 g of N-methyldiethanolamine (MDEA, as the tertiary amine-containing polyol) was added, and the reaction was continued at 60°C under nitrogen protection for 1 hour to produce a citric acid-based bioactive reactive polyurethane (CPU-NCO).

[0140] Step S3. 0.5 g of CPU-NCO, 0.1 g of hydroxyapatite (HA, as an inorganic filler), 200 μL of water (containing 0.05 g of polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous porogen), and 0.05 mL of triethylamine (as a foaming control agent) were uniformly mixed to produce a citric acid-based biodegradable self-expanding bone adhesive (labeled as CPU). The 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) of Example 1 is shown in FIG4 .

[0142] Example 2

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

[0144] Step S3. 0.5 g of CPU-NCO, 0.1 g of hydroxyapatite (HA, as an inorganic filler), 200 μL of water (containing 0.1 g of polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous porogen), and 0.05 mL of triethylamine (as a foaming control agent) were uniformly mixed to produce 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 of CPU-NCO, 0.1 g of hydroxyapatite (HA, as an inorganic filler), 200 μL of water, and 0.05 mL of triethylamine (as a foaming control agent) were uniformly mixed to produce a citric acid-based, self-expanding bone adhesive. This citric acid-based, 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 CPU-NCO prepared in Example 1 is shown in FIG4A. As shown in FIG4A, there is a characteristic peak of isocyanate (NCO) (2260 cm -1 ), indicating that CPU-NCO was successfully synthesized; and the characteristic peak of NCO disappeared after moisture curing cross-linking, indicating that the NCO group was chemically bonded to the active groups such as amino and thiol groups on the bone surface.

[0149] The porosity of the cross-linked products in Examples 1-3 is shown in FIG5B . As shown in FIG5B , cross-linking the bone adhesive with different amounts of water will result in different expansion rates and porosities, and different aqueous porogen contents will also result in different porosities under the same water dosage.

[0150] Example 4

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

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

[0153] It should be noted that since magnesium oxide absorbs the generated carbon dioxide, the porosity is reduced, and the resulting material is stronger, making it suitable for use in the repair of large segmental bone defects.

[0154] A large segmental bone defect model was constructed in rabbits. CPU-MgO was injected into the defect site, causing it to solidify and cross-link, providing both filling and support. Micro-CT, tissue section staining, and immunohistochemical staining were performed one, three, and six months after surgery to systematically investigate the effect of CPU-MgO on the repair of large segmental bone defects.

[0155] Example 5

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

[0157] Step S2: 2.20 g of a 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. The mixture was then vacuumed 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 polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a tertiary amine-containing polyol) was added, and the reaction was continued at 60°C under nitrogen protection for 1 hour to produce a citric acid-based bioactive reactive polyurethane (CPU1-NCO).

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

[0159] A 2cm long, 6mm diameter, large segmental bone defect model was constructed in rabbits. CPU1-ZnO was first injected into a cylindrical model with an inner diameter of 6mm and a height of 2cm. This self-expanding, solidifying, and cross-linking scaffold resulted in a biphasic structure with a dense outer layer and a loose, porous inner layer. The solidified, cross-linked biphasic scaffold was then implanted into the bone defect, providing both filling and support. Micro-CT, tissue section staining, and immunohistochemical staining were performed one, three, and six months after surgery to systematically investigate the effect of CPU1-ZnO on the repair of large segmental bone defects.

[0160] Example 6

[0161] Step S1. 13.41 g of L-malic acid (0.10 mol, as a bioactive polyacid), 7.71 g of bis(2-hydroxyethyl) disulfide (0.05 mol, as an environmentally responsive degradation alcohol), and 7.31 g of 1,8-octanediol (0.05 mol, as a hydrophobic polyol A) were placed in a single-necked round-bottom glass flask equipped with a magnetic stirrer. The mixture was melted in an oil bath at 160° C. to obtain a uniform, transparent solution. The temperature was then lowered to 140° C., and the reaction mixture was continuously stirred (at a speed of 600 rpm) under vacuum conditions for reaction. During the polymerization process, the speed was gradually reduced according to the viscosity of the polymer until the viscosity of the reaction system increased to a point where the stirrer was difficult to rotate at 60 rpm and the acid value was stable. Heating was stopped to obtain a 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. The mixture was then vacuumed 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 polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a tertiary amine-containing polyol) was added, and the reaction was continued at 60°C under nitrogen protection for 1 hour to produce a 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 of MPU-NCO, 0.1 g of PC-HA (as an inorganic filler), 200 μL of water (containing 0.05 g of polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous porogen), and 0.05 mL of triethylamine (as a foaming control agent) were uniformly mixed to obtain a citric acid-based biodegradable self-expanding bone adhesive (labeled as MPU-PC-HA). MPU-PC-HA completed expansion and set within 95 minutes and continued to harden, reaching its final strength after 14 hours.

[0164] A 2cm long, large segmental bone defect model (approximately 6mm in diameter) was constructed in rabbits. MPU-PC-HA was first injected into a cylindrical model with an inner diameter of 6mm and a height of 2cm. The scaffold was allowed to self-expand, solidify, and cross-link, resulting in a biphasic structure with a dense outer layer and a loose, porous inner layer. The solidified, cross-linked biphasic scaffold was then implanted into the bone defect, providing both filling and support. Micro-CT, tissue section staining, and immunohistochemical staining were performed one, three, and six months after surgery to systematically investigate the effect of MPU-PC-HA on the repair of large segmental bone defects.

[0165] Example 7

[0166] Step S1. Take 13.41g L-malic acid (0.10mol, as a bioactive polyacid), 17.06g L-cystine dimethyl ester hydrochloride (0.05mol, as an environmentally responsive degradable amine) and 7.31g 1,8-octanediol (0.05mol, as a hydrophobic polyol A), place them in a single-necked round-bottom glass flask equipped with a magnetic stirrer, melt the mixture in an oil bath at 160°C to obtain a uniform transparent solution, then cool to 140°C, and allow the reaction mixture to react under vacuum conditions with continuous stirring (speed of 600rpm). During the polymerization process, the speed is gradually reduced according to the viscosity of the polymer until the viscosity of the reaction system increases to a point where the stirrer is difficult to rotate at 60rpm and its acid value is stable; stop heating to obtain a 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. The mixture was then vacuumed 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 polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Subsequently, 1.01 g of N-methyldiethanolamine (MDEA, as a tertiary amine-containing polyol) was added, and the reaction continued at 60°C under nitrogen protection for 1 hour to produce a malic acid-based bioactive reactive polyurethane (MPU-NCO').

[0168] Step S3: 0.5 g of MPU-NCO', 0.1 g of calcium carbonate (CaC) as an inorganic filler, 200 μL of water (containing 0.05 g of magnesium sulfate (MgSO4) as an aqueous porogen), and 0.05 mL of triethylamine (as a foaming control agent) were uniformly mixed to produce a citric acid-based biodegradable, self-expanding bone adhesive (labeled as 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 in rats. MPU-CaC was injected into the bone defect, allowing it to self-expand, solidify, and cross-link, providing both filling and support. Micro-CT, tissue section staining, and immunohistochemical staining were performed 4, 8, and 14 weeks after surgery to systematically investigate the effect of MPU-CaC on femoral condyle defect repair.

[0170] Example 8

[0171] Step S1. Take 11.81g of succinic acid (0.10mol, as a bioactive polyacid), 7.71g of bis(2-hydroxyethyl) disulfide (0.05mol, as an environmentally responsive degradation alcohol) and 7.31g of 1,8-octanediol (0.05mol, as a hydrophobic polyol A), place them in a single-necked round-bottom glass flask equipped with a magnetic stirrer, melt the mixture in an oil bath at 160°C to obtain a uniform transparent solution, then cool to 140°C, and allow the reaction mixture to react under vacuum conditions with continuous stirring (speed of 600rpm). During the polymerization process, the speed is gradually reduced according to the viscosity of the polymer until the viscosity of the reaction system increases to a point where the stirrer is difficult to rotate at 60rpm and its acid value is stable; stop heating to obtain a 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. The mixture was then vacuumed 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 polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Then, 1.05 g of N-methyldiethanolamine (MDEA, as a tertiary amine-containing polyol) was added, and the reaction was continued at 60°C under nitrogen protection for 1 hour to obtain succinic acid-based bioactive reactive polyurethane (SPU-NCO).

[0173] Step S3. 0.5 g of SPU-NCO, 0.1 g of calcium phosphate (CaP, as an inorganic filler), 200 μL of water (containing 0.05 g of polyethylene glycol dimethyl ether (PEG-DM, molecular weight 2000 Da, as an aqueous porogen), and 0.05 mL of triethylamine (as a foaming control agent) were uniformly mixed to produce a citric acid-based biodegradable self-expanding bone adhesive (labeled as 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, allowing it to self-expand, solidify, and cross-link, providing both filling and support. Micro-CT, tissue section staining, and immunohistochemistry were performed 4, 8, and 14 weeks after surgery to systematically investigate the effect of SPU-CaP on femoral condyle defect repair.

[0175] Example 9

[0176] Step S1. 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 degradation alcohol), and 7.31 g of 1,8-octanediol (0.05 mol, as a hydrophobic polyol A) were placed in a single-necked round-bottom glass flask equipped with a magnetic stirrer. The mixture was melted in an oil bath at 160° C. to obtain a uniform, transparent solution. The temperature was then lowered to 140° C. The reaction mixture was stirred continuously (at a speed of 600 rpm) under vacuum conditions for reaction. During the polymerization process, the speed was gradually reduced according to the viscosity of the polymer until the viscosity of the reaction system increased to a point where the stirrer was difficult to rotate at 60 rpm and the acid value was stable. Heating was stopped to obtain an α-ketoglutaric acid-based bioactive polyester polyol.

[0177] Step S2: 4.90 g of α-ketoglutarate-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. The mixture was then vacuumed 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 polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a tertiary amine-containing polyol) was added, and the reaction was continued at 60°C under nitrogen protection for 1 hour to obtain an α-ketoglutarate-based bioactive reactive polyurethane (KPU-NCO).

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

[0179] A 2cm long, segmental bone defect model (approximately 6mm in diameter) was constructed in rabbits. KPU-MgO was first injected into a cylindrical model with an inner diameter of 6mm and a height of 2cm. The model allowed for self-expansion, solidification, and cross-linking, resulting in a biphasic structure with a dense outer layer and a loose, porous inner layer. The solidified, cross-linked biphasic scaffold was then implanted into the bone defect, providing both filling and support. Micro-CT, tissue section staining, and immunohistochemical staining were performed one, three, and six months after surgery to systematically investigate the effect of KPU-MgO on the repair of large segmental bone defects.

[0180] Comparative Example 1

[0181] In step S1 of comparative example 1, no environmentally responsive degradation acid / alcohol / amine was added when preparing the bioactive polyester polyol, as follows:

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

[0183] Step S2. 2.15 g of a thioether-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. The mixture was then vacuumed 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 polyisocyanate) were added. The mixture was reacted under nitrogen protection for 3 hours. Then, 1.01 g of N-methyldiethanolamine (MDEA, as a tertiary amine-containing polyol) was added, and the reaction was continued at 60°C under nitrogen protection for 1 hour to obtain a citric acid-based bioactive reactive polyurethane (CPU-NCO′).

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

[0185] Test example

[0186] 1. Expansion Rate Test: To facilitate quantitative measurement of the volume of the cross-linked polymer containing thioether (CPU prepared in Example 1) and the polymer without thioether (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 the components of the adhesive were uniformly mixed in a 5 mL syringe and compacted with the syringe to remove air, and the volume scale (V mix After 24 hours, the cross-linked polymer solid was removed from the syringe and placed in a new syringe. The area around the solid was filled with salt particles until the scale value was 5 mL. The salt particles were then collected in another new syringe and the volume scale of the salt (V salt ). Use the following equation to calculate the expansion ratio. For each sample, at least 5 samples were tested and the results were averaged. Expansion ratio (%) = (5-V salt ) / V mix ×100.

[0187] The test results are shown in Figure 6. As can be seen from Figure 6, the expansion rates of the CPU prepared in Example 1 (containing sulfide) and the CPU' prepared in Comparative Example 1 (not containing sulfide) are both greater than 400%, and are around 500%.

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

[0189] The test results are shown in Figure 7. As shown in Figure 7, the hardness of the CPU prepared in Example 1 (containing sulfide) and the CPU' prepared in Comparative Example 1 (not containing sulfide) are both less than 90HA, and are both around 87HA.

[0190] 3. Degradation test: In vitro degradation experiments were conducted in phosphate buffered saline (PBS, pH 7.4) at 37°C. Specifically, the cross-linked bone adhesives in Example 1 and Comparative Example 1 were cut into disc-shaped samples (diameter = 9 mm, ~0.01 g), accurately weighed (W0), immersed in a capped tube containing 10 mL of PBS, and incubated in a constant temperature shaking incubator at 37°C. At predetermined time points, the samples were removed, washed at least 3 times with pure water, freeze-dried, and weighed (W t The mass loss rate was calculated according to the following equation. In order to simulate the high concentration of reactive oxygen species (ROS) in vivo, especially in the inflammatory microenvironment (such as osteoporosis), the material was also placed in PBS (pH 7.4) + H2O2 (0.1M) for degradation testing. Mass loss rate (%) = (W0 / W t ) / W0×100%

[0191] The test results are shown in Figure 8. As shown in Figure 8, in PBS, the CPU (containing thioether) prepared in Example 1 degrades slightly faster than the CPU' (not containing thioether) prepared in Comparative Example 1. However, in PBS + 0.1M H₂O₂, the degradation rate of the CPU is significantly higher than that of the CPU', indicating that the introduction of thioether significantly accelerates the degradation of polyurethane. Even in PBS + 0.1M H₂O₂, the degradation rate of the CPU' (not containing thioether) prepared in Comparative Example 1 is not significantly different from that in PBS.

[0192] 4. In vitro biomechanical testing: To simulate the effect of bone adhesive in fixing tendons in anterior cruciate ligament (ACL) reconstruction, a braided nylon rope was used as a tendon substitute. A citric acid-based degradable self-expanding bone adhesive (CPU) was evenly applied on it and implanted into an 8mm bone tunnel formed at the femoral end of the pig knee joint. After the bone adhesive was completely cured and hardened, a pull-out strength test was performed 24 hours later. The control group was fixed with a commercial clinical 8mm diameter titanium screw. 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 10kKN sensor at a displacement rate of 5mm / min. At least 10 samples were tested in each group, and the results were averaged.

[0193] The test results are shown in Figure 9. As shown in Figure 9, the ultimate load (until failure) in the CPU group was 237.6 ± 24.94 N, significantly lower than, but somewhat comparable to, the ultimate load in the titanium screw group (332.4 ± 35.79 N). It is worth noting that the failure in the titanium screw group was almost entirely caused by the rupture of the tendon substitute at the outer edge of the bone tunnel fixed by the titanium screw, while the failure in the CPU group was caused by the tendon substitute pulling out of the bone tunnel.

[0194] These 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 that traditional interference screws are prone to causing stress concentration and tendon rupture. Self-expanding bone adhesive provides a game-changing solution that can fundamentally solve the stress concentration problem.

[0195] 5. In vivo experiment: Rabbits were anesthetized with sodium pentobarbital (30 mg / kg) by intravenous injection. After shaving the left leg and disinfecting it, the rabbit was placed flat on the operating table, supine, and the left leg was disinfected again, and then covered with surgical drapes. An incision was made along the medial side of the rabbit's patella, the patella was turned outward, the anterior cruciate ligament was exposed and removed. The semitendinosus muscle was then separated and harvested and used as a tendon substitute (autologous tendon) for subsequent ACL reconstruction. The rabbit knee joint was fixed in 45° flexion, and a 3mm diameter drill was used to drill from the femoral attachment of the anterior cruciate ligament to the posterolateral side to form a bone tunnel that was inclined from the medial cortical bone of the tibial articular surface to the joint. The bone tunnel was flushed with sterile saline. The tendon substitute was then pulled into the femoral tunnel at a 30° angle in the flexed position of the knee joint, and self-expanding bone adhesive was injected and evenly applied to the gap between the tendon and the bone tunnel. At the same time, in order to prevent the tendon substitute from being pulled out before the self-expanding bone adhesive is completely cured, the ends of the tendon substitute are fixed to the tissue near the openings of the tibial and femoral tunnels by tying knots. The tissue is then rinsed, sutured layer by layer, and disinfected with iodine. All rabbits resumed free movement 2 hours after surgery. The control samples used commercial titanium screws with a diameter of 3 mm to fix the tendon in the bone tunnel. After 4 weeks and 14 weeks of ACL reconstruction, the rabbits were killed, and the samples were taken and subjected to micro-CT and hard tissue section staining (VG staining). At the 14th week time point, some samples (3 in each group) were used for biomechanical testing to test the pull-out strength of the tendon from the bone tunnel after ACL reconstruction and tissue regeneration.

[0196] The test results are shown in Figures 10 and 11. The micro-CT 3D reconstruction results (Figure 10) show that the self-expanding bone adhesive provides more uniform compression of the tendon compared to the bone screw group, as can also be seen in Figure 11A. Furthermore, the self-expanding bone adhesive group exhibited greater amounts of new bone (the colored areas in the micro-CT images), indicating that the self-expanding bone adhesive developed in Example 1 can promote osteogenesis to a certain extent.

[0197] As can be seen in Figure 11A, the self-expanding bone adhesive fully fills the gap between the tendon and the bone tunnel and penetrates into the gap in the bone tunnel, facilitating improved tendon-bone adhesion through mechanical locking. Because the self-expanding bone adhesive fully and evenly fills the gap between the tendon and the bone tunnel and penetrates into the gap in the bone tunnel, it provides a certain degree of tendon-bone adhesion through mechanical locking and possible chemical bonding between -NCO groups and surface active groups (-NH2, -SH) of bone tissue. However, its initial strength is lower than that of bone screws (see Figure 9, in vitro biomechanical data). However, over time, the self-expanding bone adhesive releases active ingredients through degradation, promoting bone regeneration. 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 (as shown in Figure 11B). This fully demonstrates that the degradable self-expanding bone adhesive can provide good initial tendon-bone adhesion and promote subsequent bone regeneration, thereby promoting tendon-bone healing.

[0198] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned 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.

[0199] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A degradable self-expanding bone adhesive, characterized in that: Includes bioactive reactive polyurethanes and foam control agents; The bioactive reactive polyurethane contains a plurality of isocyanate groups at its end, and the raw materials for preparing the bioactive reactive polyurethane include bioactive polyester polyols, and the raw materials for preparing the bioactive polyester polyols include bioactive polyacids, hydrophobic polyol A, and environmentally responsive degradable acids / alcohols / amines, wherein the environmentally responsive degradable acids / alcohols / amines contain one or both of thioether groups and disulfide bonds; The foaming control agent is a substance that can react with carbon dioxide or absorb carbon dioxide.

2. The degradable self-expanding bone adhesive according to claim 1, wherein The environmentally responsive degradation acid / alcohol / amine comprises one or more of a monoacid / alcohol / amine containing a thioether group, a diacid / alcohol / amine containing a disulfide bond, and a diacid / alcohol / amine containing a thioether group; Optionally, the monoacid / 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; Optionally, 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; Optionally, the disulfide bond-containing dibasic acid / alcohol / amine includes one or more of L-cystine dimethyl ester and bis(2-hydroxyethyl) disulfide.

3. The degradable self-expanding bone adhesive according to claim 1, wherein The ratio of the total number of carboxyl moles to the total number of hydroxyl moles contained in the bioactive polyacid, the hydrophobic polyol A and the environmentally responsive degradation acid / alcohol / amine is 1:(0.5-3); and / or The bioactive polyester polyol has an acid value of 3 mg KOH / g to 500 mg KOH / g; and / or The bioactive polyacid comprises one or more of citric acid, malic acid, succinic acid and α-ketoglutaric acid; and / or The hydrophobic polyol A comprises a hydrophobic polyol having 3 to 22 carbon atoms; 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.

4. The degradable self-expanding bone adhesive according to claim 1, wherein The foaming control agent includes one or more of sodium hydroxide, ammonia water, N,N-dimethylethanolamine, triethylamine, morpholine, choline, magnesium oxide, calcium oxide, activated carbon, white carbon black and zeolite.

5. The degradable self-expanding bone adhesive according to claim 1, characterized in that: The raw materials for preparing the bioactive reactive polyurethane further include hydrophobic polyol B, polyol containing tertiary amine, fatty chain polyisocyanate and catalyst; Optionally, the ratio of the total number of moles of isocyanate groups to the total number of moles of hydroxyl groups contained in the bioactive polyester polyol, the hydrophobic polyol B, the tertiary amine-containing polyol and the fatty chain polyisocyanate is 1.5-2.5, optionally 1.8-2.2; Optionally, the hydrophobic polyol B includes at least one of castor oil, polyglycerol, poly(ε-caprolactone) polyol, polylactic acid polyol and poly(lactide-glycolide) polyol; Optionally, the tertiary amine-containing polyol includes one or more of triethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-n-propyldiethanolamine, tert-butyldiethanolamine and N,N'-bis(2-hydroxyethyl)piperazine; Optionally, the fatty chain polyisocyanate includes one or more of L-lysine ethyl diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate and dicyclohexylmethane diisocyanate; Optionally, the catalyst includes one or more of an organotin catalyst, an organobismuth catalyst and an amine catalyst; Optionally, the reaction raw materials of the bioactive reactive polyurethane include, by weight: 5-30 parts of the bioactive polyester polyol, 10 parts to 40 parts of the hydrophobic polyol B, 1 part to 10 parts of the tertiary amine-containing polyol, 30 parts to 60 parts of the fatty chain polyisocyanate and 0.01 parts to 5 parts of the catalyst.

6. The degradable self-expanding bone adhesive according to claim 5, characterized in that: The preparation method of the bioactive reactive polyurethane comprises: Dehydrating a mixture comprising the bioactive polyester polyol and the hydrophobic polyol B under vacuum at 90° C. to 120° C. for 1 h to 5 h to prepare a dehydrated material; The dehydrated material, the fatty chain polyisocyanate and the catalyst are mixed and reacted at 40° C. to 90° C. in a protective atmosphere for 1 hour to 24 hours to prepare an intermediate; The intermediate is mixed with the polyol containing tertiary amine, and reacted at 40° C.-90° C. in a protective atmosphere for 1 h-3 h to prepare the bioactive reactive polyurethane.

7. The degradable self-expanding bone adhesive according to any one of claims 1 to 6, characterized in that: Also included are inorganic fillers; Optionally, the inorganic filler includes one or more of modified and unmodified hydroxyapatite, calcium phosphate, calcium carbonate, zinc oxide, and magnesium oxide; Optionally, the modification method includes depositing polyphenol, dopa or dopamine on the surface of the material to be modified under alkaline or oxygen conditions.

8. The degradable self-expanding bone adhesive according to claim 7, wherein In parts by weight, the bone adhesive comprises: 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.

9. The degradable self-expanding bone adhesive according to any one of claims 1 to 6, characterized in that: Also included are aqueous phase porogens; Optionally, the aqueous phase porogen includes one or more of polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol diethyl ester, polyvinyl pyrrolidone, sodium chloride and magnesium sulfate; Optionally, the molecular weight of the aqueous porogen is 1000Da-20000Da; Optionally, the bone adhesive contains the aqueous porogen in an amount of 1 to 20 parts by weight; Optionally, the bone adhesive contains the aqueous porogen in an amount of 1 to 10 parts by weight.

10. Use of the degradable self-expanding bone adhesive according to any one of claims 1 to 9 in the preparation of materials for tendon-bone healing, materials for bone defect repair and / or porous degradable scaffolds.

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