Interface bonding composition as well as preparation method and application thereof

Abstract

The invention discloses an interface bonding composition as well as a preparation method and application thereof, and relates to the technical field of biomedical materials. The interface bonding composition includes: (1) a calcium salt; (2) a solvent; (3) at least one phosphoric acid compound selected from the group consisting of adenosine phosphate, bisphosphonate, free phosphoric acid hydroxyl group-containing compounds, phosphoric acid amino acid compounds, triphosphoric acid and polyphosphoric acid compounds; and (4) a reaction enhancer. The interface bonding composition provided by the invention can be quickly bonded after being smeared to a bone fracture surface interface, the components of the interface bonding composition are similar to those of bone tissues, and the interface bonding composition can be gradually degraded and promote bone repair while providing initial bonding and mechanical support. The material is high in biological safety and degradable, the degradation period exceeds six months, immediate and lasting fixation of a fracture part can be achieved, and the material is particularly suitable for splicing and repairing crushed bones in comminuted fractures.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to an interfacial adhesive composition, its preparation method, and its application. Background Technology

[0002] Fractures are among the most common injuries to the musculoskeletal system. In recent years, highly comminuted fractures have not only imposed a heavy economic burden, but also posed a significant challenge due to the large number of bone fragments and the difficulty in reduction. Furthermore, the adhesion between bone and metal in the use of traditional metal internal fixation devices is a pressing issue that needs to be addressed, especially in comminuted fractures where the operability and practicality of metal internal fixation devices are greatly reduced. This also limits the effectiveness of traditional metal internal fixation surgery, posing a serious challenge to clinical treatment.

[0003] Currently, materials used for fracture repair on the market are mainly divided into three categories: ① metallic materials (such as porous tantalum / titanium alloys), used for bone defect reconstruction such as the hip joint; ② cyanoacrylate (CA) adhesives, which have a certain bone adhesion ability; ③ polymeric materials (such as polyetheretherketone (PEEK), commonly used for skull repair or bone filling. However, these materials all have significant limitations: metal internal fixation devices have limited fixation effects in comminuted fractures and often require a second surgery for removal; CA adhesives, although strong, are non-degradable, brittle, and somewhat toxic, and cannot support bone tissue ingrowth, hindering healing; polymeric materials generally suffer from poor degradability and insufficient biocompatibility.

[0004] Therefore, there is an urgent need to develop an interfacial adhesive composition that can achieve both immediate fixation and support long-term rigid interfacial bonding, especially for bone repair and bone bonding materials. Summary of the Invention

[0005] To address the technical problems existing in the prior art, embodiments of the present invention provide an interfacial adhesive composition, its preparation method, and its application. The technical solution is as follows:

[0006] An interfacial adhesive composition comprising:

[0007] (1) Calcium salts;

[0008] (2) Solvent;

[0009] (3) A phosphoric acid compound selected from at least one of adenosine phosphate, bisphosphonates, compounds containing free phosphoric acid hydroxyl groups, phosphoric acid amino acid compounds, triphosphates and polyphosphates;

[0010] (4) A reaction enhancer selected from at least one of (a) to (c):

[0011] (a) A biological template selected from at least one of polyglutamic acid, chondroitin sulfate and its derivatives, carboxymethyl chitosan, mussel adhesive protein, chitosan and its derivatives, hyaluronic acid and its derivatives, silk fibroin, bovine serum albumin, collagen, gelatin and its derivatives, polyethyleneimine, polylysine, cellulose and its derivatives, and polypeptide compounds.

[0012] (b) A composition of an acid and a base, wherein the acid is selected from at least one of inositol triphosphate, inositol hexaphosphate, tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, succinic acid, caffeic acid, tannic acid, glycyrrhizic acid, 8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, and 2arm-PEG-SG / SS / SC;

[0013] The base is selected from at least one of K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, and polylysine;

[0014] (c) An organic salt containing a polycarboxylic acid structure, selected from at least one of potassium tartrate, calcium tartrate, sodium malate, sodium tartrate, sodium fumarate, sodium gluconate, sodium inositol triphosphate, sodium inositol hexaphosphate, sodium succinate, sodium α-ketoglutarate, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate.

[0015] The weight ratio of calcium salt, solvent, phosphoric acid compound and reaction enhancer is 1:(0.05-5):(0.01-2):(0.001-1).

[0016] Optionally, the calcium salt is selected from at least one of octacalcium phosphate, tetracalcium phosphate, α-tricalcium phosphate, β-tricalcium phosphate, dicalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, calcium chloride, calcium carbonate, calcium sulfate, calcium lactate, calcium gluconate, calcium tartrate, calcium acetate, and calcium glycerophosphate.

[0017] And / or, the chondroitin sulfate derivative, chitosan derivative, hyaluronic acid derivative, gelatin derivative, and cellulose derivative are each selected from at least one of their deacetylated derivatives, oxidized derivatives, acrylated derivatives, and NHS active ester modified derivatives.

[0018] Optionally, the solvent is selected from at least one of deionized water, PBS solution, SBF solution, Hanks solution, and Ringer's solution.

[0019] Optionally, the adenosine monophosphate is selected from at least one of ATP, ADP, AMP, cAMP, GTP, GMP, GDP, cGTP, dATP, dGTP, dCTP, and dTTP.

[0020] And / or, the bisphosphonate is selected from at least one of etidronate sodium, etidronate phosphoric acid, clodronate sodium, pamidronate sodium, teludronate sodium, alendronate sodium, neridronate sodium, opapadronate sodium, risedronate sodium, ibandronate sodium, and zoledronic acid;

[0021] And / or, the compound containing free phosphate hydroxyl groups is selected from at least one of creatine phosphate, inositol monophosphate, inositol diphosphate, inositol triphosphate, inositol tetraphosphate, inositol pentaphosphate, inositol hexaphosphate, inositol heptaphosphate, inositol octaphosphate, 2-methyl-2-propenyl-hydroxyethyl phosphate, pyridoxal phosphate, glucose-6-phosphate, fructose-1,6-bisphosphate, glycerol-3-phosphate, ribose-5-phosphate, methyl / ethyl / hydroxyethyl phosphate, aminomethylphosphonic acid, vinyl phosphate, and phosphate acrylate;

[0022] And / or, the phosphate amino acid compound is selected from at least one of phosphoserine, phosphotyrosine, phosphothreonine, phosphohistidine, phosphoaspartic acid, phosphoarginine, phosphoglutamic acid, and phospholysine.

[0023] And / or, the triphosphate and polyphosphate compounds are selected from at least one of sodium tripolyphosphate and sodium hexametaphosphate;

[0024] And / or, the collagen is at least one of hydrolyzed collagen, soy protein isolate, and collagen.

[0025] Optionally, the molar ratio of the reactive functional groups of the base to the acid is 1:(0.5-1).

[0026] The method for preparing the interfacial adhesive composition includes:

[0027] (1) Weigh out the calcium salt, phosphate compound, and / or biological template, and / or base respectively and mix them evenly;

[0028] (2) Mix the solvent, and / or the organic salt containing the polycarboxylic acid, and / or the acid thoroughly;

[0029] (3) Directly mix the products obtained in steps (1) and (2) or mix the mixture in steps (1) and (2) using two syringes in a double-tube manner;

[0030] (4) Apply / inject the interfacial adhesive composition of step (3) onto the fractured or injured bone to bond the bone fragments / fractures to the interfacial adhesive composition.

[0031] Optionally, in step (1), the weight ratio of the calcium salt, the phosphate compound, the biological template, and the base is 1:(0.01-2):(0-1):(0-1).

[0032] And / or, the weight ratio of the organic salt containing the polycarboxylic acid, the acid, and the solvent is (0.001-0.8):(0-0.8):1;

[0033] And / or, in step (3), the mixing method is to perform dual-tube mixing through a mixing head, or to directly pour the components in step (1) into step (2) or directly pour the components in step (2) into step (1) and stir to mix.

[0034] Optionally, the organic salt containing polycarboxylic acids is selected from at least one of potassium tartrate, calcium tartrate, sodium malate, sodium tartrate, sodium fumarate, sodium gluconate, sodium inositol triphosphate, sodium inositol hexaphosphate, sodium succinate, sodium α-ketoglutarate, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate.

[0035] The acid is selected from at least one of the following: inositol triphosphate, inositol hexaphosphate, tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, succinic acid, caffeic acid, tannic acid, glycyrrhizic acid, 8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, and 2arm-PEG-SG / SS / SC;

[0036] And / or, the base is selected from at least one of K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, and polylysine.

[0037] The application of the described interfacial adhesive composition in the preparation of bone repair materials, bone filling materials, and dental repair materials.

[0038] A bone repair material, bone filling material, or dental repair material, comprising: the aforementioned interfacial adhesive composition.

[0039] The beneficial effects of the technical solutions provided by the embodiments of the present invention include at least the following:

[0040] The interfacial adhesive composition provided by this invention can rapidly bond upon application to the bone fracture surface. Its composition is similar to bone tissue, providing initial adhesion and mechanical support while gradually degrading and promoting bone repair. This material is highly biosafe, biodegradable, and has a degradation period exceeding six months, enabling immediate and lasting fixation of fracture sites. It is particularly suitable for the splicing and repair of bone fragments in comminuted fractures.

[0041] The calcium salt, phosphate compound, and solvent form the main body of the interfacial bonding composition, with a reaction enhancer as an auxiliary agent. Among the enhancers, the calcium phosphate salt, serving as the biological template, provides mineralization sites during mineralization, promoting mineral deposition on the biological template; the heat released by the acid-base neutralization reaction during interfacial bonding provides the energy required for initial mineralization, while the salt crystals generated by the neutralization reaction provide nucleating agents for mineralization; the organic acid containing multiple carboxylic acid groups has a certain chelating and complexing effect during calcium salt mineralization / hardening, and also exhibits good biocompatibility. This composition is suitable for clinical scenarios such as bonding between hard tissue interfaces or between hard biological tissues and metal interfaces.

[0042] (1) The raw materials used to prepare the interface adhesive composition of the present invention are readily available, have good biocompatibility, high biosafety, are biodegradable, and are non-toxic and harmless.

[0043] (2) The interface adhesive composition prepared by the present invention has high interface adhesive strength and is a highly viscous paste at the beginning of mixing. It has excellent adaptability to different shapes. When bonded to the interface that needs to be repaired, it can effectively bond bone fragments / broken bones / metal together. At the same time, it can be completely compatible with the surrounding biological tissues during the biological interface repair process, reducing the rejection reaction between the interface adhesive composition and the tissue.

[0044] (3) The interface adhesive composition of the present invention has a degradation time of more than six months, so it can bond the cross-section well during the repair stage and maintain the adhesion between the cross-sections.

[0045] (4) The interfacial adhesive composition of the present invention has high support performance. The test results show that the compressive strength of the interfacial adhesive composition prepared in the embodiments of the present invention is greater than 10 MPa. Attached Figure Description

[0046] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0047] Figure 1 This is a schematic diagram of the three-point bending specimen bonding with bovine bone according to the present invention;

[0048] Figure 2 The figures show the test results of three-point bending of bovine bone adhesion test prepared in Examples 16, 17, 18, 19, 26, 27, 28, and 29 of this invention.

[0049] Figure 3 Comparison images of the interface bonding compositions provided in Examples 2, 7, 8 and 14 of this invention before and after compression of the mineralized compressed samples;

[0050] Figure 4 The figures show the test results of the mineralized compressed samples of the interfacial adhesive compositions prepared in Examples 16, 17, 18, 19, 26, 27, 28, and 29 of this invention.

[0051] Figure 5 SEM images of the brittle fracture surfaces of the interfacial adhesive compositions prepared in Examples 4, 6 and 14 of this invention after mineralization;

[0052] Figure 6 The graph shows the effect of bone adhesive extracts prepared in Examples 27, 28 and 29 of this invention on cell viability after co-culturing L929 cells for 24 hours. Detailed Implementation

[0053] The technical solution of the present invention will now be described with reference to the accompanying drawings.

[0054] In embodiments of the present invention, words such as "exemplarily," "for example," etc., are used to indicate that something is an example, illustration, or description. Any embodiment or design described as "exemplary" in the present invention should not be construed as being more preferred or advantageous than other embodiments or designs. Specifically, the use of the word "exemplary" is intended to present the concept in a concrete manner. Furthermore, in embodiments of the present invention, the meaning expressed by "and / or" can be both, or either one.

[0055] In this invention, 8arm-PEG-SG / SS / SC refers to eight-arm polyethylene glycol succinimide glutarate, a multi-arm PEG derivative containing eight identical polyethylene glycol branches, which can be used to modify materials such as proteins, peptides, and particles; 8arm-PEG-SS refers to eight-arm polyethylene glycol succinimide succinimide, a multi-arm PEG derivative with succinimide NHS ester groups at the end of each of the eight arms connected to a hexaglycerol core; 8arm-PEG-SC refers to eight-arm polyethylene glycol succinimide carbonate. 4arm-PEG-SG / SS / SC and 2arm-PEG-SG / SS / SC are similar to 8arm-PEG-SG / SS / SC, referring to the corresponding four-arm and two-arm compounds, respectively.

[0056] In order to solve the above-mentioned technical problems, the purpose of this invention is to provide an interface adhesive composition that is easy to prepare, biodegradable, biocompatible, and non-toxic.

[0057] In a first aspect, the interfacial adhesive composition comprises: calcium salt, solvent, phosphoric acid compound and reaction enhancer. When the interfacial adhesive composition is mixed from the above and applied or injected onto the bone fracture surface, the fractured bone can be bonded together.

[0058] Furthermore, in the interfacial adhesive composition, the mass ratio of the calcium salt: solvent: phosphoric acid compound: reaction enhancer is 1:(0.05-5):(0.01-2):(0.001-1).

[0059] The beneficial effects of adopting the above-mentioned further scheme are: after the interfacial adhesive composition at this ratio crystallizes and mineralizes, it has high adhesive strength and high yield stress, i.e., high support performance.

[0060] Furthermore, the phosphoric acid compound is selected from adenosine monophosphate, bisphosphonates, compounds containing free phosphoric acid hydroxyl groups, phosphoric acid amino acid compounds, triphosphates and polyphosphates, and combinations thereof;

[0061] The beneficial effect of taking the above-mentioned further measures is that compounds containing phosphate groups can provide the microenvironmental conditions required for mineralization / hardening, and enhance the strength of the interfacial adhesive composition after mineralization.

[0062] Further, in the phosphoric acid compound: adenosine phosphate is at least one of ATP, ADP, AMP, cAMP, GTP, GMP, GDP, GTP, and cGTP; the bisphosphonate is at least one of etidronate sodium, etidronate phosphate, clodronate sodium, pamidronate sodium, teludronate sodium, alendronate sodium, neridronate sodium, opaldronate sodium, risedronate sodium, ibandronate sodium, and zoledronic acid; the compound containing free phosphoric acid hydroxyl groups is creatine phosphate, inositol monophosphate, inositol diphosphate, inositol triphosphate, and inositol tetraphosphate. Phosphoric acid, inositol pentaphosphate, inositol hexaphosphate, inositol heptaphosphate, inositol octaphosphate, 2-methyl-2-propenyl-hydroxyethyl phosphate, pyridoxal phosphate, glucose-6-phosphate, fructose-1,6-bisphosphate, glycerol-3-phosphate, ribose-5-phosphate, methyl / ethyl / hydroxyethyl phosphate, aminomethylphosphonic acid, vinyl phosphate, phosphate acrylate; the phosphoric acid amino acid compound is at least one of phosphoserine, phostyrosine, and phosphothreonine; the triphosphate and polyphosphate compounds are sodium tripolyphosphate and sodium hexametaphosphate.

[0063] The beneficial effects of adopting the above-mentioned further scheme are: using phosphate-containing compounds can participate in the recrystallization of calcium salts and the mineralization process of the interfacial adhesive composition, which can further improve the adhesive strength and support performance of the interfacial adhesive composition; at the same time, an appropriate amount of phosphate groups provides the microenvironment required for the mineralization of the interfacial adhesive composition, enhancing the strength of the interfacial adhesive composition after mineralization.

[0064] Furthermore, the reinforcing agent is at least one of the following (a) to (c):

[0065] (a) Biological template: selected from polyglutamic acid (PGA), chondroitin sulfate (CS), carboxymethyl chitosan (CMC), mussel adhesive protein, chitosan and its derivatives, hyaluronic acid and its derivatives, silk fibroin, bovine serum albumin, collagen, gelatin and its derivatives, polyethyleneimine, polylysine, cellulose and its derivatives, and polypeptide compounds; wherein the chondroitin sulfate (CS) and its derivatives, chitosan and its derivatives, hyaluronic acid and its derivatives, gelatin and its derivatives, and cellulose and its derivatives are at least one of deacetylated derivatives, oxidized derivatives, acrylated derivatives, and NHS active ester modified derivatives.

[0066] (b) Acid-base composition: selected from at least one of the following, wherein the acidic compound is selected from tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, succinic acid and other di- or tri-acids, caffeic acid, tannic acid, glycyrrhizic acid, 8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, 2arm-PEG-SG / SS / SC and other acidic compounds or mixtures having the same chemical properties or chemical structure, wherein the basic compound is selected from K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, polylysine and other basic compounds having the same chemical properties or chemical structure; the acid-base composition provided by the present invention is a compound with high biological safety compared with the acid-base composition in the prior art.

[0067] (c) Organic salts containing polycarboxylic acid structures: potassium tartrate, calcium tartrate, sodium malate, sodium tartrate, potassium tartrate, sodium fumarate, sodium gluconate, sodium phytate, sodium inositol triphosphate, sodium succinate, sodium α-ketoglutarate, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate.

[0068] The beneficial effects of adopting the above-mentioned further scheme are: the biological template provides mineralization sites for calcium phosphate during mineralization, promoting mineral deposition on the biological template; the heat released by the acid-base neutralization reaction during the interfacial adhesion process can provide the energy required for initial mineralization, while the salt generated by the neutralization reaction can provide the nucleating agent required for mineralization; organic acids containing multiple carboxylic acid groups have a certain chelating and complexing effect during calcium salt mineralization / hardening, and organic acids also have good biocompatibility.

[0069] Further, the calcium salt is at least one selected from octacalcium phosphate, tetracalcium phosphate, α-tricalcium phosphate, β-tricalcium phosphate, dicalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, calcium chloride, calcium carbonate, calcium sulfate, calcium lactate, calcium gluconate, calcium tartrate, calcium acetate, calcium glycerophosphate, and hydroxyapatite. Further, the solvent is at least one selected from deionized water, PBS aqueous solution, SBF aqueous solution, Hanks aqueous solution, and Ringer's solution.

[0070] The beneficial effect of adopting the above-mentioned further scheme is that the calcium salt can change from an unstable crystal form to a stable crystal form under the condition of deionized water, while inducing mineralization.

[0071] Furthermore, the molar ratio of the basic compound to the reactive functional group of the acid is 2:(1-2).

[0072] The beneficial effect of adopting the above-mentioned further scheme is that the salt crystal grains generated after acid-base neutralization can provide the nucleating agent required for mineralization, while also providing the energy required for initial mineralization / hardening.

[0073] Further, the composition is selected from at least one of the following acids and bases, wherein the acid is selected from tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, succinic acid and other di- or tri-acids, caffeic acid, tannic acid, glycyrrhizic acid, 8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, 2arm-PEG-SG / SS / SC and other acidic compounds or mixtures having the same chemical properties or chemical structure, and wherein the base is selected from K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, polylysine and other basic compounds having the same chemical properties or chemical structure.

[0074] The beneficial effects of adopting the above-mentioned further scheme are: the alkaline compound and the acidic compound are both weakly alkaline and weakly acidic, and will not cause secondary damage when operated on organisms. At the same time, the salt crystal particles generated by the acid-base neutralization reaction can provide the nucleating agent required for mineralization, and the heat released by the acid-base neutralization reaction during bone adhesion can provide the energy required for initial mineralization.

[0075] Secondly, a method for preparing an interfacial adhesive composition includes the following steps:

[0076] (1) Weigh out calcium salt, phosphate compound, and / or biological template, and / or basic compound respectively, mix them evenly, and set aside for later use, or mix them evenly and transfer them to a syringe for later use;

[0077] (2) Weigh out and / or an organic salt containing a polycarboxylic acid, and / or an acidic compound and a solvent, while dissolving the solid compound in the solvent for later use, or dissolving it and transferring it to another syringe for later use;

[0078] (3) Add the reaction enhancer to the syringe from step (1) or step (2) and mix thoroughly;

[0079] (3) Directly mix the products obtained in steps (1) and (2) or mix the components in the two syringes in steps (1) and (2) using a dual-tube method;

[0080] (4) Apply / inject the interfacial adhesive composition of step (3) onto the fractured or injured bone to bond the bone fragments / fractures to the interfacial adhesive composition.

[0081] The beneficial effects of adopting the above scheme are: the interface bonding composition prepared by the present invention is simple to operate, has high biosafety, and good biocompatibility.

[0082] Further, in step (1), the weight ratio of the calcium salt, the phosphate compound, the biological template, and the basic compound is 1:(0.01-2):(0-1):(0-1).

[0083] And / or, the weight ratio of the organic salt containing the polycarboxylic acid, the acidic compound, and the solvent to the reaction enhancer is 1:(0.001-0.8):(0-0.8):1;

[0084] The beneficial effect of adopting the above-mentioned further scheme is that the interfacial adhesive composition at this ratio has high bone bonding strength after crystallization and mineralization.

[0085] Furthermore, the mass ratio of the solvent to the reinforcing agent in steps (2) and (3) is 1:(0.001-5).

[0086] The beneficial effect of adopting the above-mentioned further scheme is that the interfacial adhesive composition at this ratio has high yield stress after crystallization and mineralization, which means good support performance.

[0087] Furthermore, the mixing method in step (4) can be a two-tube mixing or directly pouring the components in step (1) into step (2) / directly pouring the components in step (2) into step (1) and stirring to mix;

[0088] The advantage of adopting the above-mentioned further solution is that it is simple to operate.

[0089] Furthermore, the acid is selected from di- or tri-carboxylic acids such as tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, and succinic acid, as well as acidic compounds or mixtures with the same chemical properties or structures such as caffeic acid, tannic acid, and glycyrrhizic acid (8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, 2arm-PEG-SG / SS / SC). The base is selected from basic compounds with the same chemical properties or structures such as K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, and polylysine.

[0090] The beneficial effects of adopting the above-mentioned further scheme are: the alkaline compound and the acidic compound are both weakly alkaline and weakly acidic, and will not cause secondary damage when operating on organisms. At the same time, the salt crystal particles generated by the acid-base neutralization reaction can provide the nucleating agent required for mineralization, and at the same time provide the energy required for initial mineralization / hardening.

[0091] Thirdly, the aforementioned interface adhesive composition is used in applications such as fracture interface bonding, fragmented bone interface bonding, bone-metal medical device interface, bone repair, bone filling materials, and dentistry.

[0092] Preferably, when the interface adhesive composition is used, the components are thoroughly mixed in a syringe and then injected or applied to the bone wound that needs to be repaired, whereby it adheres to the bone wound and provides certain support to the repaired bone.

[0093] After the clinical surgery is completed, the interface bonding composition material is safe, stable, and biocompatible, and the degradation products are non-toxic and harmless, making it safe and reliable.

[0094] Preferably, the interface adhesive composition can be used to prepare adhesives between interfaces of hard tissues such as human, mammals, birds, and reptiles, or between interfaces of hard biological tissues and metals.

[0095] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with the accompanying drawings and specific embodiments.

[0096] Unless otherwise specified, the experimental methods described in the following embodiments are conventional experimental methods well known to those skilled in the art, and are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Where specific conditions are not specified in the experimental methods, they are generally operated under conventional conditions.

[0097] Unless otherwise specified, all materials and reagents described in the following examples are commercially available.

[0098] Example 1

[0099] This embodiment provides an interfacial adhesive composition, the preparation method of which is as follows:

[0100] Accurately weigh 23 mg of malic acid and dissolve it in 360 mL of deionized water, which is recorded as component 1, for later use; accurately weigh 1.0 g of tetracalcium phosphate, 500 mg of adenosine triphosphate (ATP), 250 mg of polyglutamic acid, and 70 mg of Na2HPO4, and mix the above four components evenly, which is recorded as component 2; mix component 1 and component 2 evenly with a syringe or directly to obtain a paste-like interface adhesive composition. Inject / apply the paste-like interface adhesive composition to the bone interface that needs to be repaired or bonded to bond or fill the fractured bone.

[0101] Examples 2-29 and Comparative Examples 1-3

[0102] The other process steps are the same as in Example 1, except for the different types and proportions of raw materials. The selection and amount of each substance in the reaction are shown in Table 1 below.

[0103] Table 1

[0104]

[0105]

[0106] The following content discloses experimental data from some embodiments. Those skilled in the art will understand or be able to verify through simple experiments that the experimental data from other embodiments can achieve similar technical effects, and will not be elaborated upon here.

[0107] Test Example 1 – Mineralization Time

[0108] Mineralization time: The mineralization time of each example and comparative example was tested according to the formulation of Example 1 and the examples in Table 1 above, and the results are shown in Table 2.

[0109] As can be seen from the results in Table 2, the mineralization time of the interfacial adhesion composition prepared by the present invention is controllable, and therefore it can be modified according to the clinical application scenarios of the reagent.

[0110] Test Example 2—Adhesive Strength

[0111] The bond strength of bovine bone in Examples 2, 6, 7, 8, 14, 16, 17, 18, and 19 was tested using a three-point bending test. The test conditions were: speed 1 mm / min, sensor 1 kN. The test results of the bond strength are shown in Table 2. The bovine bone bonded samples are shown below. Figure 1 As shown, the test results for 16, 17, 18, and 19 are as follows: Figure 2 As shown, the test results for 26, 27, 28, and 29 are as follows: Figure 2 As shown.

[0112] From Table 2 and Figure 2 The test results show that the adhesion strength of the interface adhesion composition examples of this invention is greater than that of the comparative example.

[0113] Test Example 3 – Compressive Strength

[0114] The yield stress of the interfacial adhesive compositions of Examples 2, 6, 8, 14, 16, 17, 18 and 19 after mineralization was tested using a universal tensile testing machine. The test conditions were: speed 20 mm / min, sensor 80 N.

[0115] The test results are shown in Table 2. Comparison of the sample before and after compression. Figure 3 As shown, the test results for 16, 17, 18, and 19 are as follows: Figure 4 As shown, the test results for 26, 27, 28, and 29 are as follows: Figure 4 As shown.

[0116] As shown in Table 2, the compressive strength of the interfacial adhesion compositions prepared in the embodiments of the present invention is greater than 10 MPa. This result indicates that the interfacial adhesion compositions prepared in the embodiments of the present invention have high support properties.

[0117] As can be seen from Table 2, the compressive strength of the interfacial adhesive compositions prepared in the embodiments of this invention is greater than that of the comparative example, and the compressive strength tested in the embodiments prepared in this invention is greater than 10 MPa. This indicates that the bone adhesive prepared in this embodiment has higher support performance when used.

[0118] Table 2

[0119]

[0120] Test Example 4 – SEM Test

[0121] The microscopic brittle fracture surfaces of Examples 4, 6, and 14 were tested using scanning electron microscopy, and the results are as follows: Figure 5 As shown.

[0122] Depend on Figure 5 It can be seen that the microstructures of the interfacial adhesion compositions prepared in the various embodiments of this invention application are not significantly different.

[0123] Test Example 5 – Cytotoxicology

[0124] Five mg of the bone adhesives prepared in Examples 27, 28, and 29 were placed in centrifuge tubes, irradiated under UV light for 30 min, and then 50 ml of complete culture medium was added. The tubes were then incubated at 4°C for 6 h. After extraction, the extracts were filtered through a 0.22 μm bacterial filter for subsequent use. L929 cells were prepared in culture media with bone adhesive extract concentrations of 0 mg / L (control group), 1 mg / L, 10 mg / L, and 100 mg / L for 24 h, and cell viability was observed using the CCK-8 assay.

[0125] Experimental results are as follows Figure 6 As shown.

[0126] Depend on Figure 6 It can be concluded that when L929 cells were cultured for 24 hours in the above-mentioned extracts of different concentrations (0 mg / L, 1 mg / L, 10 mg / L and 100 mg / L), the cell survival rate was greater than 80% in the bone adhesive extracts of 0 mg / L, 1 mg / L, 10 mg / L and 100 mg / L. The experiment proved that the bone adhesive is non-toxic.

[0127] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. An interfacial adhesive composition, characterized in that, The interfacial adhesive composition comprises: (1) Calcium salts; (2) Solvent; (3) A phosphoric acid compound selected from at least one of adenosine phosphate, bisphosphonates, compounds containing free phosphoric acid hydroxyl groups, phosphoric acid amino acid compounds, triphosphates and polyphosphates; (4) A reaction enhancer selected from at least one of (a) to (c): (a) A biological template selected from at least one of polyglutamic acid, chondroitin sulfate and its derivatives, carboxymethyl chitosan, mussel adhesive protein, chitosan and its derivatives, hyaluronic acid and its derivatives, silk fibroin, bovine serum albumin, collagen, gelatin and its derivatives, polyethyleneimine, polylysine, cellulose and its derivatives, and polypeptide compounds. (b) A composition of an acid and a base, wherein the acid is selected from at least one of inositol triphosphate, inositol hexaphosphate, tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, succinic acid, caffeic acid, tannic acid, glycyrrhizic acid, 8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, and 2arm-PEG-SG / SS / SC; The base is selected from at least one of K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, and polylysine; (c) An organic salt containing a polycarboxylic acid structure, selected from at least one of potassium tartrate, calcium tartrate, sodium malate, sodium tartrate, sodium fumarate, sodium gluconate, sodium inositol triphosphate, sodium inositol hexaphosphate, sodium succinate, sodium α-ketoglutarate, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate. The weight ratio of calcium salt, solvent, phosphoric acid compound and reaction enhancer is 1:(0.05-5):(0.01-2):(0.001-1).

2. The interfacial adhesive composition according to claim 1, characterized in that, The calcium salt is selected from at least one of the following: octacalcium phosphate, tetracalcium phosphate, α-tricalcium phosphate, β-tricalcium phosphate, dicalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, calcium chloride, calcium carbonate, calcium sulfate, calcium lactate, calcium gluconate, calcium tartrate, calcium acetate, and calcium glycerophosphate. And / or, the chondroitin sulfate derivative, chitosan derivative, hyaluronic acid derivative, gelatin derivative, and cellulose derivative are each selected from at least one of their deacetylated derivatives, oxidized derivatives, acrylated derivatives, and NHS active ester modified derivatives.

3. The interfacial adhesive composition according to claim 1, characterized in that, The solvent is selected from at least one of deionized water, PBS solution, SBF solution, Hanks solution, and Ringer's solution.

4. The interfacial adhesive composition according to claim 1, characterized in that, The adenosine monophosphate is selected from at least one of ATP, ADP, AMP, cAMP, GTP, GMP, GDP, cGTP, dATP, dGTP, dCTP, and dTTP. And / or, the bisphosphonate is selected from at least one of etidronate sodium, etidronate phosphoric acid, clodronate sodium, pamidronate sodium, teludronate sodium, alendronate sodium, neridronate sodium, opapadronate sodium, risedronate sodium, ibandronate sodium, and zoledronic acid; And / or, the compound containing free phosphate hydroxyl groups is selected from at least one of creatine phosphate, inositol monophosphate, inositol diphosphate, inositol triphosphate, inositol tetraphosphate, inositol pentaphosphate, inositol hexaphosphate, inositol heptaphosphate, inositol octaphosphate, 2-methyl-2-propenyl-hydroxyethyl phosphate, pyridoxal phosphate, glucose-6-phosphate, fructose-1,6-bisphosphate, glycerol-3-phosphate, ribose-5-phosphate, methyl / ethyl / hydroxyethyl phosphate, aminomethylphosphonic acid, vinyl phosphate, and phosphate acrylate; And / or, the phosphate amino acid compound is selected from at least one of phosphoserine, phosphotyrosine, phosphothreonine, phosphohistidine, phosphoaspartic acid, phosphoarginine, phosphoglutamic acid, and phospholysine. And / or, the triphosphate and polyphosphate compounds are selected from at least one of sodium tripolyphosphate and sodium hexametaphosphate; And / or, the collagen is at least one of hydrolyzed collagen, soy protein isolate, and collagen.

5. The interfacial adhesive composition according to claim 1, characterized in that, The molar ratio of the functional groups of the base to the acid is 1:(0.5-1).

6. The method for preparing the interfacial adhesive composition according to any one of claims 1-5, characterized in that, The preparation method includes: (1) Weigh out the calcium salt, phosphate compound, and / or biological template, and / or base respectively and mix them evenly; (2) Mix the solvent, and / or the organic salt containing the polycarboxylic acid, and / or the acid thoroughly; (3) Directly mix the products obtained in steps (1) and (2) or mix the mixture in steps (1) and (2) using two syringes in a double-tube manner; (4) Apply / inject the interfacial adhesive composition of step (3) onto the fractured or injured bone to bond the bone fragments / fractures to the interfacial adhesive composition.

7. The preparation method according to claim 6, characterized in that, In step (1), the weight ratio of the calcium salt, the phosphate compound, the biological template, and the base is 1:(0.01-2):(0-1):(0-1); And / or, the weight ratio of the organic salt containing the polycarboxylic acid, the acid, and the solvent is (0.001-0.8):(0-0.8):1; And / or, in step (3), the mixing method is to perform dual-tube mixing through a mixing head, or to directly pour the components in step (1) into step (2) or directly pour the components in step (2) into step (1) and stir to mix.

8. The preparation method according to claim 6, characterized in that, The organic salt containing polycarboxylic acids is selected from at least one of potassium tartrate, calcium tartrate, sodium malate, sodium tartrate, sodium fumarate, sodium gluconate, sodium inositol triphosphate, sodium inositol hexaphosphate, sodium succinate, sodium α-ketoglutarate, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate. The acid is selected from at least one of the following: inositol triphosphate, inositol hexaphosphate, tartaric acid, malic acid, glutamic acid, maleic acid, maleic anhydride, itaconic acid, itaconic anhydride, succinic acid, caffeic acid, tannic acid, glycyrrhizic acid, 8arm-PEG-SG / SS / SC, 4arm-PEG-SG / SS / SC, and 2arm-PEG-SG / SS / SC; And / or, the base is selected from at least one of K3PO4, K2HPO4, Na3PO4, Na2HPO4, Na2CO3, K2CO3, CH3COONa, CH3COOK, 8arm-PEG-NH2, 4arm-PEG-NH2, 2arm-PEG-NH2, PEI, and polylysine.

9. The use of the interfacial adhesive composition according to any one of claims 1-5 in the preparation of bone repair materials, bone filling materials, and dental repair materials.

10. A bone repair material, bone filling material, or dental restorative material, characterized in that, It includes: The interfacial adhesive composition according to any one of claims 1-5.

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