WO2022048126A1

WO2022048126A1 - Orthopedic non-invasive implantation high-viscosity adhesive material, preparation method therefor, and application

Info

Publication number: WO2022048126A1
Application number: PCT/CN2021/079870
Authority: WO
Inventors: 曹建中
Original assignee: 曹建中
Priority date: 2020-09-04
Filing date: 2021-03-10
Publication date: 2022-03-10
Also published as: CN111973797A; CN111973797B

Abstract

An orthopedic non-invasive implantation high-viscosity adhesive material, a preparation method therefor, and an application. The high-viscosity adhesive material consists of PLGA, β-TCP, sodium chloride, ethyl acetate or a phosphate buffer, distilled water, a medical adhesive, poly(propylene fumarate) and N-vinylpyrrolidone. The preparation method comprises: respectively preparing high-viscosity glue dispersion granules and an adhesive solution, and then mixing. The high-viscosity adhesive material can be implanted into the body by means of minimally invasive injection, rapidly cures at body temperature, has effects such as high viscosity, degradability and bone healing acceleration, and can be applied in surgeries for treating bone fractures, bone diseases and bone tumors.

Description

A kind of non-invasive implantation high-viscosity adhesive material for orthopedics and its preparation method and application

technical field

The invention relates to the technical field of biological preparations, in particular to a non-invasive implanted high-viscosity adhesive material for orthopedics and a preparation method and application thereof.

Background technique

Humans have a long history of using medical adhesives. In recent decades, to reduce the complexity of surgery, medical adhesives have developed rapidly and are widely used. In surgical operations, medical adhesives are used for local adhesion and repair of certain organs and tissues; to stop microvascular bleeding at sutures after surgery; gynecology is used to block fallopian tubes to complete ligation; dentistry is used for tooth repair; orthopaedics Combination and positioning of bones and joints during surgery.

Adhesives for bone must have good biocompatibility, degradability, no organ toxicity and cytotoxicity, no carcinogenic and teratogenic effects, and can achieve rapid adhesion at room temperature without affecting callus growth. Internally degradable, with good adhesive strength and durability to ensure fracture healing. At present, various adhesives in orthopedics mainly include α-cyanoacrylates; bone cement adhesives (bone cement, calcium phosphate bone cement, magnesium phosphate bone cement); composite adhesives (composite coagulant, composite water (blood) solvent, composite enhancer, composite plasticizer, composite biological activity factor); fibrin; sodium alginate mixed glue. Biomaterials are classified according to their application properties, including anticoagulant materials (cardiovascular materials), dental materials, orthopedic materials, ophthalmic materials, adsorption and detoxification materials (for blood perfusion), prosthesis materials, sustained-release materials, and bioadhesive materials. , dialysis and ultrafiltration membrane materials, disposable medical materials, etc. Classified according to the use requirements of medical materials: non-implantable materials, implantable materials, blood-contact materials, degradable and absorbent materials.

The newly developed materials are polyglycolic acid (Polyglycolide) and polylactic acid (Polylactide)-based polymers, which are made into screws and internal fixation rods for the internal fixation of clinical fractures. After the fracture is healed, it can be degraded and absorbed by itself in the body, and there is no need to remove it by surgery. 48 hours after the polymer material is implanted into the body, the screws and rods absorb water and swell, can strengthen themselves, and have good internal fixation characteristics. And it does not interfere with fracture healing, and there is no osteolysis phenomenon. At present, it has become a commercial market, and is used in many foreign countries for internal fixation of intra-articular and peri-articular fractures and hand fractures. Among them, Finland has accumulated more than 20,000 cases in 1990, and China has also begun to apply it since 1993.

However, different polymers have different mechanical strengths and degradation rates. In addition, after repeated in vivo biological animal experiments, it was found that when the polymer was implanted into the body, edema was prone to occur around the implant, and inflammatory cell infiltration and multinucleated giant cells appeared, and fibroblasts proliferated to form fibers. After being engulfed by macrophages, there is a delayed inflammatory response in the implanted bone, and the incidence is still high.

Although biodegradable materials are eventually decomposed into H ₂ O ₂ and CO ₂ in the human body, the toxicity is extremely low, but they are highly irritating to tissues, causing tissue effusion and swelling; the particles degraded by the materials will also be regarded as foreign bodies by the human body. Stimulates the body to induce rejection - the macrophage response. Therefore, its histocompatibility is still not as good as that of the currently used metal internal fixation.

Fractures and bone defects of various diseases such as trauma, infection, tumor, bone necrosis and congenital deformities are common clinically, which makes the minimally invasive injectable biomaterials used for fracture and bone defect repair more and more important. Various injectable materials such as natural derivatives and synthetic polymers.

There is an existing in-situ mineral phase formation material for fractures, which is to inject a wetting agent made of inorganic calcium and inorganic phosphorus into the fracture gap, and it begins to harden within a few minutes to form calcium phosphate carbonate, and it is completely cured in 12 hours, and can be used for curing. Connect the fractures firmly. However, before it is fully cured, the rigidity and hardness of the fracture are not enough, and plaster external fixation must still be used to prevent the fracture from being displaced.

Bone cement is a kind of bone repair material that is easy to operate in clinical surgery and can be arbitrarily shaped and self-solidified like cement, and has a wide range of applications in bone repair and other fields. One of the materials currently used as bone cement is polymethyl methacrylate (PMMA). Since its composition is completely different from that of natural bone tissue, there is a great problem in biocompatibility. Although the traditional inorganic calcium phosphate bone cement has good biocompatibility and high biological activity, its mechanical strength is too low, the compressive strength is low, the tensile strength is low, the brittleness is high, and the elastic modulus is greatly high. in natural bones. In addition, its injectable performance is poor, and it cannot accurately fill and repair the place that needs to be treated according to the defect site, and there are also problems in that it is difficult to solidify when encountering body fluids and blood.

Molecular design of polymers is an important topic for biopolymer scientists at present. Analyzing "molecular design", that is, inferring, predicting, constituent atoms, molecular species, binding and aggregation states of polymer biomaterials, and describing the problem. The specific conformation of the structure, organization, and morphology of a molecule. The molecular design of medical biopolymers is carried out, and the purpose is how to synthesize and manufacture polymer biomaterials with specified properties and structures. The further connection between molecular design and practice is "material design", which belongs to the category of teleology and is a subject in the field of engineering.

Due to their excellent mechanical properties and good biocompatibility, biodegradable polymers have more and more applications in biomedical fields such as bone transplantation, bone cement, drug controlled release, and tissue engineering scaffolds. At present, autologous transplantation and synthetic material implantation are mostly used for the treatment of bone defects. However, the number of autologous grafts is limited by the source, which will cause the pain of secondary surgery, and it is difficult to accurately shape the defect according to the location. Allogeneic transplantation may become a source of infection. Synthetic materials such as PMMA bone cement are permanently implanted, but may cause many side effects such as infection and bone corrosion. For artificial bone materials implanted in the human body, it is required that she can withstand the corrosion and dissolution of body fluids. It has good biocompatibility and biological activity, as well as good chemical stability and mechanical properties.

β-TCP (β-tricalcium phosphate), namely β-tricalcium phosphate, powder, has been used clinically as an artificial bone substitute material since the 1970s. The composition of β-TCP is similar to the bone mineral composition. The ratio of Ca and P ions in β-TCP is 1.5:1, which is degraded into Ca and P ions in the body and provided to the new bone tissue, and is gradually replaced by the new bone tissue. , with good biocompatibility. As an implant material, β-TCP has good biodegradability. Generally, there are two pathways for the biodegradation process, namely, the humoral-mediated process and the cell-mediated process. On the other hand, β-TCP has a macroporous structure that facilitates the infiltration of body fluids and a microporous structure that facilitates the ingrowth of tissue cells. After β-TCP is implanted into the body for a period of time, the ceramic biodegrades, and finally no foreign matter remains. After the material is completely absorbed, the shape of the new stock is no longer affected by the existence of the material, and the strength of the new bone is due to the combination of the new bone and the material. Strength, changing the pore structure and physical and chemical properties (bioabsorption rate, mechanical strength, pore structure, etc.) of the material through different preparation processes can meet different clinical application requirements. However, β-TCP has low fatigue strength, high brittleness, and its fracture resistance and impact resistance cannot meet the requirements of high-load artificial bone.

At present, the biodegradable biomaterials used in tube meals include polyglycolic acid (PGA) and polylactic acid (PLA). However, due to the lack of reactive functional groups in their chemical structures and their lack of hydrophilicity, their applications as bone repair materials are greatly limited. application. Therefore, the synthesis of a new biodegradable material is a subject of development in the medical field.

Usually, this type of bone adhesive used is a one-component, commercial, solvent-free adhesive, which is rapidly cured at room temperature and cured within 10 to 30 seconds after being implanted in the body through the polymerization of tissue fluid and blood. . The curing time is not easy to control. Depending on the bone injury, the dosage of bone adhesive used during the operation is also different, and sometimes a small amount is used, which is easy to cause the remaining bone adhesive to be unfavorable for preservation, or even because it is not used in time or Preservation and rapid curing, resulting in waste. Therefore, there is a need for a bone adhesive that is stable in storage and easy to use when used.

PLGA, that is, polylactic acid-glycolic acid copolymer, is randomly polymerized from two monomers-lactic acid and glycolic acid. It is a degradable functional polymer organic compound with good biocompatibility, non-toxicity, Good encapsulation and film-forming properties are widely used in pharmaceutical, medical engineering materials and modern industrial fields. In the United States, PLGA has passed the FDA certification and was officially included in the US Pharmacopoeia as a pharmaceutical excipient. The degradation products of PLGA are lactic acid and glycolic acid, which are also by-products of human metabolic pathways, so it has no toxic side effects when used in pharmaceuticals and biological materials. Except, of course, lactose deficient. By adjusting the monomer ratio, and then changing the degradation time of PLGA, this method has been widely used in biomedical fields, such as: skin transplantation, wound closure, in vivo implantation, micro-nanoparticles, etc.

Polyhydroxypropyl fumarate (PPF) is an unsaturated linear polyester, which is a water-degradable substance and an ideal biodegradable material. It can be degraded in vivo to generate fumaric acid and propylene glycol (PG) degradation products can be Normal metabolism is excreted and has no effect on body systems such as pH. PPF with an appropriate degree of polymerization can be cured at body temperature, and by controlling its molecular weight, a material with good mechanical properties can be obtained. And the fumaric acid unsaturated double bond of PPF can react with other cross-linking agent molecules to form a cross-linked polymer material, which can be used as a scaffold material to induce bone regeneration. With degradable propylene glycol fumarate. Since PPG is biodegradable and can be arbitrarily shaped at body temperature, PPF has good fluidity before curing. As an injectable filling material, it can be well used for the repair and reconstruction of bone defects without kneeling.

N-vinylpyrrolidone, ie N-vinylpyrrolidone. Chinese synonyms: n-ethyl-2-pyrrolidone; 1-vinyl-2-pyrrolidone; 1-vinyl-2-pyrrolidone; 1-vinyl-2-pyrrolidone; 99%STAB.WITH0.1%SODIUMHYDROXID;Chemicalbook1 -Vinyl-2-pyrrolidone (with stabilizer N,N'-di-sec-butyl-p-phenylenediamine); 1-vinyl-2-pyrrolidone, 99% STAB.WITH0.1% SODIUMHYDROXIDE; vinyl-2- Pyrrolidone. English name: N-Vinyl-2-pyrrolidone. Chemical formula C6H9NO, molecular weight 111.142. Density 20℃, 1.030～1.060g/mL; 25℃, 1.04g/mL. Molar volume: 97.1 cm ³ /mol. Colorless liquid. Easy to polymerize into polyvinylpyrrolidone. It is miscible with water, ethanol, ether and other organic solvents, and easily copolymerized with other vinyl compounds. Mainly used for polymers or copolymers, and can also be used as reactive diluents for polymer systems, UV-curable coatings for decoration of walls and floors.

Ultrafine particles refer to fine particle powder materials with a diameter of less than 1 micron. Generally, particles with a size of 0.5 nm to 100 nm and in the junction area of atomic clusters and macroscopic objects are called ultrafine particles. Due to their electrical, thermal and optical properties, ultrafine particle materials have good applications in the fields of electronics, chemical industry, and nuclear technology.

Phosphate Buffered Saline (PBS) is one of the most widely used buffer solutions commonly used in biological research. PBS can be the English abbreviation of three solutions, namely phosphate buffered solution, phosphate buffered saline and phosphate buffered sodium. Due to their secondary dissociation, the buffers have a wide pH range. Its various concentrations are easy to configure, the pH value is less affected by temperature, the buffer capacity is strong, and the pH value changes little after dilution. Phosphate buffers adjust the pH without affecting the chemical reaction so that the chemical reaction can take place under optimal conditions. However, phosphate buffer is easy to associate with common calcium ions Ca ²⁺ , Mg ²⁺ and some heavy metal ions to form precipitates; it will inhibit some biochemical reaction processes, such as inhibiting the catalytic process of some enzymes. Buffers help maintain a constant pH, and the osmotic pressure and ionic concentration of the solution are usually close to the pH of the human body (isotonic). For example, PBS is a phosphate buffer with pH 7.4. The pH value is fixed and isotonic with human blood, so it is generally used for molecular cloning and cell culture experiments. The more pH values used for protein experiments are PH6.8 and PH8.8. Its preparation method is different, the pH value is different, and its biological effect is not exactly the same. Unless otherwise specified, PBS commonly used in biology is neutral phosphate buffered solution. Buffers help maintain a constant pH. The osmotic pressure and ionic concentration of the solution are usually close to the pH of the human body (isotonic).

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a non-invasive implantable high-viscosity adhesive material for orthopaedics, which has high viscosity, good plasticity, stable storage properties, and is convenient for preparation and implantation at the operation site, and its preparation method and application.

The present invention adopts the following technical solutions to achieve its purpose, a non-invasive implant high-viscosity adhesive material for orthopaedics, characterized in that it is made of the following raw materials:

PLGA: β-TCP: Sodium chloride: Ethyl acetate: Distilled water: Medical adhesive: Polyhydroxypropyl fumarate (PPF): N-Vinyl Propiopyrrolidone=760mg～1520mg: 240mg～480mg: 20mg～40mg: 8mL～12mL: 100mL～200mL: 19mL～38mL: 3mL～6mL: 3mL～6mL;

Or PLGA: β-TCP: Phosphate Buffer: Sodium Chloride: Distilled Water: Medical Adhesive: Polyhydroxypropyl Fumarate: N-Vinylpyrrolidone=760mg～1520mg: 240mg～480mg: 30mL～50mL: 10mg～ 20mg: 100mL~200mL: 19mL~38mL: 3mL~6mL: 3mL~6mL.

The PLGA ratio (molar ratio) of the present invention is DL-LA/GA=75/25; the β-TCP is a nano-scale powder; the pH of the phosphate buffer is 7.2.

A preparation method of a non-invasive implanted high-viscosity adhesive material for orthopedics, which comprises the following steps:

(1) dissolve PLGA, β-TCP and sodium chloride in ethyl acetate by proportioning to obtain solution A;

Or dissolve PLGA and β-TCP in phosphate buffer to obtain solution B; for later use;

(2) PLGA, β-TCP, sodium chloride are dissolved in distilled water to obtain solution C; for subsequent use;

(3) Under the condition of -4°C to 8°C, inject solution A or solution B into solution C under stirring at a rotational speed of 1000 rpm, and continue to stir to PLGA, β-TCP, sodium chloride under magnetic conditions become ultrafine particles and solidify;

(4) centrifuging the product obtained in step (3) at 1000 rpm, washing with water and drying, to obtain a high-viscosity glue ultrafine particle powder, then adding a required amount of distilled water, dispersing uniformly, and then sub-packing to obtain a high-viscosity glue Glue dispersible granules;

(5) Dissolve the medical adhesive, polyhydroxypropyl fumarate (PPF), and N-vinylpyrrolidone in distilled water according to the ratio, and stir at 6°C to 10°C. Hydroxypropyl ester (PPF) and N-vinylpyrrolidone are polymerized to obtain a viscous solution, and then centrifuged at 300 rpm to obtain a sizing agent solution, which is for subsequent use;

(6) After the high-viscosity glue dispersible granules obtained in step (4) and the adhesive solution obtained in step (5) are sterilized by cobalt 60 irradiation for 6 to 7 days, they are combined and packaged according to the proportion to be stored in the required specifications, that is, they are ready for use. Combination of high-viscosity adhesive materials for non-invasive implantation in orthopaedics.

The raw material ratio of the solution A described in the step (1) of the present invention is PLGA: β-TCP: sodium chloride: ethyl acetate=380mg～760mg: 120mg～240mg: 10mg～20mg: 8mL～12mL;

The raw material ratio of the solution B is PLGA:β-TCP:phosphate buffer solution=380mg～760mg:120mg～240mg:30mL～50mL;

The raw material ratio of solution C in the described step (2) is PLGA:β-TCP:sodium chloride:distilled water=380mg～760mg:120mg～240mg:10mg～20mg:50mL～100mL;

In the step (3), the diameter of the ultrafine particles is 0.1-0.2 microns;

In the step (4), drying is drying at 60°C～120°C for 2 hours～1 hour or freeze-drying;

The raw material ratio of the adhesive solution in the step (5) is medical adhesive: polyhydroxypropyl fumarate (PPF): N-vinylpyrrolidone: distilled water=19mL～38mL: 3mL～6mL: 3mL～ 6mL: 50mL～100mL.

In the step (6), the combined packaging ratio of the non-invasive implanted high-viscosity adhesive material for orthopaedics is high-viscosity glue dispersible granules: adhesive solution = 5-10 g/bottle (vial): 25-50 mL/bottle .

The application of a non-invasive implant high-viscosity adhesive material for orthopedics in the treatment of fractures, bone diseases, and bone tumors (minimally invasive injection implanted in fractures, bone disease sites or surgically open bone filling), which is proportional to high-viscosity To the glue dispersible granules, organic acid solvent and adhesive solution with no toxic and side effects to human body are added in turn to dissolve, polyhydroxypropyl fumarate (PPF) and N-vinylpyrrolidone are biodegradable, and can be combined with medical adhesive. Then, adding high-viscosity glue dispersible granules and acetic acid can be compounded into a viscous suspension-like solution, that is, a high-viscosity glue solution for orthopedic non-invasive implantation is obtained.

The organic acid solvent of the present invention is acetic acid.

The dissolving ratio of the present invention is high-viscosity glue dispersible granules: adhesive solution: acetic acid = 5 g: 25 mL: 0.5 mL.

The medical adhesive of the present invention is a commercially available adhesive, produced by Beijing Kangpaite Medical Equipment Co., Ltd. This product is colorless and transparent liquid, the main ingredient is n-butyl α-cyanoacrylate, with trace additives; according to clinical needs, it is equipped with a straw, a glue spray bottle, and a rotary arm spray pump. It can be used for surgery-free suture glue, and can be used for human hemostasis, beauty glue and animal experiments. It is non-toxic and has no side effects.

The N-vinylpyrrolidone of the present invention is produced by Jiangsu Nantong Runfeng Petrochemical Co., Ltd.

The PLGA of the present invention is produced by Shenzhen Lubao Biotechnology Co., Ltd., and the ratio is DL-LA/GA: 75/25;

DL-LA, racemic lactide wood DL-LA, namely racemic lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) English Name DL-Lactide (3, 6-Dimethyl-1, 4-dioxane-2, 5-dione) CAS.R.NO: 95-96-5 Molecular formula C6H8O4 Molecular weight 144.13 Melting point 125-127 ℃, water content ≤ 0.4%, Heavy metal≤5ppm, free acid (CH30Nag/kg)≤1, ash content≤0.05%, purity≥99.5%;

GA, namely glycolic acid, alias glycolic acid, English name Glycolic acid, chemical formula C2H4O3, molecular weight 76.05, melting point 78-79 ° C, relative density (water = 1): 1.49, no boiling point, decomposed into formaldehyde and carbon monoxide when heated at 100 ° C And water, formaldehyde will further form paraformaldehyde or formic acid, soluble in water, soluble in methanol, ethanol, ethyl acetate, slightly soluble in ether, insoluble in hydrocarbons.

The ethyl acetate described in the present invention is commercially available analytical grade purchased.

The phosphate buffer of the present invention is a commercially available 99.9% phosphate buffer with a pH value of 7.2. It is a water-based salt solution containing sodium chloride, phosphate, and (in some formulations) potassium chloride and potassium phosphate. Sodium chloride enters and dissolves gradually to form pores and promote fracture healing. Therefore, the present invention adopts a phosphate buffer with a specific pH value of 7.2, and dissolves PLGA and β-TCP in the phosphate buffer solution. The phosphate buffer solution with a pH value of 7.2 produces a good foaming agent in this material. It can make the implanted material have enough pores to allow the tissue to grow in, thereby promoting bone healing and effectively shortening the healing time.

When the present invention is used, orthopaedic professionals will reduce the fracture under the operation of the C-arm X-ray machine, and the alignment and alignment of the frontal and lateral films by the C-arm video and X-ray machine are good; Orthopaedic non-invasive implantation of high-viscosity glue dispersible granules in high-viscosity adhesive materials is followed by adding acetic acid and adhesive solution to dissolve, and then implanting fractures and bone disease sites by minimally invasive injection. It can effectively fix the fractures by adhesive fixation. It can fill various bone defects of different shapes and sizes during open operation, and has appropriate mechanical properties and physical properties to meet special applications. After implantation, a plastic membrane-type skeleton-type fixing material is formed to reconstruct bone tissue. The material can be gradually degraded in the body after a certain period of time, and finally metabolized into water and carbon dioxide, which are absorbed by the human body and excreted from the body.

Due to the adoption of the above technical solution, the present invention better achieves the purpose of the invention. It uses prefabricated non-invasive implanted high-viscosity adhesive materials for orthopaedics, adopts on-site mixing and preparation, and adds high-viscosity glue dispersible granules into adhesive solution, acetic acid It is made into a sticky liquid polymer biomaterial, that is, a high-viscosity adhesive solution for non-invasive implantation in orthopaedics. It does not solidify inside, and then solidifies rapidly at body temperature;

PLGA and β-TCP (bone meal) have good biocompatibility, and they can be made into porous solidified materials, which are conducive to the ingrowth of bone tissue, promote bone healing, and better induce and promote the proliferation and proliferation of chondrocytes during adhesion. Differentiation, the formation of cartilage tissue, the ingrowth of bone tissue to promote bone healing, non-toxic; polyhydroxypropyl fumarate (PPF) is a biodegradable material, the material is gradually degraded and excreted from the body after new bone growth; polyhydroxyl fumarate Propyl ester (PPF) and N-vinylpyrrolidone are biodegradable. When cross-linking with medical adhesives, high-viscosity glue dispersible granules are added to form a viscous adhesive solution, which dissolves after implantation with sodium chloride. Absorption of re-formed pores can allow tissue to grow in and accelerate bone healing;

The solution can be implanted by minimally invasive injection, and solidifies rapidly at body temperature to form a "plastic film-shaped" film block material. By controlling its molecular weight, a material with good mechanical properties can be obtained, which can be directly and firmly fixed at body temperature. Fractures and bone disease parts; the cross-linked polymer material increases the adsorption force, so it has the characteristics of high viscosity, at the same time, it can improve the strength of reconstruction and repair, and form a porous mesh-like strong protective film on the surface of the damaged tissue to prevent hyperplasia; it has Certain elasticity, stiffness (hardness), appropriate mechanical and physical properties to meet special applications, and during the degradation process, maintaining such mechanical properties, the degradation products have good biocompatibility, and can be The shape degrades and maintains the shape of a plastic membrane stent for a long time, and it has controllable biodegradation and no toxic side effects; it can be implanted by minimally invasive injection, and the implantation method is precise and convenient; after implantation, it can promote It also regulates the growth and differentiation of surrounding cells under the periosteum, accelerates the formation and mineralization of bone matrix, and promotes the rapid healing of fractures; the material can be gradually degraded in the body after a certain period of time, and finally metabolized into water and carbon dioxide, which are absorbed by the body and then discharged. in vitro;

It can also fill bone defects of various shapes and sizes after open reduction surgery, fix them to form the desired shape, have appropriate mechanical properties and physical properties, and repair and reconstruct bone tissue to meet special applications.

detailed description

The present invention will be further described below in conjunction with the examples.

Example 1:

A non-invasive implant high-viscosity adhesive material for orthopedics, which is made of the following raw materials:

PLGA: β-TCP: Sodium chloride: Ethyl acetate: Distilled water: Medical adhesive: Polyhydroxypropyl fumarate (PPF): N-Vinyl Propiopyrrolidone=760mg～1520mg: 240mg～480mg: 20mg～40mg: 8mL～12mL: 100mL～200mL: 19mL～38mL: 3mL～6mL: 3mL～6mL; or PLGA: β-TCP: Phosphate Buffer: Sodium Chloride: Distilled Water: Medical Adhesive: Polyhydroxypropyl Fumarate (PPF): N-vinylpyrrolidone=760mg～1520mg: 240mg～480mg: 30mL～50mL: 10mg～20mg: 100mL～200mL: 19mL～38mL: 3mL～6mL: 3mL～6mL (the raw material ratio of this example is PLGA : β-TCP: sodium chloride: ethyl acetate: distilled water: medical adhesive: polyhydroxypropyl fumarate: N-vinyl disopyrrolidone = 1520mg: 480mg: 40mg: 12mL: 200mL: 38mL: 6mL: 6mL) .

The PLGA ratio (molar ratio) of the present invention is DL-LA/GA=75/25;

The β-TCP is nano-scale powder; the pH value of the phosphate buffer is 7.2.

(5) Dissolve medical adhesive, polyhydroxypropyl fumarate (PPF), N-vinylpyrrolidone in distilled water according to the proportions, stir, medical adhesive, polyhydroxypropyl fumarate (PPF), N-vinylpyrrolidone -vinylpyrrolidone is polymerized, synthesized to obtain a sticky solution, and then centrifuged at 300 rpm to obtain a sizing agent solution, which is for subsequent use;

(6) After the high-viscosity glue dispersible granules obtained in step (4) and the adhesive solution obtained in step (5) are sterilized by cobalt 60 irradiation, they are combined and packaged according to the proportion and stored in the required specifications, that is, the orthopaedic combination for standby is obtained. Non-invasive implantation of high-viscosity adhesive materials.

The raw material ratio of solution A described in step (1) of the present invention is PLGA: β-TCP: sodium chloride: ethyl acetate=380mg～760mg: 120mg～240mg: 10mg～20mg: 8mL～12mL (this example The raw material ratio of middle solution A is PLGA: β-TCP: sodium chloride: ethyl acetate=760mg: 240mg: 20mg: 12mL);

The raw material ratio of solution C in the described step (2) is PLGA: β-TCP: sodium chloride: distilled water=380mg～760mg: 120mg～240mg: 10mg～20mg: 50mL～100mL (the solution C in the present embodiment) The raw material ratio is PLGA:β-TCP:sodium chloride:distilled water=760mg:240mg:20mg:100mL);

In the step (4), drying is drying at 60°C to 120°C for 2 hours to 1 hour or freeze-drying (in this example, drying at 120°C for 2 hours);

The raw material ratio of the adhesive solution in the step (5) is medical adhesive: polyhydroxypropyl fumarate (PPF): N-vinylpyrrolidone: distilled water=19mL～38mL: 3mL～6mL: 3mL～ 6mL: 50mL～100mL (in this embodiment, the raw material ratio of the adhesive solution is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=38mL: 6mL: 6mL: 100mL).

In the step (6), the combined packaging ratio of the non-invasive implanted high-viscosity adhesive material for orthopaedics is high-viscosity glue dispersible granules: adhesive solution = 5-10 g/bottle (vial): 25-50 mL/bottle (This example is high-viscosity glue dispersible granules: adhesive solution = 5g/bottle: 25mL/bottle).

An orthopedic non-invasive implanted high-viscosity glue material is used in the operation of treating fractures, bone diseases, bone tumors (or open bone filling in surgery), and it is sequentially added to high-viscosity glue dispersible granules in proportion to the human body. Organic acid solvents and adhesive solutions with toxic and side effects are dissolved, polyhydroxypropyl fumarate (PPF) and N-vinylpyrrolidone are biodegradable, cross-linked with medical adhesives, and added with high-viscosity glue dispersible granules, Acetic acid can be compounded into a viscous suspension-like solution, that is, a high-viscosity glue solution for non-invasive implantation in orthopedics can be obtained.

The organic acid solvent described in the application of the present invention is acetic acid.

The dissolving ratio described in the application of the present invention is high-viscosity glue dispersible granules: adhesive solution: acetic acid = 5 g: 25 mL: 0.5 mL.

Example 2:

The non-invasive implant high-viscosity adhesive material for orthopedics described in this embodiment is made of the following raw materials:

PLGA: β-TCP: Sodium Chloride: Ethyl acetate: Distilled water: Medical adhesive: Polyhydroxypropyl fumarate (PPF): N-Vinyl Propiopyrrolidone=760mg: 240mg: 20mg: 8mL: 100mL: 19mL: 3mL:3mL.

In the preparation method of a non-invasive implanted high-viscosity adhesive material for orthopaedics described in this embodiment, the raw material ratio of the solution A described in step (1) is PLGA:β-TCP:sodium chloride:ethyl acetate =380mg:120mg:10mg:8mL;

In the described step (2), the raw material ratio of solution C is PLGA: β-TCP: sodium chloride: distilled water=380mg: 120mg: 10mg: 50mL;

In the described step (4), drying is drying at 120° C. for 1 hour;

In the step (5), the raw material ratio of the adhesive solution is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=19mL:3mL:3mL:50mL.

In the step (6), the combined packaging ratio of the non-invasive implanted high-viscosity adhesive material for orthopedics is high-viscosity glue dispersible granules: adhesive solution = 5 g/bottle: 25 mL/bottle.

The same as in Example 1.

Example 3:

PLGA: β-TCP: Sodium Chloride: Ethyl acetate: Distilled water: Medical adhesive: Polyhydroxypropyl fumarate (PPF): N-Vinyl Propiopyrrolidone=1520mg: 400mg: 40mg: 10mL: 100mL: 38mL: 6mL:6mL.

In the preparation method of a non-invasive implanted high-viscosity adhesive material for orthopaedics described in this embodiment, the raw material ratio of the solution A described in step (1) is PLGA:β-TCP:sodium chloride:ethyl acetate =760mg:200mg:20mg:10mL;

In the described step (2), the raw material ratio of solution C is PLGA: β-TCP: sodium chloride: distilled water=760mg: 200mg: 20mg: 50mL;

In the described step (4), drying is drying at 120° C. for 2 hours;

The raw material ratio of the adhesive solution in the step (5) is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=38mL:6mL:6mL:50mL.

In the step (6), the combined packaging ratio of the high-viscosity adhesive material for orthopedic non-invasive implantation is high-viscosity glue dispersible granules: adhesive solution=10g/bottle:50mL/bottle.

The same as in Example 2.

Example 4:

PLGA: β-TCP: Phosphate Buffer: Sodium Chloride: Distilled Water: Medical Adhesive: Polyhydroxypropyl Fumarate: N-Vinylpyrrolidone=760mg: 240mg: 30mL: 20mg: 200mL: 19mL: 3mL: 3mL .

In the preparation method of a non-invasive implanted high-viscosity adhesive material for orthopaedics described in this embodiment, in step (1), PLGA and β-TCP are dissolved in a phosphate buffer to obtain solution B, which is for later use; The raw material ratio of solution B is PLGA:β-TCP:phosphate buffer=380mg:120mg:30mL.

In the step (2) described in this embodiment, the raw material ratio of solution C is PLGA:β-TCP:sodium chloride:distilled water=380mg:120mg:20mg:100mL;

In the described step (4), drying is freeze-drying;

In the step (5), the raw material ratio of the adhesive solution is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=19mL:3mL:3mL:100mL, and at 7°C under stirring.

The same as in Example 1.

Example 5:

PLGA: β-TCP: Sodium Chloride: Ethyl acetate: Distilled water: Medical adhesive: Polyhydroxypropyl fumarate (PPF): N-Vinyl Propiopyrrolidone=1000mg: 480mg: 30mg: 12mL: 180mL: 28mL: 4mL:4mL.

In the preparation method of a non-invasive implanted high-viscosity adhesive material for orthopaedics described in this embodiment, the raw material ratio of the solution A described in step (1) is PLGA:β-TCP:sodium chloride:ethyl acetate =500mg:240mg:15mg:12mL;

In the described step (2), the raw material ratio of solution C is PLGA: β-TCP: sodium chloride: distilled water=500mg: 240mg: 15mg: 90mL;

In the described step (4), drying is drying at 120° C. for 2 hours;

In the step (5), the raw material ratio of the adhesive solution is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=28mL:4mL:4mL:90mL.

In the step (6), the combined packaging ratio of the high-viscosity adhesive material for orthopedic non-invasive implantation is high-viscosity glue dispersible granules: adhesive solution=8g/bottle:45mL/bottle.

The same as in Example 3.

Example 6:

PLGA: β-TCP: Phosphate Buffer: Sodium Chloride: Distilled Water: Medical Adhesive: Polyhydroxypropyl Fumarate: N-Vinylpyrrolidone=1520mg: 480mg: 50mL: 15mg: 180mL: 38mL: 6mL: 6mL .

In the preparation method of a non-invasive implanted high-viscosity adhesive material for orthopaedics described in this embodiment, the raw material ratio of the solution B described in step (1) is PLGA:β-TCP:phosphate buffer=760mg: 240 mg: 50 mL.

In the step (2) described in this embodiment, the raw material ratio of solution C is PLGA:β-TCP:sodium chloride:distilled water=760mg:240mg:15mg:90mL;

In the described step (4), drying is freeze-drying;

The raw material ratio of the adhesive solution in the step (5) is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=38mL:6mL:6mL:90mL.

The same as in Example 4.

Example 7:

PLGA: β-TCP: Phosphate Buffer: Sodium Chloride: Distilled Water: Medical Adhesive: Polyhydroxypropyl Fumarate: N-Vinylpyrrolidone=1500mg: 450mg: 40mL: 10mg: 100mL: 22.8mL: 4mL: 4mL.

In the method for preparing a high-viscosity adhesive material for orthopedic non-invasive implantation described in this embodiment, the raw material ratio of the solution B described in step (1) is PLGA:β-TCP:phosphate buffer=750mg: 225 mg: 40 mL.

In the step (2) described in this example, the raw material ratio of solution C is PLGA:β-TCP:sodium chloride:distilled water=750mg:225mg:10mg:50mL;

In the described step (4), drying is freeze-drying;

The raw material ratio of the adhesive solution in the step (5) is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=22.8mL:4mL:4mL:50mL.

The same as in Example 4.

Test example

Test (1): Healing effect and properties

1. Modeling and group administration

110 rabbits were selected, weighing 1.6-2.0kg; then randomly divided into 5 groups with 22 rabbits in each group;

(A) is a blank control group: physiological saline 10 mL/kg, (B) to (E) are respectively Examples 1 to 4 of the present invention. kg, acetic acid 0.0417mL/kg dissolved non-invasive implanted high-viscosity adhesive material for orthopedics;

A hacksaw was used to interrupt the 3mm defect of the left radius, and normal saline or test drugs were injected into the fractured end according to the dose design. The wounds and the activities of the left forelimb of the rabbits were carefully observed for 3 consecutive weeks;

2. Observation indicators, methods and results

(1) Influence on the appearance time, quantity and calcification of bone callus: X-ray films were taken at the first, second, third, and four weeks after the operation of the animals in the 5 groups under the same conditions. "-" means no callus formation, "+" means that the fracture edge tends to be blurred, with a small amount of callus appearing, "++" means that the fracture edge is obviously blurred, and there is a moderate amount of callus, "+++" means the fracture edge Nearly disappear, there are more callus appear, "++++" means that the fracture edge basically disappears, the two fracture ends have been completely connected, there are a lot of callus with high density, the density is close to normal bone.

Table 1 Influence of the present invention on callus formation

Table 1 shows, group of the present invention just has more than medium callus to appear in the second week, and most of the fracture edges disappear in the third week, and the ratio of being connected into normal bone is large, and most of the fracture lines disappear in the fourth week, Fracture healing is good, and it can be seen that the present invention has obvious effect of promoting fracture healing.

(2) Influence on biomechanics: 6 rats were randomly sampled from each group at one, two, three and four weeks after the operation, respectively, and the whole left radial shaft was taken, and the radial shaft fracture strength was tested with a hydraulic universal testing machine.

Table II The influence of the present invention on the flexural strength of the backbone (unit: kg)

Table II shows that compared with the blank group, the inventive group can greatly increase the flexural strength, especially at the end of fracture healing, the strength is almost three times that of the latter, and the stiffness and hardness after fracture healing are high.

(3) Histological observation: After measuring the flexural strength, the specimen with callus was taken, fixed with 10% formaldehyde, and sent for pathological examination.

In the first week, obvious fibrous callus appeared in each group of the present invention, and new bone trabeculae were seen at the fractured end;

In the second week, there was no obvious callus connection in the "A" grade. In the other groups, the callus was continuously connected with the fractured end, and osteoblasts and cartilage were actively proliferated;

In the third week, the trabecular bone in group "A" slightly thickened and became larger, while the trabecular bone in other groups increased in thickness and size;

In the fourth week, the bone trabeculae in groups B, C, D, and E were obviously thickened and enlarged. However, the bone cells and cartilage in the blank group were less generated in the first two weeks, and the morphological changes at each stage were at least one week slower than the fracture healing process of the present invention.

The above experiments prove that the present invention can shorten the fracture healing time, enhance the flexural strength, and can better promote the fracture healing.

Test (2): Fixing time and fixing effect

1. Sampling Specimen

①Take 1 lamb rib, remove the mutton and periosteum, and the rib is intact without defects.

The length is 23cm, the middle width is 2cm, the thickness is 1.3cm, and the net weight is 26g.

Cut the lamb rib into three sections with a steel knife, and artificially create a transverse fracture of the lamb rib; the proximal fracture is 3 cm away from the joint at the adjacent end, and the distal fracture is 5 cm away from the joint at the other end (that is, the lengths of the three broken bones are : The proximal fracture segment is 3 cm long, the middle bone segment is about 15 cm long, and the distal fracture segment is 5 cm long); the proximal fracture is 2.5 cm wide and 1.3 cm thick; the distal fracture is 2 cm wide and 1.2 cm thick;

Put it in a porcelain pot, numbered No. 1, and set aside.

②Take 2 pork ribs, remove the pork and periosteum, and the ribs are intact without defects.

They are 29.5cm in length, 6cm in circumference, and 50.18g in net weight; and 25cm in length, 5.6cm in circumference, and 31.56g in net weight;

Use a hacksaw to cut one of the pig ribs (near the vertebrae in the original pig) at the proximal 10cm of the joint, and cut it into two sections (i.e., the proximal fracture section is 10 cm long and the distal fracture section is 19.5 cm long), artificially created. Pig rib transverse fracture, numbered No. 2, spare;

The other pig rib was sawed into two sections at 12 cm proximal to the joint with a hacksaw to artificially cause a comminuted fracture of the pig rib, numbered No. 3, for use.

2. Method of operation and administration

①Take 5g of high-viscosity glue dispersible granules, pour it into a container, add 0.5mL of acetic acid, mix thoroughly with a glass rod, add 25mL of adhesive solution, and further mix thoroughly to obtain a non-invasive implant high-viscosity glue solution for orthopaedics. Enter the bone cortex at the fracture end of the No. 1 sample.

The proximal (proximal fracture) broken end of sample No. 1 was only fixed to the back, the implant dose was 1.3 g, and no material was implanted on the ventral side (the convex surface of the rib was the dorsal side, and the concave surface was the ventral side); The whole implanted material around the broken end at the fracture of the end), the implant dose is 2.7g, and the net weight of No. 1 sample after fixation (two fixations) is 31g.

②Put 5g of high-viscosity glue dispersible granules into a container, add 0.5mL of acetic acid, mix thoroughly with a glass rod, and then add 25mL of adhesive solution. Within minutes, the No. 2 sample and No. 3 sample were quickly implanted at the bone cortex of the fractured end of the sample.

Sample No. 2 was implanted on the back and both sides of the fractured end (both sides in the thickness direction of pig rib), and the implant dose was 2g; Sample No. 3 was implanted on the back and both sides of the fracture end, and the implant dose was 3g. .

3. Results

① Sample No. 1 was implanted at room temperature of 15 °C and timed after implantation. It was placed in the porcelain basin immediately after 3 minutes, and the distance between the fracture was 2.5 cm. It was observed that there was no loosening of the fractured ends on both sides, and the proximal fracture was only fixed on the back. loose;

After standing in the pelvis for 2 minutes (cumulative implantation time of 5 minutes), hold the middle bone segment to hang upright in the air, and observe: there is no crack and loosening of the two broken ends;

After hanging for 1 minute (accumulated implantation time of 6 minutes), the middle bone segment was lifted laterally, and it was observed that there was no loosening of the two fracture ends;

After holding it horizontally for 2 minutes (the cumulative implantation time is 8 minutes), the lateral side of the fracture cementation tubercle was removed from the proximal end of the proximal fracture site (at 2cm) and the dorsal side (convex surface) of the bone skin graft was still held horizontally upward, and it was observed that: There is no loosening of the fractured end, and the distal end (3cm) from the distal fracture is not loosened, and it has been firmly fixed;

After 2 minutes (cumulative implantation time of 10 minutes), turn the sample over to make the dorsal side of the bone skin graft face down, hold the proximal end of the fracture, and shake it up and down for dozens of times. It is observed that the fractured end is not loose and has been firmly fixed;

The cumulative implantation time was 24 hours, and it was observed that there was no abnormal loosening of the fracture end, the fracture was fixed firmly, and the proximal end was only fixed at the dorsal side without loosening;

Dropped from a height of 2 meters, it was observed that there was no loosening or fracture at the fractured end, and the proximal end was only fixed on the back side and there was no loosening. The cortical fixation on the back side of the fracture could also play a role in firm fixation.

② Samples No. 2 and No. 3 were implanted at room temperature of 20°C and timed after implantation. After 3 minutes, the distal end of the fracture was lifted horizontally. It was observed that the fracture was not loose and was firmly fixed;

At 5 minutes of implantation, it was observed: the fracture was fixed, the fracture was not loosened, and it was firmly fixed;

Twenty-four hours after implantation, it was observed that the fractured end was firmly fixed and completely cured.

in conclusion:

1. The present invention is suitable for minimally invasive implantation treatment of traumatic fractures and other (pathological fractures, osteoporotic fractures) bone tumors (benign bone tumors).

2. The fracture adhesion site can be implanted with materials on the back and both sides of the fracture at the same time, and the effect of material fixation is satisfactory, which is equal to the firm fixation of the material implanted around the distal end of the sheep rib fracture, porcine rib transverse fracture and comminuted fracture. of. It is proved that 1.2g of material is implanted at the proximal fracture end of the sheep rib, the fixation site is the dorsal side of the bone, no material is implanted in the ventral side, and 2.7g of material is implanted at the distal end, and the strength (hardness) of the cementation is both in the test. quite. In 24 hours, two different parts were implanted with different materials. The two fractures were thrown from a height of 2 meters without loosening or breaking. In addition, the external fixation of the limbs was required after the minimally invasive surgery. Therefore, it is considered that the material has reached the According to the requirements of the clinical test, the material used for the third sample of pig rib is 3g, which proves that the material used for comminuted fractures should be increased by 33% compared with the materials used for transverse fractures. The strength (hardness) of the fracture fixation cement measured within 24 hours was comparable. It can also be considered that in order to protect the ventral side of the bone from damage to the larger blood vessels and nerves due to implantation, the dorsal side of the fracture can be implanted for fixation. Thus, the high viscosity, good plastic film properties of the present invention are demonstrated.

3. The present invention is suitable for minimally invasive implantation to treat various fractures, osteoporotic fractures of the elderly, and creative fractures (distal bone fractures, ankle fractures, finger fractures, toe fractures, etc.).

4. The material analysis and research of this product, combined with animal tests, show that the material can quickly coagulate and fix the fracture within 3 to 5 minutes under the action of body temperature, 10 to 12 hours to cure, and 24 hours to completely cure, which can effectively control the fracture movement. bit or loose.

5. The storage properties of the present invention are stable, and in the in vitro adhesion and fixation test of the sheep rib, the fracture is firmly fixed after ten minutes at room temperature of 15°C. The pig rib in vitro adhesion and fixation test was performed at room temperature below 20 °C, and there was an 8-minute time interval from the configuration of the non-invasive implant high-viscosity adhesive solution for orthopaedics to the implantation in the operating space. Facilitates preparation and implantation at the surgical site.

Claims

A non-invasive implant high-viscosity adhesive material for orthopedics is characterized in that it is made of the following raw materials:

PLGA: β-TCP: sodium chloride: ethyl acetate: distilled water: medical adhesive: polyhydroxypropyl fumarate: N-vinyl disopyrrolidone=760mg～1520mg: 240mg～480mg: 20mg～40mg: 8mL～12mL : 100mL～200mL: 19mL～38mL: 3mL～6mL: 3mL～6mL;

Or PLGA: β-TCP: Phosphate Buffer: Sodium Chloride: Distilled Water: Medical Adhesive: Polyhydroxypropyl Fumarate: N-Vinylpyrrolidone=760mg～1520mg: 240mg～480mg: 30mL～50mL: 10mg～ 20mg: 100mL~200mL: 19mL~38mL: 3mL~6mL: 3mL~6mL.
The non-invasive implant high-viscosity adhesive material for orthopedics according to claim 1, wherein the PLGA ratio is DL-LA/GA=75/25; the pH of the phosphate buffer is 7.2.
A preparation method of non-invasive implantation high-viscosity adhesive material for orthopedics, characterized in that it comprises the following steps:

(1) dissolve PLGA, β-TCP and sodium chloride in ethyl acetate by proportioning to obtain solution A;

Or dissolve PLGA and β-TCP in phosphate buffer to obtain solution B; for later use;

(2) PLGA, β-TCP, sodium chloride are dissolved in distilled water to obtain solution C; for subsequent use;

(3) Under the condition of -4°C to 8°C, inject solution A or solution B into solution C under stirring at a rotational speed of 1000 rpm, and continue to stir to PLGA, β-TCP, sodium chloride under magnetic conditions become ultrafine particles and solidify;

(4) centrifuging the product obtained in step (3) at 1000 rpm, washing with water and drying, to obtain a high-viscosity glue ultrafine particle powder, then adding a required amount of distilled water, dispersing uniformly, and then sub-packing to obtain a high-viscosity glue Glue dispersible granules;

(5) Dissolve medical adhesive, polyhydroxypropyl fumarate and N-vinylpyrrolidone in distilled water according to the proportion, stir to obtain a sticky solution, and then perform centrifugal separation at 300 rpm to obtain an adhesive solution ,spare;

(6) After the high-viscosity glue dispersible granules obtained in step (4) and the adhesive solution obtained in step (5) are sterilized by cobalt 60 irradiation, they are combined and packaged according to the proportion and stored in the required specifications to obtain non-invasive implants for orthopaedics. into high-viscosity adhesive materials.
A kind of preparation method of non-invasive implant high-viscosity glue material for orthopedics according to claim 3, is characterized in that:

The raw material ratio of solution A described in step (1) is PLGA: β-TCP: sodium chloride: ethyl acetate=380mg～760mg: 120mg～240mg: 10mg～20mg: 8mL～12mL;

The raw material ratio of the solution B is PLGA:β-TCP:phosphate buffer solution=380mg～760mg:120mg～240mg:30mL～50mL;

The raw material ratio of solution C in the described step (2) is PLGA:β-TCP:sodium chloride:distilled water=380mg～760mg:120mg～240mg:10mg～20mg:50mL～100mL;

In the step (4), drying is drying at 60°C～120°C for 2 hours～1 hour or freeze-drying;

The raw material ratio of the adhesive solution in the step (5) is medical adhesive: polyhydroxypropyl fumarate: N-vinylpyrrolidone: distilled water=19mL～38mL:3mL～6mL:3mL～6mL:50mL ~100 mL.

In the step (6), the combination packaging ratio of the high-viscosity adhesive material for orthopedic non-invasive implantation is high-viscosity glue dispersible granules: adhesive solution=5-10g/bottle: 25-50mL/bottle.
A non-invasive implantation of high-viscosity glue material for orthopedics as claimed in claim 1 in the operation of treating fractures, bone diseases, and bone tumors, characterized in that the high-viscosity glue dispersible granules are sequentially added in proportion to The organic acid solvent and the adhesive solution are dissolved to obtain a high-viscosity adhesive solution for orthopedic non-invasive implantation.
The application of a non-invasive implant high-viscosity glue material for orthopedics according to claim 5 in the operation of treating fractures, bone diseases and bone tumors, wherein the organic acid solvent is acetic acid.
The application of a non-invasive implant high-viscosity glue material for orthopedics according to claim 6 in the operation of treating fractures, bone diseases, and bone tumors, wherein the dissolving ratio is high-viscosity glue dispersible granules: adhesive Solution: acetic acid = 5 g: 25 mL: 0.5 mL.