CN118649288B

CN118649288B - A self-curing absorbable bone filling material and its application

Info

Publication number: CN118649288B
Application number: CN202411140191.1A
Authority: CN
Inventors: 刘超; 朱宏彬; 胡亚萍
Original assignee: Shanghai Penggguan Biological Mediceine Tec Co ltd
Current assignee: Shanghai Penggguan Biological Mediceine Tec Co ltd
Priority date: 2024-08-20
Filing date: 2024-08-20
Publication date: 2024-11-22
Anticipated expiration: 2044-08-20
Also published as: CN118649288A

Abstract

The invention provides a self-curing absorbable bone filler and application thereof, wherein the self-curing absorbable bone filler comprises a solid phase substrate component and a curing liquid, the solid phase substrate component comprises, by weight, 40-60 parts of calcium sulfate hemihydrate and 40-60 parts of bioactive glass, and the curing liquid comprises, by weight, 0.5-5 parts of sodium carboxymethylcellulose and 95-99.5 parts of physiological saline. The self-curing absorbable bone filler provided by the invention has proper setting time, good mechanical strength, injectability, washing resistance and good biological activity. Can promote cell ossification, is beneficial to the generation of new bone in middle and later stages, and avoids the infection problem existing after operation.

Description

Self-curing absorbable bone filling material and application

Technical Field

The invention relates to the technical field of biological materials, in particular to a self-curing absorbable bone filling material and application.

Background

Bone fracture or bone defect caused by osteoporosis is the most common disease of the old population, and the human body is difficult to heal the bone defect simply by relying on the self-repairing function of the bone. Thus, there is a need for implantation of bone repair materials to heal and repair bone defects.

Bone cement is a common orthopedic repair material and is widely applied to the fields of bone defect, dentistry, plastic surgery and the like. Currently, most of bone cement materials commonly used in the market are polymethyl methacrylate bone cement (PMMA). PMMA is not absorbable in human body, has low biological activity and no good osteoinductive capacity, and the material mixed system releases a large amount of heat in the curing process to cause tissue injury around an implantation site. Accordingly, there is a need for a more suitable orthopedic prosthetic material. Conventional calcium phosphate cements consist of a solid phase calcium phosphate powder and a liquid phase, which are mixed to cure in a physiological environment. The traditional calcium phosphate bone cement has good bioactivity, osteoinductive property and absorbability, is more suitable for bone repair than polymethyl methacrylate bone cement, but still has the problems of slow degradation time, lower mechanical strength, poor injection performance, easy collapsibility, incapability of forming a porous structure after in-situ solidification, being unfavorable for cell growth, formation of new bone tissues and the like.

The single surgical calcium sulfate is mixed with liquid to have higher initial strength and good injection operation property, but has the defects of short solidification time, poor collapsibility resistance, low mechanical strength, too fast degradation time, smaller pore diameter and porosity formed by in-situ solidification, and the like, which are unfavorable for the migration and angiogenesis of osteoblasts.

Bioactive glass (bioactiveglass, BAG) is silicate glass composed of SiO ₂,Na₂ O, caO, P ₂O₅ and other basic components. The bioactive glass is the material with the fastest bioactivity in the bone repair materials synthesized at present, and after being implanted into a human body, a bioactive carbonic Hydroxyapatite (HCA) layer is formed on the surface, so that a bonding interface is provided for tissues, the proliferation and growth of bone cells are promoted, the gene expression of the bone cells is activated, and the formation of new bones is accelerated.

Sodium carboxymethyl cellulose is an important cellulose derivative obtained by chemical modification of natural cellulose. Has no toxicity, no irritation and no immunological antigenicity to human body, and has excellent biocompatibility, and unique performance, such as viscosity, thickening, filming capacity and water stability.

As disclosed in US9433704B2, a curable bone graft paste composition and a method for preparing the same, the material comprising 20-60 parts of calcium sulfate (binder), 40-80 parts of bioactive glass and physiological saline (about 0.9% nacl) or other similar fluid mixed at a solid to liquid ratio of 0.3-0.4mL/g. However, this method does not contain a water-soluble thickener, and the material is inferior in washing resistance before being injected into the bone defect site without solidifying, and does not use porous bioactive glass, antibacterial components, and the like.

As US11338061B 2a dynamic bioactive bone graft material with engineered porosity is disclosed, said material comprising bioactive glass fibers and particles, additives, carriers and liquid compositions. Wherein the additive comprises tricalcium phosphate, calcium sulfate, carboxymethyl cellulose, collagen, hydroxyapatite, an antibacterial agent, an antiviral agent, a vitamin, an X-ray opacifier, a drug, calcium, a trace element, a metal oxide, a nutrient, or an acid; silver, copper, strontium, magnesium or zinc; an organic acid. The carrier comprises collagen. The liquid comprises blood, physiological saline, glycerol, gelatin, plasma or bone marrow. The concept of porous bioactive glass drug loading was not used in this method.

As US2007026030A1 discloses a method for preparing a rheological material for bone and cartilage repair, said material comprising a solid phase: methyl methacrylate, calcium sulfate, calcium phosphate, solid phase binders, bioactive glass, collagen, fibrin or hyaluronic acid, demineralized matrix, protein or polypeptide. The liquid phase is selected from one or more of water, aqueous solutions, bone marrow aspirate, blood, resin, organic hardener, organic monomer, and liquid of liquid biological molecules (the liquid component is sufficiently fluid or viscous to pass through a needle of 22 gauge or less and at least 1.25 cm gauge). Porous bioactive glass, antimicrobial components, and the like are not used in the method.

As US6767550B1 discloses a hydroxyapatite-based drug delivery implant for the treatment of cancer, said material comprising a hydroxyapatite-based bioabsorbable material, doxorubicin (antibacterial ingredient) and a liquid phase composition. Wherein the hydroxyapatite-based bioabsorbable material is selected from one or more of calcium phosphate, calcium sulfate, apatite carbonate, fluoroapatite, bioactive glass, biodegradable polymers, collagen, and gelatin. The liquid phase is selected from distilled water and buffer solution. However, in this method, the material does not contain a water-soluble thickener, the material is inferior in anti-washing and collapsibility before being injected into the bone defect site without being cured, and porous bioactive glass or the like is not used.

As US2009318982A1 discloses a method for the preparation of injectable calcium-based neutral, bioabsorbable bone grafts, the materials comprising biodegradable calcium-based compounds (calcium sulfate, hydroxyapatite and tricalcium phosphate), biocompatible materials, cohesive powders and adhesives (water, saline, serum or other neutral aqueous solutions). However, this method does not contain a thickening agent anti-washing component, and the material has poor anti-washing power before being injected into the bone defect site and uncured, and does not use porous bioactive glass or the like.

As US2023/0053789A1 discloses a bone graft composition, the material comprising particles of hydroxyapatite, beta-tricalcium phosphate, alpha-tricalcium phosphate and/or bioactive glass and a bioabsorbable polymer carrier. The carrier is selected from bioabsorbable polymers, polyethylene glycol (PEG, 500 g/mol to about 3000 g/mol) or methylcellulose. However, the material provided by the method cannot be solidified at the bone defect injection position, does not have certain mechanical properties, and does not use porous bioglass, antibacterial components and the like.

As disclosed in CN102085389a, the injectable bone repair material comprises 50% -90% of alpha-calcium sulfate hemihydrate, 5% -45% of bone powder particles (allograft bone), biodegradable polymers and nucleating agents, and a curing solution, which may further comprise a plasticizer. Biodegradable polymers include, but are not limited to, hyaluronic acid, chitosan, alginate, carboxymethyl cellulose, octadecanoic acid, polysaccharides, and the like. The nucleating agent is at least one selected from calcium sulfate dihydrate, potassium sulfate and sodium sulfate. The plasticizer is at least one selected from hyaluronic acid and its salt, calcium sulfate dihydrate, cellulose and its derivative, stearic acid, and glycerol, preferably carboxymethyl cellulose. The solidifying liquid is at least one selected from physiological saline, water for injection or glucose injection. However, the material provided by the method is introduced into allogeneic bone split particles, and has the defects of porous structure and good biocompatibility, but has the risks of disease transmission and immunological rejection with a host, no mention of antibacterial components, the curing time of the injectable bone material is 7-125 minutes, the injection operation difficulty is high, the curing time is long, and the like.

CN111012792B discloses a biological polysaccharide flushing fluid suitable for orthopedic surgery and a preparation method thereof, wherein the material comprises 0.5-6% of sodium carboxymethyl cellulose, 0.3-4% of carboxymethyl chitosan, 5-20% of bioglass, 0.01-0.1% of acid-base regulator and ultrapure water (the balance). However, the material provided by the method is a flushing liquid, and is applicable to bone surgery but has different modes of action (not injection into bone defect positions).

CN110302431a discloses an injectable bioactive glass containing decalcified bone matrix DBM, a preparation method and application thereof, wherein the material consists of bioactive glass powder, DBM and 5-20wt% sodium carboxymethyl cellulose solution. However, the material provided by the method cannot be solidified at the bone defect injection position, does not have certain mechanical properties, and does not use porous materials, antibacterial components and the like.

CN106075565A discloses a self-curing degradable bioactive paste bone repair material and application, wherein the material comprises 15% -30% of 45S5 bioactive glass, 30% -45% of calcium sulfate hemihydrate, 30% -40% of tricalcium silicate and curing liquid. Wherein the solidifying liquid is one or more selected from physiological saline, deionized water, carbonate solution, calcium chloride solution and phosphate solution. However, the material provided by the method does not contain a water-soluble thickener, the flushing resistance of the material before being injected into the bone defect part is poor, and porous bioglass, antibacterial components and the like are not used.

CN103800945B discloses a shapable bone repair material for bone repair and a preparation method thereof, wherein the material comprises 20-90 parts of alpha-calcium sulfate hemihydrate and hydroxyapatite, 20-40 parts of bioactive mineral powder, 10-80 parts of autologous bone powder particles or DBM particles, and hydrogel with the total dosage of 1:0.5-1:15 with the raw materials. The hydrogel is preferably a PEO-PPO-PEO block copolymer solution. However, the material provided by the method does not use porous bioglass, antibacterial components and the like.

CN114209878B discloses solid phase powder for bone cement composite material, bone cement composite material and application, said material contains calcium phosphate powder (beta-tricalcium phosphate, tetra calcium phosphate and monocalcium phosphate monohydrate), calcium sulfate hemihydrate powder, bioglass, hydroxyapatite and 5% -20% dipotassium phosphate, 5% -20% potassium dihydrogen phosphate, 5% -10% citric acid, 1% -5% high molecular compound and rest water. However, the material provided by the method does not contain a water-soluble thickener, and does not use porous bioglass, antibacterial components and the like.

CN110498664B discloses a method for preparing a high strength injectable multiphase calcium phosphate based bone cement, said material comprising alpha-tricalcium phosphate powder, calcium sulphate hemihydrate powder, bioactive glass, polyglutamic acid and 3-10% wt meglumine in water. However, the material provided by the method does not contain a water-soluble thickener, and does not use porous bioglass, antibacterial components and the like.

The existing method can not meet the clinical use requirement of the actual bone filling material, and has certain defects, so that the development of a novel injectable and washable self-curing absorbable bone filling material has important significance for bone defect filling medical use.

Disclosure of Invention

The invention aims to solve the technical problems that the existing self-curing absorbable bone filling material has long degradation time, small in-situ curing material pore diameter and pore diameter, poor injection performance, easy collapse in the implantation process, unfavorable for osteoblast growth and vascular growth, easy release of a large amount of heat and infection after operation.

In order to solve the technical problems, in a first aspect, the invention provides a self-curing absorbable bone filler, which comprises a solid phase substrate component and a curing solution, wherein the solid phase substrate component comprises, by weight, 40-60 parts of calcium sulfate hemihydrate and 40-60 parts of bioactive glass, and the curing solution comprises, by weight, 0.5-5 parts of sodium carboxymethylcellulose and 95-99.5 parts of normal saline; the bioactive glass is a combination of 45S5BG and porous bioactive glass; the 45S5BG consists of 45S5BG with the particle size of 0.5-200 mu m and 45S5BG with the particle size of 500-1500 mu m, and the porous bioactive glass consists of porous bioactive glass with the particle size of 0.5-200 mu m and porous bioactive glass with the particle size of 500-1500 mu m; the self-curing absorbable bone filler material further comprises 0.1-10 parts of antibacterial components.

The self-curing absorbable bone filler provided by the invention has proper setting time, good mechanical strength, injectability, washing resistance and good biological activity. Can promote cell ossification, is beneficial to the generation of new bone in middle and later stages, and avoids the infection problem existing after operation.

The solid phase substrate component is added with bioactive glass, so that the expression of osteogenesis genes can be stimulated and induced, cell osteogenesis is promoted, and the osteogenesis is facilitated.

The calcium sulfate hemihydrate may be 40 parts, 45 parts, 50 parts, 55 parts, 60 parts or the like, for example.

The bioactive glass 40-60 parts can be, for example, 40 parts, 45 parts, 50 parts, 55 parts or 60 parts.

Preferably, the solid phase substrate component of the self-curing absorbable bone filler material comprises, by weight, 45-50 parts of calcium sulfate hemihydrate and 50-55 parts of bioactive glass; the curing liquid comprises, by weight, 0.5-2 parts of sodium carboxymethylcellulose and 98-99.5 parts of physiological saline; the bioactive glass is a combination of 45S5BG and porous bioactive glass; the 45S5BG consists of 45S5BG with the particle size of 0.5-200 mu m and 45S5BG with the particle size of 500-1500 mu m, and the porous bioactive glass consists of porous bioactive glass with the particle size of 0.5-200 mu m and porous bioactive glass with the particle size of 500-1500 mu m; the self-curing absorbable bone filler material further comprises 5-10 parts of antibacterial components.

Preferably, the mass ratio of the porous bioactive glass to 45S5BG is 1:1-100.

Preferably, the 45S5BG can improve biological activity and bone conductivity, wherein the porous bioactive glass can be used for carrying medicine and has good slow release effect.

In the invention, 45S5BG is prepared by the following method: the laboratory mixes the calcium source, the silicon source, the phosphorus source and the sodium source powder uniformly, and places the mixture in a platinum crucible, and the high-temperature muffle furnace is provided with the procedures: raising the temperature to 300 ℃ at 0.5 ℃/min, raising the temperature to 1400 ℃ at 3 ℃/min, preserving heat for 2 hours, melting the glass to be in a yellowish red liquid state, pouring the melted glass into cold water, and quenching to obtain 45S5BG coarse particles. And placing the coarse particles in a ball milling tank, adding ball mill, and grinding to obtain 45S5BG particles.

The porous bioactive glass in the invention is porous bioactive glass derived by a sol-gel method.

In the invention, the porous bioactive glass is prepared by the following method: 4.0g of polyether P123 (Mn=5800) was dissolved in 60g of ethanol at room temperature, 1.0g of 0.5M HCl solution was added, 6.7g of tetraethyl orthosilicate (TEOS), 0.73g of triethyl phosphate (TEP) and 1.4g of calcium nitrate tetrahydrate were added, and after mixing and stirring for 24 hours, the mixture was poured into a glass plate and allowed to stand until the solvent ethanol evaporated, and hydrolyzed SiO ₂ in the solvent was polymerized by polycondensation to form gel blocks. The gel block was placed in an oven at 60 ℃ for 48h. Grinding the xerogel block, placing the xerogel block into a crucible, placing the crucible into a muffle furnace, heating to 650 ℃ at a speed of ℃/min, and preserving the temperature for 2 hours to obtain the porous bioactive glass (MBG).

The particle size of the invention specifically refers to the equivalent particle size. When a certain physical property or physical behavior of the measured particle is most similar to a homogeneous sphere (or combination) of a certain diameter, the diameter (or combination) of the sphere is taken as the equivalent particle diameter (or particle size distribution) of the measured particle.

In the invention, bioactive glass is provided in a matching way in different particle size ranges, so that the degradation rate of the bone filling material is matched with the growth rate of new bone of human body. Wherein the bioactive glass with small particle size is degraded quickly in early stage, and has good bioactivity; the degradation rate of the bioactive glass with large particle size is not too high, and the disadvantage of too high degradation of single calcium sulfate hemihydrate can be improved by mixing the bioactive glass with the calcium sulfate hemihydrate.

After the bone filling material is implanted into a defect part, the porous bioactive glass derived by the small-particle-size 45S5BG and the sol-gel method can be dissolved out and degraded together with calcium sulfate hemihydrate in early stage, so that the pH of a microenvironment is raised, effective bacteriostasis can be realized, a micropore structure is formed on the surface of the bone filling material, and the micropore structure and the porous structure formed by the undegraded bioactive glass with large particle size have certain porosity and pore diameter, thereby being beneficial to osteoblasts and new blood vessels to migrate between bioactive glass particle compositions. The porous bioactive glass derived from the later-stage large particle 45S5BG and the sol-gel method is slowly degraded and resorbed, stimulates and induces the expression of osteogenic genes among particle compositions, promotes cell osteogenesis, and is beneficial to the generation of middle-stage and later-stage new bone.

Preferably, the mass ratio of 45S5BG with the particle size of 500-1500 μm to 45S5BG with the particle size of 0.5-200 μm is 1:1-100, for example, 1:1, 1:5, 1:10, 1:20, 1:40, 1:80, 1:100, etc.

Preferably, the mass ratio of the porous bioactive glass with the particle size of 500-1500 μm to the porous bioactive glass with the particle size of 0.5-200 μm is 1:1-100, for example, 1:1, 1:5, 1:10, 1:20, 1:40, 1:80, 1:100, etc.

The invention uses sodium carboxymethyl cellulose as a thickener, and the weight part of the thickener is 0.5-5 parts, for example, 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts or 5 parts, etc.

(1) The sodium carboxymethyl cellulose has no toxicity, no stimulation and no immune antigenicity to human body and has good biocompatibility.

(2) The sodium carboxymethyl cellulose curing liquid has certain viscosity and thickening performance, can improve the injectability of the bone filling material in use, and can also improve the washing resistance (migration and collapsibility are not generated) in the curing process.

(3) Sodium carboxymethyl cellulose is a pore-forming agent, and is a water-soluble thickening agent, so that after the bone filling material is injected into a defect part and solidified in situ, the sodium carboxymethyl cellulose can be slowly dissolved and absorbed, the surface of the bone filling material can form a porous structure, and the porosity of the bone filling material is increased along with dissolution of bioactive glass with small particle size, so that a three-dimensional network structure is formed, a place is provided for cell metabolism, and the generation of later-period new bone tissues is facilitated. The problems that the pore diameter and the porosity of the traditional material in-situ curing material are small, the in-growth of osteoblasts and the growth of blood vessels are not facilitated and the like are solved.

The physiological saline may be 95 to 99.5 parts, for example, 95 parts, 96 parts, 97 parts, 98 parts, 99 parts or 99.5 parts.

The antibacterial component may be 0.1 to 10 parts, for example, 0.1 part, 1 part, 4 parts, 8 parts, 10 parts, or the like.

Preferably, the antibacterial ingredient comprises any one or a combination of at least two of gentamicin, vancomycin or rapamycin.

In the invention, the above antibiotics are selected to prevent infection and reduce the incidence of infection to the greatest extent.

Preferably, the ratio of the solidification liquid to the solid phase substrate component is 0.4 mL/g-1 mL/g.

The solidifying liquid and the solid phase substrate component are mixed according to the proportion to obtain the slurry. The slurry with the concentration of 0.4 mL/g-1 mL/g is not thin and thick, and has proper setting time. Good extrudability and strong operability.

1. When the ratio is more than 1mL/g, the slurry is too thin to be implanted into a human body, the curing is difficult to cure, the curing time is too long, and the operation is difficult to control (the injector is used for extruding all the force).

2. When the ratio is less than 0.4mL/g, the slurry is too thick, the injector needs to exert great force, the extrusion is difficult, the solidification time is short, the time for operation is short for doctors, the usability is affected by the too thick slurry in the use process, and the slurry cannot smoothly flow and fill the bone wound surface.

In the present invention, the self-curable absorbable bone filler is generally prepared by mixing the raw materials, and is not particularly limited. Preferably, the method of preparing the self-curing resorbable bone filling material is in two forms: the first method is that the antimicrobial component may be added in the form of a solid phase base component.

(1) Firstly, preparing an antibacterial solution with a certain concentration; (2) Fully soaking porous bioactive glass derived by a sol-gel method in an antibacterial solution with a certain concentration, drying, and mixing with 45S5BG and calcium sulfate hemihydrate to obtain a solid phase substrate component; (3) Preparing a thickener solution with a certain concentration by taking physiological saline as a solvent to obtain a curing solution; and finally, combining the curing liquid and the solid-phase substrate component to obtain the self-curing absorbable bone filler.

The second method is to add the antimicrobial component in the form of a solidifying liquid.

(1) Mixing 45S5BG, porous bioactive glass and calcium sulfate hemihydrate to obtain solid phase substrate component.

(2) The antibacterial component is fully dissolved in physiological saline.

(3) And dissolving a certain amount of thickener into the mixed solution of the step (2), and vigorously stirring until the solution is clear to obtain a solidified solution.

And finally, combining the curing liquid and the solid-phase substrate component to obtain the self-curing absorbable bone filler.

The two methods further comprise mixing the solidifying solution with the solid phase substrate component in a ratio of 0.4 mL/g-1 mL/g to obtain the injectable and anti-washing self-solidifying absorbable bone filling material.

In a second aspect, the present invention provides the use of a self-curing resorbable bone filler material according to the first aspect for the preparation of a bone injury repair medical device.

The self-curing absorbable bone filling material provided by the invention has higher application value in the field of actual medical use, can be prepared into different types of medical equipment according to requirements, and has excellent medical effect on bone defect filling.

For example, it may be used in the future in orthopedic and dental surgery. Including bone defect repair: the self-curing absorbable bone filler is used for filling up the gaps of fracture, bone defect or bone transplantation, can be quickly cured and combined with surrounding bone tissues, and promotes bone regeneration. Spinal fusion surgery: the self-setting resorbable bone filling material is used to fill the intervertebral disc space and promote fusion between the vertebrae to stabilize the spinal column. Dental surgery: self-setting resorbable bone filling materials are used for alveolar bone defect repair, bone augmentation prior to dental implant implantation, and bone regeneration in periodontal disease treatment. Joint repair: in joint replacement surgery, self-curing resorbable bone filler materials may be used to fill bone defects around a joint, provide mechanical support, and promote bone healing. Osteoporotic fracture: self-setting resorbable bone filler materials are used to treat osteoporotic fractures, particularly vertebral compression fractures, by filling and stabilizing the bone structure, reducing pain and promoting healing.

The implementation of the invention has the following beneficial effects:

Drawings

Fig. 1 is an extrusion picture of the bone filler material of example 1.

FIG. 2 is a graph showing the bone filler material of example 1 after being cured and immersed in physiological saline for 24 hours.

Fig. 3 is an FTIR infrared spectrum of the bone filler material of example 1 after soaking in simulated body fluid for 24 hours.

Fig. 4 is a graph of compressive strength of self-setting resorbable bone filler materials prepared in examples 1-4.

Fig. 5 is a degradation graph of the self-curing resorbable bone filling materials prepared under example 1, example 7 and example 8.

Fig. 6 is an extrusion picture of the bone filler material of comparative example 1.

Fig. 7 is a degradation graph of the bone filler material prepared under example 1 (Y1) and comparative example 1 (D1).

Fig. 8 is a degradation graph of the self-curable absorbable bone filler materials prepared under example 1, comparative example 2, and comparative example 3.

Detailed Description

The following describes specific embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating and illustrating the invention, are not intended to limit the invention.

The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.

Example 1

The embodiment provides an injectable, anti-washing self-curing absorbable bone filling material, which is prepared by the following steps:

(1) 1.6g of porous bioactive glass derived by a sol-gel method (1.0 g of 0.5-200 mu m and 0.6g of 500-1500 mu m), 1.7g of 45S5BG (1.0 g of 0.5-200 mu m and 0.7g of 500-1500 mu m) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) Adding 1g of sodium carboxymethyl cellulose into a beaker containing 99g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

The setting time of the bone filler material under this example was recorded to be 21min.

To evaluate the compressive strength of the bone filler material prepared in example 1, the filler material (slurry) mixed in example 1 was transferred to a cylindrical polytetrafluoroethylene mold, placed in an environment at 37 ℃ and 100% relative humidity for hydration for 3 days, and then taken out, 5 parallel samples were taken, the bone filler material was cylindrical with a phi of 5 x 10mm, and the loading rate was 1.0mm/min. The compression strength of the alloy after 3 days can reach 16.22+/-1.20 MPa after being recorded as Y1.

To evaluate the extrusion properties of the bone filler material prepared under example 1, the filler material mixed in example 1 was transferred to a syringe, allowed to stand for several minutes, and then extruded into a plastic petri dish. As shown in fig. 1, the bone filler material can be uniformly extruded, and the extrusion performance is good.

To evaluate the anti-collapsibility of the bone filler prepared in example 1, after the bone filler in the plastic petri dish was solidified, physiological saline was added to submerge the bone filler, and after 24 hours, it was observed that the material did not collapse. As particularly shown in fig. 2.

To evaluate the bioactivity of the bone filler material prepared in example 1, an in vitro soaking simulated body fluid is used for evaluation, 1g of the cured bone filler material is soaked in 200mL of simulated body fluid for 24 hours, a wet sample is obtained by suction filtration, ethanol and deionized water are repeatedly used for washing for several times, and after drying, a knife is used for scraping surface sediment for infrared test. As shown in fig. 3, which is an FTIR infrared reflection spectrum of the bone filler material after soaking the simulated body fluid for 24 hours, it is known that the occurrence of reflection peaks 574cm ^-1 and 608cm ^-1 indicates the formation of hydroxyapatite on the surface of the material, i.e. indicates that the bone filler material has good bioactivity.

The self-setting resorbable bone filling material was subjected to animal experiments to verify effectiveness.

Animal experiments adopt a model with a rabbit femoral condyle position, annular drilling and a bone defect diameter of 10mm, the bone defect model can not be healed by a rabbit organism, and bone filling materials are injected under the bone defect model to verify the bone repairing performance of the bone filling materials. The growth of new bone at the bone defect site in different implant phases was observed by micro-CT (micro CT) at 0 week, 8 weeks and 12 weeks, and is shown in Table 1. Wherein each sample was 3 parallel samples, designated (1), (2), (3).

TABLE 1

As shown in Table 1, as the time for implanting the bone filler material was prolonged, the diameter of the bone defect portion was gradually decreased to an average bone defect diameter of 2.9mm at 12 weeks. The bone filler gradually degrades and is absorbed, and at the same time, the new bone tissue around the defect grows from outside to inside. Demonstrating that the self-curing resorbable bone filler material of the present invention is capable of promoting new bone formation in a 10mm bone defect at the femoral condyle site of rabbits.

Example 2

(1) 1.6g of porous bioactive glass derived by a sol-gel method (1.0 g of 0.5-200 mu m and 0.6g of 500-1500 mu m), 1.7g of 45S5BG (1.0 g of 0.5-200 mu m and 0.7g of 500-1500 mu m) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) Adding 2g of sodium carboxymethyl cellulose into a beaker containing 98g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

The setting time of the bone filler material was 19min.

To evaluate the compressive strength of the bone filler material prepared in example 2, the mixed filler material (slurry) was transferred to a cylindrical polytetrafluoroethylene mold, placed in an environment at 37 ℃ and 100% relative humidity for hydration for 3 days, and taken out, 5 parallel samples were taken, the bone filler material was cylindrical with a phi of 5 x 10mm, and the loading rate was 1.0mm/min.

The cured bone filler material of this example was obtained, and after 3 days, the compressive strength thereof was 27.98.+ -. 1.89MPa, recorded as Y2.

Example 3

(1) 1.6g of porous bioactive glass derived by a sol-gel method (1.0 g of 0.5-200 mu m and 0.6g of 500-1500 mu m), 1.7g of 45S5BG (1.0 g of 0.5-200 mu m and 0.7g of 500-1500 mu m) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) Adding 3g of sodium carboxymethylcellulose into a beaker containing 97g of normal saline, and vigorously stirring until the solution is clarified to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

The setting time of the bone filler material in this example was 16min.

To evaluate the compressive strength of the bone filler material prepared in example 3, the mixed filler material (slurry) was transferred to a cylindrical polytetrafluoroethylene mold, placed in an environment at 37 ℃ and 100% relative humidity for hydration for 3 days, and taken out, 5 parallel samples were taken, the bone filler material was cylindrical with a phi of 5 x 10mm, and the loading rate was 1.0mm/min. The compression strength of the alloy is up to 37.96 +/-1.66 MPa after 3 days after being recorded as Y3.

Example 4

(1) 1.6g of porous bioactive glass derived by a sol-gel method (1.0 g of 0.5-200 mu m and 0.6g of 500-1500 mu m), 1.7g of 45S5BG (1.0 g of 0.5-200 mu m and 0.7g of 500-1500 mu m) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) Adding 4g of sodium carboxymethyl cellulose into a beaker containing 96g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

The setting time of the bone filler material in this example was 14min.

To evaluate the compressive strength of the bone filler material prepared in example 4, the mixed filler material (slurry) was transferred to a cylindrical polytetrafluoroethylene mold, placed in an environment at 37 ℃ and 100% relative humidity for hydration for 3 days, and then taken out, 5 parallel samples were taken, the bone filler material was cylindrical with a phi of 5 x 10mm, and the loading rate was 1.0mm/min. The compression strength of the alloy is 46.57+/-3.74 MPa after 3 days after being recorded as Y4.

FIG. 4 is a graph showing the compressive strength of the bone filler materials (Y1, Y2, Y3 and Y4, respectively) prepared in examples 1-4. As can be seen from fig. 4, the content of sodium carboxymethyl cellulose in the solidifying liquid increases, and the compressive strength of the bone filler increases.

Example 5

(1) Adding 0.2g of rapamycin into 10mL of aqueous solution, and uniformly stirring to obtain an antibacterial solution; (2) Fully soaking 1.6g of porous bioactive glass (0.8 g of 0.5-200 mu m and 0.8g of 500-1500 mu m) derived by a sol-gel method in an antibacterial solution, and fully and uniformly mixing the solution with 1.7g of 45S5BG (0.85 g of 0.5-200 mu m and 0.85g of 500-1500 mu m) and 2.3g of calcium sulfate hemihydrate after drying to obtain a solid phase substrate component; (3) Adding 1g of sodium carboxymethyl cellulose into a beaker containing 99g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (4) 5.5g of the solid phase base component was weighed and mixed with 3.9g of the curing liquid to obtain an injectable, wash-resistant self-curing absorbable bone filler.

Example 6

(1) 1.1g of porous bioactive glass (0.55 g of 0.5-200 mu m and 0.55g of 500-1500 mu m) derived by a sol-gel method, 1.3g of 45S5BG (0.65 g of 0.5-200 mu m and 0.65g of 500-1500 mu m) and 2.6g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) Adding 0.2g of gentamicin into 10mL of physiological saline, continuously adding distilled water to 100 g, and uniformly stirring to obtain an antibacterial solution; (3) Adding 1.0g of sodium carboxymethyl cellulose into the antibacterial solution, and stirring vigorously until the sodium carboxymethyl cellulose is dissolved to obtain a curing solution; (4) 6.0g of solid phase substrate component is weighed and mixed with 5.4g of curing liquid to obtain the injectable and anti-washing self-curing absorbable bone filling material.

Example 7

This example differs from example 1 in that the sol-gel derived porous bioactive glass and 45S5BG in this example only include small particle bioactive glass. The preparation process comprises the following steps:

(1) Fully and uniformly mixing 1.6g of porous bioactive glass (0.5-200 mu m) derived by a sol-gel method, 1.7g of 45S5BG (0.5-200 mu m) and 2.3g of calcium sulfate hemihydrate to obtain a solid phase substrate component; (2) Adding 1g of sodium carboxymethyl cellulose into a beaker containing 99g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

The setting time of the bone filler material under this example was recorded to be 13min.

To evaluate the degradation rates of the bone filler materials prepared under example 1 and example 7. In vitro soaking Tris-HCl buffer solution is adopted. In the experiment, the ratio of V _Tris-HCl/M_{Sample of （ After curing ）} = 200mL/g is adopted for soaking, the initial mass M ₀ of the material is recorded before soaking, 4 parallel samples are prepared during the test, the Tris-HCl buffer solution is replaced at different time (0 h,12h,24h,72h,120h,168h (1W), 2W,4W,8W,12W,16W,20W and 24W (6M)), the buffer solution is replaced at each time point (replaced every 24h exceeding 24 h), the sample is required to be filtered and dried at the observation point, the residual mass M _t is recorded, and then the new Tris-HCl buffer solution is replaced, so that data are obtained.

The degradation profile of the injectable, wash-resistant self-curable absorbable bone filler material prepared under examples 1 and 7 was calculated from the residual mass% = (m _t/m₀) x 100%.

Example 8

This example differs from example 1 in that the sol-gel derived porous bioactive glass and 45S5BG in this example only include large particle bioactive glass. The preparation process comprises the following steps:

(1) Fully and uniformly mixing 1.6g of porous bioactive glass (500-1500 mu m) derived by a sol-gel method, 1.7g of 45S5BG (500-1500 mu m) and 2.3g of calcium sulfate hemihydrate to obtain a solid phase substrate component; (2) Adding 1g of sodium carboxymethyl cellulose into a beaker containing 99g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

The setting time of the bone filler material under this example was recorded to be 26min.

To evaluate the degradation rates of the bone filler materials prepared under example 1 and example 8. In vitro soaking Tris-HCl buffer solution is adopted. In the experiment, the initial mass M ₀ of the material is recorded before soaking, 4 parallel samples are prepared during the test, the Tris-HCl buffer solution is replaced at different time (0 h,12h,24h,72h,120h,168h (1W), 2W,4W,8W,12W,16W,20W and 24W (6M/month)), the buffer solution is replaced at each time point (24 h more than 24 h), the sample is required to be filtered and dried at the observation point, the residual mass M _t is recorded, and then the new Tris-HCl buffer solution is replaced, so that data are obtained.

The degradation profile of the injectable, wash-resistant self-curable absorbable bone filler material prepared under examples 1 and 8 was calculated from the residual mass% = (m _t/m₀) x 100%.

As shown in fig. 5, the degradation curves of the injectable, wash-resistant self-curable absorbable bone filler materials prepared under example 1 (Y1), example 7 (Y7) and example 8 (Y8) are shown in fig. 5. As is clear from FIG. 5, when immersed for 3 months (12W), the residual mass of Y1 was 4.3649.+ -. 5.3659%, the residual mass of Y7 was 0, and the residual mass of Y8 was 70.2369.+ -. 1.8954%. When immersed for 4 months (16W), the residual mass of Y1 is 0, and the residual mass of Y8 is 59.3698 +/-1.4237%.

The degradation rate of the sample is expected to match the healing rate of the human new bone substitute clinically. The degradation rate of Y7 is too fast, and the degradation is complete before the later stage of the new bone tissue growth, and the good biological activity and bone guiding effect cannot be provided. Too slow a degradation rate (Y8) may in turn hinder the formation of new bone tissue. According to the existing products (Novaboneputty) on the market of the same variety, the clinical and bone healing time of an experimental group is 11-12 weeks in the clinical combined treatment of open reduction and internal fixation of the tibial fracture. This is consistent with the rate of in vitro simulated degradation of Y1 (bioactive glass using a combination of large and small particles), which can be matched to the clinical bone healing time.

Comparative example 1

The comparative example differs from example 1 in that sodium carboxymethylcellulose is not included in the comparative example, and the specific preparation process is as follows:

(1) 1.6g of porous bioactive glass derived by a sol-gel method (1.0 g of 0.5-200 mu m and 0.6g of 500-1500 mu m), 1.7g of 45S5BG (1.0 g of 0.5-200 mu m and 0.7g of 500-1500 mu m) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) The solidifying liquid is normal saline (0.9% sodium chloride solution); (3) 5.6g of solid-phase substrate component and 4.0g of curing liquid are weighed and mixed uniformly to obtain the injectable and washable self-curing absorbable bone filling material, which is marked as D1.

The setting time of the bone filler material in this example was 18min.

To evaluate the extrusion properties of the bone filler material prepared in comparative example 1, the filler material mixed in comparative example 1 was transferred to a syringe, allowed to stand for several minutes, and then extruded into a plastic petri dish. Fig. 6 is an extrusion picture of the bone filler material of comparative example 1. As can be seen from fig. 1, the bone filler material of example 1 can be uniformly extruded, and the extrusion performance is good; the bone filler of comparative example 1 was difficult to extrude, and was unevenly extruded and easily broken. Therefore, a certain amount of sodium carboxymethylcellulose is added into the curing liquid, so that the injection performance can be improved, the material can be extruded uniformly and smoothly, and the service performance is improved.

To evaluate the degradation rates of the bone filler materials prepared under example 1 and comparative example 1. In vitro soaking Tris-HCl buffer solution is adopted. In the experiment, the initial mass M0 of the material is recorded before soaking, 4 parallel samples are prepared during the test, the Tris-HCl buffer solution is replaced at different time (0 h,12h,24h,72h,120h,168h (1W), 2W,4W,8W,12W,16W,20W and 24W (6M/month)), the buffer solution is replaced at each time point (replaced every 24h exceeding 24 h), the sample is required to be filtered and dried at the observation point, the residual mass mt is recorded, and then the new Tris-HCl buffer solution is replaced, so that data are obtained. The degradation curve of the injectable, wash-resistant self-curable absorbable bone filler material prepared under example 1 (Y1) and comparative example 1 (D1) thus obtained was calculated from the residual mass% = (m _t/m₀) ×100%.

As shown in FIG. 7, D1 was degraded slightly faster than Y1 during the first 72h of soaking in Tris-HCl solution, because Y1 contained sodium carboxymethylcellulose, which served as plasticizer/stabilizer in the earlier stage of soaking, ca ²⁺ and Si ⁴⁺ etc. were not dissolved out as much as D1 solution in the sample. Whereas during 72h to 24W, the degradation rate of Y1 is slightly faster because sodium carboxymethylcellulose is substantially eluted at the early stage of soaking, so that Y1 is formed into a microporous structure throughout the body, which is capable of increasing the specific surface area of Y1, and the amounts of inorganic components Ca ²⁺ and Si ⁴⁺ etc. eluted from Y1 are much larger than D1 in microcosmic scale; macroscopically, Y1 is degraded faster than D1.

In summary, sodium carboxymethylcellulose dissolves out to form a porous/microporous structure throughout Y1, which is beneficial for the formation of later-stage new bone, and this particular structure facilitates cell crawling, neovascular and new bone tissue ingrowth.

Comparative example 2

(1) 1.6G of porous bioactive glass derived by sol-gel method (1.0 g of 0.5-200 μm and 0.6g of 500-1500 μm), 1.7g of 45S5BG (1.0 g of 300-425 μm and 0.7g of 1700-2360 μm) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid-phase substrate component; (2) Adding 1g of sodium carboxymethyl cellulose into a beaker containing 99g of normal saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

Comparative example 3

(1) 1.6G of porous bioactive glass derived by sol-gel method (1.0 g of 300-425 μm and 0.6g of 1700-2360 μm), 1.7g of 45S5BG (1.0 g of 0.5-200 μm and 0.7g of 500-1500 μm) and 2.3g of calcium sulfate hemihydrate are fully and uniformly mixed to obtain a solid phase substrate component; (2) Adding 1g of sodium carboxymethyl cellulose solution into a beaker containing 99g of physiological saline, and vigorously stirring until the solution is clear to obtain a solidified solution; (3) Weighing 5.6g of solid-phase substrate component and mixing with 4.2g of curing liquid, and uniformly stirring to obtain the injectable and washable self-curing absorbable bone filler.

To evaluate the degradation rates of the bone filler materials prepared under comparative example 2 and comparative example 3. As the degradation rate of the bone filler prepared in evaluation example 1, the in vitro soaking in Tris-HCl buffer solution was used for evaluation. Thus, degradation curves of the injectable, wash-resistant self-curable absorbable bone filler materials prepared under comparative example 2 (D2) and comparative example 3 (D3) were obtained.

As can be seen from fig. 8, the residual mass of D2 and D3 at 12W was 55.8388 ± 3.5698% and 51.1235 ± 5.3684%, respectively, which did not match the clinical bone healing time rate (around 12W). In contrast, Y1 has a residual mass of 5.3649 ± 5.3659% (few) at 12W, which matches the rate of bone healing in the clinic.

Therefore, the bone filling material provided by the invention has the advantage that the degradation rate of the bone filling material is matched with the growth rate of new bone of human body through the matching of the 45S5BG with large and small particle sizes and the porous bioactive glass. And if the two bioactive glass and the large and small particle size are adopted, the particle size range of the small-particle-size active glass is not 0.5-200 mu m or the particle size range of the large-particle-size active glass is not 500-1500 mu m, the in-vitro degradation rate is not matched with the clinical bone healing rate, so that the healing of bone tissues is influenced, and the effect is poor.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The self-curing absorbable bone filler is characterized by comprising a solid phase substrate component and a curing liquid, wherein the solid phase substrate component comprises, by weight, 45-50 parts of calcium sulfate hemihydrate and 50-55 parts of bioactive glass; the curing liquid comprises, by weight, 0.5-2 parts of sodium carboxymethylcellulose and 98-99.5 parts of physiological saline; the bioactive glass is a combination of 45S5BG and porous bioactive glass; the 45S5BG consists of 45S5BG with the particle size of 0.5-200 mu m and 45S5BG with the particle size of 500-1500 mu m, and the porous bioactive glass consists of porous bioactive glass with the particle size of 0.5-200 mu m and porous bioactive glass with the particle size of 500-1500 mu m; the self-curing absorbable bone filler material further comprises 5-10 parts of antibacterial components;

the mass ratio of the porous bioactive glass to 45S5BG is 1:1-100;

the mass ratio of 45S5BG with the particle size of 500-1500 mu m to 45S5BG with the particle size of 0.5-200 mu m is 1:1-100; the mass ratio of the porous bioactive glass with the particle size of 500-1500 mu m to the porous bioactive glass with the particle size of 0.5-200 mu m is 1:1-100;

45S5BG is prepared by the following method: the laboratory mixes the calcium source, the silicon source, the phosphorus source and the sodium source powder uniformly, and places the mixture in a platinum crucible, and the high-temperature muffle furnace is provided with the procedures: heating to 300 ℃ at 0.5 ℃/min, heating to 1400 ℃ at 3 ℃/min, preserving heat for 2 hours, melting glass to be in a yellow-red liquid state, pouring the melted glass into cold water, quenching to obtain 45S5BG coarse particles, placing the coarse particles in a ball milling tank, adding ball mill, and grinding to obtain 45S5BG;

the porous bioactive glass is prepared by the following steps: at room temperature, 4.0g of polyether P123 and Mn of 5800 are dissolved in 60g of ethanol, 1.0g of 0.5M HCl solution is added, 6.7g of tetraethyl orthosilicate, 0.73g of triethyl phosphate and 1.4g of calcium nitrate tetrahydrate are added, the mixture is mixed and stirred for 24 hours, the mixture is poured into a glass plate for standing, the solvent ethanol volatilizes, hydrolyzed SiO ₂ in the solvent is polymerized by polycondensation to form gel blocks, the gel blocks are placed in an oven for drying at 60 ℃ for 48 hours, the ground dry gel blocks are placed in a crucible, and the crucible is placed in a muffle furnace for heating to 650 ℃ for 2 hours to obtain the porous bioactive glass.

2. The self-curing resorbable bone filler material of claim 1 wherein said antimicrobial component comprises any one or a combination of at least two of gentamicin, vancomycin, or rapamycin.

3. The self-solidifying absorbable bone filler of claim 1, wherein the ratio of solidifying liquid to solid phase base component is 0.4 mL/g-1 mL/g.

4. Use of the self-curing resorbable bone filler material according to any one of claims 1-3 for the preparation of a bone injury repair medical device.