TWI587881B - Self-setting biodegradable bioactive bone graft putty material and application thereof - Google Patents

Description

Self-curing degradable bioactive paste bone repair material and application

The invention relates to the field of medical biomaterials, in particular to a self-curing degradable bioactive paste bone repairing material and application.

With the development of biotechnology, the medical device industry, especially orthopedic medical device technology and industry, is booming. At present, in orthopedic vertebral body formation surgery and knee hip joint replacement surgery, bone cement is required to fix the mechanical support or the replacement body. Vertebroplasty surgery in China from less than 20,000 operations per year from 2010 to 120,000 operations in 2015, is expected to increase by 15% per year. Vertebral body formation surgery is a fracture of the vertebral body of the victim patient due to various reasons, resulting in pain and failure to operate normally. The collapsed vertebral body must be propped up by surgery to slowly restore the normal function of the spine and relieve the patient's pain. In knee and hip replacement surgery, bone cement is used to fix artificial knees and hip handles, and there are no less than one million operations in China each year. In these procedures, bio-inert bone cement is used to fill the collapsed vertebral body at home and abroad, or to fill the defect to fix the artificial knee and the hip handle. The chemical name is polymethyl methacrylate. ), codenamed PMMA. Inert bone cement can be quickly formulated into the vertebral body by initial blending into a paste, and has strength to support and fix. These operations are very mature. In particular, vertebral body shaping surgery is a typical modern minimally invasive surgery. Without a knife, a dose of paste is injected into the collapse of the vertebral body fracture. Within a few hours, the patient can leave the hospital and go home to recuperate. But the biggest problem is that the inert bone cement does not degrade, It does not fuse with bone tissue. After a few years, like a hard stone exists in the patient's body, it will have a destructive effect on the surrounding tissue, and there is a possibility that the vertebral body will collapse again. Based on this shortcoming, orthopedic doctors are usually more cautious about young or middle-aged patients with vertebral fractures. They will try to avoid using inert bone cement and other complicated surgical procedures to avoid future problems caused by inert bone cement.

At present, inert knee cement is required to fix artificial knee and hip joint replacements in most knee arthroplasty operations. Since the inert bone cement does not form a bone bond with the bone tissue, the joint body that is loosened and replaced in a fixed manner for about ten years needs to be re-repaired, resulting in a larger defect.

The ideal bone cement repair material should be a paste dosage form, which can be pushed to the best; it can establish a certain mechanical strength by solidification in a reasonable time; based on the clinical application in orthopedic surgery, within 20 minutes after 10 minutes Coagulation is ideal; thus, giving the surgeon a certain amount of time for surgical preparation and operation, and rapid solidification after the bone cement repair material is placed in the filled defect; the bone cement repair material is placed in the filled defect After a certain period of time, such as 2 weeks to achieve a compressive strength of at least 20MPa; it is particularly important that the ideal bone cement repair material must have biological activity and osteoconductivity, and can slowly degrade, such as 2 to 3 years completely Degradation, can not degrade too fast, otherwise it can not achieve the supporting effect; it can not be degraded, otherwise it will become a hard stone; while slowly degrading, the material will guide the growth of the body bone by biological activity and osteoconductivity, and finally, bone cement repair When the material is completely degraded, it is completely replaced by the growing body bone. So far, there is no such ideal material and product to replace traditional inert bone cement in vertebroplasty, knee and hip replacement surgery and other orthopedic surgery.

Bioactive glass materials are the most biologically active materials in synthetic bone repair materials. The artificial bone repair products developed by bioactive glass materials have been successfully applied in orthopedic clinics in the world and in China for more than 20 years. It is currently the only product approved by the US FDA with Osteostmulation, which promotes the proliferation and growth of bone cells and activates bones. The gene expression of the cell accelerates the formation of new bone. Currently, bioactive glass products are in the form of granules, blocks and pastes, but they do not solidify to withstand gravity loads. When the bioactive glass of less than 50 μm is mixed with the liquid, the binding energy of the Si—O bond and the water hydrogen bond is solidified by the surface reaction, but the solidification strength is very weak.

Calcium sulfate is also commonly used as a material for bone repair. Calcium sulphate is mixed with the liquid to solidify in a few minutes, but the strength is not ideal. The main disadvantage is that the degradation rate of calcium sulfate is too fast, and most of the degradation may be lost within 3 months and the support at the collapse defect is lost.

Tricalcium citrate is the main chemical component of the famous Portland cement. It is characterized by its ability to solidify into a material with high strength and can be used as a building material. However, the disadvantage is that the solidification time is longer, and it usually takes more than 1 hour to solidify. This is not practical in the clinic. However, structural stability and high mechanical strength over a long period of time are required as load-bearing bone repair materials such as for vertebroplasty, knee and hip replacement surgery, and certain fracture repairs.

The technical problem mainly solved by the invention is to provide a bioactive paste bone repairing material and application thereof, and adopting a biologically active glass-calcium sulfate hemihydrate-tricalcium ternate system, which has better ideal self-curing absorbability. It can be used as an alternative material for bone repair in vertebral body shaping surgery, knee hip replacement surgery and other fracture operations.

In order to solve the above technical problem, the present invention adopts a technical solution to provide a self-curing degradable bioactive paste bone repair material, including a mixed solid material and a liquid phase, the mixed solid material including bioactive glass, hemihydrate sulfuric acid. Calcium and tricalcium citrate, the liquid phase comprising a blending liquid.

In a preferred embodiment of the present invention, the composition of the mixed solid material comprises: 15%-30% by weight of bioactive glass, 30%-45% of calcium sulfate hemihydrate, and citrate three Calcium 30%-40%; the mixing ratio of the mixed solid material to the liquid phase is 1g: 0.3ml-1g: 0.8ml; the particle diameter of the bioactive glass is 100μm or less, the calcium sulfate hemihydrate The particle diameter is 100 μm or less, and the particle size of the tricalcium citrate is 100 μm or less.

In a preferred embodiment of the present invention, the composition of the mixed solid material comprises: 27% of bioactive glass, 41.5% of calcium sulfate hemihydrate, and 31.5% of tricalcium citrate; and the mixed solid material and The blending ratio of the liquid phase was 1 g: 0.5 ml.

In a preferred embodiment of the invention, the bioactive glass is a bioactive glass having a composition of 45S5.

In a preferred embodiment of the invention, the solution is one or more of physiological saline, deionized water, and inorganic salt solution.

In a preferred embodiment of the invention, the inorganic salt solution is one or more of a carbonate solution, a calcium chloride solution, and a phosphate solution.

In a preferred embodiment of the present invention, the self-cure degradable bioactive paste bone repair material has a setting time of 10-20 minutes; the self-cure degradable bioactive paste bone repair material is in a biological environment. The mechanical strength is gradually enhanced; the self-cure degradable bioactive plaster bone repair material has a slow degradability.

In a preferred embodiment of the invention, the self-cure degradable bioactive cream bone repair material is applied in a bone defect filling procedure.

In a preferred embodiment of the present invention, the self-cure degradable bioactive plaster bone repair material is applied in orthopedic vertebral body shaping surgery and knee hip joint replacement surgery.

In a preferred embodiment of the present invention, the self-cure degradable bioactive paste bone repair material can be directly conditioned with the antibiotic when used, while maintaining the pharmacodynamic effect without affecting the setting time and strength; preferably, The antibiotic is a gentamicin liquid.

The beneficial effects of the invention are:

1. Ternary Mixture Composition The increased biological activity due to the presence of bioactive glass is the osteogenicity of the bone repair material.

2. The introduction of bioactive glass accelerates the solidification time of the system composition.

3. Due to the presence of tricalcium citrate in the system composition, in a liquid environment, tricalcium citrate will continue to react for several months and will increase the strength of the solidified body. This feature is critical to the final bone repair material for load applications.

4. At the beginning of this century, a large number of clinically proven antibiotics were introduced into bone cement to prevent infection in the early stage of surgery, and the rate of revision after surgery was significantly reduced. Since the conventional inert bone cement is reconciled with an organic solution, the antibiotic must be added to the powder in advance, which affects both the efficacy and the curing time. The invention adopts the aqueous solution to adjust the ternary mixture, and can be directly used in the use of the antibiotic aqueous solution to be blended, which can conveniently store and preserve the drug and the drug without affecting the time and strength of the coagulation reaction.

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly described below. It is obvious that the drawings in the following description are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained according to the drawings without paying for the labor of the drawings. FIG. 1 is a schematic view of the paste of the present invention; FIG. Is the infrared spectrum of the paste of the present invention after reacting in the human body solution for 1 day, 3 days, and 7 days after self-curing; FIG. 3 is a graph showing the change of the compressive strength of the paste according to the present invention with the reaction time; FIG. Is a model diagram of the experiment of the present invention for animal experiments; FIG. 5 is a histological diagram of the paste of the present invention implanted into the rabbit tibia defect for 3 months; Figure 6 is a graph showing the osseointegration rate of the paste implanted into the rabbit's tibia defect, i.e., the area percentage of the material that forms a bone bond with the bone tissue.

The technical solutions in the embodiments of the present invention will be clearly and completely described below. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without departing from the scope of the present invention are within the scope of the present invention.

A self-curing degradable bioactive cream bone repair material is provided, including bioactive glass, calcium sulfate hemihydrate, tricalcium citrate, and a solution.

The self-cure degradable bioactive paste bone repair material, that is, the bioactive glass-calcium sulfate hemihydrate-tricalcium citrate ternary system solidification reaction mechanism is as follows.

When the ternary mixture is mixed with water and mixed into a paste, the following three reactions will be carried out:

(1) The surface of the bioactive glass particles rapidly reacts with water to release calcium and barium ions.

(2) The surface of the tricalcium citrate particles first dissolves when it encounters water. At this time, calcium strontium ions are accumulated in the water between the voids of the particles to saturation, and deposition of a new phase occurs. The sediment is Calcium-Silicate-Hydrate gel (or CSH), and the reaction formula is: 2 Ca ₃ SiO ₅ +7 H ₂ O→3 CaO. 2 SiO ₂ . 4 H ₂ O+3 Ca(OH) ₂ . This process is called the hydration-deposition reaction process. The concentration of ions in the water after deposition is lowered so that the hydrolysis proceeds and then hydrolyzed after deposition, so that the hydration-deposition reaction is continuously carried out repeatedly.

(3) The reaction of calcium sulphate hemihydrate particles after water contact is similar to that of tricalcium citrate, but it is considered to be more rapid. The reaction formula is: CaSO ₄ . 1/2H ₂ O+3/2H ₂ O→CaSO ₄ . 2H ₂ O. First, the hydration reaction ion product will rapidly precipitate and crystallize into the stable phase-calcium sulfate dihydrate in the surrounding surface and the voids of the particles.

The hydration-deposition reaction in reactions (2) and (3) is a dynamic continuous process, the reaction is continued until the moisture content is reduced, and the new deposition phase fills the interparticle voids so that the density increases and the strength increases to achieve solidification. The basic reaction principle of self-curing solidification. The difference is that the calcium sulfate hemihydrate reacts quickly and reaches the final setting state in 7 minutes. The tricalcium citrate reaction is slower and usually takes more than 60 minutes to reach final setting.

When the above three reactions occur simultaneously in the ternary mixed system, the reaction (1), that is, the release of calcium and barium ions on the surface of the bioactive glass particles will greatly accelerate the speed of the reaction (2) and the reaction (3), that is, Accelerate the formation of the hydrated calcium citrate gel phase and the calcium sulfate dihydrate crystal phase. The formation of these two new phases, on the one hand, occupies the particle gap to increase the density of the material, on the other hand, the new phase formed at the same time is intertwined with the original bioactive glass particles, the tricalcium citrate particles and the calcium sulfate hemihydrate particles. Material strength. This causes the ternary material to solidify faster and the curing time becomes shorter. This feature makes the ternary system more widely applicable.

The bioactive glass used in the present invention is a bioactive glass having a composition of 45S5, and is a composition of a bioactive glass bone repair product commonly used in the world. Calcium hemihydrate hemihydrate and tricalcium citrate were prepared in accordance with the method of Chinese Patent Application No. 200610029067.3. The three components are all particles of 100 μm or less.

The experimental method of the present invention is to thoroughly mix the three materials in different proportions and the bioactive glass according to different particle sizes, and each mixture and the solution are fully conditioned for one minute according to the liquid-solid mass ratio of 0.40-0.7 ml/g, that is, The pushable paste we have described. The solution used in the present invention is one of a solution of deionized water or an inorganic salt (physiological saline, carbonate, calcium chloride, phosphate, etc.).

The setting time is the most important indicator of the above-mentioned ideal bone cement repair material, and the solidification is ideal within 20 minutes after 10 minutes. Therefore, the test of the coagulation experiment is the most important step in optimizing the composition. Considering that in actual clinical applications, the material will have bleeding in the wound of the surgical wound, In contrast, material solidification experiments were carried out in air and water, respectively. In the water coagulation experiment, the mixture was adjusted to the conditioning solution for 2 minutes, and then the formulation was placed in water to observe the test setting time. The solidification in water is closer to the environment in which the actual clinical application has bleeding.

Coagulation time experimental test method According to the international standard of ISO9597-1989E, the initial setting time (I) and the final setting time (F) of the above-mentioned bone cement paste paste were tested by Vicat instrument. The initial setting time is defined as the time required for the Vicat instrument needle (280g, 1.13mm) to fall vertically to the paste contained in the small tube at a depth of 5 ± 1mm; the final setting time is defined as the Vicat needle (350g, 2.0) Mm) The time required for the mark to be placed in the small tube to be invisible on the surface.

(1) Test of individual solidification characteristics of raw materials.

The blending solution is deionized water, the blending ratio is 1g: 0.5ml, and the solidification condition is in the air:

The blending solution is deionized water and the solidification conditions are in an aqueous solution:

(2) The solidification time test of the ternary system.

The blending solution is deionized water and the solidification conditions are in the air:

The blending solution is deionized water and the solidification conditions are in an aqueous solution:

The blending solution is a CaCl ₂ inorganic salt solution, and the solidification conditions are in an aqueous solution:

Solidification test results: Experiments show that calcium sulfate hemihydrate plays a major role in reducing the setting time. The addition of large particles of bioactive glass did not improve the solidification time of the system, and the addition of small particles (<50 μm) promoted the solidification of the ternary system. The main reason is that the small particles have a large specific surface area and a fast surface reaction, which promotes solidification. According to the above results, it can be found that the serial numbers 18, 19, and 21 are the same composition, and the solidification characteristics thereof are more practical, whether it is blended with water or an inorganic salt solution of CaCl ₂ or solidified in air or in water.

Example 1: The bolus and coagulation test of the self-curing degradable bioactive ointment bone repair material No. 18 was carried out.

3 g of the composition mixture No. 18 was weighed, and 1.5 ml of deionized water was weighed and mixed with the mixture for 60 seconds (harmonization ratio of 0.5 ml/g) to obtain a paste sample. The bolus experimental test method was to inject the sample into a 15 mL-capacity syringe with a nozzle inner diameter (D) of 2.0 mm and test its injectability. The paste can be pushed out of the syringe as shown in Figure 1.

The paste was introduced into a mold of 6-mm diameter x 6-mm height for the setting time. Coagulation time experimental test method According to the international standard of ISO9597-1989E, the initial setting time (I) and the final setting time (F) of the above paste were tested by using a Vicat instrument. Test 3 samples. The table below shows the test results.

Example 2: Bioactivity test of self-curing degradable bioactive paste bone repair material with serial number 18.

Biological activity test method: self-curing bioactive material is blended according to the ratio, the blending solution is deionized water, the blending ratio is 0.5 ml/g, and the blending time is 60 seconds. The prepared paste is then used in a mold: 6-mm diameter x 2-mm height, and solidified into a wafer. The number of samples is 3. When the SBF was soaked, the wafers were suspended in SBF according to the sample surface area/solution volume = 0.1 cm ^-1 , and reacted in an environment of 37 ° C. The reaction was 1 day, 3 days and 7 days. The reaction samples were subjected to FTIR infrared reflectance spectroscopy for surface testing. The appearance of the reflection peaks of 574 cm ^-1 and 608 cm ^-1 will indicate the formation of hydroxyapatite, indicating that the material is biologically active. The test results are shown in Figure 2.

Example 3: Compressive strength test of self-curing degradable bioactive paste bone repair material with serial number 18.

Mechanical compressive strength test method: The new self-curing bioactive product sample is determined by SBF quasi-human solution soaking reaction for different time to determine the compressive strength change. The self-curing bioactive material is blended according to the ratio, the blending solution is deionized water, the blending ratio is 0.5 ml/g, and the blending time is 60 seconds. The prepared paste is then used in a mold: 6-mm diameter x 12-mm height, and solidified into a cylinder. The number of samples is 30. When soaking SBF, change the liquid every day, and suspend the cylinders in SBF according to the sample surface area/solution volume = 0.1 cm ^-1 , and react in an environment of 37 ° C. The reaction was at 6 time points, each time point was a group, the samples were divided into 6 groups, and each group was tested 5 samples. The six time points are: 1 hour, 2 hours, 8 hours, 1 day, 3 days, and 7 days. The statistical results of each set of test results were averaged and the positive and negative differences were calculated. The results of compressive strength as a function of reaction time are shown in the following table and in Figure 3.

Example 4: Animal experiment of self-curing degradable bioactive paste bone repair material with serial number 18.

New Zealand white rabbits used 2-3 kg for animal experiments. The defect model was the distal femur condyle tibia, 6 mm x 10 mm, as shown in Figure 4. Histological observations after 3 months of implantation are shown in Figure 5. Figure 5 shows the histology of the 18th paste implanted into the rabbit's tibia defect 3 months later. From the picture, the material generally retains its shape characteristics (the implant is a cylindrical block), there is no obvious crack inside the material, no obvious particle peeling on the surface of the material, the material edge is white, and the surface active reaction is formed. The porous phase indicates the start of the dissolution absorption reaction. Explain how the material is degraded Can be mainly absorbed from the outside to the inside. During the dyeing process, it was found that the inside of the material was dyed blue and the ethanol was not washed away. Observing the surface of the material revealed significant new bone formation. Figure 6 shows the osseointegration rate of the material after implantation, that is, the percentage of the area where the material forms a bone bond with the bone tissue. This indicates that the material surface and bone tissue exhibit a good bone bond. The usual bioactive bone repair materials show significant degradation at 3 months. The preferred composition of the present invention No. 18 exhibited degradation on the surface at 3 months but the material substantially retained its shape, indicating a very slow rate of degradation. This is a paste which can be solidified and can bear the load and is biologically active, which will slowly degrade, guide the formation of bone tissue, and finally be replaced by the body bone tissue, which is the most ideal bone repair product.

The invention discloses a pushable self-curing degradable bioactive paste bone repairing material formed by a bioactive glass-calcium sulfate hemihydrate-tricalcium ternate system, which can be used instead of the currently used inert bone cement. Orthopedic vertebral body surgery, knee and hip replacement surgery, and other fracture defect filling procedures. The new generation of bone cement repairing material provided by the invention can solidify in a reasonable time and gradually establish a certain mechanical strength. Of particular importance is the new generation of bone cement repair materials that accelerate the setting time due to the introduction of bioactive glass, enhancing bioactivity and osteoconductivity as well as slow degradation. At the same time of slow degradation, the material will guide the growth of the body bone by biological activity and osteoconductivity. Finally, when the bone cement repair material is completely degraded, the grown body bone is completely replaced. Another important point is that this new generation of bone cement repair material, unlike other traditional bone cements, can be directly blended with antibiotics (such as gentamicin) and has no significant effect on solidification time and mechanical strength. The antibiotic is introduced into the system for sustained release to prevent infection at the wound site.

The inventors of the present invention have patented and disclosed a self-curing bioactive material composited with a calcium sulfate hemihydrate/tricalcium citrate system, a preparation method thereof and application thereof, and the specific application numbers are 200610029067.3 and 200810204780.6. In order to develop a more ideal bone cement repair material, the present invention introduces a biologically active glass with the most biological activity and the fastest osteogenicity and has been successfully applied clinically for more than 20 years, which is coded as 45S5, making it a biological activity. Glass-semi-sulfur Calcium acid-tricalcium ternate system. Due to the introduction of micron bioactive glass particles, the new material solidification time will be practical, the degradation rate will be improved, and the biocompatibility and osteogenic properties will be improved. A more desirable self-curing self-cure absorbable plaster cement repair material can be used as an alternative to bone repair for vertebral body shaping surgery, knee hip replacement surgery, and other fracture operations.

The above is only the embodiment of the present invention, and thus does not limit the scope of the patent of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the specification of the present invention, or directly or indirectly applied to other related technical fields, The same is included in the scope of patent protection of the present invention.

Claims (9)

A self-cure degradable bioactive paste bone repair material comprising: a mixed solid material comprising bioactive glass, calcium sulfate hemihydrate and tricalcium citrate; and a liquid phase comprising a blending liquid, wherein the self-cure degradable The bioactive plaster bone repair material can be directly conditioned with an antibiotic liquid while being used, while maintaining the efficacy without affecting the setting time and strength. The self-cure degradable bioactive cream bone repair material according to claim 1, wherein the composition of the mixed solid material comprises: 15%-30% by weight of bioactive glass, 30% calcium sulfate hemihydrate by weight percentage - 45% and tricalcium citrate 30%-40%; the mixing ratio of the mixed solid material to the liquid phase is 1g: 0.3ml-1g: 0.8ml; the particle size of the bioactive glass is less than or equal to 100μm; The particle size of the calcium sulfate hemihydrate is 100 μm or less; and the particle size of the tricalcium citrate is 100 μm or less. The self-cure degradable bioactive paste bone repair material according to claim 2, wherein the composition of the mixed solid material comprises: 27% by weight of the bioactive glass, and 41.5% of the calcium sulfate hemihydrate by weight percentage. % and the tricalcium citrate 31.5%; and the blending ratio of the mixed solid material to the liquid phase is 1 g: 0.5 ml. The self-curing degradable bioactive cream bone repair material according to any one of claims 1 to 3, wherein the bioactive glass is a bioactive glass having a composition of 45S5. The self-cure degradable bioactive cream bone repair material according to any one of claims 1 to 3, wherein the solution is one or more of deionized water and an inorganic salt solution. The self-curing biodegradable bioactive plaster bone repair material according to claim 5, wherein the inorganic salt solution is one or more of a carbonate solution, a calcium chloride solution, a phosphate solution, and a physiological saline. The self-curing biodegradable bioactive paste bone repair material according to claim 1, wherein the self-curing biodegradable bioactive paste bone repair material has a setting time of 10-20 minutes; the self-cure degradable The mechanical strength of the bioactive plaster bone restorative material is gradually enhanced in a biological environment; and the self-curing degradable bioactive plaster bone repair material has a slow degradability. The self-curing biodegradable bioactive plaster bone repair material according to claim 1, wherein the self-curing degradable bioactive plaster bone repair material is applied in a bone defect filling operation. The self-cure degradable bioactive paste bone repair material according to claim 8, wherein the self-cure degradable bioactive paste bone repair material is applied in orthopedic vertebral body shaping surgery and knee hip joint replacement surgery.