WO2018006618A1

WO2018006618A1 - Self-hardening degradable bioactive bone repair material paste and use thereof

Info

Publication number: WO2018006618A1
Application number: PCT/CN2017/076980
Authority: WO
Inventors: 钟吉品
Original assignee: 盐城倍尔生生物科技有限公司
Priority date: 2016-07-05
Filing date: 2017-03-16
Publication date: 2018-01-11
Also published as: CN106075565B; TW201801756A; CN106075565A; TWI587881B

Abstract

Provided is a self-hardening degradable bioactive bone repair material in the form of a paste, comprising: a bioactive glass material, calcium sulfate hemihydrate, tricalcium silicate and a blending liquid. The bone repair material can substitute for polymethylmethacrylate (PMMA) and is applied in orthopedic procedures including vertebroplasty, knee and hip replacement procedures and other procedures for filling bone fractures and defects. The bone repair material can be directly mixed with an antibiotic.

Description

Self-curing degradable bioactive paste bone repair material and application

Technical field

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

Background technique

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. Vertebroplasty is the pain caused by the fracture of the vertebral body of the victim patient due to various reasons, and the normal operation of the vertebral body. The collapsed vertebral body must be propped up by surgery to slowly restore the spine to normal work 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 for filling the collapsed vertebral body or filling the defect in the international and domestic countries for many years. 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, vertebroplasty is a typical modern minimally invasive surgery. There is no need to open 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 to the hospital to recover. But the biggest problem is that the inert bone cement does not degrade and does not fuse with the 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, this inert bone cement is required to fix artificial knee and hip joint replacements in most knee hip replacement surgery. Because inert bone cement does not form a bone bond with bone tissue, generally in a decade or so If the fixation will be loose and the replacement of the joint body needs to be repaired again, it will produce 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, the surgeon is given time to perform surgical preparation and operation, and can be rapidly solidified 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 reach the supporting effect; it can not become a hard stone without degradation; while slowly degrading, the material will guide the growth of the body bone by biological activity and osteoconductivity, and finally, the bone cement repair material When fully 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 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 gene expression of bone cells, thus accelerating 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 silicate 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. But the structure remains stable over a longer period of time. High mechanical strength is required as a load-bearing bone repair material such as for vertebroplasty, knee and hip replacement surgery, and certain fracture repairs.

Summary of the invention

The main technical problem to be solved by the present invention is to provide a bioactive paste bone repairing material and application thereof, which adopts a bioactive glass-calcium sulfate hemihydrate-tricalcium silicate system, which has a more ideal self-curing absorption. Sexuality 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 and semi-aqueous water. Calcium sulfate and tricalcium silicate, 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 30% of tricalcium silicate. 40%; the blending ratio of the mixed solid material to the liquid phase is 1 g: 0.3 ml-1 g: 0.8 ml; the particle diameter of the bioactive glass is 100 μm or less, and the particle size of the calcium sulfate hemihydrate is less than or equal to 100 μm, the particle size of the tricalcium silicate is 100 μm or less.

In a preferred embodiment of the present invention, the composition of the mixed solid material comprises: 27% by weight of bioactive glass, 41.5% of calcium sulfate hemihydrate, and 31.5% of tricalcium silicate; 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 present invention, the inorganic salt solution is a carbonate solution, a calcium chloride solution, One or more of the phosphate solutions.

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 silicate in the system composition, in the liquid environment, the tricalcium silicate will continue to react for several months, and the strength of the solidified body will continue to increase. 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 inert bone cement is blended with an organic solution, the antibiotic must be added to the powder in advance, which affects both the efficacy and the curing time. However, the present invention uses an aqueous solution to reconcile the ternary mixture, and can be directly used in an aqueous solution of an antibiotic solution during use, which is more convenient. The storage and preservation of the drug and the medicinal properties do not affect the time and intensity of the coagulation reaction.

DRAWINGS

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 these drawings without any creative work, wherein:

Figure 1 is a schematic illustration of a pushable shot of the paste of the present invention;

2 is a reaction of the present invention after self-curing in a human body solution for 1 day, 3 days, and 7 days;

Infrared spectra;

Figure 3 is a graph showing the results of the compressive strength of the paste of the present invention as a function of reaction time;

Figure 4 is a model diagram of the paste of the present invention for animal experiments;

Figure 5 is a histological diagram of the plaster of the present invention implanted into the rabbit tibia defect for 3 months;

Figure 6 is a view showing the osseointegration rate of the paste implanted into the rabbit tibia after the paste of the present invention, that is, the material and the bone tissue form bone

A graph of the area percentage of sexual association.

detailed description

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 creative efforts are within the scope of the present invention.

A self-cure degradable bioactive ointment bone repair material is provided, including bioactive glass, calcium sulfate hemihydrate, tricalcium silicate, and a solution.

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

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

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

(2) The surface of the tricalcium silicate particles first dissolves when it encounters water. At this time, calcium and silicon ions are accumulated in the water between the voids of the particles to saturation, and a new phase deposition 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 decrease in the ion concentration in the water after deposition causes the hydrolysis to proceed and then the deposition will occur again, so that the hydration-deposition reaction proceeds continuously.

(3) The reaction of calcium sulphate hemihydrate particles after water contact is similar to that of tricalcium silicate, 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 silicate 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 silicon 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 silicate 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 silicate 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, which is currently international The composition of commonly used bioactive glass bone repair products. Calcium sulfate hemihydrate and tricalcium silicate are prepared according to 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 tempered for 1 minute at a liquid-solid mass ratio of 0.40-0.7 ml/g, that is, Get the pushable paste we have described. The solution used in the present invention is one of a solution of physiological saline, deionized water, inorganic salts (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. As a comparison, the 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) Raw material individual solidification characteristics test

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) Solidification time test of ternary system

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

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

Solidification experiment results:

Experiments have shown 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 the solidification. According to the above results, it can be found that the serial numbers 18, 19, and 21 are the same composition, and whether it is conditioned with water or an inorganic salt solution of CaCl ₂ or condensed in air or water, the solidification property of the solid exhibits an ideal practicability.

Embodiment 1:

Bolus and coagulation test of self-curing degradable bioactive ointment bone repair material No. 18:

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 following table shows the test results:

Embodiment 2:

Bioactivity test of self-curing degradable bioactive ointment bone repair material No. 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 °. 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.

Embodiment 3:

Compressive strength test of self-curing degradable bioactive paste bone repair material No. 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 the SBF, change the liquid every day, and suspend the cylinders in the SBF according to the sample surface area/solution volume = 0.1 cm ^-1 and react in an environment of 37 °. The reaction was at 6 time points, each time point was a group, the samples were divided into 6 groups, and 5 samples were tested in each group. 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.

Embodiment 4:

Animal experiment with self-curing degradable bioactive paste bone repair material No. 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. It indicates that the degradation mode of the material may be mainly absorbed by the outward inward dissolution. 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 percentage of the bone binding rate after material implantation, that is, the area where the material forms bone binding 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 optimum composition of the present invention No. 18 showed 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 silicate ternary system, which can be used instead of the commonly used inert bone cement. For orthopedic vertebral body surgery, knee and hip replacement surgery and other fracture defect filling operations. This new generation of bone cement repair material can establish a certain mechanical strength by solidification in a reasonable time. Of particular importance is the fact that this new generation of bone cement repair materials accelerates clotting 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, and finally, the bone cement repair material will drop completely. When the solution is solved, it is completely replaced by the growing body bone. 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 liquid, with 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.

One of the inventors of the present invention has reported a self-curing bioactive material composited with a calcium sulfate hemihydrate/tricalcium silicate system, a preparation method thereof, and its application, and the specific application numbers are 200610029067.3 and 200810204780.6. In order to develop a more ideal bone cement repairing material, the present invention introduces the bioactive glass with the most biologically active osteogenicity and has been successfully applied for more than 20 years in clinical practice, which is coded as 45S5, making it a bioactive glass- Calcium sulfate hemihydrate - tricalcium silicate ternary 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

A self-curing degradable bioactive paste bone repairing material, comprising: a mixed solid material comprising a bioactive glass, calcium sulphate hemihydrate and tricalcium silicate, said liquid phase Includes blending fluid.
The self-cure degradable bioactive paste bone repair material according to claim 1, wherein the composition of the mixed solid material comprises: 15%-30% by weight of bioactive glass, calcium sulfate hemihydrate 30%-45%, tricalcium silicate 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 100 μm, the particle size of the calcium sulfate hemihydrate is 100 μm or less, and the particle size of the tricalcium silicate 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 biologically active glass, 41.5% of calcium sulfate hemihydrate, Tricalcium silicate 31.5%; the blending ratio of the mixed solid material to the liquid phase is 1 g: 0.5 ml.
The self-curing degradable bioactive paste 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 paste bone repair material according to any one of claims 1 to 3, wherein the solution is one or more of physiological saline, deionized water, and inorganic salt solution.
The self-cure degradable bioactive paste bone repair material according to claim 5, wherein the inorganic salt solution is one or more of a carbonate solution, a calcium chloride solution, and a phosphate solution.
The self-cure degradable bioactive paste bone repairing material according to claim 1, wherein the self-curing biodegradable bioactive plaster bone repairing material has a setting time of 10-20 minutes; The mechanical strength of the degraded bioactive paste bone repair material in the biological environment is gradually enhanced; the self-cure degradable bioactive paste bone repair material has a slow degradability.
The self-cure degradable bioactive paste 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 performed in orthopedic vertebral body shaping surgery and knee hip joint replacement surgery. application.
The self-cure degradable bioactive paste bone repair material according to claim 1, wherein the self-cure degradable bioactive paste bone repair material can directly reconcile with the antibiotic when used, while maintaining the efficacy The nature does not affect the setting time and strength; preferably, the antibiotic is a gentamicin liquid.