阅读说明：本技术 一种具备组织自粘结性能的可注射骨水泥及制备方法与应用 (Injectable bone cement with tissue self-bonding performance and preparation method and application thereof ) 是由 于涛 钟伟彬 周长忍 于 2019-09-23 设计创作，主要内容包括：本发明提供了一种具备组织自粘结性能的可注射骨水泥及制备方法与应用。本发明的固化液在水化前期通过柠檬酸维持氧化海藻酸钠的醛基活性的同时,适当地避免醛基跟钙离子螯合,当水化进行到一定程度时,所述的醛基与组织、血液中的氨基发生键合产生粘合力,以提高材料的抗溃散性；同时加强材料与组织之间的整合性,提高界面强度。由所述的固化液组成的具备组织自粘结性能的可注射骨水泥通过科学巧妙地设计,使其中的组分在水化、固化过程中有机地协同配合,实现了组织与材料之间的粘结,并改善材料本身的抗溃散性能及其促水化性能,具有优异的可注射性、可塑性及促骨组织粘结性,可应用于骨损伤修复医用材料的制备中,具有良好的应用前景。(The invention provides injectable bone cement with tissue self-bonding performance, and a preparation method and application thereof. The solidification liquid disclosed by the invention maintains the aldehyde group activity of oxidized sodium alginate through citric acid in the early stage of hydration, and simultaneously properly avoids aldehyde groups from being chelated with calcium ions, and when the hydration is carried out to a certain degree, the aldehyde groups are bonded with amino groups in tissues and blood to generate adhesive force so as to improve the collapsibility resistance of the material; meanwhile, the integration between the material and the tissue is enhanced, and the interface strength is improved. The injectable bone cement with tissue self-bonding performance, which is composed of the curing liquid, is scientifically and skillfully designed, so that the components in the injectable bone cement are organically and cooperatively matched in the hydration and curing processes, the bonding between tissues and materials is realized, the anti-collapsibility and the hydration promotion performance of the materials are improved, and the injectable bone cement has excellent injectability, plasticity and bone tissue bonding promotion performance, can be applied to the preparation of medical materials for repairing bone injury and has good application prospect.)

1. A curing fluid suitable for calcium phosphate-based bone cement, comprising:

solution A: a mixed solution containing citric acid and disodium hydrogen phosphate;

and B, liquid B: oxidizing the sodium alginate solution.

2. The setting fluid for calcium phosphate-based bone cement according to claim 1, wherein:

the molecular weight of the oxidized sodium alginate is 1000-200000;

the oxidized sodium alginate is oxidized sodium alginate with low oxidation degree;

the liquid A and the liquid B are proportioned according to the volume ratio of 1: 1.

3. The setting fluid for calcium phosphate-based bone cement according to claim 1, wherein:

in the solution A, the concentration of the citric acid is 0.2 mol/L; the concentration of the disodium hydrogen phosphate is 10 wt%;

the concentration of the oxidized sodium alginate in the solution B is 2 to 24 weight percent;

the oxidized sodium alginate is obtained by reacting sodium alginate with soluble periodate;

the oxidation degree of the oxidized sodium alginate is 25-35%.

4. The setting fluid for calcium phosphate-based bone cement according to claim 3, wherein:

the soluble periodate is sodium periodate;

the molar ratio of the sodium alginate to the periodate is 1: 1.

5. A preparation method of injectable bone cement with tissue self-bonding performance is characterized in that:

the calcium phosphate-based bone cement is prepared by blending the calcium phosphate-based bone cement with the curing liquid suitable for calcium phosphate-based bone cement as defined in any one of claims 1 to 4.

6. The method for preparing injectable bone cement with tissue self-binding properties according to claim 5, characterized in that:

adding the solution A in the curing solution suitable for the calcium phosphate-based bone cement, and then adding the solution B;

the calcium phosphate-based bone cement and the curing liquid suitable for the calcium phosphate-based bone cement are blended according to the solid-liquid ratio of 0.6 mL/g.

7. An injectable bone cement with tissue self-bonding performance is characterized in that:

the injectable bone cement with tissue self-binding property of claim 5 or 6.

8. The injectable bone cement with tissue self-bonding properties according to claim 7, wherein the injectable bone cement with tissue self-bonding properties has one or more of the following characteristics:

(1) bone tissue adhesion promoting performance: filling the just prepared composite bone cement into the bone defect part until 2min before coagulation, wherein the maximum extrusion stress is 5-50N;

(2) the injection rate is as follows: 41 to 71 percent;

(3) setting time: 18-93 minutes;

(4) compressive strength: and after curing for 2 days, the compressive strength is more than 12 MPa.

9. Use of the curing fluid for calcium phosphate-based bone cement according to any one of claims 1 to 4 and/or the injectable bone cement with tissue self-adhesion property according to claim 7 or 8 for preparing a medical material for repairing bone injury.

10. The use of the curing fluid for calcium phosphate-based bone cement and/or the injectable bone cement with tissue self-binding properties according to claim 9 for the preparation of medical materials for bone injury repair, characterized in that:

the medical material comprises orthopedic and dental medical materials;

the medical material for repairing bone injury is used for minimally invasive treatment or filling of complex bone defect shapes.

Technical Field

The invention belongs to the technical field of biomedical materials, and particularly relates to injectable bone cement with tissue self-bonding performance, and a preparation method and application thereof.

Background

Bones are important organs of human bodies, and complex bone defects and massive bone defects caused by various reasons have poor self-repairing property, so that a large amount of bone repairing materials are needed to fill and repair defect parts, and the extensive research on the bone repairing materials is initiated. The biomedical inorganic self-curing bone repair material has good low-temperature curing, injectability, arbitrary shaping according to the shape of a bone defect part and good biocompatibility, and becomes a research hotspot of the bone repair material in recent years.

alpha-TCP is an important inorganic self-curing bone repair material and has good self-curing property, osteoconductivity, biocompatibility and the like. But still has the problems of lower compressive strength, mismatched degradation speed and osteogenesis speed, long solidification time, poorer collapsibility resistance and osseointegration property, and the like. Therefore, the development and development of a novel bone cement system have great significance.

Sodium alginate is widely used in the biomedical field due to its good biocompatibility, low toxicity and relatively low cost. Sodium Alginate (SA) reacts with calcium (Ca) ions to generate calcium alginate hydrogel, so that the collapsibility of the bone cement is effectively inhibited, but because a human body lacks enzymes for degrading sodium alginate, the degradation in vivo is slow, the molecular weight of a degradation product is large, and a long time is needed for discharging the degradation product out of the body. If the composite bone cement capable of being injected and promoting tissue self-adhesion can be developed, the composite bone cement is expected to be better used for treating and repairing bone defects.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide the curing liquid suitable for the calcium phosphate-based bone cement.

The invention also aims to provide injectable bone cement with tissue self-bonding performance and a preparation method thereof.

Still another object of the present invention is to provide the use of the curing fluid for calcium phosphate-based bone cement and/or injectable bone cement having tissue self-binding properties.

The purpose of the invention is realized by the following technical scheme:

a setting fluid suitable for calcium phosphate-based bone cement, comprising:

solution A: a mixed solution containing citric acid and disodium hydrogen phosphate;

and B, liquid B: oxidizing the sodium alginate solution.

The liquid A and the liquid B are preferably mixed according to the volume ratio of 1: 1.

In the solution A, the concentration of the citric acid is preferably 0.2 mol/L; the concentration of the disodium hydrogen phosphate is preferably 10 wt%.

The concentration of the oxidized sodium alginate in the solution B is preferably 2 to 24 weight percent.

The solution B is preferably prepared by the following method: adding oxidized sodium alginate into water, and stirring for 1-5 hours to obtain the sodium alginate.

The molecular weight of the oxidized sodium alginate is preferably 1000-200000; the oxidation degree of the oxidized sodium alginate is preferably low oxidation degree oxidized sodium alginate (the oxidation degree is 25-35%).

The oxidized sodium alginate is preferably obtained by reacting sodium alginate with soluble periodate; more preferably, it is prepared by the following method: adding periodate into sodium alginate solution, reacting for 2h in a dark place, adding diethylene glycol to stop the reaction for 1h, adding the reaction solution into absolute ethyl alcohol, carrying out solid-liquid separation, taking precipitate, dialyzing, and freeze-drying to obtain the oxidized sodium alginate.

The soluble periodate is preferably sodium periodate.

The molar ratio of sodium alginate to periodate is preferably 1: 1.

The dialysis is preferably carried out by using a dialysis bag with the dialysis molecular weight of 3500 kDa; the dialysis time is preferably 3 days, and the water is changed at least 3 times per day.

A preparation method of injectable bone cement with tissue self-bonding performance is characterized in that calcium phosphate-based bone cement is blended with the curing liquid suitable for calcium phosphate-based bone cement.

Preferably, the solution A in the curing solution suitable for the calcium phosphate-based bone cement is added firstly, and then the solution B is added.

The calcium phosphate-based bone cement and the curing liquid suitable for the calcium phosphate-based bone cement are preferably blended according to the solid-liquid ratio of 0.6 mL/g.

The calcium phosphate-based bone cement refers to tricalcium phosphate system bone cement commonly used in the field; the cement is any one of calcium biphosphate-alpha-tricalcium phosphate-calcium carbonate system cement, tetracalcium phosphate-alpha-tricalcium phosphate system cement, tetracalcium phosphate-beta-tricalcium phosphate-monocalcium phosphate system cement, or calcium hydrophosphate-alpha-tricalcium phosphate-calcium carbonate system cement.

An injectable bone cement with tissue self-bonding performance is obtained by the preparation method.

The injectable bone cement with the tissue self-bonding performance has one or more of the following characteristics:

(1) bone tissue adhesion promoting performance: filling the just prepared composite bone cement into the bone defect part until 2min before coagulation, wherein the maximum extrusion stress is 5-50N;

(2) the injection rate is as follows: 41 to 71 percent;

(3) setting time: 18-93 minutes;

(4) compressive strength: and after curing for 2 days, the compressive strength is more than 12 MPa.

The curing liquid suitable for calcium phosphate-based bone cement and/or the injectable bone cement with tissue self-bonding performance are/is applied to preparing a bone injury repairing medical material; including orthopedic, dental, and the like.

The medical material for repairing bone injury is preferably a material for minimally invasive treatment or filling of complex bone defect shapes.

The curing liquid and the calcium phosphate cement are uniformly mixed to be blended into paste, and the paste is directly implanted into an operation position for clinical application through an instrument.

Sodium alginate is partially oxidized by sodium periodate, so that a cis-vicinal diol structure in an uronic acid unit is broken to form a dialdehyde structure, the degradability of the sodium alginate is increased, and introduced dialdehyde can perform reversible dynamic reaction with tissue amino to generate imine bonds, so that integration of a repair material filled in a defect part and surrounding tissues is promoted; meanwhile, the characteristic that the G unit of the sodium alginate is chelated with calcium ions to form gel is kept. Meanwhile, citric acid as a curing liquid can be chelated with calcium ions faster than aldehyde groups in the early stage of hydration, and aldehyde groups can be prevented from being chelated with calcium ions to a certain extent; the pre-acid environment may also maintain the activity of the aldehyde group. When the pH value of the whole bone cement system (injectable bone cement with tissue self-bonding performance) rises to about 7 along with the progress of hydration, aldehyde groups can react with amino groups at the time, and better integration is just generated with tissues. The bone cement system of the invention bonds amino on the tissue and amino in blood thereof with the oxidized alginic acid substance of the material per se in the curing process to generate a bonding force, thereby effectively preventing the tissue material from being dispersed by the blood and improving the collapsibility resistance of the material; meanwhile, the integration between the material and the tissue is enhanced, and the interface strength is improved. Therefore, the citric acid, the disodium hydrogen phosphate (accelerating hydration and playing a competitive role in combining calcium ions) and the oxidized alginic acid in the invention are all absent, and a good synergistic effect is formed.

Compared with the prior art, the invention has the following advantages and effects:

1. the curing liquid and the bone cement system composed of the curing liquid are scientifically and skillfully designed, so that the components in the curing liquid are organically and cooperatively matched in the hydration and curing processes, and particularly, the synergistic effect of the sodium alginate oxide and the citric acid in the bone cement system not only realizes the bonding between tissues and materials, but also can improve the anti-collapse performance and the hydration promotion performance of the materials.

2. The composite bone cement material capable of being injected and promoting bone bonding has good viscosity, and the properties of injectability, plasticity, setting time, mechanical strength and the like can be regulated and controlled by adjusting the components.

3. The invention has the advantages of simple and easy preparation process, low cost, easy large-scale preparation and the like.

Drawings

FIG. 1 is an analysis chart of the results of the compressive strength of the bone cement slurries obtained in examples 1 to 6.

FIG. 2 is an analysis graph showing the setting time results of the bone cement slurries obtained in examples 1 to 6.

FIG. 3 is an analysis chart of the injectability results of the bone cement slurries obtained in examples 1 to 6.

FIG. 4 is a photograph showing the erosion resistance of the bone cement slurries obtained in examples 1 to 6.

FIG. 5 is a graph showing a viscosity mechanical experiment of the bone cement slurries obtained in examples 1 to 6.

FIG. 6 is an XRD pattern of bone cements obtained in examples 1 to 6.

FIG. 7 is an infrared spectrum of a bone cement obtained in examples 1 to 6, wherein a is TCP-con; b is TCP + 1% sodium alginate oxide; c is TCP + 3% sodium alginate oxide; d is TCP + 6% sodium alginate oxide; e is TCP + 9% sodium alginate oxide; f is TCP + 12% sodium alginate oxide.

FIG. 8 is an SEM photograph showing the hydrated crystal of the fracture surface of the bone cement obtained in examples 1 to 6.

FIG. 9 is an SEM photograph showing the adhesion between the composite bone cement and bone tissue of example 5, wherein A and B are the results of TCP bone cement without OSA (TCP-con) of example 1, and C and D are the composite bone cement prepared in example 5.

FIG. 10 shows the nuclear magnetic spectrum (A) and the infrared spectrum (B) before and after oxidation of sodium alginate.

Detailed Description

The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.

In the following examples, the oxidized sodium alginate with different oxidation degrees (25%, 30%, 35%) is systematically tested, and the presented results have no significant difference in a certain oxidation degree range (25% to 35%), so the oxidized sodium alginate with the oxidation degree of about 35% is selected for presentation in the following examples.

FIG. 10 shows the nuclear magnetic spectrum (A) and the infrared spectrum (B) before and after sodium alginate oxidation, and the synthetic OSA is confirmed by 1H NMR and FTIR spectrum, and after oxidation, one FTIR spectrum of about-1732 cm appears in the OSA^-1(aldehyde carbonyl) signal (FIG. 10-B), due to the formation of aldehyde product. But peak intensity (1732 cm)^-1) Is weaker; therefore, the nuclear magnetic resonance hydrogen spectrum is used for verifying the infrared spectrum result. As shown in FIG. 10-A, a new CHO signal peak at about 8.4ppm, characteristic of OSA, was observed in the 1H NMR spectrum of OSA.