CN117531050A

CN117531050A - Bone cement material and preparation method thereof

Info

Publication number: CN117531050A
Application number: CN202210922798.XA
Authority: CN
Inventors: 白艳洁; 杨磊; 张瑞; 刘慧玲
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2022-08-02
Filing date: 2022-08-02
Publication date: 2024-02-09
Also published as: WO2024027650A1

Abstract

The application relates to a bone cement material containing starch component and a preparation method thereof. The bone cement has higher mechanical strength, better curing time suitable for operation, good injectability and collapsibility resistance, excellent operation performance, good degradation performance and the like, and excellent comprehensive performance. The application also relates to a kit for preparing the bone cement.

Description

Bone cement material and preparation method thereof

Technical Field

The application belongs to the field of biomedical materials, and particularly relates to a bone cement material and a preparation method thereof.

Background

Diseases such as osteoporosis or accidental injury can cause damage to the bone structure of the human body. Although the bone structure of the human body itself has a certain repairing ability and can heal by itself when the damage is small, when there is a large damage, bone grafting is required. Currently, about millions of bone injury patients worldwide need surgical treatments such as bone grafting. Bone grafting may be achieved by autograft and allograft. However, autograft has the problem that the donor is limited and the requirement of the damaged part cannot be met well, and allograft has the risk of rejection reaction and the like. Thus, artificial bone repair materials are becoming an important point of research in the field of medical biomaterials. The bone cement as one kind of bone repairing material has the advantages of in-situ solidification, simple operation, capacity of being injected into bone defect, etc. and has excellent application foreground.

Bone cement is an injectable biomimetic bone material. Currently, common bone cements are polymethyl methacrylate bone cement (PMMA), calcium phosphate bone cement (CPC), and the like. The solid phase of the polymethyl methacrylate bone cement is mainly PMMA copolymer powder, the liquid phase is methyl methacrylate monomer, and the solid is generated through polymerization reaction, so that the polymethyl methacrylate bone cement has good injectability and high mechanical strength. Currently, the medical bone cement used in percutaneous vertebroplasty for treating osteoporotic vertebral compression fractures is generally a non-degradable polymethyl methacrylate material. PMMA bone cement belongs to a biological inert material, can not form organic chemical interface combination with host bone tissue, and has limited clinical application due to the defects of heat generation, monomer cytotoxicity, limited operable time and the like in the solidification polymerization process.

Calcium Phosphate Cement (CPC) has been widely used in orthopaedics treatment and correction since the 1980 s as a replacement product for polymethyl methacrylate bone cement. Calcium phosphate bone cements are bioactive inorganic materials whose main components are different calcium phosphate salts. Under physiological conditions, has self-curing properties, etc. The calcium phosphate bone cement has the characteristics of good injectability, arbitrary plasticity, isothermal in-situ curing and the like, but the existing calcium phosphate bone cement has the limitations of poor bearing, low strength and large brittleness, and is easy to collapse in the in-vivo curing process.

Disclosure of Invention

Aiming at the technical problems in the prior art, the application provides bone cement, wherein the bone cement matrix phase, the reinforcing phase and the developing agent and the curing liquid are in sufficient quantity for realizing development.

The application provides a preparation method of bone cement, which comprises the following steps: the matrix phase, reinforcing phase, and an amount of developer sufficient to effect development are mixed with the curing liquid to form an bone cement paste.

The present application provides a kit for preparing bone cement comprising a matrix phase, a reinforcing phase, and an amount of a developer sufficient to effect visualization. In one embodiment, the kit further comprises a liquid phase portion. In one embodiment, the liquid phase portion comprises a solidification liquid capable of reacting with at least a calcium phosphate salt in the matrix phase to form hydroxyapatite.

In one embodiment, the matrix phase comprises a calcium phosphate salt; in one embodiment, the matrix phase comprises one or more selected from tricalcium phosphate, calcium hydrogen phosphate dihydrate (DCDP), anhydrous calcium hydrogen phosphate, tetra calcium phosphate, octacalcium phosphate, monocalcium phosphate, hydroxyapatite, fluorapatite. In one embodiment, the matrix phase comprises a mixture of both tricalcium phosphate and dibasic calcium phosphate dihydrate (DCDP).

In one embodiment, the solidification liquid is at least capable of reacting with a calcium phosphate salt in the matrix phase to form hydroxyapatite. In one embodiment, the curing liquid comprises one or more selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, dilute phosphoric acid, calcium hydroxide, citric acid, glycerol, and/or malonic acid.

In one embodiment, the reinforcing phase mass is 1% to 100% of the matrix phase mass; in one embodiment, the reinforcing phase has a mass of 5% to 95% of the mass of the matrix phase; in one embodiment, the reinforcing phase mass is 10% to 50% of the matrix phase mass.

In one embodiment, the developer is selected from barium-based developer, zirconium-based developer, bismuth-based developer, strontium-based developer, copper-based developer, aluminum-based developer, and/or combinations thereof.

In one embodiment, the developer is selected from barium sulfate, zirconium oxide, bismuth subcarbonate, strontium carbonate, strontium halide, and/or combinations thereof.

In one embodiment, the developer is selected from barium sulfate, zirconia, and/or combinations thereof.

In one embodiment, the reinforcing phase comprises gelatinized starch. In one embodiment, the gelatinized starch is recovered by a method selected from one or a combination of alcohol precipitation, freeze drying and/or spray drying. In one embodiment, the gelatinized starch is recovered by a freeze-drying process. In one embodiment, the lyophilization temperature is no greater than-10 ℃, or no greater than-20 ℃, or no greater than-30 ℃, or no greater than-40 ℃, or no greater than-50 ℃, or no greater than-60 ℃, or no greater than-70 ℃, or no greater than-80 ℃, or no greater than-90 ℃, or no greater than-100 ℃.

In one embodiment, the gelatinized starch has an amylose content of less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or less than 3%.

In one embodiment, the starch comprises one or more selected from the group consisting of common corn starch, waxy corn starch, high amylose corn starch, tapioca starch, and potato starch. In one embodiment, the starch comprises waxy corn starch and/or normal corn starch.

In one embodiment, the gelatinized starch has a viscosity of less than 10 at 0.1rad/s ⁴ Less than 10 at 10rad/s ³ . In one embodiment, the gelatinized starch has a viscosity of less than 10 at 0.1rad/s ³ Less than 10 at 10rad/s ² . In one embodiment, the gelatinized starch has a swelling degree of greater than 20%. In one embodiment, the gelatinized starch exhibits only one broad peak in XRD diffractogram that is shape-dispersive and smooth.

In one embodiment, the starch scanning electron microscope image displays an irregular sheet; in one embodiment, the starch scanning electron microscopy image is substantially as shown in D6 or D7 of FIG. 3-2.

In one embodiment, the bone cement has a compressive strength greater than 20MPa; in one embodiment, the bone cement has a compressive strength greater than 30MPa; in one embodiment, the bone cement has a compressive strength greater than 40MPa; in one embodiment, the bone cement has a compressive strength greater than 50MPa; in one embodiment, the bone cement has a compressive strength greater than 60MPa.

In one embodiment, the bone cement cross-section shows no needle-like structure aggregation via scanning electron microscopy; in one embodiment, the bone cement cross-section is substantially as shown in G6 of fig. 9-4 via scanning electron microscopy; in one embodiment, the bone cement cross-section is substantially as shown in G7 of fig. 9-4 via scanning electron microscopy.

In one embodiment, the bone cement has an initial setting time of 5min to 30min and a final setting time of 10min to 40min; in one embodiment, the bone cement has an initial setting time of 15min to 30min and a final setting time of 20min to 40min; in one embodiment, the bone cement has an initial setting time of 20min to 30min and a final setting time of 25min to 40min; in one embodiment, the bone cement has an initial setting time of 25min to 30min and a final setting time of 35min to 40min.

The application also provides an application of the starch material in preparing the bone cement. The starch material comprises gelatinized starch.

The bone cement realizes good operability, is easy to inject, is not easy to collapse, has good mechanical property, and can be well matched with autologous bone. In particular, the bone cement of the application has high mechanical strength and can be used for bearing structural bone parts.

Drawings

Some embodiments of the present application will now be described in further detail with reference to the accompanying drawings, in which:

FIG. 1 is a bar graph of the strength of a composite bone cement with added starch reinforcement phase.

FIG. 2 is a graph of viscosity results for modified starches.

Fig. 3, 4 and 5 are respectively a starch scanning electron microscope (sem), an XRD pattern and an infrared spectrogram.

Fig. 6 is a photograph showing the results of injectability and anti-collapse of bone cement.

Fig. 7 is a graph of the viscosity results of the composite bone cement.

Fig. 8 is an XRD pattern of bone cement.

Fig. 9 is a scanning electron microscope image of bone cement.

Fig. 10 is an infrared spectrum of bone cement.

Detailed Description

For the purposes of making the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.

In the case where not indicated to the contrary herein, the "matrix phase" is the component constituting the body of the bone cement. In the powder state, the matrix phase comprises one or more calcium phosphate salt powders, for example comprising one or more selected from tricalcium phosphate (alpha or beta form), dibasic calcium phosphate dihydrate, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, octacalcium phosphate, monobasic calcium phosphate, hydroxyapatite, fluorapatite.

After mixing one or more calcium phosphate powders in the matrix phase in powder form with the liquid phase, self-curing may continue after initial setting, eventually forming hydroxyapatite, brushite and/or amorphous calcium phosphate. In some embodiments, the matrix phase in the powder state may include a meta-acidic calcium phosphate powder and a meta-basic calcium phosphate powder.

In some embodiments, one or more calcium phosphate salt powders in the matrix phase in powder form undergo a series of hydration reactions to ultimately form a degree of crystalline Hydroxyapatite (HA). In some embodiments, hydroxyapatite (HA) crystals may also be added to the matrix phase. The added Hydroxyapatite (HA) crystal can help the hydration process of the matrix phase, reduce the setting time and enable the bone cement matrix phase to be self-set more easily.

In some embodiments, the matrix phase in the powder state comprises tricalcium phosphate. Tricalcium phosphate mainly has three crystal forms of low-temperature phase beta-TCP and high Wen Xiang-TCP and alpha' -TCP, wherein the alpha-TCP crystal form can exist stably at room temperature through quenching. In some embodiments, the matrix phase in powder form comprises a mixture of both α -tricalcium phosphate (α -TCP) and dibasic calcium phosphate dihydrate (DCDP). In some embodiments, tetra-calcium phosphate may also be added to the matrix phase comprising alpha-tricalcium phosphate (alpha-TCP) and dibasic calcium phosphate dihydrate (DCDP). The hardening strength can be improved by adding tetracalcium phosphate to the matrix phase. In some embodiments, the matrix phase contains at least two calcium phosphate salt powders, the different calcium phosphate salt powders being mixed by dry method. In some embodiments, the dry blending includes a ball milling step, for example, mixing the heterogeneous calcium phosphate powder with agate balls at a ball to material ratio, for example, a ball to material ratio of 1:2. in some embodiments, the mixed calcium phosphate salt after ball milling is sieved to control the particle size level of the matrix phase powder, so as to ensure that the matrix phase particles and the liquid phase can be dissolved quickly and fully to promote the hydration reaction.

In some embodiments, the calcium phosphate salt in the matrix phase may be made from carbonate apatite. For example, the carbonate apatite synthesized in the solution is heated for several hours, and the resulting solid is ground to obtain matrix phase powder whose main components are calcium sodium phosphate, tetra calcium phosphate and tricalcium phosphate.

In some embodiments, the alpha-tricalcium phosphate powder in the calcium phosphate powder in the matrix phase is obtained by high temperature calcination and quenching. For example, the alpha-tricalcium phosphate may be obtained by first maintaining at high temperature for 4 hours and then quenching.

In some embodiments, in addition to calcium phosphate salts, compounds may be added to the matrix phase to supplement the human body with trace elements zinc, magnesium, strontium, fluorine, etc. to optimize the osteogenesis of the bone cement.

Without being represented to the contrary, the "reinforcing phase" is an additive component, such as starch, that optimizes the properties of the bone cement. In some embodiments, the starch comprises one or more selected from the group consisting of common corn starch, waxy corn starch, high amylose corn starch, tapioca starch, and/or potato starch.

In some embodiments, the starch may be subjected to one or more of physical or chemical modification treatments, such as gelatinization treatments, molecular crosslinking treatments, cationic modification treatments, calcium ion modification treatments, molecular chain length reduction treatments, branching degree increasing treatments, crosslinking degree increasing treatments.

In some embodiments, the enhancing phase is gelatinized starch. In some embodiments, the gelatinized starch may be recovered by methods of precipitation with an alcohol solution (also referred to as "alcohol precipitation"), recovery by methods of spray drying, and/or recovery by methods of freeze drying (also referred to as "lyophilization"). The gelatinization can destroy the original crystal structure of the starch, and eliminate the formation of an amorphous irregular state of the original spherical particle state of the starch. The starch is gelatinized and modified, can be dissolved at room temperature, and can be uniformly mixed with other components of bone cement to form a solidified three-dimensional network. The recycling process should be kept as amorphous as possible in an irregular state to obtain, for example, irregular blocks and/or flakes, etc. In some embodiments, the recovery treatment means of the gelatinized modified starch should avoid the generation of microcrystalline structure as much as possible, reduce the number of crystals, and improve the swelling capacity of the starch at normal temperature. In some embodiments, gelatinized starch, i.e., starch recovered via gelatinization modification, may achieve one or more of the following: has a lower amylose content, increases the swelling capacity of the starch, and reduces the viscosity of the starch formed in the addition to the liquid phase. The above treatment of starch is helpful for improving physical and chemical properties of bone cement.

In some embodiments, the starch of the reinforcing phase may be starch recovered by an alcohol precipitation process. Illustratively, the starch recovered by the alcohol precipitation process may be prepared by mixing the starch with water or an aqueous liquid, gelatinizing the starch to form a gelatinized starch. Cooling gelatinized starch to room temperature, adding absolute ethyl alcohol into cooled starch, standing at room temperature for a period of time, layering, removing supernatant, adding absolute ethyl alcohol into precipitate, standing, filtering, drying, pulverizing and sieving to obtain starch recovered by alcohol precipitation method.

In some embodiments, the starch of the reinforcing phase may also be starch recovered by a freeze drying process. Illustratively, the starch recovered by the freeze-drying method may be prepared by dissolving starch in water or an aqueous liquid under stirring and heating to gelatinize the starch, forming gelatinized starch after a certain period of time, cooling the gelatinized starch to room temperature, freeze-drying in a freeze-drying apparatus, and pulverizing and sieving to obtain starch recovered by the freeze-drying method.

In some embodiments, the reinforcing phase may also be starch recovered by a spray drying process. Illustratively, the starch recovered by the spray drying method may be prepared by dissolving starch in water or an aqueous liquid under stirring and heating to gelatinize the starch, forming gelatinized starch after a certain period of time, cooling the gelatinized starch to room temperature, feeding the gelatinized starch into a spray drying apparatus, spray drying in the spray drying apparatus, and pulverizing and sieving to obtain the starch recovered by the spray drying method.

In some embodiments, the enhancing phase may be selected from waxy corn starch and normal corn starch having a lower amylose content, which are gelatinized modified and recovered by freeze drying. In some embodiments, the reinforcing phase has a higher amylopectin content, a higher degree of swelling, an apparent morphology under a starch scanning electron microscope shows a loose structure, a flaky shape, a larger contact area, no obvious crystallization, an X-ray diffraction pattern shows no obvious peak, a diffuse and smooth broad peak, and a lower viscosity is formed by dissolving in a liquid phase.

Herein, unless indicated to the contrary, a "developer" is a component that imparts a developability to bone cement, such as barium sulfate, zirconia, and/or combinations thereof. In some embodiments, the addition of sufficient developer to effect visualization, enabling visualization of the bone cement, may satisfy the need for visualization during surgery.

Herein, unless indicated to the contrary, a "curing liquid" is a liquid phase used to mix with a matrix phase, a developer and/or a reinforcing phase in a powder state to form an bone cement paste. Bone cement paste is a paste-like bone cement. Common curing liquids include one or more selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, dilute phosphoric acid, calcium hydroxide, citric acid, glycerol, and/or malonic acid. The solidifying liquid may be in the form of a liquid such as a solution or a solid which is formulated to form a liquid. In some embodiments, the solidifying fluid may also be physiological saline, serum, and/or blood, etc.

And finally, forming solid after the bone cement paste is self-cured, thus obtaining the solid bone cement. In this process, the matrix phase is hydrated with water in the solidifying fluid, for example, α -tricalcium phosphate (α -TCP) and dibasic calcium phosphate dihydrate (DCDP) are hydrated to ultimately produce hydroxyapatite similar to the mineral phase of human bone tissue.

In the present context, unless indicated to the contrary, "ordinary calcium phosphate cement" refers to a calcium phosphate cement that contains only a matrix phase, and does not contain a reinforcing phase and a developer.

In the present context, unless otherwise indicated, "developed calcium phosphate cement" refers to a calcium phosphate cement that contains a matrix phase, but does not contain a reinforcing phase other than the matrix phase, and contains a developer.

In the present context, without being represented to the contrary, "composite bone cement" refers to a bone cement comprising a matrix phase, in addition to the matrix phase, together with a reinforcing phase and a developer.

Comparative example 1 preparation and characterization of calcium phosphate bone Cement

In this comparative example, a general calcium phosphate cement was prepared according to the following method: mixing alpha-tricalcium phosphate (alpha-TCP) and calcium hydrophosphate dihydrate (DCPD) according to the mass ratio of 9:1, adding 3 times of absolute ethyl alcohol, grinding, uniformly mixing, pouring into a tray, putting into a 50 ℃ oven for drying for 4 hours, and then heating to 120 ℃ for drying for 9 hours. Grinding the dried mixture and sieving with a 60-mesh sieve to obtain matrix phase powder. And adding the matrix phase powder into the disodium hydrogen phosphate solution, and uniformly mixing to obtain the bone cement paste. The resulting bone cements were tested as follows.

1. And (5) mechanical testing. Filling the bone cement paste into a mould, putting the mould into a constant temperature and humidity box (37 ℃ and more than 60% RH) until the mould is at a certain hardness, and taking out the mould. And then placing the bone cement into a constant temperature and humidity box (37 ℃ and 60% RH) for curing for 72 hours, and taking out the bone cement after curing. A universal mechanical tester (Shanghai scale wing precision instruments Co., ltd., specification HY-1080) is adopted, a 10kN weighing sensor is adopted as a test instrument, and the test speed is 0.5mm/min. The measurements of all samples were repeated multiple times and reported as mean ± standard deviation of compressive strength (in MPa). The compressive strength of the bone cement in this example was found to be 15.4.+ -. 1.8MPa.

2. Injectability test. The bone cement paste is packaged into a 1mL injector, the diameter of a discharge hole is 2mm, the bone cement paste is fixed on a mechanical testing machine, and the bone cement paste is injected and extruded at the speed of 1mm/min until the maximum thrust reaches 50N, and the injection is stopped. The injection was observed and photographed. The mass of the extruded cement slurry as a percentage of the total mass of the slurry is defined as the injectability of the bone cement. The bone cement injectability calculation in this example was <90%.

3. And testing collapsibility resistance. The bone cement paste was packaged in a 1mL syringe, then directly injected into a petri dish filled with deionized water at 37 ℃, the petri dish was placed on a vibrating device (purchased from Scilogex USA, model SK-O330-Pro), the vibration speed was set at 180r/min and maintained for 1min, then left stand in deionized water at 37 ℃ for 24h, if bone cement did not fracture, indicating that it had good anti-collapsibility, observing if collapsibility occurred and taking a photograph. The results of the bone cement in this example are shown in FIG. 6-1. The results show that the comparative calcium phosphate cement has poor collapsibility.

4. And (5) testing the curing time. The cure time test was performed according to ASTM C191-03 standard method. The cement slurry was filled into stainless steel molds (diameter 6mm, height 12 mm) and crushed with a spatula. The initial setting time and the final setting time of the bone cement were measured respectively with an initial setting needle (weight 113.4g, diameter 2.12 mm) and a final setting needle (weight 453.6g, diameter 1.06 mm) of a Vicat, and each sample was tested five times, and the results were expressed as mean.+ -. Standard deviation. The result of the setting time of the bone cement in this example was 3.3.+ -. 0.5min, and the final setting time was 9.0.+ -. 0.4min.

5. And (5) analyzing the surface morphology of the bone cement. Filling the obtained bone cement paste into a cylindrical mold with the diameter of 6mm and the height of 12mm, taking out a cement sample in the mold after solidification, and storing the cylindrical sample for 3 days at 37 ℃ and humidity of >60% RH. And then breaking off the cylindrical sample to expose the cross section, adhering the sample to the double-sided conductive adhesive, and enabling the cross section of the sample to face upwards. And (3) placing the sample in an ion sputtering instrument, spraying metal for 60 seconds, plating a layer of conductive film on the sample, then sending the sample disc into a scanning electron microscope sample chamber, adjusting the position of a sample stage, setting the voltage to be 15kV, and starting scanning photographing. The SEM results of the bone cement in this example are shown in FIG. 9-1.

Comparative example 2 preparation and characterization of developed calcium phosphate bone cements

In this comparative example, a developed calcium phosphate cement was prepared according to the following method: the matrix phase powder was prepared according to the method of comparative example 1. Barium sulfate powder (BaSO) ₄ ) Grinding and sieving with 200 mesh sieve. Adding a certain amount of barium sulfate powder into the matrix phase powder, and grinding for 2min. And adding the obtained mixed powder into a disodium hydrogen phosphate solution, and uniformly mixing to obtain the developed calcium phosphate bone cement paste taking barium sulfate as a developer.

The mechanical strength, injectability, collapsibility resistance, sem structure and curing time of the resulting bone cements were evaluated with reference to the method in comparative example 1.

Further, the porosity and density of the resulting bone cement were analyzed.

1. Porosity: injecting the bone cement paste into a stainless steel mould (diameter is 6 mm and height is 12 mm), taking out a cement sample in the mould after solidification, storing the sample at 37 ℃ and 60RH% for 3 days, drying the sample in a baking oven at 150 ℃ for 5 hours, putting the dried sample into an dilatometer, keeping the dried sample horizontal, and carrying out low-pressure analysis. During low pressure analysis, firstly, a mercury pressure meter is used for vacuumizing a sample, the absolute pressure value reaches less than 50 mu mHg (0.0067 kPa), then vacuumizing is continued for 5min, mercury is filled into an dilatometer through a siphoning method, nitrogen is introduced into the dilatometer for maintaining pressurization to 0.5psi (3.4 kPa), the dilatometer is taken out after the low pressure analysis is finished and put into a high pressure chamber, the pressure is applied to the mercury through an oil pump, the mercury inlet amount is detected through an oil pump, the volume of mercury pressed into the sample under a series of different pressures is obtained, and therefore the porosity of the sample is obtained.

2. Density: the bone cement slurry was poured into a stainless steel mold (diameter 6 mm, height 12 mm) and the sample was taken out after solidification. Preserving the sample at 37deg.C saturated humidity for 3 days, taking out the sample, weighing, and weighing with mass of m ₁ . The water was then poured into a beaker of a density balance (the flatter the sea, model FA 2104J), and the basket was hung in the water, ensuring that there was no air bubbles. Placing the sample into a hanging basket, weighing the weight of the sample in water to be m ₂ . The density of the bone cement sample can be calculated as follows:

wherein ρ represents the bone cement density (g/cm) ³ )，ρH ₂ O represents the density of water (g/cm) ³ ),ρ _air Represents the density (g/cm 3) of air, m ₁ Represents the mass (g), m of bone cement in air ₂ The mass (g) of bone cement in water is indicated. The results are reported as mean ± standard deviation in parallel measurements.

The results of developing the above characteristics of the calcium phosphate cement are shown in table 1 below.

TABLE 1

EXAMPLE 1 preparation of composite bone Cement with reinforcing phase added

The matrix phase powder was prepared by the method of comparative example 1; grinding barium sulfate powder, and sieving with a 200-mesh sieve to obtain a developer; pregelatinized starch (available from Henan Jianje starch products Co., ltd.) was used as the reinforcing phase.

The reinforcing phase and a proper amount of barium sulfate developer are added into the matrix phase powder for mixing. The mass ratio of matrix phase to reinforcing phase is 12:1, 6:1, 4:1 or 3:1. Grinding the obtained mixed powder, and then mixing with a disodium hydrogen phosphate solution to obtain the composite bone cement paste. Filling the composite bone cement paste into a stainless steel die with the diameter of 6 mm and the height of 12 mm, putting the die into a constant temperature and humidity box (37 ℃ and 60 RH%) until the die has certain hardness, and taking out the die. Then putting the bone cement into a constant temperature and humidity box (37 ℃, >60 RH%) for stabilization for 72 hours, and taking out the bone cement to obtain the composite bone cement. The mechanical properties of the obtained bone cement samples were analyzed, and the results are shown in fig. 1, wherein the ordinate "Compressive Strength" represents compressive strength; the abscissa indicates the mass ratio of the matrix phase and the reinforcement phase, for example, 12:1 indicates that the reinforcement phase mass is 1/12 of the matrix phase mass.

EXAMPLE 2 composite bone cements with different types of developers

The matrix phase powder was prepared by the method of comparative example 1; grinding barium sulfate powder, and sieving with a 200-mesh sieve to obtain a developer 1; grinding zirconia developer powder, and sieving with a 200-mesh sieve to obtain a developer 2; pregelatinized starch (available from Henan Jianje starch products Co., ltd.) was used as the reinforcing phase.

The reinforcing phase and a proper amount of zirconia developer are added into the matrix phase powder for mixing. The mass ratio of matrix phase and reinforcing phase was 3:1. The resulting mixed powder was ground and then mixed with a disodium hydrogen phosphate solution to obtain a composite bone cement paste using the developer 2. The resulting bone cement paste was measured for compressive strength as in example 1, and as a result, it was 57.7.+ -. 4.0MPa.

And repeating the steps, and replacing the zirconia developer powder with the barium sulfate developer powder with the same amount to obtain the composite bone cement paste using the developer 1, namely the composite bone cement paste using the barium oxide as the developer. The resulting bone cement paste was measured for compressive strength as in example 1, and as a result, it was 46.2.+ -. 1.8MPa.

The results show that the composite bone cement containing different kinds of developers has ideal mechanical strength.

EXAMPLE 3 preparation of reinforcing phase

Waxy corn starch (Qin Royal Li Co., ltd.), normal corn starch (Qin Royal Li Co., ltd.), high amylose corn starch (Shanghai Bicai Co., ltd.), tapioca starch (Homew starch processing plant), and potato starch (inner Mongolian European starch Co., ltd.) were selected and subjected to the following modification treatments.

Method 1: 10g of starch, 490mL of deionized water were added to a 1000mL beaker and stirred and heated in a boiling water bath for 30min. After cooling to room temperature, 1500mL of absolute ethanol was added to the starch solution, and the mixture was allowed to stand at room temperature for 1 hour. Standing for layering, pouring out supernatant, adding 500ml of absolute ethyl alcohol into the precipitate, standing for one hour, and filtering to obtain a filter cake. Crushing the filter cake, drying overnight in a baking oven at 40-45 ℃, crushing the dried sample, and sieving the crushed sample with a 100-mesh sieve to obtain the modified starch treated by the method 1.

Method 2: weighing starch with a certain mass, adding deionized water, preparing starch slurry with a mass fraction of 5%, heating in a boiling water bath, and stirring for 30min. And (5) cooling the starch slurry to room temperature, freezing, and processing by a freeze dryer. And (3) taking out the starch after freeze drying, crushing and sieving to obtain the modified starch treated by the method 2.

Waxy corn starch, normal corn starch, high amylose corn starch, tapioca starch and potato starch treated by method 1 are numbered D1-D5, respectively; waxy corn starch, normal corn starch, high amylose corn starch, tapioca starch and potato starch treated by method 2 are numbered D6-D10, respectively; untreated waxy corn starch, normal corn starch, high amylose corn starch, tapioca starch and potato starch are numbered D11-D15, respectively.

I. Amylose content of starch

Amylose content of the aforementioned starches (starches corresponding to the aforementioned numbers D1 to D10 in example 3) were measured separately using the amylose/amylopectin assay kit K-AMYL (available from Megazyme int, ireland ltd.co., wicklow, ireland) and the calculation formula is as follows:

at least 3 times in parallel are tested to ensure data reliability, and the results are expressed as mean ± standard deviation. The results of the amylopectin content obtained are shown in table 2 below.

TABLE 2

From the results of the above table, waxy corn starch has the lowest amylose content. At the same time, the common corn starch treated by method 2 achieved a significantly lower amylose content than the common corn starch treated by method 1.

Viscosity of starch

The viscosity of the different starches (corresponding to the starches numbered D1-D10 in example 3) was measured separately using a rheometer (from TA Instruments, model AR 2000) using frequency sweep, setting an angular frequency sweep interval of 0.1-10rad/s with a strain amplitude of 1% and observing changes in material properties at 25 ℃.

Starch is dissolved in deionized water according to a certain proportion respectively, and is sampled after being stirred uniformly. The results of the viscosity of the samples are shown in FIG. 2, wherein FIGS. 2-1 and 2-2 show the viscosity of the starch treated in method 1 (corresponding to the starches numbered D1-D5 as described in example 3) and the starch treated in method 2 (corresponding to the starches numbered D6-D10 as described in example 3), respectively. In the figure, the abscissa "Angular frequency" represents the angular frequency, and the ordinate "Complex viscosity" represents the complex viscosity. The upper right corner of the figure identifies the corresponding starch numbers D1-D10.

From the results of the above figures, all starches exhibited shear thinning. Comparing the viscosity of the different starches, the waxy corn starch was found to have the lowest viscosity. In addition, the freeze-dried recovery treatment produced a better viscosity-reducing effect, particularly for ordinary corn, and the freeze-dried recovery treatment showed a significantly further reduction in viscosity compared to the alcohol precipitation recovery treatment.

III degree of swelling of starch

The degree of swelling of the different starches (corresponding to the starches numbered D1 to D10 in example 3) was measured separately as follows:

the centrifuge tube was charged with about 100mg of dry sample weight recorded as W, and the total mass of sample and centrifuge tube recorded as W ₁ Adding 10mL of water into the centrifuge tube, shaking uniformly, placing the centrifuge tube in a water bath kettle at 95 ℃ for 30min (taking out and shaking uniformly every 15min in the period), and taking out. Centrifuge (model TD5A-WS from Hunan Instrument) at 4000g for 20min, then separate supernatant, record centrifuge tube mass W with sediment ₂ The calculation formula of the expansion degree is as follows:

at least 3 times in parallel were tested to ensure data reliability, the results were expressed as mean ± standard deviation, and the results are shown in table 3.

TABLE 3 Table 3

Starch numbering	Expansion degree (%)	Starch numbering	Expansion degree (%)
				D1	19.92±1.34	D6	23.68±0.81
D2	12.25±1.76	D7	20.48±0.51
				D3	8.92±0.07	D8	11.02±0.38
D4	16.87±0.47	D9	20.39±0.14
				D5	15.57±0.86	D10	16.09±0.67

The results of the above table show that the samples numbered D6-D10 achieved higher swelling compared to the starches numbered D1-D5. Of these, starches numbered D1 and D6 have a relatively higher degree of swelling. The starch numbered D7 had a significantly higher degree of swelling than the starch numbered D2.

IV apparent morphology of starch

The apparent morphology of the starch was characterized by Scanning Electron Microscopy (SEM) (fig. 3). The results indicated that the non-gelatinized starch was in the form of spherical granules with a smooth surface (FIGS. 3-3). The modified starch treated by the method 1 is in irregular granular shape (fig. 3-1, wherein the upper left corner marks D1-D5 correspond to starch numbers D1-D5 respectively). The modified starch treated by method 2 is in the form of flakes (FIG. 3-2, wherein the upper left hand corner marks D6-D10 correspond to starch numbers D6-D10, respectively). The original structure of the starch granules is destroyed by gelatinization of the starch. The crystallization area in the starch granule is changed from a compact arrangement state to a loose state, and is continuously absorbed with water to expand to form irreversible phase change, after the expansion to a certain extent, the granule is broken, the original granule shape is destroyed to form disordered gel, and the granule can be in an irregular shape after being recovered by drying and the like.

In the recovery process in the method 1, branches of amylose and amylopectin molecules all tend to be arranged in parallel again and are mutually close to each other, and are recombined into mixed microcrystals after being combined with hydrogen bonds, so that irregular blocks are easily displayed finally, and the structure is relatively compact. The starch recovered in method 2 has a looser structure compared with the starch with the structure of the starch, particularly the starch with the numbers D6 and D7, and the apparent morphology of the starch under an electron microscope is in an irregular sheet shape, because the drying temperature is rapidly reduced in the recovery process in method 2, and the movement of starch chains is limited, so that the looser and porous morphology of the starch obtained by the treatment of method 2 is provided.

V. crystalline state of starch

The crystalline morphology of the starch was analyzed by means of an X-ray diffractometer (from Bruker, model D8 Discover, germany). The specific method comprises the following steps: spreading a powder starch sample in a sample stage, and scanning: nickel filtered Cu ka radiation,graphite monochromatic tube, tube voltage 40kV (v=40 kV), current 40mA (i=40 mA). The scanning diffraction angle is 5-40 degrees, and the scanning speed is 2 degrees/min.

The results show that waxy corn starch, normal corn starch and tapioca starch in the raw starch (i.e. unmodified starch) are of type a with typical crystal structures, and potato starch and high amylose corn starch are of type B with crystal structures (see fig. 4-3). After modification treatment, the crystal structure of the starch is significantly changed. After treatment by method 1, the starch crystal structure is destroyed, in particular waxy corn starch (number D1), and no obvious crystal diffraction exists, and the starch is amorphous (see FIG. 4-1). After the treatment of method 2, the crystal structure of the starch is obviously destroyed, and each starch has no obvious diffraction peak of the crystal (see fig. 4-2).

From the figures, it was found that the starch samples in fig. 4-2 were all free of distinct crystallization spikes. In particular, the waxy corn starch (code D6) and normal corn starch (code D7) patterns of FIGS. 4-2 show only a single broad peak with a diffuse shape, and the broad peak is smooth in shape and has no obvious bulge, indicating that the corresponding starch sample has no relatively complete crystalline region, the starch structure is extremely loose, and the degree of amorphous is high. In contrast, other samples exhibiting multiple diffuse peaks still present smaller crystallite structures. It was also observed that the starch sample treated in method 2 lost the starch crystalline structure more thoroughly and the resulting starch structure was more fluffy than the starch sample treated in method 1. The recovery process in method 2 can better limit the movement of starch chains, so that the links among the starch chains are less, the starch quickly passes over the aging temperature, and the starch retrogradation is well avoided, so that a starch sample with a loose structure can be obtained.

Characterization of functional groups of starch

By infrared spectrometer (purchased from sameifer, model Nicolet ^TM iS 20) the starch of example 3, numbered D1-D15, was subjected to functional group analysis as follows: 1-2 mg of completely dried starch is taken and placed in a testing area of a spectrum analyzer. Setting the scanning range to 500-4000 cm ^-1 Resolution of 0.25cm ^-1 Testing was performed. The results obtained are shown in FIG. 5. Wherein, FIG. 5-1 shows the starch treated by the method 1, corresponding to the starch numbers D1-D5 respectively; FIG. 5-2 shows the starch treated by method 2, corresponding to starch numbers D6-D10, respectively; FIGS. 5-3 show raw starch without gelatinization, corresponding to starch numbers D11-D15, respectively.

In the infrared spectrogram of the starch, the infrared spectrogram is 2850 cm to 2900cm ^-1 Within the range of CH ₂ Asymmetric stretching vibration peak of C-H bond in the material, and stretching vibration absorption band of hydroxyl appears in 3000-3600 cm ^-1 Which constitute the overall structure of the starch and are mainly generated by the stretching vibrations of the intramolecular, intermolecular and intermolecular free hydroxyl groups. 1661-1623 cm ^-1 The characteristic peak at which represents extension of the c=o bondAnd (5) shrinking vibration. C-C and C-O stretching vibration peak is 1145cm ^-1 The C-O-C bending vibration peak is 995cm ^-1 。

The infrared spectrogram results show that the absorption spectrograms of the original starch and the modified starch are not obviously changed, and the characteristic absorption peak positions are not obviously changed, so that the basic chemical structure of the modified starch is not changed, the starch is not subjected to chemical reaction in the modification treatment process, and new functional groups are not generated.

Example 4: preparation of composite bone cement and characterization thereof by using different modified starches as reinforcing phases

The matrix phase powder was prepared by the method of comparative example 1; grinding barium sulfate powder, and sieving with a 200-mesh sieve to obtain a developer; the bone cements were prepared according to the following description method using the aforementioned starches having numbers D1 to D10 as reinforcing phases, respectively, and the obtained bone cement samples had numbers G1 to G10, respectively.

The reinforcing phase and a proper amount of developer are added into the matrix phase powder for mixing. The mass ratio of matrix phase and reinforcing phase was 3:1. Grinding the obtained mixed powder for 2min, and then mixing with the disodium hydrogen phosphate solution to obtain the composite bone cement paste. The resulting bone cement paste is further cured to form solid bone cement.

The mechanical strength, injectability, collapsibility resistance, curing time, sem structure, porosity and density of the resulting bone cements were evaluated, respectively, with reference to the method in comparative example 2, and the results are shown in table 4.

TABLE 4 Table 4

The results show that compared with the control samples (control example 1 and control example 2), the mechanical strength of the bone cement is obviously improved by adding the modified starches D1-D10 as the reinforcing phases, and the mechanical strength of the bone cement prepared by the modified starches D6-D10 treated by the method 2 is higher. In addition, the original starch sources of different reinforcing phases, and the mechanical strength of the bone cement is improved to different degrees. The setting time of the bone cements G6-G10 is significantly improved over the bone cements G1-G5, making longer working times possible. Each group of samples had good injectability and collapsibility resistance. The treatment of method 2 can lead the sample to obtain lower porosity, higher density, better mechanical strength and curing time which is more suitable for operation. In particular the starch samples, numbered G6 and G7, showed lower porosity, higher density and a high level of mechanical strength.

EXAMPLE 5 physicochemical Properties of composite bone Cement

I. Composite bone cement viscosity analysis

The bone cement viscosity was tested using a rheometer (available from TA Instruments, model AR 2000). Starch samples D1-D5 were selected as reinforcing phases, respectively, and the matrix phase was mixed with the starch reinforcing phase and a proper amount of developer powder according to the method in example 4, and the obtained mixed powder was subjected to grinding for 2 minutes, and then a disodium hydrogen phosphate solution was added to obtain a uniform bone cement paste. 1mL of bone cement paste was taken for rheology testing. The reinforcing phases were respectively the starch samples D1-D5 of example 3, and the obtained bone cement slurries were numbered J1-J5.

The results of sample viscosity at different frequencies are shown in figure 7. In the figure, the abscissa "Angular frequency" represents the angular frequency, and the ordinate "Complex viscosity" represents the complex viscosity. The upper right hand corner designation indicates the corresponding bone cement paste J1-J5.

The ordinary calcium phosphate cement in comparative example 1 and the developed calcium phosphate cement in comparative example 2 did not exhibit significant viscosity because starch was not added.

Comparing fig. 7, it can be seen that the composite bone cement also exhibits shear thinning properties similar to the viscosity characteristics of starch. The viscosity of the composite bone cement is consistent with the viscosity trend of the reinforcing phase starch therein. That is, by using starch having a lower viscosity as the reinforcing phase, the viscosity of the composite bone cement can be reduced, and accordingly the composite bone cement attains higher mechanical strength. The lower viscosity of the starch can influence the uniform distribution of the starch in the bone cement, thereby influencing the flow property and mechanical property of the bone cement.

II, composite bone cement knotCrystal analysis

And (5) carrying out crystal structure analysis on the composite bone cement sample. Taking the starch samples D1, D2, D3, D6, D7, D8 of example 3 as reinforcing phases, bone cement samples (corresponding to the bone cement numbers G1, G2, G3, G6, G7, G8) were prepared in the same manner as in example 4. The bone cement paste obtained above was poured into a cylindrical stainless steel mold having a diameter of 6mm and a height of 12mm and counted from the addition of the liquid phase, after solidification, the sample was pushed out, and the cylindrical sample was left at 37 ℃ for 3 hours and 1 day, respectively, at saturated humidity, after which the cylindrical sample was ground into powder with a mortar. 10% by weight of silica powder was added as an internal standard and mixed well. Spreading the mixed powder in a sample stage, and scanning: nickel filtered Cu ka radiation,graphite monochromatic tube, tube voltage 40kV (v=40 kV), current 40mA (i=40 mA). The scanning diffraction angle is 20-50 degrees, and the scanning speed is 1.5 degrees/min. The results are shown in FIG. 8. Wherein FIG. 8-1 shows the result of the reaction for 3 hours, and FIG. 8-2 shows the result of the reaction for 1 day. In the figure, the abscissa "deviee (2θ)" represents the peak position, and the ordinate "Intensity (a.u.)" represents the diffraction Intensity. The figure identifies the corresponding bone cement sample number and reaction time. The bone cement powder in the initial state has an alpha-TCP characteristic peak at a diffraction angle of 2 theta of 31 deg.. The characteristic peak of alpha-TCP gradually disappears after the calcium phosphate salt in the composite bone cement is hydrated, the characteristic peak of hydroxyapatite at the diffraction angles of 2 theta of 32 DEG, 47 DEG and 49 DEG gradually increases with time, the characteristic peak of alpha-TCP starts to decrease after 3 hours, and the characteristic peak disappears after 1 d. Meanwhile, baSO ₄ The characteristic peak of (2) remains constant during the coagulation. Starch reinforcing phase and BaSO ₄ The addition of (2) does not affect the formation of hydroxyapatite, the final product of the hydration reaction of the calcium phosphate cement.

III, analysis of functional groups of composite bone cement

By infrared spectrometer (purchased from sameifer, model Nicolet ^TM iS 20) carrying out functional group characterization on common calcium phosphate bone cement and composite bone cement, wherein the method comprises the following steps: bone is made up ofThe cement paste was poured into a cylindrical stainless steel mold of 6mm diameter and 12mm height, and the sample was pushed out of the mold and left to stand at 37 ℃ saturated humidity for 3 days to complete reaction curing. Grinding the sample with a mortar, taking a trace amount of powder sample, placing the powder sample in a test area of a spectrometer, and setting the scanning range to be 500-4000 cm ^-1 Resolution of 0.25cm ^-1 Testing was performed.

The infrared spectrogram of the composite bone cement is shown in figure 10; wherein FIG. 10-1 is an infrared spectrum of a composite bone cement with starch treated by method 1 as the reinforcing phase; fig. 10-2 is an infrared spectrum of a composite bone cement with starch treated by method 2 as a reinforcing phase and an infrared spectrum of a general calcium phosphate bone cement. Wherein, G1-G10 respectively correspond to the compound bone cements with corresponding numbers, and CPC represents common calcium phosphate bone cement.

Similar to ordinary calcium phosphate cements, most of the spectral bands in the infrared spectrum of the composite calcium phosphate cement shown in fig. 10 are attributed to hydroxyapatite crystallized by the DCPD and α -TCP reactions. PO is present in the infrared spectrogram ₄ ^3- Band, mainly concentrated at 563cm ^-1 、606cm ^-1 And 1030-1090cm ^-1 Characteristic peak at 1030-1090cm ^-1 Is PO (PO) ₄ ^3- Is 563cm ^-1 、606cm ^-1 The place is PO ₄ ^3- Bending vibration absorption peak. While 1030cm ^-1 And 1120cm ^-1 The characteristic peak at the position corresponds to starch and PO ₄ ^3- C-O-C group of (C). The characteristic peaks of organic groups characteristic of starch are also covered by the characteristic peaks of calcium phosphate and hydroxyapatite. It follows that the starch reinforcing phase in the composite bone cement does not interfere with the chemical composition of the matrix phase, it does not participate in chemical reactions, and no new groups are generated.

Example 6: degradation performance of composite bone cement

The composite calcium phosphate cement containing the starch reinforcing phase and the developer of the present application was injected into sheep bone, and the sheep bone injected with the composite calcium phosphate cement (the calcium phosphate cement containing the starch reinforcing phase and the developer) was continuously tracked and observed, and the degradation period was found to be more than 28 weeks after the degradation of the composite calcium phosphate cement of the present application (the calcium phosphate cement containing the starch reinforcing phase and the developer) was found to occur, as a result, the composite calcium phosphate cement of the present application (the composite calcium phosphate cement containing the starch reinforcing phase and the developer) had good degradation performance.

By combining the results of the foregoing examples, it can be found that both the developed calcium phosphate cement and the composite cement have an improved mechanical strength, but the composite cement has a significantly improved mechanical strength, as compared to the conventional calcium phosphate cement. By controlling the properties of the reinforcing phase starch, a mechanical strength of 30MPa can be achieved, which strength level makes it possible for the bone cement to be used in the bone structure of the load-bearing part. In particular, the strength of the composite bone cement can be increased to above 50MPa under the characteristic conditions of the partially enhanced phase starch (e.g., freeze-dried recovered modified waxy corn starch and modified normal corn starch). This level of strength not only allows the composite bone cement to be used in load bearing site bone structures, but also allows for good safety.

The modified starch added composite bone cement can also realize the improvement of the curing time. The initial setting time of the common calcium phosphate bone cement is less than 5min, and the final setting time is less than 10min. The non-gelatinized starch was added with an initial set time of approximately 10min and a final set time of approximately 15min. The results in the above examples show that the addition of gelatinized starch can more effectively improve the setting time, for example, by improving the initial setting time to approximately 15min or even slightly more than 25min, and by improving the final setting time to more than 20min or even slightly more than 35min, such setting time making the bone cement more suitable for surgical procedures. In practical applications, curing times of up to about 15 minutes are generally required to meet the operational requirements of bone cements for surgery; more preferably, the curing time can be further optimized, e.g. up to about 30 minutes, in order to obtain a sufficient handling time. Adequate operating time can achieve good injection and filling of bone cement, e.g., setting time is too short, and when bone cement is injected into a bone structure, the bone cement is prematurely set, resulting in insufficient injection of the slurry, and also insufficient uniform and adequate filling.

The composite bone cement added with the modified starch can also improve injectability and collapsibility resistance. The injectability results show that the injectability results of the common calcium phosphate bone cement are less than 90%, while the composite bone cement containing the modified starch reinforcing phase has excellent injectability, and the injectability results are more than 90%.

It can also be observed from the photographs of fig. 6-3 and 6-4 that the composite bone cement was smoothly injected from the syringe. 50N is the maximum thrust of the operator, under which smooth and smooth pouring out can be achieved without breakage, which means that in practical operation, adequate injection can be achieved.

The results of the anti-collapsibility properties of the bone cements are also shown in fig. 6-3 and 6-4. The modified starch serving as a reinforcing phase can obviously improve the collapsibility resistance of the bone cement, keeps the integrity under the test condition, and does not have collapsibility. In summary, the modified starch can enable the composite bone cement to achieve excellent injectability and collapsibility resistance at the same time.

The bone cement performance results in example 4 combined with the starch characterization results in example 3 show that the starch characterization significantly affects the performance parameters of bone water. By changing the starch reinforcing phase, the parameters of the composite bone cement can be adjusted, so that the bone cement has higher mechanical strength and more proper curing time, and simultaneously has the characteristics of easy injection and difficult collapse. For example, waxy corn starch, particularly freeze-dried and recovered waxy corn starch, exhibits higher mechanical strength as the reinforcing phase, while exhibiting more desirable setting times, ease of injection, and less susceptibility to collapse. For another example, compared with the common corn starch recovered by freeze drying, the common corn starch has better flowing property, can enable the bone cement to be easier to inject and not easy to collapse, simultaneously optimizes the curing time of the bone cement, is more beneficial to operation and has higher mechanical strength. The properties of the reinforcing phase starch and the properties of the bone cement can be improved by the gelatinization treatment, in particular when recovered by a freeze-drying method, so that the bone cement obtains better properties in terms of curing time, mechanical strength, injectability, anti-collapsibility and the like.

The scanning electron microscope results of the starch in the previous examples show that the modification and recovery method significantly affects the apparent morphology of the starch. The waxy corn starch and the common corn starch are recovered by a freeze drying method, the apparent morphology of the waxy corn starch and the apparent morphology of the common corn starch are in an irregular sheet shape under an electron microscope, the starch structure is loose and porous, better contact can be formed between the waxy corn starch and water, the waxy corn starch and the water are easy to form gel, the waxy corn starch and the common corn starch show good swelling capacity at normal temperature, the viscosity of the waxy corn starch is lower, the waxy corn starch and the common corn starch can also have good fluidity when used in bone cement, and the waxy corn starch and the common corn starch have good mechanical strength and good operability.

Different starch crystal structures can affect the performance parameters of bone cements. For example, the freeze-dried and recovered starch can better maintain the state in which the crystalline region is completely destroyed. Compared with starch recovered by alcohol precipitation, the starch recovered by freeze drying can improve the curing time of bone cement to a greater extent and improve the mechanical strength.

The surface morphology of the bone cement is analyzed by observing a scanning electron microscope image, so that the microscopic surface morphology of the common calcium phosphate bone cement and the developed calcium phosphate bone cement has more obvious needle-shaped structures. The apparent needle-like structure belongs to the morphology of typical hydroxyapatite crystals. The same needle-like crystal particles can be observed for the composite bone cement containing the starch reinforcing phase, indicating that the hydration product of CPC is not significantly changed after the modified starch is added. Surprisingly, the common calcium phosphate bone cement and the developing calcium phosphate bone cement have obvious clustered aggregation of needle-shaped structures, while the composite bone cement containing the starch reinforcing phase shows smaller clustered aggregation of needle-shaped structures, and the holes are smaller, so that the surface morphology structure in the scanning electron microscope image shows more uniform and less clustered aggregation of needle-shaped crystal structures, and correspondingly, the bone cement can obtain higher mechanical strength, relatively better curing time and better operation performance. In particular, waxy corn starch and ordinary corn starch exhibit more uniform surface morphology and smaller pores than other samples when used as the reinforcing phase.

As can be seen from the analysis of the results in the above examples, by adjusting the characteristics of starch, a lower amylose content, a lower starch viscosity, a higher starch swelling capacity, a looser apparent morphology, a lower bone cement porosity and a higher bone cement density are obtained, the surface morphology of the bone cement is affected, aggregation of needle-like crystal structures is weakened or even eliminated, and the improvement of the properties of the bone cement, such as the improvement of the mechanical strength, the acquisition of a curing time more convenient to operate, the improvement of the operation performance, and the like, can be achieved. Surprisingly, by controlling the characteristic of the starch reinforcing phase, the compressive strength of the composite bone cement can be improved by more than 4 times compared with that of the common calcium phosphate bone cement, reaches 50-60 MPa, fully meets the mechanical requirement of the bearing bone, and has good injectability and collapsibility. In addition, the composite calcium phosphate bone cement has good effect in the aspects of degradability and the like. Compared with the existing bone cement, the bone cement has the advantages in main performances of strength, curing time, degradability, injectability, collapsibility resistance and the like, and can realize good comprehensive effects.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control.

The terms "comprising," "including," "having," "containing," and variations thereof herein are intended to be open-ended terms, or words that do not exclude the possibility of additional operations or structures. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments "comprising," consisting of, "and" consisting essentially of the embodiments or elements presented herein, whether or not explicitly presented.

The term "or" includes any and all combinations of one or more of the listed elements associated with the term. For example, the phrase "a device containing a or B" may refer to a device that includes a but where B is not present, a device that includes B but where a is not present, or a device where both a and B are present. The phrase "A, B,..at least one of and N" or "A, B,..n, or at least one of a combination thereof is defined in its broadest sense to mean one or more elements selected from A, B,..and N, that is, any combination of one or more of element A, B,..or N, including either element alone or in combination with one or more of the other elements, which also may include additional elements not listed in combination.

All numerical values are herein assumed to be modified by the term "about" or "approximately", whether or not explicitly indicated. In the context of using numerical values, the term "about" or "approximately" generally refers to a range that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result) and its neighbors. "about" or "approximately" should also be considered to disclose a range defined by the absolute values of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4". The term "about" or "approximately" may refer to +or-10% of the indicated value. For example, "about 10%" may refer to a range of 9% to 11%, and "about 1" may refer to 0.9-1.1. In many instances, the term "about" or "approximately" may include values rounded to the nearest significant figure, e.g., "about 1" may also refer to 0.5 to 1.4. Unless otherwise specified, other uses of the term "about" (i.e., in contexts other than the use of numerical values) may be assumed to have their ordinary and customary definitions.

The above embodiments are provided for illustrating the present invention and not for limiting the present invention, and various changes and modifications may be made by one skilled in the relevant art without departing from the scope of the present invention, therefore, all equivalent technical solutions shall fall within the scope of the present disclosure.

Claims

1. A bone cement comprising a matrix phase, a reinforcing phase, a developer in an amount sufficient to effect development, and a setting fluid, wherein the matrix phase comprises a calcium phosphate salt, the setting fluid is capable of reacting with at least the calcium phosphate salt in the matrix phase to form hydroxyapatite, the reinforcing phase comprises starch, the starch being gelatinized starch, wherein the gelatinized starch has an amylose content of less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or less than 3%.

2. The bone cement of claim 1, wherein the reinforcing phase mass is 1% to 100%, or 5% to 95%, or 10% to 50% of the matrix phase mass.

3. The bone cement of claim 1, wherein the matrix phase comprises one or more selected from tricalcium phosphate, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, tetracalcium phosphate, octacalcium phosphate, monocalcium phosphate, hydroxyapatite, fluorapatite.

4. A bone cement according to claim 3, wherein the matrix phase comprises a mixture of both tricalcium phosphate and dibasic calcium phosphate dihydrate.

5. The bone cement of claim 1, wherein the setting fluid comprises one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, dilute phosphoric acid, calcium hydroxide, citric acid, glycerol, and/or malonic acid.

6. The bone cement according to claim 1, wherein the gelatinized starch is recovered by a method selected from one or a combination of alcohol precipitation, freeze drying and/or spray drying.

7. The bone cement of claim 6, wherein the freeze-drying temperature is no higher than-10 ℃, or no higher than-20 ℃, or no higher than-30 ℃, or no higher than-40 ℃, or no higher than-50 ℃, or no higher than-60 ℃, or no higher than-70 ℃, or no higher than-80 ℃, or no higher than-90 ℃, or no higher than-100 ℃.

8. The bone cement of claim 1, wherein the starch comprises one or more selected from the group consisting of common corn starch, waxy corn starch, high amylose corn starch, tapioca starch, and potato starch.

9. A method of preparing bone cement, the method comprising: mixing a matrix phase comprising calcium phosphate salt, a reinforcing phase capable of reacting with at least the calcium phosphate salt in the matrix phase to form hydroxyapatite, a developer in an amount sufficient to effect development, and a curing liquid comprising gelatinized starch, wherein the gelatinized starch has an amylose content of less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or less than 3%.

10. The method of claim 9, wherein the reinforcing phase mass is 1% to 100%, or 5% to 95%, or 10% to 50% of the matrix phase mass.

11. The method of claim 9, wherein the starch comprises one or more selected from the group consisting of common corn starch, waxy corn starch, high amylose corn starch, tapioca starch, and potato starch.

12. Use of a starch material comprising gelatinized starch having an amylose content of less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or less than 3% for the preparation of bone cement.

13. The use according to claim 12, wherein the gelatinized starch is recovered by a method selected from one or more of alcohol precipitation, freeze drying, or spray drying.

14. The use of claim 13, wherein the freeze drying temperature is no higher than-10 ℃, or no higher than-20 ℃, or no higher than-30 ℃, or no higher than-40 ℃, or no higher than-50 ℃, or no higher than-60 ℃, or no higher than-70 ℃, or no higher than-80 ℃, or no higher than-90 ℃, or no higher than-100 ℃.

15. The use of claim 12, wherein the starch comprises one or more selected from the group consisting of common corn starch, waxy corn starch, high amylose corn starch, tapioca starch, and potato starch.

16. A kit for preparing bone cement, the kit comprising a matrix phase, a reinforcing phase, and a sufficient amount of a developer to effect development; wherein the enhancing phase comprises gelatinized starch, wherein the gelatinized starch has an amylose content of less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or less than 3%, and wherein the gelatinized starch is recovered by lyophilization.

17. The kit of claim 16, further comprising a liquid phase portion comprising a solidifying liquid capable of reacting with at least calcium phosphate in the matrix phase to form hydroxyapatite.