KR20110129007A

KR20110129007A - Graular porous bone substitute and method for preparing the same

Info

Publication number: KR20110129007A
Application number: KR1020100048388A
Authority: KR
Inventors: 이병택; 장동우; 쿠마르 사르카 스와판
Original assignee: 순천향대학교 산학협력단
Priority date: 2010-05-25
Filing date: 2010-05-25
Publication date: 2011-12-01

Abstract

PURPOSE: A granular porous bone transplantation material and a manufacturing method thereof are provided to have a desired mechanical strength while maintaining high porosity. CONSTITUTION: A manufacturing method of a granular porous bone transplantation material comprises: a step of forming a filament having one carbon rod core by placing the mixture of binder and biomaterial ceramic powder around a carbon rod and extruding the mixture; a step of removing binder by heat-treating the compressed filament; a step of removing carbon by heat-treating the heat-treated filament; and a step of forming a filament having a plurality of carbon rod cores by placing a plurality of filaments in an extrusion die and extruding the filaments.

Description

Granular porous bone substitute and method for preparing the same {Graular porous bone substitute and method for preparing the same}

The present specification describes a granular porous bone graft material and a method of manufacturing the same, for example, a granular porous bone graft material that can be implanted into a human body for quick and easy treatment of damaged and injured areas of the cortical bone, and The manufacturing method is related.

Hard tissue transplantation from the patient (autograft) himself or the donor (allograft or xenograft) is required at the defect site to support mechanical stress and also to enhance natural bone regeneration and treatment.

Recently, bone grafts have received medical attention as fillers for injured bone replacement or filling of hard tissue cavities.

The best method of bone graft is autografting, ie transplantation from other parts of the body, but there are limitations depending on the recipient's condition and the likelihood of harvesting. Therefore, although bone grafts made from bones of animals or carcasses have been applied in clinical practice, they may be exposed to potential infections such as mad cow disease or AIDS.

To remedy these problems, calcium-phosphate-based ceramic bone grafts such as hydroxyapatite (HAp), tricalcium phosphate (α / β-TCP) and biphasic calcium phosphate (BCP), similar to those of natural bone, are being developed, especially BCP. Ceramics are used in dentistry and orthopedics because of their balance of mechanical strength and biodegradability.

Hard tissue replacement materials, on the other hand, have different requirements depending on the clinical application.

Block-type bone graft is required when the defect is large, but a long time is required in the manufacturing process, and thus there is a limitation in preparing a bone graft having a shape most suitable for the defect. In addition, the block-type bone graft material has a disadvantage that shows a slow biodegradation characteristics because of the thick skeleton structure.

In the case of the implantable bone graft, the above-mentioned disadvantages of the block-type bone graft material can be compensated for, but the porosity, which is an important factor affecting remineralization and bone formation, cannot be controlled and the strength is low.

Granular bone graft has the potential to compensate for the above disadvantages, and can be used as an excellent bone graft because it has excellent strength and easy applicability.

According to the research of the present inventors, granular bone grafts generally have a limit in controlling the size of pores because they are very small in size. Biodegradation and bone-like behavior, the process of fusion between bone grafts and natural bones, depend on the extent of osteoblasts and physiological fluids penetrating into the bone graft. Porosity of bone grafts is a very important factor, but the porosity and mechanical properties are inversely related. As the porosity increases, the mechanical properties and stability are significantly reduced.

Accordingly, the present inventors provide a granular porous bone graft material having a desired mechanical strength while maintaining high porosity and further excellent in biocompatibility, and a method for producing the same.

In embodiments of the present invention, the step of placing a mixture of a ceramic material, a binder and a lubricant material of the biological material around the carbon rod as a pore forming agent and primary extrusion to form a filament having one carbon rod core (S1); Primary heat treatment of the extruded filaments to remove a binder (S3); It provides a method for producing a granular porous bone graft material comprising a; and (S4) to remove the carbon as a pore-forming agent by the second heat treatment of the first heat-treated filament.

In an exemplary embodiment, between the steps S1 and S3, the plurality of filaments may be aligned in an extrusion die and further extruded to form a filament having a plurality of carbon rod cores (S2). Additional extrusion process can be performed to be repeated.

In embodiments of the present invention, there is also provided a granular porous bone graft material having one or more pore channels.

In an exemplary embodiment, the granular porous bone graft material preferably further includes silicon and strontium.

The granular porous bone graft material according to the embodiments of the present invention has a desired mechanical strength while maintaining a high porosity, and is also particularly excellent in biocompatibility. Such bone graft material can control important factors such as biodegradability and mineralization by controlling the thickness of the skeleton. In addition, since the bone graft material is small in size, it can be applied regardless of the size or location of the defect site during clinical application.

1 is a photograph showing an optical image of a cross section of a cylindrical granular porous bone graft prepared in various sizes and arrangements in an embodiment of the present invention.
Figure 2 is a SEM photograph showing a cross-section of the granular porous bone graft material without added silicon and strontium prepared in the embodiment of the present invention.
3A-3C show SEM images of the channel inner surface of FIGS. 2A-2C, respectively, in embodiments of the invention. FIG. 3D shows the surface roughness of the enlarged SEM image, 3E (FIG. 3D shows an enlarged image of 3E). 3f shows the thermally etched frame microstructure (FIG. 3f is an enlarged image of 3 (c)).
Figure 4 using the MTT extract method for diluted extracts of pure BCP implants without silicon and strontium added, silicon doped BCP bone implants, strontium doped bone implants, according to an embodiment of the present invention. A graph showing the relative cellular activity for L929, respectively (in FIG. 4, control represents 100% fibroblast L929).

Hereinafter, exemplary embodiments of the present invention will be described.

Embodiments of the present invention to form a pore channel in order to have a desired mechanical strength while maintaining a high porosity in the granular porous bone graft material. The pore channel can form unidirectional pores exhibiting a desired porosity without degrading mechanical properties, and can also improve cell proliferation.

In the embodiments of the present invention, in order to form the above-mentioned pore channel, the extrusion process into a filament shape using a carbon rod as a pore forming agent together with a ceramic material which is a biomaterial. Extrusion into such a filament shape makes it possible to form a pore channel.

Using the extrusion process can also control the pore size and porosity of the bone graft material. This extrusion process can easily control the unidirectional microstructure, by using it can control the size of the ceramic material and the pore-forming carbon of the biomaterial in the bone graft material.

In the embodiments of the present invention, it is also possible to exhibit more excellent biocompatibility than the general biomaterial ceramics such as BCP by preparing by adding silicon and / or strontium in the preparation of granular porous bone graft material.

Specifically, the granular porous bone graft material according to an exemplary embodiment of the present invention is prepared as follows.

First, a mixture of ceramic material, a binder, and a lubricant, which is a biomaterial, is placed around the carbon rod, which is a pore former, which is mixed in a shear mixer, for example, and extruded to form a filament having one carbon rod core ( S1).

The ceramic powder as the biomaterial is not particularly limited, and biphasic calcium phosphate (BCP) is typically used. The BCP is a mixture of hydroxyapatite (HAp) and tricalcium phosphate (TCP). In addition to the BCP, other calcium phosphate-based bio ceramics such as HAp alone and TCP alone may be used. In addition, zirconia (ZrO ₂ ), alumina (Al ₂ O ₃ ), and the like may also be used.

In an exemplary embodiment of the present invention, when BCP is used, Ca (NO ₃ ) ₂ 4H ₂ O and (NH ₄ ) ₂ HPO ₄ are dissolved in distilled water, respectively, and the (NH ₄ ) ₂ HPO ₄ solution is placed in an ultrasonic machine. Ca (NO ₃ ) ₂ 4H ₂ O solution is slowly mixed to obtain a powder. The powder obtained is dried and then calcined at 750 ° C. to produce ceramic powder.

For example, EVA (ethylene vinyl acetate) may be used as the binder of the ceramic powder. In addition, polyethylene, wax, polypropylene, paraffin, or the like may be used.

Stearic acid (CH ₃ (CH ₂ ) ₁₆ COOH) may be used as the lubricant. The lubricant is intended to assist shear mixing and extrusion processes, in addition to the stearic acid, polyethylene waxes, oxidized polyethylene waxes, esters, amides (eg, oleamide, erucamide), fatty acids (eg, , lauric acid, myristic acid, palmitic acid).

The binder polymer and lubricant in the composition of the mixed powder are used to maintain the viscosity of the thermoplastic lumps. They can contribute to making fine microstructures during uniform extrusion.

In a preferred embodiment of the present invention, the granular porous bone graft material may be prepared by adding silicon and / or strontium. To this end, silicon and / or strontium may be added to the ceramic powder itself.

In an exemplary embodiment of the invention, when adding silicon and strontium to BCP, Na ₂ SiO ₃ is dissolved in distilled water together with (NH ₄ ) ₂ HPO ₄ , while Sr (NO ₃ ) ₂ is Ca (NO ₃₎ ) ₂ 4H ₂ O and then dissolved in distilled water, Na ₂ SiO ₃ And (NH ₄ ) ₂ HPO ₄ mixed solution with an ultrasonic machine and slowly mixed with the mixed solution of Sr (NO ₃ ) ₂ and Ca (NO ₃ ) ₂ 4H ₂ O to obtain a powder. The powder obtained may be dried and then subjected to a calcination process at 750 ° C. to prepare a ceramic powder to which silicon and strontium are added.

In an exemplary embodiment, silicon and strontium are allowed to be added at 2% by weight or less, such as 1.5% by weight of the ceramic powder.

For reference, silicon plays an important role in the calcification process and early stages of bone formation and promotes the proliferation and growth of osteoblasts. In addition, genes such as collagen and BMP-2 may be overexpressed. Silicate hydroxyapatite supports can improve response in treating bone. In addition, strontium is used for the treatment of osteoporosis, and can increase osteoblast differentiation and proliferation, as well as help bone formation and calcification. It can also inhibit osteoclast formation and bone uptake.

The carbon rod, which is the pore former, is used for forming a pore channel in an extrusion process described later, and is removed through a secondary heat treatment process.

In other words, the carbon rod forming the core in the filament during the extrusion process is removed in the secondary heat treatment process to form a void space, that is, a pore channel corresponding to the core portion.

In embodiments of the present invention, in order to have a plurality of channels in the filament, the primary extruded filament (filament with one core) is aligned in a plurality of extrusion dies and further extruded to have a plurality of carbon rod cores To form a filament (S2). The additional extrusion process may be repeatedly performed as the extrusion process using a plurality of filaments subjected to the second extrusion process again. By this additional extrusion process it is possible to control the number and dimensions of the pore channels.

In the extrusion process, the temperature may be, for example, 190 to 120 ° C.

The volume ratio of the cell consisting of the ceramic component (a mixture component of the ceramic, the binder and the lubricant) and the core consisting of the carbon component in the primary extruded filament or a plurality of further extruded filaments may be, for example, 50:50.

The extrusion ratio of the diameter of the first filament (filament having one core) and the second filament (filament having a plurality of cores) in the extrusion may range from 27 to 217.

For reference, when the size of the channel is 100 ~ 500㎛ bone cell proliferation and adhesion is good. Maintaining the extrusion ratio can maintain a channel size of 150 ~ 400㎛.

For reference, the extrusion ratio may be controlled according to the diameter of the die, and the diameter of the primary extruded filament may also be controlled to match the size required for the secondary extruded filament. Accordingly, it is possible to determine the skeleton size of the bone graft material. In addition, it is possible to control the size of the pore channel of the bone graft material according to the extrusion ratio in each extrusion process. In addition, the final extruded body can be cut to control the length of the bone graft agent. The rough pore surface generated while repeating such an extrusion process can further improve the adhesion of osteoblasts.

After the extrusion process is completed, the first heat treatment process is performed to remove the binder from the obtained filament (S3). This heat treatment process is, for example, inert atmosphere N ₂ In the atmosphere, the temperature ranges from 650 ° C to 750 ° C (preferably 700 ° C), slowly increasing the temperature to 100 to 120 hours to degrease the binder during this process. By maintaining the above temperature range and the time required to reach the temperature range, the binder can be removed while preventing deformation of the granules.

In addition, a second heat treatment process is performed to remove carbon, which is a pore former, after the first heat treatment process (S4). The second heat treatment process is preferably 25 to 30 hours to reach a temperature range of 950 ~ 1050 ℃ (preferably 1000 ℃) because it can remove the carbon while preventing the deformation of the granules.

Finally, the sintering process (S5), for example, to perform a sintering process for 2 hours at 1300 ° C under an air atmosphere to produce a granular porous bone graft material.

The obtained granular porous bone graft material is a pore channel uniformly distributed by carbon as a pore former. In one embodiment, the obtained granular porous bone graft material has a diameter of about 110 ~ 220㎛, porosity of about 41.6 ± 1.3%, extrusion strength was about 16MPa.

The microstructure of the granular porous extruded body according to the embodiments of the present invention, that is, the pore size and the thickness of the skeleton may be controlled in various forms according to the composition of the ceramic and carbon and the extrusion conditions. For reference, the control of the pore size and the thickness of the skeleton in the manufacture of bone graft material is an essential factor. In addition, the strength of the granular porous bone graft material is different depending on the shape and arrangement of the pores and the shape of the skeleton.

Hereinafter, one or more exemplary embodiments of the present invention will be described in more detail by way of non-limiting exemplary embodiments and comparative examples.

[Manufacturing Example]

Porous bone grafts with round granules and pore channels were prepared. The bone graft base material was bi-phasic calcium phosphate ceramic (BCP), and silicon and strontium were added.

Specifically, calcium nitrate tetra hydrate (Ca (NO ₃ ) ₂ 4H ₂ O) and di ammonium hydrogen phosphate ((NH ₄ ) ₂ HPO ₄ ) may be synthesized by BCP ceramic powder of nanoparticles by ultrasonic preparation.

Such ultrasonic preparation is well known and will not be described separately.

For silicon and strontium doping, sodium silicate solution (Na ₂ SiO ₃ ) is mixed with di ammonium hydrogen phosphate ((NH ₄ ) ₂ HPO ₄ ) and strontium nitrate solution (Sr (NO ₃ ) ₂ ) is calculated as Calcium nitrate tetra hydrate. After mixing with (Ca (NO ₃ ) ₂ 4H ₂ O), silicon and strontium doped BCP ceramic powders are synthesized by the same ultrasonic preparation method. The prepared powder is subjected to a calcination process.

In the extrusion of the ceramic powder, ethylene vinyl acetate (EVA), a thermoplastic polymer, was used as a binder, and stearic acid (CH ₃ (CH ₂ ) ₁₆ COOH) was mixed as a lubricant. Carbon rods were used as pore formers. These BCP powders, EVA and stearic acid were mixed in a shear mixer.

The filaments were then extruded by placing a mixture of the BCP powder, EVA and stearic acid around the carbon rod and performing an extrusion process on an extrusion die. Here hot extrusion was allowed to be carried out. Extrusion temperature was carried out at 90 ~ 120 ° C.

The binder polymer and lubricant mixed with BCP powder were placed around a 21 mm diameter carbon rod. The extrusion die diameter was set to 30 mm so that the diameter of the shell before extrusion was set to 30 mm. The volume ratio of core and shell was 50:50.

The primary extruded filaments were 3.5 mm in diameter and cut to 8 cm in length.

The primary extruded filaments were again placed in a new extrusion mold (extrusion mold diameter 10 mm), 7 (for 7 channel production) and 9 (for 19 channel production), and second extruded.

Subsequently, EVA (binder) was removed through a first heat treatment process. To this end, the temperature was slowly raised to 700 ° C. in N ₂ atmosphere to degrease by performing a first heat treatment for 5 days. Carbon continues to remain during the low temperatures at which the binder polymer is removed.

After the second heat treatment, the pore former carbon was completely removed. To this end, secondary heat treatment was performed at 1000 ° C. under air atmosphere. In the process, carbon was removed to form pore channels.

The final sintering process was performed at 1300 ° C for 2 hours under air atmosphere. Through this sintering process, the total volume is reduced.

[Evaluation of results]

1 is a photograph showing an optical image of a cross section of a cylindrical granular porous bone graft prepared in various sizes and arrangements in an embodiment of the present invention.

1 a and b each have seven pore channels, and c has 19 channels.

The pore channel was well formed even though the granule diameter was changed to 1 mm (FIG. 1A) and 1.5 mm (FIG. 1B) while maintaining the pore array in 7 channels.

On the other hand, when the pore channel is set to 19 channels, the mechanical properties are deteriorated, so that the compressive strength is lower than that of the 7 channel.

In order to prepare granular bone grafts with different mechanical and physical properties, the microstructures with different reduction rates were investigated in each extrusion step. The reduction ratio was analyzed according to the degree of compression.

Tables 2 to 4 show the results by way of example.

Extrusion step Diameter before extrusion
(mm) Number of cores Diameter after extrusion
(mm) Extrusion rate First extrusion
filament 29.5 One 3.5 72 Second extrusion
filament 3.5 7 2 27

Extrusion step Diameter before extrusion
(mm) Number of cores Diameter after extrusion
(mm) Extrusion rate First extrusion
filament 29.5 One 2 217 Second extrusion
filament 2 19 2 27

Extrusion step Diameter before extrusion
(mm) Number of cores Diameter after extrusion
(mm) Extrusion rate First extrusion
filament 29.5 One 3.5 72 Second extrusion
filament 10.5 7 2 27 Second extrusion
filament 10.5 7 1.5 42 Second extrusion
filament 10.5 7 One 110

Figure 2 is a SEM photograph showing a cross-section of the granular porous bone graft material without added silicon and strontium prepared in the embodiment of the present invention. 2a to 2c are (a) 0.75 mm, (b) 1.2 mm, and (c) 1.5 mm, respectively, and (d), (e), and (f) are the corresponding (a), (b), ( The pore part of c) is enlarged and shown.

Table 5 exemplarily shows pore sizes and skeletal thicknesses of granules having a diameter of 0.75 mm, 1.2 mm, and 1.5 mm in the prepared granules.

diameter Pore size (㎛) Skeleton thickness (㎛) 0.75 mm, 350 240 1.2 mm 280 175 1.5 mm 180 125

Table 6 shows the extrusion strength and relative density of granules having a diameter of 0.75 mm, 1.2 mm and 1.5 mm in the prepared granules.

diameter Compressive strength (MPa) Relative Density (%) 0.75 mm, 16.4 ± 3.5 58.4 ± 1.3 1.2 mm 11.4 ± 2.8 55.7 ± 1.9 1.5 mm 6.2 ± 2.6 51.2 ± 2.1

As can be seen from Table 6, the compressive strength and the relative density decreased because the thickness of the frame decreased with decreasing diameter.

3A-3C show SEM images of the channel inner surface of FIGS. 2A-2C, respectively, in embodiments of the invention. 3D shows the surface roughness of the magnified SEM image of 3E.

3F shows the thermally etched frame microstructure of FIG. 3C. The frame area of the bone graft was dense and the crystal size of the sintered bone graft was 4-8 μm. This indicates that grains are coarsened but that no process defects are observed.

As can be seen in Figure 3, the inside surface of the channel was observed by scanning electron microscopy, the surface was very rough, two modes appeared. One is roughness with sharp faces along the channel, and the other is inherent surface roughness due to irregular crystal arrangement of the surface. The rough surface is ideal because it facilitates the attachment of proliferated cells and, furthermore, serves to help mechanical linkage to cell proliferation and can also enhance the interaction between cells and bone fillers.

Figure 4 using the MTT extract method for diluted extracts of pure BCP implants without silicon and strontium added, silicon doped BCP bone implants, strontium doped bone implants in an embodiment of the present invention. Each exhibits relative cellular activity against L929.

As can be seen from Figure 4, by using the MTT extract method to measure the cytotoxicity of each bone graft, and looking at the proliferation pattern of the cells, the survival rate of all the cells was confirmed that there is almost no toxicity at more than 90%. It also verified that it meets the requirements of ISO.

Claims

Positioning (S1) a filament having one carbon rod core by placing and first extruding the mixture of the ceramic material and the binder as the biomaterial around the carbon rod as the pore former;
Primary heat treatment of the extruded filaments to remove a binder (S3); And
And (S4) removing the carbon, which is a pore former, by performing a second heat treatment on the first heat-treated filament.

The method of claim 1,
Between the step S1 and step S3, granular porous bone graft material manufacturing step characterized in that performing the step (S2) to form a filament having a plurality of carbon rod core by aligning and further extruding the plurality of filaments in an extrusion die Way.

The method of claim 2,
Method for producing a granular porous bone graft material, characterized in that to repeat the process of aligning a plurality of filaments obtained through the step S2 to the extrusion die and further extrusion.

The method of claim 1,
The ceramic powder is biphasic calcium phosphate; Or a biphasic calcium phosphate comprising at least one of silicon or strontium.

The method of claim 4, wherein
The silicon or strontium is granular porous bone graft material manufacturing method characterized in that it is contained in less than 2% by weight relative to biphasic calcium phosphate.

The method of claim 1,
The binder is ethylene vinyl acetate, characterized in that the granular porous bone graft material manufacturing method.

The method of claim 1,
The method of producing a granular porous bone graft material, characterized in that the mixture further comprises a lubricant in step S1.

The method of claim 7, wherein
The lubricant is a method of producing a granular porous bone graft material, characterized in that stearic acid.

The method of claim 1,
The step S3 is granular porous bone graft material manufacturing method, characterized in that it takes 100 to 120 hours to reach a temperature range of 650 ~ 750 ℃.

The method of claim 1,
The step S4 is granular porous bone graft material manufacturing method, characterized in that it takes 25 to 30 hours to reach a temperature range of 950 ~ 1050 ℃.

Granular porous bone graft material having at least one pore channel.

The method of claim 11,
The bone graft material is biphasic calcium phosphate; Or granular porous bone graft material comprising a biphasic calcium phosphate containing one or more of silicon (silicon) or strontium (Strontium).