KR101219871B1 - Method for preparing porous strut of biomaterials and porous strut of biomaterials prepared thereby - Google Patents

Abstract

Disclosed are a method for producing a porous body of a biomaterial in which a biocompatible polymer is infiltrated into a porous body of a biomaterial, and a porous body of a biomaterial. The method not only easily obtains the interconnected open pore structure but also can easily solve the problem of low strength of the conventional biomaterial porous body.

Description

Method for preparing porous strut of biomaterials and porous strut of biomaterials prepared}

The present specification relates to a method for preparing a porous body of a biomaterial and a porous body of a biomaterial, and more particularly, to a method for preparing a porous body of a biomaterial using a polymer infiltration method and a porous body of the biomaterial according to the same.

Among calcium phosphate ceramics, in particular, biomaterials such as hydroxyapatite (HAp) and tricalcium phosphate (TCP) have excellent biocompatibility, bioactivity, and bone conduction properties with human tissue. It has been used a lot as.

Since hydroxyapatite shows excellent bioactivity, excellent bone conduction, and tricalcium phosphate shows excellent biodegradability, biphasic calcium phosphate (BCP), which is a mixture of two materials, has recently been in the spotlight. . By controlling the ratio of hydroxyapatite (HAp) and tricalcium phosphate, the properties of the material and the rate of biodegradation can be controlled.

In the biomaterial porous body such as a porous body composed of hydroxyapatite (HAp) and tricalcium phosphate, the importance of open pores having an interconnected form has been emphasized, and the pore size is 150 to suit bone conduction characteristics. More than a micrometer is required.

Accordingly, various methods have been developed for producing a biomaterial porous body such as a porous body composed of hydroxyapatite (HAp) and tricalcium phosphate.

Conventionally, the method for preparing a porous porous material is generally a gel-casting method, a coating method using a polymer sponge, a method combining gel-casting and a sponge coating method, template directed (template directed), salt leaching, unidirectional ice crystal growth, freeze casting, and extrusion are used.

According to the research of the present inventors, the coating method using a sponge, which is a method used to prepare a porous body of a conventional biomaterial such as BCP, has a difficulty in producing a porous body that satisfies the strength required as artificial bone. In addition, since the higher the porosity, the higher the porosity, the lower the strength, and thus the limit is imposed on actual clinical application.

Accordingly, the present inventors have been able to manufacture interconnected open pore structures suitable for bone conduction properties, and have come to the present invention as a result of intensively studying the porous material of the biomaterial having high strength and the porous material of the biomaterial accordingly.

In embodiments of the present invention, it provides a method for producing a porous body of a biomaterial comprising; infiltrating the biocompatible polymer into the porous body of the biomaterial.

In an exemplary embodiment, the method comprises the steps of preparing a suspension comprising a biomaterial, a pore former, an organic solvent, a binder; Immersing a sponge in the suspension and drying it; Heating the sponge coated with the biomaterial to remove organic solvents, binders, sponges, and pore formers, and sintering to prepare a porous material of the biomaterial; And infiltrating the biocompatible polymer into the porous body.

Embodiments of the present invention also provide a porous material of a biomaterial in which a biocompatible polymer is infiltrated inside the porous material of the biomaterial.

Gel-casting, gel-casting and sponge coating methods, and template directed methods, which are conventionally used to prepare biomaterial porous bodies. Compared with salt leaching, unidirectional ice crystal growth, freeze casting, extrusion, etc., not only can the interconnected open pore structure be easily obtained, but also the low strength problem of the conventional biomaterial porous body is easily solved. Can be.

1 is a flow diagram schematically illustrating a method of making a biomaterial porous body in an exemplary embodiment of the present invention.
FIG. 2 shows the BCP porous open pores (FIG. 2A) without using the internal pore formers prepared in the exemplary embodiment of the present invention, and the skeleton of the porous body of FIG. 2A (FIG. 2B), PMMA as the internal pore formers. SEM image showing the BCP porous body (FIG. 2D) in which the BCP porous body (FIG. 2C) and the polymer (PCL) were infiltrated after PMMA was removed.
3 is a BCP porous body (FIG. 3A) without using the internal pore forming agent prepared in an exemplary embodiment of the present invention, BCP porous body (FIG. 3B) using PMMA as the internal pore forming agent and polymer (PCL) infiltrate It is an SEM photograph which shows the cross section which cut | disconnected the BCP porous body (FIG. 3C) which was made into the lateral direction.
4 is an XRD profile analyzing the phases of the BCP porous body and initial powder prepared in an exemplary embodiment of the invention.
Figure 5 is a graph showing the pore distribution of the BCP porous body infiltrated BCP porous body and polymer (PCL) prepared in an exemplary embodiment of the present invention.
6 is a graph showing the biocompatibility of the BCP porous body infiltrated with the BCP porous body and the polymer (PCL) prepared in an exemplary embodiment of the present invention.
Figure 7 is a photograph showing the cell adhesion in the BCP porous body (PCL-BCP scaffold) infiltrated BCP porous body (BCP scaffold) and polymer (PCL) prepared in an exemplary embodiment of the present invention.

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

In embodiments of the present invention, the strength of the porous body of the biomaterial can be easily improved by infiltrating the biocompatible polymer into the porous body of the biomaterial.

1 is a flow diagram schematically illustrating a method of making a biomaterial porous body in an exemplary embodiment of the present invention.

As shown in FIG. 1, in an exemplary embodiment of the present invention, a mucus suspension is first prepared by mixing a biomaterial, an internal pore former, an organic solvent, and a binder.

The mucus suspension may be prepared by first mixing and ball milling a biomaterial and an internal pore-forming agent to prepare a biomixture, followed by mixing an organic solvent and a binder.

The biological material is not particularly limited, and biphasic calcium phosphate (BCP) is typically used, and besides, calcium phosphate such as hydroxyapatite (HAp) and tricalcium phosphate (TCP) Type bio-ceramics can be used. In addition, zirconia (ZrO ₂ ), alumina (Al ₂ O ₃ ), and the like may also be used.

The pore former is not particularly limited, and for example, polymethyl methacrylate (PMMA) may be used. Other spherical polymer powders such as spherical polymer powders of about 15 μm in size may be used.

In an exemplary embodiment, the biomaterial and the pore former are 65 to 75% by volume of the biomaterial: 25 to 35% by volume of the pore former.

An organic solvent and a binder are mixed with the biological mixture prepared from the biomaterial and the pore-forming agent and stirred to prepare a mucus suspension.

As the organic solvent, methanol, ethanol, propanol, butanol, and the like may be used. The organic solvent may be used together with a polyvinyl butyral as a binder. When using the organic solvent and the binder together, the binder may be used in 3 to 5% by weight of the total mucus suspension.

The organic solution including the biological mixture may be mixed with stirring, and then ultrasonic waves may be added to minimize the aggregation phenomenon of the powder.

The organic mixture in the organic solution is 88-92% by volume of the organic solution: 8-12% by volume of the biological mixture. In particular, 90% by volume of the organic solution: 10% by volume of the biological mixture is easy to form the open pores and easy to make a skeleton of the desired thickness. If it is out of the above range, closed pores are formed or the skeleton is too thin, the strength may be lowered.

Next, the sponge is dipped in the viscous liquid suspension and allowed to dry.

Polyurethane sponge can be used as the sponge. The sponge is dipped in the previously prepared mucus suspension so that the sponge is coated on the suspension. At this time, the compressed air is sprayed to uniformly coat the open pores. This is followed by a drying process. The coating and drying is preferably performed two or more times, preferably three times.

Next, the sponge coated with the biomaterial obtained in the above process is degreased to remove the organic material, the sponge and the pore former, and sintered to prepare a porous material of the biomaterial.

The degreasing can be carried out, for example, at 1000 ° C., thereby removing organic matter (organic solvents, binders), sponges and pore formers. Subsequently, sintering is performed for densification of the specimen. For example, it is possible to prepare a porous body by maintaining at 1300 ℃ for 10 minutes using microwave sintering.

Next, the polymer is infiltrated into the porous body from which the sponge is removed.

In detail, the biocompatible polymer is to be infiltrated into the inner space of the porous body remaining after the sponge is removed.

The biocompatible polymer to be infiltrated is not particularly limited, but polycaprolactone (PCL) is preferable. Polycaprolactone not only has excellent biocompatibility, but also has excellent strength. In addition, various biopolymers such as gelatin, poly latic acid (PLA), and polylactic-co-glycolic acid (PLGA) may be used.

The eluted polymer is dissolved in an organic solvent such as N, N-dimethylformamide (DMF) to form a polymer solution, and then placed in a high pressure vessel together with the porous body and maintained in a vacuum state. This removes the air inside the porous body.

The vessel is then pressurized to ensure that the polymer solution is evenly infiltrated into the porous body interior space. In order to maintain the open pore structure, a centrifuge is used to separate the macroporous polymer solution that is not infiltrated.

According to the above process, the porous material of the polymer material in which the polymer is infiltrated can easily obtain the interconnected open pore structure necessary for bone conduction properties, and can improve the strength by polymer infiltration.

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

1. Biomixture Manufacturing

A biomixture was prepared by ball milling and mixing 70 vol% of BCP powder as a biomaterial and 30 vol% polymethyl-methacrylate (PMMA) as an internal pore-forming agent.

2. Preparation of Mucus Suspension

An organic solution was prepared by mixing polyvinyl butyral (PVB) as a binder with ethanol as an organic solvent. An organic solution was prepared by mixing 5% by weight of polyvinyl butyral and 95% by weight of ethanol, and mixing the prepared biological mixture with the organic solution while stirring to minimize the aggregation phenomenon of the powder. Thereafter, the mixture was stirred for 1 hour using a stirrer to prepare a slime suspension.

3. Sponge  deposition

The polyurethane sponge was deposited on the prepared mucus suspension, and then compressed air was sprayed to uniformly coat the open pores and then dried at 80 ° C. for 1 hour. The coating and drying process was repeated three times.

4. Degreasing and sintering

The sponge coated with BCP slurry obtained in the above process was degreased at 1000 ° C. to remove organic matter (the organic solvent and binder), polyurethane sponge and pore former, and microwave sintering was used to densify the specimen. After maintaining at 1300 ℃ for 10 minutes to prepare a BCP porous body.

5. Polymer Invasion

After the sponge is removed, 15% by weight of polycaprolactone (PCL) is dissolved in N, N-dimethylformamide (DMF) to infiltrate the polymer into the remaining space of the porous body. The BCP porous body was placed together with the corresponding BCP porous body and kept in vacuum for 30 minutes to remove air inside the porous body. Then, the pressure of the container was gradually raised to 0.5 MPa so that the polymer solution (PCL solution) was uniformly infiltrated into the porous body internal space. In order to maintain the open pore structure, a large pore PCL solution was separated using a centrifuge.

Property evaluation

To compare the physical properties of the biomaterial porous material before the polymer infiltration and the biomaterial porous material in which the polymer was infiltrated, the porosity and the compressive strength of the BCP porous material (Comparative Example) and the PCL infiltrated BCP porous material (Example) were measured. It was. Mercury porosity measuring devices (PoreMaste ^TM , Quantachrome Instruments, FL) were used to measure porosity, and compressive strength was measured at a rate of 0.5 mm / min using a universal testing machine (UnitechTM, R & B, Daejeon, Korea).

In addition, the toxicity test and cell adhesion shape were observed to evaluate biocompatibility and cell adhesion.

result

Table 1 shows the porosity and compressive strength evaluation results of the porous body.

Porosity (%) Compressive strength (MPa) Comparative example 88 ± 2.353 1.3 ± 0.2 Example 86 ± 1.95 2 ± 0.2

As can be seen from Table 1, the porosity is similar to that of the comparative example, but the compressive strength is about 0.7 MPa.

FIG. 2 shows BCP porous body pores (FIG. 2A) without using internal pore formers prepared in the exemplary embodiment of the present invention, and the skeleton of the porous body of FIG. 2A (FIG. 2B), PMMA as internal pore formers SEM image showing the BCP porous body (FIG. 2D) in which the BCP porous body (FIG. 2c) and the polymer (PCL) were infiltrated after PMMA was removed.

As can be seen from Figure 2a and b, the coarse open pores were evenly distributed in the BCP porous body and had a structure similar to the spongy bone of the actual human body. The diameter of open pores was distributed evenly between about 100 ~ 1000㎛, the thickness of the skeleton was about 50 ~ 100㎛. In addition, it was possible to confirm the pores generated on the surface after the PMMA was removed (FIG. 2C), and confirmed the PCL coated on the surface during the PCL infiltration process (FIG. 2D).

3 is a BCP porous body (FIG. 3A) without using an internal pore forming agent, a BCP porous body (FIG. 3B; comparative example) using PMMA as an internal pore forming agent, and a BCP porous body infiltrating a polymer (PCL) (FIG. 3C). SEM image which shows the cross section which cut | disconnected the Example) transversely.

The voids formed inside the skeleton after the sponge is removed are important factors indicative of low strength. In addition, it is difficult to infiltrate the polymer through a fully densified skeleton as shown in Figure 3a. Therefore, after forming pores using PMMA in the skeleton for polymer infiltration as shown in Figure 3b, the polymer was infiltrated from the outside to the inside along the pores (see Figure 3c).

Figure 4 is an XRD profile of the phase of the BCP porous body and the initial BCP powder infiltrated polymer (PCL).

Specifically, in FIG. 4, a is a powder after calcination at 750 ° C., and b is a XRD analysis of a porous body sintered at 1300 ° C., and the ratio of HAp and TCP is about 71% at a. : It was 29% and the ratio of TCP increased to about 32% due to the phase transition of HAp after sintering. The reason for the small phase transition ratio is that sintering was performed in a short time due to the microwave sintering characteristics.

5 is a graph showing the pore distribution of the BCP porous body of Comparative Example and the polymer (PCL) infiltrating BCP porous body of Example.

As shown in Figure 5, the pores of the porous body before and after infiltration is distributed between about 80 ~ 1000㎛. In addition, pores between 100 and 300 μm are most present. In the case of the comparative example it can be confirmed that the pore distribution between 10 ~ 20㎛, while the embodiment after the polymer infiltration was reduced in the pore of the corresponding range. This is because the voids and pores generated inside the skeleton after degreasing the sponge and PMMA, because the inside of the skeleton is filled with a polymer after the polymer infiltration process. Thus, it can be seen that the polymer was evenly infiltrated into the porous body.

6 is a graph showing the biocompatibility of the BCP porous body of Comparative Example and the polymer (PCL) infiltrating BCP porous body of Example.

As shown in FIG. 6, when the MG-63 cell was used to evaluate the toxicity of the porous body, it was confirmed that both the BCP porous body and the porous body infiltrated with the polymer (PCL) did not exhibit toxicity.

7 is a photograph showing cell adhesion between the BCP porous body of Comparative Example and the polymer (PCL) infiltrating BCP porous body of Example.

As shown in FIG. 7, after 15, 30 and 60 minutes, the cell adhesion of MG-63 osteoblasts was confirmed. filopodia) was expressed and cell spread was better at 60 minutes. This is because PCL is a hydrophobic polymer and forms a smooth surface during the infiltration process. However, in terms of mechanical aspects such as the strength of the porous body, polymer infiltration is considered to be very important.

Claims (21)

delete A method for producing a porous material of a biomaterial, which infiltrates a biocompatible polymer into a porous body of a biomaterial,
The method comprises a first step of preparing a suspension comprising a biomaterial, a pore former, an organic solvent, a binder;
Dipping a sponge in the suspension and then drying the sponge;
Applying a heat to the sponge to which the biomaterial is applied to remove the organic solvent, the binder, the sponge, and the pore former, and then sintering to prepare a porous body of the biomaterial; And
A fourth step of infiltrating the porous polymer into the porous body;
The fourth step is a method for producing a porous material of a biomaterial, characterized in that the porous material is put in a biocompatible polymer solution mixed with the biocompatible polymer in an organic solvent and kept in a vacuum state. The method of claim 2,
In the first step, a biomaterial is prepared by mixing a biomaterial and a pore-forming agent, and then a suspension is prepared by mixing the biomixture with an organic solvent and a binder. The method of claim 3, wherein
Method for producing a porous material of a biological material, characterized in that the ball milling the biological material and the pore-forming agent during the preparation of the biological mixture. The method of claim 3, wherein
A method for producing a porous material of a biomaterial, characterized in that the suspension is prepared by mixing the organic solvent, the binder and the biomixture, adding ultrasonic waves, and stirring the mixture. The method of claim 2,
The second step is a method for producing a porous material of a biomaterial, characterized in that the compressed air is injected after the sponge is deposited in the suspension. The method according to claim 6,
Method for producing a porous material of a biomaterial, characterized in that the deposition, compressed air injection and drying are repeated two or more times. delete The method of claim 2,
And maintaining the vacuum state to increase the pressure to infiltrate the biocompatible polymer solution into the porous body. The method of claim 9,
In the fourth step, a method for producing a porous material of a biomaterial, characterized in that to remove the biocompatible polymer solution that is not infiltrated by a centrifuge after the infiltration. The method according to any one of claims 2 to 7, 9, 10,
The biomaterial is a biphasic calcium phosphate (BCP) method of producing a porous material of a biomaterial, characterized in that. The method according to any one of claims 2 to 7, 9, 10,
The biocompatible polymer is polycaprolactone (Polycaprolactone; PCL), characterized in that the porous material manufacturing method of the biomaterial. The method according to any one of claims 2 to 7, 9, 10,
The pore former is polymethyl methacrylate (polymethyl-methacrylate; PMMA) of the porous material manufacturing method of the biomaterial, characterized in that. 6. The method according to any one of claims 3 to 5,
The biological mixture is a porous material manufacturing method of a biological material, characterized in that consisting of 25 to 35% by volume of the pore-forming agent and 65 to 75% by volume of the biomaterial. The method according to any one of claims 2 to 7, 9, 10,
The organic solvent is methanol (Ethanol), ethanol (Ethanol), propanol (propanol) or butanol (butanol) method for producing a porous material of a biomaterial, characterized in that. The method according to any one of claims 2 to 7, 9, 10,
The binder is polyvinyl butyral (PVB), characterized in that the porous material manufacturing method of the biomaterial. 6. The method according to any one of claims 3 to 5,
The organic solution and the biological mixture comprising the organic solvent and the binder are mixed in 88 to 92% by volume of the organic solution and 8 to 12% by volume of the biological mixture. The method according to any one of claims 2 to 7, 9, 10,
The sponge is a porous material manufacturing method of a biological material, characterized in that the polyurethane sponge. The method according to any one of claims 2, 9 and 10,
Wherein said biocompatible polymer solution is a mixed solution of polycaprolactone and N, N-dimethylformamide (DMF). delete delete

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