WO2015072806A1

WO2015072806A1 - Double porous synthetic bone wedge and method for manufacturing same

Info

Publication number: WO2015072806A1
Application number: PCT/KR2014/011066
Authority: WO
Inventors: 송해룡; 김학준; 김성은; 윤영필; 유창국
Original assignee: 고려대학교산학협력단
Priority date: 2013-11-18
Filing date: 2014-11-18
Publication date: 2015-05-21
Also published as: KR101493752B1

Abstract

The present invention relates to a double porous synthetic bone wedge having pores of which the sizes are 200-450μm and 0.5-2μm and a method for manufacturing the same, wherein the double porous synthetic bone wedge can improve a regenerative capability of an autogenous bone due to an easy influx of blood vessels and an easy attachment of bone cells through the pores.

Description

Double-pore synthetic bone wedge and its manufacturing method

The present invention relates to a double-pore synthetic bone wedge having macro and micro sized pores and a method for producing the same.

Currently, orthopedic surgery is commonly used to treat arthritis and knee injuries. The artificial joint procedure is not only complicated but also requires the removal of a large amount of autogenous bone during the procedure. In addition, since there is an expected life cycle, there is a limit in treating knee injuries caused by artificial knee surgery.

On the other hand, High Tibial Osteotomy (HTO) changes the support angle of the tibial bone through simple fractures, thereby changing the area where the knee joint is engaged, and thus can be treated simply for arthritis and knee injury. have.

A wedge-shaped empty space is formed at the site of the fracture by the proximal tibial fracture procedure, and a procedure of fixing the lower portion and the upper portion of the empty space with a bone plate is usually used while leaving the empty space empty. However, when using this procedure, a relatively large empty space is formed, so a very long time is required for bone regeneration, and the burden on the pain of the patient is increased and the time for cure is long.

In order to compensate for this, the wedge-shaped synthetic bone wedges are currently used, but the commercially available wedges are mostly disposed of closed holes or partially open holes. Korean Patent Registration No. 10-0331990 discloses a biodegradable porous bone graft material using biodegradable calcium metaphosphate (CMP) and a method of manufacturing the same. The structure of the closed pores is difficult to enter the blood vessels and bone cells, and remains after foreign transplantation, and bone fusion is also limited, there is a disadvantage that the autogenous bone occupancy is not high.

Therefore, the present inventors have made diligent efforts to solve the above problems, and produced a double-pore synthetic bone wedge having a macro- and micro-sized double pore structure, and when it is used for regeneration of autologous bone, inflow of blood vessels and bone through the pores It was confirmed that the adhesion of cells is easy, and the regeneration ability of the autogenous bone is improved, thereby completing the present invention.

Summary of the Invention

Disclosure of Invention An object of the present invention is to provide a double-pore synthetic bone wedge having a macro- and micro-sized double pore structure and easy to introduce blood vessels and osteocytes, and a method of manufacturing the same.

Another object of the present invention is to provide a scaffold for bone regeneration containing the double pore synthetic bone wedge.

In order to achieve the above object,

The present invention is to prepare a calcium phosphate paste by mixing (1) calcium phosphate powder and aqueous binder solution;

(2) coating a polyurethane sponge surface-treated with the prepared calcium phosphate paste;

(3) drying and firing the polyurethane sponge coated with the calcium phosphate paste to prepare a synthetic bone wedge having macropores of 200 to 450 μm in size;

(4) coating the surface of the synthetic bone wedge with a calcium phosphate slurry prepared by mixing a calcium phosphate powder and a binder aqueous solution having a particle size of 200 ~ 800nm; And

(5) drying and firing the synthetic bone wedge coated with the calcium phosphate slurry to prepare a double-pore synthetic bone wedge having a micro-pores of 0.5 ~ 2μm size and macropores of 200 ~ 450μm size It provides a method of manufacturing.

The present invention also provides a double-pore synthetic bone wedge comprising a macro-pores of 200 ~ 450μm size and micropores of 0.5 ~ 2μm size prepared by the above method.

The present invention also provides a scaffold for bone regeneration containing the double pore synthetic bone wedge.

1 is a photograph showing a double pore synthetic bone wedge.

2 is a SEM photograph showing the macropores of the double pore synthetic bone wedge.

Figure 3 is a SEM photograph showing the micro pores of the double pore synthetic bone wedge.

Figure 4 (a) is a SEM picture showing the open pore structure of the biporous synthetic bone wedges connected to each other, (b) is a SEM picture showing the bone cells attached to the double pore synthetic bone wedge.

Figure 5 (a) is a SEM image of a conventional synthetic bone wedge, (b) is an SEM image of the enlarged (a), (c) is a SEM image of the double-pore synthetic bone wedge of Example 1, (d) SEM image of enlarged (c), (e) SEM image of double pore synthetic bone wedge of Example 2, (f) SEM image of enlarged (e), (g) double pore synthesis of Example 3 SEM photograph of the goal wedge and (h) are SEM photographs which expanded (g).

Figure 6 (a) is a SEM photograph showing the micro-sized pores of the double-pore synthetic bone wedge of Example 1, (b) is a SEM photograph showing the micro-sized pores of the double-pore synthetic bone wedge of Example 2 and ( c) is a SEM photograph showing the micro-sized pores of the double-pore synthetic bone wedge of Example 3.

Figure 7 is a graph showing the cell diffusion over time of the conventional synthetic bone wedge and the bi-pore synthetic bone wedge of Examples 1-3.

Detailed Description of the Invention and Specific Embodiments

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 to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

Throughout this specification, when a part is said to "include" a certain component, it means that it can further include other components, without excluding the other components unless specifically stated otherwise.

In the present invention, using a calcium phosphate paste and calcium phosphate slurry was prepared a synthetic bone wedge having micropores of 0.5 ~ 2μm size and macropores of 200 ~ 450μm size. In addition, when using the prepared double-pore synthetic bone wedge for the regeneration of autologous bone it was confirmed that the inflow of blood vessels and adhesion of bone cells through the pores to improve the regeneration of autologous bone.

Accordingly, the present invention provides a method for producing a double-pore synthetic bone wedge having a micro-pores of 0.5 ~ 2μm size and macropores of 200 ~ 450μm size, the manufacturing method is as follows.

(1) mixing calcium phosphate powder and aqueous binder solution to prepare a calcium phosphate paste;

(5) preparing a synthetic bone wedge having 0.5 ~ 2μm micropores and 200 ~ 450μm macropores by drying and firing the synthetic bone wedge coated with the calcium phosphate slurry.

The calcium phosphate powder of step (1) and (4) is one selected from the group consisting of apatite hydroxide, α-tricalcium phosphate, β-tricalcium phosphate, calcium phosphate, calcium metaphosphate, calcium polyphosphate and bioglass The above is preferable, and it is preferable to use biphasic calcium phosphate (BCP) prepared by mixing apatite hydroxide and β-tricalcium phosphate at 3: 7 to 7: 3.

In addition, the binder aqueous solution of step (1) and (4) is preferably PVA (Polyvinyl alcohol) or cellulose-based binder aqueous solution, more preferably PVA binder aqueous solution.

In step (1), the calcium phosphate powder and the binder aqueous solution are mixed at a weight ratio of 1: 0.5 to 1: 3 to prepare a calcium phosphate paste, and the polyurethane sponge used in step (2) is 40 to It has a pore size of 80 ppi and is soaked in basic aqueous solution and subjected to surface treatment with ultrasonic waves. Then, the calcium phosphate paste is penetrated into the polyurethane sponge surface-treated in step (2) and coated therein, and dried in step (3) and calcined at a temperature of 1100 to 1250 ° C. to provide macropores having a size of 200 to 450 μm. Synthetic bone wedges can be prepared.

In addition, in step (4), the calcium phosphate powder and the binder aqueous solution of 200 to 800 nm particle size are mixed in a weight ratio of 1: 0.5 to 1: 8 to prepare a calcium phosphate slurry, preferably 1: 3 to 1: 1. 6, More preferably, it is a weight ratio of 1: 5-1: 6. In the step (4), the synthetic bone wedges having the macropores of 200-450 μm size prepared in the step (3) are dipped in the calcium phosphate slurry, taken out and blown with compressed air to remove the excess calcium phosphate slurry and coated thinly and uniformly. To obtain a synthetic bone wedge, the synthetic bone wedge in step (4) is dried and calcined at a temperature of 1100 ~ 1250 ℃ to obtain a synthetic bone wedge having a micro-pores of 0.5 ~ 2μm size.

Synthetic bone wedge prepared by the above method is a dual-pore synthetic bone wedge, characterized in that it has a macropores of 200 ~ 450μm size and micropores of 0.5 ~ 2μm size.

Therefore, in another aspect, the present invention relates to a double-pore synthetic bone wedge comprising a macro-pores of 200 ~ 450μm size and micropores of 0.5 ~ 2μm size prepared by the above method.

Blood vessels grow and enter the macropores, and bone cells can also move inside. In addition, the conventional synthetic bone wedge has a smooth surface, it was difficult to attach the bone cells, while the dual-pore synthetic bone wedge of the present invention has a micropore on the surface has a very advantageous structure of the attachment of bone cells, the micro-pores Through the circulation of blood and body fluids can be easily regenerated autologous bone at the same time inside and outside the wedge.

The double pore synthetic bone wedge of the present invention has a porosity of 60 to 80%, and because autologous bone regeneration occurs outside and inside the pores, autologous bone of 60 to 80% can be regenerated. In addition, despite the high porosity, it has a structure strong enough to withstand a pressure of 5Mpa.

In addition, the double-pore synthetic bone wedges have an inclination angle of 6 to 14 ° and 6 to 14 ° in width, and thus are applicable to both left and right legs.

Dual-pore synthetic bone wedge according to the present invention has a much higher autogenous bone regeneration share than the conventional synthetic bone wedge, and despite having a high porosity, having a rigid structure, both legs can be used, proximal tibial osteotomy (High Tibial Osteotomy) , HTO) and the like can be used suitably.

Accordingly, the present invention relates to a scaffold for bone regeneration containing the double pore synthetic bone wedge from another aspect.

The bi-porous synthetic bone wedge can be used alone as a scaffold for bone regeneration, such as BMP (Bone Morphogenetic Protein) -2, BMP-4, BMP-7, BMP-14, TGF (Transforming Growth Factor) -β1, etc. It can be mixed with bone formation promoting proteins.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following Examples and Experimental Examples are for illustrating the present invention, and the scope of the present invention is not limited to the Examples and Experimental Examples.

Example 1 Preparation of Double Pore Synthetic Bone Wedge

Apatite hydroxide and β-tricalcium phosphate were mixed at a ratio of 6: 4 to prepare biphasic calcium phosphate (BCP) powder. The BCP powder and 2% PVA binder aqueous solution were mixed and mixed at a weight ratio of 1.5: 1 to prepare a BCP paste.

A polyurethane sponge having a pore size of 60 ppi was immersed in a 2% aqueous sodium hydroxide solution, surface treated with ultrasonic waves for 10 minutes, washed with running water, and dried at 60 ° C. Thereafter, the surface-treated polyurethane sponge was immersed in a BCP paste and then rolled with a rod to penetrate and coat the BCP paste into the sponge, and remove the remaining BCP paste by passing through the roller.

The polyurethane sponge uniformly coated with BCP paste was dried at room temperature for 24 hours and then heated at a rate of 5 ° C./min and calcined at 1200 ° C. for 3 hours to prepare a synthetic bone wedge having a pore size of 200˜450 μm.

BCP powder of 600-800 nm particle size was mixed with a 2% PVA aqueous binder solution in a weight ratio of 1: 2 and dispersed in an ultrasonic bath to prepare a BCP slurry. Synthetic bone wedges having a macropore size of 200 ~ 450μm prepared above were immersed in a BCP slurry, taken out, and blown dry compressed air to remove residual BCP slurry to prepare a synthetic bone wedge uniformly coated with BCP slurry. Thereafter, after drying at room temperature for 6 hours or more, the temperature was raised at a temperature increase rate of 5 ° C./min, followed by heat treatment at 1200 ° C. for 2 hours to prepare a double pore synthetic bone wedge having a micro pore of 0.5-2 μm and a pore size of 200-450 μm. .

The bi-porous synthetic bone wedge prepared in Example 1 is as shown in Figure 1, as shown in the SEM photograph (Fig. 2 and 3) of the double-pore synthetic bone wedge, to confirm that it has macro pores and micro pores Could.

Example 2

A double-pore synthetic bone wedge was prepared in the same manner as in Example 1 except that a BCP slurry was prepared by mixing a BCP powder having a particle size of 600-800 nm with a 2% PVA aqueous solution in a weight ratio of 1: 3.

Example 3

A double-pore synthetic bone wedge was prepared in the same manner as in Example 1 except that the BCP powder having a particle size of 600-800 nm was mixed with a 2% PVA aqueous binder solution in a weight ratio of 1: 6.

Comparative example

Phosphoric acid was reacted with coral to make hydroxy apatite, thereby cutting synthetic bone wedges.

Experimental Example 1: Osteocell adhesion behavior of the biporous synthetic bone wedges of Examples 1 to 3

The bone cell adhesion behavior of the biporous synthetic bone wedges prepared in Examples 1 to 3 was observed by SEM (FIG. 4). As a result, as shown in Figure 4 (a), it was confirmed that the double-pore synthetic bone wedge has an open pore structure connected to each other.

In addition, as a result of attaching 1 × 10 ⁵ bone cells (stromal cell, obtained from Kyungpook National University) to each of the double pore synthetic bone wedges prepared in Examples 1 to 3, as shown in FIG. 4 (b). As described above, it was confirmed that the bone cells were attached to the double pore synthetic bone wedge.

On the other hand, while the conventional synthetic bone wedge (Figs. 5 (a) and (b)) is a smooth surface, the surface of the double-pore synthetic bone wedge of Examples 1 to 3 (Fig. 5 (c) ~ (h)) is micro It was observed that the surface was not smooth due to the pores of the size (FIG. 5). Conventional synthetic bone wedges form only closed pores and macropores but do not form open pores and micropores, resulting in poor cell adhesion.

In addition, as a result of observing the double-pore synthetic bone wedge of Examples 1 to 3 to 5000 times, it was confirmed that the higher the weight ratio of the PVA binder aqueous solution when producing the BCP slurry, the more micro-sized pores are produced (FIG. 6). .

Since more pores result in more cell adhesion, culture the bone cells for 1 to 7 days using conventional synthetic bone wedges and the dual-pore synthetic bone wedges of Examples 1 to 3 in order to determine the autologous bone regeneration ability according to the pores. The cell adhesion was confirmed according to the pores. The conventional synthetic bone wedges did not differ in the spread of bone cells over time, but the double-pore synthetic bone wedges of Examples 1 to 3 occurred in the diffusion of osteocytes over time, especially the concentration of BCP slurry ( BCP powder: aqueous solution of PVA binder 1: 6) showed the highest osteocytic diffusion in the thinnest Example 3 (FIG. 7).

Through the above results, the lower the concentration of the BCP slurry, the more pores of the double-pore synthetic bone wedge are formed, and thus, the surface is unevenly manufactured, thereby providing an environment in which bone cells can be easily attached, thereby increasing autologous bone regeneration ability. I could confirm that.

Having described the specific parts of the present invention in detail, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

The dual pore synthetic bone wedge of the present invention has macro and micro size pores, so that macro pores facilitate the inflow of blood vessels and osteocytes, and micro pores facilitate the circulation of blood and body fluids for the growth and metabolism of bone cells. Can provide a useful environment for the attachment of osteocytes.

In addition, the dual pore synthetic bone wedge of the present invention exhibits a porosity of about 80% to increase autologous bone regeneration rate by the autogenous bone regeneration occurs through the pores.

Claims

(1) mixing calcium phosphate powder and aqueous binder solution to prepare a calcium phosphate paste;

(2) coating a polyurethane sponge surface-treated with the prepared calcium phosphate paste;

(3) drying and firing the polyurethane sponge coated with the calcium phosphate paste to prepare a synthetic bone wedge having macropores of 200 to 450 μm in size;

(4) coating the surface of the synthetic bone wedge with a calcium phosphate slurry prepared by mixing a calcium phosphate powder and a binder aqueous solution having a particle size of 200 ~ 800nm; And

(5) drying and firing the synthetic bone wedge coated with the calcium phosphate slurry to prepare a double-pore synthetic bone wedge having a micro-pores of 0.5 ~ 2μm size and macropores of 200 ~ 450μm size Manufacturing method.
The method of claim 1, wherein the calcium phosphate powder of step (1) and (4) is composed of apatite hydroxide, α-tricalcium phosphate, β-tricalcium phosphate, calcium phosphate, calcium metaphosphate, calcium polyphosphate and bioglass Method for producing a double-pore synthetic bone wedge, characterized in that at least one selected from the group.
3. The method of claim 2, wherein the calcium phosphate powder is biphasic calcium phosphate obtained by mixing apatite hydroxide and β-tricalcium phosphate in a weight ratio of 3: 7 to 7: 3.
The method of claim 1, wherein the aqueous binder solution of steps (1) and (4) is a PVA binder solution or a cellulose-based binder solution.
The method of claim 1, wherein the polyurethane sponge has a pore size of 40 to 80 ppi.
[Claim 2] The method of claim 1, wherein the calcium phosphate powder and the binder aqueous solution having the particle size of 200 to 800 nm in the step (4) are mixed at a weight ratio of 1: 0.5 to 1: 8.
The method of claim 1, wherein the firing temperature of the step (3) and (4) is 1100 ~ 1250 ℃.
A double-pore synthetic bone wedge comprising a macropores of 200 ~ 450μm size and micropores of 0.5 ~ 2μm size prepared by the manufacturing method of claim 1.
The method of claim 8, wherein the double pore synthetic bone wedge has a porosity of 60 to 80%.
According to claim 8, The double pore synthetic bone wedge is a bi-pore synthetic bone wedge, characterized in that the horizontal and vertical inclination angle of 6 ~ 14 ° and 6 ~ 14 °, respectively.
10. The biporous synthetic bone wedge of claim 8, wherein the biporous synthetic bone wedge is applicable to both left and right legs as one biporous synthetic bone wedge.
A scaffold for bone regeneration comprising the double pore synthetic bone wedge of claim 8.