KR102027563B1 - polymeric Implants using bioactive materials - Google Patents

Abstract

The present invention relates to a polymer implant using a bioactive material, and more particularly, by coating a surface of a synthetic peptide having osteoblast differentiation or bone formation promoting ability on the surface to further increase the biocompatibility and bone formation ability to shorten the procedure time and The present invention relates to a polymer implant having a high functionality capable of preventing the release of the implant.
The polymer implant using the bioactive material of the present invention includes a support layer formed of a polymer material and a coating layer formed by coating a surface of the support with a coating composition containing a peptide having osteoblast differentiation or bone formation promoting ability.

Description

Polymeric Implants Using Bioactive Materials

The present invention relates to a polymer implant using a bioactive material, and more particularly, by coating a surface of a synthetic peptide having osteoblast differentiation or bone formation promoting ability on the surface to further increase the biocompatibility and bone formation ability to shorten the procedure time and The present invention relates to a polymer implant having a high functionality capable of preventing the release of the implant.

In order for the surgical implant inserted into the body to be maintained for a long time, the bonding surface of the bone and the biomaterial must be kept stable. Rapid bone fusion and biocompatibility of the implant procedure is associated with this long-term implant use. In general, implants that are inserted into the body, in spite of their good mechanical properties, do not have good bone fusion and biocompatibility.

Recently, surface treatment methods for stimulating cellular action between bone and implant surfaces are increasing. In the medical application of the implant is more important is to fix the bioactive material on the surface of the biomaterial used in the implant. Therefore, the method of delivering bone-forming protein to the bone-implant junction by implant coating technology has been widely used for effective fixation of the implant and healing of the treatment site.

Calcium phosphate, consisting mainly of hydroxyapatite, is a ceramic material that is typical and very good in biocompatibility for implant applications. However, while hydroxyapatite has the advantage of increasing bone fusion, there is a disadvantage that the peeling phenomenon occurs.

Recently, bioactive substances such as BMP (Bone matrix protein), a protein belonging to the TGF-β family that promotes proliferation and differentiation of osteoblasts, have been applied directly to the surface of implants or spread around the surgical site. .

Since it has been reported that BMP family proteins play an important role in bone formation, bone differentiation and alveolar bone formation, many experiments have been conducted. BMP family proteins are involved in bone formation and differentiation in humans as well as animals. It has been reported to regenerate and strengthen.

However, BMP is not only expensive but also rapidly decomposed and disappeared by an enzyme present in the body, so that it is difficult to apply effectively.

1. Republic of Korea Patent No. 10-1744763: BMP-derived peptide and its use 2. Republic of Korea Patent No. 10-0630903: Bone Membrane Enhancement Penetration Membrane and Implants

The present invention has been made to improve the above problems, by coating the surface of the peptide containing an amino acid sequence derived from SDF-1d synthesized based on a specific site of human chemokines (Chemokines) to improve the biocompatibility and bone formation ability It is an object of the present invention to provide a polymer implant having a high functionality that can be further increased to shorten the procedure time and prevent the release of the implant.

The polymer implant using the bioactive material of the present invention for achieving the above object is a support formed of a polymer material; And a coating layer formed by coating a surface of the support with a coating composition containing a peptide having osteoblast differentiation or bone formation promoting ability.

And the peptide comprises an SDF-1d-derived amino acid sequence.

The support is molded into a three-dimensional porous structure by 3D printing.

The polymer is polycaprolactone (PCL).

The coating layer may coat the coating composition by electrospraying.

As described above, the present invention further increases biocompatibility and bone formation ability by coating a surface containing a peptide containing an amino acid sequence derived from SDF-1d synthesized based on a specific site in human chemokines. It is possible to provide a polymer implant having a high functionality that can prevent shortening and separation of the implants.

Therefore, the present invention has no side effects when treating osteoporosis, osteoarthritis, and bone defect disease, and has excellent bone formation effect, and uses a peptide having advantages of relatively low manufacturing cost, thereby reducing and preparing side effects after the procedure. Can improve economics.

Hereinafter, a polymer implant using a bioactive material according to a preferred embodiment of the present invention will be described in detail.

A polymer implant using a bioactive material according to an embodiment of the present invention is composed of a support and a coating layer formed on the surface of the support.

The support is a part forming the skeleton of the implant and is formed of a polymer material.

As the polymer material, various polymer materials having excellent biocompatibility may be used. For example, polycaprolactone (PCL) may be used as the polymer material. Polycaprolactone has excellent biological stability and low toxicity in vivo, and has appropriate elasticity and mechanical strength.

Such a polymer material can be made into a support having a specific form through various molding methods.

Preferably, the support is formed in a three-dimensional shape by 3D printing. This support has a porous structure in which fine pores are formed therein.

Forming the support by 3D printing can accurately realize the support of the intended three-dimensional shape and can easily produce complex shapes. In addition, the size and shape of the pores can be precisely adjusted. In addition, the three-dimensional scaffold produced through this method has an excellent internal connection structure with pores, so that cell proliferation and differentiation can be improved through infiltration of cells, and uniform tissue regeneration can be expected.

The coating layer is formed by coating a coating composition on the surface of the support.

The coating composition applied to the present invention contains a peptide having osteoblast differentiation or bone formation promoting ability. A peptide refers to a linear molecule formed by binding amino acid residues to each other by peptide bonds. Peptides can be prepared according to chemical synthesis methods known in the art, in particular solid-phase synthesis techniques.

Peptides applied in the present invention preferably comprise an amino acid sequence from SDF-1d. That is, it is a peptide synthesized based on a part of the delta type of stromal cell-derived factor 1 (SDF-1) known as C-X-C motif chemokine12 (CXCL12).

Chemokines are cytokines that selectively regulate cell adhesion, chemoattraction, and activation of leukocyte subpopulations. Cell chemokines act as the main cytokines. It is classified into two types, CC chemokine and CXC chemokine, depending on the position of two consecutive cysteins.

Such SDF-1d-derived peptides have the same or superior function or function as peptides derived from bone morphogenetic proteins (BMPs), but have superior stability and lower cost than natural BMPs.

Peptides derived from SDF-1d perform a function similar to one or more of natural BMP or chemokine to bind to receptors to perform functions such as differentiation factors. In particular, it promotes the differentiation of osteoblasts or vascular endothelial cells. Peptides derived from SDF-1d exhibit physiological activity with almost the same or better activity than natural BMP or chemokine, as well as excellent thermal stability and stability against physicochemical factors such as acids and alkalis.

Peptide applied to the present invention consists essentially of the amino acid sequence of SEQ ID NO: 1 sequence disclosed in Korean Patent Registration No. 10-1747824. The peptide of the first sequence may be called bone forming peptiede 5 (BFP 5).

The coating composition contains the peptide described above. For example, the coating composition may have a peptide concentration of 0.005 to 0.5M.

The coating composition may be used by mixing various known excipients, additives and the like with the peptide to form a putty, paste, moldable strip, block, chip, and the like. In addition, the coating composition may be used in the form of powder, paste, tablets, pellets and the like. In addition, the coating composition may be used in the form of an aqueous solution.

For example, the coating composition in the form of an aqueous solution may be formed by adding a peptide to a phosphate buffer solution.

Before coating, the support may be washed with ethanol and distilled water and dried to remove organic matter remaining on the surface.

Various coating methods may be applied to form a coating layer on the surface of the support using the coating composition. For example, any one of coating methods such as dipping, coating, spraying, and coating by physical or chemical vapor deposition may be applied.

Preferably, the electrospray method may be used as the coating method.

Electro spraying is a method of producing very fine liquid aerosol by using electricity. In an electrospray device, an aqueous solution containing peptides is passed through a spray port, creating a droplet of droplets by applying a very high voltage to the aqueous solution to charge it electrically. As the charged aqueous solution in the nozzle becomes more and more charged, it becomes unstable, and when the aqueous solution reaches the critical point at which it cannot hold any more charge, the strong-charged aqueous solution at the tip of the nozzle is in the form of fine particles. It will come out.

In the present invention, it is possible to use an electrospray which is commonly used for electrospray. The voltage at the time of electrospray may be 0.1 ~ 30kV, preferably 5 ~ 15kV. In addition, the injection speed may be 0.005 ~ 1ml / min, preferably 0.010 ~ 0.050ml / min.

And the distance between the end of the injection hole and the support to be coated during the electrospray is preferably 2 ~ 50cm.

The coating by electrospray can prevent the destruction of the peptide and can greatly increase the performance of the coating film by a simpler and more economical coating method. In addition, since the surface is uniformly coated with particles of a certain size can improve the coating efficiency.

Meanwhile, the surface treatment process may be performed to impart the roughness to the surface of the support before coating.

The surface treatment of the support is roughened to increase the surface area by electrochemical treatment, mechanical treatment by sandblasting or chemical treatment by acid corrosion. Can be given.

As an example of chemical treatment, a method of immersing the support in a sodium hydroxide solution may be applied. For example, the support may be immersed in a 10N NaOH solution for 2 to 4 hours, followed by washing the distilled water for surface treatment.

In particular, such chemical treatments are useful when forming supports with polycaprolactone. Since polycaprolactone has a methyl group in its structure, it has a relatively high hydrophobicity and may have difficulty in protein attachment. Therefore, adhesion can be improved by adjusting the roughness of the surface of a support body using sodium hydroxide.

As described above, the present invention coats the surface of the support with a peptide derived from SDF-1d synthesized based on a specific site in human chemokines, thereby further increasing biocompatibility and bone formation ability, thereby shortening the procedure time and implanting. It is possible to provide a polymer implant having a high functionality that can prevent the release of paper.

Therefore, the present invention has no side effects when treating osteoporosis, osteoarthritis and bone defect disease, and has excellent bone formation effect and uses a peptide having advantages of relatively low manufacturing cost, thus reducing and preparing side effects after the procedure. Can improve economics.

As described above, the present invention has been described with reference to one embodiment, which is merely exemplary, and those skilled in the art will understand that various modifications and equivalent embodiments are possible therefrom. Therefore, the true scope of protection of the present invention should be defined only by the appended claims.

Claims (5)

Forming a support of a polymer material having a three-dimensional porous structure by 3D printing;
Immersing the support in 10N sodium hydroxide (NaOH) solution for 2 to 4 hours, followed by washing with distilled water to surface treatment;
And coating a coating composition containing a peptide having osteoblast differentiation or bone formation promoting ability on the surface of the support by electrospray to form a coating layer.
The polymer material is polycaprolactone (PCL),
The coating composition is prepared by adding a peptide to the concentration of 0.005 ~ 0.5M in the phosphate buffer solution,
The method of producing a polymer implant using a bioactive material, characterized in that the electrospray voltage 0.1 ~ 30kV, injection rate 0.005 ~ 1ml / min. The method of claim 1, wherein the peptide comprises an amino acid sequence derived from SDF-1d.


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