KR101347726B1 - Method for producing porous biodegradable synthetic polymer/sol-gel derived silica membrane and porous biodegradable synthetic polymer/sol-gel derived silica membrane manufactured thereby - Google Patents

Abstract

The present invention relates to a method for preparing a porous biodegradable synthetic polymer / bioactive silica composite support membrane, and to a porous biodegradable synthetic polymer / bioactive silica composite support membrane prepared by the present invention. A method for preparing a porous biodegradable synthetic polymer / bioactive silica composite support membrane having mechanical properties and biological properties superior to pure biodegradable synthetic polymers by maintaining the properties of uniformly distributed and mesoporous bioactive silica in the synthetic polymer base. It relates to a porous biodegradable synthetic polymer / bioactive silica composite support membrane produced thereby.

Description

Method for producing porous biodegradable synthetic polymer / bioactive silica composite support membrane and porous biodegradable synthetic polymer / sol-gel derived silica membrane and porous biodegradable synthetic polymer / sol-gel derived silica membrane manufactured thereby}

The present invention relates to a method for producing a porous biodegradable synthetic polymer / bioactive silica composite support membrane and a porous biodegradable synthetic polymer / bioactive silica composite support membrane produced thereby.

Biodegradable synthetic polymer is a material widely used for making scaffolds in tissue engineering because of its excellent biocompatibility and biodegradability, and is widely used in various medical and tissue engineering fields. Biodegradable synthetic polymers have the advantages of good biocompatibility, good mechanical properties, and biodegradability, but they have limitations such as poor bioactivity and low stiffness, such as causing inflammation during degradation. have. Therefore, many studies have been developed to address these limitations in the field of tissue engineering.

Recently, in order to compensate for the shortcomings of the biodegradable synthetic polymer, a method of preparing an organic / inorganic composite that emphasizes the advantages of each material and supplements the shortcomings by adding biominerals has been continuously studied. . This organic / inorganic complex is a bio-inorganic material with high bioactivity in the biodegradable synthetic polymer to compensate for the disadvantages of low stiffness, limited bioactivity and hydrophobic nature. The organic / inorganic complex structure can be manufactured in various forms due to the excellent flexibility of the organic material, and is expected to be useful for tissue regeneration in the field of tissue engineering.

The organic / inorganic complex may be polycaprolactone ((Poly (ε-carprolactone); PCL), polylactic acid (PLA), polylactic glycoic acid (Poly (D, L-lactic-) co-glycolic acid (PLGA), polyetherethereketone (PEEK) and other bioabsorbing polymers, and bioactive glass (bioglass), collagen (Collagen), hydroxyapatite (Hydroxyapatite), bioactive silica In the mixed composite, excellent physical properties can be obtained by uniformly structuring, arranging, and uniformly distributing the inorganic material in the organic base at the nano-unit, in particular, the mechanical and biological properties of the organic / inorganic complex are In addition to the particle content, it is greatly influenced by the unique properties of the inorganic particles such as the chemical composition or morphology of the organic / inorganic complex.

Bioactive silica used as an inorganic material in the present invention has excellent bioactivity and biodegradability and is used in various medical fields [Non-Patent Documents 7-9]. In addition, bioactive silica prepared by using the sol-gel method has been widely used in comparison with other bioactive silica production methods in terms of uniform particle size distribution, the possibility of controlling chemical components in the composite manufacturing process, and ease of preparation. Since the bioactive silica prepared in this way has the advantages of excellent bioactivity, biodegradability, bone conduction, etc., it is advantageous for the bone formation reaction in the human body, inducing and conducting bone formation as well as increasing the biocompatibility. To make it possible. When the bioactive silica is used in the organic / inorganic composite based on the polymer, it is expected to improve the mechanical properties as well as the biological properties.

Therefore, there is a need for the development of new technologies to improve the mechanical and biological properties of pure biodegradable synthetic polymers.

Wang, Z. B., H. L. Tang, et al. (2011). "Morphology Change of Biaxially Oriented Polytetrafluoroethylene Membranes Caused by Solvent Soakage." Journal of Applied Polymer Science 121 (3): 1464-1468 Kawase, T., T. Tanaka, et al. (2011). "Improved adhesion of human cultured periosteal heets to a porous poly (L-lactic acid) membrane scaffold without the aid of exogenous adhesion biomolecules." Journal of Biomedical Materials Research Part A 98A (1): 100-113. Yang, Q., N. Adrus, et al. (2011). "Composites of functional polymeric hydrogels and porous membranes." Journal of Materials Chemistry 21 (9): 2783-2811. Kim, H., E. Lee, et al. (2005). "Effect of fluoridation of hydroxyapatite in hydroxyapatite-polycaprolactone composites on osteoblast activity." Biomaterials 26 (21): 4395-4404. Tonda-Turo, C., C. Audisio, et al. (2011). "Porous Poly (epsilon-caprolactone) Nerve Guide Filled with Porous Gelatin Matrix for Nerve Tissue Engineering." Advanced Engineering Materials 13 (5): B151-B164. Jang, J.-H., O. Castano, et al. (2009). "Electrospun materials as potential platforms for bone tissue engineering ☆." Advanced Drug Delivery Reviews 61 (12): 1065-1083. Miyamoto, M., K. Nagata, et al. (2008). "Highly permeable mesoporous silica membranes synthesized by vapor infiltration of tetraethoxysilane into non-ionic alkyl poly (oxyethylene) surfactant films." Journal of Membrane Science 325 (2): 698-703. Kotoky, T., B. C. Ray, et al. (2003). "Synthesis and characterization of hybrid organic-inorganic composites derived from polystyrene / copolymers of styrene and methylvinyldichlorosilane with silica through the sol-gel method." Journal of Polymer Materials 20 (3): 257-265. Mishra, A. K. and A. S. Luyt (2008). "Effect of sol-gel derived nano-silica and organic peroxide on the thermal and mechanical properties of low-density polyethylene / wood flour composites." Polymer Degradation and Stability 93 (1): 1-8

Thus, the present inventors utilize the mesoporous properties of the bioactive silica prepared by using the sol-gel method, and dissolve the biodegradable synthetic polymer in a solvent / non-solvent solution to secure pores and at the same time, the biodegradable synthetic polymer solution. The biodegradable synthetic polymer / bioactive silica composite with improved mechanical and biological properties is supported by uniformly distributing the bioactive silica on the biodegradable synthetic polymer by stirring the bioactive silica sol in situ. The membrane was prepared.

Accordingly, an object of the present invention is to provide a method for preparing a porous biodegradable synthetic polymer / bioactive silica composite support membrane and a porous biodegradable synthetic polymer / bioactive silica composite support membrane prepared therefrom.

As means for solving the above problems,

Dissolving the biodegradable synthetic polymer in a mixed solution of a solvent and a non-solvent to prepare a biodegradable synthetic polymer solution;

Mixing the biodegradable synthetic polymer solution with a bioactive silica sol, and then adding a drug to prepare a complex solution; And

Removing the solvent from the complex solution;

It provides a method for producing a biodegradable synthetic polymer / bioactive silica composite support membrane comprising a.

Further, as another means for solving the above-mentioned problems,

It provides a porous biodegradable synthetic polymer / bioactive silica composite support membrane prepared by the above method.

The present invention induces a uniform distribution of each substance by mixing in situ in a biodegradable synthetic polymer solvent / non-solvent solution in a bioactive silica sol, and by using a solvent casting method, as well as biological properties of the biodegradable synthetic polymer It is a new technology that can produce biodegradable synthetic polymer / bioactive silica composite support membrane with improved properties.

In addition, it is expected that the biodegradable synthetic polymer / bioactive silica support membrane and the preparation method thereof according to the present invention will be very useful in tissue engineering fields such as a biosupport membrane supporting a drug or a growth factor.

1 is a schematic view of the manufacturing process of the PCL / bioactive silica composite support membrane according to an embodiment of the present invention.
Figure 2 is a photograph of the surface of the PCL / bioactive silica composite support membrane prepared in Example 1 by scanning electron microscopy (Scanning Electron Microscopy, SEM) [(A) 0 vol%, (B) 10 vol%, (C ) 20 vol%, (D) 30 vol%].
Figure 3 shows the microstructure of the fracture surface of the PCL / bioactive silica composite support membrane by SEM [(A) 0, (B) 10, (C) 20, (D) 30 vol%.
4 is a graph showing the contact angle with water to evaluate the hydrophilicity of the PCL / bioactive silica composite support membrane.
5 is an FT-IR spectra confirming the chemical structure of the PCL / bioactive silica composite support membrane.
6 are graphs showing the maximum tensile strength, modulus of elasticity and fracture strain of the PCL / bioactive silica composite support membrane.
7 is a graph showing the bioactivity of the PCL / bioactive silica composite support membrane.
8 is a graph showing the drug release behavior of the PCL / bioactive silica composite support membrane.
FIG. 9 shows surface photographs (A) and fracture surface photographs (B) when only DCE as a solvent is used in the preparation of the PCL / bioactive silica composite support membrane.

The present invention

Dissolving the biodegradable synthetic polymer in a mixed solution of a solvent and a non-solvent to prepare a biodegradable synthetic polymer solution;

Mixing the biodegradable synthetic polymer solution with a bioactive silica sol, and then adding a drug to prepare a complex solution; And

Removing the solvent from the complex solution;

It relates to a method for producing a biodegradable synthetic polymer / bioactive silica composite support membrane comprising a.

Hereinafter, a method for preparing the biodegradable synthetic polymer / bioactive silica composite support membrane will be described in detail.

First, a biodegradable synthetic polymer is dissolved in a mixed solution of a solvent and a nonsolvent to prepare a PCL solution.

The biodegradable synthetic polymer may be polycaprolactone (PCL), polylactide (PLA), polylactide glycolide random copolymer (Polylactide glycolide, PLGA), polyglycolide (PGA) or their It is preferably a mixture, but is not limited thereto.

The solvent is preferably at least one selected from the group consisting of dichloroethane DCE, chloroform, and tetrahydrofuran (THF), but is not limited thereto.

The non-solvent is preferably dimethylformamide (DMF), but is not limited thereto.

The solvent and the non-solvent are mixed at a volume ratio of 5 to 2: 1, and the biodegradable synthetic polymer is dissolved to prepare a biodegradable synthetic polymer solution. In this case, when the amount of solvent used is excessively high, a solution having low viscosity is prepared and thus there is a limitation in controlling the thickness of the support membrane. If the amount is too small, the solvent is evaporated selectively during solvent removal.

In addition, the biodegradable synthetic polymer is preferably used in an amount of 5 to 30 parts by volume based on 100 parts by volume of a mixture of a solvent and a nonsolvent for reasons of viscosity control of the solution and morphology of the biodegradable synthetic polymer forming a matrix.

In the present invention, a magnetic stirring method was used to prepare a biodegradable synthetic polymer solution. In addition, mechanical stirring, vortexing, and the like are possible.

Next, after mixing the biodegradable synthetic polymer solution and bioactive silica sol, a drug is added to prepare a complex solution.

The bioactive silica sol is a glass material having several nano-sized pores, and is a silicate (SiO 2) inorganic material formed through a process of hydrolysis and condensation of silicon-based alcohol (alkoxide). Refer. When the bioactive silica sol is prepared by sol-gel method by mixing raw material reagents at room temperature, reaction by-products such as ethanol, methanol, water and hydrochloric acid can be easily removed by drying and washing process, and can be easily prepared. Has the advantage. In addition, in order to control the porous structure of the bioactive silica sol, it is possible to adjust the ratio of an alcohol oxide material and a solvent, a catalyst material, and the like during hydrolysis, which can be appropriately controlled within a conventional range in the art. The catalyst is preferably an acidic catalyst, but is not limited thereto.

Mixing the biodegradable synthetic polymer solution and the bioactive silica sol is a homogeneous stirring of the biodegradable synthetic polymer solution and the bioactive silica sol, especially the volume ratio of the biodegradable synthetic polymer solution and bioactive silica sol 100: 10 ~ 30 By using the mixture, it is possible to achieve a porous support membrane having a desired porosity and pore size.

The drug is preferably an antibiotic, but is not limited thereto. Specific examples of the antibiotics include betalactam antibiotics (penicillins and cephalosporins), tetracycline antibiotics (tetracycline, metacycline, minocycline, etc.), aminoglycoside antibiotics (kanamycin, gentamicin, Ribostamycin, tobramycin, neomycin, and the like), lincoside antibiotics (lincomycin, clindamycin), vancomycin, ceparexin, sefacller, and sephamandol.

Preferably, the drug is added 0.05 to 1 mg per 1 ml of a mixed solution of biodegradable synthetic polymer solution and bioactive silica sol. This is because when the drug is added in excess, there is a problem in that a precipitate is formed, and in the case where a small amount is added, there is a problem that is minutely detected in the release behavior analysis.

Finally, the solvent is removed from the complex solution by the solvent casting method.

The present invention also relates to a porous biodegradable synthetic polymer / bioactive silica composite support membrane prepared by the above method.

The porous biodegradable synthetic polymer / bioactive silica composite support membrane according to the present invention has a porosity of 20 to 35% and a pore average size of 5 to 15 μm.

The porous biodegradable synthetic polymer / bioactive silica composite support membrane can be utilized as a support membrane for regenerating tissues, composites, etc. carrying various active factors.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by the following examples.

Example  1: porosity Polycaprolactone Of Bioactivity  Silica composite Of the support membrane  Produce

Using PCL as a biodegradable synthetic polymer, a PCL solution was first prepared for preparing a PCL / silica composite support membrane. The PCL solution was made by dissolving 8 g (6.99 ml) of PCL in a solution of 30 ml of DCE and 10 ml of DMF. Thereafter, TMOS (tetramethyl orthosilicate), 11.15ml, distilled water 1.3ml, catalyst (1N HCl), 0.05ml, and 2.9ml ethanol were first mixed and stirred for 1 hour, and then magnetically stirred at room temperature for 120 minutes. To induce hydrolysis (preparation of bioactive silica sol). The bioactive silica sol obtained through agitation and the prepared PCL solution were mixed in a specific volume ratio, and 1.32 mg of the tetracycline hydrate was added to 13.2 ml of the mixed solution of the PCL solution and the silica sol, followed by uniform stirring through magnetic stirring. Induced to prepare a PCL / bioactive silica composite liquid composite. The prepared liquid mixture was transferred to a glass petri dish and dried at room temperature for at least 24 hours to remove water, a chemical by-product of DCE DMF and bioactive silica sol used as a solvent / non-solvent of PCL.

2 shows the porosity and pore size of the surface according to the content of bioactive silica sol ((A) 0, (B) 10 vol%, (C) 20 vol%, (D) 30 vol%) 3 (A) is a fractured surface microstructure of the PCL polymer support membrane that does not contain bioactive silica, while relatively small pores and random pores exist, while (B)-( D) is a fractured microstructure of PCL / bioactive silica support membrane in which bioactive silica is added at a ratio of 10,20,30 vol% to PCL, respectively. It was confirmed that the distribution of sizes was also relatively uniform.

Comparative Example  One

A polycaprolactone / bioactive silica composite support membrane was prepared in the same manner as in Example 1, without using a non-solvent [FIG. 9].

As shown in FIG. 9, when no non-solvent is used, pores in the support membrane may not be formed.

Experimental Example  1: check hydrophilicity

In order to evaluate the hydrophilicity of the PCL / bioactive silica composite support membrane of Example 1 by using a PHX300 of SEO company to drop a small amount of water on the specimen at a constant rate to obtain a droplet form, the contact angle between the specimen and the droplet surface Observed. In FIG. 4, in contrast to the contact angle of the PCL polymer, the contact angle of the PCL / bioactive silica composite support membrane tended to be lower. In addition, hydrophilicity was increased by adding hydrophilic bioactive silica to the hydrophobic PCL polymer.

Experimental Example  2: check the chemical structure

Example 1 Fourier Transform Infrared Spectroscopy (FT-IR) is used to analyze the chemical structure of the PCL / bioactive silica composite support membrane. The peak analysis of the graph analyzes the chemical bonds of the components to examine the components that make up the substance.

As shown in FIG. 5, a typical band of spectra, PCL polymer and bioactive silica was observed to analyze the chemical structure of the PCL / bioactive silica composite support membrane, but no specific band was found due to the addition of the drug tetracycline. That is, it was confirmed that the chemical structure was maintained even if the drug was added to the PCL / bioactive silica composite support membrane of the present invention.

Experiment 3: Checking Physical Properties

In order to evaluate the mechanical properties of the PCL / bioactive silica composite support membrane of Example 1 to prepare a specimen in ~ 0.06 x 10 x 20 mm using an Oriental testing machine using a screw driven load frame speed of 5 mm / min Tensile experiment was conducted with

In FIG. 6, the mechanical properties of the PCL / bioactive silica support membrane of Example 1 and the elastic modulus (Young's modulus) are higher than that of the PCL polymer support membrane when elongation is applied to the support membrane. In addition, the increase in the content of the bioactive silica in the PCL / bioactive silica composite support membrane showed a decrease in stress strength and strain at failure.

Experimental Example  4: bioactivity evaluation

In order to evaluate the bioactivity of the PCL / bioactive silica composite support membrane of Example 1, MC3T3 (osteoblast cells) were cultured on the surface of the composite support membrane for 14 days and the degree of differentiation of the cells was measured using the protein measurement kit.

As a result, it was confirmed that the differentiation of the improved cell by adding the bioactive silica, in particular the excellent bioactivity of the PCL / bioactive silica composite support membrane [Fig. 7].

Experimental Example  5: confirm drug release behavior

In order to confirm the drug release behavior of the PCL / bioactive silica composite support membrane of Example 1, 10, 20, 30 vol% bioactive silica sol of the PCL / bioactive silica composite support membrane of Example 1 compared to the PCL solution volume Each mixture was put in a PBS solution and maintained at 37 ° C., and drug release behavior was evaluated by UV-spectrometer.

The presence of bioactive silica in the support membrane increased the hydrophilicity of the support membrane and increased porosity, thereby controlling the release of the drug tetracycline [FIG. 8].

Claims (10)

Polycaprolactone (PCL) is selected from the group consisting of dimethylformamide (DMF) and at least one solvent selected from the group consisting of dichloroethane (DCE), chloroform (Chloroform) and tetrahydrofuran (THF). Dissolving in a mixed solution to produce a polycaprolactone solution;
Mixing the polycaprolactone solution with the bioactive silica sol and then adding an antibiotic to prepare a complex solution; And
Removing the solvent from the complex solution;
Method for producing a porous polycaprolactone / bioactive silica composite support membrane comprising a.
delete delete delete The method of claim 1,
A method for producing a porous polycaprolactone / bioactive silica composite support membrane, in which a solvent and dimethylformamide are mixed at a volume ratio of 5 to 2: 1.
The method of claim 1,
The polycaprolactone is a method for producing a porous polycaprolactone / bioactive silica composite support membrane using 5 to 30 parts by volume based on 100 parts by volume of a mixture of a solvent and dimethylformamide.
The method of claim 1,
The bioactive silica sol is a method for producing a porous polycaprolactone / bioactive silica composite support membrane of 10 to 30 vol% of the volume of the polycaprolactone solution.
delete A porous polycaprolactone / bioactive silica composite support membrane prepared by the method according to claim 1 and carrying a drug having a pore average size of 5 μm to 15 μm .
The method of claim 9,
Porous biodegradable synthetic polymer / bioactive silica composite support membrane loaded with drug with 20 ~ 35% porosity.

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