KR101646899B1 - Three dimensional polymer scaffold having surface pattern and manufacture there of - Google Patents
Three dimensional polymer scaffold having surface pattern and manufacture there of Download PDFInfo
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- KR101646899B1 KR101646899B1 KR1020150047294A KR20150047294A KR101646899B1 KR 101646899 B1 KR101646899 B1 KR 101646899B1 KR 1020150047294 A KR1020150047294 A KR 1020150047294A KR 20150047294 A KR20150047294 A KR 20150047294A KR 101646899 B1 KR101646899 B1 KR 101646899B1
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- opal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
- C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
Abstract
The present invention relates to a process for producing a three-dimensional porous polymer scaffold, and more particularly, to a method for producing scaffolds using fine particles having a regular pattern structure on a surface thereof. The support of the present invention can have an improved effect on the cell support by increasing the surface area due to the pattern structure of the surface.
Description
The present invention relates to a process for producing a three-dimensional porous polymer scaffold, and more particularly, to a method for producing scaffolds using fine particles having a regular pattern structure on a surface thereof. The support of the present invention can have an improved effect on the cell support by increasing the surface area due to the pattern structure of the surface.
The three-dimensional polymer structure provides a framework for applications in various fields such as photonic crystal applications, membranes, and tissue engineering.
In order to apply such a three-dimensional polymer structure to tissue engineering, the porous structure should be made to have a porous structure capable of promoting cell proliferation and tissue regeneration as well as safety in vivo as well as the entire support. . Various attempts have been made to fabricate a support with a three-dimensional porous structure, but the effect is insufficient.
A typical three-dimensional porous structure is an inverse opal structure. The opal structure refers to a three-dimensional structure in which nano-sized spherical particles are layered in multiple layers. Opposite to the structure of opals, reverse opal structure is called.
In addition to having a porous structure, such a support has a uniform pore distribution as compared with a three-dimensional porous structure manufactured by a conventional salt extraction process or freeze-drying, because the pores are three-dimensionally connected. Reproducibility is excellent.
In order to form an opal, a three-dimensional array of particles is prepared, and then a process of inhibiting the breakdown of the structure through heat treatment is introduced. It is difficult to produce a patterned three-dimensional porous stereostructure because post-treatment is required to manufacture the opal in order to suppress the collapse of the pattern structure of the particle surface.
In order to solve this problem, the present invention provides a method for producing an opal template by preparing particles of uniform size having a regular pattern structure on the surface (for example, a golf ball dimple structure) Finally, the inverse opal having a regular pattern structure on the surface is manufactured.
That is, in order to obtain such a reverse opal support, an opal opaque support can be obtained by forming an opal template through a three-dimensional array of uniform spherical particles, and then impregnating the opal template with the solution to remove the template.
In order to form an opal template, a heat treatment process is introduced to suppress the breakdown of the structure after the three-dimensional array of particles is prepared. The present invention provides a method for manufacturing a porous reverse opal support in which such post-treatment is eliminated and a regular pattern is formed on the surface.
In order to achieve the above object,
(a) preparing a polymer solution including a pattern forming polymer and a pattern forming agent;
(b) preparing microparticles having a pattern on the surface thereof by using the polymer solution;
(c) arranging the prepared microparticles to form an opal template;
(d) absorbing the support polymer to the opal template; And
(e) removing the particulate of the opal template with a solvent to produce a reverse opal support.
The present invention provides a support produced by the above-mentioned production method.
Since the supporter using fine particles having a regular pattern structure on the surface according to the present invention has an excellent effect of increasing cell attachment and proliferation, it can be used for reconstructing artificial skin tissue three-dimensionally or for developing biomaterials , It can be usefully used as a three-dimensional polymer scaffold in various fields.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a scanning electron micrograph of a polymer microparticle prepared according to Example 1. Fig.
Fig. 2 is a scanning electron micrograph of a support having a pattern of irregularities on its surface prepared according to Example 1. Fig.
3 is a SEM micrograph of the polymer microparticles prepared according to Comparative Example 1. Fig.
Fig. 4 is a scanning electron micrograph of a surface-free support obtained according to Comparative Example 1. Fig.
5 is data showing the MTT analysis results of the support prepared in Example 1 and Comparative Example 1. Fig.
Hereinafter, the method for producing the support of the present invention and the support made therefrom will be described in more detail.
TECHNICAL FIELD The present invention relates to a support for tissue engineering using a fine particle having a regular pattern on its surface and having a pattern having irregularities on the surface of the support and having a large surface area and a method for producing the same.
The regular pattern refers to a pattern repeatedly formed by an artificial method. For example, in the present invention, a dimple structure having a pattern like a golf ball shape is formed.
In a preferred production process of the present invention,
(a) preparing a polymer solution including a pattern forming polymer and a pattern forming agent;
(b) preparing microparticles having a pattern on the surface thereof by using the polymer solution;
(c) arranging the prepared microparticles to form an opal template;
(d) absorbing the support polymer to the opal template; And
(e) removing the particulate of the opal template with a solvent to produce a reverse opal support.
The step (a) is a step of preparing a polymer solution containing a pattern forming polymer and a pattern forming agent, and the pattern forming polymer should be biocompatible because it is a constituent material of porous particles for the purpose of human use.
The pattern-forming polymer has a weight average molecular weight of 5,000 to 300,000 g / mol. The pattern-forming polymer may be a copolymer of poly (lactic acid-co-glycolic acid) (PLGA) (D, L-lactic acid-co-caprolactone) of poly (D, L-lactic acid) or poly D, L-lactic acid-polycaprolactone have. However, the biocompatible polymers used for this purpose are not limited thereto.
The glass transition temperature of the pattern-forming polymer is preferably 10 to 65 占 폚. When the opal is laminated using the fine particles, the pattern structure can be connected without being collapsed through the heat treatment at a temperature lower than the glass transition temperature. The polylactic acid-polycaprolactone polymer of the present invention has a glass transition temperature of 18 캜 and is connected at room temperature, so that heat treatment is not required.
When the polylactic acid-polycaprolactone is polymerized, the weight ratio of the monomers D, L-lactide and? -Caprolactone may be 100: 0 to 50:50, preferably 80:20 to 75:25 .
The pattern forming agent in the step (a) is a phase change material (PCM), which is a volatile hydrocarbon material in which the phase is changed by a change in temperature, and 2-methylpentane is used to prepare fine particles at room temperature .
The solvent of step (a) is required to be miscible with the pattern-forming polymer and the hydrophilic surfactant, and is required to undergo phase separation with water. The solvent is not particularly limited as long as it satisfies the above requirements, but it is preferable to use dichloromethane.
It is preferable that the pattern-forming polymer and the pattern forming agent are dissolved in an amount of 5 to 10% by weight based on the total solvent concentration at which the particles become spherical. In addition, the mass ratio of the pattern-forming polymer and the pattern-forming agent is 8: 2 to 6: 4, and it is preferable to form fine particles having a dimple on the surface while having a spherical shape.
In the step (b), the hydrophilic surfactant is dissolved in a polyvinyl alcohol aqueous solution to form a continuous phase (water phase) by using the polymer solution obtained in the step (a) as a non-emulsion phase (oil phase) And then connecting the continuous phase and the non-continuous phase microfluidic device with a tube to produce polymer microparticles by an oil-in-water (O / W) method.
The continuous phase of the step (b) may be an aqueous solution of polyvinyl alcohol (PVA), and the polyvinyl alcohol may be added so that the concentration thereof is preferably 1 to 3% by weight. At this time, the molecular weight of polyvinyl alcohol is 13,000 to 23,000, and the degree of hydrolysis is preferably 87 to 89%.
The hydrophilic surfactant is used to uniformly disperse drug particles having a saturation concentration or higher. The hydrophilic surfactant may be at least one selected from the group consisting of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene sorbitan fatty ester (Tween series). And polyoxyethylene sorbitan fatty acid ester type surfactants are preferably used, and polyoxyethylene sorbitan monolaurate (trade name: Tween 20) may be used therein. The hydrophilic surfactant is added so that the concentration thereof is preferably 0.02% by weight in water, and 0.01% by weight of sodium azide may be further added to prevent microbial propagation.
The tube of step (b) had an inner diameter of 800 micrometer and a needle of a non-coinjection needle was 30G. The particle diameter of the polymer fine particles having the dimple structure can be controlled by the speed of the homogenizer. In order to increase the cell attachment effect, the fine particles having a regular pattern according to the present invention have an average particle diameter of 100 to 250 μm .
In the step (c), the prepared spherical fine particles are arranged to form an opal template. A centrifuge tube was used to arrange the microparticles.
To prepare the opal template, a polyvinyl alcohol aqueous solution having fine particles dispersed therein is placed in a centrifuge tube. The centrifugal separator rotates to deposit the fine particles on the lower part, and the polyvinyl alcohol aqueous solution remaining on the upper part is removed. The unremoved polyvinyl alcohol aqueous solution may be vacuum dried to form a particulate opal template having a laminated structure. The method for producing the template may be by a manufacturing method commonly used by a person skilled in the art, and is not particularly limited.
Among the plurality of fine particles of the opal structure stacked in the step (c), the fine particles may have a void in the center surrounded by at least three particles, and the fine particle layer may be a layer of three or more layers.
The step (d) is a step of absorbing the support polymer to the opal template. The support polymer may be a water-soluble biocompatible polymer, and may be chitosan alginate, carboxymethyl cellulose, pectine, hyaluronic acid or the like, and preferably chitosan Can be used. Chitosan is excellent in non-toxicity, environmental compatibility, biodegradability and biocompatibility, and chlorthoamine, which is a constituent unit of chitosan, has an effect of promoting wound healing. However, the polymer used for the support is not limited thereto.
The step (e) is a step of preparing a polymer scaffold having an opaque structure by removing fine particles of an opal structure with a solvent.
Pores having a size ranging from 100 μm to 500 μm can be formed by impregnating the solution with the fine particles contained in the support of the laminated opal structure.
Since the support polymer forming the opaque template and the opaque polymer of the opal template have different dissolution characteristics, a solvent which dissolves the fine particle polymer of the opal template is injected to remove the fine polymer, whereby a support of the opaque structure can be formed.
In the three-dimensional polymer scaffold according to the present invention, the fine particles of the dimple structure are removed to form multiple pores having a regular pattern on the surface.
Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
[Example 1]
1. Pattern Formation Polymer Manufacturing
The monomer (D, L-lactide, epsilon -caprolactone) and the catalyst Tin (II) 2-ethylhexanoate diluted in toluene of 0.1wt% in total were kept in an oil bath at 150 ° C for 24 hours. At this time, the mass ratio of D, L-lactide and? -Caprolactone was 75:25. And then precipitated using methanol (non-solvent). The polymer was dried at room temperature for 24 hours and then vacuum-dried for 24 hours.
2. Production of regular patterned microparticles
KF100 and KDS LEGATO200 from KD Scientific were used as fluids devices in oil phase and water phase, respectively. The Fluidic device consists of a TYGON-R tube (1/32 in. Inner diameter, 3/32 in. Outer diameter) and a 30G needle. A 30G needle was inserted into the TYGON-R tube.
Poly (D, L-lactic acid-co-caprolactone) copolymer (Mw = 64000) of the poly D, L-lactic acid-polycaprolactone prepared in the above 1 was used as the pattern forming polymer. At this time, the volatile phase transition material (2-methylpentane) was dissolved in dichloromethane at a mass ratio of polymer: 2-methylpentane = 7: 3 to 10 wt%.
The oil phase, in which the polymer was completely dissolved in dichloromethane, was injected into a syringe equipped with a 30G needle. The polyvinyl alcohol used as the water phase was dissolved in distilled water at 1 wt% and the hydrophilic surfactant tween 20 at 0.02 wt%. The aqueous solution was injected into a 100 ml glass syringe. The oil phase velocity was 0.1 mL / hr and the water phase velocity was 100 mL / hr. A droplet was formed at the tip of the needle, flowed along the tube, collected in a Petri dish, and held for 2 hours to evaporate the solvent. The fine particles were washed three times in distilled water after preparation. After drying for 24 hours at room temperature, it was dried under reduced pressure for 24 hours to completely remove water. Fig. 1 shows a scanning electron microscope photograph of the surface of the formed microparticles.
3. Formation of support of inverted opal structure
The fine particles prepared from the polymer dispersed in the polyvinyl alcohol aqueous solution are put into a 50 ml centrifuge tube. The centrifugal separator is rotated to deposit the fine particles on the lower part, and the polyvinyl alcohol aqueous solution remaining on the upper part is removed. The unremoved polyvinyl alcohol aqueous solution can be removed by vacuum drying for 24 hours to form an opal template having a laminated structure. Dip the surface of the opal with distilled water and remove the opal with a spatula.
The opal was dripped with a mixture of distilled water and ethanol (5: 5, v / v) to wet the surface, then placed in a Buchner funnel and absorbed chitosan solution (1 wt% in 200 mM acetic acid) under vacuum. The opal, in which the chitosan solution was absorbed, was frozen in the freezer (-20 ° C) for 5 hours and then impregnated with dichloromethane for one day to dissolve the polymer-made microparticles. Fig. 2 shows a scanning electron microscopic photograph of a support having a pattern on its surface.
[Comparative Example 1]
The procedure was carried out under the same conditions as in Example 1 except that the phase transition material having volatility was removed, and dichloromethane and a polymer weight ratio of 9: 1 were used to produce fine particles having smooth surfaces. Fig. 3 shows a scanning electron microscope photograph of the surface of the formed microparticles. FIG. 4 shows a scanning electron microscope photograph of a support having a smooth surface formed thereon.
To confirm the biocompatibility of each of the supports prepared through Examples and Comparative Examples, the diffusion of the cells was quantitated using MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) And the results of the first day and the values after 7 days of cultivation are shown in FIG. The MTT absorbance was measured at a wavelength of 570 nm.
From these experimental results, it was found that the support (Example 1) made of golf ball-shaped fine particles having dimples on the surface had a significantly higher number of cells as compared with the support made of fine particles having a smooth surface (Comparative Example 1) , Which means that chitosan induces proliferation more actively in the support due to its large surface area.
Claims (11)
(b) dispersing the polymer solution in a polyvinyl alcohol aqueous solution to prepare an aqueous solution in which fine particles are dispersed by an oil-in-water (O / W) method;
(c) centrifuging the aqueous solution in which the fine particles are dispersed, and then vacuum-drying at room temperature to prepare an opal template having fine particles having a concavo-convex pattern on the surface thereof;
(d) absorbing the support polymer to the opal template; And
(e) removing the fine particles of the opal template with a solvent to produce a reverse opal support;
Wherein a pattern of irregularities is formed on the surface of the opaque opaque support.
Wherein the pattern forming agent in step (a) has a pattern of irregularities on the surface including 2-methylpentane.
Wherein the pattern-forming polymer and the pattern-forming agent in the step (a) have a concavo-convex pattern on the surface in a concentration of 5 to 10 wt% with respect to the whole polymer solution.
Wherein the weight ratio of the pattern forming polymer to the pattern forming agent in the step (a) is 8: 2 to 6: 4.
Wherein the polymer solution is dispersed in a polyvinyl alcohol aqueous solution obtained by dissolving a hydrophilic surfactant in the step (b), wherein a pattern of irregularities is formed on a surface of the support.
The oil-in-water (O / W) method is a method for producing microparticles using a microfluidic device, wherein a pattern of irregularities is formed on a surface of the microfluidic device.
Wherein the hydrophilic surfactant is at least one selected from the group consisting of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene sorbitan fatty acid ester compound, and a method for producing an inverted opal support for a cell support .
In the step (d), the support polymer may have a pattern of irregularities formed on at least one surface selected from the group consisting of chitosan alginate, carboxymethyl cellulose, peptine, and hyaluronic acid. A method for manufacturing an inverted opal support for cell support.
A method for manufacturing an inverted opal support for a cell support, wherein a pattern of irregularities is formed on a surface of the inverted opal support having pores having a size of 100 μm to 500 μm.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20120018913A (en) * | 2010-08-24 | 2012-03-06 | 공주대학교 산학협력단 | Preparation of biodegradable microparticles with structural complexity on the surface and inside |
| KR20120080267A (en) * | 2011-01-07 | 2012-07-17 | 공주대학교 산학협력단 | Preparation of biodegradable microparticles with structural complexity on the surface and inside by using a microfluidic device |
| KR101181738B1 (en) | 2010-04-14 | 2012-09-12 | 인하대학교 산학협력단 | Process for producing 3-dimentional nanofibrous scaffold having micro-size pores |
| KR20140128553A (en) * | 2013-04-26 | 2014-11-06 | 공주대학교 산학협력단 | Microparticle with surface dimples capable of embodying active ingredients and preparation thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101181738B1 (en) | 2010-04-14 | 2012-09-12 | 인하대학교 산학협력단 | Process for producing 3-dimentional nanofibrous scaffold having micro-size pores |
| KR20120018913A (en) * | 2010-08-24 | 2012-03-06 | 공주대학교 산학협력단 | Preparation of biodegradable microparticles with structural complexity on the surface and inside |
| KR20120080267A (en) * | 2011-01-07 | 2012-07-17 | 공주대학교 산학협력단 | Preparation of biodegradable microparticles with structural complexity on the surface and inside by using a microfluidic device |
| KR20140128553A (en) * | 2013-04-26 | 2014-11-06 | 공주대학교 산학협력단 | Microparticle with surface dimples capable of embodying active ingredients and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| Choi, S.W. et al., Advanced materials (2009) Vol. 21, No.29, pp.2997-3001* * |
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