KR20190005474A - A method for fabricating a bioactive membrane using spin coating technology and freeze-drying technology, and bioactive membranes fabricated by the method - Google Patents

Abstract

Disclosed are a method for fabricating a bioactive membrane by combining spin coating technology and freeze-drying technology, and a bioactive membrane fabricated by the method. The method to fabricate the bioactive membrane, according to an embodiment of the present invention, comprises the following steps: (a1) preparing a polymeric solution containing biodegradable polymers and a solvent; (a2) forming a thin film composed of the polymeric solution by the spin coating; (a3) freezing the thin film; and (a4) drying the thin film by sublimating the solvent in the frozen thin film. It is possible to provide a bioactive membrane which has a porous structure and biodegradability and a method to fabricate the same, which can be used widely in a surgery part or wounded skin.

Description

[0001] The present invention relates to a method for producing a bioactive membrane by fusion of a spin coating technique and a freeze-drying technique, and a bioactive membrane produced by the method.

The present invention relates to a method for producing a bioactive membrane by fusion of a spin coating technique and a freeze-drying technique, and a bioactive membrane prepared by the method, and more particularly, to a bioactive membrane prepared by fusing the two techniques, Layer and a bioactive film produced by the method.

Surgical cover materials are commonly used to protect the surgically treated surgical site. For example, surgical cover materials are used at various surgical sites, such as alveolar bone tissue undergoing dental surgery, bone tissue undergoing orthopedic surgery, organs undergoing surgery or gynecologic surgery.

As surgical cover materials, thin gauze or films are generally used.

The cover material in the form of a gauze is characterized by having a plurality of pores. Since the size of the pores is excessively larger than the preferred size of 10 to 100 mu m during tissue regeneration, it is difficult to expect the effect of promoting tissue regeneration, There is a disadvantage that bacteria or surrounding tissues penetrate the surgical site by the pores. Since the film-like cover material has a dense structure without pores, it is effective in preventing bacteria or surrounding tissues from penetrating the surgical site, but the effect of promoting tissue regeneration due to the pore structure can not be expected at all.

On the other hand, a skin cover material for protecting the scarred skin is often used. Representative skin cover materials include a foam layer directly contacting a wound site and an adhesive tape for adhering the foam layer.

Here, the foam layer serves to prevent external stimuli from being applied to the wound area and to provide a wet environment for rapid recovery of the wound area, and is generally provided as a polyurethane foam.

Such a foam layer can be suitably used for skin, but is not biodegradable and therefore is difficult to be used for covering the in-vivo surgical site.

The present invention provides a bioactive membrane having a porous structure and biodegradability so as to be extensively used in a surgical site, scarred skin, and a method for producing the same.

 (A1) preparing a polymer solution containing a biodegradable polymer and a solvent; (a2) forming a thin film of the polymer solution by spin coating; (a3) freezing the thin film; And (a4) sublimating a solvent in the frozen thin film to dry the thin film, and a single-layer porous bioactive film produced by the method.

The polymer solution preferably further comprises a crosslinking agent.

The crosslinking agent may be glutaraldehyde.

The biodegradable polymer may be methyl cellulose, and the solvent may be water.

(B1) preparing a first polymer solution containing a first biodegradable polymer and a first solvent, and a second polymer solution containing a second biodegradable polymer and a second solvent; (b2) forming a first layer of the first polymer solution by spin coating; (b3) evaporating the first solvent in the first layer to dry the first layer; (b4) forming a second layer of the second polymer solution on the first layer by spin coating; (b5) freezing the second layer; (b6) sublimating the second solvent in the second layer to dry the second layer, and a bi-layer porous biologically-active membrane produced thereby.

It is preferable that each of the first and second polymer solutions further includes a crosslinking agent.

The crosslinking agent may be glutaraldehyde.

The first and second biodegradable polymers may be the same material, and the first and second solvents may be the same material.

The first and second biodegradable polymers may be methyl cellulose, and the first and second solvents may be water.

The content of the first biodegradable polymer in the first polymer solution and the content of the second biodegradable polymer in the second polymer solution may be 2 to 14 wt%, respectively.

The second polymer solution may further include an artificial bone substance.

The second polymer solution may further include at least one kind of drug substance.

In the bi-layer porous bioactive layer, the thickness of the first layer may be 5 to 10 mu m and the thickness of the second layer may be 100 to 300 mu m.

(C1) a first polymer solution containing a first biodegradable polymer and a first solvent, a second polymer solution containing a second biodegradable polymer and a second solvent, and a third polymer solution containing a third biodegradable polymer and a third solvent, Preparing a third polymer solution including a solvent; (c2) forming a first layer of the first polymer solution by spin coating; (c3) evaporating the first solvent in the first layer to dry the first layer; (c4) forming a second layer of the second polymer solution on the first layer by spin coating; (c5) evaporating the second solvent in the second layer to dry the second layer; (c6) forming a third layer of the third polymer solution on the second layer by spin coating; (c7) freezing the third layer; (c8) subliming the third solvent in the third layer to dry the third layer, and a triple layer porous bioactive film produced by the method.

It is preferable that each of the first to third polymer solutions further includes a crosslinking agent.

The crosslinking agent may be glutaraldehyde.

The first to third biodegradable polymers may be the same material, and the first to third solvents may be the same material.

The first to third biodegradable polymers may be methyl cellulose, and the first to third solvents may be water.

The content of the first biodegradable polymer in the first polymer solution, the content of the second biodegradable polymer in the second polymer solution, and the content of the third biodegradable polymer in the third polymer solution are 2 to 14 wt% %. ≪ / RTI >

At least one of the second polymer solution and the third polymer solution may further include an artificial bone substance.

At least one of the second polymer solution and the third polymer solution may include at least one kind of drug substance.

In the triple layer porous bioactive film, the first layer and the second layer may each have a thickness of 5 to 10 mu m, and the third layer may have a thickness of 100 to 300 mu m.

According to the present invention, a bioactive membrane having a porous structure can be produced through a relatively simple process and system by applying a spin coating technique and a freeze drying technique. It is also possible to produce a multi-layered bioactive membrane consisting of one or more dense layers and one porous layer in such a manner that one or more dense layers are formed by natural drying or oven drying and the porous layer is formed thereon by lyophilization. Such multi-layer bioactive membranes are one body because each layer is chemically bonded to one another.

The biologically active membrane of the present invention is biodegradable because it is produced using a biodegradable polymer as a raw material and has excellent structural stability by using a cross-linking agent in the manufacturing process. In addition, the bioactive membrane of the present invention has high stretchability and excellent wound ability, and can be easily attached to a curved object such as a bone.

The bioactive membrane of the present invention can be used as a medical cover material for various purposes such as a surgical cover material and a skin cover material.

When used as a surgical cover material, the bioactive membrane of the present invention has a porous structure, which can contribute to the rapid regeneration of tissues and effectively prevents bacteria or surrounding tissues from penetrating the surgical site when having a dense layer located outside can do.

When used as a skin cover material, the bioactive membrane of the present invention has a porous structure, so that it is possible to maintain the wound area in a wet environment and to effectively absorb the foreign matter from the wound area, thereby facilitating quick recovery of the wound, The intrusion of bacteria and the like can be effectively prevented.

1A to 1D are views for explaining a method of manufacturing a bioactive film according to an embodiment of the present invention.
2 is a schematic view of a single-layer porous bioactive film produced by the production method.
3 is a photograph of a sample of a single-layer porous bioactive film actually produced by the production method.
4 to 6 are SEM photographs of the single layer porous bioactive film sample.
Figs. 7 to 9 are photographs for explaining characteristics of the single-layer porous bioactive film sample.
10A to 10E are views for explaining a method of manufacturing a bioactive film according to another embodiment of the present invention.
11 is a view schematically showing a double-layer porous bioactive film produced by the production method.
FIG. 12 is a photograph of a sample of a double-layer porous bioactive film actually produced by the production method.
13 to 16 are SEM photographs of a sample of the bi-layer porous bioactive film.
17A to 17F are views for explaining a method of manufacturing a bioactive film according to another embodiment of the present invention.
18 is a view schematically showing a triple layer porous bioactive film produced by the production method.
Fig. 19 is a photograph of a triple layer porous bioactive film sample actually produced by the production method.
20 to 23 are SEM photographs of the triple layer porous bioactive film sample.

Hereinafter, the present invention will be described in more detail with reference to the embodiments shown in the drawings.

One. Single layer  Porous Bioactive membrane

1.1. Manufacturing method

A method of manufacturing a single-layer porous bioactive film will be described with reference to Figs. 1A to 1D.

Referring to FIG. 1A, a polymer solution 100a is first prepared.

The polymer solution 100a is a solution to be the material of the bioactive film. The polymer solution 100a includes a biodegradable polymer and a solvent, and the biodegradable polymer is dissolved in the solvent and dispersed evenly.

As the biodegradable polymer, a polymer having no toxicity to the human body and stably maintaining its shape at room temperature is used. As the biodegradable polymer, methyl cellulose may be suitably used. The content of the biodegradable polymer in the polymer solution 100a may range from 2 to 14% by weight.

As the solvent, a liquid capable of dissolving the biodegradable polymer is used. When a water-soluble polymer such as methyl cellulose is used, water can be suitably used as a solvent.

The polymer solution 100a preferably further comprises a cross linking agent. The crosslinking agent is used for enhancing the structural and chemical stability of the bioactive film. For example, glutaraldehyde can be used as a crosslinking agent. The content of the crosslinking agent in the polymer solution may be 1 to 5% by weight.

When a crosslinking agent is contained in the polymer solution 100a, an acid catalyst may be added to the polymer solution 100a to provide an acid catalyst environment for crosslinking. As the acid catalyst, hydrochloric acid (HCl) may be used.

The polymer solution 100a may also include an artificial bone substance as an additive.

The polymer solution 100a may also contain more than one kind of drug substance as an additive. For example, the polymer solution 100a may contain antibiotics such as THF (tetrahydrofolate) or a growth promoting agent such as BMP (bone morphogenetic proteins) as a drug component.

Referring to FIG. 1B, a thin film 100b made of a polymer solution is formed by spin coating.

Specifically, an appropriate amount of the polymer solution is poured into the dish 20, and the dish 20 is rotated at a high speed by the spin coating apparatus 10 so that the polymer solution becomes the shape of the thin film 100b.

A separation film may be laid on the upper surface of the dish 20 before the polymer solution is poured into the dish 20. [ The separation film is intended to allow the bioactive film to be well separated from the dish 20 after the manufacturing process, and an OHP film or a Teflon film can be used as a separation film.

Referring to FIG. 1C, the thin film made of the polymer solution is frozen by using the freezing apparatus 300.

The freezing apparatus 300 may include a pedestal 31, a dry ice 32, and a metal plate 33. 1C, the metal plate 33 is placed on the dry ice 32, and the dish 20 is placed thereon. As the dry ice 32 sublimes, the thin film in the dish 20 is cooled and frozen, at which time the metal plate 33 helps to uniformly cool the thin film over the entire area. As the metal plate 33, a copper plate may be used.

By this freezing, a porous structure is formed in the thin film 100c. Specifically, in the freezing process, the solvent contained in the thin film begins to be frozen from the bottom of the thin film to the upper side, as when the tree grows. At this time, the structure of the space occupied by the freezing solvent in the thin film becomes a porous structure.

In this process, the volume of the thin film is greatly inflated, and therefore, the thickness of the frozen thin film 100c is greatly increased compared to the thickness of the thin film 100b before it is frozen. The thickness of the roughly frozen thin film 100c is 10 to 30 times greater than the thickness of the thin film 100b before the freezing.

Referring to FIG. 1D, the thin film is then dried by sublimating the solvent in the thin film.

The drying apparatus 40 of FIG. 1D having a vacuum vessel 41, a vacuum pump 42 and a cooler 43 may be used for thin film drying. Specifically, a dish 20 containing a thin film frozen on a pedestal 41a in a decompression vessel 41 is placed. While keeping the internal temperature of the decompression vessel 41 below the set temperature by the cooler 43, The inner pressure of the decompression vessel 41 is lowered through the vacuum pump 42 so that the solvent contained in the thin film is sublimated and discharged outside the decompression vessel 41.

At this time, maintaining the internal temperature of the decompression vessel 41 below the set temperature is intended to prevent the solvent in the thin film from melting before sublimation. For example, the set temperature may be the freezing point of the solvent.

Thus, the thin film is dried by sublimating and removing the solvent in the thin film through the drying device 40. In this process, the thin film 100d is solidified in an inflated form and the porous film 100d filled in the freeze- The structure becomes empty space.

After the drying step, the washing step for the thin film 100d is carried out, whereby the bioactive film 100 is completed.

As described above, it is possible to produce a single-layer porous bioactive film 100 with a relatively simple manufacturing process and system by applying a spin coating technique and a freeze-drying technique.

1.2. Single layer The bioactive film 100  Characteristic

2 schematically shows a bioactive film 100 manufactured by the above-described production method. Note that the film thickness in this figure is shown to be much thicker than the actual thickness for convenience of explanation. 2, the bioactive membrane 100 has a porous structure formed from the bottom surface 101 to the top surface 102, although not shown in FIG.

A sample of the single-layer porous bioactive film of FIG. 3 was prepared by applying the above-described manufacturing method and the conditions shown in Table 1 below, and photographs of the sample obtained by enlarging the sample using an electron microscope (SEM) are shown in FIGS. 4 to 6 Respectively. FIGS. 4, 5, and 6 show bottom, top, and longitudinal sections of the sample, respectively.

Single layer Bioactive membrane  Manufacturing conditions

Polymer solution composition
① Solvent: Water
② Polymer: Methylcellulose 4 wt%
3) Crosslinking agent: 2 wt% of glutaraldehyde (crosslinking time: 1 hr)
④ Acid catalyst: hydrochloric acid 1 wt%

Spin coating

Rotation speed: 1000 rpm Time: 45 sec
freezing

Refrigerant: Dry Ice Time: 5 min
Drying (sublimation)

Temperature: -60 占 폚 Pressure: 60 kPa Time: 3 hr

Referring to FIGS. 4 to 6, it can be seen that the bioactive film 100 is composed of a single layer and has a thickness of approximately 300 μm. The thickness of the bioactive membrane 100 can be varied by adjusting the polymer content in the polymer solution.

It can be seen that a porous structure composed of numerous pores arranged closely and three-dimensionally throughout the membrane is formed in the bioactive membrane 100. Comparing the bottom view (FIG. 4) and the top view (FIG. 5), it can be seen that the size of the pores at the bottom surface 101 is somewhat greater than the top surface 102 because the freezing of the solvent, And proceeds to the upper surface side, and the porous structure is formed through the growth of such freezing solvent. It can be seen that the pores formed in the bioactive membrane 100 have a size of about 10 to 100 μm.

The bioactive membrane 100 is biodegradable and biocompatible because it is made of a biodegradable polymer that is not toxic like methylcellulose.

Since the bioactive membrane 100 is manufactured to have a high structural safety (or morphological safety) through crosslinking, even when it is immersed in a liquid such as water or blood, as shown in FIG. 7, Is stably maintained.

Also, as shown in FIG. 8, since the bioactive membrane 100 has high stretchability, it is stretched well and exhibits a characteristic that it is well restored to its original shape. As shown in FIG. 9, the bioactive membrane 100 exhibits excellent wound ability when wetted with a liquid such as saline, so that a round object such as a bone can be easily covered.

In addition, since the bioactive membrane 100 has a porous structure composed of numerous pores, it exhibits a property of absorbing blood or nutrients. Therefore, when used for covering biological tissues such as skin or bones, the tissue can contribute to recovery or growth.

2. Double layer  Porous Bioactive membrane

2.1. Manufacturing method

A method for producing a bi-layer porous bioactive film will be described with reference to FIGS. 10A to 10E. In the description of the above-described single layer porous bioactive film production method, what has already been described above will be briefly mentioned or omitted.

Referring to FIG. 10A, a first polymer solution 210a including a first biodegradable polymer and a first solvent and a second polymer solution 220a including a second biodegradable polymer and a second solvent are prepared.

The first polymer solution 210a is a solution to be the material of the first layer (dense lower layer) of the bioactive film and the second polymer solution 220a is the solution to be the material of the second layer (porous upper layer) of the bioactive film.

The same material can be applied to the first and second biodegradable polymers, but does not preclude the application of other materials. For example, methyl cellulose may be commonly used as the first and second biodegradable polymers.

The content of the first biodegradable polymer in the first polymer solution 210a and the content of the second biodegradable polymer in the second polymer solution 220a may be 2 to 14% by weight, respectively.

The same material may be applied to the first and second solvents, but does not preclude the application of other materials. For example, water may be commonly applied as the first and second solvents.

The first and second polymer solutions 210a and 220a preferably each include a crosslinking agent, and glutaraldehyde may be used as a glue agent. The content of the crosslinking agent in each polymer solution may range from 1 to 5% by weight. When a crosslinking agent is used, an acid catalyst may be added to each polymer solution, and hydrochloric acid (HCl) may be used as the acid catalyst.

At least one of the first and second polymer solutions 210a and 220a may include an artificial bone component or a drug component as an additive.

Referring to FIG. 10B, a first layer 210b made of a first polymer solution is formed by spin coating. The spin coating apparatus 10 described above may be used for this spin coating.

Next, the first layer 210b is dried. This drying step is performed by evaporating the first solvent contained in the first layer 210b, and an oven drying method or a natural drying method may be applied.

Referring to FIG. 10C, a second layer 220b made of a second polymer solution is formed on the first layer 210c in a dried state by spin coating. The spin coating apparatus 10 described above may be used for this spin coating.

The amount m2 of the second polymer solution 220a used for forming the second layer 220b may be an amount m1 of the first polymer solution 210a used for forming the first layer 210b, It is preferable to be equal to or larger than the above. For example, the ratio m1: m2 may be from 1: 1 to 1: 3.

Referring to Fig. 10D, the second layer is then frozen using a freezing device. As the freezing device, the above-described freezing device 30 can be used. During the freezing process, the second layer 220c is largely inflated to form a porous structure in the second layer 220c. Thus, the thickness of the frozen second layer 220c is increased by about 10 to 30 times compared to that before freezing.

Referring to FIG. 10E, the second layer is then dried by sublimating the solvent in the second layer. The drying apparatus 40 described above may be used for this drying step. In this drying process, the second layer 220d is solidified in an inflated form, and the solvent contained therein is sublimated and removed, so that the porous structure of the empty space is obtained.

It should be noted that a covalent bond between the first layer 210c and the second layer 220d proceeds during the solidification of the second layer 220d. This means that the first layer 210c and the second layer 220d become one body by chemical bonding. Therefore, there is no need for the help of a bonding means such as an adhesive to bond the two layers.

Finally, the bioactive membrane 100 is completed through the washing step.

As described above, by applying a spin coating technique and a freeze-drying technique, a relatively simple manufacturing process and system can form a dense layer or a non-porous layer, it becomes possible to produce a bi-layer porous biologically active membrane 200 composed of a porous layer and a second layer chemically bonded to each other.

2.2. Double layer The thickness of the bioactive film 200  Characteristic

11 schematically shows a bi-layer porous biomolecule 200 produced by the above-described production method. Note that the film thickness in this figure is shown to be much thicker than the actual thickness for convenience of explanation.

The bioactive film 200 is composed of a first layer 210 which is a dense layer (non-porous layer) and a second layer 220 which is a porous layer. The dashed line 205 shown in the figure indicates a boundary between the two layers 210 and 220. This is a conceptual illustration to facilitate the description of the layer structure of the bioactive film 200. The two layers 210 and 220, The boundary between the two layers 210 and 220 does not appear on the outer surface of the bioactive film 200. In this case,

The bi-layer porous bioactive film 200 sample of FIG. 12 was prepared by applying the above-described manufacturing method and the conditions shown in Table 2 below. Photographs of the double-layer porous bioactive film 200 obtained by enlarging the sample using an electron microscope (SEM) . Figs. 13, 14, and 15 show bottom, top, and longitudinal sections of the sample, respectively. Fig. 16 is a photograph of the longitudinal section of the sample taken at a larger magnification than the photograph of Fig.

Double layer Bioactive membrane  Manufacturing conditions


Polymer solution composition
① Solvent: Water
② Polymer: Methylcellulose 4 wt%
3) Crosslinking agent: 2 wt% of glutaraldehyde (crosslinking time: 1 hr)
④ Acid catalyst: hydrochloric acid 1 wt%

Spin coating
Rotation speed: 1000 rpm Time: 45 sec

First layer drying (evaporation)

Temperature: 43 캜 Time: 3 hr
freezing

Refrigerant: Dry Ice Time: 5 min
Second layer drying (sublimation)

Temperature: -60 占 폚 Pressure: 60 kPa Time: 3 hr

Referring to Figures 13-16, the bioactive membrane 200 comprises a dense non-porous first layer 210 having a thickness of approximately 10 microns and a porous second layer 220 having a thickness of approximately 200 microns Can be confirmed. The thickness of each layer can be varied in various ways by controlling the polymer content of the corresponding polymer solution.

Referring to FIGS. 15 and 16, it can be seen that a porous structure is formed in the porous second layer 220, in which many pores are three-dimensionally connected. 16, it can be seen that the dense first layer 210 and the porous second layer 220 form one body. It can be seen that the pores formed in the second layer 220 have a size of about 10 to 100 mu m.

As with the single layer porous bioactive membrane 100, the bi-layer porous bioactive membrane 200 is biodegradable, biocompatible, has high structural (or morphological) stability, has high stretchability and excellent woundability And has a characteristic of absorbing blood or nutrients due to its porous structure.

In addition, since the bi-layer porous bioactive film 200 has a dense layer (first layer) covering one side of the porous layer (second layer), it is unnecessary to add a separate protective film for preventing bacterial penetration The dense layer can function as a protective film.

3. Triple layer  Porous Bioactive membrane

3.1. Manufacturing method

17A to 17F, a method for manufacturing a triple layer porous bioactive film will be described. In the description of the above-described single layer porous bioactive film production method, what has already been described above will be briefly mentioned or omitted.

Referring to FIG. 17A, a first polymer solution 310a including a first biodegradable polymer and a first solvent, a second polymer solution 320a including a second biodegradable polymer and a second solvent, and a third biodegradation And a third polymer solution 330a including the first polymer and the third solvent is prepared.

The first polymer solution 310a is a solution to be the material of the first layer (dense lower layer) of the bioactive film and the second polymer solution 320a is the solution to be the material of the second layer (dense intermediate layer) of the bioactive film, The third polymer solution 330a is a solution which becomes the material of the third layer (porous upper layer) of the bioactive film.

The same material may be applied as the first, second and third biodegradable polymers, but does not preclude the application of other materials. For example, methyl cellulose may be commonly used as the first, second and third biodegradable polymers.

The content of the first biodegradable polymer in the first polymer solution 310a, the content of the second biodegradable polymer in the second polymer solution 320a, and the content of the third biodegradable polymer in the third polymer solution 330a are 2 To 14% by weight.

The same material may be applied to the first, second and third solvents, but does not preclude the application of other materials. For example, water may be commonly applied as the first and second solvents.

The first, second, and third polymer solutions 310a, 320a, and 330a preferably each include a crosslinking agent, and glutaraldehyde may be used as a binder. The content of the crosslinking agent in each polymer solution may range from 1 to 5% by weight. When a crosslinking agent is used, an acid catalyst may be added to each polymer solution, and hydrochloric acid (HCl) may be used as the acid catalyst.

At least one of the first, second, and second polymer solutions 310a, 320a, and 330a may include an artificial bone component or a drug component as an additive.

Referring to FIG. 17B, a first layer 310b made of a first polymer solution is formed by spin coating. The spin coating apparatus 10 described above may be used for this spin coating.

Next, the first layer 310b is dried. This drying step is performed by evaporating the first solvent contained in the thin film 310b, and an oven drying method or a natural drying method may be applied.

Referring to FIG. 17C, a second layer 320b made of a second polymer solution is formed on the first layer 310c in a dried state by spin coating. The spin coating apparatus 10 described above may be used for this spin coating.

Next, the second layer 320b is dried. This drying step is performed by evaporating the first solvent contained in the second layer 320b, and an oven drying method or a natural drying method may be applied.

Covalent bonding between the first layer 310c and the second layer 320b proceeds in the process of drying and solidifying the second layer 320b. This means that the first layer 310c and the second layer 320b become one body by chemical bonding. Thus, there is no need for the help of an adhesive means such as an adhesive to bond the two layers 310c, 320b.

Referring to FIG. 17D, a third layer 320b made of a third polymer solution is formed on the dried second layer 320c by spin coating. The spin coating apparatus 10 described above may be used for this spin coating.

The amount m3 of the third polymer solution 320a used for forming the third layer 320b may be an amount m1 of the first polymer solution 310a used for forming the first layer 310b, (M < 2 >) of the second polymer solution 320a used for forming the first layer 320a and the second layer 320b. For example, the ratio m1: m2 and the ratio m1: m3 may be 1: 1 to 1: 3, respectively.

Referring to Figure 17E, the third layer is then frozen using a freezing device. As the freezing device, the above-described freezing device 30 can be used. During the freezing process, the third layer 330c is largely inflated to form a porous structure in the third layer 330c. Therefore, the thickness of the frozen third layer 330c is elongated to approximately 10 to 30 times that before the freezing.

Referring to Fig. 17F, the solvent in the third layer is then sublimated to dry the third layer. The drying apparatus 40 described above may be used for this drying step. In this drying process, the third layer 330d is solidified in an inflated form, and the solvent contained therein is sublimated and removed, thereby having a porous structure in an empty space.

It should be noted that a covalent bond between the second layer 320c and the third layer 330d proceeds during the solidification of the third layer 330d. This means that the second layer 320c and the third layer 330d become one body by chemical bonding. Therefore, there is no need for the help of a bonding means such as an adhesive to bond the two layers.

Finally, the bioactive film 300 is completed through the washing step.

As described above, by applying a spin coating technique and a freeze-drying technique, a relatively simple manufacturing process and system can be used as a dense layer or a non-porous layer, Layer and a third layer that is a porous layer, and the three layers are chemically bonded to produce a triple layer porous bioactive film 300. [

3.2. Triple layer The bioactive film 300  Characteristic

18 schematically shows a triple layer porous bioactive film 300 produced by the above-described production method. Note that the film thickness in this figure is shown to be much thicker than the actual thickness for convenience of explanation.

The bioactive film 300 is composed of a dense layer (non-porous layer), a first layer 310, a second layer 320, and a third layer 330, which is a porous layer. The dashed lines 305 and 306 shown in the figure indicate the boundaries between the layers 310 and 320 and 330 but are conceptually shown to facilitate the description of the layer structure of the bioactive film 300, Since the second layers 310 and 320 are chemically coupled to each other and the second and third layers 320 and 330 are chemically bonded to each other, the three layers 310, 320, It should be noted that the boundary separating the three portions 310, 320, and 330 does not appear on the external appearance of the bioactive film 300.

A sample of the triple layer porous bioactive film 300 of FIG. 19 was prepared by applying the above-described manufacturing method and the conditions shown in Table 3 below, and photographs of the sample were observed by an electron microscope (SEM) 23. Figs. 20, 21 and 22 show bottom, top, and longitudinal sections of the sample, respectively, and Fig. 23 is a longitudinal section photograph of the sample taken at a larger magnification than the photograph of Fig.

Triple layer Bioactive membrane  Manufacturing conditions


Polymer solution composition
① Solvent: Water
② Polymer: Methylcellulose 4 wt%
3) Crosslinking agent: 2 wt% of glutaraldehyde (crosslinking time: 1 hr)
④ Acid catalyst: hydrochloric acid 1 wt%
⑤ Artificial bone powder (hydroxyapatite): 1 wt% (applies only to the 2nd layer)

Spin coating
Rotation speed: 1000 rpm Time: 45 sec

First layer drying (evaporation)
Temperature: 43 캜 Time: 3 hr

freezing
Refrigerant: Dry Ice Time: 5 min

Second layer drying (sublimation)
Temperature: -60 占 폚 Pressure: 60 kPa Time: 3 hr

20 to 23, the bioactive film 300 includes a dense first layer 310 and a second layer 320 having a thickness of approximately 7 占 퐉 and a porous third layer 320 having a thickness of approximately 200 占 퐉. (220). The thickness of each layer can be varied in various ways by controlling the polymer content of the corresponding polymer solution.

Referring to FIGS. 22 and 23, it can be seen that in the porous third layer 330, a porous structure in which many pores are three-dimensionally connected is formed. As shown in FIG. 23, it can be seen that the three layers 310, 320, and 330 are formed as one body. It can be seen that the pores formed in the third layer 330 have a size of about 10 to 100 mu m.

4. In the case of the bioactive membranes 100, 200 and 300  Usage

The bioactive membranes 100, 200, and 300 may be used for a variety of applications, and may be typically used as a surgical cover material and a skin cover material. This will be described in detail as follows.

4.1. Surgical As cover material  uses

The bioactive membranes 100, 200, and 300 may be suitably used as cover materials for covering the surgical site.

The bioactive membranes 100, 200, and 300 are biodegradable, have a high structural stability and are not broken even when a liquid such as blood or water is wetted, and have a property of being well adhered to a bendable object such as a bone. Therefore, a variety of surgical sites such as alveolar bone tissue, orthopedic bone tissue, organs treated with surgery or gynecologic surgery can be applied to bioactive membranes (100, 200, 300) The porous structure provided in the active membranes (100, 200, 300) facilitates rapid regeneration of the surgical site tissues. Specifically, the porous structure of the bioactive membranes 100, 200, and 300 has a size of about 10 to 100 占 퐉, which is a preferred size of cells constituting a living tissue, and is an ideal size for sucking blood or nutrients by capillary phenomenon The regeneration of the surgical site tissue can be promoted by the porous structure.

However, rather than the single-layer bioactive film 100, a plurality of bioactive films 200 and 300 may be more suitably used as a surgical cover material. The bi-layer biologically active membrane 200 can be used to position the second layer 220, which is a porous layer, in contact with the surgical site and the first layer 210, which is a dense layer (non-porous layer), on the outside, It is possible to prevent bacteria or surrounding tissues from penetrating into the surgical site. The triple layer bioactive film 300 can be used such that the third layer 330, which is a porous layer, is located in contact with the surgical site and the first layer 310, which is a dense layer, is located at the outermost position. It is possible to prevent bacteria or surrounding tissues from penetrating into the surgical site. On the other hand, the single-layer bioactive membrane 100 is composed of only one layer having a porous structure and is relatively weak in terms of preventing infiltration of bacteria or surrounding tissues because it does not have a dense layer.

When used for covering the bone tissue, the bioactive membranes 100, 200, and 300 may include an artificial bone substance that is provided to the bone tissue in the process of decomposing the membrane to help regenerate the membrane. In the case of the bi-layer biologically active membrane 200, it is preferable that the second layer 220, which is a porous layer, includes an artificial bone component. In the case of the tri-bioactive membrane 300, It is preferred that bone components are included.

Also, the bioactive membranes 100, 200, and 300 may include one or more drug substances. For example, the drug substance may be an antibiotic such as THF (tetrahydrofolate) or a growth promoter such as bone morphogenetic proteins (BMP). In the case of the bi-layer biologically active membrane 200, it is preferable that the second layer 220, which is a porous layer, contains a drug component. In the case of the tri-bioactive membrane 300, Component is preferably included.

4.2. skin As cover material  uses

The bioactive membranes 100, 200, and 300 may also be suitably used as cover materials for covering wounded skin.

Since the bioactive membranes 100, 200, and 300 have a porous structure including numerous pores, they can maintain the wound area in a wet environment and effectively absorb the foreign substances from the wound area.

When a plurality of bioactive layers 200 and 300 are used as a skin cover material, the first layers 210 and 310 which are dense layers (non-porous layers) located outside are effectively prevented from entering bacteria.

Since the bioactive membranes 100, 200 and 300 can be made much thinner by the conventional polyurethane foam, they can be particularly useful when the skin cover material is to be made thin.

10: spin coating apparatus
20: Plate
30: Freezing device
40: Drying device
100: single-layer porous bioactive membrane
200: bi-layer porous bioactive membrane
210a: first polymer solution
220a: second polymer solution
210: First layer
220: Second layer
300: triple layer porous bioactive membrane
310a: first polymer solution
320a: second polymer solution
330a: Third polymer solution
310: first layer
320: Second layer
330: Third Floor

Claims (30)

(a1) preparing a polymer solution containing a biodegradable polymer and a solvent;
(a2) forming a thin film of the polymer solution by spin coating;
(a3) freezing the thin film; And
(a4) sublimating a solvent in the frozen thin film to dry the thin film;
Lt; RTI ID = 0.0 > porous bioactive < / RTI > membrane.
The method according to claim 1,
Wherein the polymer solution further comprises a crosslinking agent.
A method for producing a single layer porous bioactive membrane.
The method according to claim 1,
Wherein the crosslinking agent is glutaraldehyde,
A method for producing a single layer porous bioactive membrane.
The method according to claim 1,
Wherein the biodegradable polymer is methyl cellulose,
A method for producing a single layer porous bioactive membrane.
The method according to claim 1,
Wherein the solvent is water,
A method for producing a single layer porous bioactive membrane.
A single-layer porous bioactive membrane produced by the process according to any one of claims 1 to 5.
(b1) preparing a first polymer solution containing a first biodegradable polymer and a first solvent, and a second polymer solution containing a second biodegradable polymer and a second solvent;
(b2) forming a first layer of the first polymer solution by spin coating;
(b3) evaporating the first solvent in the first layer to dry the first layer;
(b4) forming a second layer of the second polymer solution on the first layer by spin coating;
(b5) freezing the second layer;
(b6) sublimating a second solvent in the second layer to dry the second layer;
Lt; RTI ID = 0.0 > porous < / RTI > bioactive membrane.
The method of claim 7,
Wherein the first and second polymer solutions each further comprise a cross-
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 8,
Wherein the crosslinking agent is glutaraldehyde,
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 7,
Wherein the first and second biodegradable polymers are the same material and the first and second solvents are the same material,
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 10,
Wherein the first and second biodegradable polymers are methyl cellulose,
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 10,
Wherein the first and second solvents are water,
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 7,
Wherein the content of the first biodegradable polymer in the first polymer solution and the content of the second biodegradable polymer in the second polymer solution are each 2 to 14 wt%
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 7,
Wherein the second polymer solution comprises an artificial bone substance.
A method for preparing a bi-layer porous bioactive membrane.
The method of claim 7,
Wherein the second polymer solution comprises at least one kind of drug substance.
A method for preparing a bi-layer porous bioactive membrane.
A bi-layer porous biologically active membrane produced by the process according to any one of claims 7 to 15.
18. The method of claim 16,
Wherein the first layer and the second layer are chemically bonded to each other by covalent bonds,
Double layer porous bioactive membrane.
18. The method of claim 16,
Wherein the thickness of the first layer is 5 to 10 占 퐉 and the thickness of the second layer is 100 to 300 占 퐉,
Double layer porous bioactive membrane.
(c1) a first polymer solution containing a first biodegradable polymer and a first solvent, a second polymer solution containing a second biodegradable polymer and a second solvent, and a second polymer solution containing a third biodegradable polymer and a third solvent 3 < / RTI >
(c2) forming a first layer of the first polymer solution by spin coating;
(c3) evaporating the first solvent in the first layer to dry the first layer;
(c4) forming a second layer of the second polymer solution on the first layer by spin coating;
(c5) evaporating the second solvent in the second layer to dry the second layer;
(c6) forming a third layer of the third polymer solution on the second layer by spin coating;
(c7) freezing the third layer;
(c8) sublimating a third solvent in the third layer to dry the third layer;
Lt; RTI ID = 0.0 > 3, < / RTI >
The method of claim 19,
Wherein each of the first to third polymer solutions further comprises a crosslinking agent,
A method for producing a triple layer porous bioactive membrane.
The method of claim 20,
Wherein the crosslinking agent is glutaraldehyde,
A method for producing a triple layer porous bioactive membrane.
The method of claim 19,
Wherein the first to third biodegradable polymers are the same material and the first to third solvents are the same material,
A method for producing a triple layer porous bioactive membrane.
23. The method of claim 22,
Wherein the first to third biodegradable polymers are methyl cellulose,
A method for producing a triple layer porous bioactive membrane.
23. The method of claim 22,
Wherein the first to third solvents are water,
A method for producing a triple layer porous bioactive membrane.
The method of claim 19,
The content of the first biodegradable polymer in the first polymer solution, the content of the second biodegradable polymer in the second polymer solution, and the content of the third biodegradable polymer in the third polymer solution are 2 to 14 wt% % sign,
A method for producing a triple layer porous bioactive membrane.
The method of claim 19,
Wherein at least one of the second polymer solution and the third polymer solution comprises an artificial bone substance.
A method for producing a triple layer porous bioactive membrane.
The method of claim 19,
Wherein at least one of the second polymer solution and the third polymer solution includes at least one kind of drug substance.
A method for producing a triple layer porous bioactive membrane.
A triple layer porous bioactive membrane produced by the process according to any one of claims 19 to 27.
29. The method of claim 28,
Wherein the first layer and the second layer and the second layer and the third layer are chemically bonded to each other by covalent bonding,
Triple layer porous bioactive membrane.
29. The method of claim 28,
Wherein the first layer and the second layer each have a thickness of 5 to 10 mu m and the third layer has a thickness of 100 to 300 mu m,
Triple layer porous bioactive membrane.

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