KR101840021B1 - Tissue engineering scaffold composed of three-dimensional shell structure and bioreactor provided with the same - Google Patents

Abstract

The present invention relates to a scaffold for tissue engineering and a bioreactor using the scaffold. A scaffold according to the present invention is a scaffold for tissue engineering using a three-dimensional thin film structure whose inner side is divided into two inter-tangled sub-spaces by an interface, wherein the interface is made of a porous thin film through which specific substances can be selectively passed, and wherein a first space of the two sub-spaces is provided as a space for culturing cells and a second space is provided as a moving path for metabolite. The scaffold can be accommodated into a housing having an entrance and an exit for metabolite to form a bioreactor.

Description

TECHNICAL FIELD [0001] The present invention relates to a scaffold for tissue engineering comprising a three-dimensional thin film structure, and a bioreactor including the same. [0002]

The present invention relates to a scaffold for tissue engineering, and a bioreactor using such a scaffold. The present invention also relates to a three-dimensional thin film structure used in the scaffold and a method of manufacturing the same.

Tissue engineering generally refers to techniques for understanding the growth principles of living tissues and applying them to produce functional alternative tissues for medical purposes. A scaffold is an artificial structure that plays a role in supporting living tissue to be formed in three dimensions. It is a key element of tissue engineering. Conventionally, a scaffold for soft tissues such as a hydrogel and an electrospun nanofiber, and a porous, irregularly shaped porous body such as a sphongalon manufactured by a gas-foamed or salt-leached method A scaffold for cartilage or bone tissue having a structure is traditionally known. In addition, a bioreactor capable of culturing a living tissue under an environment controlled in vitro for the purpose of transplanting into the body is used. A support for culturing the biotissue in such a bioreactor is also included in the scaffold.

For these scaffolds, the first is to have a three-dimensional porous structure with interconnected internal spaces to allow for the growth and nutrients of cells, the flow of oxygen and the metabolic waste, and biocompatibility and bioabsorbability bioresolbable (specifically bioabsorbable) that can regulate the rate at which it is degraded or absorbed in response to cell and tissue growth in vitro or in the body. Third, the surface should have chemical properties suitable for cell attachment, proliferation, and differentiation , And fourthly, it is required to have appropriate mechanical strength and stiffness so as to be suitable for the surrounding tissue of the part to be implanted. Particularly, the second to fourth conditions are independent on the scaffold for cartilage or bone tissue (DW Hutmacher. Scaffolds in tissue engineering bone and cartilage. Biomaterials Vol. 21, pp.2529- 2543, 2000).

Among the conventional conventional scaffolds, for example, a cartilage or bone preparation scaffold made of a gas-foamed or salt-leached method and having a porous irregular structure such as a sponge is limited in internal flow There is a disadvantage that the mechanical strength is low due to local defects. In the 2000s, periodical cellar materials with periodic micro-architecture have been known to have high strength and low flow resistance, and CAD and 3D printing technology have been developed recently. Recently, various attempts have been made to utilize such a regular microstructure as a scaffold.

As a part of it, attempts have been made to utilize TPMS (Triply Periodic Minimal Surface) as a scaffold with a regular microstructure. The TPMS is a curved surface structure that is periodically repeated without non-self intersecting on a three-dimensional space, and has a zero mean curvature (Gesammelte Mathematische Abhandlungen, Springer). Here, the mean curvature means an average value of a maximum curvature and a minimum curvature in two directions perpendicular to each other at a point on a three-dimensional surface, and represents the degree of curvature of the three-dimensional surface. In the 1960s, A. Schoen summarized and added several new TPMSs (S. Hyde et al., The Language of Shape, Elsevier, 1997, ISBN: 978-0-444-81538-5). As shown in FIG. 1, there are various types of TPMS, and P-, D-, and G-surfaces are cited most commonly in the chemical and biological fields. TPMS in nature is found in water-emulsifier mixtures, cell membranes, urchin epidermis, silicate meso-phase, and most of them exist as an interface separating two phases. In addition, the TPMS having a zero mean curvature of the above-mentioned zero-sphere divides the space into two continuous subvolumes, wherein the volume ratio of the two subspaces is equal to 1: 1. It is also possible to define a minimal surface with a constant average curvature that divides both subspaces, even when the volume ratio is different (see also M. Maldovan and EL Thomas Periodic Materials and Interference Lithography. 2009 WILEY-VCH Verlag GmbH & Co. KGaA, ISBN: 978-3-527-31999-2). If a three-dimensional thin film structure is manufactured in the form of a TPMS, the curvature of the thin film has a uniform average curvature anywhere, so that when the external load is applied, the stress is not concentrated in any one part, The mechanical properties of the shell and the ultralow-density cellular material are discussed in detail in the following section of this paper. 103, pp. 595-607, 2016.), a practical process for manufacturing a TPMS-type thin film structure, a method of manufacturing a thin film multi-layer structure based on photolithography is applied to form a P- (SC Han, JW Lee, K. Kang, A new type of low density material, Shellular. Advanced Materials, Vol.27, pp.5506-5511, 2015.).

FIG. 2 shows a concrete example of a method of utilizing a recent TPMS as a scaffold with a regular microstructure. FIG. 2 (a) is a scaffold in which one subvolume of the TPMS is filled with a solid, which is higher in mechanical strength and rigidity than the truss or lattice microstructure, (S. Rajagopalan, RA Robb. Schwarz meets Schwann: Design and fabrication of biomorphic and durataxic tissue engineering scaffolds. Med Image Anal., Vol.10, pp.693-712 , 2006.). 2 (b) is a scaffold in which the two sub-spaces separated by the TPMS are empty and the interface thereof is solid, and it has been proposed that the strength relative to the weight of FIG. 2 (a) is excellent (SC Kapfer, ST Hyde, K. Mecke, CH Arns, GE Schroder-Turk. Minimal surface scaffold designs for tissue engineering, Vol. 32, pp. 6875-6882, 2011.). Kapfer et al. Named 'network solid' in FIG. 2 (a) and 'sheet solid' in FIG. 2 (b) while distinguishing them from each other.

However, both the conventional scaffold mentioned above and the scaffold utilizing the recent TPMS have the following problems. First, fluid flow that carries the nutrients and oxygen required for cell activity within the subspace, and the metabolic waste resulting from cell activity is limited. For example, in a scaffold having an irregular structure, there is a limitation that the in-vitro tissue growth depth is limited to about 500 탆 or less from the surface (LE Freed, G. Vunjak-Novakovic, Culture of organized cell communities. Adv. Drug Deliver Rev., Vol. 33, pp. 15-30, 1998.). This is also due to low fluid permeability in the empty space in the scaffold, but also due to the phenomenon that the flow path is clogged by the proliferating cells. This problem can occur as time hardens in 'network solid' or 'sheet solid' using TPMS which is proposed to have excellent fluid permeability. Secondly, when used as a scaffold for cartilage or bone tissue, the bulk of the solid in the scaffold must be large in order to obtain the required strength, and therefore, it must be decomposed or absorbed in vitro or in vivo in accordance with cell and tissue growth The amount of the solid material is increased, so that the selection of the material is limited and the human body may be burdened. Moreover, the volume of the pores varies so much that the permeability of the fluid tends to deteriorate.

- D.W. Hutmacher. Scaffolds in tissue engineering bone and cartilage. Biomaterials Vol. 21, pp. 2529-2543, 2000. - Gesammelte Mathematische Abhandlungen, Springer - S. Hyde et al. The Language of Shape. Elsevier, 1997, ISBN: 978-0-444-81538-5 - M. Maldovan and E. L. Thomas. Periodic Materials and Interference Lithography. 2009 WILEY-VCH Verlag GmbH & Co. KG KGaA, ISBN: 978-3-527-31999-2 - Min Geun Lee, Jeong Woo Lee, Seung Chul Han, Kiju Kang. Mechanical Analyzes of "Shellular", an Ultralow-density Cellular Metal. Acta Materialia, Vol. 103, pp. 595-607, 2016. - S.C. Han, J.W. Lee, K. Kang. A new type of low density material; Shellular. Advanced Materials, Vol. 27, pp. 5506-5511, 2015. S. Rajagopalan, R.A. Robb. Schwarz meets Schwann: design and fabrication of biomorphic and durataxic tissue engineering scaffolds. Med Image Anal., Vol. 10, pp. 693-712, 2006. - S.C. Kapfer, S.T. Hyde, K. Mecke, C.H. Arns, G.E. Schroder-Turk. Minimal surface scaffold designs for tissue engineering, Biomaterials. Vol. 32, pp. 6875-6882, 2011. - L.E. Freed, G. Vunjak-Novakovic. Culture of organized cell communities. Adv. Drug Deliver Rev., Vol. 33, pp. 15-30, 1998.

It is an object of the present invention to provide a method for producing a microorganism having excellent flowability and excellent rigidity against external load And to provide a scaffold which can be freely designed in any three-dimensional shape and a bioreactor including the scaffold. It is another object of the present invention to provide a three-dimensional thin film structure that can be utilized in such a scaffold and a method of manufacturing the same.

In order to solve the above-mentioned problems, the inventors of the present invention intensively studied a method of utilizing a three-dimensional structure separated and divided into two subvolumes in which the interior is twisted by an interface like a TPMS, The three-dimensional structure can be divided into two subvolumes which are twisted with each other by the interface, and attention is paid to the geometrical structure in which each subspace is continuous, The space separating the space is composed of a porous thin film and all the two subspaces of the three-dimensional structure are utilized. One subspaces is a space where the cells are cultured. Another subspaces is formed by the nutrients, oxygen Water, and metabolic wastes. When these three-dimensional structures are implemented in the form of TPMS, The present inventors came to the present invention by devising a variety of bioreactors including scaffolds of this type. Also, with regard to a method of implementing the interface separating two sub-spaces in the TPMS type three-dimensional structure as a porous thin film, a permeable film is formed on a template, which is a sacrificial structure, . The gist of the present invention regarding the recognition of the above-mentioned problems and the solution means based on the above is as follows.

(1) is a scaffold for tissue engineering using a three-dimensional thin film structure which is divided into two sub-spaces which are internally twisted with each other by an interface, wherein the interface is constituted by a porous thin film capable of selectively passing only a specific substance, Wherein a first one of the two subspaces is provided in a space in which the cells are cultured and a second space is provided in a path of movement of the metabolite.

(2) The scaffold for tissue engineering according to (1), wherein the porous thin film is any one of biomaterial, metal, polymer and ceramic.

(3) The scaffold for tissue engineering according to (1), wherein the interface is a triply periodic minimal surface (TPMS).

(4) The scaffold for tissue engineering according to (1) above, wherein the surface area of the interface and the space in which the cells are cultured are controlled by controlling the size of the unit structure in which the first space and the second space are separated by the porous thin film

(5) A scaffold according to any one of (1) to (4) above. And a housing receiving the scaffold therein and having an inlet and an outlet of a metabolite.

(6) The bioreactor according to (5), wherein the first space and the second space are provided with independent inlets and outlets, respectively.

(7) The bioreactor according to (5), wherein an inlet and an outlet are provided only in the second space.

(8) The bioreactor according to (5), wherein the first space is provided with an outlet only and the second space is provided with only an inlet.

(9) A method for manufacturing a three-dimensional thin film structure which is divided into two sub-spaces in which the inside is twisted by a porous thin film, comprising the steps of: preparing a template; Forming a porous thin film outside the template; Exposing a template by removing a portion of the porous thin film; And removing the template. 2. The method of manufacturing a three-dimensional thin film structure according to claim 1,

(10) forming the porous thin film comprises: forming a mixed coating layer of chitosan and polyethylene glycol (Chitosan / PEG); Forming a polylactic acid (PLA) coating layer; And a hydrophilic treatment of the polylactic acid (PLA) coating layer on the surface of the three-dimensional thin film structure.

(11) The polylactic acid (PLA) coating layer is removed along with the removal of the template, and then the polyethylene glycol (PEG) is removed from the chitosan and polyethylene glycol (PEG) mixed coating layer. (10). ≪ / RTI >

According to the present invention, the interface separating the two sub-spaces is constituted by a porous thin film, and the two sub-spaces of the three-dimensional structure are utilized. One sub-space is used as a space where the cells are cultured, By constructing a scaffold with a structure that is used as a pathway for the metabolism of nutrients, oxygenated water, and metabolic waste accompanying cell culture, there is no clogging of the channel for supplying nutrients and oxygen by the cells to be proliferated, It is possible to provide a scaffold and a bioreactor including the scaffold which are made of a solid material and easy to be decomposed or absorbed in accordance with tissue growth, excellent in fluid permeability and rigidity against an external load, .

1 is a structural view of various types of TPMS (Triply Periodic Minimal Surface).
2 is a structural view of a scaffold utilizing a conventional TPMS.
3 is a structural view of a scaffold according to an embodiment of the present invention;
4 is a structural view of a bioreactor according to an embodiment of the present invention.
5 is a view illustrating a process for manufacturing a three-dimensional thin film structure having a porous thin film according to an embodiment of the present invention.
6 is a photograph of a product of a three-dimensional thin film structure manufactured according to an embodiment of the present invention.

Hereinafter, the present invention will be described in detail with reference to examples. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately The present invention should be construed in accordance with the meaning and concept consistent with the technical idea of the present invention. Therefore, the configuration of the embodiment described in the present specification is merely the most preferred embodiment of the present invention, and does not represent all the technical ideas of the present invention, so that various equivalents And variations may be made. On the other hand, in the drawings, the same or similar reference numerals are given to the same or equivalent elements in the drawings, and, in the entire specification, when a component is referred to as being "comprising" But may include other components.

Scaffold

First, the structure of a scaffold according to a preferred embodiment of the present invention will be described with reference to FIG. The scaffold 10 according to the embodiment of FIG. 3 is configured such that the two sub-spaces 110 and 120 are separated by the porous thin film 130 and the porous thin film 130 is divided into two sub-spaces 110 and 120 ). ≪ / RTI > When the porous membrane 130 is used directly in the body, it is preferable that the porous membrane 130 is made of a biomaterial such as chitosan. However, in the case of a bioreactor, When it is used, it may be made of a material such as metal, ceramic, polymer and the like.

In this case, the curved surface of the porous thin film 130 is preferably a variety of TPMS including a G-surface, but not limited thereto, and other smooth curved surface shapes capable of dividing two sub-spaces 110 and 120 .

A first space 110 of the two sub-spaces is provided to a space where cells are cultured, and another second space 120 is provided as a path of movement of a metabolite. In this case, the metabolites include nutrients, oxygen, water and their wastes needed for metabolism.

In this scaffold structure, the second space 120, in which a metabolite such as nutrients, oxygen, water, and metabolic waste are moved, is separated from the first space 110 in which the cells are cultured, It is possible to induce uniform cell culture and to obtain a large tissue while solving the problem of the conventional scaffold in which the channel is blocked.

Also, since the two sub-spaces 110 and 120 are twisted together and each forms a smooth continuous space, the flow resistance during movement of the metabolite in the second space 120 is significantly reduced, The permeability can be greatly improved as a whole. Particularly, when the curved surface of the porous thin film 130 is of the TPMS type, early local buckling can be suppressed at the time of external load, and it can be higher than the weight, so that the requirements for permeability and rigidity, which are difficult to achieve in the conventional scaffold, .

In addition, since the interface between the two sub-spaces 110 and 120 is made of a porous thin film, the porous thin film 130 having a large surface area can improve the transport efficiency of the metabolite, and the curved surface of the transmission thin film 130 can be formed in the form of TPMS , The amount of the solid matter necessary for maintaining the strength is minimized, so that it is advantageously decomposed or absorbed into the body according to the tissue growth.

Since the scaffold 10 has a structure in which a unit sturucture of small size in which two sub-spaces 110 and 120 are separated by the porous thin film 130 is regularly repeated on the three-dimensional space, It is possible to arbitrarily design the scaffold in a desired shape freely. In this case, by controlling the size of the unit structure to several to several thousand micrometers, the surface area of the interface of the porous thin film 130 can be controlled and a proper space for tissue culture can be provided.

Bioreactor

Next, a bioreactor according to an embodiment of the present invention, which can be implemented by including the scaffold 10 of FIG. 3 as a component, will be described with reference to FIG. In FIG. 4, the scaffold 10 is represented by two-dimensionally representing a structure in which two sub-spaces 110 and 120 are separated by an interface of the porous thin film 130. A bioreactor refers to a device capable of culturing an organism under controlled conditions in order to produce a specific substance or cell or to perform a specific biological reaction. In the embodiment, a bioreactor is used for culturing a living tissue in vitro .

4 (a) to 4 (c) are basically composed of a scaffold 10 and a housing 20 for accommodating the scaffold 10 therein, and the housing 20 And is provided with an inlet and an outlet for supplying and discharging nutrients, oxygen, water and its waste, and can be modified as shown in the embodiments illustrated below according to the use and requirements of the bioreactor 1.

4 (a) shows a configuration diagram of the bioreactor 1 according to the first embodiment of the present invention. In the first embodiment, the first space 110 and the second space 120 provided in the scaffold 10 are provided with independent inlets and outlets, respectively. The inlet 110a and the outlet 110b are formed in the first space 110 and the inlet 120a and the outlet 120b are formed in the second space 120 as well. In this case, the pressure of the second space 120 is made slightly higher than that of the first space 110, and the supply of nutrients and oxygen is activated through the porous thin film 130 through the water, Is discharged to the separate outlet (110b), so that contamination of the second space (120) can be minimized.

Fig. 4 (b) shows the configuration of the bioreactor 1 according to the second embodiment of the present invention. In the second embodiment, the first space 110 has no separate inlet and outlet, while the second space 120 has a separate inlet 120a and an outlet 120b. In this case, a fluid containing nutrients and oxygen necessary for metabolism is supplied through the inlet 120a, a fluid including the metabolism waste is discharged through the outlet 120b, and the second space 120 and the first space 110 ) Is carried out only through the porous membrane 130, it is possible to minimize the possibility that the cells cultured in the first space 110 are lost due to the flow of the metabolite. On the other hand, although the amount of the moving substance can be expected to be relatively small since the movement of the metabolite between the two sub-spaces 110 and 120 is made only through the porous thin film 130 depending on the diffusion and osmosis phenomenon, Unlike the conventional scaffold, since the area density of the porous thin film 130 is large, the unit microstructure in which the two sub-spaces 110 and 120 are separated from each other by the interface of the porous thin film 130 in the scaffold 10, Micrometer, it is possible to secure a sufficient area for the porous membrane 13 as a moving path of the metabolite, so that there is no problem in the movement amount of the whole metabolite. However, in the case of the second embodiment, since the circulating flow path is a single system, separate means for filtering the discharged metabolism waste may be required. In the case of the bioreactor according to the present embodiment, after the tissue is cultured up to a certain level in the scaffold, only the scaffold can be implanted into the body without any additional action.

4 (c) shows the structure of the bioreactor 1 according to the third embodiment of the present invention. In the third embodiment, the first space 110 is provided with only the outlet 110b and the second space 120 is provided with only the inlet 120a. In this case, the pressure of the second space 120 is made higher than that of the first space 110, and a fluid containing nutrients and oxygen necessary for the metabolism is discharged from the second space 120 through the porous thin film 130 into the first space 110 and all the fluid including the metabolic waste generated in the first space 110 and unused nutrients and oxygen is discharged through the outlet 110b provided in the first space 110, do. In this operating mode, there is an advantage that the movement of the material from the second space 120 to the first space 110 can be maximized. However, as in the case of the second embodiment shown in FIG. 4 (b), since the circulating flow path is a single system, separate means for filtering the discharged metabolism waste may be required.

For scaffolding  Manufacture of 3D thin film structure

Next, a method of manufacturing a three-dimensional thin film structure applicable to the scaffold according to FIG. 3 will be described with reference to FIG. In this case, the three-dimensional thin film structure 10 used as a scaffold in FIG. 5 is represented by a structure in which two sub-spaces 110 and 120 are separated from each other by an interface of the porous thin film 130, The template 30 functioning as a mold of the thin film structural body 10 is expressed in a two-dimensional diagram.

Referring to FIG. 5, the manufacturing method includes: (S10) fabricating a template 30 that is a sacrificial structure; Forming a porous thin film 130 'outside the template 30 (S20); Removing a portion of the porous thin film 130 'to expose the template 30 (S30); And removing the template 30 (S40), thereby separating the inner space into two sub-spaces (110, 120) in which the inner portion is twisted together by the porous thin film (130) Dimensional thin film structure 10 for a scaffold is obtained (S50). In the figure, identifier 130 represents the final porous thin film, and identifier 130 'represents the porous thin film as the intermediate product to the final porous thin film pre-stage.

The overall process of such a three-dimensional thin film structure can be manufactured by applying a fabrication method based on photolithography, for example, which the present inventors have disclosed through previous studies (SC Han, K. Kang. A new type of Low Density Material, Shellular. Advanced Materials, Vol. 27, pp. 5506-5511, 2015.), the contents of which are incorporated herein by reference in their entirety. The present invention is characterized in that the thin film referred to in the above-mentioned prior art is implemented as a porous thin film. In the following, the detailed process related to this part will be mainly described, and the porous thin film will be made of Chitosan do. However, the present invention is not limited to the TPMS structure similar to the P-surface mentioned in the above-mentioned prior art, but may include various types of TPMS structures mentioned in FIG. 1, and the material of the porous thin film may be, It is needless to say that it may be made of a material other than a biomaterial such as metal, ceramics, and polymers, depending on the use thereof, in addition to the biomaterial of chitosan.

First, the liquid phase thiolene monomer resin is irradiated with ultraviolet rays in four directions through a mask to obtain an intaglio-shaped solid phase polymer template 30, and then secondary cured in an oven at 120 DEG C (S10).

Next, separately, chitosan (with a molecular weight of 100,000 Da and degree of deacetylation of 83%) and polyethylene glycol (PEG: polyethylene glycol, wiith molecular weight 20000 (PEG20000)) were mixed at a mass ratio of 1: Dissolve in aqueous solution and dilute to 4% concentration. The solution is slowly stirred at room temperature for 5 to 6 hours to make it transparent. The template 30 is immersed in the above-mentioned chitosan and polyethylene glycol (PEG) solution, placed in a sealed container, and vacuum is applied to fill the template 30 with chitosan and polyethylene glycol (Chitosan / PEG) solution without voids. This is removed and processed in a centrifuge for a few minutes to keep the chitosan and polyethylene glycol (Chitosan / PEG) solution coated on the sacrificial structure surface only. This is dried at room temperature for about one hour. The above chitosan and polyethylene glycol (Chitosan / PEG) coating is repeated 2-3 times. The solution prepared by dissolving polylactic acid (PLA) in chloroform at a concentration of 2% is coated on the substrate by a process such as chitosan and polyethylene glycol (Chitosan / PEG) solution coating method and dried. The above process can be repeated several times to obtain a porous thin film 130 'having a desired final thickness. Since the polylactic acid (PLA) layer has hydrophobicity, it is immersed in a 1% aqueous solution of sodium hydroxide for 30 seconds (S20).

In this case, the chitosan and polyethylene glycol (Chitosan / PEG) mixed coating layer functions as a precursor layer of the final Chitosan porous thin film 130, and the polylactic acid (PLA) layer is formed of a mixture of chitosan and polyethylene glycol . That is, after 2 to 3 times of coating with chitosan and polyethylene glycol (Chitosan / PEG), it is not effectively thickened even after the additional coating is performed. Therefore, polylactic acid (PLA) The porous thin film 130 'is formed by repeating the coating process, and the polylactic acid (PLA) layer is removed in the subsequent process to obtain the chitosan thin film 130 having the overlapped structure of the desired thickness in the final product .

Subsequently, a part of the porous thin film 130 'made of chitosan and polyethylene glycol (Chitosan / PEG) mixed coating layer and polylactic acid (PLA) layer is removed by polishing to expose the thiolene polymer material of the template 130 Next, in step S30, the polylactic acid (PLA) coating layer is hydrolyzed in step S40 by completely removing the thiolene polymer by immersing in a 4% sodium hydroxide aqueous solution for 2 to 3 hours.

Finally, the resulting thin film structure consisting of chitosan and polyethylene glycol (Chitosan / PEG) was thoroughly washed with distilled water to make it neutral. The thin film structure was immersed in water at 80 ° C for 8 hours to remove polyethylene glycol (PEG) The three-dimensional thin film structure 10 composed of the porous chitosan thin film 130 can be obtained (S50).

FIG. 6 shows a product photograph of the three-dimensional thin film structure manufactured by the above method. The product of FIG. 6 was designed to have a P-surface shape and shrinkage occurred in the drying process, but when used in an aqueous solution as a scaffold, the product may expand to have a more smooth curved surface.

The foregoing is a description of specific embodiments of the present invention. While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed embodiments or constructions. It will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention. It should be understood that this is possible. It is therefore to be understood that all such modifications and alterations are intended to fall within the scope of the invention as disclosed in the following claims or their equivalents.

1: bioreactor
10: scaffold, three-dimensional thin film structure
110: First space
120: Second space
110a, 120a: entrance
110b, 120b:
130, 130 ': Porous thin film
20: Housing
30: Template

Claims (11)

The present invention relates to a scaffold for tissue engineering using a three-dimensional thin film structure divided into two sub-spaces each consisting of a first space and a second space of which the inside is twisted by an interface,
Wherein the interface is composed of a porous thin film having selective permeability,
The first of the two sub-spaces is provided as a space in which cells are cultured,
Wherein a second space of the two subspaces is provided as a path for movement of a metabolite including a substance necessary for culturing the cell and a substance excreted in the course of culturing the cell,
Wherein the metabolite is exchanged between the first space and the second space through the porous thin film. The scaffold for tissue engineering according to claim 1, wherein the porous thin film is any one of a biomaterial, metal, polymer, and ceramic. The scaffold for tissue engineering according to claim 1, wherein the interface is a Triply Periodic Minimal Surface (TPMS). The scaffold for tissue engineering according to claim 1, wherein a size of the unit structure in which the first space and the second space are separated by the porous thin film is controlled so that the surface area of the interface and the space in which the cells are cultured are controlled. A scaffold according to any one of claims 1 to 4; And a housing receiving the scaffold therein and having an inlet and an outlet of a metabolite. 6. The bioreactor according to claim 5, wherein the first space and the second space are provided with independent inlets and outlets, respectively. The bioreactor according to claim 5, wherein an inlet and an outlet are provided only in the second space. 6. The bioreactor according to claim 5, wherein only the outlet is provided in the first space and only the inlet is provided in the second space. A method for fabricating a three-dimensional thin film structure that is divided into two sub-spaces in which the inside is twisted by a porous thin film, comprising: preparing a template; Forming a porous thin film outside the template; Exposing a template by removing a portion of the porous thin film; And removing the template. 2. The method of manufacturing a three-dimensional thin film structure according to claim 1, [10] The method of claim 9, wherein the porous thin film is formed by forming a mixed coating layer of chitosan and polyethylene glycol (PEG). Forming a polylactic acid (PLA) coating layer; And treating the polylactic acid (PLA) coating layer with a hydrophilic treatment. 11. The method of claim 10, wherein the polylactic acid (PLA) coating layer is removed following the removal of the template, and thereafter polyethylene glycol (PEG) is removed from the chitosan and polyethylene glycol (PEG) Wherein the three-dimensional thin film structure is formed on the substrate.

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