KR20160096829A - 3D hydrogel scaffold manufacturing method using bio-printing technology - Google Patents

3D hydrogel scaffold manufacturing method using bio-printing technology Download PDF

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KR20160096829A
KR20160096829A KR1020150018381A KR20150018381A KR20160096829A KR 20160096829 A KR20160096829 A KR 20160096829A KR 1020150018381 A KR1020150018381 A KR 1020150018381A KR 20150018381 A KR20150018381 A KR 20150018381A KR 20160096829 A KR20160096829 A KR 20160096829A
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collagen
gelatin
alginate
hydrogel
mixture
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KR1020150018381A
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Korean (ko)
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이준희
이수희
박수아
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한국기계연구원
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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
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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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Abstract

The present invention relates to a method for producing a three-dimensional hydrogel scaffold using bio-printing technology. One purpose of the present invention is to provide a method for producing a three-dimensional hydrogel scaffold using bio-printing technology which is capable of preparing a hydrogel that is suitable for fabricating a scaffold by a three-dimensional plotting device. Other purpose of the present invention is to provide a method for producing a three-dimensional hydrogel scaffold using bio-printing technology which is capable of preparing various types of hydrogels to obtain a scaffold formed in the form that is suitable with respect to each of various tissues in the human body. A method for producing a three-dimensional hydrogel scaffold using bio-printing technology according to the present invention comprises: a step of containing a hydrogel comprising alginate or collagen in a containing part; a step of applying a pressure within a range of 10 to 300 kPa to the containing part to discharge the hydrogel to a nozzle having an outlet diameter within a range of 0.1 to 0.5 mm; a step of producing a scaffold by plotting the hydrogel while moving the nozzle at a speed within a range of 50 to 400 mm/min by a moving part.

Description

Technical Field [0001] The present invention relates to a 3D hydrogel scaffold manufacturing method using bio-printing technology,

The present invention relates to a method for producing a three-dimensional hydrogel scaffold using a bioprinting technique.

Tissue engineering is a technology that is based on the basic concepts and technologies of life sciences, medicine, and engineering to create a substitute for living tissue and transplant it into the living body to make it possible to maintain, improve and restore the function of the living body. will be. The practical implementation of biotissue engineering is to collect the necessary tissues from the body of the patient, separate the cells from the tissue, and then proliferate the separated cells by the required amount through cultivation, plant them in a porous biodegradable polymer scaffold, (Also referred to as a " cell culture support "), which is formed by implanting a scaffold into a human body. After transplantation, most tissues and organs are fed with oxygen and nutrients by diffusion of body fluids until new blood vessels are formed. When blood vessels enter the body and blood is supplied, cells multiply and differentiate into new tissues and organs And the biodegradable polymer scaffold has disintegrated and disappeared in the meantime.

The main requirements of the support material used for the regeneration of human tissue are as follows. First of all, it is essential that the tissue cells should be well adhered thereon, and that the tissue cells have a mechanical strength enough to function as a substrate or support so as to form a tissue having a three-dimensional structure by adhering to the surface of the material do. It should also act as an intermediate barrier between the transplanted cells and host cells, which requires a non-toxic biocompatibility that does not result in blood clotting or inflammation after transplantation. In addition, when the transplanted cells function as a new body tissue, they must have biodegradability that can be completely decomposed and disappeared in a desired period of time.

There have been various studies related to scaffold fabrication techniques to satisfy various conditions as described above. In general, synthetic polymer materials such as PLA, PGA, PCL, PLGA, PU, and PEG are used as a polymer solution used in the production of a scaffold. Proteins such as collagen, albumin and amino acids and F127 And the like are also used. Among them, a natural polymer material is preferably used in order to maximize biocompatibility.

A cell culturing method using a hydrogel made of a natural polymer material is disclosed in Korean Patent Registration No. 1449906 entitled " METHOD FOR 3-DIMENSIONAL BIOLOGICAL TRANSPORTATION OF BIOLOGICAL CELLS USING AGROSS-COLLAGEN-ALGINATE COMPLEX HYDROGEL SUPPORT "(Apr. As described above, in the technique of culturing cells using a conventional hydrogel, the hydrogel was formed into a bead form or a disk form on a cell culture plate without pores to cultivate the cells. Therefore, only one type of cell can be cultured on one type of hydrogel, and there is no pore or shape in the cell culture support. Cells in the human body are surrounded by various types of extracellular matrix of various types of cells. In this conventional way, it is difficult to make three-dimensional tissue similar to human body.

On the other hand, SFF (Solid Freeform Fabrication) has been introduced to produce a scaffold that can reproduce complex shapes of the human body. It has the advantage of making the desired three-dimensional shape freely so that it can very easily realize a fairly complicated shape such as a pinna shape and the like. In addition, it can improve the pore size, porosity and interconnectivity between pores of a scaffold, It has the advantage of being able to penetrate into the interior and to increase nutrient circulation and oxygen supply.

3D Plotting, which is one of the representative technologies of the arbitrary shape fabrication technology, is a technology for producing a scaffold of a three-dimensional shape by melting a polymer suitable for living tissue and pushing it through a nozzle by pneumatic pressure, The head is formed so as to be freely movable in the X, Y, and Z directions, and the melted polymer is cured instantly as it passes through the nozzle and reaches the bottom or the scaffold surface, so that a three-dimensional shape can be freely formed. There are many advantages such as the possibility of forming in the solution or in the air by using the 3D floating. Korean Patent Publication No. 2010-0072326, filed by the present applicant, entitled " Cell Culture Support Manufacturing Method "(Feb. 26, 2012), describes a three-dimensional scaffold fabrication technique based on such a three-dimensional floating technique.

A variety of polymer solutions can be used for the scaffold fabrication using the three-dimensional plotting. The conditions of the polymer solution are as follows. In order to enable the 3-dimensional floating to be performed well, it is necessary to have an appropriate viscosity so that it can be easily ejected into the nozzle, and the problem of disintegration of the shape of the scaffold formed by quick curing after ejection should not occur. In addition, it is natural that for the purpose of scaffold production, it is necessary to be able to create a cell culture environment similar to the tissue in the human body.

However, hydrogels such as alginate and collagen, which are natural polymers, are difficult to maintain a viscosity capable of floating when applied to a three-dimensional floating device, and are suitable for maintaining a gel state having suitable physical properties for cell proliferation and differentiation after fabrication There is a case not to be done. More specifically, in the case of alginate, various prior studies have been conducted on a suitable concentration for making a three-dimensional structure as a cell printing material or a good concentration for cell growth. However, alginate is disadvantageous in that it has relatively low biocompatibility compared to other materials, and when it is decomposed after about 2 weeks, it is difficult to apply it when it is needed to be used for a long time. In addition, collagen has a disadvantage in that it is difficult to maintain its shape due to its low viscosity to stand alone. In addition, although gelatin has a high biocompatibility, it has a low viscosity and it is difficult to withstand the body temperature because it melts at about 37 ° C. In other words, there is a considerable limitation in producing a three-dimensional scaffold with only one type of hydrogel.

In consideration of this point, it is necessary to study in detail how to prepare a hydrogel made of a natural polymer material suitable for scaffold fabrication using 3-dimensional floating and how to deal with the 3-dimensional floating device.

1. Korean Patent Registration No. 1449906 entitled "3-D Cell Culture Method Using Biological Simulation Using Agarose-Collagen-Alginate Complex Hydrogel Support" (2014.10.02) 2. Korean Patent Publication No. 2010-0072326 "Method for manufacturing cell culture support" (2012.02.06)

SUMMARY OF THE INVENTION Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide a bioprinting technique capable of producing a hydrogel suitable for producing a scaffold with a three- Dimensional hydrogel scaffold using the same. It is also an object of the present invention to provide a method for producing a three-dimensional hydrogel scaffold using a bioprinting technique capable of producing various kinds of hydrogels so as to obtain scaffolds suitable for respective types of tissues in various human bodies. . In addition, an object of the present invention is to provide a three-dimensional hydrogel scaffold produced by such a method.

In order to accomplish the above object, the present invention provides a method for manufacturing a three-dimensional hydrogel scaffold using a bioprinting technique, comprising the steps of: providing a receptacle 1, a nozzle 2 connected to the receptacle 1, Dimensional hydrogel scaffold using a bio-printing technique for producing a scaffold made of a hydrogel material by using a three-dimensional floating device 10 including a moving part 3 for moving the three- , Comprising the steps of: receiving a hydrogel made up of alginate or collagen in the receptacle (1); Applying a pressure within a range of 10 to 300 kPa to the receiving part 1 to discharge the hydrogel to the nozzle 2 having an outlet diameter in the range of 0.1 to 0.5 mm; Forming a scaffold by floating the hydrogel while the nozzle (2) moves at a speed within a range of 50 to 400 mm / min by the moving unit (3); . ≪ / RTI >

In this case, the hydrogel is based on alginate, and the method for preparing the hydrogel based on alginate comprises: a step of preparing a culture medium mixture by adding a CaCl 2 solution to the culture medium to prepare a culture medium mixture; A cell mixture preparation step of mixing cells counted in a predetermined number into the culture medium mixture and then vortexing to prepare a cell mixture; Preparing an alginate-based hydrogel by adding alginate powder-like alginate to the cell mixture to gelate the alginate-based hydrogel; . ≪ / RTI > At this time, in the alginate-based hydrogel preparation step, the alginate concentration ratio to the cell mixture is preferably in the range of 0.5 to 4%. The CaCl 2 solution preferably has a concentration within a range of 0.05 to 1%.

Also, the alginate-based three-dimensional hydrogel scaffold of the present invention can be produced by a method for producing a three-dimensional hydrogel scaffold using the bioprinting technique as described above.

Or the hydrogel is based on collagen, and the method for preparing the collagen-based hydrogel comprises: a step of preparing a collagen mixture solution by adding a CaCl 2 solution to a liquid collagen solution to prepare a collagen mixture; A cell-collagen mixture preparation step of mixing cells counted in a predetermined number into the collagen mixture and vortexing the cells to produce a cell-collagen mixture; Preparing a collagen-based hydrogel by adding alginate powder-like to the cell-collagen mixture to gelate the collagen-based hydrogel; . ≪ / RTI > At this time, it is preferable that the collagen concentration ratio in the liquid type collagen solution is formed within the range of 0.1 to 5% in the step of producing the collagen mixture. Also, in the step of preparing the collagen-based hydrogel, it is preferable that the ratio of alginate to the cell-collagen mixture is within a range of 0.5 to 4%. The CaCl 2 solution preferably has a concentration within a range of 0.05 to 1%.

The collagen and alginate-based three-dimensional hydrogel scaffolds of the present invention can be produced by a process for producing a three-dimensional hydrogel scaffold using the bioprinting technique as described above.

Or the hydrogel is based on collagen and gelatin. The method for producing the hydrogel based on collagen and gelatin comprises mixing cells in a predetermined number of cells in a liquid form of collagen solution, (vortexing) to produce a collagen cell line mixture; A step of preparing a collagen-gelatin mixture solution to prepare a collagen-gelatin mixture by adding powdered gelatin to the collagen gel cell mixture; A step of preparing collagen and gelatin-based hydrogel to produce collagen and gelatin-based hydrogel by heating the gel-like mixture solution to gel; . ≪ / RTI > At this time, it is preferable that the collagen concentration ratio in the liquid type collagen solution is formed within the range of 0.1 to 5% in the step of preparing the collagen line cell mixture. In addition, in the step of preparing the collagen-gelatin mixture, it is preferable that the gelatin concentration ratio of the collagen precursor cell mixture is within a range of 1 to 10%. In the step of preparing the collagen-gelatin-based hydrogel, it is preferable that the collagen-gelatin mixture is gelled by heating the mixture at a predetermined temperature within a range of 30 to 37 ° C for 20 to 50 minutes.

The collagen and gelatin-based three-dimensional hydrogel scaffolds of the present invention can be produced by a method of manufacturing a three-dimensional hydrogel scaffold using the bioprinting technique as described above.

Or the hydrogel is based on alginate and gelatin, and the method for producing the hydrogel based on alginate and gelatin is a method for preparing a hydrogel by adding a CaCl 2 solution to a culture medium mixture in a liquid form, a mixture after vortexing (vortexing) and CaCl 2 line manufacturing cell mixture to prepare a CaCl 2 line cell mixture; Gelatin mixture prepared step-CaCl 2 for preparing a gelatin mixture was added the gelatin powder form to the CaCl 2 line cell mixture and CaCl 2; A step of preparing alginate and gelatin based hydrogels for producing alginate and gelatin based hydrogel by adding powdered alginate to the CaCl 2 - gelatin mixed solution to gel; . ≪ / RTI >

At this time, it is preferable that the ratio of gelatin concentration to CaCl 2 precursor cell mixture is in the range of 1 to 10% in the CaCl 2 -gelatin mixture preparation step. In addition, in the step of preparing the alginate and gelatin-based hydrogel, it is preferable that the ratio of the alginate concentration to the CaCl 2 -gelatin mixture is within the range of 0.5 to 4%. The CaCl 2 solution preferably has a concentration within a range of 0.05 to 1%.

Also, the alginate and gelatin-based three-dimensional hydrogel scaffolds of the present invention can be manufactured by a method of manufacturing a three-dimensional hydrogel scaffold using the bioprinting technique as described above.

Or the hydrogel is based on collagen, alginate and gelatin, and the method for preparing the hydrogel based on collagen, alginate and gelatin comprises mixing a predetermined number of cells in a liquid form of collagen solution A step of preparing a collagen precursor cell mixture to produce a collagen precursor cell mixture by vortexing; A step of preparing a collagen-gelatin mixture solution to prepare a collagen-gelatin mixture by adding powdered gelatin to the collagen gel cell mixture; An alginate addition step of adding a powdery alginate to the collagen-gelatin mixture to produce a collagen-alginate-gelatin mixture; Preparing a collagen, alginate and gelatin-based hydrogel for producing collagen, alginate and gelatin-based hydrogel by adding a CaCl 2 solution to the collagen-alginate-gelatin mixture; . ≪ / RTI > At this time, it is preferable that the collagen concentration ratio in the liquid type collagen solution is formed within the range of 0.1 to 5% in the step of preparing the collagen line cell mixture. In addition, in the step of preparing the collagen-gelatin mixture, it is preferable that the gelatin concentration ratio of the collagen precursor cell mixture is within a range of 1 to 10%. In addition, in the alginate addition step, the alginate concentration ratio to the collagen-alginate-gelatin mixture is preferably in the range of 0.5 to 4%. The CaCl 2 solution preferably has a concentration within a range of 0.05 to 1%.

The collagen, alginate and gelatin-based three-dimensional hydrogel scaffolds of the present invention can be produced by a method of manufacturing a three-dimensional hydrogel scaffold using the bioprinting technique as described above.

According to the present invention, a hydrogel based on a natural polymer material such as alginate or collagen can be used to effectively manufacture a scaffold with a three-dimensional floating device. More specifically, there has been a technique of manufacturing a scaffold using a three-dimensional floating device, and there has been a technique of manufacturing a scaffold using a hydrogel based on a natural polymer material. However, It has not been widely applied to manufacture a scaffold by putting it in a floating device because it is not suitable for viscosity, curing rate, biocompatibility, and the like. However, according to the present invention, it is possible to produce a hydrogel based on a natural polymer material having a viscosity that is very suitable for three-dimensional floating, and accordingly, such a hydrogel can be applied to a three- Can be obtained.

Therefore, according to the present invention, there is a great effect that both advantages of a scaffold using a hydrogel and advantages of a scaffold made of a three-dimensional floating device can be obtained at the same time. In other words, a complicated shape such as an auricle can be easily manufactured by a three-dimensional floating device, so that a scaffold can be manufactured in a customized form even for a portion where a human body is lost, and a hydrogel made of a natural polymer material The biocompatibility is maximized and the like can be obtained at the same time.

According to the present invention, there is an advantage that various hydrogels can be obtained which can be used in a three-dimensional floating device. According to the present invention, various types of hydrogels can be obtained. Therefore, it is possible to obtain various types of hydrogels, such as extracellular matrix, which have different physical properties such as cartilage and skin, Can be manufactured in a similar form to the human body. That is, according to the present invention, it is possible to select hydrogel materials most suitable for various tissues in the human body, and ultimately to manufacture scaffolds most suitable for various tissues in the human body, Effect is obtained.

1 is a schematic view of a three-dimensional floating device;
2 is a flow chart of a method for manufacturing a three-dimensional hydrogel scaffold using the bioprinting technique of the present invention.
3 is a flow chart of a first embodiment for producing a three-dimensional floating hydrogel of the present invention.
FIG. 4 is a flow chart of a second embodiment for producing a three-dimensional floating hydrogel of the present invention. FIG.
5 is a flow chart of a third embodiment for producing a three-dimensional floating hydrogel of the present invention.
6 is a flow chart of a fourth embodiment for producing a three-dimensional floating hydrogel of the present invention.
7 is a flow chart of a fifth embodiment of producing a three-dimensional floating hydrogel of the present invention.
Figure 8 is an illustration of various scaffolds made by the present invention.

Hereinafter, a method for manufacturing a three-dimensional hydrogel scaffold using the bio-printing technique according to the present invention will be described in detail with reference to the accompanying drawings.

FIG. 1 shows a schematic view of a three-dimensional floating device. 1, the three-dimensional floating device 10 includes a receiving portion 1, a nozzle 2 connected to the receiving portion 1, a moving portion 3 for moving the nozzle 2 in three dimensions ). A method for manufacturing a scaffold having a three-dimensional arbitrary shape by the three-dimensional floating device 10 will be briefly described. First, the polymer solution is contained in the receiving part 1, and the polymer solution is injected through the nozzle 2 The moving part 3 moves the nozzle 2 in X, Y and Z directions to form a three-dimensional shape of the discharged polymer solution. At this time, locus of movement of the moving unit 3 can be determined by programming in advance, and a scaffold having a somewhat complicated shape can be manufactured as desired. A detailed configuration example of such a three-dimensional floating device 10 can employ the configuration disclosed in Korean Patent Publication No. 2010-0072326, "Method for manufacturing a cell culture support body" (2012.02.06) and the like, It is omitted.

As described above, a synthetic polymer material can be used as a polymer solution used for producing a scaffold using such a three-dimensional floating device, or a natural polymer material can be used. Considering the biocompatibility, it is preferable to use a hydrogel type natural polymer material. However, as described above, in the case of a conventional hydrogel type natural polymer material, viscosity and curing rate are not suitable for three-dimensional floating In many cases, hydrogels have not been widely used as scaffold materials for three-dimensional floating.

However, in the present invention, various hydrogels having suitable physical properties as a scaffold material for a three-dimensional floating material are prepared, and the process conditions of the three-dimensional floating device optimized for the physical properties of the hydrogel thus prepared are set, It is possible to effectively manufacture a scaffold using a hydrogel as a material while using a floating device.

Hereinafter, the process steps and process conditions of the three-dimensional floating device according to the present invention will be described in more detail. FIG. 2 is a flowchart illustrating a method of manufacturing a three-dimensional hydrogel scaffold using the bioprinting technology of the present invention.

As shown in the figure, a hydrogel made of alginate or collagen is first accommodated in the receiving portion 1 (the method of preparing the hydrogel will be described in more detail hereinafter through various embodiments) ).

Next, a pressure within a range of 10 to 300 kPa is applied to the receiving portion 1 to discharge the hydrogel to the nozzle 2 having an outlet diameter in the range of 0.1 to 0.5 mm. The above-described pressure range and diameter range are determined in consideration of the physical properties of the hydrogel (composed of alginate or collagen) proposed in the present invention. If the pressure is too strong, there is a danger that the load applied to the nozzle increases to cause damage, or the hydrogel can not be smoothly discharged in the form of a thread and may be discharged in an unbalanced shape with the mass being too weak. The smooth discharge from the nozzle may not be achieved due to the viscosity resistance of the hydrogel. On the other hand, if the diameter is too small, the discharge pressure becomes large, and the risks when the pressure is strong can occur equally, and if the diameter is too large, the precision of the three-dimensional shape may be reduced when the scaffold is manufactured. The pressure range and the diameter range described above can be appropriately smoothly and easily discharged in consideration of all the points described above, and at the same time, the accuracy of the scaffold shape to be manufactured can be appropriately attained to a desired level As determined by experiment.

Lastly, the nozzle 2 is moved at a speed within a range of 50 to 400 mm / min by the moving unit 3 to float the hydrogel to produce a scaffold. The moving speed of the nozzle 2 is also determined in consideration of the physical properties of the hydrogel proposed in the present invention. If the moving speed is too high, the discharged hydrogel may not be sufficiently cured and the scaffold may be manufactured. If the moving speed is too slow, the scaffold making speed itself may be slowed and the productivity may be deteriorated. The above-mentioned range of the moving speed is experimentally determined in consideration of the above-mentioned points, considering the curing speed of the hydrogel and also achieving the desired level of scaffold productivity.

Hereinafter, various examples of the production method of the three-dimensional floating hydrogel of the present invention having properties suitable for being used as a material of a scaffold manufactured using the three-dimensional floating device will be described.

[Example 1: Alginate]

FIG. 3 shows a flow chart of a first embodiment for producing a three-dimensional floating hydrogel of the present invention. In the first embodiment, the hydrogel is made based on alginate. As shown in FIG. 3, the method for producing the hydrogel based on alginate according to the first embodiment includes a step of preparing a culture medium mixture, a step of preparing a cell mixture, and a step of producing an alginate-based hydrogel.

In the culture medium mixture preparation step, a CaCl 2 solution is added to the culture medium to prepare a culture medium mixture. The CaCl 2 solution is added to promote gelation, and it is preferable that the CaCl 2 solution is formed at a concentration within a range of 0.05 to 1%.

In the cell mixture preparation step, cells counted in a predetermined number are mixed in the culture medium mixture, and vortexed to prepare a cell mixture. In general, methods for mixing reagents in a laboratory include vortexing, stiring, pippeting, tapping, and inverting. In particular, in the case of tapping or inverting, So that no impact occurs. Vortexing is not only good in blending speed and efficiency, but also it is most preferable to use vortexing in this case, since even if cells and solution are mixed with vortexing, there will not be a shock that may cause a problem to the sample.

In the alginate-based hydrogel preparation step, the alginate-based hydrogel is prepared by adding powdery alginate to the cell mixture to gel. At this time, the alginate concentration ratio with respect to the cell mixture is preferably in the range of 0.5 to 4%.

[Example 2: collagen + alginate]

FIG. 4 shows a flow chart of a second embodiment for producing a three-dimensional floating hydrogel of the present invention. In the second embodiment, the hydrogel is made based on collagen and alginate. As shown in FIG. 4, the method for producing the hydrogel based on collagen and alginate according to the second embodiment may include a step of preparing collagen mixture, a step of producing a cell-collagen mixture, a step of producing collagen and alginate-based hydrogel .

In the step of preparing the collagen mixture, CaCl 2 solution is added to the liquid collagen solution to prepare a collagen mixture. Similar to the first embodiment, the CaCl 2 solution is added in order to promote gelation. Again, it is preferable that the concentration is formed within the range of 0.05 to 1%. At this time, it is preferable that the collagen concentration ratio in the liquid form collagen solution is formed within the range of 0.1 to 5%.

In the cell-collagen mixture preparation step, the cells counted in a predetermined number are mixed with the collagen mixture, followed by vortexing to prepare a cell-collagen mixture.

In the step of preparing collagen and alginate-based hydrogels, alginate in the form of powder is added to the cell-collagen mixture to gel, thereby producing collagen and alginate-based hydrogel. At this time, the alginate concentration ratio with respect to the cell mixture is preferably in the range of 0.5 to 4%.

[Example 3: collagen + gelatin]

5 shows a flowchart of a third embodiment of producing a three-dimensional floating hydrogel of the present invention. In the third embodiment, the hydrogel is based on gelatin, but collagen is added thereto. As shown in FIG. 5, the method for producing the hydrogel based on collagen and gelatin according to the third embodiment includes the steps of preparing a collagen gel cell mixture, preparing a collagen-gelatin mixture, forming collagen and gelatin-based hydrogel And a manufacturing step.

In the step of preparing the collagen cell mixture, a predetermined number of cells counted in a liquid form collagen solution are mixed and then vortexed to prepare a collagen cell mixture. At this time, it is preferable that the collagen concentration ratio in the liquid form collagen solution is formed within the range of 0.1 to 5%.

In the step of preparing the collagen-gelatin mixture, powder-type gelatin is added to the mixture of collagen precursor cells to prepare a collagen-gelatin mixture. At this time, it is preferable that the ratio of the gelatin concentration to the collagen precursor cell mixture is within the range of 1 to 10%.

In the step of preparing collagen and gelatin-based hydrogel, the collagen-gelatin mixed solution is heated and gelated to produce collagen and gelatin-based hydrogel. At this time, it is preferable that the collagen-gelatin mixture is gelled by heating for a predetermined time within a range of 20 to 50 minutes at a predetermined temperature formed within a range of 30 to 37 ° C.

[Example 4: alginate + gelatin]

FIG. 6 shows a flowchart of a fourth embodiment of producing a three-dimensional floating hydrogel of the present invention. In the fourth embodiment, the hydrogel is based on gelatin and is made by adding alginate thereto. As shown in FIG. 6, the method for preparing the hydrogel based on alginate and gelatin according to the fourth embodiment may include a step of preparing CaCl 2 line cell mixture, a step of preparing CaCl 2 -gelatin mixture, an alginate and a gelatin- And a hydrogel production step.

In the CaCl 2 pre-cell mixture preparation step, a predetermined number of cells counted in a liquid culture broth mixed with CaCl 2 solution is mixed and vortexed to prepare a CaCl 2 pre-cell mixture. Similar to the above-described other embodiments, the CaCl 2 solution is added to promote gelation. Again, it is preferable that the concentration is formed within the range of 0.05 to 1%.

The CaCl 2 - gelatin mixed solution In the manufacturing stage, by the addition of gelatin in powder form to the CaCl 2 CaCl 2 line cell mixture - is prepared gelatin mixed solution. At this time, it is preferable that the gelatin concentration ratio to the CaCl 2 precursor cell mixture is formed within the range of 1 to 10%.

In the step of preparing alginate and gelatin-based hydrogel, alginate and gelatin-based hydrogel are prepared by adding powdered alginate to the CaCl 2 -gelatin mixture to gel. At this time, it is preferable that the ratio of the alginate concentration to the CaCl 2 -gelatin mixture is within the range of 0.5 to 4%.

[Example 5: collagen + alginate + gelatin]

FIG. 7 shows a flowchart of a fifth embodiment of producing a three-dimensional floating hydrogel of the present invention. In the fifth embodiment, the hydrogel is based on gelatin and is made by adding collagen and alginate thereto. As shown in FIG. 7, the method for preparing the hydrogel based on collagen, alginate and gelatin according to the fifth embodiment is characterized in that the step of preparing a collagen gel cell mixture, the step of preparing a collagen-gelatin mixture, Collagen, alginate and gelatin-based hydrogel.

In the step of preparing the collagen cell mixture, a predetermined number of cells counted in a liquid form collagen solution are mixed and then vortexed to prepare a collagen cell mixture. At this time, it is preferable that the collagen concentration ratio in the liquid form collagen solution is formed within the range of 0.1 to 5%.

In the step of preparing the collagen-gelatin mixture, powder-type gelatin is added to the mixture of collagen precursor cells to prepare a collagen-gelatin mixture. At this time, it is preferable that the ratio of the gelatin concentration to the collagen precursor cell mixture is within the range of 1 to 10%.

In the alginate addition step, powdery alginate is further added to the collagen-gelatin mixture to prepare a collagen-alginate-gelatin mixture. At this time, it is preferable that the ratio of the alginate concentration to the collagen-alginate-gelatin mixture is within the range of 0.5 to 4%.

In the step of preparing the collagen, alginate and gelatin-based hydrogel, CaCl 2 solution is added to the collagen-alginate-gelatin mixture to gel, thereby producing collagen, alginate and gelatin-based hydrogel. Similar to the above-described other embodiments, the CaCl 2 solution is added to promote gelation. Again, it is preferable that the concentration is formed within the range of 0.05 to 1%.

[Production Example]

Figure 8 shows an embodiment of the various scaffolds made by the present invention. 8 (A) shows a scaffold (that is, an alginate based on the first embodiment) using 3% alginate but made by gelation with CaCl 2 , FIG. 8 (B) shows the results of using a 3% collagen and 3% alginate the CaCl scaffold made by gelling a 2 (that corresponds to the second embodiment as collagen and alginate-based), Figure 8 (C) is, but using a 3% collagen scaffold made by gelling a 3% gelatin (i.e. collagen and gelatin (Corresponding to the third embodiment as a base), FIG. 8D shows a scaffold (i.e., collagen, alginate and gelatin based) prepared by using 3% collagen and 3% alginate as a gelation with 3% gelatin Respectively).

As described above, the physical properties of the scaffold prepared according to mixing ratio of collagen, alginate, and gelatin can be variously formed. Actually, various kinds of tissues such as cartilage and skin are present in the human body, and they have extracellular matrix and cells having different physical properties. According to the present invention, since a scaffold having such various physical properties can be produced, It is possible to manufacture a scaffold having physical properties faithfully simulating the physical properties of the scaffold. In addition, since scaffolds are produced by three-dimensional floating using the hydrogel according to the present invention, a scaffold having various and complex shapes can be manufactured. Therefore, Things are also possible.

It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. It goes without saying that various modifications can be made.

10: Three-dimensional floating device 1:
2: nozzle 3: moving part

Claims (26)

A three-dimensional floating device (10) comprising a housing (1), a nozzle (2) connected to the housing part (1) and a moving part (3) for moving the nozzle A method for producing a three-dimensional hydrogel scaffold using a bio-printing technique for producing a scaffold made of a gel,
Receiving a hydrogel made of alginate or collagen into the receptacle 1;
Applying a pressure within a range of 10 to 300 kPa to the receiving part 1 to discharge the hydrogel to the nozzle 2 having an outlet diameter in the range of 0.1 to 0.5 mm;
Floating the hydrogel while the nozzle (2) moves at a speed within a range of 50 to 400 mm / min by the moving unit (3) to produce a scaffold;
The method according to claim 1, wherein the bio-printing technique comprises the steps of: preparing a three-dimensional hydrogel scaffold using the bio-printing technique;
The method of claim 1, wherein the hydrogel
Based on alginate,
A method of producing the hydrogel based on alginate,
A culture medium mixture liquid preparation step of adding a CaCl 2 solution to the culture medium liquid to prepare a culture medium mixture liquid;
A cell mixture preparation step of mixing cells counted in a predetermined number into the culture medium mixture and then vortexing to prepare a cell mixture;
Preparing an alginate-based hydrogel by adding alginate powder-like alginate to the cell mixture to gelate the alginate-based hydrogel;
The method according to claim 1, wherein the bio-printing technique comprises the steps of: preparing a three-dimensional hydrogel scaffold using the bio-printing technique;
3. The method of claim 2, wherein in the alginate-based hydrogel preparation step
Wherein the ratio of alginate to the cell mixture is within a range of 0.5 to 4%. ≪ RTI ID = 0.0 > 11. < / RTI >
The method of claim 2, wherein the CaCl 2 solution
And the concentration is in the range of 0.05 to 1%. The method of manufacturing a three-dimensional hydrogel scaffold using the bio-printing technique.
An alginate-based three-dimensional hydrogel scaffold prepared by a method for producing a three-dimensional hydrogel scaffold using a bioprinting technique according to any one of claims 2 to 4.
The method of claim 1, wherein the hydrogel
Based on collagen and alginate,
A method for producing the hydrogel based on collagen and alginate,
A collagen mixture liquid preparation step of adding a CaCl 2 solution to a liquid collagen solution to prepare a collagen mixture liquid;
A cell-collagen mixture preparation step of mixing cells counted in a predetermined number into the collagen mixture and vortexing the cells to produce a cell-collagen mixture;
A step of preparing collagen and alginate-based hydrogel to produce collagen and alginate-based hydrogel by adding alginate powder-like to the cell-collagen mixture and gelation;
The method according to claim 1, wherein the bio-printing technique comprises the steps of: preparing a three-dimensional hydrogel scaffold using the bio-printing technique;
The method according to claim 6, wherein in the collagen mixture preparation step
Wherein the collagen concentration ratio in the liquid type collagen solution is in the range of 0.1 to 5%.
7. The method of claim 6, wherein in the collagen and alginate-based hydrogel preparation step
Wherein the ratio of alginate to the cell-collagen mixture is in the range of 0.5 to 4%.
The method of claim 6, wherein the CaCl 2 solution
And the concentration is in the range of 0.05 to 1%. The method of manufacturing a three-dimensional hydrogel scaffold using the bio-printing technique.
A collagen and alginate-based three-dimensional hydrogel scaffold prepared by a method of manufacturing a three-dimensional hydrogel scaffold using a bioprinting technique according to any one of claims 6 to 9.
The method of claim 1, wherein the hydrogel
Based on collagen and gelatin,
A method of producing the hydrogel based on collagen and gelatin,
A step of preparing a collagen precursor cell mixture solution in which a pre-determined number of cells are mixed with a liquid type collagen solution, followed by vortexing to prepare a collagen precursor cell mixture;
A step of preparing a collagen-gelatin mixture solution to prepare a collagen-gelatin mixture by adding powdered gelatin to the collagen gel cell mixture;
A step of preparing collagen and gelatin-based hydrogel to produce collagen and gelatin-based hydrogel by heating the gel-like mixture solution to gel;
The method according to claim 1, wherein the bio-printing technique comprises the steps of: preparing a three-dimensional hydrogel scaffold using the bio-printing technique;
12. The method according to claim 11, wherein in the step of preparing the collagen cell mixture
Wherein the collagen concentration ratio in the liquid type collagen solution is in the range of 0.1 to 5%.
12. The method of claim 11, wherein in the step of preparing the collagen-gelatin mixture
Wherein the gelatin concentration ratio of the collagen precursor cell mixture is in the range of 1 to 10%.
12. The method of claim 11, wherein in the step of preparing collagen and gelatin-based hydrogel
Wherein the gelatin is heated by heating the mixture of collagen and gelatin at a predetermined temperature within a range of 30 to 37 ° C for 20 to 50 minutes to form a gel.
A collagen and gelatin-based three-dimensional hydrogel scaffold prepared by a method for producing a three-dimensional hydrogel scaffold using a bioprinting technique according to any one of claims 11 to 14.
The method of claim 1, wherein the hydrogel
Based on alginate and gelatin,
A method of producing the hydrogel based on alginate and gelatin,
CaCl After mixing the liquid phase in the form of a cell counting to a predetermined count in the culture medium was added to a mixture solution of 2 vortexing (vortexing) and CaCl 2 line cell mixture for producing a CaCl 2 line cell mixture prepared step;
Gelatin mixture prepared step-CaCl 2 for preparing a gelatin mixture was added the gelatin powder form to the CaCl 2 line cell mixture and CaCl 2;
A step of preparing alginate and gelatin based hydrogels for producing alginate and gelatin based hydrogel by adding powdered alginate to the CaCl 2 - gelatin mixed solution to gel;
The method according to claim 1, wherein the bio-printing technique comprises the steps of: preparing a three-dimensional hydrogel scaffold using the bio-printing technique;
The method according to claim 16, wherein in the step of preparing the CaCl 2 -gelatin mixture
Wherein the gelatin concentration ratio of the CaCl 2 precursor cell mixture is in the range of 1 to 10%.
17. The method of claim 16, wherein in the alginate and gelatin-based hydrogel preparation step
Wherein the ratio of alginate to CaCl 2 -gelatin mixture is in the range of 0.5 to 4%.
17. The method of claim 16, wherein the CaCl 2 solution
And the concentration is in the range of 0.05 to 1%. The method of manufacturing a three-dimensional hydrogel scaffold using the bio-printing technique.
An alginate and gelatin-based three-dimensional hydrogel scaffold prepared by a method for producing a three-dimensional hydrogel scaffold using a bioprinting technique according to any one of claims 16 to 19.
The method of claim 1, wherein the hydrogel
Based on collagen, alginate and gelatin,
The method for producing the hydrogel based on collagen, alginate and gelatin comprises the steps of:
A step of preparing a collagen precursor cell mixture solution in which a pre-determined number of cells are mixed with a liquid type collagen solution, followed by vortexing to prepare a collagen precursor cell mixture;
A step of preparing a collagen-gelatin mixture solution to prepare a collagen-gelatin mixture by adding powdered gelatin to the collagen gel cell mixture;
An alginate addition step of adding a powdery alginate to the collagen-gelatin mixture to produce a collagen-alginate-gelatin mixture;
Preparing a collagen, alginate and gelatin-based hydrogel for producing collagen, alginate and gelatin-based hydrogel by adding a CaCl 2 solution to the collagen-alginate-gelatin mixture;
The method according to claim 1, wherein the bio-printing technique comprises the steps of: preparing a three-dimensional hydrogel scaffold using the bio-printing technique;
The method according to claim 21, wherein in the step of preparing the collagen precursor cell mixture
Wherein the collagen concentration ratio in the liquid type collagen solution is in the range of 0.1 to 5%.
The method according to claim 21, wherein in the step of preparing the collagen-gelatin mixture
Wherein the gelatin concentration ratio of the collagen precursor cell mixture is in the range of 1 to 10%.
22. The method of claim 21, wherein in the alginate addition step
Wherein the ratio of alginate to the collagen-alginate-gelatin mixture is in the range of 0.5 to 4%.
The method of claim 21, wherein the CaCl 2 solution
And the concentration is in the range of 0.05 to 1%. The method of manufacturing a three-dimensional hydrogel scaffold using the bio-printing technique.
A three-dimensional hydrogel scaffold based on collagen, alginate and gelatin, which is produced by a process for producing a three-dimensional hydrogel scaffold using a bioprinting technique according to any one of claims 21 to 25.
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