KR102533864B1 - Apparatus for manufacturing artificial tissue amd method of manufacturing the same - Google Patents

Abstract

The present invention is an artificial tissue manufacturing apparatus comprising: a spraying unit configured to spray molten polymer and cell solution; a spraying unit transfer unit configured to transfer the spraying unit; a base member configured to apply the polymer or cell solution sprayed from the injection unit; a base member rotational drive unit configured to supply a rotational driving force for rotating the base member; and a control unit configured to control at least one of the injection unit, the injection unit transfer unit, and the rotary driving unit, wherein the control unit manufactures a hollow artificial tissue that is axially symmetric but has a profile that is not constant in an axial direction. It is characterized in that the formation of the polymer layer and the cell layer is controlled so as to

Description

Artificial tissue manufacturing apparatus and manufacturing method {Apparatus for manufacturing artificial tissue amd method of manufacturing the same}

The present invention relates to an artificial tissue manufacturing apparatus and manufacturing method, and more particularly, to an artificial tissue manufacturing apparatus and manufacturing method capable of manufacturing a hollow artificial tissue having an axially symmetrical shape but an external profile that changes along the axial direction.

In general, tissue engineering refers to collecting necessary tissue pieces from a patient's body, isolating cells from the tissue pieces, culturing the separated cells to a required amount, and attaching them to a porous biodegradable polymer scaffold. After being planted and cultured outside the body for a certain period of time, the scaffold, which is a hybrid type cell culture support, is transplanted back into the human body.

After transplantation, cells are supplied with oxygen and nutrients by the diffusion of bodily fluids until new blood vessels are formed in most tissues or organs. It is to apply a technique in which the polymer support is formed and the polymer support is decomposed and disappears in the meantime.

Therefore, for such tissue engineering research, it is important to first prepare a cell culture scaffold similar to living tissue.

Cell culture using a conventional cell culture support generally uses a method in which cells are separately seeded on an already manufactured cell culture support. However, this method has a limitation in that it is inevitable to produce a flat artificial tissue by scattering cells on a cell culture support placed on a flat surface. In addition, it was impossible to fabricate an artificial tissue in which two or more different types of cells are distributed according to location.

In particular, organs and blood vessels in the human body are generally formed in a long tube shape with a hollow central portion, and it is difficult to manufacture a tube-shaped artificial tissue composed of various types of cells by the conventional method.

In order to solve this problem, the present applicant has already proposed a plurality of conduit-type artificial tissue manufacturing devices.

[Related Patent Literature]

1. Republic of Korea Patent No. 10-1569680

2. Republic of Korea Patent Publication No. 10-2019-0048751

However, this prior art has a problem in that there is no change in the diameter of the ductal tissue along the axial direction, such as a straw, and it is applicable only to the production of a ductal-type artificial tissue having a relatively simple structure.

Accordingly, there is a need to develop a manufacturing technology capable of producing hollow artificial tissues having an external shape that is axially symmetrical and changes along the axial direction, such as, for example, an artificial uterus.

The present invention aims to solve the above problems and other problems related thereto.

An exemplary object of the present invention is to provide an artificial tissue manufacturing apparatus and manufacturing method capable of manufacturing an axially symmetrical hollow artificial tissue having a diameter change along an axial direction.

The technical problem to be achieved by the artificial tissue manufacturing apparatus and manufacturing method according to the technical idea of the technology disclosed in this specification is not limited to the above-mentioned problem, and another problem not mentioned is clearly apparent to those skilled in the art from the description below. You will be able to understand.

An artificial tissue manufacturing apparatus according to an embodiment of the present invention includes a spraying unit configured to spray a molten polymer and cell solution; a spraying unit transfer unit configured to transfer the spraying unit; a base member configured to apply the polymer or cell solution sprayed from the injection unit; a base member rotational drive unit configured to supply a rotational driving force for rotating the base member; and a control unit configured to control at least one of the injection unit, the injection unit transfer unit, and the rotary driving unit, wherein the control unit manufactures a hollow artificial tissue that is axially symmetric but has a profile that is not constant in an axial direction. It is characterized in that the formation of the polymer layer and the cell layer is controlled so as to

The injection unit includes: a first injection unit configured to form a first polymer layer; a second spraying unit configured to form a second polymer layer; and a third spraying unit configured to form a cell layer, wherein the first polymer layer sprayed by the first spraying unit has a shape corresponding to the inner space having the irregular profile.

The first polymer layer is composed of a biocompatible water-soluble polymer to be removed after the second polymer layer and the cell layer are formed.

A control condition of the first injection unit is different from a control condition of the second injection unit or the third injection unit.

The controller is configured to extract sections satisfying a predetermined height based on the profile, and spray the first polymer while moving the first injection unit over each of the extracted sections.

The controller controls the spraying of the first spraying unit so that the moving speed or rotational speed is higher or the spraying amount is greater than that of the second spraying unit or the third spraying unit.

The base member has a shape corresponding to the inner space having the irregular profile, and is configured such that the polymer and biological solution are sprayed onto the base member.

The base member is configured to be removed after each of the polymer layer and the cell layer is formed.

The base member is composed of a biocompatible water-soluble polymer and can be removed by water.

An artificial tissue manufacturing method according to another embodiment of the present invention includes forming a first polymer layer on a rotating base member; stacking and forming a second polymer layer or cell layer on the first polymer layer; and removing the base member and the first polymer layer, wherein the artificial tissue has a hollow shape that is axially symmetric but has a non-constant profile in the axial direction, and wherein the first polymer layer has a non-constant profile. It is characterized in that the stacking thickness is different along the longitudinal direction to have a shape corresponding to the inner space having.

The removing of the first polymer layer includes removing the first polymer layer by dissolving it in water.

The step of forming the first polymer layer includes extracting sections satisfying a predetermined height based on the profile and spraying a first polymer over each of the extracted sections,

It is characterized in that the movement speed, rotational speed or spraying amount for forming the first polymer layer is controlled to be faster or greater than the moving speed, rotational speed or spraying amount for forming the second polymer layer or the cell layer.

An artificial tissue manufacturing method according to another embodiment of the present invention includes forming a polymer layer or cell layer on a rotating base member; and removing the base member, wherein the artificial tissue has a hollow shape that is axially symmetric but has a non-constant profile in the axial direction, and wherein the base member corresponds to an internal space having the non-constant profile. It is characterized by having a shape.

The removing of the base member includes removing the base member by dissolving it in water.

An artificial tissue manufacturing method according to another embodiment of the present invention includes forming a polymer layer on a rotating base member; and forming a cell layer laminated on the polymer layer, wherein the artificial tissue is axially symmetric but has a non-constant diameter profile in the axial direction, and the polymer layer and the cell layer have the non-constant diameter profile. It is characterized in that the stacking thickness is different along the longitudinal direction to have.

A storage medium on which a computer program is recorded according to another embodiment of the present invention is for manufacturing a hollow artificial tissue having an axially symmetrical but non-constant profile in an axial direction, the computer program including instructions , the instructions are configured to cause a computer to perform the manufacturing method described above.

An artificial tissue according to another embodiment of the present invention is a hollow artificial tissue having an axially symmetrical but non-constant profile in the axial direction, and is characterized in that it is manufactured by the manufacturing method described above.

The artificial tissue includes the uterus.

According to an embodiment of the present invention, it is possible to manufacture various hollow artificial tissues, such as an artificial uterus, which are axially symmetrical and whose external shape changes along the axial direction.

On the other hand, the effects described above are merely exemplary, and effects predicted or expected from the detailed configuration of the present invention from the viewpoint of those skilled in the art may also be added to the unique effects of the present invention.

1 is a diagram schematically showing an artificial tissue manufacturing apparatus according to the present invention;
2 is a view showing an operating state of the artificial tissue manufacturing apparatus of FIG. 1;
3 is a view showing the uterus as an example of an artificial tissue,
4 is a view showing a layered structure (intermediate product) of an artificial uterus according to the first embodiment;
5 and 6 are views schematically showing a method for manufacturing an artificial uterus according to the first embodiment,
7 is a diagram schematically showing a method for manufacturing an artificial uterus according to the first embodiment;
Figure 8 is a flow chart for the artificial tissue manufacturing method according to the present invention,
FIG. 9 shows an exemplary graph of a control method for each section used in the artificial tissue manufacturing method of FIG. 8 .

Hereinafter, the embodiments disclosed in this specification will be described in detail with reference to the accompanying drawings, but the same reference numerals will be given to the same or similar components regardless of reference numerals, and overlapping descriptions thereof will be omitted. The suffixes "module" and "unit" for components used in the following description are given or used together in consideration of ease of writing the specification, and do not have meanings or roles that are distinct from each other by themselves. In addition, in describing the embodiments disclosed in this specification, if it is determined that a detailed description of a related known technology may obscure the gist of the embodiment disclosed in this specification, the detailed description thereof will be omitted. In addition, the accompanying drawings are only for easy understanding of the embodiments disclosed in this specification, the technical idea disclosed in this specification is not limited by the accompanying drawings, and all changes included in the spirit and technical scope of the present invention , it should be understood to include equivalents or substitutes.

Terms including ordinal numbers, such as first and second, may be used to describe various components, but the components are not limited by the terms. These terms are only used for the purpose of distinguishing one component from another.

It is understood that when an element is referred to as being "connected" or "connected" to another element, it may be directly connected or connected to the other element, but other elements may exist in the middle. It should be. On the other hand, when an element is referred to as “directly connected” or “directly connected” to another element, it should be understood that no other element exists in the middle.

Singular expressions include plural expressions unless the context clearly dictates otherwise.

In this application, terms such as "comprise" or "have" are intended to designate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, but one or more other features It should be understood that the presence or addition of numbers, steps, operations, components, parts, or combinations thereof is not precluded.

While the present disclosure has been illustrated and described in detail in the drawings and foregoing description, the present disclosure is to be considered illustrative rather than restrictive in nature, with only certain embodiments shown and described, and within the spirit of the present disclosure. It will be appreciated that all changes and modifications that enter are preferably protected.

1. Manufacturing target

The artificial tissue to be manufactured according to the present invention (eg, see FIG. 4) is made of an axially symmetrical shape as a whole and has a shape in which the internal and external profiles change along the axial direction, which means a hollow artificial tissue having an internal space. As such, for example, a woman's uterus may correspond to this. Artificial tissue terms described herein should be understood as having such a shape unless otherwise specified.

2. Manufacturing equipment

Hereinafter, an artificial tissue manufacturing apparatus according to an embodiment of the present invention will be described in detail with reference to the accompanying drawings.

The artificial tissue manufacturing apparatus 1000 according to the present embodiment is a device for forming artificial tissue by spraying a solution to form each cell layer constituting a predetermined artificial tissue, and largely includes a spraying unit 100 and a spraying unit transfer unit 200. ), a base member 300, a rotary driving unit 400, and a control unit 500.

injection part

As exemplarily shown in FIGS. 1 and 2 , the spraying unit 100 includes one or more first spraying units 110, second spraying units 120, and third spraying units 130, , Additional injection units may be provided according to the cell layer to be manufactured.

The first injection unit 110 is configured to receive the first polymer 1, heat and melt the first polymer 1, and spray the molten first polymer 1. The first polymer layer 10 is configured to have the same space as the inside of the uterus shown in FIG. 3 and serves as a support for forming the second polymer layer 20 and the cell layer 30 described later (see FIG. 4 ). ). In this way, the first polymer 1 must be removed after ultimately serving as a support, and polyethylene glycol (PEG)/polyethylene oxide (PEO), which is a water-soluble material harmless to a living body, may be used.

The second spraying unit 120 is configured to receive the second polymer 2, heat and melt the second polymer 2, and spray the molten polymer 2 onto the first polymer layer 10. .

The second polymer 2 sprayed by the second spray unit 120 is a biocompatible polymer, and polycaprolactone (PCL) or the like may be used.

A heater unit capable of heating and melting the polymers 1 and 2 is installed in the first and second injection units 110 and 120. When the accommodated polymers 1 and 2 are melted by the heater and become a liquid state, pressurization is performed. By operating the means, the molten polymers 1 and 2 are sprayed through the nozzle to the base member 300 to be described later.

The third spraying unit 130 is configured to accommodate the cell solution 3 containing cells and hydrogel and spray the cell solution 3. A space in which the cell solution 3 is accommodated is provided in the third spray unit 130, and a pressure means is operated to spray the cell solution 3 through a nozzle to the base member 300 to be described later. The cell solution described herein may be understood in the same sense as bioink in which a material such as a hydrogel such as collagen and cells are mixed.

In this embodiment, two third spraying units 130 may be provided, and may be configured to spray different cell solutions 3 . For example, when the artificial tissue to be manufactured is the uterus, one of the third spraying units 130 sprays a cell solution in which cultured uterine mucosal cells and hydrogel are mixed, and the other of the third spraying units 130 A cell solution in which cultured muscle layer cells and hydrogel are mixed can be sprayed.

When the number of cell solutions 3 to be sprayed is determined according to the artificial tissue to be manufactured, the number of third spray units 130 may be changed correspondingly.

The third injection unit 130 may further include a temperature controller installed in a portion where the cell solution 3 is accommodated to heat or cool the unit. Cells in the cell solution 3 accommodated in the third injection unit 130 may have improved survival rates when maintained at a constant temperature, for example, about 36.5 degrees. In this way, in order to improve the viability of cells in the cell solution 3 accommodated in the third spray unit 130, the third spray unit 130 is heated to a certain temperature by using a temperature controller.

Meanwhile, in some cases, the hydrogel in the cell solution 3 accommodated in the third injection unit 130 needs to be cooled to a certain temperature so that desired physical properties can be realized. In this way, in order to improve the physical properties of the hydrogel in the cell solution 3 accommodated in the third spray unit 130, the third spray unit 130 is cooled to a certain temperature by using a temperature controller.

The temperature control unit may be implemented in various configurations, and may include, for example, a Peltier element, a heat dissipation fin, and a fan. When the cell solution 3 contained in the third injection unit 130 is heated, heat generated from the Peltier element is supplied to the cell solution 3 using a Peltier element, and the cell solution contained in the third injection unit 130 ( When cooling 3), the heat of the cell solution 3 is released to the outside using a Peltier element. At this time, heat can be quickly dissipated using a heat dissipation fin and a fan.

On the other hand, the first polymer layer 10 described above is configured to provide a space such as the inside of the uterus, and serves as a support for forming the second polymer layer 20 and the cell layer 30. The implemented support (Example 1) may be replaced with a base member having the same shape (Example 2), which will be described later.

Injection unit transfer part

The spray unit transfer unit 200 is configured to transfer the first to third spray units 110 to 130 in a horizontal or vertical direction.

1 and 2, when the first polymer 1 is applied to the base member 300, the first spray unit 110 is moved so that the first spray unit 110 is close to the base member 300. After the vertical transfer, the first spraying units 110 and 120 in which the first polymer 1 is sprayed are horizontally transferred in the longitudinal direction of the base member 300 while rotating the base member 300 . This operation is repeated until a shape corresponding to the internal space of the artificial tissue is manufactured.

When the second polymer 2 is applied to the completed first polymer layer 100, the second spray unit 120 is vertically moved so that the second spray unit 120 approaches the first polymer layer 100. Then, while the base member 300 is rotated, the second spray unit 120 in which the second polymer 2 is sprayed is maintained at a constant distance from the first polymer layer 10 in the longitudinal direction of the base member 300. horizontal transfer to

Similarly, when the cell solution 3 is applied to the laminate, the third spray unit 130 is moved vertically so that the third spray unit 130 approaches the second polymer layer 20, and then the base member 300 While rotating the cell solution 3, the third spray unit 130 spraying the cell solution 3 is horizontally transferred in the longitudinal direction of the base member 300 while maintaining a constant distance from the second polymer layer 20.

In this way, in the process of applying the polymers 1 and 2 or the cell solution 3 to the base member 300 and the intermediate laminate, the spray unit transfer unit 200 moves the first to third spray units 110 to 130 ), at least one of which may be transferred in a horizontal or vertical direction.

The injection unit transfer unit 200 may adjust the spray position of the sprayed solution by moving at least one of them in the x, y, and z directions so that the relative position between the spray unit 100 and the base member 300 is changed. A general linear transport structure, such as a structure combining a linear motor, a rotary motor and a ball screw, may be used as the injection unit transport unit 200, and the configuration of such a linear transport structure will be apparent to those skilled in the art. For example, the injection unit transfer unit 200 includes a fixed bracket having a z-axis guide rail for moving the spray unit 100 in the z-axis direction, and an x-axis guide rail and a y-axis guide for moving the fixing bracket in the x and y axes, respectively. It may be formed including a rail.

On the other hand, the artificial tissue manufacturing apparatus 1000 according to the present embodiment, as described above, by moving the injection unit 100 by the injection unit transfer unit 200, not only can adjust the injection position, but also the base member 300 The injection position may be adjusted by moving in the x, y, and z directions.

In addition, as in the embodiment of FIG. 1, when one or more spraying units 100 are formed, the spraying unit transfer unit 200 moves the plurality of spraying units 100 together to adjust the spraying position, or Various controlling embodiments of the spraying unit are possible, such as controlling the spraying position by separately controlling the spraying unit 100 .

base member

The base member 300 is one on which the first polymer 1 sprayed from the first spray unit 110 or the second polymer 2 sprayed from the second spray unit 120 is applied to the surface, and the first to third 3 is disposed on the lower side of the injection unit (110 to 130).

In general, the base member 300 is preferably provided in the shape of a cylindrical rod member, but a polygonal rod member may be used depending on the purpose. In addition, the base member 300 may be made of a metal material, or a polymer material may be used depending on the purpose. The minimum diameter of these base elements is usable up to 1 mm.

In particular, since the artificial tissue to be manufactured in the present invention has an axially symmetrical shape like the uterus and is characterized by a shape in which the overall internal and external profiles change along the axial direction, an internal space having such an internal and external profile must be provided.

This inner space may be formed by the previously described first polymer layer 10, but may also be formed by the base member 300 having a shape corresponding to the inner space. That is, a base member 300 having substantially the same shape as the support structure to be formed by the first polymer layer 10 is provided, and while rotating the base member 300 having this shape, the second polymer 2 and/or Alternatively, the cell solution 3 may be directly sprayed onto the base member. At this time, the base member 300 must be removed from the artificial tissue on which the second polymer layer 20 and/or the cell layer 30 are formed, but physical removal is impossible due to the shape of the base member itself corresponding to the internal space. may also exist. In this case, the base member itself having an internal space profile is made of a water-soluble material harmless to the living body, and it can be finally removed by dissolving it in water.

In this way, the polymer layers 10 and 20 and the cell layer 30 are laminated on the base member 300, respectively, and after the polymer layers 10 and 20 and the cell layer 30 are laminated, the first polymer layer 10 and the base When the member 300 is separated/removed, a hollow artificial tissue composed of the second polymer layer 20 and the cell layer 30 can be manufactured while finally having an irregular inner/outer profile space.

The rotary driving unit 400 supplies a rotational driving force to rotate the base member 300 so that the first and second polymers 1 and 2 or the cell solution 3 are applied while surrounding the base member 300 .

As the rotary driving unit 400, a general rotary driving structure such as a rotary motor coupled directly to the base member 300 or a structure combining a rotary motor and a belt may be used, and the configuration of such a rotary driving structure is obvious to those skilled in the art. Therefore, the description thereof is omitted.

The first temperature controller 310 is configured to heat or cool the base member 300 .

Referring to FIG. 1 , when applying the polymers 1 and 2 or the cell solution 3 to the base member 300, it is preferable to heat the base member 300. When the polymers 1 and 2 are applied to the base member 300 at an excessively low temperature, rapid curing of the polymers 1 and 2 may cause a problem in that a desired shape cannot be obtained, and the base member 300 at an excessively low temperature When the cell solution 3 is applied to the member 300, an environment in which cells in the cell solution 3 can grow may not be formed. Therefore, it is preferable to heat the base member 300 to a predetermined appropriate temperature in order to realize a normal curing process of the polymers 1 and 2 or an environment in which cells in the cell solution 3 can grow normally.

On the other hand, in the case of using a cylindrical member having a certain diameter as the base member 300, when separating the laminated polymer layers 10 and 20 and the cell layer 30 from the base member 300, the base member 300 is cooled. it is desirable In order to finally obtain the artificial tissue, a process of separating the base member 300 from the polymer layers 10 and 20 and the cell layer 30 is performed, but a problem in that the base member 300 is not easy to separate may occur due to the bonding force. . Therefore, the base member 300 can be easily separated from the polymer layers 10 and 20 and the cell layer 30 by cooling and heat-shrinking the base member 300 made of metal, for example.

For example, the first temperature controller 310 manufactures the base member 300 in a hollow shape, supplies warm air to the inside of the base member 300 when heating, and cools the base member 300. It may be implemented in the form of supplying cold air to the inside.

control unit

As shown in FIG. 1, the control unit 500 controls the transfer position, transfer speed and rotation drive unit 150 of the base member 150 to transfer the first to third spray units 110 to 130 by the spray unit transfer unit 200. The rotation speed for rotating the 300 is respectively controlled.

As described above, the manufacturing target in the present invention is characterized in that it is a three-dimensional artificial tissue having an axially symmetrical shape, such as a uterus, in which the internal and external profiles of the tissue change along the axial direction.

The structure in which the internal and external profiles change is such that the control unit 500 interlocks the spraying unit transfer unit 200 and the base member 300 or the spraying unit 100 according to a predetermined profile based on section-by-section control and/or coordinate-by-coordinate control. It can be produced by controlling.

A specific control method will be described in detail in the manufacturing method section below.

3. Manufacturing method

The manufacturing method according to this embodiment is largely divided into two.

As shown in FIG. 5, in the manufacturing method according to Example 1, the first polymer layer 10, the second polymer layer 20, and the cell layer 30 are sequentially laminated on the base member 300 described above. way to form

The first polymer layer 10, as a support structure, is a part that is ultimately decomposed and removed, and only needs to have structural strength sufficient to support the second polymer layer 20 or the cell layer 30, so that the layers to be subsequently stacked In comparison, it will be said that speed is required rather than precision. This is a profile shape corresponding to an internal space such as a uterus, and the stacking thickness is different along the axial direction, and a control method for each section described later may be applied.

The second polymer layer 20 and the cell layer 30 are sequentially stacked on the completed first polymer layer 10, and the second spray unit 120 and the third spray unit 130 form the first polymer layer. Each layer is sequentially formed by spraying while moving horizontally and vertically while maintaining regular intervals along the external profile of (10) (see FIG. 5). Subsequently, after physically separating the base member 300 by the method described above, the first polymer layer 10 is physically separated or, as shown in FIG. complete the organization.

In the manufacturing method according to Example 2, after preparing a base member 300 in which an internal space having a specific profile shape is already formed, the second polymer layer 20 and the cell layer 30 are formed on the base member 300 having a predetermined shape. It is characterized by sequential formation.

The base member in which an internal space having a specific profile shape is already formed corresponds to the first polymer layer 10 in the manufacturing method of Example 1. That is, as shown in FIG. 7, the second spray unit 120 and the third spray unit 130 move horizontally and vertically while maintaining a constant distance from the intermediate laminate along the outer profile of the base member 300. While spraying, each layer is sequentially formed. After forming each layer, the base member 300 itself of the inner space shape profile is physically separated or dissolved in water to complete the final artificial tissue in which the inner space is formed.

In addition, the manufacturing method according to Example 3 is characterized in that the base member has a constant diameter, and the second polymer layer and the third cell layer have different diameters to manufacture the artificial tissue.

That is, a step of forming a polymer layer on a rotating base member and layering a cell layer on the polymer layer, wherein the artificial tissue is axially symmetric but has a profile of a diameter that is not constant in the axial direction, and the polymer layer and the cell layer is formed such that the laminated thickness is different along the longitudinal direction so as to have a profile of non-constant diameter.

A control method of the injection unit/rotation drive unit applicable to the above manufacturing method will be described with reference to FIGS. 8 and 9 .

9 shows an exemplary external profile of an artificial tissue to be manufactured. For convenience, the x-axis represents the length of the artificial tissue through which the spraying unit 100 moves horizontally, and the y-axis represents the width of the artificial tissue through which the spraying unit 100 moves vertically. It has a profile (P) that During actual manufacturing, since the base member 300 rotates around the x-axis, the artificial tissue has a symmetrical three-dimensional contour surface with a variable profile.

First, with reference to FIG. 8, a control method for each section according to the present embodiment will be described. Sectional control is characterized in that the movement speed of the injection unit and / or the rotational speed of the base member is constant within a specific section.

Step S11: First, information on the external profile P of a tissue to be manufactured is input and stored in the controller 500 (S11). For example, the base member 300 is set to the x-axis, which is the axis of rotation, and (x, y) coordinates according to the external profile P are stored.

Step S12: Among the stored (x, y) coordinates, those having the same y-axis coordinates are sequentially extracted and classified. Sequential means that the y coordinate increases sequentially, and a predetermined increment Δy can be taken as a standard. Δy may be appropriately set in consideration of manufacturing yield or resolution, and may also be set by, for example, the diameter of the material to be injected. In fact, as the number of layers increases, collapse or deformation may occur, so it can be changed to 1x, 1.9x, 2.8x, etc.

For example, assuming that the minimum thickness of the artificial tissue to be manufactured is y ₀ as shown in FIG. 9, y ₁ = y ₀ +Δy, y ₂ = y ₀ +2Δy, y ₃ = y ₀ +3Δy, y ₄ = y ₀ +4Δy, y ₅ = y ₀ +5Δy … If y _n = y ₀ +nΔy is set, a plurality of x-coordinate intervals satisfying each of y ₁ to y _n can be extracted from the external profile data. If the x coordinates corresponding to y ₁ are x ₁ and x ₁ ', set the start point for the height (thickness) of y ₁ to x ₁ and the end point to x ₁ ' as the first coordinate interval, and similarly y ₂ and y ₃ , … , y _n are set to the second to nth coordinate intervals, respectively.

Step S13: The polymer or cell fluid is sequentially sprayed for each of the coordinate sections at the specific height set as described above. First, spraying proceeds as the spraying unit moves over the minimum thickness y ₀ coordinate range x ₀ to x ₀ ', which is the smallest thickness section. When the spraying for the y ₀ coordinate area is completed, the spraying unit is moved to the first coordinate area (x ₁ to x ₁ ') having a profile y ₁ thicker by Δy than the minimum thickness y ₀ and spraying is added over the same coordinate area. proceeds with

Step S14: After the sequential movement for each coordinate section, injection is performed up to the nth coordinate section for yn corresponding to the maximum height.

On the other hand, it is preferable that the moving speed of the spray unit and/or the rotational speed and/or the spraying amount of the base member are constant within the specific (coordinate) section, but the moving speed, rotational speed, and spraying amount are the same in a plurality of specific sections. You don't have to. For example, considering the use of the polymer layer, the overall manufacturing yield, and the detailed shape of the profile, at least one of the movement speed of the spray unit in the coordinate interval for y ₀ , the rotational speed of the base member, and the spray amount from the spray unit It may be set differently from that in the nth coordinate range for y _n . In addition, while the injection unit is moving between the coordinate intervals, the base member may rotate again from the point of initiating injection within the coordinate interval after being stopped without rotating.

The above-described control method is particularly useful in a manufacturing method in which a layer corresponding to a significant volume of the internal space is to be formed in advance, as in the formation of the first polymer layer 10 . The first polymer layer 10 functions as a support for the second polymer layer 20 and the cell layer 30 formed thereon and corresponds to an object to be eventually removed. Therefore, when the first polymer layer 10 is formed, this section-by-section control method is used, and when the second polymer layer 20 and the cell layer 30 are subsequently formed, the first polymer layer 10 is formed. Unlike the control method, a control method may be used in which the second polymer and the cell solution are sprayed uniformly as a whole while moving horizontally and vertically to maintain a predetermined interval along a trajectory corresponding to an external profile.

The controller 500 may adjust the thickness or pitch of the first polymer layer 10, the second polymer layer 20, and the cell layer 30 differently according to the artificial tissue to be manufactured. For example, in order to form the second polymer layer 20 or the cell layer 30 having a relatively thin thickness, the second spray unit 120 and the third spray unit 130 are transferred in a horizontal direction to increase the transfer speed, The thickness can be adjusted to be thin by increasing the rotational speed of the base member 300 . On the other hand, in order to form the second polymer layer 20 or the cell layer 30 having a relatively thick thickness, the transfer speed for transporting the second spray unit 120 and the third spray unit 130 in the horizontal direction is slowed, The thickness can be adjusted to be thick by slowing the rotation speed of the base member 300 .

In addition, the control unit 500 controls the spray pressure of the first and second polymers 1 and 2 sprayed from the first and second spray units 110 and 120 and the cell solution 3 sprayed from the third spray unit 130. By controlling the injection pressure of the first polymer layer 10, the second polymer layer 20 and the thickness of the cell layer 30 can be adjusted. For example, when the second injection unit 120 or the third injection unit 130 is manufactured in a screw type, the injection pressure of the second polymer 2 and the injection pressure of the cell solution 3 can be adjusted by controlling the rotational speed of the screw. If the second injection unit 120 or the third injection unit 130 is manufactured to be controlled by pneumatic pressure, the injection pressure of the second polymer 2 and the cell solution 3 are controlled by controlling the pressure of the supplied air. ) can control the injection pressure.

On the other hand, by adjusting the diameter (inner diameter) of the nozzles mounted on the first and second spray units 110 and 120 and the third spray unit 130 to adjust the thickness of the polymer layers 10 and 20 and the cell layer 30 There is also a way. The thickness of the polymer layers 10 and 20 and the cell layer 30 stacked when the small diameter nozzle is mounted becomes thin, and when the large diameter nozzle is mounted, the thickness of the stacked polymer layers 10 and 20 and the cell layer 30 gets thicker

Meanwhile, an alternative, additional or partial control method for each coordinate may be used for the above-described control method for each section. The coordinate-specific control method extracts the coordinate values (x, y) corresponding to the external profile and uses the injection conditions (injection part transport speed, base member rotation speed, It means to control spray pressure, nozzle by spray unit capacity, etc.). This coordinate-specific control method can be usefully used in forming the second polymer layer 20 or the cell layer 30 .

4. Control program

The above-described device and its control may be implemented as hardware components, software components, and/or a combination of hardware components and software components. For example, devices and components described in the embodiments include a processor, a controller, an arithmetic logic unit (ALU), a digital signal processor, a microcomputer, a field programmable gate array (FPGA), and a programmable PLU (programmable logic unit). logic unit), microprocessor, or any other device capable of executing and responding to instructions. The processing device may run an operating system (OS) and one or more software applications running on the operating system. A processing device may also access, store, manipulate, process, and generate data in response to execution of software. For convenience of understanding, there are cases in which one processing device is used, but a person skilled in the art will understand that the processing device may include a plurality of processing elements and/or a plurality of types of processing elements. it can be seen that there is For example, a processing device may include a plurality of processors or a processor and a controller. Other processing configurations are also possible, such as parallel processors.

Software may include a computer program, code, instructions, or a combination of one or more of the foregoing, which configures a processing device to operate as desired or, independently or in combination, instructs the processing device. can do. Software and/or data may be permanently or temporarily stored in any tangible machine, component, physical device, virtual device, computer storage medium or device for interpretation by a processing device or to provide instructions or data to a processing device. can materialize. Software may be distributed on networked computer systems and stored or executed in a distributed manner. Software and data may be stored on one or more computer readable media.

The method according to the embodiment may be implemented in the form of program instructions that can be executed through various computer means and recorded on a computer readable medium. The computer readable medium may include program instructions, data files, data structures, etc. alone or in combination. Program commands recorded on the medium may be specially designed and configured for the embodiment or may be known and usable to those skilled in computer software. Examples of computer-readable recording media include magnetic media such as hard disks, floppy disks and magnetic tapes, optical media such as CD-ROMs and DVDs, and magnetic media such as floptical disks. - includes hardware devices specially configured to store and execute program instructions, such as magneto-optical media, and ROM, RAM, flash memory, and the like. Examples of program instructions include high-level language codes that can be executed by a computer using an interpreter, as well as machine language codes such as those produced by a compiler. The hardware devices described above may be configured to operate as one or more software modules to perform the operations of the embodiments, and vice versa.

As described above, although the embodiments have been described with limited examples and drawings, those skilled in the art can make various modifications and variations from the above description. For example, the described techniques may be performed in an order different from the method described, and/or components of the described system, structure, device, circuit, etc. may be combined or combined in a different form than the method described, or other components may be used. Or even if it is replaced or substituted by equivalents, appropriate results can be achieved.

Therefore, other implementations, other embodiments, and equivalents of the claims are within the scope of the following claims.

1000: artificial tissue manufacturing device
100: injection unit
200: injection unit transfer unit
300: base member
400: rotary drive unit
500: control unit

Claims (19)

As an artificial tissue manufacturing device,
a spraying unit configured to spray the molten polymer and cell solution;
a spraying unit transfer unit configured to transfer the spraying unit;
a base member configured to apply the polymer or cell solution sprayed from the injection unit;
a base member rotational drive unit configured to supply a rotational driving force for rotating the base member; and
A control unit configured to control at least one of the injection unit, the injection unit transfer unit, and the rotary driving unit;
The control unit controls the formation of the polymer layer and the cell layer to manufacture an artificial tissue having a hollow shape with an axially symmetrical but non-constant profile in the axial direction,
Characterized in that the hollow shape is formed by physically or chemically removing from the artificial tissue,
Artificial tissue manufacturing device.
According to claim 1,
The injection unit:
a first spraying unit configured to form a first polymer layer;
a second spraying unit configured to form a second polymer layer; and
And a third spraying unit configured to form a cell layer,
The first polymer layer sprayed by the first spray unit has a shape corresponding to the inner space having the non-constant profile,
Artificial tissue manufacturing device.
According to claim 2,
The first polymer layer is composed of a biocompatible water-soluble polymer to be removed after the second polymer layer and the cell layer are formed.
Artificial tissue manufacturing device.
According to claim 2,
The control condition of the first injection unit is different from the control condition of the second injection unit or the third injection unit,
Artificial tissue manufacturing device.
According to claim 4,
The controller
Extracting sections satisfying a certain height based on the profile, and injecting the first polymer while moving the first spraying unit over each of the extracted sections,
Artificial tissue manufacturing device.
According to claim 4,
The controller, in the case of spraying the first spraying unit, controls the moving speed or rotational speed to be faster or the spraying amount larger than the case of spraying the second spraying unit or the third spraying unit,
Artificial tissue manufacturing device.
According to claim 1,
The base member has a shape corresponding to the inner space having the non-constant profile, and is configured to spray a polymer and a biological solution onto the base member.
Artificial tissue manufacturing device.
According to claim 7,
The base member is configured to be removed after each of the polymer layer and the cell layer is formed.
Artificial tissue manufacturing device.
According to claim 8,
The base member is composed of a biocompatible water-soluble polymer and can be removed by water.
Artificial tissue manufacturing device.
As an artificial tissue manufacturing method,
Forming a first polymer layer on the rotating base member;
stacking and forming a second polymer layer or cell layer on the first polymer layer; and
Forming a hollow shape by physically or chemically removing the base member and the first polymer layer, the hollow shape being axisymmetric but having an axially non-constant profile,
The first polymer layer is characterized in that the laminated thickness is different along the longitudinal direction to have a shape corresponding to the inner space having the non-constant profile,
Artificial tissue manufacturing method.
According to claim 10,
The removing of the first polymer layer includes dissolving and removing the first polymer layer in water.
Artificial tissue manufacturing method.
According to claim 10,
The first polymer layer forming step includes extracting sections satisfying a predetermined height based on the profile and spraying a first polymer over each of the extracted sections.
Artificial tissue manufacturing method.
According to claim 12,
Characterized in that the moving speed, rotational speed or spraying amount for forming the first polymer layer is controlled to be faster or greater than the moving speed, rotational speed or spraying amount for forming the second polymer layer or the cell layer,
Artificial tissue manufacturing method.
As an artificial tissue manufacturing method,
Forming a polymer layer or a cell layer on the rotating base member; and
forming a hollow shape by physically or chemically removing the base member, the hollow shape being axisymmetric but having an axially non-constant profile;
Characterized in that the base member has a shape corresponding to the inner space having the non-constant profile,
Artificial tissue manufacturing method.
According to claim 14,
The step of removing the base member includes dissolving and removing the base member in water.
Artificial tissue manufacturing method.
delete A storage medium in which a computer program for manufacturing a hollow artificial tissue that is axially symmetrical but has a profile that is not constant in an axial direction is recorded, wherein the computer program includes instructions, and the instructions cause a computer to operate according to claim 10 to A storage medium on which a computer program is recorded, configured to perform the manufacturing method according to any one of claims 15 to 16.
A hollow artificial tissue that is axially symmetrical but has a profile that is not constant in the axial direction, characterized in that it is manufactured by the manufacturing method according to any one of claims 10 to 15.
According to claim 18,
The artificial tissue is an artificial tissue comprising a uterus.

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